Dennis M.

Styne

Pediatric
Endocrinology

A Clinical Handbook

123
Pediatric Endocrinology
Dennis M. Styne

Pediatric Endocrinology
A Clinical Handbook
Dennis M. Styne
Pediatrics
University of California
Davis School of Medicine
Sacramento, CA, USA

ISBN 978-3-319-18370-1 ISBN 978-3-319-18371-8 (eBook)

DOI 10.1007/978-3-319-18371-8

Library of Congress Control Number: 2015940868

© Springer International Publishing Switzerland 2016

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To my loving wife Donna and my amazing children
Rachel, Jonathan, Juliana, and Aaron, my wonderful
son-in-law Michael, and my beautiful grandchildren
Cooper and Samara all of whom immeasurably enrich my life.
Preface

This book is written for practitioners ranging from students to residents, fam-
ily physicians, and pediatricians puzzling over the approach to a child who
seems to have an endocrine disorder in order to help readers evaluate and
treat the more straightforward pediatric endocrine issues. The information in
the text might prepare a provider for a meeting with parents of a child with an
endocrine condition in order to improve communication or alternatively
might provide the facts that will allow the practitioner to avoid an unneces-
sary consultation. The chapters begin with the basic physiologic processes
and concepts of endocrinology before putting this knowledge into action by
addressing the major signs and symptoms and the diagnosis and management
of pediatric endocrine disorders. This work is provided for anyone who
wishes to have a consultation with a pediatric endocrinologist in absentia still
realizing that an actual person-to-person consultation sets the gold standard.
There are a multitude of more complex issues within pediatric endocrinology
that cannot be mastered without adequate experience; managing a baby with
ambiguous genitalia is only one example of the issues that are introduced in
this text to allow the reader to understand the basics, but this small volume
cannot possibly cover the complexities in their entirety. This volume is not
meant to replace the outstanding larger and more detailed texts, manuscripts,
and websites to which I refer the reader in the “suggested reading” section at
the conclusion of each chapter. The concepts covered are designed to address
in varying detail the subjects in the first ten headings in the content outline of
the Sub-board of Pediatric Endocrinology of The American Board of
Pediatrics dealing with clinical conditions. However, there is no claim that
this book will give the reader the expertise of a pediatric endocrinologist; for
that a 3-year fellowship is only the first step!

Sacramento, CA, USA Dennis M. Styne

vii
Acknowledgements

I am indebted to my colleagues in the field of pediatric endocrinology across

the world whose wisdom in print and in words I value and have tried to reflect
in this book. This text grew out of my teaching and clinical experiences and
I am grateful to the innumerable students, house officers, and postgraduate
practitioners I have encountered in the last 45 years that I have pursued this
field. Presentations to them helped me organize my thoughts and their probing
questions led me to look at the issues in new ways. I am grateful to my first
teachers of this field, Melvin M. Grumbach, Felix Conte, and the late Selna
Kaplan, at the University of California San Francisco. They deserve much of
the credit for my accomplishments as they started me in this wonderful field.
I am indebted to my coworkers at the University of California Davis School
of Medicine, Drs. Nicole Glaser, Lindsey Albrecht, Abigail Fruzza, and
Yvonne Lee: they have daily imparted their wisdom to me. My clinical team
that provide outstanding care every day, especially to our numerous patients
with diabetes mellitus, include Sultanna Iden, RN, CDE; Erin Conboy-Heiser,
RN, CDE; Alexander Nella, RD, CDE; Dayna Green-Burgeson, RD, CDE;
Vincent Fong, LCSW; and Breanne Harris, BS Diabetes Concierge. Edna
Gun Utter, our AA (administrative assistant), helped me organize and for-
mat this volume expertly. The supportive staff at Springer including Richard
Lansing and Joseph Quatela gave indispensable editorial help. I acknowledge
Dr. Edward Steinberg who provided initial support in my redirection into
pediatric obesity and continues to provide constant wisdom. I am deeply
indebted to the Yocha Dehe Wintun Nation who have endowed my faculty
position and unwaveringly supported my work in pediatric endocrinology
and health disparities over the last 15 years.

ix
Contents

1 Introduction to Pediatric Endocrinology:

The Endocrine System .................................................................. 1
Suggested Readings ........................................................................ 10
2 The Evaluation of a Child or Adolescent
with Possible Endocrine Disease .................................................. 11
The Medical History ....................................................................... 11
Physical Examination...................................................................... 13
3 Disorders of the Hypothalamic–Pituitary Axis .......................... 17
Physiology....................................................................................... 17
Pathology ........................................................................................ 19
Central Nervous System Tumors .................................................... 19
Craniopharyngioma..................................................................... 20
Germinomas ................................................................................ 21
Pituitary Adenomas......................................................................... 22
Other Central Nervous System Disorders ....................................... 23
Langerhans Cell Histiocytosis .................................................... 23
Postinfectious Inflammatory Lesions of the Central
Nervous System, Vascular Abnormalities,
and Head Trauma ........................................................................ 23
Irradiation of the Central Nervous System ..................................... 24
Developmental Defects of the Midline ........................................... 24
Septo-Optic and Optic Dysplasia ................................................ 24
The Solitary Median Maxillary Incisor Syndrome ..................... 25
Idiopathic Hypopituitary Dwarfism ................................................ 25
Suggested Readings ........................................................................ 27
4 The Posterior Pituitary Gland and Disorders
of Vasopressin Metabolism ........................................................... 29
Normal Vasopressin Physiology ..................................................... 29
Diabetes Insipidus ........................................................................... 33
Central Diabetes Insipidus .......................................................... 33
Nephrogenic Diabetes Insipidus ................................................. 35
Clinical Features of Diabetes Insipidus ...................................... 36

xi
xii Contents

Diagnosis of Diabetes Insipidus.................................................. 36

Treatment of Central Diabetes Insipidus .................................... 39
Treatment of Nephrogenic Diabetes Insipidus............................ 41
The Syndrome of Inappropriate Secretion
of Antidiuretic Hormone ................................................................. 41
Nephrogenic Syndrome of Inappropriate Antidiuresis ................... 42
Other Causes of Hyponatremia ....................................................... 43
The Treatment of Syndrome of Inappropriate
Secretion of Antidiuretic Hormone ................................................. 43
The Triphasic Response After Surgery
for Craniopharyngioma ................................................................... 44
Suggested Readings ........................................................................ 45
5 Disorders of Growth ..................................................................... 47
Measurement of Growth ................................................................. 47
Endocrine Factors in Postnatal Growth .......................................... 58
Growth Hormone ........................................................................ 58
Insulin-Like Growth Factor or IGF ............................................. 62
Epidermal Growth Factor............................................................ 66
Erythropoietin ............................................................................. 66
Oncogenes ................................................................................... 66
Dental Development ....................................................................... 67
Abnormalities of Growth ................................................................ 67
Short Stature................................................................................ 67
Growth and Attention-Deficit Disorder ...................................... 73
Tall Stature .................................................................................. 86
Suggested Readings ........................................................................ 89
6 Disorders of the Thyroid Gland ................................................... 91
Normal Thyroid Physiology and Anatomy ..................................... 91
Fetal Thyroid Development in the Newborn .................................. 95
Laboratory Evaluation..................................................................... 97
Imaging of Thyroid ......................................................................... 98
Disorders of the Thyroid Gland ...................................................... 99
Goiter .......................................................................................... 99
Hypothyroidism .............................................................................. 101
Congenital Hypothyroidism (CH)............................................... 101
Acquired Hypothyroidism .......................................................... 108
Thyroid Hormone Overdose ....................................................... 117
Neoplasms ................................................................................... 117
Painful Thyroid Glands ............................................................... 120
Further Reading .............................................................................. 120
7 Disorders of Calcium Metabolism and Bone .............................. 123
Calcium Metabolism ....................................................................... 123
Storage and Absorption of Calcium............................................ 123
The Calcium-Sensing Receptor .................................................. 124
Phosphate .................................................................................... 124
Magnesium.................................................................................. 125
Parathyroid Hormone and Parathyroid
Hormone-Related Protein ........................................................... 126
Contents xiii

Vitamin D and Its Metabolites .................................................... 127

Calcitonin .................................................................................... 129
Alkaline Phosphatase .................................................................. 129
Hypocalcemia ................................................................................. 130
Hypocalcemia in the Infant ......................................................... 130
Hypocalcemia in the Child and Adolescent ................................ 133
Diagnosis of Hypocalcemia ........................................................ 139
Normal Bone Growth .................................................................. 139
Vitamin D and Calcium Deficiency ............................................ 140
Rickets......................................................................................... 141
Hypercalcemia ................................................................................ 147
Primary Hyperparathyroidism .................................................... 149
Familial Hypocalciuric Hypercalcemia ...................................... 149
Miscellaneous Causes ................................................................. 150
Treatment of Hypercalcemia ....................................................... 152
Evaluation of Hypercalcemia ...................................................... 152
Aluminum Toxicity ..................................................................... 156
Suggested Readings ........................................................................ 157
8 Disorders of Sexual Differentiation ............................................. 159
Normal Sexual Differentiation ........................................................ 159
Genotype ..................................................................................... 159
Gonadal Sex ................................................................................ 161
Phenotypic Sex............................................................................ 162
Social Gender .............................................................................. 165
Disorders of Sexual Differentiation ................................................ 166
46, XX DSD: Conditions Causing Genetic
Females to Become Virilized (Previously Called
Female Pseudohermaphroditism)................................................ 166
46, XY DSD: Disorders Causing Inadequate
Virilization of a Genetic Male (Previously Called
Male Pseudohermaphroditism) ................................................... 175
Gonadal DSD .............................................................................. 179
Endocrine Disruptors .................................................................. 180
The Diagnosis and Treatment of Ambiguous Genitalia.................. 180
Treatment ........................................................................................ 184
The Decision of Sex of Rearing ...................................................... 184
Multidisciplinary Team Management ............................................. 186
Youth with Gender Dysphoria .................................................... 186
Suggested Readings ........................................................................ 186
9 Disorders of Puberty ..................................................................... 189
Normal Pubertal Development........................................................ 189
Physical Development................................................................. 189
Age at Onset of Puberty .............................................................. 191
Ages of Pubertal Stages and Duration ........................................ 193
Skeletal Development and Bone Mineral Density ...................... 193
The Endocrine Changes of Puberty ................................................ 193
Gonadarche ................................................................................. 195
xiv Contents

Spermarche ................................................................................. 200

Adrenarche .................................................................................. 200
Pediatric Sex Steroid and Gonadotropin\ Assays ........................ 200
Ovulation and Menarche ............................................................. 201
Miscellaneous Metabolic Changes ............................................. 202
Abnormalities of Puberty ................................................................ 202
Delayed Puberty .......................................................................... 202
Sexual Precocity.......................................................................... 217
Endocrine Disruption in Puberty .................................................... 224
Variations of Early Pubertal Development.................................. 224
Macroorchidism .......................................................................... 225
Differential Diagnosis of Precocious Puberty............................. 225
Treatment of Precocious Puberty ................................................ 226
Polycystic Ovarian Syndrome ......................................................... 229
Suggested Readings ........................................................................ 230
10 Disorders of the Adrenal Gland................................................... 233
Normal Adrenal Gland Physiology ................................................. 233
Measurement of Steroids ................................................................ 239
Disorders of the Adrenal Cortex ..................................................... 240
Hypoadrenal States ..................................................................... 240
Aldosterone Insufficiency or Resistance ..................................... 248
Adrenal Calcifications................................................................. 248
Hyperadrenal States .................................................................... 249
Hypertension due to Adrenal Disease ......................................... 256
Adrenal Medulla ............................................................................. 257
Normal Physiology ..................................................................... 257
Disorders of the Adrenal Medulla............................................... 258
Suggested Reading .......................................................................... 261
11 Diabetes Mellitus ........................................................................... 263
Insulin Biosynthesis and Action ..................................................... 265
Glucagon ......................................................................................... 266
Other GI Hormones......................................................................... 267
Diabetes Mellitus ............................................................................ 270
Type 1 Diabetes Mellitus ................................................................ 270
Clinical Presentation of Diabetes Mellitus ................................. 272
Dietary Management ................................................................... 280
Preparation for Discharge ........................................................... 280
Home Measurement by Glucometer ........................................... 281
Subcutaneous Insulin Management ............................................ 282
Glycosylated Hemoglobin or Hemoglobin A1c ........................... 287
The Honeymoon Period .............................................................. 288
Sick Day Management ................................................................ 288
Hypoglycemia ............................................................................. 289
Somogyi Phenomenon ................................................................ 290
Dawn Phenomenon ..................................................................... 291
Surgery and Diabetes .................................................................. 291
Contents xv

Diabetes Team Management ........................................................... 291

Iatrogenic or Other Acquired Forms
of Diabetes Mellitus Type 1 ........................................................ 293
Neonatal Diabetes ........................................................................... 297
Transient Neonatal Diabetes Mellitus ......................................... 297
Permanent Neonatal Diabetes Mellitus ....................................... 298
Type 2 Diabetes Mellitus ................................................................ 298
Wolfram Syndrome ..................................................................... 301
Maturity-Onset Diabetes of the Young
or Monogenic Diabetes ............................................................... 301
Mitochondrial Disease and Diabetes .......................................... 301
Nonketotic Hyperosmotic Coma................................................. 302
Summary ......................................................................................... 303
Suggested Readings ........................................................................ 303
12 Hypoglycemia ................................................................................ 305
Normal Carbohydrate Metabolism ................................................. 305
Glucose Regulatory Factors ........................................................ 306
Transition of the Fetus to Neonatal Life ..................................... 309
Hypoglycemia ................................................................................. 309
Hypoglycemia in the Newborn ................................................... 310
Hypoglycemia in Older Children ................................................ 316
Diagnosis of Hypoglycemia........................................................ 319
Treatment of Hypoglycemia ....................................................... 322
Suggested Reading .......................................................................... 324
13 Obesity ........................................................................................... 325
Definition ........................................................................................ 325
Etiology of Obesity ......................................................................... 329
Genetic Factors and the CNS Control of Appetite...................... 329
Dietary Intake.............................................................................. 331
Energy Expenditure..................................................................... 336
Gut Microbiome .......................................................................... 336
Epigenetics .................................................................................. 336
The Obesogenic Environment ..................................................... 337
Endocrine Causes ........................................................................ 338
Iatrogenic Causes ........................................................................ 339
Comorbidities of Childhood and Adolescent Obesity .................... 339
Psychological Conditions............................................................ 340
Type 2 Diabetes........................................................................... 340
The Metabolic Syndrome and Insulin Resistance ....................... 340
Polycystic Ovarian Syndrome ..................................................... 342
Hyperlipidemia and Risk for Cardiovascular Disease ................ 342
Hypertension ............................................................................... 347
Liver Disease............................................................................... 349
Obstructive Sleep Apnea ............................................................. 350
Dermal Findings.......................................................................... 351
Orthopedic Conditions ................................................................ 351
Increased Growth and Advanced Skeletal Development ............ 351
xvi Contents

Earlier Puberty ............................................................................ 351

Enuresis ....................................................................................... 351
Cholelithiasis............................................................................... 351
Asthma ........................................................................................ 351
Pseudotumor Cerebri .................................................................. 351
Psoriasis ...................................................................................... 352
Laboratory Evaluation of Childhood Obesity ................................. 352
Treatment .................................................................................... 352
Lifestyle Modification................................................................. 353
Medication .................................................................................. 355
Surgery ........................................................................................ 356
Prevention ................................................................................... 357
Encourage Parental Modeling ..................................................... 357
Expose Children to Healthy Food in a Young Age ..................... 357
Encourage Breast-Feeding .......................................................... 357
Decrease or Eliminate the Intake of Sugar Sweetened
Beverages and Limit the Intake of Juice ..................................... 358
Increase Public Safety ................................................................. 358
Modify the Diet ........................................................................... 358
Decrease Sedentary Time............................................................ 358
Suggested Readings ........................................................................ 360
14 Pediatric Endocrine Emergencies................................................ 363
Acute Adrenal Insufficiency ........................................................... 363
Diabetic Ketoacidosis ..................................................................... 365
Hypocalcemia ................................................................................. 366
Hypercalcemia ................................................................................ 368
Hyperthyroidism in the Neonate ..................................................... 370
Thyroid Storm in Children and Adolescents .................................. 370
Hypoglycemia ................................................................................. 371
Hyponatremia/Hyperkalemia Due to Adrenal Insufficiency .......... 373
Hyponatremia Resulting from Syndrome
of Inappropriate Secretion of Antidiuretic Hormone ...................... 374
Hypernatremia Due to Diabetes Insipidus ...................................... 374
Hypertension Due to Pheochromocytoma ...................................... 375
Suggested Reading .......................................................................... 375
15 Medications for Pediatric Endocrinology ................................... 377
Calcitonin, Human .......................................................................... 377
Calcitriol (1,25-Dihydroxycholecalciferol) .................................... 377
Calcium ........................................................................................... 377
Calcium Carbonate, Oral ............................................................ 377
Calcium Citrate, Oral .................................................................. 378
Calcium Glubionate, Oral ........................................................... 378
Calcium Gluconate IV ................................................................ 378
Hypocalcemia ............................................................................. 378
Calcium Lactate, Oral ................................................................. 378
DDAVP ........................................................................................... 378
Ergocalciferol (Vitamin D2) ........................................................... 378
Dietary Supplementation ............................................................ 379
Vitamin D Deficiency.................................................................. 379
Contents xvii

Nutritional Rickets ...................................................................... 379

Vitamin D-Resistant Rickets ....................................................... 379
Vitamin D-Dependent Rickets .................................................... 379
Hypoparathyroidism or Pseudohypoparathyroidism .................. 379
Estrogen ...................................................................................... 379
Fludrocortisone Acetate (Florinef) ................................................. 379
Glucagon HCl ............................................................................. 379
Glucocorticoid Preparations............................................................ 379
Growth Hormone Secretagogue Testing ......................................... 379
Hydrochlorothiazide ....................................................................... 380
Insulin Preparations ........................................................................ 380
Thyroxine (Levo) ............................................................................ 380
Magnesium Sulfate ......................................................................... 380
Hypomagnesemia or Hypocalcemia ........................................... 380
Daily Maintenance ...................................................................... 381
Mannitol (5, 10, 15, 20, 25 %) ........................................................ 381
Medroxyprogesterone Acetate .................................................... 381
Metformin ....................................................................................... 381
Mecasermin (rhIGF-1) .................................................................... 381
Methimazole ................................................................................... 381
Hyperthyroidism ......................................................................... 381
Nitroprusside ............................................................................... 381
Pamidronate .................................................................................... 381
Hypercalcemia ............................................................................ 381
Osteogenesis Imperfecta ............................................................. 382
Phosphate Supplements .................................................................. 382
Maintenance/Replacement .......................................................... 382
Potassium Iodide ............................................................................. 382
Potassium Supplements .................................................................. 382
Hypokalemia ............................................................................... 382
Monitor Serum K Closely and Watch EKG at All Times ............... 382
Propranolol...................................................................................... 382
Hypertension ............................................................................... 382
Sodium Bicarbonate ........................................................................ 383
Somatropin (Growth Hormone) ...................................................... 383
Growth Hormone Deficiency ...................................................... 383
Noonan’s Syndrome .................................................................... 383
Prader-Willi Syndrome ............................................................... 383
SGA............................................................................................. 383
SHOX Deficiency........................................................................ 383
Turner Syndrome ........................................................................ 383
Spironolactone ................................................................................ 383
Diuretic ....................................................................................... 383
Primary Aldosteronism ............................................................... 383
Hirsutism or Acne in Women...................................................... 383
Testosterone .................................................................................... 384
Vasopressin ..................................................................................... 384
Diabetes Insipidus ....................................................................... 384
Subcutaneous/Intramuscular ....................................................... 384
Suggested Reading .......................................................................... 384
xviii Contents

16 Laboratory Values for Pediatric Endocrinology ........................ 385

Adrenocorticotropic Hormone (ACTH) Quest ............................... 385
Adrenal Antibody Screen with Reflex Titer QUEST .................. 386
Albumin (Microalbumin), 24-h Urine Quest .................................. 386
Albumin Serum Quest..................................................................... 386
Aldosterone, 24-h Urine Quest ....................................................... 386
Aldosterone Serum, LC/MS/MS Quest .......................................... 387
Alkaline Phosphatase, Serum Quest ............................................... 387
Alkaline Phosphatase, Bone-Specific Labcorp ............................... 387
Androstenedione LC/MS/MS Quest ............................................... 388
Angiotensin II Quest ....................................................................... 388
Anti-Mullerian Hormone (AMH) Quest ......................................... 389
Arginine Vasopressin Quest ............................................................ 389
Congenital Adrenal Hyperplasia 21-Hydroxylase
Deficiency Common and Rare Mutations Quest ............................ 389
C Peptide, Serum Quest .................................................................. 389
Calcitonin Quest.............................................................................. 390
Calcium, 24-h Urine Quest ............................................................. 390
Calcium Ionized, Serum Quest ....................................................... 390
Calcium, Serum Quest .................................................................... 391
Carnitine, Serum Quest ................................................................... 391
Carotene Quest ................................................................................ 391
Catecholamines, Fractionated, 24-h Urine Quest ........................... 391
Catecholamines, Fractionated, Plasma Quest ................................. 392
Catecholamines, Fractionated, Random Urine Quest ..................... 393
Corticosterone LC/MS/MS Quest ................................................... 394
Corticotropin-Releasing Hormone (Mainly Use
for Ectopic Production of CRH) Quest ........................................... 395
Cortisol-Binding Globulin (Transcortin) Quest .............................. 395
Cortisol Urinary Free 24-h Quest ................................................... 395
Cortisol-Free Serum Quest ............................................................. 395
Cortisol, Salivary......................................................................... 396
Cortisol Serum Total LC/MS/MS Esoterix ..................................... 396
Creatinine 24-h Urine Quest ........................................................... 397
Creatinine Random Urine Quest ..................................................... 397
Creatinine Clearance Quest............................................................. 397
Creatinine Serum Quest .................................................................. 398
DHEA Serum Quest Esoterix ......................................................... 398
DHEA Sulfate, Serum Esoterix ...................................................... 399
Deoxycorticosterone (DOC), Serum Esoterix ................................ 399
11-Deoxycortisol (Compound S) Corticosterone,
Serum Esoterix ................................................................................ 400
Dihydrotestosterone Esoterix .......................................................... 400
Dihydrotestosterone, Free, Serum Quest ........................................ 401
Estradiol, Serum Esoterix ............................................................... 401
Estrone, Serum Esoterix.................................................................. 402
Follicle-Stimulating Hormone, Third Generation,
Serum Esoterix ................................................................................ 402
Contents xix

Fructosamine, Serum Quest ............................................................ 403

Gastrin Serum Quest ....................................................................... 403
Glucagon Quest............................................................................... 404
Glucose, Serum ............................................................................... 404
Glutamic Acid Decarboxylase-65 Autoantibodies Quest ............... 404
Glycated Albumin Quest................................................................. 404
1,5-Anhydroglucitol Esoterix ..................................................... 405
Growth Hormone, Serum Esoterix.................................................. 405
Growth Hormone Antibody Quest .................................................. 405
Growth Hormone-Binding Protein (GHBP) Esoterix ..................... 405
Growth Hormone-Releasing Hormone Quest ................................. 406
Hemoglobin A1C, Blood Quest ........................................................ 406
Homovanillic Acid, 24-h Urine Quest ............................................ 406
17-Hydroxycorticosteroids, 24-h Urine Quest................................ 407
18-Hydroxycorticosterone, Serum Esoterix.................................... 407
5-Hydroxyindoleacetic Acid (5-HIAA), 24-h
Urine Quest ..................................................................................... 408
5-Hydroxyindoleacetic Acid (5-HIAA),
Random Urine Quest....................................................................... 408
17-Hydroxypregnenolone, Serum Esoterix .................................... 408
17-Hydroxyprogesterone (17OHP), Serum Esoterix ...................... 409
Insulin-Like Growth Factor 1 (IGF-1) (Previously
Called Somatomedin C) Esoterix.................................................... 410
IGF-2 Esoterix ................................................................................ 411
IGF-Binding Protein-1 (IGFBP-1) Quest ....................................... 411
IGF-Binding Protein-2 (IGFBP-2) Quest ....................................... 411
IGF-Binding Protein-3 (IGFBP-3) Esoterix ................................... 412
Inhibin B Quest ........................................................................... 412
Insulin Antibodies, Highly Sensitive Quest .................................... 413
Insulin, Free Quest .......................................................................... 413
Insulin, Serum Quest....................................................................... 413
Islet Cell Antibody Quest................................................................ 413
Leptin, Serum Quest ....................................................................... 413
Luteinizing Hormone (LH), Third-Generation
Serum Esoterix ................................................................................ 414
Metanephrine and VMA, Fractionated 24-h Urine Quest .............. 414
Metanephrine, Fractionated Random Urine Quest ......................... 415
Metanephrine, Fractionate Free Plasma Quest ............................... 416
Microalbumin .................................................................................. 416
Osmolality, Random Urine Quest ................................................... 416
Osmolality, Serum Quest ................................................................ 416
Osteocalcin, Serum Quest ............................................................... 416
Pancreatic Polypeptide Quest ..................................................... 417
Parathyroid Hormone Antibody, Serum Quest ............................... 417
Parathyroid Hormone (PTH), Intact, Serum Quest ......................... 417
Parathyroid Hormone and Related Protein (PTH-RP) Quest.......... 418
Pregnenolone, Serum Esoterix ........................................................ 418
xx Contents

Progesterone, Serum Esoterix ......................................................... 418

Progesterone, Free, HPLC-MS/MS ................................................ 419
Proinsulin, Serum Quest ................................................................. 419
Prolactin, Serum Quest ................................................................... 420
Renin Activity (PRA), Plasma Esoterix.......................................... 420
Sex Hormone-Binding Globulin (SHBG) Esoterix ........................ 420
Somatostatin Quest ......................................................................... 421
T3 (Triiodothyronine), Free, Nondialysis Quest.............................. 421
T3 (Triiodothyronine), Free, Dialysis Esoterix................................ 422
T3 (Triiodothyronine), Reverse Esoterix ......................................... 422
T3 (Triiodothyronine), Total, Radioimmunoassay Esoterix ............ 422
T4 (Thyroxine), Free, Direct Dialysis Serum Quest........................ 423
T4 (Thyroxine), Free, Nondialysis, Serum Esoterix........................ 423
T4 (Thyroxine), Total, Serum Quest ................................................ 424
Testosterone, Total, Serum Esoterix ............................................... 424
Testosterone Free, Serum or Plasma Esoterix................................. 425
Testosterone Saliva Esoterix ....................................................... 426
Testosterone Bioavailable Esoterix ................................................. 426
Thyroglobulin Antibody, Serum Quest ........................................... 427
Thyroid Peroxidase Antibody (Anti-TPO), Serum Quest............... 427
Thyroid-Stimulating Hormone (TSH), Serum Quest...................... 427
Thyroid-Stimulating Immunoglobulin (TSI) Quest ........................ 428
TSH Receptor Antibody (TRAb) Esoterix. .................................... 428
Thyroxine-Binding Protein/Globulin (TBG), Serum Quest ........... 428
Vanillylmandelic Acid (VMA), Random Urine Quest ................... 429
Vanillylmandelic Acid (VMA), 24-h Urine Quest .......................... 429
Vitamin D, 1,25-Dihydroxy, Serum Esoterix.................................. 429
Vitamin D, 25-Hydroxy, Serum or Plasma Esoterix ....................... 430
S.I. Unit Conversion Table from Esoterix/Labcorp ........................ 431
Suggested Reading .......................................................................... 434
Laboratory values from ............................................................... 434

Index ....................................................................................................... 435

 Introduction to Pediatric
Endocrinology: The Endocrine
System
The endocrine system regulates reproduction,
growth and development, homeostasis of the
organism (or maintenance of the internal envi-
ronment), and the production, storage, and utili-
zation of energy. The endocrine system was
originally understood to regulate metabolism by
biochemical messengers or hormones that were
released from specialized organs (glands) into
the general circulation so that they could act at a
distance. Thus, hormones were classically
defined as circulating messengers, with the loca-
tion of their action far from the site of secretion,
endocrine action. Hormone action also may be
paracrine (acting on adjacent neighboring cells
to the cell of origin of the hormone by diffusion),
autocrine (acting on the cell of origin of the hor-
mone itself by diffusion), or intracrine (acting on
the cell of origin without actually being secreted);
often agents acting in these ways are called fac-
tors rather than hormones. Indeed, these factors
(e.g., growth factors) may be produced in most
cells of the body rather than discrete endocrine
glands (Fig. 1.1). The effects of hormones and
factors may be generally considered to be
directed toward the processes of cell differentia-
tion, cell growth, and metabolism of the cell and
the organism.
In the past, some of the endocrine glands
appeared to be controlled by the pituitary gland,
which was therefore considered to be “the master
gland.” The discovery of the hypophysiotropic
hormones of the hypothalamus and their role in
the control of pituitary secretion made it clear
© Springer International Publishing Switzerland 2016
D.M. Styne, Pediatric Endocrinology, DOI 10.1007/978-3-319-18371-8_1
1
that a higher level of control of these functions
exists. Now it is recognized that various regions
of the brain regulate the hypothalamus with
complex interconnections in the central nervous
system. Many of the hormones of the pituitary–
hypothalamic axis or molecules that share much
of their structure and function are also found in
the gastrointestinal tract and other tissues
throughout the body, as well as the placenta.
Overlap occurs between the control of the endo-
crine system and the nervous system; hormone
secretion can be regulated by nerve cells, and
endocrine agents can serve as neural messengers.
Further, the endocrine system is regulated by fac-
tors important in the immune system (e.g., cyto-
kines interact with the secretion of glucocorticoids,
which then exert an influence on inflammation).
An entire system of regulation, rather than the
simplistic view of the endocrine system, best
describes the control of metabolism.
Many hormones are regulated in a feedback
loop, so that the production of a hormone is
controlled by its effect; for example, the
corticotropin-releasing factor (CRF) stimulates
the adrenocorticotropic hormone (ACTH) to
produce cortisol, which in turn feeds back to
suppress CRF and ACTH production so that
equilibrium is reached and serum cortisol and
ACTH remain in the normal range (Fig. 1.2,
Table 1.1). The set point of the equilibrium may
change with development; in prepuberty, small
amounts of sex steroids strongly suppress
gonadotropin secretion, but during pubertal
1
2 1 Introduction to Pediatric Endocrinology: The Endocrine System
Fig. 1.1 Endocrine, paracrine, autocrine, and intracrine
effects. Endocrine effects occur when a hormone is
secreted by a cell into the bloodstream to be carried a dis-
tance until it leaves the bloodstream to interact with the
cellular receptor, in this case a peptide cellular membrane
receptor, to exert intracellular activity. Paracrine effects
occur when a cell secretes a substance to cause biologi-
cal effects on a neighboring cell, in this case via a pep-
tide cellular membrane receptor, without entering the
bloodstream. Autocrine effects occur when the cell
secretes a substance to cause biological effects on the
development, the sensitivity of this feedback loop
decreases. Thus increased sex steroid production
that brings about the ensuing physical changes of
puberty occurs because these pubertal levels of
sex steroids can no longer suppress gonadotropin
secretion, as would occur at a similar level of sex
steroid secretion in the prepubertal state.
A clinician may deduce the level of an endo-
crine defect in the system by measuring the con-
centrations of hormones in serum or plasma at
various steps of the process (e.g., a low serum
cortisol and high adrenocortical-stimulating hor-
mone (ACTH) indicates a primary defect at the
level of the adrenal gland, whereas a low serum
cortisol along with a low ACTH indicates a disor-
der of the pituitary gland or the hypothalamus
(Table 1.1)). Positive feedback loops occur as
well; the midcycle LH peak which triggers ovula-
tion occurs due to positive estrogen feedback on
higher CNS centers. In most cases, it is not suf-
ficient to obtain a single hormone measurement
cell of origin, in this case via a peptide cellular membrane
receptor, without entering the bloodstream nor necessarily
affecting nearby cells. Intracrine effects occur when a
substance acts within the cell in which it was produced
without crossing the cell membrane, in this case via an
intracellular receptor. Endocrine effects are measured by
assays on blood samples, but paracrine and autocrine
effects cannot be directly measured by assaying blood
samples. In fact, the results of blood sample analyses only
provide a reflection of what might be going on locally
without considering its controlling factors or the
effects it exerts.
Endocrine disorders may manifest in several
ways:
1. By excess hormone effect (e.g., in Cushing syn-
drome, an excess of glucocorticoid is present;
e.g., if the excess is secondary to autonomous
glucocorticoid secretion by a target organ (cor-
tisol secretion by the adrenal gland), the trophic
hormone ACTH will be suppressed).
2. By deficient hormone: e.g., in glucocorticoid
deficiency, inadequate cortisol is present; if
the deficiency is at the target organ (the adre-
nal gland), the trophic hormone (ACTH) will
be elevated.
3. By an abnormal response of end organ to a
hormone: e.g., in pseudohypoparathyroidism,
resistance to parathyroid hormone (PTH)
occurs, and so PTH is elevated, but the para-
thyroid hormone exerts no effects.
1 Introduction to Pediatric Endocrinology: The Endocrine System
a Third ventricle
Neuroendocrine
cell nuclei
Superior
hypophyseal
artery
Long portal
vessels
Adrenocorticotrophs
Secreting cells
Anterior
pituitary
Hormone
secretion
Aldosterone Cortisol Androgens Catecholamines
Fig. 1.2 Logic of evaluation of hypothalamic–pituitary
feedback loops using the hypothalamic–pituitary–adrenal
axis as an example. (a) The normal situation where the
target gland (adrenal gland) regulates the stimulatory hor-
mone by negative feedback inhibition. (b) Primary defect
due to failure of the target gland and decrease in its secre-
tion of hormone: the stimulatory hormone (ACTH)
4. By gland enlargement that may cause effects as
a result of size rather than function; with a large
nonfunctioning pituitary adenoma, abnormal
visual fields and other neurological signs and
symptoms will result, and pituitary endocrine
cells may cease to function, even though no
hormone is produced by the tumor itself.
Tumors of other nonendocrine organs also
may produce hormones as with the ectopic
3
Hypothalamus
CRF secreting cells
Stalk
Inferior
hypophyseal
artery
Posterior
pituitary
Short portal
vessel
Glomerulosa
ACTH
Fasciculata
Reticularis
Medulla
increases due to absence of negative feedback inhibition.
(c) Decreased or “hypo” situation whereby the stimula-
tory hormone is absent and the target gland’s hormone
product falls. In the hypothalamic–pituitary–target gland
axis, this would be a secondary (ACTH secretory defect
illustrated here) or tertiary (CRF secretory defect not
illustrated in the figure) defect
production of ACTH from an oat cell carcinoma
of the lung in adults. Endocrine disorders may be
revealed by the response of various organs to an
excess or deficiency of various hormones well
before the size of the endocrine tumor makes it
apparent (adrenal carcinoma may cause viriliza-
tion before it exerts a mass effect).
Hormones have various molecular structures.
Thus there are peptide (e.g., TRF), glycoprotein
(LH), monoamine (epinephrine), amino acid
4 1 Introduction to Pediatric Endocrinology: The Endocrine System
b Third ventricle
Neuroendocrine
cell nuclei
Superior
hypophyseal
artery
Long portal
vessels
Adrenocorticotrophs
Secreting cells
Anterior
pituitary
Hormone
secretion
Aldosterone Cortisol Androgens Catecholamines
Fig. 1.2 (continued)
derivative (thyroxine), steroid (testosterone), and
lipid (prostaglandin) structures of hormones.
Different structures of hormones necessitate
different receptors. Receptors are then linked to
intracellular processes that bring about the (in
normal situation) desirable effects. Some hor-
mones exert a limited effect on a single organ
(GnRH) or a few organs, and others have wide-
spread effects (thyroxine). Some hormones are
stored in their gland of origin (peptide hormones),
while others have limited storage and must be
synthesized to exert effects (steroids). Many hor-
mones circulate in a protein-bound state that acts
as a reservoir for future use or limits biological
effect (SHBG for sex steroids or growth hor-
mone- binding protein for growth hormone).
Hypothalamus
CRF secreting cells
Stalk
Inferior
hypophyseal
artery
Posterior
pituitary
Short portal
vessel
Glomerulosa
ACTH
Fasciculata
Reticularis
Medulla
Peptide hormones are produced by various
endocrine organs or in an ectopic manner by the
cells of certain neoplasms. Peptide hormones act
through specific cell membrane receptors; the
receptors consist of an extracellular domain,
which directly interacts with the ligand hormone,
a transmembrane domain that connects actions
outside the cell with the actions destined to occur
within the cell, and the intracellular domain that
contains the cellular constituents that cause vari-
ous biological actions (Fig. 1.3). These internal
cellular actions include phosphorylation of pep-
tides or proteins and the generation of other mol-
ecules that cause a cascade of events, ultimately
leading to the metabolic action expected by the
presence of the hormone on the receptor (Fig. 1.3).
1 Introduction to Pediatric Endocrinology: The Endocrine System 5

c Third ventricle Hypothalamus

Neuroendocrine
cell nuclei

CRF secreting cells

Superior
hypophyseal
artery
Stalk

Long portal
vessels
Inferior
Adrenocorticotrophs hypophyseal
artery

Secreting cells

Anterior Posterior
pituitary pituitary

Hormone Short portal

secretion vessel
Glomerulosa
ACTH
Fasciculata

Reticularis

Medulla

Aldosterone Cortisol Androgens Catecholamines

Fig. 1.2 (continued)

Table 1.1 The differential diagnosis of primary versus secondary or tertiary endocrine disease or autonomous
function
Target organ hormone
Trophic hormone secretion (e.g., adrenal
secretion (e.g., ACTH) gland) Condition Example
Normal Normal Normal
Low High Autonomous function of Adrenal adenoma
target gland (see Fig. 10.6)
High High Target gland is stimulated by Cushing disease caused by
hypothalamic–pituitary axis pituitary microadenoma
(see Fig. 10.5)
Low Low Secondary or tertiary failure ACTH deficiency (see
of target gland Fig. 1.2c)
High Low Primary failure of target Addison’s disease (see
gland Fig. 1.2b)
6 1 Introduction to Pediatric Endocrinology: The Endocrine System
Cell Insulin
membrane
IR
IRS1 Shc
p85
P13K GRB2
p110
Akt
MAPK
cascade
NUCLEUS
Protein synthesis
glycogen synthesis +
inhibition of
gluconeogenesis
inhibition of lipolysis
regulation of
cell survival
Fig. 1.3 Schematic structure of cell-surface heterodi-
meric insulin/insulin-like growth factor 1 (IGF-1) recep-
tor and GH receptor (GHR) on an exemplary cell surface.
The insulin receptor is a heterodimer composed of two α-
and two β-subunits. The type 1 IGF receptor has a similar
structure to the insulin receptor. Both have similar cellular
responses to the ligand binding to the receptor, more the
insulin sequence favors the IRS-1 to Akt pathway while
the IGF-1 receptor proceeds through the MAPK pathway.
In a situation in which there is excess insulin, such as
found in the infant of a diabetic mother, insulin can cross-
react with the IGF-1 receptor leading to increased growth.
Conversely, IGF-1 can interact with the insulin receptor,
causing insulin effects including hypoglycemia. Two
independent GH receptor (GHR) molecules must interact
with one molecule of GH to cause intracellular activities.
This leads to the recruitment of Janus kinase 2 (JAK2),
which phosphorylates the GHR, which provides a dock-
ing site for STAT (signal transducer and activator of tran-
scription). STAT is then phosphorylated and migrates
uncoupled to the nucleus, where it regulates transcription
G protein-coupled receptors (including ACTH,
vasopressin, luteinizing hormone (LH), follicle-
stimulating hormone (FSH), TSH, gonadotropin-
releasing hormone (GnRH), thyroid-releasing
factor (TRF), growth hormone-releasing factor
(GHRH), CRF, somatotropin-releasing inhibiting
factor (SRIF or SS), glucagon, PTH receptors)
IGF-1 GH
IGF1R GHR
JAK2
IRS1 Shc IRS Shc
p85
p110
P13K GRB2
Akt
STAT5
MAPK
cascade
IGF-1
SOCS
Cell proliferation
and growth
through binding elements of target genes. SOCS (suppressor
of cytokine signaling) provides a localized feedback loop
in which the consequences of GH binding to its receptor
can be regulated. IGF-1 also provides a localized feed-
back loop. The amino acid sequence of the extramem-
brane portion of the GH receptor is cleaved from the GHR
and becomes the circulating GH-binding protein (GHBP)
which thereby reflects the abundance of GHRs.
Abbreviations: IGF-1 – insulin-like growth factor 1, GH –
growth hormone, IR – insulin receptor, IGF-1R – insulin-
like growth factor 1 receptor, GHR – growth hormone
receptor, IRS-1 – insulin receptor substrate 1, Shc – Shc
protein, GRB2 – growth factor receptor-bound protein 2,
PI3K – phosphatidylinositol 3-kinase, Akt – Akt protein,
JAK2 – Janus kinase 2, STAT5 – signal transducer and
activator of transcription 5, SOCS – suppressor of cyto-
kine signaling (Modified from Trobec K, von Haehling S,
Anker SD, Lainscak M. Growth hormone, insulin-like
growth factor 1, and insulin signaling-a pharmacological
target in body wasting and cachexia. J Cachexia
Sarcopenia Muscle. 2011 Dec;2(4):191–200)
have seven transmembrane domains and a G
protein complex that regulates the second mes-
sengers such as calcium and cyclic adenosine
monophosphate (AMP). Cytokine receptors for
GH, prolactin, and leptin consist of extracel-
lular, transmembrane, and cytoplasmic domains
(Fig. 1.3). The extra membrane domain may
1 Introduction to Pediatric Endocrinology: The Endocrine System
Peptide hormone
Peptide ␣s
hormone
receptor ␤ ␥
G-protein ␣s
Adenyl cyclase
(inactive)
A A
Phosphorylated CAT CAT
molecules PKA (active)
Fig. 1.4 The binding of a peptide hormone to its cell mem-
brane receptor, triggering intracellular events which elicit a
response. Note the seven-transmembrane structure of the
G-protein-coupled peptide hormone receptor (GPCR)
which in this case is a receptor for glucagon used as an
example for the general class of membrane-bound recep-
tors. When the ligand attaches to its receptor, the GPRC
undergoes a conformational change leading to activation of
the associated heterotrimeric G protein compound by
exchanging its bound GDP for GTP which then associates
reflect the structure of circulating binding pro-
teins; e.g., the extracellular domain of the growth
hormone receptor (GHR) bears the same amino
acid sequence as a circulating growth hormone-
binding protein (GHBP) with which GH circu-
lates. The cytokine receptors must dimerize (two
receptor molecules must join) to trigger a meta-
bolic effect. The intracellular domain causes
phosphorylation of tyrosine molecules (JAK2
kinases), which then phosphorylate signal trans-
ducers, and activators of transcription (signal
transducer and activator of transcription; STAT),
which then travel to the nucleus to regulate deoxy-
ribonucleic acid (DNA) action.
Peptide hormone receptor number and avidity
may be regulated by hormones; continuous rather
than episodic exposure to GnRH downregulates
GnRH-receptor number as well as receptor activ-
ity on pituitary gonadotropes. This phenomenon
is utilized in treatment with super-active gonado-
tropin-releasing hormone agonists. Mutations of
7
␣s
active adenyl cyclase
ATP cAMP
A A
CAT CAT
PKA (inactive)
with a specific G protein subunit, in this case, a Gs-alpha
protein subunit, which converts inactive adenyl cyclase to
the active form which in turn catalyzes the conversion of
ATP into cyclic adenosine monophosphate (cAMP). cAMP
then activates protein kinase A (PKA) by binding to the
regulatory subunits of PKA (noted by an A). The regulatory
subunits then dissociate from PKA and the remaining cata-
lytic subunits in turn phosphorylate other proteins. Various
effects can occur in the system based upon the G protein
involved. Adapted from biochemistrypage.org, 2015
receptors may cause disease by rendering the
receptor inoperative, or alternatively, the receptor
may be stimulated without the presence of the
hormone in constitutive activation. The G protein
complex may be abnormal in certain diseases;
e.g., McCune–Albright syndrome is associated
with constitutive activation of G stimulatory pro-
tein in affected cells. A constitutively active
mutation in the seven-transmembrane domain
may be present, as occurs in familial germ cell
and Leydig cell maturation. Alternatively, dimer-
ization may fail to occur in some cases of GH
insensitivity.
The family of insulin receptors includes the
insulin and insulin-like growth factor (IGF)-1
receptors (Fig. 1.4). These are heterodimeric,
consisting of two α- and two β-chains. When the
appropriate hormone binds to the extracellular
domain, the conformation is altered, and phos-
phorylation of tyrosine occurs in the intracellular
portion. Through a cascade of effects involving
8 1 Introduction to Pediatric Endocrinology: The Endocrine System
Plasma Steroid hormone
membrane
Receptor−
Cell
hormone
membrane Receptor
complex
protein
Nuclear
membrane Hormone
Nucleus response
elements
DNA
mRNA
Cytoplasm
New protein
Fig. 1.5 Molecular pathway of steroid hormone action.
The steroid circulates with a binding protein, from which
it dissociates to pass through the cell membrane and reach
the cytoplasm. The receptor is complexed with heat shock
proteins (not shown), which dissociate, allowing the ste-
roid to bind to the receptor. Once bound to the steroid, the
steroid receptor is activated and is transported into the
nucleus. The steroid receptor complex changes conforma-
tion, allowing it to bind to the hormone response elements
insulin-receptor substrates (IRSs), activation of
mitogenesis and proliferation as well as effects
on carbohydrate metabolism occur. Insulin and
IGF-1 have differing effects on cell growth and
metabolism, and while each molecule has greater
effect on its own specific receptor, insulin can
bind to the IGF-1 receptor, and IGF-1 can bind to
the IR exerting effects characteristic of the other
molecule. In states of elevated insulin such as in
the infant of a diabetic mother, interaction of the
insulin with a receptor similar to the insulin
receptor, in this case the IGF-1 receptor, occurs
stimulating growth.
Steroid hormones circulate noncovalently
bound to various binding proteins. Steroid hor-
mones exert their effects by diffusion through the
The unbound steroid hormone
diffuses through the plasma
membrane
The steroid hormone binds to
its receptor and enters the
nucleus
The steroid hormone−receptor
complex binds to a specific
DNA sequence, the hormone
response element
Transcription of the gene to
mRNA results from the binding
of the complex to the DNA
Specific protein synthesis
results are determined by the
mRNA
(HREs), or receptor sites, of DNA causing the subsequent
transcription of DNA into mRNA and translation of the
mRNA into proteins which exert their subsequent effects.
Similar mechanisms are employed by members of the thy-
roid receptor (TR) gene family, though most of the latter
are concentrated in the nuclear compartment and are not
associated with the heat shock protein (HSP) complex
prior to binding with the ligand. Adapted from Studyblue.
com, 2015
cell wall into the cytoplasm. Specific cytoplasmic
steroid receptors bind to the steroid molecule, and
the hormone–receptor complex translocates to
the nucleus (Fig. 1.5). The steroid receptor
then binds to DNA hormone response elements
to produce the synthesis of messenger RNA
(mRNA) which leads to translation of the mRNA
on ribosomes and the production of proteins or
peptides predicted by the steroid hormone that
result in changes in cell function.
Thyroid hormone receptors are similar to
steroid receptors in structure and function and are
members of the steroid hormone superfamily.
The receptors are present either as monomers
(TR), heterodimers with retinoid X receptor
(TR/RXR), or homodimers (TR/TR). TR/RXR
Suggested Readings
heterodimers are the most transcriptionally active
complex. In the absence of hormones, TR exists
in a complex with corepressor proteins binding to
hormone response elements (HREs) in DNA in
an inactive state. Binding of thyroid hormone
results in a conformational change in TR which
displaces corepressors from the receptor/DNA
complex while adding coactivator proteins to the
complex. Once the DNA/TR/thyroid hormone/
coactivator complex is formed, RNA polymerase
transcribes DNA into mRNA which leads to
translation of the mRNA on ribosomes and the
production of proteins or peptides predicted by
the hormone that result in changes in cell
function.
Because of the feedback loops, interpretation
of serum hormone levels must be related to their
controlling factors; a given value of PTH may
be normal in a eucalcemic patient, but the same
value may be inadequate in a hypocalcemic
patient with partial hypoparathyroidism, and this
same value of parathyroid hormone may be
excessive in a hypercalcemic patient who might
have hyperparathyroidism. Thus a single endo-
crine test may be inadequate to evaluate anoma-
lies of a feedback loop.
A diurnal rhythm of hormone secretion occurs
in some systems (e.g., serum ACTH increases
in the early morning hours, followed by an increase
in serum cortisol and by a decrease in both during
the afternoon and evening). If the rhythm is dis-
turbed, the amount of hormone present will vary
from the normal pattern, and disease might occur;
if the normal decrease of cortisol does not occur in
the evening, Cushing syndrome might result, sim-
ply because the p.m. cortisol values match the a.m.
values and total daily cortisol secretion is exces-
sive. Thus, although there is little increase in serum
cortisol values above normal a.m. values, a great
increase in cortisol effect occurs in such patients
affected by Cushing disease.
Knowing the basic functions of hormones and
their interactions lends logic to the evaluation of
patients with endocrine diseases. This volume
attempts to emphasize such a systematic evalua-
tion of endocrine disease. The chapters are based
on organ systems and begin with a brief explana-
tion of the basic physiology at work.
9
Many of the conditions in this book are caused
by gene mutations. If there is a genetic link for
a given condition, a reference to the Online
Mendelian Inheritance in Man (OMIM) is placed
after the first mention of the condition. Further
information can be found on the OMIM website,
http://www.ncbi.nlm.nih.gov/Omim/. (OMIM
can also be found under a pulldown menu tab
entry on the PubMed site).
The format is as follows as described verbatim
on the OMIM website:
Each OMIM entry is given a unique six-digit
number as summarized below:
1----- (100000-) 2----- (200000-) Autosomal loci
or phenotypes (entries created before May 15,
1994)
3----- (300000-) X-linked loci or phenotypes
4----- (400000-) Y-linked loci or phenotypes
5----- (500000-) Mitochondrial loci or phenotypes
6----- (600000-) Autosomal loci or phenotypes
(entries created after May 15, 1994)
Allelic variants are designated by the MIM
number of the entry, followed by a decimal point
and a unique 4-digit variant number. For exam-
ple, allelic variants in the factor IX gene (300746)
are numbered 300746.0001 through 300746.
0101.
The symbols preceding a MIM number
represent:
An asterisk (*) before an entry number indi-
cates a gene.
A number symbol (#) before an entry number
indicates that it is a descriptive entry, usually of a
phenotype, and does not represent a unique locus.
The reason for the use of the number symbol
is given in the first paragraph of the entry.
Discussion of any gene(s) related to the pheno-
type resides in another entry(ies) as described in
the first paragraph.
A plus sign (+) before an entry number
indicates that the entry contains the description
of a gene of known sequence and a phenotype.
A percent sign (%) before an entry number indi-
cates that the entry describes a confirmed Mendelian
phenotype or phenotypic locus for which the
underlying molecular basis is not known.
10 1 Introduction to Pediatric Endocrinology: The Endocrine System
No symbol before an entry number generally
indicates a description of a phenotype for which the
Mendelian basis, although suspected, has not been
clearly established or that the separateness of this
phenotype from that in another entry is unclear.
A caret (^) before an entry number means the
entry no longer exists because it was removed
from the database or moved to another entry as
indicated.
*, The gene location is reliably matched with
the clinical situation.
#, Two or more genes can cause the phenotype.
Lack of either symbol, no mode of inheritance
has been proven.
The website often has a link to photographs
demonstrating any dysmorphic characteristics of
a condition. This source is frequently updated
with clinical and basic information on the sub-
jects referenced. There is a useful clinical synop-
sis of many conditions that are listed. The reader
may benefit from frequently accessing this
resource or the associated GeneTests website. It
will be apparent if an entry has that many of the
entries have been recently updated with new ref-
erences and new information as indicated by a
date noted at the bottom of the entry; other entries
may still await such updates and may date from
several years earlier.
It is important to remember that many of the
autosomal-dominant conditions in OMIM may
actually arise de novo rather than in an inherited
pattern.
Two other websites are listed below for genetic
information. GeneReviews is a peer-reviewed
website which addresses various genetic syn-
dromes, some of which are listed in this book.
The GeneTests website lists genetic clinics and
locations, and genetic tests can be obtained from
research labs or commercial laboratories.
Suggested Readings
Online Mendelian Inheritance in Man, OMIM®.
McKusick-Nathans Institute of Genetic Medicine,
Johns Hopkins University (Baltimore, MD). World
Wide Web URL: http://omim.org/ https://www.genet-
ests.org/
Pagon RA, Adam MP, Ardinger HH, et al.,
editors. GeneReviews® [Internet]. Seattle (WA):
University of Washington, Seattle; 1993–2015.
Available from: http://www.ncbi.nlm.nih.gov/books/
NBK1116/
Kublaoui B, Levine MA. Chapter 3—Receptor transduc-
tion pathways mediating hormone action. In: Pediatric
Endocrinology (Fourth Edition). Sperling MA editor.
2014: 34–89.
Menon RK, et al. Chapter 2—Molecular endocrinology
and endocrine genetics. In: Pediatric Endocrinology
(Fourth Edition). Sperling MA, editor, 2014:9–33.
Habener JF. Mechanism of action of hormones that act on
nuclear receptors. In: Williams textbook of endocri-
nology. Kronenberg HM, Mel. Med S, Larsen PR,
Polonsky KS, editors. Elsevier/Saunders 2011.
Spiegel AM, Carter-Su C, Taylor SI, Kulkarni
RN. Mechanism of action of hormones that act at the
cell surface. In: Williams textbook of endocrinology.
Kronenberg HM, Mel. Med S, Larsen PR, Polonsky
KS, editors, Elsevier/Saunders. 2011.
Gardner DG, Anderson M, Nissenson RA. Hormones and
Hormone Action. In: Greenspan’s Basic & Clinical
Endocrinology (9th edition). Gardner DG, Shoback
DM, Greenspac FS, editors. New York: McGraw-Hill
Medical, 2011.
 The Evaluation of a Child
or Adolescent with Possible
Endocrine Disease
As in all disciplines, the history and physical
examination are crucial in determining a course
of evaluation. A standard pediatric history and
physical examination will serve the evaluator
well, but in a few areas, increased attention is
required. The type of problem under consider-
ation may change the direction of questioning
and evaluation. The following general approach
is discussed in more detail in the following chap-
ters regarding specific disorders, but this outline
is meant to direct the initial evaluation.
The Medical History
In many cases, the diagnosis is apparent from the
medical history (Table 2.1). In general, the parents
will be the sources of information, but in most
cases, it will be useful to obtain previous medical
records, often from several sources because of the
recent tendency of transferring care of a child if
the child moves to new locations or has a manda-
tory change of insurance. Modern electronic
medical records have menus for medical, surgi-
cal, family, and birth histories, which should be
carefully filled out once and easily accessed in
future visits for reference or updating.
All aspects of the pregnancy history may be of
importance. This includes medical complica-
tions, nutritional status, toxic or medication
exposures (smoking, infections, medications),
gestational age, complications or difficulties of
delivery, and Apgar scores.
© Springer International Publishing Switzerland 2016
D.M. Styne, Pediatric Endocrinology, DOI 10.1007/978-3-319-18371-8_2
2
Medical history must aim to uncover any
possible chronic disorders that might have con-
tributed to the disease under evaluation or might
complicate the treatment. Many chronic disor-
ders may decrease growth rate; it might be said
that almost every page of a pediatric textbook has
a reason for impaired growth. If no previous
height measurements are available, a history of
changes in shoe or clothing size can be of value
to determine whether the child is growing ade-
quately, although follow-up measurements over a
period of at least 3 months (and longer if possi-
ble, as accuracy increases with the length of time
of follow-up) are necessary for diagnosis. In older
girls, or younger ones if the issue requires it, a
menstrual history is necessary; age of menarche
(onset), regularity, and amount of flow and dis-
comfort are important. Inquire about abnormal
patterns of urination or defecation.
The interview to obtain a medication history
must often be specific, as many do not consider
vitamins or “natural substances” as medicine,
although excessive vitamins might be the very
cause of a disorder (e.g., hypervitaminosis D). In
addition, medications found around the house may
be of importance; did the child get into the oral
contraceptives or hormone replacement therapy
used by another member of the family? Lotions,
creams, and hair treatments may contain hor-
mones; tea tree oil may cause feminizing effects
while testosterone gel can be transferred from the
intended recipient to children by touch or by the
use of a common towel. Diet and nutritional
11
12 2 The Evaluation of a Child or Adolescent with Possible Endocrine Disease

Table 2.1 Medical history for pediatric endocrinology

Chief complaint
History of present illness
Birth history and prenatal history
Gestational age
Complications of pregnancy
Toxic exposures
Maternal accidents
Medication taken including vitamins and “natural” treatments
Substances used, including cigarettes
Were ultrasounds obtained, and was the growth normal?
Was fetal motion normal?
Newborn period
Method of delivery
Complications of delivery
Orientation of delivery
Apgar scores
Birth weight % related to gestational age
Developmental assessment
Use of oxygen or other types of support or treatment
Hypoglycemia; documented by blood sugar value or inferred by activity or behavior?
Development
Age of milestones: sitting, cruising, walking; speaking words, sentences. Perform a developmental test if problems
are noted
Family history
Direct questions are often necessary, as family might not volunteer information to general questions. Refer to
chapters for associated conditions of importance
Note full siblings, half siblings, stepparents, or biologic parent relationships
Construct a family tree if possible
Were there any miscarriages?
Age and percentile of height and weight of siblings
Height and weight of parents; approximate weight, if obesity is noted, is important
Ethnicity of parents
Area where parents spent their childhood, especially if there is a possibility of famine, war, or refugee status in
their history
Is there consanguinity?
Age of menarche in mother and sisters if old enough
Age father stopped growing or started to shave and the same information from brothers, if old enough
History of disease similar to patient or otherwise of importance in related individuals
Ask about early deaths due to heart disease or strokes specifically in all conditions under evaluation
Social: who lives at home, what is their relationship, how do they interact, and are there adequate funds for the
child’s benefit especially for nutrition?
Diet: is there adequate food and of a healthful quality? Is there any aversion to eating, is there lack of satiety, or is
there an unusual diet? In evaluation of obesity, much more detail of diet composition and a dietician consultation are
important
Surgical procedures
Allergies
Accidents, especially to the head
(continued)
Physical Examination 13

Table 2.1 (continued)

Medications taken, including vitamins or “natural substances.” Direct questions are often necessary, as family might
not volunteer information to general questions such as, “Does the child take any medications?” Does anyone have
high blood pressure may be answered negatively until you find that the individual is taking medications to make the
blood pressure normal!
School history: grade level, grades obtained, any changes, interrelationships with schoolmates, teasing or bullying
interactions?
Educational achievement in patient and in siblings and parents
Review of systems in general and directed specifically to the issues under consideration
Areas of concern will vary with the disease under consideration, so check the appropriate chapters to determine
specific symptoms and signs of importance
In most situations today, ask about amount of television viewing or screen time per day, amount of activity, sports or
other forms of exercise, and especially do so in children with obesity

patterns are of general importance but also may
contribute to the etiology of a condition. Significant
levels of estrogen or other substances might be
found in a noncommercial source of beef.
Educational achievement, ability, and history
are important. In addition, it is important to deter-
mine if of psychological problems if related to
the condition the child is manifesting (e.g., severe
short stature or precocious puberty)?
Family history is of great importance in the
evaluation. Family history of chronic disease,
including neurologic or endocrine conditions, is
determined, and the construction of a family tree
is helpful. In many cases, the questions must be
direct, such as, “Has anyone in the family had thy-
roid disease?” rather than a general query since
many feel that once treated, there is no disease;
asking if someone in the family has hypertension
may elicit “no” as an answer; asking whether some
of the family members take medication for hyper-
tension might be returned with the statement
“I do but it is all under control now.” Because par-
ents of pediatric patients are young and subject to
developing new medical conditions (such as type
2 diabetes, hypertension, or dyslipidemia) which
are of importance in the evaluation of the child,
family medical history must be obtained repeat-
edly at subsequent visits. Did the parents immi-
grate from a developing country or live an
underprivileged life to account for their own his-
tory or stature, if abnormal? Was the child
adopted, or should another biologic parent who is
no longer in the house be included in the history?
If an autosomal recessive defect is suspected,
determine whether consanguinity is present. Are
there relatives who died young without diagno-
ses? Indeed in this era of obesity, all cardiac events
or strokes at a young age (various definitions are
used for “young,” but one suggested is the occur-
rence of an event before age 50 years in men and
before age 60 years in women) must be noted.
Even though it may be an endocrine visit, queries
about dyslipidemia or hypertension are important
in this age of obesity. The examiner must ask the
age of menarche in the mother or of the growth
spurt or age at first shaving in the father (a father
will rarely recall his age of onset of puberty!).
Interfamilial interactions can be observed dur-
ing the interview process to evaluate the possibil-
ity of psychosocial dwarfism or other psychosocial
complications.
A history of surgery, allergies, and accidents
to the central nervous system (CNS) or other
important areas is pertinent.
Physical Examination
Physical examination must be complete (Table 2.2).
Accurate determination and plotting of height
(in centimeters) as described in Chap. 5, weight
(in kilograms), and body mass index (BMI) must
accompany the determination of vital signs (see
Chap. 13 for details). An infant should have weight
and height interpreted in terms of gestational age
(by using intrauterine growth charts; see Chap. 5).
A patient who has stature below the third per-
centile for height according to the Centers for
14 2 The Evaluation of a Child or Adolescent with Possible Endocrine Disease

Table 2.2 Physical examination for pediatric endocrinology

All vital signs will vary with the age of the child, so refer to the Harriet Lane Manual or other sources for standards for
age
Pulse
Blood pressure (interpret in terms of blood pressure for height, and make sure there is an adequate-sized cuff; see
Chap. 13)
Respiratory rate
Temperature if pertinent to disease under consideration or intercurrent illness
Infant length, measured as described in Chap. 5, performed by two adults
After age 2 years, measure height in centimeters on a stadiometer without shoes on; repeat 2 or 3 times if stature is
the main complaint, and make sure measurements are consistent and repeatable within 0.3 cm
Weight in kilograms in light or no clothes
Calculated body mass index (BMI) (kg/m2) interpreted on chart for sex and age
Upper/Lower-segment ratio as necessary (especially in boys with disorders of puberty) (see Chap. 5)
Arm span as necessary (especially in chondrodystrophies or abnormalities of puberty) (see Chap. 5)
HEENT (head, eyes, ears, nose, throat)
Look for midline defects, including cleft palate or lip
Observe for signs of syndromes
Cataracts or colobomas?
Development and status of dentition for age. Single central maxillary incisor as a midline defect that might relate to
hypopituitarism?
Acne or comedones?
Beard?
Voice change?
Neck
Motion
Goiter? Measure width and height of thyroid lobes, and estimate thickness (e.g., 25 % or 50 % greater than normal)
Nodules? Bruits?
Acanthosis nigricans at back of neck?
Lungs: customary pediatric examination
Heart: customary pediatric examination
Abdomen: customary pediatric examination
Axillary hair or odor; enlarging axillary sweat glands?
Breast stage in girls (see Chap. 9)
Stage of pubic hair (see Chap. 9)
Stage of genital development in boys (see Chap. 9)
Extremities: customary pediatric examination unless chondrodystrophy is suspected, and then note ratio of proximal
to distal portions of extremities. Look for Madelung deformity in short stature (see Chaps. 5 and 9). Note motion of
joints and back. Evaluate upper-to-lower segment ratio. Observe for contractures or subtle signs of cerebral palsy.
Scoliosis evaluation
Skin
Café-au-lait spots (number, type, shape, and size), subcutaneous calcifications, acanthosis nigricans
Neurologic: customary pediatric examination with special attention to the CNS in most cases
Cranial nerves: signs of central nervous system (CNS) disease, optic disk development, visual fields, and, in delay of
puberty, sense of smell
Chvostek or Trousseau signs
Tremor
Deep tendon reflexes: customary pediatric examination but look for delayed relaxation of ankle reflexes
Physical Examination
Disease Control (CDC) or WHO charts, who is
growing at a rate less than the fifth percentile for
height velocity for age, or is below the third per-
centile for corrected mid parental height is wor-
thy of evaluation; a combination of two or more
of these characteristics warrants increased concern.
Determination of arm span and upper-to-lower
segment ratio is useful in the evaluation of short
stature (e.g., to indicate hypochondroplasia or
achondroplasia or other abnormalities of dispro-
portionate growth) or of delay in puberty (e.g., to
look for the long arms and lower upper-to-lower
segment ratio of hypogonadism known as
eunuchoid proportions). The arm span is mea-
sured with the patient standing with the back to
the wall with arms spread horizontally and is the
distance from one outstretched middle fingertip
to the other. The lower segment is measured from
the top of the symphysis pubis to the floor,
whereas the upper segment is calculated by sub-
tracting the lower segment from the height of the
child. The upper-to-lower segment ratio varies
with age (Fig. 5.7). A decreased upper-to-lower
segment ratio is found in Klinefelter syndrome,
and an increased ratio is found in untreated hypo-
thyroidism, among other possibilities.
If a problem of growth or pubertal progression
is under evaluation, one must consider whether a
low body weight is the source of the problem.
If nutrition is suboptimal, usually the problem is
not endocrine in origin, and other causes must be
considered. Alternatively, if the child is starting
puberty early or progressing too fast, is excess
weight the cause? Every child must have a BMI
calculated and interpreted on a chart. Body mass
index charts are found at www.CDC.com; low
BMI for age might indicate malnutrition due to
chronic disease, whereas elevated BMI for age
might indicate rapid growth due to obesity.
The general appearance of the child may fur-
nish a clue as to the chronicity of the problem and
its emotional effects. Levels of energy and activ-
ity are important. Suspicion of a syndrome must
be clarified by the examination. The head, eyes,
ears, nose, and throat (HEENT) examination may
15
point to a midline defect, syndrome, or neuro-
logic condition. Is there a goiter or nodule of the
thyroid gland? Cardiac, pulmonary, and abdomi-
nal examinations must be thorough but do not
differ appreciably from those in a general pediat-
ric examination. Skin examination might reveal
café-au-lait spots or subcutaneous calcifications.
The extremities may appear to be curved or
abnormal or an abnormality of gait may be noted,
as an indication of rickets. Neurologic examina-
tion is essential in many disorders considered in
the book. Signs of dysfunction might suggest a
neoplasm or a congenital defect associated with
an endocrine condition.
In almost all conditions, it is important to
determine the stage of pubertal development.
This must be done with care and consideration, as
the patient, especially in the teenage years, may
be embarrassed; if the patient refuses and the
caregiver cannot achieve acquiescence, this por-
tion of the examination may have to be omitted
on this visit, as it should not be done by force.
Even with cooperation, a nonrelated adult chaper-
one should be in the room during the examina-
tion. Determination of stage of breast and pubic
hair growth is performed in girls and genitalia
and pubic hair (as well as beard) in boys, accord-
ing to standard rating techniques (see Chap. 9).
If a child refuses the exam, pictures as in Figs. 9.1,
9.2, and 9.3 may be presented to the patient to ask
which figure they think they look most like their
stage of development; this is not as accurate as
a detailed exam, but it may be all it is possible.
In addition, the development of axillary odor or
hair, the presence of comedones or acne, and the
maturation of facial features are noted in all; if
the child refuses genital examination, at least this
other information is helpful. The appearance of
abnormal distribution or amount of facial or body
hair may be an indication of a problem.
Often when no other diagnosis is found in the
general clinician’s office, an endocrine disorder
is considered and referral made. The results are
often disappointing as not every obscure symp-
tom or finding can be related to endocrinology!
 Disorders of the Hypothalamic–
Pituitary Axis
The hypothalamic–pituitary axis might be
considered as a translator of the action of higher
central nervous system activity into endocrine
secretion. In many cases, hypopituitarism is the
term used to describe a defect in the secretion of
pituitary hormones, but in fact, the condition may
be a hypothalamic problem; growth hormone defi-
ciency most often is caused by the lack of growth
hormone-releasing factor from the hypothalamus
rather than a defect in the growth hormone-
secreting cells of the pituitary gland. Thus, hypopi-
tuitarism is a vague term although it is in frequent
use.
Physiology
The hypothalamus is located in the forebrain
below the thalamus, hence the name. Under the
influence of higher central nervous system centers
the hypothalamus exerts endocrine effects either
directly, in the production and release of vasopres-
sin and oxytocin from the posterior pituitary, or
indirectly, through the release of hypothalamic-
releasing or inhibiting factors, small peptides pro-
duced in minute quantities, which reach the
anterior pituitary gland from the median eminence
of the hypothalamus through the hypophysiotro-
(A more detailed discussion of specific hormones is found
in the chapters related to their functions (e.g., growth hor-
mone (GH) is presented in Chap. 5))
© Springer International Publishing Switzerland 2016
D.M. Styne, Pediatric Endocrinology, DOI 10.1007/978-3-319-18371-8_3
3
pic, or hypothalamic–pituitary, portal vessels to
regulate anterior pituitary hormone secretion
(Fig. 3.1). Thus, disorders of any of these intercon-
nected regions, the CNS, the hypothalamus, or the
pituitary gland, can cause endocrine disease.
A sequence of homeodomain proteins and
transcription factors cause primordial cells to
develop into the characteristic cells of the ante-
rior pituitary gland, the gonadotroph, the thyro-
troph, the lactotroph, the somatotroph, and the
corticotroph. Mutations in several of these, PROP
1, PIT 1, LHX3, LHX4, HESX1, and TPIT lead
to hypopituitarism with a varying array of pituitary
hormone defects depending on the mutation.
There are commercial tests available to screen for
these mutations.
The pituitary gland receives arterial blood from
the superior hypophyseal artery which gives rise
to the capillary bed that bathes the endocrine cells
of the median eminence of the hypothalamus and
into which they release their trophic hormones.
These capillaries form the long hypophysiotropic,
or hypothalamic–pituitary, portal system which
carries the hypothalamic trophic factors to ensure
that they reach the cells of the anterior pituitary
gland to stimulate the secretion of their pituitary
hormones. There is a second short portal system
which connects the posterior and anterior pituitary
glands as well. A second capillary bed drains the
pituitary secretions into the venous system.
The hypothalamic factors are peptides—the
shortest, TRF, composed of three amino acids—
that regulate anterior pituitary function. These
17
18
GRF SRIF or SS
Hypothalmic
hormone
Effect + –
GH
Pituitary hormone
Target organ Many tissues,
including the liver,
produce IGF-1
Fig. 3.1 The hypothalamic factors, the pituitary hormones that they control, and the target organs of the pituitary hormones
peptides are growth hormone-releasing factor
(GRF) which stimulates the release of growth
hormone (GH), gonadotropin-releasing hormone
(GnRH) which stimulates the release of the
gonadotropins (luteinizing hormone (LH) and
follicle-stimulating hormone (FSH)), thyrotropin-
releasing factor (TRF) which stimulates the
release of thyrotropin (TSH), and prolactin, corti-
cotropin-releasing factor (CRF) which stimulates
the release of adrenocorticotropin (ACTH) and
vasopressin, and prolactin inhibitory factor (PIF
or dopamine) which suppresses the release of pro-
lactin. Somatostatin (SRIF) has many functions
throughout the body including the gastrointestinal
(GI) tract, but for the purposes of this discussion,
somatostatin suppresses growth hormone secre-
tion as well as TSH and prolactin secretion. The
glycoprotein hormones LH, FSH, TSH, and hCG
are heterodimers composed of an alpha and a beta
subunit. The alpha subunit is common for all of
these hormones, but the beta subunits confers
specificity on each hormone.
Prolactin and growth hormone share some
structural homology to human placenta lactogen
and derive from a common gene of origin.
3 Disorders of the Hypothalamic–Pituitary Axis
GnRH TRF CRF PIF
+ + + –
LH⁄FSH TSH and Prl ACTH Prolactin
Gonads: Thyroid gland: Adrenal gland: Mammary gland
testosterone T4 and T3 Cortisol in females
(and DHEAS)
and mammary
gland in females
acting through
or estradiol prolactin
Prolactin is released in a pulsatile manner and
increases during stress. Dopamine is secreted by
tuberoinfundibular dopamine (TIDA) neurons of
the arcuate nucleus and exerts inhibitory effect on
the D2 receptors of lactotrophs, causing suppres-
sion of prolactin secretion, and also on the D2
receptors of the thyrotroph, causing suppression
of TSH secretion. Estrogen exerts a stimulatory
effect on prolactin secretion, and pregnancy is a
period of increased prolactin secretion. Prolactin
is high in the neonatal period and then reaches a
plateau in childhood only to decrease during male
puberty. Prolactin remains stable during female
puberty. Like growth hormone, prolactin exerts its
effects by binding to a cytokine-like receptor on
the cell membrane. Prolactin’s most notable endo-
crine effect relates to the production of breast milk
but it exerts many other effects on the immune sys-
tem, cell cycle, growth differentiating and anti-apop-
tosis, hematopoiesis and angiogenesis, and blood
clotting.
After secretion into the peripheral circulation,
the pituitary hormones exert their effects on target
glands and organs specific for that pituitary
hormone. Target endocrine glands in most cases
Central Nervous System Tumors
produce their own hormones that provide feed-
back to suppress their controlling hypothalamic
and pituitary hormones in turn (e.g., cortisol from
the adrenal gland provides negative feedback
inhibition to the hypothalamic–pituitary system to
suppress hypothalamic corticotropin-releasing
hormone that stimulates pituitary adrenocortico-
tropin that in turn stimulates the release of adrenal
cortisol). Prolactin is the only pituitary hormone
that is mainly suppressed by a hypothalamic fac-
tor, prolactin inhibitory factor (dopamine) and
GABA (although centrally administered GABA
may also stimulate prolactin secretion), whereas
all other pituitary hormones are mainly stimulated
by hypothalamic factors (it is true that GH is sup-
pressed by the somatotropin release-inhibiting
factor (SRIF), but it is also stimulated by the
growth hormone-releasing factor (GRF)). Thus
hypothalamic disease may lead to a decrease in
secretion of most pituitary hormones and an
increase in prolactin secretion, whereas a pituitary
gland disorder may cause a decrease in prolactin
secretion as well as a decrease in other pituitary
hormones, a useful diagnostic feature.
The hypothalamus contains the terminal of the
axons of vasopressin-secreting neurons while also
serving as a location through which other vaso-
pressin-secreting axons pass on their way to their
own axon terminal in the posterior pituitary gland.
Thus hypothalamic damage will cause diabetes
insipidus, whereas the result of pituitary stalk sec-
tion is variable, depending on the level of lesion. If
a pituitary stalk section or disorder is high on the
pituitary stalk, all vasopressin-secreting neurons
may be affected, and the result is diabetes insipi-
dus, whereas if the pituitary stalk section is low,
some vasopressin-secreting neurons may survive
intact, and vasopressin secretion and action are still
possible, so that diabetes insipidus may not develop
or may only be transient (Chap. 4, Fig. 4.4).
Oxytocin is produced in the hypothalamus and
transported by neurophysin 1 to and stored in the
posterior pituitary. Oxytocin is released with dila-
tion of the uterus and cervix and plays a role in nor-
mal parturition; exogenous oxytocin is invoked to
promote the delivery of the baby in certain circum-
stances. Oxytocin plays a role in maternal bonding
with a newborn baby and plays a role in lactation
after stimulation of the nipples by suckling.
19
Pathology
Disorders of the hypothalamus or pituitary gland
affect endocrine function, but disorders else-
where in the CNS or radiation therapy to the CNS
for other conditions may also cause significant
endocrine effects. Although destructive lesions
of the hypothalamic–pituitary axis usually
decrease endocrine activity (e.g., hypogonado-
tropic hypogonadism), depending on location,
some diseases of the hypothalamic–pituitary axis
may instead cause increased function (e.g., pre-
cocious puberty). Alternatively, functioning
lesions may cause endocrine effects because of
their secretions rather than exerting effects due to
destruction of tissue by their size or location
(e.g., pinealomas secrete the human chorionic
gonadotropin (hCG) and cause precocious
puberty in boys, while nonfunctioning adenomas
of the pituitary gland destroy cell structure and
can cause decreased pituitary secretion).
Specific terminology relates to the level of the
endocrine lesion. A disorder of the target gland
(e.g., thyroid, adrenal gland) is considered a pri-
mary disease. A lesion of the pituitary gland is
considered a secondary defect, and a lesion of the
hypothalamus is a tertiary condition (see Chap. 1,
Fig. 1.2).
Central Nervous System Tumors
Most CNS tumors affecting the hypothalamic–
pituitary axis will cause multiple pituitary
defects. A hypothalamic tumor may, for example,
be detected by the presence of galactorrhea, due
to increased prolactin secretion from the pituitary
gland in the absence of prolactin inhibitory factor
from the hypothalamus, occurring along
with deficiencies of other pituitary hormones.
However, in hypothalamic disease, GH is most
often affected, and GH deficiency is the most
common outcome. GH deficiency may at first
appear to be an isolated finding until more careful
endocrine evaluation reveals other pituitary
defects.
Because tumors of this area are manifest
well after birth, compared to congenital defects
which exert effects soon after birth, late onset of
20
hypothalamic–pituitary deficiencies without
contributing history (e.g., surgery or trauma to
the area) may very well indicate the development
of a CNS tumor, especially if anterior and poste-
rior deficiencies occur together. In contrast,
congenital defects of hypothalamic–pituitary
hormones appear at or soon after birth, so that
early onset of combined posterior and anterior
deficiencies may cause significant effects but do
not necessarily reflect the development of a
tumor. Nonetheless, a magnetic resonance imag-
ing (MRI) evaluation of a child with onset of
hypopituitarism of any age is indicated to deter-
mine whether a definable anatomic defect is
causing the condition.
Craniopharyngioma
Craniopharyngioma is a rare embryonic malfor-
mation of nonglial origin in childhood (0.5–2.0
new cases/million population/year or 1.2–4 %
of pediatric intracranial tumors) but is a more
common CNS neoplasm in pediatrics. It is the
most common brain tumor associated with
hypothalamic–pituitary dysfunction and sexual
infantilism and comprises 80–90 % of neo-
plasms found in the pituitary and up to 15 % of
all intracranial tumors in childhood. Symptoms
usually arise before the age of 20 years with a
peak incidence between the ages of 6 and 14
years with about 30–50 % occurring in the
pediatric age range. Harvey Cushing introduced
the term “craniopharyngioma” and said that
they were “the most formidable of intracranial
tumors.”
Various theories of the embryologic origin of
this nonglial intracranial tumor are current: one
theory favors development from ectodermal rem-
nants of Rathke’s pouch and another develop-
ment from residual embryonic epithelium of the
anterior pituitary gland and of the anterior infun-
dibulum. Craniopharyngiomas may reside within
or above the sella turcica, or, more rarely, they
may be found in the nasopharynx or the third
ventricle.
3 Disorders of the Hypothalamic–Pituitary Axis
Craniopharyngioma appears to be a monoclonal
tumor, and about 50 % have genetic abnormali-
ties such as gains in activity at 1q, 12q, and 17q.
About 70 % of cases of craniopharyngioma in
childhood are the adamantinomatous type with
cyst formation. These types have dysregulation
of the Wnt signaling pathway and a mutation in
the β-catenin gene (CTNNB1) in contrast to the
papillary type of craniopharyngioma which has
BRAF mutations and is more often found in adult
patients.
CNS signs of craniopharyngiomas develop as
the tumor encroaches on surrounding structures.
Symptoms of craniopharyngioma include head-
ache, visual disturbances, short stature, diabetes
insipidus, vomiting, and weakness of one or more
limbs. Visual defects including bilateral temporal
field deficits due to impingement on the optic chi-
asm), optic atrophy or papilledema, and signs of
GH deficiency, delayed puberty, and hypothy-
roidism are features of craniopharyngiomas.
Although most patients are shorter than the mean
in height and have decreased height velocity at
diagnosis, a long, indolent course is possible.
Deficiencies of gonadotropins, GH, thyrotropin
(TSH), ACTH, and arginine vasopressin are com-
mon. The serum concentration of prolactin may be
decreased. The bone age reading may be delayed
and is common and may point to the age of onset
of tumor growth.
About 70 % of patients with a craniopharyn-
gioma have suprasellar or intrasellar calcification
(found in fewer than 1 % of normal individuals)
and an abnormal sella turcica, which are some-
times found on radiographs taken for other indi-
cations, including orthodontia. CT reveals fine
calcifications that are not apparent on lateral skull
radiographs. MRI scan before and after gadolin-
ium is the diagnostic procedure of choice for sus-
pected craniopharyngioma and can determine
whether the tumor is cystic or solid and indicate
the presence of hydrocephalus; if necessary, a CT
scan can be used to search for calcifications. The
new susceptibility weighted imaging (SWI) tech-
nique allows MRIs to reveal calcifications where
older techniques did not.
Central Nervous System Tumors
Smaller craniopharyngiomas, usually intrasellar,
can be treated by transsphenoidal microsurgery,
but larger or suprasellar masses which are more
frequently found in childhood require craniot-
omy, and the approach must be individualized.
Shunting may be required for hydrocephalus
prior to surgical treatment of the tumor. The
reported post surgical 5-year overall survival is
88–94 %, the 10-year overall survival is 70–92 %,
and the 20-year survival is 76 %. The combina-
tion of limited tumor removal and radiation ther-
apy leads to a satisfactory neurologic prognosis,
better cognitive outcome, and better endocrine
outcome compared with attempts at complete
surgical extirpation. Frequent and early tumor
relapse after apparently complete resection and
tumor progression after incomplete resection
suggest the wisdom of radiation therapy after sur-
gery. Alternative approaches include proton beam
therapy, and, in mainly cystic craniopharyngioma
cases, instillation of radioisotopes or sclerosing
substances such as bleomycin or interferon-alpha
is being investigated. Nonetheless, the preferred
manner of treatment to retain the best quality of
life is not yet established, but longitudinal studies
such as the randomized multinational trial
KRANIOPHARYNGEOM 2007 may answer
this question. It is recommended that craniopha-
ryngioma be considered a chronic disease requir-
ing constant monitoring.
The hypothalamic syndrome is comprised of
obesity; fatigue; behavioral changes; circadian
rhythm irregularities; abnormal sleep patterns;
dysregulation of body temperature, heart rate,
and blood pressure, as well as abnormalities in
thirst and is found in approximately one-third of
patients at diagnosis in childhood. After surgery,
these findings may occur in 65–80 % of patients.
Postoperative hyperphagia and obesity (e.g.,
BMI >5 SD above normal) can be striking and
correlate with the magnitude of hypothalamic
damage on cranial MRI. Injury to the hypo-
thalamic ventromedial nuclei (associated with
increased parasympathetic activity and hyperin-
sulinemia) or to the paraventricular nuclei
may cause these findings, and suppression of the
increased insulin secretion may be helpful with
the use of octreotide. Short-term follow-up
21
studies demonstrate the efficacy of bariatric
surgery in the management of obesity in affected
patients. Hypothalamic-sparing surgery decreases
the risk of postoperative hyperphagia and obe-
sity. Aberrant sleep patterns and even narcolepsy
and daytime somnolence may follow surgical
treatment of craniopharyngiomas, with melato-
nin improving sleep patterns in some. Although
the endocrine complications are more manage-
able, the combination of antidiuretic hormone
insufficiency (i.e., diabetes insipidus) and
impaired sense of thirst that arises after surgery
in some patients remains a complex management
problem.
A Rathke-cleft cyst is often discovered as an
incidental finding on MRI, but it can produce
symptoms and signs indistinguishable from those
of a craniopharyngioma, such as precocious or
delayed puberty. Surgical drainage and excision
of the cyst wall are customary approaches.
Germinomas
Germinomas (i.e., pinealomas, ectopic pinealo-
mas, atypical teratomas, or dysgerminomas) and
other germ cell tumors of the CNS are the most
common extrasellar tumors that arise in the
suprasellar hypothalamic region and in the pineal
region that commonly cause sexual infantilism.
Germinomas constitute 66 % of all intracranial
germ cell tumor (GCT) which comprise 3–11 %
of pediatric brain tumors. About 84 % are found
in the pineal and the neurohypophyseal regions.
Peak incidences occur in the second decade and
during infancy. They are found more often in
males. Polydipsia and polyuria are the most com-
mon symptoms, followed by visual difficulties
and abnormalities of growth and puberty or
movement disorders. Diagnosis is often delayed
for months to years because the findings are
sometimes attributed to psychiatric disorders.
Deficiencies of vasopressin and GH are most
common, but other anterior pituitary hormone
deficiencies (including gonadotropin deficiency)
and elevated serum prolactin levels are also
frequent. Determination of the concentration of
hCG in spinal fluid and in serum and assessment
22
of α-fetoprotein levels provide useful tumor
markers in children and adolescents with germ
cell tumors. Germ cell tumors in boys can cause
isosexual GnRH-independent sexual precocity by
secretion of hCG (see Chap. 9). Subependymal
spread of germ cell tumors along the lining of the
third ventricle is common, and seeding may
involve the lower spinal cord and cauda equina.
MRI with contrast enhancement is useful in the
detection of isolated enlargement of the pituitary
stalk, an early finding of germinomas that requires
periodic MRI monitoring, especially in patients
with diabetes insipidus. The size of the pituitary
gland increases by 100 % between year 1 and
year 15, but the pineal gland does not normally
change in size after the first year of life; any later
enlargement indicates a mass lesion. Pineal cysts
are a rare cause of central precocious puberty.
Irradiation is the preferred treatment for pure
germ cell tumors such as germinomas; surgery is
rarely indicated, except for biopsy to establish a
tissue diagnosis. However, attempts to decrease
the long-term morbidity of radiation therapy leads
to consideration of chemotherapy. Chemotherapy
alone is inadequate, but the combination of che-
motherapy and radiation therapy can be success-
ful, and both treatment methods are recommended
for a mixed germ cell tumor. Because testicular
germ cell tumors are occasionally found years
after successful therapy for CNS germ cell
tumors, long-term surveillance is indicated.
Hypothalamic and optic gliomas or astrocyto-
mas, occurring as part of neurofibromatosis (von
Recklinghausen disease (*162200 NEURO-
FIBROMATOSIS, TYPE I; NF1, due to muta-
tions in the neurofibromin gene)) or arising
independently, can also cause sexual infantilism.
Gliomas and meningiomas are the most common
CNS tumors to develop in childhood cancer sur-
vivors treated with CNS radiation, often in the
young adult or even late teenage years.
Pituitary Adenomas
Only 2–6 % of all surgically treated pituitary
tumors occur in childhood and adolescence,
with about 1 in 1,000,000 children affected.
3 Disorders of the Hypothalamic–Pituitary Axis
Most functional pituitary adenomas are ACTH
secreting, with prolactinomas, GH secreting, or
nonfunctioning adenomas occurring less com-
monly. Most pituitary tumors are monoclonal
lesions caused by mutations of guanine
nucleotide-binding protein, GNAS; a transcript
of the GNAS gene, Gs-alpha, encodes the alpha
subunit of the stimulatory guanine nucleotide-
binding protein (G protein). Gs-alpha is expressed
biallelically in nearly all tissues and plays essen-
tial roles in a multitude of physiologic processes.
Adolescent onset of pituitary tumors may be the
first manifestation of multiple endocrine neopla-
sia type I (see Chap. 10). Familial isolated
pituitary adenoma (FIPA) (#102200 PITUITARY
ADENOMA) is diagnosed in a family with a his-
tory of pituitary adenomas including prolactino-
mas. About 20 % of cases of FIPA have a germline
mutation in aryl hydrocarbon receptor-interacting
protein (AIP).
With more sensitive imaging techniques,
the presence of a pituitary incidentaloma, a
previously unsuspected pituitary lesion that is
discovered on an imaging study performed for an
unrelated reason, may be discovered. Evaluation
of secretory activity of such a lesion, consideration
of mass effects, and follow-up to monitor a change
in size are important, but some lesions detected
will not be related to the endocrine abnormality for
which the imaging procedure was ordered.
The incidence of prolactinoma is low in child-
hood, but one in five presents in the 15–24-year
age group. A case survey reported that 61 % of
prolactinomas were macroadenomas (more often
in boys; hypopituitarism and growth failure were
common) and 39 % were microadenomas (more
often in girls; delayed puberty was common).
Delayed onset of puberty was rare, although pri-
mary amenorrhea was the presenting symptom in
more than 50 % of pubertal females. Presenting
symptoms included oligomenorrhea and galac-
torrhea in the girls and headache in the boys.
Galactorrhea may be demonstrable only by man-
ual manipulation of the nipples (blood samples
for prolactin should be obtained before examina-
tion or many hours later, because manipulation of
the nipples raises prolactin levels). The degree of
elevation of prolactin may indicate the size of the
Other Central Nervous System Disorders
prolactinoma. Microadenomas may demonstrate
prolactin levels over 100 ng/mL, while values
over 500 ng/mL are suggestive of a macroprolac-
tinoma. Certain medications will also raise pro-
lactin to levels suggestive of an adenoma when in
fact there is no adenoma; risperidone and meto-
clopramide are two examples although there are
many more psychiatric medications that can raise
serum prolactin values.
Dopaminergic therapy is often successful
in decreasing prolactin values. The dopamine
agonist bromergocriptine may decrease serum
prolactin concentrations and decrease tumor size,
which is a useful approach before surgery of large
macroprolactinomas is undertaken and when
resection of the adenoma is incomplete. Pubertal
progression and normal menstrual function in
girls usually follow reduction of serum prolactin
levels. Caberogline is a D2 receptor agonist that
can be given 2 times per week (not approved for
children). Pituitary apoplexy followed caberog-
line treatment of a macroprolactinoma in a
16-year-old girl; this complication has been seen
in adults treated with bromocriptine. Tricuspid
regurgitation may occur as a cumulative effect of
treatment. Transsphenoidal resection of microp-
rolactinomas in children and adolescents is an
effective treatment if medication is ineffective.
High serum levels of macroprolactin, a complex
of immunoglobulin G and monomeric prolactin
with little biologic activity in vivo, cross-react in
commercial prolactin assays, leading to a finding
of pseudohyperprolactinemia; high prolactin val-
ues should be rechecked with subfractionation
after polyethylene glycol precipitation to elucidate
this potential confusion. When prolactin levels are
truly quite high, the molecule may complex with
IgG antibodies used in certain assays causing a
“hook effect” leading to artifactually low prolactin
levels when values actually are quite high. In this
situation, a 1–100 dilution of serum before analy-
sis is necessary. As prolactin rises in stress, an
upset child may have a falsely elevated prolactin
suggesting a disorder when there is none.
It is recommended that screening for multiple
endocrine neoplasia type I (MENIN gene) and
FIPA (AIP gene) occur in anyone with a pituitary
adenoma under 21 years of age.
23
Other Central Nervous System
Disorders
Langerhans Cell Histiocytosis
Langerhans cell histiocytosis (604856 ICD+
LANGERHANS CELL HISTIOCYTOSIS) is a
clonal proliferative disorder of Langerhans his-
tiocytes or their precursors characterized by the
infiltration of the skin, viscera, and bone with
lipid-laden histiocytic cells or foam cells. The
cause is not clear, but there are features of a neo-
plasm and features of a reactive immunologic dis-
order. Diabetes insipidus, caused by infiltration of
the hypothalamus or the pituitary stalk, is the
most common endocrine manifestation, with GH
deficiency and delayed puberty as possible out-
comes. The lung, liver, and spleen may be
involved with this infiltration, and exophthalmos
due to infiltration of the orbit is seen. Other find-
ings include cyst-like areas in flat and long bones
of the skull, the ribs, the pelvis, and the scapula
and the long bones of the arms and legs and in the
dorsolumbar spine. The appearance of “Floating
teeth” within rarefied bone of the mandible and
absent or loose teeth are found. Mastoid or tem-
poral bone involvement may lead to chronic otitis
media. Treatment with glucocorticoids, antineo-
plastic agents, and radiation therapy is promising
in terms of survival, but more than 50 % of
patients have late sequelae or disease progression.
The natural waxing and waning course of this rare
disease makes evaluation of therapy difficult and
highlights the importance of national treatment
protocols. Letterer–Siwe disease (%246400
ICD+LETTERER-SIWE DISEASE) has similar-
ities to Langerhans' cell histiocytosis but may
occur in an autosomal recessive pattern.
Postinfectious Inflammatory
Lesions of the Central Nervous
System, Vascular Abnormalities,
and Head Trauma
Postinfectious or other inflammatory lesions of
the CNS, granulomatous disease of the area and
vascular abnormalities, and head trauma may
24
cause abnormal hypothalamic–pituitary function.
Tuberculous or sarcoid granulomas of the CNS
are associated with delayed puberty. The original
case of adiposogenital dystrophy, or Fröhlich’s
syndrome characterized by decreased growth and
delayed puberty with obesity, is thought to have
been caused by tuberculosis infection rather than
a neoplasm.
Hydrocephalus may cause hypopituitarism,
but precocious puberty also is a possible result,
depending on the amount of pressure exerted on
various central nervous system locations. Clinical
findings will include signs of increased intra-
cranial pressure. When hydrocephalus or sub-
arachnoid cysts, which can cause similar effects,
are decompressed, pituitary abnormalities may
improve.
Irradiation of the Central
Nervous System
Radiation of the head for treatment of CNS
tumors, leukemia, or neoplasms of the head and
the face, in which the radiation field involves the
hypothalamus or pituitary field, may result in the
gradual onset of hypothalamic–pituitary failure
over a period of months to a few years. This
occurs mainly due to hypothalamic rather than
pituitary damage by the radiation and is dose-
dependent. This etiology comprises an growing
group of patients with hypopituitarism because
of the increasing success in radiation treatment of
such neoplasms. GH deficiency is the most com-
mon hormone disorder resulting from radiation
of the CNS, but gonadotropin deficiency, hypo-
thyroidism, and decreased bone density also
occur. Self-reported fertility was reported to be
lower in women who received CNS radiotherapy
for acute lymphoblastic leukemia at about the
time of menarche, although the average age of
women in a long-term study was in the early 20s,
and longer follow-up of fertility may change the
results. Conversely, early or central precocious
puberty may occur after radiation therapy for
CNS lesions. The combination of GH deficiency
and precocious puberty is a possible outcome of
3 Disorders of the Hypothalamic–Pituitary Axis
central nervous system radiation for a brain
tumor and may be difficult to detect clinically, as
the growth rate of the child is greater than that
found in patients with GH deficiency alone,
because the sex steroid secretion increases
growth rate during pubertal development (see
Chaps. 5 and 9). Irradiation of the CNS in early
life predisposes the patient to later onset of sec-
ondary CNS tumors sometimes in just a few
years after treatment of the first tumor. Such
patient must be monitored to determine what
pituitary defects have developed so that it may be
treated appropriately.
Developmental Defects
of the Midline
Congenital defects of pituitary secretion also may
result from anatomic malformations of the hypo-
thalamus, from pituitary hypoplasia or aplasia, or
from more subtle defects of hormone secretion.
Congenital defects of the midline associated with
hypopituitarism range from holoprosencephaly
(cyclopia, cebocephaly, orbital hypotelorism) to
single maxillary incisor and even to cleft palate
(4 % of cases of cleft lip and/or palate are associ-
ated with GH deficiency, so that all growth failure
in cleft palate should not necessarily be attributed
to poor feeding or nutrition alone). Individuals
with myelomeningocele (myelodysplasia) have
an increased frequency of endocrine abnorma-
lities, including hypothalamic hypothyroidism,
hyperprolactinemia, and decreased gonadotropin
concentrations, whereas some patients demon-
strate central precocious puberty.
Septo-Optic and Optic Dysplasia
Septo-optic dysplasia (optic nerve hypoplasia,
absent septum pellucidum, or variations of
both caused by abnormal development of
the prosencephalon) (# 182230. SEPTOOPTIC
DYSPLASIA due to a mutation at 3p21.2-p21.1).
The HESX1 homeobox gene or SOX2 (see
below), SOX3, and OTX2 may be associated with
Idiopathic Hypopituitary Dwarfism
significant visual impairment which often leads
to pendular nystagmus (to-and-fro nystagmus
due to inability to focus on a target). Small, pale
optic disks occur, but not the appearance of
optic atrophy, which would suggest previous
development of the optic nerves with subsequent
deterioration due to acquired pathology.
A midline hypothalamic defect may lead to
the combination of GH deficiency and diabetes
insipidus and may be associated with deficient
ACTH, TSH, and gonadotropin secretion as well.
Short stature and delayed puberty may be the
most obvious results, although true precocious
puberty is an alternative outcome in rare cases of
this midline defect. The septum pellucidum is
absent in about 50 % of cases of optic hypoplasia
or dysplasia, and this defect is readily demon-
strable by CNS imaging techniques, most fre-
quently by MRI.
The MRI findings of congenital hypopituita-
rism may include an ectopic posterior pituitary
gland “hot spot” and the appearance of what
appears to be a “pituitary stalk transection” and
a hypoplastic pituitary gland due to the lack
of hypothalamic stimulatory factors. In some
patients, the neurohypophysis may appear
absent because of a missing hot spot although
physiologic changes in hydration may affect the
hot spot, which represents vasopressin content,
with no true anatomic defect. Abnormalities of
the corpus callosum and cerebellum are com-
mon on MRI. Four groups are described: those
with normal MRI results, those with abnormali-
ties of the septum pellucidum and with a normal
hypothalamic–pituitary area, those with abnor-
malities of the hypothalamic–pituitary area and
a normal septum pellucidum, and those with
abnormalities in both areas. No endocrine
abnormalities were described in the first group,
but the others had progressively more endocrine
abnormalities, with precocious puberty most
common in the second group. Early diagnosis is
important because of the risk of sudden death
associated with adrenal insufficiency if ACTH
is inadequate.
Delayed puberty is rarely described in dupli-
cation of the hypophysis.
25
The Solitary Median Maxillary
Incisor Syndrome
(#147250 SOLITARY MEDIAN MAXILLARY
CENTRAL INCISOR; SMMCI) Solitary median
maxillary incisor is associated with the eponymous
midline defect and with a prominent midpalatal
ridge (torus palatinus) and hypopituitarism. The
defect in this autosomal dominant condition is in the
sonic hedgehog gene (SHH) at gene map locus 7q3.
Idiopathic Hypopituitary Dwarfism
In addition to HESX1 homeobox mutations, auto-
somal recessive mutations in homeobox genes
encoding transcription factors involved in the
early aspects of pituitary development lead to
hypogonadotropic hypogonadism and other pitu-
itary hormone deficiencies (Table 3.1). PROP1
mutations (#262600 PITUITARY HORMONE
DEFICIENCY, COMBINED, 2; CPHD2) at gene
map locus 5q35.3 cause GH and TSH deficiency
and produce delayed puberty or late onset of sec-
ondary hypogonadism in adulthood and more
rarely may also cause ACTH deficiency. In one
study of 73 patients with idiopathic multiple pitu-
itary hormone deficiencies, 35 had a mutation in
PROP1. Homozygous Arg73Cys mutation of
PROP1 allowed spontaneous puberty in 2 of 10
affected family members. ACTH deficiency may
develop later and is more rarely a feature of
PROP1 deficiency; patients must be monitored
for this serious complication.
Mutations of POU1F1 (PIT *173110
POU DOMAIN, CLASS 1, TRANSCRIPTION
FACTOR 1; POU1F1 at 3p11) cause deficiency
in GH, TSH, and prolactin.
Homozygous mutations occur in the LHX3
gene (#221750 PITUITARY HORMONE
DEFICIENCY, COMBINED, 3; CPHD3) at gene
map locus 9q34.3. The LHX3 gene encodes a
member of the LIM class of homeodomain pro-
teins, which are associated with multiple pituitary
hormone deficiencies, including LH and FSH,
and often with severe restriction of head rotation.
LH4 (#262700
 26

Table 3.1 Genetic forms of multiple pituitary/hypothalamic hormone deficiencies

Defect Hormones deficient Inheritance Mutations Other features
POU1F1 GH, Prl, TSH Auto-recessive and autosomal Missense, nonsense, Severe impairment of postnatal growth, variable
dominant frameshift, splicing pituitary hypoplasia
PROP1 GH, Prl, TSH, LH, FSH, Auto-recessive Nonsense, frameshift, Transient pituitary hyperplasia in some
and ACTH developing later splicing
in some
HEX1 Any or all, including Auto-recessive and autosomal Missense, frameshift Septo-optic dysplasia or hypoplasia
vasopressin dominant
LIM HOMEO BOX GH, Prl, TSH, LH, FSH, Auto-recessive Missense, nonsense, Limited neck rotation, short cervical spine,
GENE 3; LIM3 LHX3 and ACTH in some frameshift, splicing sensorineural deafness
LIM HOMEO BOX GH, Prl, TSH, LH, FSH, Autosomal dominant Missense, frameshift Cerebellar abnormalities, very small sella turcica
GENE 4; LIM4 LHX4 and ACTH in some, abnormal petrous bone
SOX2 LH,FSH, variable GH Autosomal dominant Missense, nonsense, Anophthalmia/microphthalmia, esophageal
frameshift atresia, genital tract abnormalities, hypothalamic
hamartoma, sensorineural hearing loss, diplegia
GLI2 GH, Prl, TSH, LH, FSH, Haploinsufficiency Missense, frameshift Holoprosencephaly, craniofacial abnormalities,
3

and ACTH polydactyly, partial agenesis of the corpus

callosum
FGF8 LH, FSH, and vasopressin Auto-recessive and autosomal Missense, chromosome Anosmia, holoprosencephaly, Moebius
dominant deletion syndrome, septo-optic dysplasia
SOX3 Isolated GHD or GH, Prl, X-linked Variations in polyalanine Mental retardation, infundibular hypoplasia,
TSH, LH, FSH, and ACTH tract length, chromosome ectopic posterior pituitary, midline abnormalities
duplication
OTX2 Isolated GHD or GH, Prl, Autosomal dominant Missense, nonsense, Anophthalmia/microphthalmia, coloboma,
TSH, LH, FSH, and ACTH microdeletion developmental delay
TBX19 ACTH Autosomal recessive Missense, nonsense, Neonatal hypoglycemia, neonatal cholestatic
frameshift, splicing jaundice
GH growth hormone, Prl prolactin, TSH thyroid-stimulating hormone, LH luteinizing hormone, FSH follicle-stimulating hormone, ACTH adrenocorticotropic hormone
Disorders of the Hypothalamic–Pituitary Axis
Suggested Readings
PITUITARY HORMONE DEFICIENCY,
COMBINED, 4; CPHD4) and GLI2 (#610829
HOLOPROSENCEPHALY 9; HPE9) mutations
may cause isolated GH deficiency or combined
pituitary hormone deficiencies including
gonadotropin deficiency. The X-linked form
of hypopituitarism can be associated with
duplication of the SOX3 gene (#312000
ICD + PANHYPOPITUITARISM, X-LINKED;
PHPX). Deficiency of SOX2 (#206900
ICD+ MICROPHTHALMIA, SYNDROMIC 3;
MCOPS3), a transcription factor involved in early
hypothalamic–pituitary embryonic development,
leads to anterior pituitary hypoplasia. Patients with
SOX2 mutations have major eye abnormalities,
including anophthalmia, microphthalmia, and col-
oboma. They also have hypogonadotropic hypogo-
nadism (HH) as the most common pituitary defect,
in contrast to most other types of pituitary hypopla-
sia, demonstrating GH deficiency most frequently.
There is an association between breech delivery
(especially for male infants), perinatal distress, and
idiopathic hypopituitarism. Malformations of the
pituitary stalk demonstrable by MRI are common
in these patients. Other types of birth trauma or
complications may lead to hypopituitarism as well.
Common to many patients with congenital hypo-
pituitary dwarfism is early onset of growth failure;
late onset of diminished growth is an ominous find-
ing, suggesting the presence of a CNS tumor.
27
Suggested Readings
1. Romero CJ, Pine-Twaddell E, Radovick S. Novel
mutations associated with combined pituitary hormone
deficiency. J Mol Endocrinol. 2011;46(3):R93–R102.
2. Tsai SL, Laffan E, Lawrence S. A retrospective
review of pituitary MRI findings in children on growth
hormone therapy. Pediatr Radiol. 2012;42(7):
799–804.
3. Deal C, Hasselmann C, Pfaffle RW, Zimmermann
AG, Quigley CA, Child CJ, Shavrikova EP, Cutler Jr
GB, Blum WF. Associations between pituitary imag-
ing abnormalities and clinical and biochemical phe-
notypes in children with congenital growth hormone
deficiency: data from an international observational
study. Horm Res Paediatr. 2013;79(5):283–92.
4. Cavarzere P, Biban P, Gaudino R, Perlini S, Sartore
L, Chini L, et al. Diagnostic pitfalls in the assessment
of congenital hypopituitarism. J Endocrinol Invest.
2014;37(12):1201–9.
5. Castinetti F, Reynaud R, Quentien MH, Jullien N,
Marquant E, Rochette C, et al. Combined pituitary
hormone deficiency: current and future status.
J Endocrinol Invest. 2015;38(1):1–12.
6. McCabe MJ, Dattani MT. Genetic aspects of hypotha-
lamic and pituitary gland development. Handb Clin
Neurol. 2014;124:3–15.
7. Keil MF, Stratakis CA. Pituitary tumors in childhood:
update of diagnosis, treatment and molecular genet-
ics. Expert Rev Neurother. 2008;8(4):563–74.
8. Xekouki P, Azevedo M, Stratakis CA. Anterior pitu-
itary adenomas: inherited syndromes, novel genes and
molecular pathways. Expert Rev Endocrinol Metab.
2010;5(5):697–709.
9. Griffith R Harsh, Lawrence D Recht, Karen J Marcus.
Craniopharyngioma. In: UpToDate. http://www.upto-
date.com/contents/craniopharyngioma.
 The Posterior Pituitary Gland
and Disorders of Vasopressin
Metabolism
The posterior pituitary gland, also known as the
neurohypophysis, may share a term in its name
with the anterior pituitary gland but unlike the
anterior pituitary gland has a direct connection to
the brain as the posterior pituitary contains the
nerve endings of the vasopressin and oxytocin
neurons which originate in the periventricular
and supraoptic nuclei. Vasopressin is secreted
from the posterior pituitary gland as is oxytocin.
Disorders of vasopressin metabolism may cause
increased or decreased urine formation and sub-
sequent abnormalities in body water and serum
osmolality and electrolytes. Rather than being
controlled by secretions of the median eminence
of the hypothalamus through the hypophysiotro-
pic portal system, these nerve endings in the pos-
terior pituitary directly secrete their product into
the general circulation. The axons of these neu-
rons may be interrupted by trauma or surgery, and
the level of the interruption determines the out-
come. If the pituitary stalk section is low, some
intact vasopressin neurons will remain as some
terminate at the top of the pituitary stalk and dia-
betes insipidus may be mild or not occur. If the
stalk section is high, it is more likely that all vaso-
pressin neurons will be affected and that diabetes
insipidus will be permanent.
Although lack or excess of antidiuretic hormone
(ADH) is a main focus of the chapter, nephrogenic
diabetes insipidus which presents in a relatively
similar manner is also covered. Further, excessive
urination also may be due to the desire for second-
ary gain in psychogenic polydipsia, to habitual
© Springer International Publishing Switzerland 2016
D.M. Styne, Pediatric Endocrinology, DOI 10.1007/978-3-319-18371-8_4
4
excessive drinking, to urinary tract defects in con-
centrating ability, possibly due to urinary tract
infections, as well as to osmotic diuresis. The most
common etiology of a pathologic cause of polyuria
is the glucosuria of diabetes mellitus (translated as
“sweet urine”) in contrast to the rarer condition of
diuresis due to the lack of ADH that leads to central
diabetes insipidus (DI; “weak urine”). Diabetes
mellitus is the province of Chap. 11.
Normal Vasopressin Physiology
Arginine vasopressin (AVP) is the human antidi-
uretic hormone (ADH) (Fig. 4.1). AVP is pro-
duced in the magnocellular cells of the
paraventricular and supraoptic nuclei of the hypo-
thalamus in a large precursor molecule coded by a
gene at 20p13 along with neurophysin II (NPII).
The two molecules are synthesized within the
neurosecretory granules of the magnocellular
cells and then reassembled into AVP–NPII com-
plexes before secretion. There are about 30–50
days’ worth of AVP stored for secretion in normal
circumstances, but with maximal use, only a
5–10-day supply is available. Neurophysin I is a
molecule of unknown function which is secreted
with and transported with oxytocin.
The magnocellular neurons terminate, for
the most part, in the posterior pituitary gland
(the neurohypophysis), but some terminate in
the third ventricle, and some terminate high in the
pituitary stalk or in the median eminence of the
29
30 4  The Posterior Pituitary Gland and Disorders of Vasopressin Metabolism
+
Osmoreceptors and
sense of thirst
+
–
Hypothalamus and + +
pituitary gland
+ +
Heart
– volume
AVP – Increased
Increased
serum osmolality
+ +
aldosterone +
Adrenal angiotensin
gland
renin
+ Concentrated
Kidney
urine
Fig. 4.1 Regulation of serum sodium and water. Solid
lines indicate a positive effect and dashed lines indicate a
negative effect. Increased serum osmolality stimulates the
osmoreceptor and sense of thirst, causing an individual to
take in more water and stimulates the release of arginine
vasopressin (AVP) from the posterior pituitary gland. AVP
stimulates the kidney to concentrate the urine by making
the distal collecting tubule permeable to water and thus
decreases serum osmolality which thereby decreases water
intake and decreases sense of thirst. Decrease in blood
pressure or blood volume will likewise stimulate the
osmoreceptors and volume or pressure sensor in the car-
diovascular system to stimulate the release of arginine
hypothalamus. Vasopressin also is produced in
the parvocellular cells of the paraventricular
nuclei, as is corticotropin-releasing hormone
(CRH), and both stimulate the secretion of adre-
nocorticotropic hormone (ACTH); in this situa-
tion, the vasopressin neurons do terminate in the
median eminence, and their secretions are carried
through the portal system to the pituitary gland.
An intracellular osmotic detector (organum vas-
culosum of the lamina terminalis and anterior
hypothalamus) is located close to the supraoptic
nuclei but separate from the nuclei containing
ADH; the osmotic detector may reside outside of
the blood–brain barrier. This sensor detects
Water
Intake
–
Decreased
blood pressure/
blood pressure/
volume
Decreased
serum osmolality
+
vasopressin. Increased blood pressure or blood volume
will cease the stimulation of the volume and baroreceptors
in the cardiovascular system from simulating vasopressin
release, allowing appropriately increased urinary excre-
tion. Low extracellular volume or hyponatremia will stim-
ulate the kidney to activate the renin–angiotensin system
to stimulate the adrenal gland to produce aldosterone
which will retain sodium and increase serum osmolality.
Concentration of sodium in the renal tubule will also tend
to decrease urinary concentration and volume. Increased
blood pressure or volume causes the heart to release atrial
natriuretic peptide which antagonizes the aldosterone
affect and allows urinary sodium loss
changes in plasma osmolality as subtle as 1–2 %,
reaching a sensitivity that is better than many
laboratory tests can accomplish. Serum osmolality
is determined by osmotically active substances in
the blood which include sodium chloride (unless
glucose is significantly elevated). An increase in
osmolality due to dehydration, or the infusion of
a hypertonic solution such as concentrated saline,
triggers the release of sufficient vasopressin to
cause the kidney to retain water, thereby decreas-
ing the serum osmolality to normal. When plasma
osmolality is less than 280 mOsm/kg, vasopres-
sin is not released to any appreciable degree, val-
ues range from 0.5 to 1 pg/mL, but when
Normal Vasopressin Physiology
osmolality reaches 283 mOsm/kg or more, vaso-
pressin is secreted in increasing amounts, until
maximum secretion occurs at 320 mOsm/kg
which leads to a serum level of about 20 pg/mL.
Low-pressure baroreceptors in the right atrium
and pulmonary venous circulation and high-­
pressure baroreceptors in the carotid sinus and
aortic arch also regulate the release of vasopres-
sin, so that a decrease in blood volume of 8–10 %
(equivalent to a major hemorrhage) will stimulate
a large release in vasopressin. Lung disease and
respiratory support with ventilator therapy will
trigger vasopressin secretion because of the
increase in intrathoracic pressure, as detected by
the stretch receptors of the atrium; increased fluid
management as is often used in pneumonia,
example, may trigger the syndrome of inappro-
priate secretion of ADH (SIADH; see later).
During the daily routine of standing and walking,
vasopressin concentrations change from moment
to moment because of stimulation of the carotid
baroreceptors. In states of dehydration and low
plasma volume, vasopressin is released by physi-
ologic stimulation. If vasopressin is released at
times of elevated plasma volume, this release is
inappropriate.
Vasopressin may be released in other situa-
tions regardless of plasma volume. Other stimuli
of vasopressin secretion include nausea and cer-
tain drugs, such as chlorpromazine and antime-
tabolites, used in the treatment of cancer; nausea
in cancer treatment should therefore be an
expected stimulus for vasopressin secretion and
may cause the syndrome of inappropriate secre-
tion of ADH if fluids are administered in excess
(SIADH; see later). Nicotine exerts its effects
through the precipitation of nausea, which stimu-
lates the release of vasopressin.
There are several situations in which vaso-
pressin secretion is increased and the patient has
an inability to excrete water load. Vasopressin
secretion is inhibited by glucocorticoids and in
Cushing’s syndrome urination increases; alterna-
tively, decreased glucocorticoids increase vaso-
pressin secretion, and in Addison’s disease the
individual’s inability to excrete a water load may
lead to overhydration with a subsequent decrease
in serum sodium. Like­wise, ­hypothyroidism will
31
inhibit the ability to excrete water and urine and
may lead to overhydration. Exogenous medica-
tions that may inhibit the ability to excrete adequate
urine volume include medications which are used
in children and adolescents such as lisinopril
which is used in diabetic nephropathy, carbam-
azepine and valproic acid, sulfonylureas, tricyclic
antidepressants, and selective serotonin uptake
inhibitors among others.
Vasopressin exerts two major biologic effects:
it increases permeability of the collecting duct of
the nephron to water filtered in the urine and, in
large concentrations, ADH stimulates the contrac-
tion of arterial muscle, which increases blood
pressure (BP), hence the name vasopressin. V2
receptors located in the renal collecting duct
mediate the actions of vasopressin on urine con-
centration. Of the three vasopressin receptors, the
membrane-bound V2 vasopressin receptor (V2R),
a G-protein-coupled receptor encoded by the X
chromosome on the basolateral membrane of
renal collecting duct epithelial cells, is the most
important in water balance. Increased intracellu-
lar cyclic adenosine monophosphate (cAMP)
results after V2R activation, which mediates shut-
tling of the water channel aquaporin 2 (AQP-­2) to
the apical membrane of collecting duct epithelial
cells, resulting in increased water permeability
and antidiuresis. Other receptors allow vasopres-
sin to exert other effects. The V1 receptor is found
in the vasculature, in the platelets, and in the liver.
The V3 receptor is found in the anterior pituitary
gland where it modulates the effects of vasopres-
sin on ACTH secretion.
The medulla of the kidney normally maintains
a high osmotic concentration of urea and sodium
built up by the countercurrent exchange system.
When vasopressin allows water filtered in the
urine to pass through the walls of the collecting
ducts, the water will, through the osmotic gradi-
ent, be drawn to the medulla, and the urine in the
lumen of the collecting ducts will become more
concentrated. The effects of vasopressin on salt
balance are mostly mediated through its effect on
changes in water balance as fluid retention will
lower serum sodium although vasopressin can
activate the epithelial Na(+) channel (ENaC) to
decrease sodium excretion to a lesser effect. Thus
32 4  The Posterior Pituitary Gland and Disorders of Vasopressin Metabolism
if water is lost, serum sodium and osmolality
increase, whereas if water is retained, serum
sodium and osmolality decrease.
If vasopressin from the posterior pituitary is not
produced or cannot be released, central diabetes
insipidus (DI) develops. If the collecting duct
cannot respond to the vasopressin, nephrogenic
DI occurs. If a patient has been drinking large
amounts of water for a prolonged period because
of habit or psychogenic polydipsia, the medullary
interstitial gradient becomes progressively more
dilute (“washes out”), so that the maximal con-
centrating ability of the kidney is decreased, and
polyuria results. Infection or various types of
kidney disease also can decrease the concentrat-
ing ability of the kidney (causing functional
nephrogenic DI).
The sensor responsible for the sense of thirst
is located in the lateral hypothalamus. The sensa-
tion of thirst arises when serum osmolality
increases to more than 293 mOsm/kg, a 2–3 %
rise from normal, which is 13 mOsm/kg higher
than the lower limit of stimulation of vasopressin
secretion. A decrease of 1–4 % of blood volume
will likewise trigger the sensation of thirst. Other
sensors in the oral cavity interact with both the
sense of thirst and vasopressin secretion, so that
fluid ingestion is modulated quite closely, as
appropriate fluid balance is essential for life.
Thus two basic mechanisms control serum
osmolality: (a) vasopressin secretion exerting
effects on the nephron and (b) fluid dynamics
mediated by fluid loss and the sense of thirst that
affects fluid intake. Either mechanism can com-
pensate for a defect in the other, but if both mecha-
nisms fail, and the individual has neither sense of
thirst nor ability to concentrate urine, swings in
osmolality may reach a life-threatening degree. An
infant is dependent on others to supply water and
may not be able to communicate its needs, leading
to overhydration or underhydration. An older child
who lacks vasopressin can usually drink enough
water to maintain fluid balance for a while if the
child’s thirst mechanism operates normally.
The consequences of hyperosmolality or
hypoosmolality can be severe. The obvious
impairment of renal function due to severe vol-
ume constriction and the pulmonary edema and
heart failure that can be caused by volume excess
are well appreciated. However, the effects of rapid
fluid shifts on brain cells and brain function can
be devastating and may be permanent, and these
may occur because of DI or SIADH. A rapid
increase in plasma osmolality can draw fluid from
the brain and, especially in young infants, cause
brain shrinkage and rupture of veins that bridge
the distance from the rigid cranium to the more
malleable brain substance. Although the brain is
slower to correct osmolar balance than is the vas-
cular compartment, during a more gradual increase
in intravascular osmolality, the brain can produce
“idiogenic osmoles” (or osmolytes including tau-
rine, glycine, glutamine, sorbitol, and inositol) that
increase intracellular osmolality to balance an
intravascular hyperosmolality. These osmolar-
active molecules rise within 4 h of increased extra-
cellular osmolality and remain in the brain for
hours to days after a decrease in intravascular
osmolality occurs, leading to an imbalance of
osmolar forces with the net shift of fluid toward
the brain if serum osmolality decreases, result-
ing in cerebral edema that could cause cerebellar
tonsillar herniation and death. Thus both hypoos-
molality and hyperosmolality are damaging to
the brain.
The renin–angiotensin system also affects
water balance as it affects sodium and potassium
balance described in Chap. 10. Decreased intra-
vascular volume stimulates the renin–angiotensin
system leading to increasing blood pressure,
increasing potassium excretion, and increasing
sodium resorption from the distal tubule whereby
water is likewise retained. Manipulation of the
renin–angiotensin system is one manner of treat-
ing nephrogenic diabetes insipidus (see below).
The family of three natriuretic peptides plays
a role in total body sodium retention. Atrial natri-
uretic peptide (ANP) is produced not only in the
atrium but in the brain and other areas of the cen-
tral nervous system and serves to decrease blood
pressure and limit cardiac hypertrophy. B natri-
uretic peptide (BNP due to initial isolation from
the brain) is produced in the ventricle of the heart
as well as the brain and acts in a similar manner
to ANP. C natriuretic peptide (CNP) which is
produced in the central nervous system also
­
Diabetes Insipidus
r­egulates bone growth. While there are three
receptors for the atrial natriuretic peptides, the
atrial natriuretic peptide receptor A is located in
the kidney, interacts with ANP and BNP, and
most directly affects sodium balance. ANP is
secreted in response to stretching of the atrial
wall due to increased intravascular volume and
BNP is secreted in response to stretching of the
ventricular wall in states of congestive heart fail-
ure. When ANP binds to the atrial natriuretic pep-
tide receptor A, diuresis ensues with natriuresis
as a result of antagonistic effects on the renin–­
angiotensin system; vasorelaxation and increased
endothelium permeability also occur.
Diabetes Insipidus
Central Diabetes Insipidus
The inability to release adequate arginine vaso-
pressin in the face of increased serum osmolality
can be caused by central nervous system (CNS)
tumor, trauma, infection, or granuloma as well as
by a congenital defect of the brain structure
(Table 4.1; Fig. 4.2) or mutations in the AVP-­NPII
gene all leading to central diabetes insipidus.
Some vasopressin secretion may remain in spite
of DI, but the amount of vasopressin secreted is
not commensurate with the need for water conser-
vation, and excessive urination occurs. Depending
on the nature of the defect, the sense of thirst may
or may not remain intact, determined by whether
the thirst center of the CNS is affected as well as
the vasopressin neurons. If impairment of the
sense of thirst occurs, maintenance of serum
osmolality in the normal range becomes most
difficult, as voluntary water intake must replace
previously automatic functions, sensing thirst and
drinking when thirsty. Home management of the
patient with diabetes insipidus and a loss of thirst
sensation is complicated by the fact that there is
no home device to measure serum sodium or
serum osmolality as there is for glucose with a
home glucometer. Frequent laboratory visits are
necessary in such patients.
Any hypothalamic–pituitary tumor can cause DI
with or without other hypothalamic–pituitary
33
d­isorders. Most commonly in the pediatric age
group, a craniopharyngioma or germinoma is
involved. The germinoma may be associated with
elevated beta hCG levels (or a positive pregnancy
test due to elevated hCG) leading to peripheral
­precocious puberty. Langerhans cell histiocytosis
comprises several conditions characterized by infil-
tration of tissues by cells similar to Langerhans cells
from the bone marrow as well as various hemato-
poietic cells, including T cells, macrophages, and
eosinophils: Langerhans cell histiocytosis (604856
ICD+ LANGERHANS CELL HISTIOCYTOSIS)
and Letterer–Siwe disease (%246400 ICD+
LETTERER-SIWE DISEASE) are examples
which are associated with DI. The late onset of pos-
terior pituitary disease, well after birth, manifest by
DI is an urgent reason for a full effort to diagnose a
tumor or infiltrative lesion; if this is associated with
anterior pituitary deficiency, the concern rises fur-
ther. The presence of a thickened pituitary stalk in a
patient with central diabetes insipidus may be an
early indicator of the developing germinoma; it
may take years of observation before the second
pituitary stalk grows further to reveal the tumor.
Trauma, whether accidental, such as a fall off a
horse or an automobile accident, or iatrogenic pro-
cedures, such as surgery near the posterior pitu-
itary for a craniopharyngioma, can lead to DI.
Hydrocephalus or other types of increased intra-
cranial pressure also can lead to vasopressin defi-
ciency and DI. Radiation to the central nervous
system will cause a deficit in various releasing fac-
tors, but it does not cause diabetes insipidus.
Idiopathic, congenital DI without anatomic
abnormalities can occur sporadically, in an auto-
somal dominantly inherited familial pattern
(#125700 ICD+ DIABETES INSIPIDUS,
NEUROHYPOPHYSEAL at 20p13) with facial
abnormalities such as hypertelorism and low bone
density or can occur in an autosomal recessive or
X-linked pattern (304900 DIABETES
INSIPIDUS, NEUROHYPOPHYSEAL TYPE)
because of defects in the gene for AVP-­NPII. A
recent prospective study demonstrated that the
majority of cases with “idiopathic central diabetes
insipidus” actually had an autoimmune basis to
the condition. The authors found that after the
identification of diabetes insipidus, multiple
 34

Table 4.1  Causes of disturbances of osmolality and serum sodium

Plasma
anti-­
Urine Serum Serum natriuretic
Condition Serum Na Urine Na Plasma Osm Osm AVP PRA Serum Aldo Urine Aldo K hormone
Central diabetes High (can be normal if Nl/low High Low, Low Nl Nl Nl Nl
insipidus adequate water taken in) rises after
dose of
AVP
Nephrogenic diabetes High (can be normal if Nl/low High Low, does High Nl Nl Nl Nl
insipidus adequate water taken in) not rise
after dose
of AVP
Psychogenic polydipsia Low/normal Nl Low/normal Low Low Nl Nl Nl Nl Nl
SIADH Low Nl-high Low High High Nl Nl Nl Nl High
Hyper-aldosteronism Nl with hypertension Nl-low Nl Nl Nl Low High High Low High
Hypo-aldosteronism Low High Nl Nl Nl High Low Low High
Hyporeninemic Nl High Nl Nl Nl Nl-low Low Low High
hypo-aldosteronism
Pseudohypo-­ Low High Nl Nl Nl High High High High
aldosteronism
Cerebral salt wasting Low High Low High Nl High High High low High
Glucocorticoid Low Low Low High Nl (high Nl-high Depends on Depends on Low-Nl Low
insufficiency (dilutional in some cause of ad-renal cause of adrenal
hyponatremia) studies) insufficiency insufficiency
Hypothyroidism Low Low Low High Nl Low Low
(dilutional
hyponatremia)
Hyponatremia due to Low (1.6 mEq/mL Osmotic High High High
hyperglycemia decrease per 100 mg/dL diuresis
elevation of glucose)
Partially based upon table from Quest Diagnostics/Nichols Institute and sources in Suggested Readings
AVP arginine vasopressin, PRA plasma renin activity, Aldo aldosterone, Nl normal, SIADH syndrome of inappropriate secretion of antidiuretic hormone
4  The Posterior Pituitary Gland and Disorders of Vasopressin Metabolism
Diabetes Insipidus
High transection
Low transection
Anterior
pituitary Posterior
pituitary
Fig. 4.2  Level of transection of the pituitary stalk and
central diabetes insipidus. If a transection of the pituitary
stalk is high, the axons of all vasopressin-containing neu-
rons are likely to be cut and to degenerate, leading to cen-
tral diabetes insipidus. If the transection is low on the
pituitary stalk, sufficient vasopressin-containing neurons
are likely to remain to avoid central diabetes insipidus
p­ ituitary deficiencies often appeared and growth
hormone deficiency was the most common condi-
tion that developed. The authors recommended
monitoring the pituitary stalk every 6 months for
3 years to see if further changes in thickness
occurred but found no further changes occurred
after 3 years. Congenital midline defects of the
CNS also may lead to DI in addition to anterior
pituitary deficiencies (see Chap. 3). Absence of
the septum pellucidum may be associated with
optic hypoplasia or dysplasia and is often associ-
ated with hypothalamic abnormalities (#182230
ICD+ SEPTOOPTIC DYSPLASIA at 3p21.2-
p21.1); initial clinical presentation may be a
visual deficiency (with to-and-fro or pendular
nystagmus due to the defect in the optic nerve) or
an endocrine disorder, including DI. The Wolfram
(#222300 ICD+ WOLFRAM SYNDROME 1;
WFSOMIM) also called DIDMOAD (DI, diabe-
tes mellitus, optic atrophy, and deafness) syn-
drome is caused by a mutation of a gene at 4p16.1.
Although histiocytosis X and craniopharyngio-
mas usually occur at a later age, and the early
onset of anterior and posterior pituitary disorders
usually carries a more benign prognosis than does
late onset, MRI evaluation for a potential CNS
35
tumor or anatomic abnormality should be carried
out even in young cases, unless a clear family pat-
tern or gene diagnosis is made. All of these condi-
tions are detailed in other chapters.
Nephrogenic Diabetes Insipidus
If the defect is in the nephron, ADH is produced in
normal or increased amounts but is ineffective in
controlling the production of urine. Originally,
nephrogenic DI (NDI) was thought to be solely an
X-linked disorder, but numerous cases of sporadic
occurrence or autosomal dominant inheritance
have since been described. Thus congenital neph-
rogenic DI (NDI) may be the result of an X-linked
mutation in the renal vasopressin receptor (V2) at
Xq28 (*304800 DIABETES INSIPIDUS,
NEPHROGENIC, X-LINKED), type 1 NDI. In
this condition, a defect in the G protein of the
adenyl cyclase system of the renal tubular cells
leads to inability of vasopressin to increase uri-
nary levels of cyclic AMP. This is the cause of
90 % of congenital NDI cases. Alternatively an
autosomal recessive or autosomal dominant muta-
tion in the renal water channel aquaporin-1 at
12q13 (#125800 DIABETES INSIPIDUS,
NEPHROGENIC, AUTOSOMAL DOMINANT),
type 2 NDI leads to type 2 NDI. In this condition,
vasopressin does cause increased urinary levels of
cAMP but urine excretion remains excessive.
These are the remaining 10 % of cases.
Because the disorder classically is found as a
congenital condition, these babies are more prone to
dehydration than are the majority of patients with
central DI who have DI as an acquired defect.
Severe dehydration due to fluid loss may cause epi-
sodes of unexplained fevers, vomiting, failure to
thrive, and growth failure and even lead to develop-
mental delay; hypernatremia may be demonstrated
during the episodes of dehydration. Intracerebral
calcifications of the frontal lobes and basal ganglia
may be noted after repeated episodes of dehydra-
tion. Nonobstructive ­hydronephrosis, hydroureter,
and megabladder may develop due to massive pro-
duction and flow of urine in untreated cases.
Usually, when the child reaches an age at
which water can be obtained ad lib, the symptoms
36 4  The Posterior Pituitary Gland and Disorders of Vasopressin Metabolism
will decrease except at time of illnesses, when
debilitation may cause a decrease in oral intake.
Acquired nephrogenic DI may be due to drugs
such as lithium chloride and demeclocycline or
to electrolyte abnormalities such as hypercalce-
mia or hypokalemia, all of which affect the abil-
ity to concentrate the urine.
Clinical Features of Diabetes Insipidus
Clinical features of DI of either the central or nephro-
genic variety relate mostly to patterns of drinking and
urinating. The patient will urinate large quantities of
dilute urine throughout the day and night, awakening
several times every night while constantly drinking
(usually drinking cool water, as other fluids are less
requested, at least in the US experience) because of
continuous thirst. As noted, except for congenital
defects, DI usually is first seen after infancy. If infants
are affected, they will cry if deprived of their bottle
and may drink their bath water or suck on their wash-
cloths; these symptoms may be more common in
those with nephrogenic DI than in those with the cen-
tral form. Older children and adults will go to bed
with liters of water at their side for use throughout
the night. At times of disability or when water can-
not be obtained, the patient with DI will become
severely dehydrated and could develop shock with
high serum sodium values. Remarkably increased
urine flow, virtually clear in color, into the diaper of
an infant or enuresis in an older child may be seen.
Because of the high flow of urine, the renal pelvises
and ureters may be dilated on intravenous pyelogram
as secondary complications. These features are in
contradistinction to those found in the compulsive
water drinker, who usually will get through the night
without awakening, and the child drinking for second-
ary gain, who drinks small amounts frequently and
who urinates frequently but in small quantities (psy-
chogenic polydipsia).
Diagnosis of Diabetes Insipidus
Before proceeding with any detailed evaluation
for DI, it should be established that a patient
who has polyuria and polydipsia does not have
Table 4.2  Water-deprivation test
A water-deprivation test can be very difficult for patient
and the family. The child will be uncomfortable in
many cases and cry for fluids which of course would
negate the test if administered. There is also danger of
dehydration if the child has true diabetes insipidus, so
careful observation is mandatory.
Determine if patient is taking medications that can
cause polyuria or has diabetes mellitus or other chronic
disease that can cause decreased urine concentration
(see text). Does patient have apparent psychological
condition leading to psychogenic polydipsia? If not,
proceed.
Normal overnight fast: if the patient does not normally
drink overnight, fast, but if the patient does need to
drink, allow this, but document time of intake and
amount.
Determine first a.m. urine, serum osmolality, and
hematocrit; if urine osmolality >600 (some have stated
450) mOsm, with serum osmolality ≤300 mOsm,
vasopressin function is usually adequate.
If urine and serum do not match these guidelines, start
observed fast (some suggest giving normal breakfast and
then start observed fast, but if patient is stable and fasted
overnight, this may be omitted to shorten the test).
Check weight and urine osmolality hourly, and keep
track of urine volume. Measure serum sodium and
osmolality hourly, and measure serum vasopressin at 0
time and the end of the test (certainly before any
vasopressin is given) for future reference. All tests
other than vasopressin should be ordered stat.
If urine osmolality >600 mOsm (some say 450) with
serum osmolality ≤300 mOsm, or if urine osmolality
>1,000 mOsm at any serum osmolality, function is
normal.
If by 8 h after beginning of observed fast, urine
osmolality <600 (some say 450) mOsm, or at any time,
if serum osmolality is >300 mOsm/L and urine
osmolality stays below the guidelines, give 1 U/m2 of
aqueous vasopressin. If urine osmolality doubles the
previous value over the next hour, the diagnosis is
central DI. If no change occurs, the diagnosis is
nephrogenic DI or some variant.
If blood pressure drops, pulse rises abnormally, or if
weight drops >5 %, consider stopping the test and
obtaining last samples as listed. If the patient appears
clinically stable, the test may be continued under
careful scrutiny.
DI diabetes insipidus
diabetes mellitus, chronic renal disease, or urinary
tract infection that explains the symptoms
(Table  4.2; Fig. 4.3). A urine sample should be
free of sugar and be dilute compared with plasma
osmolality to suggest diabetes insipidus. The first
Diabetes Insipidus 37

History reveals large volume of urine and frequent episodes of drinking during night and day, not frequent episodes of drinking small volumes
Yes No

immediately test urine for sugar and ketones possibly psychogenic polydipsia or urinary tract infection
negative positive

test first AM urine evaluate for diabetes mellitus

by serum glucose

concentration < 1.010 concentrated over 1.010

perform water deprivation test yes

can't concentrate urine concentrates urine

after deprivation

eliminates classic diabetes insipid,

exogenous vasopressin partial defect is possible

concentrates urine doesn't concentrate urine

central diabetes insipidus nephrogenic diabtes insipidus

Fig. 4.3  The diagnosis of polyuria/polydipsia. This is a be useful to ask the parents to keep a logbook of how much
general schema for the diagnosis of the child who is appar- the child drinks and how often the child urinates. If urinary
ently urinating too much. Before any evaluation, it would volume could be measured, it would be even more useful

question of importance is whether the patient of osmolality is preferable). Serum osmolality

really is ­urinating frequently in large quantities
through the day and night or whether it is simply
a pattern of frequent but small episodes of urina-
tion. A diary of intake and output should be con-
structed, and determination of the 24-h urine
volume at home under the watch of reliable par-
ents should be done to determine if this informa-
tion supports a pattern suggestive of DI. If
urination occurs during the day while the child is
awake and not at night and there is no enuresis,
diabetes insipidus becomes much less likely. The
history should support a pattern suggestive of DI,
and observation in the hospital or under the watch
of reliable parents should be the first step to con-
firming increased urine volume output and fluid
intake. The first voided urine sample in the morn-
ing is normally the most concentrated of the
whole day, and a sample should be subjected to
analysis of specific gravity and osmolality to see
if this sample is concentrated more than
750 mOsm/L, which would eliminate the diagno-
sis in most cases (specific gravity may be
increased fallaciously by contamination with non-
osmotic substances, e.g., stool, so measurement
and sodium should be determined; in DI, the val-
ues will be normal or slightly elevated if the
patient has free access to water and a normal thirst
mechanism, whereas in psychogenic polydipsia,
the values will be normal or even low because of
the dilutional effect of excessive water drinking.
An ambulatory, conscious patient without a thirst
mechanism will often have a high osmolality and
sodium because such patients do not have the nor-
mal drive to increase water intake as their serum
sodium becomes increasingly concentrated; this
condition has been called primary hypernatremia
in some reports.
Urine volume greater than 4 mL/kg/h and
plasma osmolality over 300 mOsm/L and serum
sodium over 145 Eq/L is compatible with a diag-
nosis of diabetes insipidus. Since a conscious
patient with a thirst mechanism can keep up with
the sodium loss, the serum sodium and serum
osmolality do not necessarily have to be elevated.
If the tests noted still suggest that the patient
has DI, a careful water-deprivation test should be
performed. If not carried out appropriately, there
is danger of severe dehydration with such a test.
38 4  The Posterior Pituitary Gland and Disorders of Vasopressin Metabolism
These tests are difficult for the child and perhaps
even more so for the family. The child will be
expected to complain about lack of water whether
DI or psychogenic polydipsia is involved, and the
parents likewise might be uncomfortable over the
procedure as the child cries for water. The most
important consideration of such a test is to
observe the child constantly for signs of dehydra-
tion that may be dangerous or for “cheating”
when the child takes or gets water surreptitiously,
which will nullify the test results. The test should
be done only with full staffing, and the later part
of the thirst phase of the test should not occur at
night if staffing is low and the child might not be
well observed.
The child should have a normal dinner, and
the usual nighttime routine should continue.
If the child stays at home for this night, whatever
is the usual routine is followed (no fluid intake, if
the child has been able to tolerate this schedule
in the past, or fluid intake, if that is the norm).
The next morning, the first voided urine should be
analyzed for osmolality, the body weight and BP
should be determined, and serum sodium, osmo-
lality, and hematocrit should be determined.
Assuming that the urine is not concentrated to
600–750 mOsm/L or greater and the serum
osmolality is less than 300 mOsm/L (reaching
these values demonstrates normal vasopressin
physiology), the test may commence. At that
time, all oral intake should cease if it had not
ceased during the night. Weight and BP should be
taken hourly, serum osmolality and hematocrit
determined every 2 h, and all urine volume moni-
tored and osmolality measured at every void.
The test should cease if the BP decreases 10 %,
or the serum osmolality increases above
300 mOsm/L. If the urine osmolality increases
above 600–750 mOsm/L but the serum osmolal-
ity is not above 300 mOsm/L, the test should
stop, as there is no likelihood of DI. If the serum
osmolality does not rise above 300 mOsm/L and
the urine osmolality does not rise above
450 mOsm/L, the water-deprivation test should
continue as the next few hours may lead to the
diagnosis. Otherwise, at the end of 8 h or up to
10 h, if adequate staffing is available, the serum
and urine osmolality should be compared and a
serum vasopressin determination obtained to match
with the osmolality determination (the vasopressin
value will not return for weeks from the laboratory
but may prove useful if the diagnosis is still in
doubt later).
As a patient becomes dehydrated, the urine
osmolality will increase because of the delivery
of increasingly concentrated filtrate to the kidney,
but a patient with DI cannot concentrate the urine
to more than 1.5–2 times the serum osmolality.
If the serum osmolality increases to 300 mOsm/L
or higher, the urine concentration should nor-
mally be more than 450 mOsm/L and ideally
more than 600–750 mOsm/L. In an intermediate
situation in which a trend toward dehydration is
developing, a continuation of the fast may be
necessary; this will be safe only if careful obser-
vation of state of hydration, BP, and pulse is con-
tinued. Further, in partial DI, a patient may pass
one test with just adequate urinary concentration,
whereas, if the test is repeated the next day, the
patient may be virtually unable to concentrate the
urine because of the exhaustion of the patient’s
meager supply of vasopressin.
If the serum osmolality has increased without
concentration of the urine and therefore no
increase in urine osmolality, 0.05–0.15 mL of
d-arginine-d-amino-vasopressin (DDAVP, see
later for explanation of this medication) in a nos-
tril (or, if DDAVP is unavailable or there is
pathology of the nasal mucosa, a 1-U/m2 subcuta-
neous dose of aqueous vasopressin) is adminis-
tered, and the volume of urine and the urine
concentration in the next 30–60 min is compared
with the values obtained before the DDAVP or
exogenous vasopressin was given. In central DI,
at the end of the fast, the patient has secreted the
maximal vasopressin that he or she is capable of
secreting, but this diminished store of vasopres-
sin is inadequate for the task of concentrating the
urine. Thus, the exogenous vasopressin will fur-
ther concentrate the urine twofold. A patient with
nephrogenic DI will not be able to concentrate
urine past 450 mOsm/L in spite of increasing
serum osmolality, and the addition of exoge­
nous vasopressin will not further increase urine
Diabetes Insipidus
o­ smolality or reduce urine volume, because the
patient is resistant to vasopressin.
The diagnosis of psychogenic polydipsia may
sometimes present problems. Because of the
patient’s excessive drinking habits and the excess
water load chronically presented to the kidney,
the patient may have developed a dilute or
“washed out” medullary gradient, leading to a
situation which might be considered similar to
moderate nephrogenic diabetes insipidus. If this
is owing to a long history of excess water intake,
the patient may not reach full urinary concentra-
tion even if the fast is continued and if endoge-
nous vasopressin is adequate. However,
exogenous vasopressin at the end of the water-
deprivation test will not cause further concentra-
tion of the urine because in a patient with psycho-
genic polydipsia exogenous vasopressin exerts
no further effect than the endogenous vasopres-
sin. Usually, the psychological history in addition
to the results of the water-deprivation test will
lead to the correct diagnosis, as most children
with psychogenic polydipsia will not have such a
degree of urinary dilution after a fast as will those
with nephrogenic DI.
Because central DI is possibly due to a con-
genital anatomic defect of the CNS or an acquired
CNS tumor, an MRI is indicated. Loss of the T1-­
weighted bright spot of the posterior pituitary
gland during gadolinium MRI scan will suggest
central DI associated with the loss of vasopressin
and neurophysin production that are responsible
for the hot spot. However, in nephrogenic DI, a
loss of the bright spot may be due to continued
increased release of vasopressin. The changes
in the bright spot may be found in normal indi-
viduals as well as in situations of extreme thirst
or overhydration and so is not highly specific. In
congenital loss of pituitary function, the appear-
ance of an interrupted pituitary stalk or ectopic
bright spot might be indicative of the diagnosis.
In some cases, a thickening of the pituitary stalk
is all that suggests a developing tumor; sequential
follow-up MRI is indicated, as it may take years
for the tumor to be truly discernible. Tumor
markers in the blood or CSF (e.g., hCG in germi-
nomas) should be monitored if a tumor is strongly
suspected.
39
 reatment of Central Diabetes
T
Insipidus
An untreated patient with DI, if old enough and
able enough to take in sufficient water, will
likely survive but will develop dilated ureters
and dilated renal pelvises because of the
increased urinary flow and will be on the brink
of severe dehydration if anything disturbs the
balance achieved (see Chap. 14 for description
of emergency treatment of hypernatremia due
to DI). The appropriate therapy is vasopressin
replacement in a convenient form. Native vaso-
pressin has a short half-life and exerts hyperten-
sive effects. Desamino-d-arginine vasopressin,
or desmopressin or DDAVP, an altered vaso-
pressin molecule that has 140 times the urine-­
concentrating ability but almost none of the
vasoactive effects of native arginine vasopres-
sin, is the treatment of choice. A dose of DDAVP
will usually last approximately 12 h (or even
24 h), whereas native vasopressin has a half-life
of 20 min. Oral DDAVP tablets are available in
doses of 01 and 0.1 mg given 1 to 3 times per
day. The dose of oral DDAVP tablets is titrated
until adequate antidiuresis is achieved after a
nighttime administration. A second morning
dose is given if significant polyuria still occurs
during the day and a third dose may be needed
as well in some. Alternatively, DDAVP is
administered in measured doses through inhala-
tion by the nostrils. A dose of 0.025 mL of a
solution of 10 μg/0.1 mL (yielding 2.5 μg) is
given with a plastic tube inserted into the nostril
and is repeated when the child complains of
increasing thirst or an infant begins to increase
urinary frequency again. A syringe may be used
to squirt DDAVP into the nostrils of the young-
est children. A measured dispenser of nasal
spray is another treatment, with a dose of 10 μg
per spray (0.1-mL volume). Lysine vasopressin
or Diapid is given as a nasal spray (50 U/mL or
2 U per spray) that lasts 2–8 h, if a short action
is desired (e.g., in infants). This treatment is
rarely used at present.
A patient must have a phase of urinary dilu-
tion or breakthrough urination before the next
dose of DDAVP is given to ensure that water
40 4  The Posterior Pituitary Gland and Disorders of Vasopressin Metabolism
intoxication does not result. Hyponatremic sei-
zures are a concern if the patient does not have
some urination during the day. In the presence of
an intact thirst mechanism, the patient should be
able to maintain a normal sodium concentration
with DDAVP treatment.
The treatment of young infants with diabetes
insipidus presents significant difficulty in maintain-
ing stable serum sodium levels with the use of
DDAVP. Some have been treated with breast milk
or low solute formula (Similac 60/40) and water,
but this has been associated with poor growth. The
use of hydrochlorothiazide in 5–10 mg/kg adminis-
tered two or three times per day to foster sodium
retention leads to free water retention and a more
stable situation. Parental DDAVP is not yet approved
for infants but might offer a future therapy.
Intravenous fluid management of hospitalized
patients with diabetes insipidus cannot be carried
out by the customary formula for maintenance
fluid management. A patient without diabetes
insipidus will in the basal state have about 60 %
of their maintenance requirements due to urinary
output. The patient with diabetes insipidus will
have more or less than that 60 % based upon hos-
pital fluid management and exogenous vasopressin
preparations rather than normal physiology. Thus
the standard formulas do not apply.
Patients with diabetes insipidus in the postop-
erative state in the intensive care unit for some
other illness may be best managed without long-­
acting vasopressin which may complicate fluid
management. A hospitalized patient not managed
appropriately may very well be underhydrated
leading to hypernatremia and then overhydrated
leading to hyponatremia. Acute diabetes insipi-
dus that occurs intraoperatively during central
nervous system surgery or in the postoperative
state in a patient with chronic diabetes insipidus
can be carried out with intravenous fluids admin-
istered according to the schema of output equals
input with a small basal infusion maintained
throughout even without vasopressin administra-
tion. The patient will receive 40 mL/kg/h of
appropriate maintenance fluid with extra fluid
added with electrolytes, to cover urinary volume
output. Thus careful records of urinary output are
kept, and intravenous fluid for urinary volume
replacement is administered at 1–4-h intervals
equal to the output for the last 1–4 h above 40 mL/
kg/h; replacing one-hour output volume over the
next hour of intravenous fluids is the best method.
A limited maximal fluid replacement might be set
at 120 mL/kg/h to avoid the development of
hyponatremia. Glucose may rise during this regi-
men, and there are reports of exceptionally high
blood glucose values due to volumes of replace-
ment higher than recommended above with fluids
containing more than 5 % dextrose.
Vasopressin administration in short-term prep-
arations is an alternative treatment to full intrave-
nous fluid replacement in patients with diabetes
insipidus. However, the administration of vaso-
pressin may cover up the development of diabetes
insipidus in the triphasic response after pituitary
surgery as noted below, so a high index of suspi-
cion for diabetes insipidus must be upheld; fur-
ther administration of excessive fluids while
vasopressin is released can lead to an SIADH-like
picture. Intravenous (i.v.) vasopressin manage-
ment during surgery or recovery is 0.5–2 mU/
kg/h of vasopressin while carefully monitoring
fluid intake to ensure appropriate fluid balance.
Intravenous vasopressin may stick to the intrave-
nous tubing, and a slightly higher dose may be
required so the dose needs to be titrated to the uri-
nary output in a manner rather similar to titrating
intravenous insulin by measuring the change in
blood sugar in diabetic ketoacidosis. When vaso-
pressin is used in fluid management, it is recom-
mended that total fluid administered over 24 h
does not exceed 1 L/m2/day which is equivalent to
two-thirds maintenance. Excessive fluid adminis-
tration with i.v. vasopressin or any of the forms of
vasopressin listed earlier will lead to an SIADH-
like condition. If the patient is undergoing sur-
gery, a nursing order after surgery is frequently
“push fluids”; if the patient has been treated with
a vasopressin dose when the increased “pushed”
fluids are administered, an SIADH-like syn-
drome is a risk. The best way to lower the risk for
overhydration in the child that has a normal thirst
mechanism is to switch to oral fluids as soon as is
possible. Then taking the direction from the
child’s thirst mechanism will make excessive
fluid administration less likely.
Patients with an absent thirst mechanism and
diabetes insipidus are extremely difficult to treat.
The Syndrome of Inappropriate Secretion of Antidiuretic Hormone
A set regimen is empirically determined under
careful observation so that a given number of
glasses of water or a volume of water per day suf-
ficient to keep the serum sodium in the normal
range is prescribed. An extra glass of water or
more should be given for moderately increased
activity, exposure to high temperature, or illness
especially with fevers. Measurement of urine
output matched with administration of an equal
volume of oral fluids with insensible loss added
to this will be the best way to maintain normal
osmolality. Every week or two, the serum sodium
should be measured, with determinations more
often if stability has not been reached. The seri-
ous consequences of dehydration or overhydra-
tion should not be minimized in this complex
condition as serious illness or death may occur if
not adequately treated.
 reatment of Nephrogenic
T or syndrome of inappropriate antidiuresis (SIAD).
Diabetes Insipidus
The goal of treatment of nephrogenic DI is to
cause the kidney to retain water in the absence of
any effects of vasopressin; the method may seem
paradoxical, as a low-sodium diet and diuretic
therapy is prescribed. With decreased serum sol-
ute due to the low sodium intake and the loss of
sodium due to iatrogenic diuresis, the site of
reabsorption of water shifts from the collecting
duct where vasopressin exerts its effect to the
proximal tubule where aldosterone, maximally
stimulated by whole-body sodium loss, will act
to retain all available sodium and thereby carry
water back into the vascular compartment along
with the sodium, thereby leading to decreased
urine flow. Thus the treatment bypasses the
tubule where vasopressin exerts effects to an
area where aldosterone exerts its effect. A thia-
zide diuretic with the addition of amiloride (0.4–
0.625 mg/kg/day) to counteract the hypokalemia
caused by thiazide is commonly employed.
Alternatively, thiazide diuretics and indometha-
cin (2 mg/kg/day) or amiloride are used, with a
careful observation for nephrotoxicity.
New therapy that may enter general use
involves cell permeable lipid-soluble vasopressin
41
analogs called pharmacologic chaperones that
cross the plasma membrane and reach misfolded
AVPR2 receptors, helping them to refold and
reach the plasma membrane where endogenous
vasopressin displaces the vasopressin analogue
and activates the receptor. Thus the mutant recep-
tor is rescued by these “chaperones” which treat
the nephrogenic DI. Chaperones are not in clini-
cal use in children as yet.
 he Syndrome of Inappropriate
T
Secretion of Antidiuretic Hormone
In the presence of increased vasopressin secretion
or vasopressin effect and excessive water intake,
hyponatremia will develop in the absence of the
ability to excrete adequate fluid, and the condition
is known as the syndrome of inappropriate secre-
tion of antidiuretic hormone (SIADH used here)
(If the stimulus for the ­vasopressin secretion is
physiologic such as volume depletion, e.g., due to
diarrhea, the term syndrome of appropriate antidi-
uretic hormone secretion (SAADH) has been sug-
gested although is not widely used.)
Classic features of SIADH are (1) plasma
hypoosmolality (<275 mOsm/kg), (2) less than
maximally dilute urine (urine osmolality
>100 mOsm/kg), (3) euvolemia (secondary to reg-
ulatory adaptations after initial increased intravas-
cular volume), (4) natriuresis, (5) normal renal
function, and (6) no evidence of thyroxine or cor-
tisol deficiency which would promote water reten-
tion. This constellation is paradoxical because the
low serum sodium and osmolality could be cor-
rected if the urine is maximally diluted and if max-
imal urinary sodium reabsorption is accomplished.
(SAADH is found with these features except the
patient is hypovolemic.)
Because the combination of vasopressin
secretion and water intake is responsible for
SIADH, the syndrome is often iatrogenic; the
patient already may be under a physician’s care
and may be kept on the same regimen of fluid
therapy after vasopressin secretion begins fol-
lowing an episode of temporary DI which has
resolved or has been given excess fluids after
42 4  The Posterior Pituitary Gland and Disorders of Vasopressin Metabolism
vasopressin is administered as a treatment for
DI. Atrial natriuretic peptide may be responsible
for the sodium ­diuresis, as it is elevated in times
of volume overload. If fluid therapy in the treat-
ment of conditions predisposing to SIADH was
appropriately regulated, and if serum sodium
concentrations were monitored routinely,
SIADH would be far less likely. Patients with
cancers that produce vasopressin in ectopic
locations may be in the habit of drinking a set
amount of fluid before the tumor developed; if
the same fluid intake is continued after the ecto-
pic vasopressin is present, SIADH may develop
even before the cancer itself is diagnosed.
Any disorder of the lungs, including those
requiring ventilator support, can cause increased
release of vasopressin, mediated by the volume
or stretch receptors in the right atrium. Thus, the
common prescription for increased fluid intake
during episodes of pneumonia or other disorders
of the lungs may precipitate an episode of
SIADH. Patients supported on ventilators for
extended periods must have serum sodium regu-
larly monitored. Infant botulism may lead to
SIADH during ventilator support as this may
trigger increased vasopressin secretion and
SIADH. Most neurologic conditions, including
meningitis, tumors, postsurgical condition, and
trauma, can increase vasopressin secretion;
these potential complications are well recog-
nized and account for the usual orders for
reduced fluid administration in neurologic dis-
ease. However, after any surgery, increased
vasopressin secretion occurs, and the patient is
susceptible to SIADH. Any condition causing
nausea and emesis, including carcinomatosis or
the administration of chemotherapy, can
increase vasopressin secretion. Further, drugs
often used in cancer therapy, such as vancomy-
cin, vincristine, and cyclophosphamide
(Cytoxan), increase vasopressin secretion in
addition to the increased vasopressin secretion
due to nausea. Many types of cancers produce
vasopressin in an ectopic hormone-­ secreting
syndrome, so that a patient with cancer may be
susceptible to SIADH from the cancer, from the
nausea of the cancer therapy, and from the che-
motherapeutic agent itself.
Another condition combining hyponatremia
associated with various types of CNS disease is
cerebral salt wasting (CSW); CSW is described
in head injury, brain tumor, intracranial surgery,
craniosynostosis repair, stroke, intracerebral
hemorrhage, and tuberculous meningitis. In this
condition, hyponatremia along with increased
urinary sodium excretion which may exceed
150 mEq/L, polyuria with decreased vasopressin
secretion, is characterized by hypovolemia in
contrast to SIADH, in which intravascular volume
is normal or increased. In cerebral salt wasting,
atrial natriuretic peptide concentrations are
increased over 20 pmol/L and may be the primary
defect although increase in CNP is also suggested
as an etiology. The values of serum aldosterone
and vasopressin are normal or decreased in cere-
bral salt wasting. Treatment involves the replace-
ment of sodium losses and volume and if possible,
treatment of the underlying central nervous
­system condition.
Determination of plasma volume is most
accurately carried out by central venous line. If
there is no central venous line, laboratory studies
can be supportive of the determination. In hypo-
volemia, plasma renin, angiotensin II, aldoste-
rone, vasopressin, urinary sodium, and fractional
excretion of sodium are low. In hypervolemia,
urinary sodium and fractional excretion of
sodium are high, while urine osmolality is low.
Fractional excretion of sodium is calculated as
U Na ´ PCr
FE Na = ´100
PNa ´ U Cr
It must be stated that there is controversy as to
the existence and prevalence of cerebral salt
wasting in the literature with a critical assessment
suggesting that plasma volume is rarely accu-
rately determined in states of hyponatremia.
Nephrogenic Syndrome
of Inappropriate Antidiuresis
Recently, the nephrogenic syndrome of inap­
propriate antidiuresis (NSIAD) (#300539
NEPHROGENIC SYNDROME OF
The Treatment of Syndrome of Inappropriate Secretion of Antidiuretic Hormone
INAPPROPRIATE ANTIDIURESIS; NSIAD)
was described as a consequence of a gain-of-­
function mutations in the gene encoding the vaso-
pressin V2 receptor (AVPR2; 300538). These
patients have what clinically appears to be classic
SIADH but without measurable AVP values.
Other Causes of Hyponatremia
Not all episodes of hyponatremia are due to
SIADH. The most frequent cause of hyponatre-
mia in pediatrics is fluid overload with hypo-
tonic fluids while receiving i.v. therapy under a
physician’s care. Indeed some authorities rec-
ommend avoidance of hypotonic fluids for
maintenance or repair in most situations and
instead to use isotonic fluids. However, the basis
of pediatric fluid management, as developed
more than 50 years ago, recommends isotonic
fluid for repair of fluid deficit but consideration
of lower tonicity fluids for maintenance. These
controversies cannot be addressed in this chap-
ter except to reemphasize the basics of fluid
management as noted.
In addition, congestive heart failure and the
oliguric phase of acute renal failure may lead to
hyponatremia due to inappropriate fluid adminis-
tration in the face of decreased urinary output.
Total body sodium is depleted in diabetic keto-
acidosis as described in Chaps. 11 and 14.
While glucose does not normally play a sig-
nificant role in serum osmolality, when glucose
cannot enter cells through insulin-dependent glu-
cose transporters due to insulin deficiency or
resistance, glucose becomes an important osmot-
ically active ion when hyperglycemia develops.
Thus osmolality is higher in the extracellular
space then the intracellular space which will trig-
ger vasopressin secretion.
An elevation of atrial natriuretic factor occurs
in some cases of diabetic ketoacidosis which is a
condition which causes true hyponatremia requir-
ing replacement therapy. Fluid retention will
lower serum sodium adding to the decrease in
serum sodium due to sodium depletion.
Measurement of serum sodium can be corrected
for the hyperglycemic effect of glucose; each
43
elevation of blood glucose of 100 mg/dL causes a
decrease in serum sodium by 1.6 mEq/mL.
Low serum sodium or pseudohyponatremia
will result from hyperlipidemia and hyperpro-
teinemia (such as in multiple myelosis). Of
course, if the sodium sample was taken from an
intravenous line or downstream from an intrave-
nous line, the sample will be composed of
­hypotonic fluid, and the serum sodium will fal-
laciously decrease in the laboratory determina-
tion. Pseudohyponatremia is asymptomatic and
is not a physiologic problem, as the cells are actu-
ally exposed to normal amounts of sodium in
spite of abnormal sodium on laboratory determi-
nations. Thus in pseudohyponatremia, correction
of the underlying condition is indicated, but
sodium administration is rarely necessary.
 he Treatment of Syndrome
T
of Inappropriate Secretion
of Antidiuretic Hormone
The treatment of SIADH is first and foremost
prevention (see Chap. 14 for discussion of emer-
gency treatment of hypernatremia due to SIADH).
This is often an iatrogenic disease, and monitor-
ing fluid therapy and frequent serum sodium
concentration determinations will lessen the
­
possibility of severe shifts of sodium. Once
­
SIADH develops, fluid restriction to the ­minimum
possible but safe level is the first approach.
In many cases, maintaining i.v. fluids at a level
just able to keep the i.v. line open is appropriate
for a time as the attainment of fluid balance is
accomplished. With less severe hyponatremia,
replacing urine output with an equal volume of
i.v. fluid calculated every 2–4 h is adequate fluid
replacement. Because the urine flow is so low in
SIADH, the tendency will be to fear that inade-
quate intravascular volume is the problem, and
it may appear that administration of boluses of
fluid to increase urinary output is appropriate.
If the oliguria is due to dehydration, the boluses
are appropriate and will allow urination, but if
SIADH has been diagnosed, the boluses will only
intensify the SIADH, as the fluid will be retained.
Careful review of the records, including an
44 4  The Posterior Pituitary Gland and Disorders of Vasopressin Metabolism
accounting of all fluids administered (a balance
sheet of intake and output is essential), changes
in body weight, and an estimation of intravascular
volume or measurement of central venous pressure
should clarify the diagnosis.
Other methods are available to break through
the SIADH and allow urine flow so that intravas-
cular volume decreases and the condition is mod-
ified. Lithium and demeclocycline will interfere
with ADH action on the kidney causing iatro-
genic NDI, but the inherent side effects limit their
use (especially demeclocycline) in younger chil-
dren. Urea has been used as an osmotic diuretic
in pediatric SIADH and NSIAD. Clinical
research studies using nonpeptide V2R antago-
nists (known as vaptans) progress in children but
are not in general use in pediatrics although some
vaptans have been approved by the Food and
Drug Administration for use in adults.
Replacement of the volume loss with 3 % saline
will help correct symptomatic hyponatremia
without administering excessive fluid volume to
worsen the problem. The administration of
12 mL/kg of 3 % saline will cause a 10 mEq/L
rise in serum sodium. If hyponatremia is severe
and seizures have resulted, furosemide may be
administered to decrease serum volume along
with 3 % saline which is administered in a vol-
ume smaller than the diuresis caused by furose-
mide, to bring about a net increase in serum
sodium values thus fostering urination without
inappropriately increasing volume. This proce-
dure of diuretic and hypertonic fluid administra-
tion can cause rapid fluid shifts, causing dilution
and concentration at various times, and is poten-
tially dangerous. Careful monitoring and main-
taining a patent i.v. line to administer fluid
volume if necessary are essential.
It should be emphasized that the sodium diure-
sis characteristic of SIADH is continuous during
the active phase of the disorder, and sodium admin-
istered by any route will quickly be passed out in
the urine and will not offer a long-­term cure of
hyponatremia. However, if seizures are intractable,
the use of hypertonic saline or the combination of
furosemide (Lasix) and hypertonic saline described
earlier may be the only appropriate ­ therapy.
Whatever therapy is offered, constant observation
must be given for severe fluid shifts.
Rate of correction of SIADH is of importance.
If the hyponatremia of SIADH lasted more than
48 h, correction of hyponatremia too rapidly can
lead to central pontine myelinolysis which will
develop in 24–48 h and may be diagnosed on
MRI. It is recommended to correct serum sodium
to 120–125 mEq/L at a rate of no greater than
0.5 mEq/L/h, with no more than 12 mEq/L cor-
rection occurring in the initial 24 h and 18 mEq/L
in the initial 48 h of treatment.
 he Triphasic Response After
T
Surgery for Craniopharyngioma
A patient with a craniopharyngioma or other
tumors of the hypothalamus or posterior pituitary
area already may have DI before surgery is car-
ried out for the tumor; if not, when the pituitary
stalk is cut, DI may manifest immediately, pos-
sibly while the patient is in the operating suite
(Fig. 4.4). After this, in a few days, often unre-
strained release of vasopressin will occur as the
cut nerve cells degenerate. If the high level of
fluid replacement originally necessary for treat-
ment of the DI is continued during this secondary
phase of vasopressin secretion, SIADH will
develop. During the following days, a third phase
of permanent DI will occur in most patients.
However, some patients who receive the surgical
transection low on the pituitary stalk will resume
adequate vasopressin secretion for needs, and the
DI will cease. It is imperative that fluid output be
monitored carefully after pituitary stalk surgery
so that intake is matched to output, and fluid
overloading does not occur during these chang-
ing fluid dynamics, or that dehydration does not
occur. This triphasic response occurs in about a
third of patients having such surgery.
Suggested Readings
More concentrated
Urine
Concentration
and Phase 2 of
Phase 1 of DI
SIADH
Normal
Less concentrated
1 2 3 4 5 2
Hours
Fig. 4.4  The triphasic pattern of urine concentration after
pituitary surgery, usually for a craniopharyngioma. On the
left Y-axis is urine concentration relative to a conceptional
normal value and on the right axis is urine flow relative to a
conceptional ­normal flow volume. Immediately following
pituitary–hypothalamic surgery, the patient will have an
inability to concentrate urine and large volumes of output
results. The second phase when damaged neurons may
Suggested Readings
1. Majzoub JA, Muglia LJ, Srivatsa A. Chapter 11—
Disorders of the posterior pituitary. In: Sperling MA,
editor. Pediatric endocrinology. 4th ed. Philadelphia,
PA: Elsevier; 2014. p. 405–443.
2. Di Iorgi N, Allegri AE, Napoli F, Calcagno A,
Calandra E, Fratangeli N, Vannati M, Rossi A,
Bagnasco F, Haupt R, Maghnie M. Central diabetes
insipidus in children and young adults: etiological
diagnosis and long-term outcome of idiopathic
cases. J Clin Endocrinol Metab. 2014;99(4):
1264–72.
3. Hannon MJ, Behan LA, O’Brien MM, Tormey W,
Ball SG, Javadpour M, Sherlock M, Thompson CJ.
Hyponatremia following mild/moderate subarach-
noid hemorrhage is due to SIAD and glucocorticoid
deficiency and not cerebral salt wasting. J Clin
Endocrinol Metab. 2014;99(1):291–8.
4. Matsuyama J, Ikeda H, Satoh S, Yamamoto K,
Ohashi G, Watanabe K. Early water intake restric-
tion to prevent the inappropriate antidiuretic hor-
mone secretion following transsphenoidal surgery;
low body mass index predicts postoperative
45
High volume
Phase 3 of DI in most
Urine Flow
and
++++++++++
+++++ Normal
+ ++++
++ Phase 3
+
+++
Reverts to normal
in some
Low volume
3 4 5
Days
release their content of arginine vasopressin leads to highly
­concentrated urine and decreased urinary excretion. This is
a period in which the syndrome of inappropriate ADH secre-
tion may develop especially if fluid volume is maintained at
a high level as was necessary in phase I. If the transection is
low on the pituitary stalk, normalization of urine flow
(++++++) and urine concentration may occur (........) in the
third phase, rather than permanent diabetes insipidus
SIADH. Eur J Endocrinol. 2014. doi:10.1530/
EJE-14-0530.
5. Moritz ML, Ayus JC. Intravenous fluid management
for the acutely ill child. Curr Opin Pediatr. 2011;
23(2):186–93.
6. Wang J, Xu E, Xiao Y. Isotonic versus hypotonic
maintenance IV fluids in hospitalized children: a
meta-analysis. Pediatrics. 2014;133(1):105–13.
7. Foster BA, Tom D, Hill V. Hypotonic versus isotonic
fluids in hospitalized children: a systematic review and
meta-analysis. J Pediatr. 2014;165(1):163–169.e162.
8. Maghnie M, Cosi G, Genovese E, Manca-Bitti ML,
Cohen A, Zecca S, Tinelli C, Gallucci M, Bernasconi
S, Boscherini B, Severi F, Arico M. Central diabetes
insipidus in children and young adults. N Engl J Med.
2000;343(14):998–1007.
9. Rivkees SA. Differentiating appropriate antidiuretic
hormone secretion, inappropriate antidiuretic hor-
mone secretion and cerebral salt wasting: the com-
mon, uncommon, and misnamed. Curr Opin Pediatr.
2008;20(4):448–52.
10. Bichet DG. Clinical manifestations and causes of
nephrogenic diabetes insipidus. http://www.uptodate.
com/contents/clinical-manifestations-and-causes-of-
nephrogenic-diabetes-insipidus.
 Disorders of Growth
Short stature is one of the most common complaints
that bring a child to a pediatric endocrinologist,
either by parental choice or by referral from the fam-
ily’s physician. Growth can be considered a bioassay
of the state of health of the child as a normal growth
rate usually is a good indicator of health. Short stat-
ure, rather than universally indicating an endocrine
abnormality, can herald the onset of nonendocrine
systemic disease, a state of malnutrition, or simply a
variation of normal. Since the goal of this chapter is
the evaluation of endocrine disorders that affect
growth, other chronic conditions should be ruled out
before embarking on a sophisticated endocrine eval-
uation. Thus initial history and physical examination
should determine whether a search for endocrine
conditions is warranted. It is especially important to
determine whether a nutritional condition has caused
decreased growth rather than starting an endocrine
evaluation. Tall stature or increased growth rate may
also indicate an important condition.
Measurement of Growth
Measurement of stature is the cheapest procedure
available in the pediatric office and the one often
incorrectly performed if even performed at all!
Failing to measure a child at a visit is a serious
mistake that limits the assessment of the health of
the child. Further, if a growth deficiency is devel-
oping as a consequence of the medical condition
that precipitated the office visit, the most impor-
tant measure of an inflection point in the growth
© Springer International Publishing Switzerland 2016
D.M. Styne, Pediatric Endocrinology, DOI 10.1007/978-3-319-18371-8_5
5
chart reflecting a decrease in the growth rate cannot
be assessed until another visit occurs, because
two height measurements at least 3 months apart
(and optimally longer) are needed to determine
growth rate accurately. If previous accurate
height measurements from well-child visits were
available, any change in growth rate would be
noted earlier. Because many systemic diseases
affect growth, a decrease in growth rate, which
would serve as an early indication of the onset of
such a disease, would be missed. Incorrect mea-
surements are responsible for numerous inappro-
priate referrals for short stature. Further, incorrect
measurement can obscure the effects of a medi-
cation meant to correct an abnormality of stature
(e.g., the positive effects of growth hormone
(GH) treatment can be evaluated only with accu-
rate, sequential measurements) (Fig. 5.1).
An accurate measurement of infant length
always requires two adults. The child must be laid
on a flat surface with a device that has one plate
horizontal to the plane of the top of the child’s
head and another plate horizontal to the first in the
plane of the child’s feet. The two plates should be
at a 90° angle to a ruler on which the child’s
height is read. Several available devices range
from inexpensive portable plastic caliper-like
devices (e.g., infantometer) to scales with the
measuring arms permanently attached (Fig. 5.2).
The worst method of measurement of infants
is all too frequently in common use; a single
observer makes a mark on the paper covering the
examining table at the foot of the child and
47
48 5 Disorders of Growth

a 5000 b
60

+250
55 +250
4000

Length, crown-heel (cm)

Mean
Mean 50
Birthweight (g)

3000 –250
–250 45

2000
40

1000
35

0 30
24 28 32 36 40 44 24 28 32 36 40 44
Week of gestation Week of gestation

c 40

36 +250
Mean
–250
32
Head (cm)

28

24

20
24 28 32 36 40 44
Week of gestation

Fig. 5.1 Intrauterine growth charts showing the normal growth of live-born Caucasian infants at sea level:
values of body weight (a), length (b), and head circumfer- Standards obtained from measurements in seven dimen-
ence (c) for infants born at different gestational ages at sea sions of infants born between 25 and 44 weeks of
level (Montreal) (from Usher R, McLean FM. Intrauterine gestation. J Pediatr 1969;74:901, with permission)

Sliding plate for the head

perpendicular to the board

Fixed plate for the feet perpendicular to the board

Fig. 5.2 A commercially available device used for mea- a movable perpendicular plate for the infant’s feet. It takes
suring lying length in infants. There is a ruler in centime- two adults to measure an infant after placing the infant
ters fixed to the horizontal board. There is a fixed straight on its back in the device
horizontal plate where the infant’s head is to be placed and
Measurement of Growth 49

another mark at the head to measure the distance

between the marks as an indication of the length
of the child. It should be obvious that the paper is
so crumpled by the weight of the child as to make
the distance between the head and feet quite vari- Horizontal plate that slides vertically
and is always perpendicular to the
able and that the movement of even a relatively backboard and is always parallel to the floor
quiet child will make such measurements useless.
It may be glib to say so, but guessing the length
of a term newborn as 21 in. is usually more accu-
rate than using the paper technique described for
a newborn!
The measurement of a patient older than 2
years is done with the child standing. The switch
from lying to standing measurements is respon-
sible for a large number of inappropriate referrals
because of the 1–2-cm decrease in height mea-
surements that occurs when switching positions.
It is important that the position of measurement
be indicated on the chart next to the numeric
measurement for children at this age of transi- Ruler in centimeters fixed to the
backboard
tion, so that unfounded worry about a declining
growth rate does not develop.
The device used to measure standing height
must be a variation of a standard stadiometer (e.g., Child’s back is firmly pressed to the upright
Harpenden stadiometer), which can measure to section. Child stands barefoot on flat surface
upon which the ruler abuts
0.1 cm. The child must have their back straight
against the wall or against a hard, flat surface on Fig. 5.3 A stadiometer allows the accurate measurement
which the stadiometer is attached. The device of standing height to an accuracy of a few tenths of a cen-
must be checked with a standard measure, often timeter. There is an indicator on the sliding plate which is
perpendicular to the back plate that indicates the height.
60 cm long, as measurements will vary over time There are mechanical and electronic versions of this
unless recalibrated daily. The child’s back must be device. A standard bar (usually of 2 m in length) is used to
straight and the heels and back must press calibrate the measurement daily. The child’s shoulders,
posteriorly to the surface. The feet must be on a buttocks, and heels are firmly pressed to the back plate
while the child stands barefoot on a flat surface which is
floor or hard surface, not on carpet, as the bottoms perpendicular to the back plate with the ruler. The child is
of the feet are considered to be the lower limit of to look straight ahead holding the head in the Frankfort
the measurement. The top of the measurement plane to standardize the position for the measurement
must be a plate completely parallel to the plane of with the top of the head parallel to the upper plate. The
examiner can gently hold the child’s jaw in position,
the feet, and the measurement must be read off a insuring that there is no slouching. Hair barrettes or other
stationary ruler that is at right angles to the planes ornaments must be removed. Unfortunately, if there is sig-
at the feet and head. The head is gently supported nificant braiding of the hair, it will be more difficult to
at the angle of the jaw with the child looking for- make an accurate measurement especially if the braiding
is not present on the next measurement as there is no way
ward horizontally into the distance (Frankfort to compare the two measurements
plane) to make sure that the head is horizontal to
the feet. A Harpenden stadiometer or an electronic
stadiometer is the most accurate of such devices, correct measurement procedures are followed
as it indicates the height in millimeter increments, (Fig. 5.3). Unfortunately, the old-fashioned
but inexpensive devices that follow these guide- floppy-arm device attached to a pole rising above
lines should give accurate measurements if the common office scale is used in many offices;
50
because the plate at the top of the pole is rarely
parallel to the floor, there is no way to straighten
the patient’s back against a thin pole, and the child
may slouch, and the measurements are useless.
Weight measurements are performed on a digital
scale on a firm surface rather than carpet with
coats and other heavy clothes removed.
The child must be measured with the shoes
off; if a child is measured in shoes one time and
without them another time, a guaranteed 2–4-cm
variation in height is found per visit, and this
all too often happens during casual evaluations.
A great quantity of hair, braiding, or barrettes on
the top of the head will likewise impair accuracy.
It is strongly recommended that all measure-
ments be made by using the metric system. The
tendency to round off numbers becomes problem-
atic when an inch is the unit of measure; an inac-
curacy of an inch or a half inch is a more serious
error than a mistake of 1 or 0.5 cm; remember that
a rounding error of one half-inch (1.25 cm) less
than the true measurement at the beginning and a
Fig. 5.4 (a) Infant boy
growth chart developed by
the WHO as recommended
by the CDC for use in boys
under 2 years of age.
(b) Infant girl growth chart
developed by the WHO as
recommended by the CDC
for use in girls under 2
years of age. Accessed
from http://www.cdc.gov/
growthcharts/
5 Disorders of Growth
rounding error of one half-inch (1.25 cm) more
than the true measurement at the end of a 6-month
period can mean a fallacious 5 cm of increased
growth per year when there may be no growth
due to a serious condition. Errors in the other
direction can lead to an absence of 5-cm growth
in a normal child, suggesting a disorder of growth
when none exists.
After the measurement is obtained, it must be
displayed graphically on the growth chart. An
abnormality of stature or growth rate is far more
obvious on a graph than written as a number on
the page; a decrease in growth rate in which a
child significantly “falls away from the curve” or
“crosses percentiles of stature” becomes obvious
on the graph. The most commonly used charts of
stature for age after 2 years of age (as well as
weight for age and BMI) from the National
Center for Health Statistics are available at www.
cdc.gov; they may be downloaded or printed
(Fig. 5.4a, b). These reference charts are devel-
oped from measurements of a population of US
Measurement of Growth
Fig. 5.4 (continued) Birth to 24 months: Girls
Length-for-age and Weight-for-age percentiles
Published by the Centers for Disease Control and Prevention, November 1, 2009
SOURCE: WHO Child Growth Standards (http://www.who.int/childgrowth/en)
children. The charts to be chosen show the 3rd to
97th percentile (not the 5th to 95th as they
exclude too many normal children). The WHO
produces standards of growth in optimal condi-
tions displayed on charts which are now the pre-
ferred chart for children under 2 years of age also
available at the CDC website (Fig. 5.4). Many
providers now use electronic medical records
(EMRs) which readily display the percent of
height to a fraction which enhances diagnosis.
The NCHS data tables which are available at
http://www.cdc.gov/nchs/data/series/sr_11/
sr11_252.pdf are used to compute standard devi-
ation scores (SDS) for children falling below the
3rd percentile. Specialty growth charts for Turner
syndrome, achondroplasia, and Down syndrome
among others are available.
When charting a child on a growth chart, the
examiner must accurately determine the child’s
age at the visit date. EMR will usually calculate
the fractional age of the child thus eliminating the
cumbersome process that follows. This involves
51
98
95
90
75
50
25
10
5
2
98
95
90
75
50
25
10
5
2
subtracting the birth date from the date of visit. If
the month or the numerical day of the month of the
birth date is greater than the month or the day of
the month of the visit, a conversion must be used
to allow the subtraction to occur. One year is
subtracted from the numerical year of the visit so
that, e.g., 2014 is converted into 2013. One month
is subtracted from the numerical month of the visit
so that April which is represented by 4 is converted
to 3, and 12 months are added on to the result (3 in
this case) to represent 1 year that was taken off the
numerical year. The value of the number of days in
the month of the visit (e.g., 28 for February, 31 for
July, 30 for November) is added to the numerical
day of the month of the visit: February 8 is con-
verted into 36. If the number of days in the result-
ing age is between 0 and 15, the numerical value
of the resulting age is left alone, but if the number
of days and the resulting age are between 16 and
the end of the month, 1 month is added to the
resulting age of the child. Thus a child born on
09/15/94 examined on 04/04/98 leads to a resulting
52
age of 3 years, 6 months, and 19 days old. The
child described above is 3 years and 7 months old
by this calculation. Now the month of the child’s
age must be converted into fraction of the year to
allow easy plotting; February to April is one-quar-
ter of a year, April to July is one-half of a year, and
August to October is three-quarters of a year, and
if the numerical month of birth of the child is
November or December, represented by 11 or 12,
another year is added to round up to the next year
of age. The child described above is 3 and one-half
years old which can be easily plotted on the growth
chart. (This entire process is described in the CDC
website at http://www.cdc.gov/nccdphp/dnpa/
growthcharts/resources/growthchart.pdf.)
Growth velocity charts (Fig. 5.5) demonstrate
the rate of growth, are more sensitive to devia-
tions from the normal growth velocity, and reveal
abnormalities before they become apparent on
the standard height-for-age charts found in
Fig. 5.4 (see examples in Fig. 5.6). US growth
data were used to develop growth velocity charts
for US children; while 1985 charts used cross-
sectional data, recently developed charts used
longitudinal data.
Crossing percentiles on a growth chart can be
an ominous sign of disease but in infancy can be
normal if the change is not excessive. Since the
length of healthy term babies clusters around
21 in. but adult heights are spread out wider, the
channel of growth followed on the growth curve
must change during the growing years, and this
adjustment occurs before 2 years of age and usu-
ally before 1 year of age by a gentle deceleration
or acceleration of growth rate. However, a flatten-
ing growth curve or weight curve means signifi-
cant organic disease. The difference between
these two patterns is not clear early in the course
of the change in growth channels, and many
referrals to pediatric endocrinologists occur dur-
ing this period to rule out significant illness even
though the child is clinically well.
Determination of arm span and upper-to-lower
segment ratio is useful in the evaluation of short
stature (e.g., to indicate hypochondroplasia or
achondroplasia in which arms and legs are short)
or of delay in puberty (e.g., to look for the long
arms and decreased upper-to-lower segment ratio
5 Disorders of Growth
of eunuchoid proportions of hypogonadism where
legs and arms are long). The arm span is mea-
sured with the patient standing with the back to
the wall with arms spread horizontally and is the
distance from one outstretched middle fingertip to
the other. The arm-span measurement should be
close to the measurement of the height; on the
average, normal prepubertal children have arm
span 1 cm less than their height, pubertal children
have arm span equal to height, and adults have
arm span 5 cm greater than height. If the arm span
is shorter than the height by more than the general
guidelines above, a chondrodystrophy may limit
long-bone growth, whereas if it is longer than the
height, an abnormality of the growth of the spine
may be present, perhaps due to spinal radiation
therapy, among other possibilities. The lower seg-
ment is measured from the top of the symphysis
pubis to the floor, whereas the upper segment is
calculated by subtracting the lower segment from
the measured height of the child. The upper-to-
lower segment ratio varies with age (Fig. 5.7). A
decreased upper-to-lower segment ratio is found
in Klinefelter syndrome or other forms of hypo-
gonadism due to longer legs, and an increased
ratio is found in hypothyroidism and chondrodys-
trophies due to poor growth of legs. Measurement
of occipitofrontal head circumference and deter-
mination of percent of SDS are part of the stan-
dard examination using CDC charts as various
central nervous system problems may lead to dis-
orders of growth (Fig. 5.8).
Skeletal development or bone age is sug-
gested to be more closely correlated with certain
developmental landmarks than with chronologic
age in conditions of delayed or advanced puberty.
It is considered a reflection of the physiologic
rather than the chronologic age of the child.
However, careful study shows that the bone age
does not always accurately reflect these goals, so
the result should be interpreted with some suspi-
cion. A bone-age determination does not provide
a diagnosis but may support a condition under
consideration. The bone age is determined by a
radiograph of the left hand and wrist as com-
pared with the standards in the Greulich and Pyle
atlas in the USA, although Europeans may prefer
the Tanner–Whitehouse (TW2 or TW3) method.
Measurement of Growth 53

2 to 20 years: Boys NAME

Stature-for-age and Weight-for-age percentiles RECORD #

12 13 14 15 16 17 18 19 20
Mother’s Stature Father’s Stature cm in
Date Age Weight Stature BMI*
AGE (YEARS) 76
95
190
74
90
185 S
75
72
180 T
50 70 A
175 T
25 68 U
170 R
10 66
165 E
in cm 3 4 5 6 7 8 9 10 11 5
64
160 160
62 62
155 155
S 60 60
T 150 150
A 58
T 145
U 56
140 105 230
R
54
E 135 100 220
52
130 95 95 210
50
125 90 200
90
48 190
120 85
46 180
115 80
75
44 170
110 75
42 160
105 50 70
150 W
40
100 65 140 E
25
38 I
95 60 130 G
10
36 90 5 H
55 120
T
34 85 50 110
32 80 45 100
30
40 90
80 35 35 80
W 70 70
30 30
E 60 60
I 25 25
G 50 50
H 20 20
40 40
T
15 15
30 30
10 10
lb kg AGE (YEARS) kg lb
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Published May 30, 2000 (modified 11/21/00).
SOURCE: Developed by the National Center for Health Statistics in collaboration with
the National Center for Chronic Disease Prevention and Health Promotion (2000).
http://www.cdc.gov/growthcharts

Fig. 5.5 (a) Height-for-age percentiles in boys from 2 to girls from 2 to 20 years (from CDC website, www.cdc.
20 years (from Centers for Disease Control website, www. gov/growthcharts)
cdc.gov/growthcharts). (b) Height-for-age percentiles in
54 5 Disorders of Growth

2 to 20 years: Girls NAME

Stature-for-age and Weight-for-age percentiles RECORD #

12 13 14 15 16 17 18 19 20
Mother’s Stature Father’s Stature cm in
Date Age Weight Stature BMI*
AGE (YEARS) 76
190
74
185 S
72
180 T
70 A
97 175 T
90
68 U
170 R
75 66
165 E
in cm 3 4 5 6 7 8 9 10 11 50
64
160 25 160
62 62
155 10 155
S 60 60
T 3
150 150
A 58
T 145
U 56
140 105 230
R
54
E 135 100 220
52
130 95 210
50
125 97 90 200
48 190
120 85
46 180
115 80
44 170
110 90 75
42 160
105 70
150 W
40 75
100 65 140 E
38 I
95 60 130 G
50
36 90 H
55 120
25 T
34 85 50 110
10
32 80 3 45 100
30
40 90
80 35 35 80
W 70 70
30 30
E 60 60
I 25 25
G 50 50
H 20 20
40 40
T
15 15
30 30
10 10
lb kg AGE (YEARS) kg lb
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Published May 30, 2000 (modified 11/21/00).
SOURCE: Developed by the National Center for Health Statistics in collaboration with
the National Center for Chronic Disease Prevention and Health Promotion (2000).
http://www.cdc.gov/growthcharts

Fig. 5.5 (continued)

Measurement of Growth
Fig. 5.6 (a) Incremental growth charts for boys derived
from data in Flemish children and generally applicable
to the US population. Height velocity can be compared
with the percentiles. Increments in height are calcu-
lated over periods of no less than 10.2 months (0.85
years) and no more than 13.8 months (1.15 years) in
order to avoid the effect of seasonal variation in growth
and to reduce the effect of measurement error on the
estimation of yearly increment in stature. The yearly
increment in stature is calculated as the difference
55
between measurements of height (g2 − g1) divided by
the size of the interval (t2 − t1). This formula is also
shown on the charts for yearly increments in height. It
is important to plot the increments at an age which cor-
responds to the center of the interval, i.e., at the age
(t1 + t2)/2. Accessed at http://www.vub.ac.be/groeicur-
ven/files/2-20050604-EP2-20M.pdf and reproduced
with premission. (b) Incremental growth charts for
girls derived from data in Flemish children which
should be generally applicable to the US population
56 5 Disorders of Growth

+3 +2 +1 0 −1 −2 −3
a In cm cm
60
59 150 150 −4
58
57 145 145 −5
56
55 140 140
54
53 135 135
52
51 130 130
50
49 125 125
48
47 120 120
46
45 115 115
44
Stature

110 110
43
42
41 105 105
40
100 100
39
38
95 95
37
36
90 90
35
34
85 85
33
32
80 80
31
30 Physical growth (NCHS)
75 75
29 Boys 2-18 y
28
70 70
27
In cm cm
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Age (y)

Fig. 5.7 Demonstration of the sensitivity of the growth-
velocity charts compared to standard stature versus age
charts. (a) The growth-velocity chart of the growth chart
with squares showing the more striking changes of growth
rate at various ages. The growth rate between two ages is
plotted as a horizontal bar, with the height of the bar dem-
onstrating the annualized growth rate and the lateral limits
spanning the ages under consideration. (b) A growth chart
of two boys. The circles represent a boy who has a pro-
found decrease in growth rate at age 3–4 years. At age 6
years, some intervention occurs (red arrow), and growth
catches up at greater-than-average growth velocity. This
could be the institution of thyroxine in hypothyroidism,
growth hormone (GH) in GH deficiency, or removal of a
glucocorticoid-secreting tumor. The squares represents a
growth chart of a child growing faster than normal early in
life, who slows to a normal growth rate at 9 years and
decreases thereafter, until ceasing to grow by age
~13 years; this is found in untreated precocious puberty.
(c) The growth-velocity chart of the boy with the growth
chart with circles. The decrease in growth rate is more
striking earlier than is apparent on the statural growth
chart. The growth rate between two ages is plotted as a
horizontal bar, with the height of the bar demonstrating
the annualized growth rate and the lateral limits spanning
the ages under consideration. Redrawn from Styne DM:
Growth. In: Greenspan FS and Strewler FJ, eds.
Greenspan’s Basic and Clinical Endocrinology, 9th edi-
tion. Appleton and Lange, Stamford, Connecticut. 2011
with permission
Measurement of Growth 57

Stature
boys
b 6

4
Increment (cm/6 months)

97
2

90
1
75
50
0 25
10

3
–1
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Age (y)

Stature
boys
c 6

4
Increment (cm/6 months)

97

90

1 75
50
25
0
10

3
–1
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Age (y)

Fig. 5.7 (continued)

58
1.20
1.10
+2 SD
1.00
+1 SD
US:LS
Mean
0.90 –1 SD
–2 SD
0.80
4 6 8 10 12 14 16
Age (y)
Fig. 5.8 Upper-to-lower segment ratio (redrawn from
Heritable Disorders of Connective Tissue St. Louis: C. V.
Mosby Company, 1972 , with permission)
The delay or advancement in bone age is
expressed in standard deviations from the mean
reading for chronologic age which is listed in the
Greulich and Pyle atlas. Standard deviations
vary with age; 1 standard deviation may be only
2 months during the first year up to a standard
deviation of 1 year at 15 years (this means that a
normal 15-year-old boy may have a bone age
between 13 and 17 years!). Increased accuracy
in the technique is accomplished by radiologists
with the most practice; unfortunately, most gen-
eral radiologists who are not associated with a
pediatric center do not read many bone ages, and
their readings may not be accurate. With a bone
age over 6 years and an accurate determination
of stature, adult height can be predicted by the
Bayley–Pinneau tables found at the end of the
Greulich and Pyle atlas. The Roche–Wainer–
Thissen (RWT) method allows prediction of
eventual adult height in younger children. Other
methods of height prediction are in use in
Europe, and computerized methods of bone-age
evaluation are used in Europe in an attempt to
5 Disorders of Growth
increase accuracy of the reading. Of course, the
closer a child’s age is to adulthood, the more
accurate the prediction for adult height. A bone
age is not a perfect test, but the information gar-
nered is nonetheless of use in evaluating a child.
Bone age will be delayed in malnutrition as well
as in some endocrine diseases. Bone age will be
advanced in many cases of obesity reportedly more
prevalent in MC4R mutations.
Long-bone X-rays may demonstrate growth
arrest (or Harris or Park lines) which are dense
metaphyseal, trabecular lines thought to occur
after normal growth resumes, after nutritional
deprivation, immobilization, and illness includ-
ing infectious disease in growing children.
Endocrine Factors in Postnatal
Growth
18
Growth Hormone
Growth hormone (GH) is a single-chain 191-
amino-acid peptide hormone with two disulfide
bonds produced in the anterior pituitary gland. It
resembles prolactin, chorionic somatomam-
motropin, or placental lactogen in structure.
While primate growth hormone will exert effects
on other mammals, e.g., cows, bovine growth
hormone will not exert metabolic effects in
human beings, and thus natural sequence human
growth hormone is necessary for treatment in
children. Production and secretion of GH are
stimulated by growth hormone-releasing factor
or GHRH (or GRF in some texts) which is pro-
duced in the median eminence of the hypothala-
mus (Fig. 5.9a). GH deficiency may be caused by
GHRH deficiency or GH deficiency (Fig. 5.9b).
GH secretion is suppressed by somatostatin
(growth hormone-releasing inhibitory factor or
SRIF or SS) which has far-ranging effects in the
body including inhibiting the secretion of TSH,
insulin, and glucagon; impairment of gut motil-
ity; and reduction of intestinal absorption of
nutrients. The balance between GHRH and SRIF
leads to the pulsatile release of GH in normal
individuals. GH secretion is inhibited by insulin-
like growth factor I (IGF-1) through negative
Endocrine Factors in Postnatal Growth
a Third ventricle
Neuroendocrine
cell nuclei
Superior
hypophyseal
artery
Long portal
vessels
Somatotrophs
Anterior
pituitary
Hormone
secretion
IGF-1
Fig. 5.9 (a) Normal growth hormone physiology in which
growth hormone-releasing hormone (GHRH) from the
hypothalamus reaches the pituitary gland through the hypo-
physiotropic portal system to cause growth hormone secre-
tion. Growth hormone interacts with its receptors on the
liver and other organs to produce insulin-like growth factor
I (IGF-1) which exerts influences on cells throughout the
body and provides feedback inhibition on the pituitary
gland and hypothalamus to suppress GHRH and growth
hormone secretion until a normal equilibrium is reached.
(b) Growth hormone deficiency due to the absence of
growth hormone-producing cells, somatotrophs. The same
physiology applies if GHRH cells are defective. In the
feedback inhibition. GH itself inhibits GH secre-
tion, providing another level of control of GH
secretion. In states of IGF-1 deficiency such as
GH receptor mutations, GH levels rise (Fig. 5.9c).
59
Hypothalamus
GHRH secreting cells
Stalk
Inferior
hypophyseal
artery
Posterior
pituitary
Short portal
vessel
GH
absence of growth hormone, no IGF-1 is produced and both
growth hormone and IGF-1 levels are low, leading to
growth hormone deficiency. (c) Growth hormone resis-
tance in which growth hormone receptors are either absent
or defective. Thus no IGF-1 can be produced and there is
no negative feedback inhibition on the pituitary gland or
hypothalamus. GHRH and growth hormone rise in an
unsuccessful attempt to stimulate IGF-1 production, lead-
ing to the elevated growth hormone levels and depressed
IGF-1 levels characteristic of growth hormone resistance.
This condition is also called Laron dwarfism or primary
IGF-1 deficiency. Similar changes occur in starvation in
which GH receptors are decreased
Growth hormone exerts direct effects but also
produces effects through the production of IGF-1
in an indirect manner. Acute effects of GH admin-
istration are insulin-like, as GH increases amino
60 5 Disorders of Growth

b Third ventricle Hypothalamus

Neuroendocrine
cell nuclei

GHRH secreting cells

Superior
hypophyseal Stalk
artery

Long portal
vessels Inferior
hypophyseal
artery
Somatotrophs

Anterior Posterior
pituitary pituitary

Short portal
Hormone vessel
secretion

GH

IGF-1

Fig. 5.9 (continued)

acid uptake and incorporation into protein in the
liver and muscle, stimulates glucose uptake and
glucose utilization, and antagonizes the lipolytic
effects of catecholamines. Chronic effects of
GH are diabetogenic or anti-insulin and include
increased mobilization of FFA from adipose tis-
sue due to increased triglyceride lipolysis,
increased sensitivity to lipolytic effects of
catecholamines, as well as inhibition of glucose
uptake and utilization. GH indirectly stimulates
insulin secretion via the increase in serum glucose
concentrations.
GH secretion is high in the 48 h after birth,
decreases in the child, and rises during puberty
as, with rising IGF-1, it mediates the pubertal
growth spurt. Sex steroids affect growth hormone
secretion, and it is estradiol that increases growth
hormone secretion during puberty in both boys
and girls. GH decreases with aging in normal
adults. GH rises with stress, slow-wave sleep,
exercise, hypoglycemia, and fasting and decreases
with obesity, sugar ingestion, rising free fatty
acids, exogenous growth hormone administra-
tion, and REM sleep. Estradiol stimulates GH
Endocrine Factors in Postnatal Growth 61

c Third ventricle Hypothalamus

Neuroendocrine
cell nuclei

GHRH secreting cells

Superior
hypophyseal Stalk
artery

Long portal
vessels Inferior
hypophyseal
artery
Somatotrophs

Anterior Posterior
pituitary pituitary

Short portal
Hormone vessel
secretion

GH

IGF-1

Fig. 5.9 (continued)

secretion in moderate doses but suppresses GH (GHS-R1a). Galanin is another hypothalamic

secretion at high levels. Estradiol has similar
effects on IGF-1 levels.
Synthetic six-amino-acid peptides (hexapep-
tides) are also known to stimulate GH release and
have been used as GH secretagogues in testing.
The study of these factors led to the discovery of
the endogenous growth hormone secretagogue,
ghrelin, which is produced in the gastrointestinal
tract; ghrelin is considered an orexigenic or appe-
tite-stimulating hormone; the natural receptor for
ghrelin is the GH secretagogue receptor type 1a
peptide that stimulates growth hormone release
without affecting other pituitary hormones.
GH exerts its effects through the cell mem-
brane GH receptor (see Fig. 1.3). There is a com-
plex chain of events that occur once GH is
available to bind to GH receptors, and all can go
awry in disorders. The growth hormone (GHR)
receptor, once bound to a single GH molecule,
dimerizes with another unoccupied receptor,
leading to a complex of one GH molecule and
two GHR molecules in a dimeric complex.
62
This complex causes activation of the Janus
kinase-signal transducer and activator of tran-
scription (Jak-STAT) pathway. Recruitment of
Janus kinase 2 (JAK2) stimulates tyrosine kinase.
The phosphorylated receptor provides a site for
STAT to attach and become phosphorylated
itself. The phosphorylated STAT molecule then
dissociates from the receptor site to move to the
nucleus where it binds to target genes and regu-
lates transcription to produce proteins.
The amino acid sequence of the extra-
membrane portion of the GH receptor is cleaved
off to give rise to the GH-binding protein (GHBP)
found in the circulation. About ½ of circulating
GH is noncovalently bound to GHBP. The abun-
dance of the membrane receptor for GH is
reflected by the value of circulating GHBP. In
classic GH resistance (e.g., Laron dwarfism) in
which there are decreased or no cell membrane
growth hormone receptors, the serum GHBP val-
ues are low, whereas serum GH is high. In other
forms of GH resistance, the number of receptors
and the measurement of GHBP are normal, but
the function of the receptor is defective (Fig. 5.9c).
Growth hormone-binding protein is decreased in
starvation, indicating that a decrease in growth
hormone receptors occurs in a situation where
growth hormone is elevated so that GH can exert
no effect on growth. On the contrary, increased
body mass index and obesity increase growth
hormone receptors as reflected in increased
growth hormone-binding protein levels and sub-
sequent normal or even high normal IGF-1 val-
ues even though growth hormone is low.
Every step in GH action is subject to a
genetic error that will lead to short stature. For
example, mutation of STAT 5b leads to short
stature that is GH resistant and is associated
with immune deficiency (#245590 GROWTH
HORMONE INSENSITIVITY WITH
IMMUNODEFICIENCY). Serum GH concen-
trations are low throughout most of the day in
normal individuals but increase at intervals,
and these peaks differentiate a GH-sufficient
patient from a GH-deficient subject in most
cases. Thus, random GH measurements do not
reveal abnormalities of secretion unless GH
resistance or pituitary gigantism is suspected
5 Disorders of Growth
when elevated levels of GH will be diagnostic;
only sequential measurements of GH through a
12- or 24-h period (rarely performed because of
expense) or measurements after the administra-
tion of a GH secretagogue are of interest in the
diagnosis of GH deficiency. However, even
secretory tests are suspect, as some children
with normal GH secretion on testing can benefit
from GH treatment, and others with low values
on such a test grow normally and need no GH.
In GH deficiency, bone-age development is
delayed, whereas the upper-to-lower segment ratio
is normal for bone age. This is in contrast to hypo-
thyroidism, in which bone age is severely delayed,
but the upper-to-lower segment ratio is increased
due to lack of appropriate growth of the lower
limbs. Patients with untreated GH deficiency may
have delay in the onset of puberty until the absent
GH is replaced with treatment, and puberty pro-
gresses. It is thus difficult to determine which
patient with delayed puberty and untreated GH
deficiency has only GH deficiency and which has
gonadotropin deficiency in addition.
Insulin-Like Growth Factor or IGF
GH has some direct metabolic effects (e.g., diabe-
togenic insulin-resistant effects, lipolysis, cell dif-
ferentiation) and exerts direct growth-promoting
effects on the growth plate, but much of the
growth-promoting action of GH is indirectly medi-
ated by insulin-like growth factor 1. Growth fac-
tors can be secreted to affect other cells with
endocrine activity and affect neighboring cells
with paracrine activity or the cell of origin with
autocrine activity or intracrine within a cell.
Insulin-like growth factors (IGFs, previously
called somatomedins) are produced in tissue
throughout the body, but most IGF-1 is detected in
the serum derives from the liver. IGF-1 has mito-
genic effects in most dividing cells in the body and
stimulates sulfate uptake (and it was originally
known as sulfation factor), DNA synthesis, RNA
synthesis, and protein synthesis and exerts anti-
apoptotic effects. IGF-1 values are most closely
associated with the growth of children. Plasma val-
ues of IGF-1 decrease in states of GH deficiency
Endocrine Factors in Postnatal Growth
and increase in GH excess. IGF-1 concentrations
are low in the neonate and increase slowly through
childhood until a peak is reached during the puber-
tal period with an earlier peak in girls than boys,
reflecting the differential timing of the pubertal
growth spurt in the sexes. Normal values of IGF-1
at puberty are in the range characteristic of acro-
megalic adults. The major problems with the inter-
pretation of IGF-1 concentrations as a reflection of
GH secretion are the following: (a) the values in
the first 3 years of postnatal life are close to those
found in the hypopituitary state; (b) the values in
constitutional delay in growth are appropriate for
bone age rather than chronologic age and are often
reported as abnormally low if correlated with
chronological age alone while, if corrected for
bone age, the values would be reported as normal;
and (c) in states of poor nutrition, a condition that
is extremely common that by itself can cause poor
growth, IGF-1 values are as low as those in a
GH-deficient subject. Of further importance is the
variation between measured IGF-1 concentrations
in different laboratories and the lack of the stan-
dardized assay. Thus the use of serum IGF-1 con-
centrations must be tempered with caution in the
diagnosis of growth deficiency, and strict attention
must be paid to nutritional status and physiologic
state of development. Protein calorie malnutrition
decreases plasma IGF-1 values due to decreased
binding of GH to the GHR. Further IGF-1 mea-
sured in the serum is only a reflection of local
activity within tissue of origin the growth factor.
IGF-1 production is found in certain cancer
cells. Serum levels of IGF-1 may be related to
some malignancies.
Insulin-like growth factors I and II are bound to
one of a family of more than six IGF-binding pro-
teins, each identified with a different number such
as IGFBP1, IGFBP2, and IGFBP3. The structure
of the different IGF-binding proteins are relatively
similar but quite different than growth hormone-
binding protein or steroid-binding proteins.
Binding proteins keep IGF-1 levels relatively con-
stant throughout 24 h in contrast to the episodic
secretion characteristic of growth hormone. IGF-
binding protein 3 measurements can be indicative
of GH status. IGF-binding protein can modify the
biological effects of insulin-like growth factor.
63
IGFBPs characteristically decrease the activity of
IGF-1 by holding it in the reservoir of inactive
complex but in some cases, others can enhance the
effects of IGF-1. For example, binding proteins
can also allow IGF-1 to transit cell membranes in
some cases. IGFBP-3 is GH dependent, and low
serum values in association with low serum values
of IGF-1 make the diagnosis of GH deficiency
more likely than a decrease in serum IGF-1 by
itself, especially in children before 3 years of age
when IGF-1 values are normally low. IGFBP3 is
also responsive to IGF-1 so that values of IGFBP3
rise in conditions of GH and/or IGF-1 excess.
About 80–85 % of serum IGF-1 and IGF-2 are
found in a ternary complex of 150 kDa composed
of one molecule each of IGF-1, IGFBP3, and a
protein that is found only in serum, the acid-labile
subunit (ALS). The tertiary compounds of IGF 1,
IGFBP3, and ALS reflect growth hormone secre-
tory levels.
On the contrary, IGF-binding protein 1 is insu-
lin dependent but not GH dependent. In states of
hyperinsulinism, IGFBP 1 is suppressed.
IGF-1 attaches to a specific IGF-1 receptor which
is structurally similar to the insulin receptor (Fig.
1.3). Cross-reaction of insulin with IGF-1 receptors
is possible when insulin levels are elevated as in an
infant of a diabetic mother. Alternatively, the admin-
istration of IGF-1 may cause low blood sugar due to
interaction with insulin receptor.
Some suggest the abandonment of secretory
tests of GH secretory ability and argue that reli-
ance on serum IGF-1 and IGFBP-3 is sufficient for
diagnosis of GH deficiency. In California, some
insurance companies have adhered to this view,
and the state funding agency, California Children’s
Services, at present has ceased requiring GH stim-
ulatory testing to establish GH deficiency in most
cases. However, not all insurance companies or
state agencies agree to pay for GH treatment with-
out a GH secretory test, so such stimulatory testing
procedures cannot be abandoned.
IGF-1 is important in late fetal growth as an
individual with an IGF-1 loss of function receptor
mutation suffered from severe IUGR. As growth
hormone receptors are low in the fetus compared
to postnatal life, it is insulin that regulates IGF-1
in the fetus rather than growth hormone.
64
IGF-2 is present in high concentrations after
birth but does not have the relationship to
growth found with IGF-1. Concentrations of
IGF-2 are decreased in GH deficiency but not
increased in GH excess. Although plasma
IGF-2 concentrations alone may not be reliable
in the diagnosis of GH deficiency, the finding of
both low values of IGF-1 and IGF-2 has been
stated to be reliable in pointing to the diagnosis
of growth hormone deficiency. In general, how-
ever, IGF-2 measurements are not used clini-
cally in the diagnosis of disorders of growth
although IGF-2 does play a role in neoplasia
and in the evaluation of carcinoma as, e.g., lev-
els may be increased in patients with osteosar-
coma. The insulin-like growth factor 2 receptor
(IGF2R encoded by the IGF2R gene) is quite
different in structure and function from the
IGF-1 receptor and is also known as the cation-
independent mannose-6-phosphate receptor
(CI-MPR) indicating its other functions.
Thyroid hormone is essential for postnatal
growth but has little effect on fetal longitudinal
growth, as congenital hypothyroidism is associ-
ated with normal or even slightly greater than
normal birth length. Thyroid hormone is also
necessary for the normal secretion of GH, as
hypothyroid patients may not respond to GH
stimulation tests with GH secretion, thereby
confusing the diagnosis of hypothyroidism with
GH deficiency. Hypothyroid patients who also
have GH deficiency cannot respond to GH ther-
apy unless they are rendered euthyroid. In the
absence of adequate thyroid hormone, a patient
has reduced lower limb growth, leading to a
delayed or higher upper-to-lower segment ratio.
Bone-age development is also retarded in hypo-
thyroidism, and when the epiphyses do appear,
they are often irregular and abnormal, with mul-
tiple epiphyses (epiphyseal dysgenesis). Usually
puberty is delayed if thyroid hormone is
decreased, but with profound primary hypothy-
roidism, pubertal development may occur early,
particularly in girls, apparently due to cross-reac-
tion of elevated TSH values with gonadotropin
receptors; this is known as the Van Wyk-Grumbach
syndrome (see Chaps. 7 and 8). Hypothyroidism
inhibits the ability to secrete growth hormone,
5 Disorders of Growth
and hypothyroidism may be confused in this way
with growth hormone deficiency. IGF-1 levels
are also low in hypothyroidism.
Sex steroids advance growth, skeletal age, and
pubertal development in the postnatal state.
Gonadal steroids are essential for the pubertal
growth spurt and are responsible for approximately
half of the growth achieved during puberty. If
excessive sex steroid concentrations are maintained
for a long period (e.g., virilizing congenital adrenal
hyperplasia), the epiphyses will fuse prematurely,
and the previously tall child will become a short
adult; epiphyseal fusion is owing to the action of
estrogen, which may be secreted directly or result
from the aromatization of testosterone. Absence of
gonadal steroids will delay skeletal maturation and
decrease the pubertal growth spurt, but hypogonad-
ism can also allow prolonged growth, leading to
taller-than-predicted adult stature.
Glucocorticoids significantly suppress growth
when present in excess; thus, Cushing syndrome
due to endogenous (e.g., an adrenal adenoma) or
exogenous (e.g., given for rheumatoid arthritis or
renal disease) glucocorticoids can cause the ces-
sation of growth and result in short stature. Inhaled
glucocorticoids for asthma therapy may have
measurable but smaller effects on growth than do
oral glucocorticoids. Even dermal application of
glucocorticoids in excess can affect growth, espe-
cially if the skin barrier is breached. If glucocorti-
coids for treatment of a chronic disease can be
minimized by the use of decreased dosage, alter-
nate-day treatment, or even alternative therapy,
growth will usually benefit. Decreased glucocorti-
coids will not affect growth as long as the patient
is not disabled or anorexic from the condition.
Insulin in excess will increase growth rate in
the fetus (e.g., infant of a diabetic mother) and
after birth (e.g., patients with insulinomas or islet
cell hypertrophy) due to interaction of insulin
with IGF-1 receptors. Insulin deficiency will
decrease growth if replacement is inadequate
because of the many serious effects of diabetes.
Further, in the absence of insulin receptors, as in
Donohue’s “leprechaun” syndrome (#246200
ICD+DONOHUE SYNDROME at 19p13-2), an
autosomal recessive condition, fetal and postna-
tal growth will be poor.
Endocrine Factors in Postnatal Growth
Fig. 5.10 Calculation of target height for children by using
the stature-for-age percentiles for boys aged 2–20 years
growth chart (from CDC website, www.cdc.gov/ growth-
charts). The father’s height (in yellow) is plotted on the right
directly, while the mother’s height (lower thin red) must be
Genetic factors are of significant importance
in growth as it is estimated that about 40–50 % of
stature is inherited. The correlation between
midparental height and children’s height can be
used to adjust the position of a child on a growth
chart to better reflect the genetic milieu of the
family. The average difference in adult stature of
about 13 cm which is usually rounded out to 5 in.
between men and women in the USA is used for
the process; thus 5 in. is subtracted from a
father’s height for a girl to allow plotting his
65
increased by 5 in. on a boyl’s chart (upper thin red line).
The midparental height (MPH) (thick red line) is the aver-
age of the father’s height and the corrected mother’s height.
The limit of 2 standard deviations (SD) is approximately 4
in. above and below the MPH indicated by the black lines
adjusted height appropriately on a daughter’s
chart (as shown in Fig. 5.10) or 5 in. is added to
a mother’s height to allow plotting her adjusted
height on a son’s chart (plotted at 18–20 years,
an age when growth normally ceases and is the
adult height). Then the father’s height and
adjusted mother’s height are averaged, and the
midparental height that results (the adjusted
midparental height) is plotted on the far right of
the son’s growth chart (e.g., at 18 years, or adult
stature) or the mother’s height and the adjusted
66
father’s height are averaged, and the resulting
midparental height plotted on the far right of the
daughter’s growth chart (Fig. 5.10). The limits of
2 standard deviations (in the USA, a standard
deviation is about 2 in. for adult height, so 2 SD
is 4 in.) or 4 in. are noted above and below the
midparental height. This then is the target height
of the child. One can conceptually adjust the
growth chart for the family by interpreting the
midparental height as the 50th percentile for this
particular family and interpreting the height of
the child by the resulting new percentiles on the
conceptual chart. Thus, a boy who plots at the
3rd percentile for the USA who has short parents
might plot well within the target height (or on the
conceptually reinterpreted chart at the 10th per-
centile for the family; Fig. 5.10).
Nutrition is one of the most essential factors for
growth and reproductive development. In the eval-
uation of children immigrating to the USA from
developing countries or from countries torn by war
or famine, it may be inappropriate to consider the
parents’ heights in the evaluation of the child; the
parents may have been subject to malnutrition dur-
ing their growing years and may be inappropri-
ately short, whereas the child may benefit from
better nutrition in their new home and have the
opportunity to be taller than the parents. Decrease
in nutrients from excessive dieting or anorexia ner-
vosa as well as chronic disease can exert the same
effect as malnutrition due to economic causes on
decreasing growth. Thus, socioeconomic and psy-
chosocial factors are important considerations in
the interpretation of growth rate. Of course it is
important to ensure that the parents reporting their
heights are indeed the biological parents, informa-
tion that might not be volunteered automatically.
Chronic disease may decrease growth apart
from effects on decreasing nutritional intake. For
example, the decrease in stature in children with
juvenile rheumatoid arthritis and celiac disease is
not explained solely on nutritional grounds.
Psychological problems can affect growth
either from a nutritional standpoint or through an
endocrine effect. Psychosocial dwarfism is a
temporary condition of hypopituitarism precipi-
tated by abnormal parent-child interaction which
is not thought to be due to malnutrition. Affected
children will test positive for GH deficiency on
5 Disorders of Growth
stimulatory testing as they will not normally raise
their growth hormone values; the test results will
likely revert to normal by moving the child out of
the home and into a more welcoming environ-
ment where growth may again resume.
Epidermal Growth Factor
Epidermal growth factor (EGF) binds to its own
EGF receptor (EGFR), a member of the ErbB fam-
ily of receptors that have tyrosine kinase activity,
leading to dimerization of the receptors causing
stimulation of cell growth, proliferation, and
differentiation. In the normal state epidermal growth
factor is a mitogen for ectodermal tissue but in neo-
plastic conditions, excess epidermal growth factor
may be produced.
Erythropoietin
Erythropoietin is the growth factor produced in the
interstitial fibroblasts in the kidney which stimu-
lates red blood cell production. Erythropoietin val-
ues rise in anemia and hypoxemia. Erythropoietin
is also stimulated by thyroid hormone, adrenal
cortical steroids, androgens, and growth hormone.
Oncogenes
Oncogenes are any genes that encode a protein
able to transform cells to induce cancer. Oncogenes
are able to stop cell from undergoing programmed
cell death, apoptosis, often in concert with envi-
ronmental factors or viruses. Most oncogenes
originate from normal genes, proto-oncogenes,
which encode for positive-acting growth factors
and their receptors, signal-transduction proteins,
transcription factors, and cell-cycle control pro-
teins. When proto-oncogenes undergo activation
or mutation, they produce the tumor-causing onco-
genes. An oncogene may cause the growth factor-
producing cell to secrete growth factors in
increased amounts or to make cells that are not
supposed to produce growth factors to secrete
them. Oncogenes are similar to genes that nor-
mally function in fetal development: for example,
Abnormalities of Growth
the WT 1 or Wilms tumor gene is implicated in
numerous other types of tumors as well. However,
the WT 1 gene is essential for the development of
many organs and tissues in the fetus.
Dental Development
Orthodontic treatment is predicated upon the
development of teeth, but a remarkable and com-
prehensive theory that controls the development
of teeth is not available. It is useful however to
predict the likelihood of future dental develop-
ment in delayed puberty, growth hormone defi-
ciency and short stature. Certain milestones in
dental development are reflected by the age of
tooth eruption but this is a single event in the his-
tory of tooth, while calcification of the tooth
might be considered a more reliable indicator.
Various methods of estimating dental maturity
using either eruption or calcification are avail-
able, and some data is available on the effect of
tooth development in endocrine disorders. It is
generally agreed that the first permanent teeth
erupt between an average age of 6 and 7 years
and that the first teeth are the first molar and lat-
eral/central incisors which emanate from differ-
ent tooth groups. Either eruption may precede the
other and the eruptions are uncoordinated.
Growth hormone-deficient and growth hormone-
resistant children have delayed dental eruption,
but GH treatment does not usually decrease the
degree of delay in dental development. Severe
hypothyroidism is associated with severe delay in
dental development.
Abnormalities of Growth
Short Stature
The criteria for awakening concern over a disor-
der of growth depend upon the defining group
(Pediatric Endocrine Society, FDA, Growth
Hormone Research Society), but for this discus-
sion, we suggest evaluation if:
1. The definition of short stature varies by the
organization making the definition and the
67
purpose of the definition: the Growth Hormone
Research Society uses <3 SD below the mean
or the <0.1 percentile for idiopathic short stat-
ure (ISS), the Pediatric Endocrine Society
uses <2 SD below the mean for age and gen-
der or 2.3 %, and the FDA uses −2.25 standard
deviations for consideration of growth hor-
mone therapy for ISS. For the purposes of
this chapter we will adhere to the −2 standard
deviation definition which is the 2.3 percentile
and which comes close to the 3rd percentile
line on a CDC growth chart.
2. Height velocity <2 SD below mean for bone
age.
3. Height corrected for midparental height of
<−2 SD or <2.3 % (the Growth Hormone
Research Society uses <1.5 SD).
4. Signs indicative of an intracranial lesion.
5. Signs of multiple pituitary hormone deficiency.
6. Neonatal symptoms and signs of growth hor-
mone deficiency.
7. History of central nervous system radiation.
The more of the criteria met, the more likely
an abnormality.
Nonendocrine Causes of Short Stature
Constitutional Delay in Growth
Constitutional delay in growth and adolescence
(CDP or constitutional delay) is best considered a
variation of normal development (Table 5.1). After
a normal birth length and weight, growth rate sub-
tly decreases during the first 2 years so that stature
becomes shorter than average for age 2–3 years,
but the child then follows the channel of growth on
the chart just reached (i.e., growth rate then nor-
malizes (Fig. 5.11)). In addition, bone age is
delayed at least 2 SDs by the definition of constitu-
tional delay. Thus the condition is a variation in the
normal tempo of development rather than a dis-
ease. The child is usually thin, often male, but with
the obesity epidemic, a subgroup of obese consti-
tutional delay has emerged, so weight is no longer
an accurate indicator. The growth rate is appropri-
ate for the skeletal development but not for the
chronologic age. Thus the growth rate must be
interpreted in terms of bone age rather than chron-
ologic age. If the patient has genetic short stature
68 5 Disorders of Growth

Table 5.1 Etiologies of short stature Table 5.1 (continued)

Variations of normal Noonan syndrome (pseudo-Turner syndrome)
Constitutional delay in growth and puberty Autosomal trisomy 13, 18, 21
Genetic short stature with short familial heights Prader-Willi syndrome
Endocrine disorders Bardet-Biedl syndromes
GH deficiency Autosomal abnormalities
Congenital Dysmorphic syndromes (Russell-Silver, Cornelia de
Isolated GH deficiency Lange)
With other pituitary hormone deficiencies Pseudohypoparathyroidism/Albright’s hereditary
With midline defects osteodystrophy
Pituitary agenesis Chronic disease
With gene deficiency Cardiac disorders
Acquired Left-to-right shunt
Hypothalamic/pituitary tumors Congestive heart failure
Histiocytosis X (Langerhans cell histiocytosis) Pulmonary disorders
CNS infections and granulomas Cystic fibrosis
Head trauma (birth and later) Asthma
Hypothalamic/pituitary radiation GI disorders
CNS vascular accidents Malabsorption
CNS surgery Celiac disease
Hydrocephalus Disorders of swallowing
Empty sella syndrome Inflammatory bowel disease
Autoimmune hypophysitis Hepatic disorders
Functional GH deficiency Hematologic disorders
Psychosocial dwarfism Sickle cell anemia
GH resistance or primary IGF deficiency Thalassemia
Various forms of GH resistance Renal disorders
Laron dwarfism (increased GH and decreased IGF-1) Renal tubular acidosis
Pygmies (normal GH and IGF-2 but decreased IGF-1) Chronic uremia
IGF 1 resistance Immunologic disorders
Hypothyroidism Connective tissue disease
Glucocorticoid excess Juvenile rheumatoid arthritis
Endogenous Chronic infection
Exogenous AIDS
Diabetes mellitus under poor control Hereditary fructose intolerance
Diabetes insipidus (untreated) Malnutrition
Hypophosphatemic vitamin D-resistant rickets Fad diets and anorexia nervosa
Virilizing congenital adrenal hyperplasia (tall child, Kwashiorkor, marasmus
short adult) P-450c21, P-450c11 deficiencies Iron deficiency
Skeletal dysplasias Zinc deficiency
Osteogenesis imperfecta Anorexia due to chemotherapy for neoplasms
Osteochondroplasias Amphetamine treatment for hyperactivity with
Lysosomal storage diseases decreased caloric intake
Mucopolysaccharidoses Modified from Styne DM. Growth disorder. In: Fitzgerald
Mucolipidoses PA, ed. Handbook of clinical endocrinology. Norwalk,
CT: Appleton & Lange, 1986: 73–99, with permission
Syndromes of short stature AIDS acquired immunodeficiency syndrome, CNS central
Turner syndrome (syndrome of gonadal dysgenesis) nervous system, GI gastrointestinal, IGF insulin-like
SHOX deficiency growth factor, GH growth hormone
 cm In In
200
78 78
195
76 76
190
Stature-for-age percentiles: 97th
74 Boys, 2 to 20 years 95th
90th
74
185
72 72
75th
180
70 70
50th
175
68 68
25th
170
66 10th 66
165 5th
64 3rd 64
160
62 62
155
60 60
150
58 58
145
56 56
140
54 54
135
52 52
130
50 50
125
48 48
120
46 46
115
44 44
110
42 42
105
40 40
100
38 38
95
36 36
90

34 34
85

80 32 32

30 30
75
cm In In
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Age (years)
Published May 30, 2000.
SOURCE: Developed by the National Center for Health Statistics in colaboration with
the National Center for Chronic Disease Prevention and Health Promotion (2000).

Fig. 5.11 Growth chart demonstrating the various patterns
of growth. A: Blue line. A boy with genetic short stature who
parallels the normal curve below the 3rd percentile and who
has no delay in bone age. He reaches an adult height at a
percentile similar to the percentile at which he grew during
childhood. B: Green line. A boy with constitutional delay in
growth, who parallels the normal growth curve but is below
it in a manner similar to a boy with genetic short stature but
has a delayed bone age, and so has a late pubertal growth
spurt and continues to grow after the average boys have
stopped. He will reach an adult height in the normal range
above the percentile he followed during childhood; however
his adult height may not reach his genetic potential as indi-
cated by parental heights. C: Red line. Growth of a boy with
a serious disease, which could be a brain tumor that interferes
with growth hormone secretion, glucocorticoid-induced
growth failure, or a host of other chronic diseases. His growth
decreases from about the 50th percentile remarkably at about
age 10 years, which is the age at onset of his disorder. He
should have been diagnosed with a problem soon after the
change in growth velocity based upon this plot but the line is
extended as if he was not diagnosed and treated, for emphasis
(drawn on chart redrawn from CDC website, www.cdc.gov/
growthcharts)
70
in addition to constitutional delay in growth, the
degree of short stature may be so obvious that the
patient will seek advice sooner; if constitutional
delay occurs in a child without genetic short stat-
ure, the degree of short stature may not stimulate a
medical evaluation until a delay in puberty is
noted. Often one parent or a sibling has a history of
constitutional delay (e.g., mother did not begin
menstruating until 15–16 years or father continued
to grow or started to shave well after high school).
Patients with constitutional delay will enter
puberty at a later age than their peers (by defini-
tion, older than 13 years in girls and 14 years in
boys) but at an age appropriate for their bone age.
Although considerable variation exists, as a rule
of thumb, boys will enter puberty when their
bone age is 12 years and girls when their bone
age is 11 years. The predicted height of children
with significant delay in bone age calculated by
the use of the Bayley–Pinneau tables in the
Greulich and Pyle atlas may overestimate adult
height; thus their adult height, although within
the normal range, might be lower than expected.
Genetic Short Stature
Genetic short stature refers to the child of shorter-
than-average parents. These children are expected
to reach an adult height below average, as their
short stature is not accompanied by a delay in bone
age. Adjustment for midparental height is of impor-
tance in evaluating such children (Fig. 5.10).
It bears mentioning that the heights of the biologi-
cal and not the step parents are the ones to be con-
sidered; information about step-parenting or even
adoption may not be offered without specific ques-
tioning. Further, it is useful to determine the grow-
ing environment of the parents to determine if their
present adult stature truly reflects their genetic
potential: Did they grow in a war zone or were they
deprived of adequate nutrition?
Idiopathic Short Stature
ISS denotes a child in whom no other cause of
short stature can be found. The cause of ISS is
unknown but may be due to large effects of a few
genes or small additive effects of numerous
polymorphisms. Unfortunately, many studies on
growth mix genetic short stature and constitutional
5 Disorders of Growth
delay in growth in their patient populations confus-
ing the conclusions. The FDA defines children with
ISS as being −2.25 SD below the mean or below
the 1.2 % which is well below the 3rd percentile
shown on standard growth charts. Further, if an
otherwise normal child has a predicted height less
than 63 in. (160 cm) for males and less than 59 in.
(149 cm) for girls, they meet the FDA approved
criteria for growth hormone treatment, but not all
insurance companies will pay for such treatment.
A review of randomized controlled studies and
other studies indicates a mean adult height gain of
5.5 cm with treatment if started by 10 years of age.
Small for Gestational Age
Small for gestational age (SGA) infants are born
with birth weights below the tenth percentile for
their gestational age; for a term baby, this translates
into an approximate weight less than 2,500 g
(although there are other weight definitions pro-
posed in various publications). Standards are avail-
able (e.g., Fig. 5.1a) for weight according to
gestational age to interpret the birth weight of pre-
mature infants. Intrauterine growth-retarded or
growth-restricted (IUGR) babies have poor intra-
uterine growth monitored by ultrasound and usually
are born SGA. The terminology is often confused in
various texts, but we adhere to the definition of
SGA based on birth weight compared with gesta-
tional age and IUGR based on fetal growth rate.
Symmetrical SGA indicates that a decreased head
circumference accompanies the decreased length,
whereas asymmetrical SGA indicates that the head
circumference is spared and is normal for age; sym-
metrical SGA may indicate a more severe condi-
tion, whereas asymmetrical SGA is less severe.
Approximately 80 % of affected SGA children will
catch up to the normal growth percentiles by age 2
years, but a minority remain small for their entire
growing period and attain short adult heights; the
symmetrical SGA subjects are those most likely to
continue to have retarded growth. SGA patients are
characteristically thin, have bone age appropriate
for chronologic age, and usually have a rate of
growth within the normal range for bone age. SGA
is a risk factor for a decreased age of onset of
puberty although many enter at the usual age range.
GH treatment is approved by the FDA for those
Abnormalities of Growth
with SGA who do not catch up to the normal height
distribution by 2 years of age. Numerous syn-
dromes, some discussed in this chapter, are related
to an SGA birth weight. Neonatal diabetes is associ-
ated with intrauterine growth restriction and SGA.
Turner Syndrome and SHOX Mutation
Turner syndrome is caused by a loss or abnor-
mality of one X chromosome or a portion of it.
Classic cases of Turner syndrome have a 45X
karyotype although variants are common. Turner
syndrome has a prevalence between 1:2,000 and
1:5,000 live births, making it a common cause of
short stature (also see chapters on sexual differ-
entiation and puberty, Chaps. 8 and 9). Physical
features of Turner syndrome include short stat-
ure (average adult height is 143 cm), streak
gonads (a normal complement of ova is present
at birth, but accelerated oocyte death occurs in
the postnatal period), sexual infantilism, and a
female phenotype. Other findings include down-
turned edges of the mouth (leading to a “fish-
mouth appearance”) with retrognathia and
high-arched palate, ptosis and epicanthal folds,
broad shield-like chest, the appearance of wide-
spaced and hypoplastic poorly pigmented nip-
ples, short webbed neck with low hairline, short
fourth metacarpals, Madelung abnormality of the
wrist (radial shortening and bowing with dorsal
subluxation of the distal ulna), wide carrying
angle of the arms (cubitus valgus), knock-knee
appearance (genu valgum), multiple nevi, spoon-
shaped (hyperconvex) hypoplastic nails, and
lymphedema of the extremities, particularly in
infancy. At birth, many patients have lymph-
edema of the extremities and loose skin folds
around the neck, which later transforms into the
classic webbed neck and also accounts for the
low-set ears; this newborn appearance of Turner
syndrome is termed the Bonnevie–Ullrich syn-
drome. A tendency exists toward keloid forma-
tion, which can complicate attempts to correct
the webbed neck surgically. A girl with Turner
syndrome may not manifest all the physical find-
ings and may appear as an average short girl, so
a high index of suspicion in any short girl with-
out a diagnosis is indicated; rarely, girls with
taller familial heights will not even be short and
hypogonadism will be the indicator. In fact, rare
71
Turner’s patients may go into puberty spontane-
ously and may even be fertile; variation is promi-
nent in Turner syndrome due to mosaicism.
Frequent episodes of otitis media in childhood
may lead to conductive hearing loss, although
sensorineural hearing loss is possible, as well.
Abnormalities of the shape of the kidneys (e.g.,
horseshoe kidneys or duplications) may lead to
frequent urinary tract infections in those with
abnormal kidney function, so ultrasound evalua-
tion of kidneys is indicated. Left-sided heart
anomalies (such as coarctation of the aorta often
first noted due to hypertension soon after birth)
are common. Affected girls require cardiac evalu-
ation for heart defects and appropriate follow-up
care. Even normotensive patients require regular
screening for aortic dilation every 5–10 years as
adults. Increased incidence of Hashimoto thyroid-
itis and insulin insensitivity are other features.
Variants of Turner syndrome occur with
abnormal X chromosome or mosaicism (e.g.,
XO/XX). Other variants of Turner syndrome
include patients with mosaicism involving the Y
chromosome, such as XO/XY. A fluorescent in
situ hybridization (FISH) probe for Y chromo-
some material should be performed if this situa-
tion is suspected. These patients with Y
chromosome material may have dysgenetic testes
rather than streak gonads and are at risk for
gonadoblastoma or malignant degeneration of
the gonad, so gonadectomy is indicated. A new
molecular probe for Turner syndrome has been
described for an alternative method of diagnosis.
The SHOX gene (*312865 SHORT STATURE
HOMEOBOX; SHOX at Xpter-p22.32) on the
short arm of the X chromosome near the pseudo-
autosomal region is absent on the aberrant X
chromosome or if there is no second X chromo-
some. This gene is related to the short stature of
Turner syndrome and gives rise to the Madelung
deformity of the wrist. Growth hormone (GH)
treatment is approved for Turner syndrome; treat-
ment increases stature in Turner syndrome above
the average adult height of 143 to 152 cm or
more. The age to initiate estrogen replacement is
controversial; if it is offered too early and in high
dosage, it will decrease the adult height, while
late start may intensify psychological problems.
Recent evidence shows that low doses of estrogen
72
offered at the average age of puberty will not
affect height when used in conjunction with GH.
The short stature of Turner syndrome is due to
the absence of the short stature homeobox (SHOX)
gene. However SHOX deficiency may occur with
dysmorphic characteristics or in otherwise normal
children who demonstrate decreased rate of growth
early in life. Leri–Weill dyschondrosteosis
(#127300 ICD+LERI-WEILL DYSCHONDROS-
TEOSIS; LWD) is an autosomal dominant condi-
tion more often found in females with multiple
skeletal anomalies; short stature is common, but
normal stature is possible. Patients have scoliosis,
mesomelia, increased carrying angle, limited elbow
mobility, bowing of the radius, dorsal subluxation
of ulna, and short, mildly curved tibia. Patients fre-
quently have Madelung wrist deformity (74 % of
LWD patients) as found in Turner syndrome with
limited wrist mobility.
Langer mesomelic dysplasia (#249700 ICD+
LANGER MESOMELIC DYSPLASIA; LMD)
is an autosomal recessive condition also due to
mutations in the SHOX gene and associated with
disproportionate, mesomelic short stature and the
Madelung deformity of the wrist. Affected chil-
dren have micrognathia; increased lumbar lordo-
sis; short, broad ulna; spontaneous subluxation of
the distal ulna; bowed dorsolateral; short radii
with triangularization; pyramidalization, lucency
of distal radius on forearm X-ray; short femoral
neck; marked shortening of tibia; laterally angu-
lated tibia; and rudimentary fibula.
Syndromes of Short Stature
Noonan Syndrome
Noonan syndrome (*163950 NOONAN
SYNDROME 1; NS1 at 12q24) is an autosomal
dominant condition occurring in 1 in 1,000–1 in
2,500 births that includes many features that resem-
ble those of Turner syndrome and others that do not,
but does not include SGA (see Chap. 7). Some
characteristics are short stature (of postnatal onset);
failure to thrive in infancy; triangular, low-set poste-
riorly rotated ears; nerve deafness; ptosis; hyper-
telorism; down-slanting palpebral fissures;
epicanthal folds; myopia; blue-green irides;
deeply grooved philtrum; high peaks of upper lip
5 Disorders of Growth
vermilion border; high-arched palate; microgna-
thia; dental malocclusion; low posterior hairline;
webbed neck; cystic hygroma; congenital heart
defect (usually of the right side rather than left-
sided heart disease as in Turner syndrome) including
pulmonic stenosis, septal defects, and patent ductus
arteriosus; shield-like chest; pectus carinatum supe-
riorly and pectus excavatum inferiorly;
hypogonadism and cryptorchidism; vertebral
abnormalities; cubitus valgus; clinodactyly; brachy-
dactyly; blunt fingertips; lymphedema; wooly-like
consistency of hair; articulation difficulties; and
25 % have developmental delay. Fifty percent of
Noonan patients have gain-of-function mutations in
the tyrosine phosphatase, nonreceptor type 11
(PTPN11) gene. Noonan syndrome is considered a
Rasopathy disorder. While GH is FDA approved
for Noonan syndrome, patients with this mutation
demonstrate less growth in response to GH therapy
as do those without the mutation in some studies.
Russell–Silver Dwarfism Syndrome
Russell–Silver dwarfism syndrome (180860
RUSSELL-SILVER SYNDROME; RSS at 7p12-
p11.2) in addition to SGA is characterized by
hemihypertrophy, lateral asymmetry, asymmetry
of arms and/or legs, fifth finger clinodactyly, syn-
dactyly of toes, craniofacial disproportion, delayed
fontanel closure, triangular facies, turned-down
corners of the mouth, and sometimes cryptorchi-
dism. On radiograph, vertebral abnormalities
including absent sacrum and absent coccyx may
be seen. It is usually sporadic but is rarely described
with maternal uniparental disomy (UPD). The
main genetic defects detected are at the epigenetic
level: hypomethylation of the imprinting control
region 1 (ICR1) on 11p15 in around 44 % of cases
and maternal uniparental disomy of chromosome
7 (UPD(7)mat) in 5–10 % of cases. The ICR1
abnormality results in biallelic expression of H19
and loss of IGF-2 expression in pathologic cells.
Fetal Alcohol Syndrome
Fetal alcohol syndrome leads to IUGR and is
associated with microcephaly, short palpebral
fissure, epicanthal folds, small jaws and short
philtrum of the lip, cardiac defects, and delay in
mental development.
Abnormalities of Growth
Syndromes of Obesity and Short
Stature
Other syndromes combine short stature and obe-
sity, a combination that should awaken concern
over an organic etiology for short stature, as
patients with otherwise uncomplicated obesity
are usually tall for age unless they also have con-
stitutional delay.
Prader–Willi Syndrome
The Prader–Willi syndrome (#176270 PRADER-
WILLI SYNDROME; PWS—due to deletion or
maternal uniparental disomy of 15q11.2-q12) is
manifested by poor weight gain in infancy and
early childhood because of poor neonatal feeding
caused by diminished swallowing and sucking
reflexes. This condition is followed by insatiable
polyphagia and rapid weight gain occurring after
1 year, leading to obesity. Other features include
narrow bitemporal head dimension, almond-
shaped eyes, strabismus, myopia, thin upper lip,
down turned corners of mouth, viscous saliva,
hypoventilation and hypoxia, hypogonadotropic
hypogonadism (HH), cryptorchidism, small
penis and scrotum, hypoplastic labia, amenor-
rhea, and limb and skeletal abnormalities includ-
ing scoliosis, kyphosis, osteopenia, small hands
and feet (acromicria), and narrow hands with a
straight ulnar border. CNS abnormalities include
fetal and neonatal hypotonia (such poor fetal
motion leads to the assumption of fetal death by
pregnant mothers in some cases), developmental
delay, behavioral problems, sleep disturbances,
hyporeflexia, articulation difficulty, skin and scab
picking, and high pain threshold.
GH therapy is approved for PWS, and caution
in its use is important as fatal respiratory failure
has developed in some treated patients (see Chap.
9 and below).
Bardet–Biedl Syndrome
Laurence–Moon syndrome is now combined with
the Bardet–Biedl (#209900 Bardet-Biedl syn-
drome) syndrome with an autosomal recessive
pattern of inheritance. Obesity, short stature,
developmental delay, and retinitis pigmentosum
can be associated with hypogonadotropic
hypogonadism or alternatively hypergonadotropic
73
hypogonadism. Spastic paraplegia, polydactyly,
and other features noted in Chap. 9 are found.
Miscellaneous Syndromes
Numerous syndromes, some including abnormal
karyotypes, will have short stature and often SGA
as one of their characteristics. A complete list of
such conditions is beyond the compass of this vol-
ume, so the reader is referred to a more complete
source such as Smith’s Recognizable Patterns of
Human Malformation in Suggested Reading.
Growth and Attention-Deficit
Disorder
An increasing number of children are treated with
medications for ADHD and its variants. Data from
over 40 years ago demonstrated a decreased growth
rate which may normalize after few years of treat-
ment. Untreated children with ADHD appeared to
grow at a normal rate, so the medication appears to
be the etiology for growth diminished related to
appetite suppression and reduced nutrition.
Remarkable growth retardation associated with sig-
nificant weight loss or failure to gain weight may
occur with the use of this class of medications.
Chronic Disease and Malnutrition
Chronic conditions frequently affect growth,
and any pediatrics textbook will have numerous
etiologies on virtually every page. Chronic
infectious diseases causing diminished growth
include diarrhea, respiratory tract infections,
intestinal parasitic infections, malaria, HIV
infection, schistosomiasis, Cryptosporidium
parvum infection, and Helicobacter pylori
infection. The effects of infectious disease on
growth may be mediated by diminished nutrition
or the effect of inflammatory cytokines.
A chronic disease of any organ system (cardiac,
pulmonary, gastrointestinal, hematologic, renal,
immunologic) can cause growth retardation. Indeed,
the onset of a chronic disease may be indicated by
an inflection point demonstrating a decrease in
growth rate noted on the child’s growth chart; this is
why height must be measured accurately at each
visit. A few examples are highlighted below.
74
Celiac disease occurs in close to 1 % of the
general population, is more frequent in
Caucasians than in other groups, and 7–10 % of
those with type 1 diabetes mellitus have celiac
disease with a rising incidence in the years after
diagnosis. Celiac disease affects growth, pubertal
development, bone growth, and fertility and must
always be considered in undiagnosed short stat-
ure. Crohn’s disease is associated with short stat-
ure. Juvenile arthritis also manifests with short
stature as do other autoimmune disorders with
growth failure.
Many environmental influences (nutrition,
infection, psychosocial stress, food contami-
nants, pollution, and hypoxia) are considered
as proximate factors influencing growth which
interact with culture, behavior, socioeconomic
status, social status, poverty, and political
economy which represent distant effects on
growth. These proximal and distal factors are
superimposed on a genetic endowment for stat-
ure in a manner described as genetics × envi-
ronment. Pollutants reported to affect growth
are low levels of lead (below 25 μg/dL), PCBs,
polychlorinated dibenzofurans, and polychlori-
nated and the effects of aflatoxin contamination
of foods.
IUGR results from prenatal exposure to
cocaine, other drugs of abuse, and cigarettes as
well as alcohol. Environmental influences can
affect pubertal growth as described in Chap. 9.
Malnutrition, a frequent cause of short stature
in the world, may be due to maternal neglect, pov-
erty and lack of available food, neurologic impair-
ment that decreases interest in food or causes
inability to swallow it, malabsorption, or volun-
tary or involuntary decrease in food intake. Serum
IGF-1 may be decreased with any of these condi-
tions, and the unwary diagnostician may incor-
rectly consider that GH deficiency is at fault; in
states of malnutrition or starvation, GH is often
elevated, whereas IGF-1 is decreased, and GH
administration will do no good. On the other hand,
obesity suppresses growth hormone secretion
while IGF-1 levels remain normal. Malnutrition is
the major cause of short stature in the developing
world. Parasite infestation can stunt growth even if
adequate nutrition is available.
5 Disorders of Growth
“Failure to thrive” includes a wide variety of
conditions in which an infant is not growing well.
Usually, the weight is affected before and to a
greater degree than the length or height; this is in
contrast to the effects of hypothyroidism and GH
deficiency where weight for height is maintained
or increased, but growth slows, leading to a chubby
appearance. These infants may have as an etiology
parents inexperienced in feeding infants, aberrant
intrafamilial dynamics, gastric reflux, and many
other chronic conditions found in general pediat-
rics texts. Substantial decrease in BMI is usually
an indication of a nutritional disease rather than an
endocrine problem, although some endocrine con-
ditions (e.g., long-standing hyperthyroidism or the
diencephalic syndrome) can indeed have decreased
weight for height. There is no reason to search for
an endocrine cause of poor growth without first
determining if nutritional status is adequate.
Chronic kidney disease impairs growth through
numerous factors including acidosis, decreased
nutrition, and renal osteodystrophy. Growth post-
transplant improves especially if transplant occurs
before 6 years of age and is increased with
decreased use of growth-suppressing immunosup-
pressive agents such as glucocorticoid therapy.
Growth rate increases with GH treatment as chronic
kidney disease is an FDA-approved use of GH.
Cystinosis (#219800 ICD+ CYSTINOSIS,
NEPHROPATHIC; CTNS) is an autosomal
recessive disorder due to a mutation in the cysti-
nosin gene (CTNS) in which there is defective
cystine transport from lysosomes to the cyto-
plasm. This leads to membrane-bound cystine
crystal accumulation leading to impairment of
various organs, particularly kidneys where renal
tubular Fanconi syndrome develops causing
polyuria, polydipsia, dehydration, urate and cal-
cium oxalate calculi, acidosis, and hypophos-
phatemic rickets. Besides impacting postnatal
growth, cystinosis is associated with primary
hypothyroidism, insulin-dependent diabetes
mellitus due to pancreatic insufficiency, and
delayed puberty due to primary gonadal failure.
Other features of cystinosis include impairment
of the eyes (photophobia, peripheral retinopa-
thy, decreased visual acuity, corneal crystals,
recurrent corneal erosions), hepatomegaly, and
Abnormalities of Growth
splenomegaly. Laboratory features include pro-
teinuria, glucosuria with normal blood glucose,
hyponatremia, hypokalemia, carnitine defi-
ciency, hypophosphatemia, generalized amino-
aciduria, microscopic hematuria, and elevated
white blood cell cystine. Various neurological
defects develop.
Endocrine Causes of Short Stature
Congenital Growth Hormone Deficiency
Congenital GH deficiency occurs more fre-
quently than one might expect as estimates range
to 1 in 3,500 children. When acquired GH defi-
ciency (such as that caused by head and neck irra-
diation used to treat children with cancer) is
added to the equation, the condition is even more
common. GH deficiency must always be consid-
ered as a possible etiology in a patient with
growth failure and no other identified cause.
Congenital GH deficiency does not strongly
affect fetal growth, as the child has a near-normal
birth length (GH receptors are normally decreased
in fetal life compared to postnatal life limiting the
effect of GH in fetal life), although a minor
decrease in birth size may occur. Soon after birth,
however, careful observation will indicate an
abnormally low growth rate on careful measure-
ments, and plotting an accurate growth chart will
demonstrate this finding. The patient will be
obviously short for age by 2–4 years, and the
diagnosis often will be made at this point but can
be made much earlier with careful measurements.
Classic GH-deficient patients will have a cheru-
bic appearance because of their chubbiness. They
will speak with a high-pitched voice caused by
their small larynx but have adequate intellectual
and vocal ability to speak appropriately for
chronologic age. They appear precocious because
their appearance suggests a younger age, but
their speech and abilities suggest an older one.
Male children may have microphallus (stretched
penis length less than 2 cm, which is 2.5 standard
deviations below the mean), especially if there is
associated gonadotropin deficiency (see Chap.
9). Hypoglycemia may occur because of the
absence of the gluconeogenic effects of GH and
the lack of insulin antagonism normally caused
75
by GH. If adrenocorticotropic hormone (ACTH)
also is absent, more profound hypoglycemia is
possible (cortisol also stimulates gluconeogene-
sis and opposes insulin action), and in either situ-
ation, hypoglycemic seizures may occur. The
combination of hypoglycemic seizures and nor-
mal birth length without a history of complica-
tions of the birth process should alert the observer
of the possibility of neonatal hypopituitarism; if
the patient is a boy with microphallus, the diag-
nosis is even more likely. Midline defects ranging
from cleft palate to encephalocele are associated
with congenital hypopituitarism. Optic hypopla-
sia (not atrophy which occurs at an older age)
with any degree of visual impairment, usually
associated with pendular or horizontal nystagmus
(to and fro without any predominant direction), is
a classic indication of associated congenital
hypopituitarism. Absence of the septum pellu-
cidum is found in about 50 % of patients with
optic hypoplasia and pituitary impairment, lead-
ing to the diagnosis of septo-optic dysplasia
described below. Thus, if there is diminished
vision in association with hypoglycemia and, in a
boy, microphallus, the diagnosis of hypopituita-
rism is more likely. If hypoglycemia is apparent
and not adequately treated, developmental delay
may be the outcome instead of the usually normal
intellect found in children with GH deficiency.
Hypoglycemia in the newborn period due to GH
or cortisol deficiency requires a lower glucose
infusion rate to maintain (less than 10 mg/kg/
min) than states of insulin excess (often more
than 12–15 mg/kg/min) to maintain normal blood
sugar (see Chap. 12).
Breech delivery occurs in greater prevalence
in patients with congenital hypopituitarism, espe-
cially in boys. Any type of birth trauma may
increase the risk of congenital hypopituitarism.
Isolated GH Deficiency
Idiopathic, isolated GH deficiency is the most
common diagnosis. However, familial GH defi-
ciency may occur in autosomal recessive or dom-
inant patterns or in an X-linked pattern due to
mutations in the gene for GH or for pituitary
development. Decreased hypothalamic GHRH
action due to a mutation of the GHRH receptor
76
gene (*139191 GROWTH HORMONE-
RELEASING HORMONE RECEPTOR;
GHRHR) is autosomal recessive (#262400
ICD+ISOLATED GROWTH HORMONE
DEFICIENCY, TYPE IA; IGHD1A), while a
loss of function mutation in the GH gene
(#612781 ISOLATED GROWTH HORMONE
DEFICIENCY, TYPE IB; IGHD1B) is autoso-
mal dominant. GH deficiency with hypogamma-
globulinemia is inherited in an X-linked pattern
(#307200 ICD+ISOLATED GROWTH
HORMONE DEFICIENCY, TYPE III; IGHD3).
With GH treatment and therefore exposure to GH
for the first time in a patient lacking the growth
hormone gene GH antibodies may develop and
eliminate the effects of GH treatment on growth.
The Growth Hormone Research Society uses
hypoglycemia, prolonged jaundice, microphallus,
or traumatic delivery and craniofacial midline
abnormalities as findings that should awaken con-
cern about neonatal growth hormone deficiency.
Combined Pituitary Defects
Congenital defects of the CNS may be associated
with single hypothalamic–pituitary defects or
more commonly multiple deficiencies.
Septo-optic dysplasia (#182230 SEPTOOPTIC
DYSPLASIA at 3p21.2-p21.1, which may be due
to a mutation of the homeobox gene HESX1) or
the appearance of small, pale optic disks is asso-
ciated with impaired vision ranging from mild
defects to blindness and is often found with hori-
zontal or pendular (to and fro) nystagmus. Optic
hypoplasia is to be differentiated from optic atro-
phy which may be an ominous signs of a tumor
causing the degeneration of a previously nor-
mally formed optic disk. About 50 % of patients
with optic dysplasia have absence of the septum
pellucidum. A prospective study of 47 children
with septo-optic dysplasia found hormone defi-
ciencies in 71.7 % with 64.1 % of subjects having
GHD, 48.5 % with hyperprolactinemia, 34.9 %
with central hypothyroidism, 17.1 % with central
adrenal insufficiency, and 4.3 % with central
diabetes insipidus (DI). There was a significant
risk of obesity. Endocrine defects are not univer-
sal but should be considered in all patients with
septo-optic dysplasia (see Chap. 9).
5 Disorders of Growth
Other midline defects of the central nervous
system associated with pituitary deficiencies
range from a simple cleft palate (6 % have growth
hormone deficiency) up to holoprosencephaly or
anencephaly. A single maxillary incisor is associ-
ated with pituitary dysfunction (see below).
Rarely patients have absent anterior pituitary
glands and therefore no somatotrophs. Loss of
ACTH function leads to a potentially fatal adrenal
failure when untreated. However, most patients
with congenital hypopituitarism are less strik-
ingly affected. Hypopituitarism due to a defect in
the LHX1 gene (#262600 PITUITARY
DWARFISM III at 9q34.3) leads to loss of GH,
prolactin (Prl), luteinizing hormone (LH), and
follicle-stimulating hormone (FSH) and thyroid-
stimulating hormone (TSH) in an autosomal
recessive pattern associated with severe restric-
tion of head rotation. Mutation of PROP-1
(*601538 PROPHET OF PIT1, PAIRED-LIKE
HOMEODOMAIN TRANSCRIPTION
FACTOR; PROP1 at 5q) causes GH, gonadotro-
pin, and TSH deficiency and more rarely, ACTH
deficiency, which may develop later; affected
patients must be monitored for the late onset of
the serious additional complication of ACTH
deficiency. Mutations of POU1F1 (PIT *173110
POU DOMAIN, CLASS 1, TRANSCRIPTION
FACTOR 1; POU1F1 at 3p11) cause deficiency in
GH, TSH, and Prl.
GH Resistance
GH resistance is indicated by elevated GH with
decreased serum IGF-1. The first described form
of hereditary GH insensitivity, Laron dwarfism
(#262500 pituitary dwarfism II at 5p13-p12), is
due to an absence of receptors for GH, and serum
GHBP is low as a reflection of absent GH recep-
tors. The pattern is autosomal recessive. Other
forms of GH resistance have postreceptor defects,
so that serum GHBP is normal. Affected patients
cannot respond to GH administration with
increased growth or increased IGF-1 concentra-
tions; patients do respond to IGF-1 administra-
tion with increased growth, and this is the only
modality that will be effective. In this syndrome,
puberty is delayed, the forehead is prominent,
sclerae are blue, and dentition is delayed. This is
Abnormalities of Growth
an autosomal recessive condition; the GHR gene
is mapped to 5p13-p12 (*600946 GROWTH
HORMONE RECEPTOR; GHR). Less severe
mutations of the GHR appear to lead to short stat-
ure of a moderate nature.
Children resistant to GH are now considered
to have severe primary IGF-1 deficiency, char-
acterized by unresponsiveness to GH in IGF-1-
producing tissues. This is the indication for the
use of IGF-1 (rhIGF-1 or mecasermin) therapy
which is approved by the FDA for clinical use.
Since some children with ISS do not have
excellent growth response to GH, some suggest
that these may benefit from IGF-1 treatment
even without a specific FDA-approved indica-
tion. Other clinical researchers suggest that the
combination of GH and IGF-1 will lead to a
greater response than IGF-1 alone in selected
patients. rhIGDF-1 therapy is given twice per
day subcutaneously. Hypoglycemia is a risk of
therapy, and a snack or meal must accompany
the dose within 20 min or the dose must be
omitted. If hypoglycemia persists, the dose
must be decreased.
Pygmies (#265850 PYGMY) are individuals
in Africa, Philippines, and other geographic
locations that have normal GH concentrations
and normal IGF-1 but very low IGF-2 concentra-
tions; defects in the functioning of IGF-1 recep-
tors are reported to be major influences on their
poor growth in some. Because the population is
described with nutritional deficiencies as well as
the genetic defect, multiple causes of short stat-
ure may exist, but IGF-1 receptor defects are
found by some but not all investigators.
Biologically inactive GH (#262650 KOWARSKI
SYNDROME or biologically inactive GH.
PITUITARY DWARFISM IV) is postulated as a
cause of growth failure with normal serum GH
concentrations as measured by radioimmunoas-
say but poor growth; growth rate increases with
administration of exogenous GH, even though
the endogenous GH appears ineffective. The
prevalence of affected patients is unknown; auto-
somal recessive inheritance is suggested. Partial
GH deficiency appears to be a more common
explanation for this condition in many cases and
is represented by subjects who have adequate
77
GH secretion on testing but respond to GH
administration with increased growth.
Mutations of the ALS gene (+601489
INSULIN-LIKE GROWTH FACTOR-BINDING
PROTEIN, ACID-LABILE SUBUNIT; IGFALS)
will hamper growth and delay puberty. The main
genetic defects detected are at the epigenetic
level: hypomethylation of the imprinting control
region 1 (ICR1) on 11p15 in around 44 % of
cases and maternal uniparental disomy of chro-
mosome 7 (UPD(7)mat) in 5–10 % of cases.
There is a poor growth response to GH treatment
and low levels of plasma IGF-1 and IGFBP3; the
growth failure is milder than expected with the
low IGF-1 and IGFBP3.
A rare cause of growth failure is a mutation in
the insulin-like growth factor I gene (#608747
INSULIN-LIKE GROWTH FACTOR I
DEFICIENCY) described in an autosomal reces-
sive pattern. Besides growth failure, delayed bone
age, and a thin appearance, other characteristics are
intrauterine growth restriction and SGA, micro-
cephaly, micrognathia, sensorineural deafness,
deafness, ptosis, osteopenia, clinodactyly, delayed
motor development with developmental delay in
general, hyperactivity, and short attention span.
This condition should respond to IGF-1 therapy.
Another rare condition in children with
growth failure is a mutation of the IGF-1 receptor
(#270450 INSULIN-LIKE GROWTH FACTOR I,
RESISTANCE TO) found in an autosomal domi-
nant or autosomal recessive pattern. Characteristic
features besides growth failure, delayed bone age,
and a thin appearance are intrauterine growth retar-
dation and SGA, microcephaly, facial abnormali-
ties including receding hairline, long smooth
philtrum, broad nasal bridge, thin upper lip, fleshy
lower lip as well as pectus excavatum, wide-set
nipples, clinodactyly, delayed motor development,
speech delay, anxious affect, obsessive tendencies,
and agitation. Insulin-like growth factor 1 values
are elevated with growth hormone values either
normal or elevated.
Acquired GH Deficiency
Abnormalities of the central nervous system.
These conditions can be devastating or fatal and
are prime examples of why the diagnosis of the
78
etiology of acquired short stature must be care-
fully established. Abnormalities of puberty may
be caused by many of these same conditions so
making diagnosis equally important when puberty
is affected (longer discussion found in Chap. 9).
Central nervous system tumors. Acquired growth
failure is an ominous sign since it may be due to
a CNS tumor. If both anterior and posterior pitu-
itary deficiencies are noted, a central nervous
system tumor should be even more highly sus-
pected. To reemphasize, late onset of growth
failure or a cessation of pubertal development
that has already started is of great concern.
Central Nervous System Tumors
Craniopharyngiomas occur with a peak incidence
between 6 and 14 years of age. Patients may be
asymptomatic or symptomatic with complaints of
headache, visual loss, polyuria, and polydipsia.
Signs on physical exam may be either short stature
or cessation of previously normal growth, findings
of hypothyroidism, and sexual infantilism.
Papilledema or optic atrophy (not congenital optic
dysplasia) might be found as well. Pituitary calcifi-
cations may be found on a radiograph taken for
other reasons such as orthodontic evaluation. CT
scans will show flecks of calcium within the tuber
cinereum in more than 80 % of cases. MRI scans
before and after gadolinium will define the shape
and size of the tumor better although it will not
show calcification unless susceptibility weighted
imaging is used. This tumor might be cystic, and
the sella turcica may be eroded by expansion of the
tumor. Transsphenoidal microsurgery can be used
for extirpation if the tumor is intracellular. Larger
tumors that cannot be completely removed by this
method may be treated with radiation as the tumors
are radiosensitive with a combination of surgery
and radiation usually recommended. Late effects
of radiation are possible with CNS irradiation,
however, such as secondary tumors of local tissue.
Other tumors of the central nervous system
reside outside of the sella turcica such as germino-
mas of the pineal, which by their mass may affect
growth. Astrocytomas and gliomas (which may or
may not be associated with neurofibromatosis) are
other CNS tumors that may cause growth failure.
5 Disorders of Growth
Other Conditions
Histiocytosis X may be associated with diabetes
insipidus, but other hypothalamic hormones may
also be deficient and HH can occur. Granulomas
of tuberculosis, rare nowadays, or sarcoidosis,
postinfectious inflammation, or vascular lesions
of the central nervous system can impair hypo-
thalamic pituitary function. CNS trauma due to
accidents, child abuse, or surgery for tumors near
the area can also affect hypothalamic pituitary
gonadal function. Hydrocephalus can cause GH
deficiency as may any other etiology of increased
intracranial pressure.
Oncofertility is a new field growing out of the
increasing number of cancer survivors following
successful treatment who show late effects of
treatment. Radiation treatment may cause growth
hormone deficiency or gonadotropin deficiency
but also, when used to treat a central nervous sys-
tem tumor, may lead to a combination of preco-
cious puberty and growth hormone deficiency.
The growth hormone deficiency will not be dem-
onstrated by extremely slow growth if the puberty
is progressing rapidly as the sex steroid secretion
stimulates growth masking the GH deficiency
(read below). Long-term follow-up of children
treated with CNS irradiation for leukemia dem-
onstrated atrophy of the pituitary gland or empty
sella 10–40 years later.
Psychosocial Dwarfism
Psychosocial dwarfism (also known as psychoso-
cial short stature and sometimes grouped with
hyperphagic short stature) may occur in one child
among several other normal siblings. Abnormal
parent–child interaction leads to functional hypo-
pituitarism with GH deficiency on provocative
testing; GH secretion will revert to normal within
days after removal from the offending situation.
Affected children have a pot-bellied, immature
appearance. They may exhibit aberrant behavior
such as drinking from toilet bowls, begging for
food from neighbors, and foraging for food in
garbage cans, in spite of apparently acceptable
caloric intake at home. These patients may have
had psychological abuse but rarely have signs of
physical abuse. When removed from their homes,
Abnormalities of Growth 79

Complete history and physical with careful measurement of height and weight

height is below the 3rd percentile on the CDC growth charts or is below the 5th percentile for corrected midparental height or growth rate is below the 5th percentile
Yes No

BMI is low probably normal variation; reassurance is best approach

No Yes

historical feautures of chronic disease or malnutrition evaluate for nutritional problem before embarking upon endocrine evaluation
No Yes (although some endocrine conditions such as diencephalic syndrom may still be possible)

physical features compatible with syndrome of chondrodystrophy

No Yes
chemistry panel, cbc, sed rate normal
Yes No

free T4 and TSH normal calcium low and phosphorous high

Yes No Yes No

history or celiac panel compatible with celiac disease evaluate for hypothyroidism evaluate appropriately
No Yes
evaluate for pseudohypoparathyroidism by measuring serum PTH
IGF-1 and IGFBP3 normal
GI consult with possible small bowel biopsy
No Yes

re-evaluate nutritional status with dietary evaluation

adequate nutrition abnormal

perform GH stimulation test rectify

peak is low normal

GH deficiency; still possibly responsive to GH; individualize approach

likely response
to GH treatments MRI of Hypothalamus ⁄ pituitary to search for etiology

Fig. 5.12 The basic evaluation of short stature. Referred to the text for suggestions of detailed diagnostic procedures
and gene defects

such children may exhibit catch-up growth in effective than wished. Some patients respond to
foster homes or in the hospital, environments GH treatment without demonstrating classic GH
where one would not expect a child to thrive. deficiency; most of these more subtle indications
Even if psychotherapy is administered for pro- are beyond the range of this text, as all short stat-
longed periods, the outcome is uncertain. Growth ure conditions requiring GH treatment are best
hormone is not an appropriate treatment for psy- diagnosed and certainly treated by a pediatric
chosocial dwarfism however. endocrinologist.
Maternal deprivation (perhaps a sexist term, Classic GH deficiency is defined by the inabil-
but as the mother usually is responsible for feed- ity to increase GH concentration above an
ing the child, an often-used term) is the diagnosis accepted limit, generally 10 ng/mL in most labo-
applied to infants with poor growth rates due to ratories (although certain assays are more sensi-
parental neglect. These children may have actual tive, and lower cutoff of normal levels is used)
caloric deprivation in addition to psychological after two stimulatory tests. This limit is arbitrary
neglect. The term also is applied to situations in and is higher than values used in previous
which the mother is inexperienced in child- decades. Further, prepubertal children may not
feeding practices in which education can provide respond as well as pubertal children to GH stimu-
marked improvement. latory tests, so that different standards may be
These conditions are often grouped into the useful at different ages (according to published
term “nonorganic failure to thrive.” studies), but such standards for stimulated tests
are not available from commercial laboratories.
Diagnosis of Growth Hormone Deficiency To standardize the responses before and after
(Fig. 5.12) puberty, some investigators suggest priming the
The diagnosis of GH deficiency has become prepubertal child with a dose of estrogen or pro-
more complex with increased knowledge of GH pranolol (propranolol can precipitate hypoglyce-
physiology. The dividing line between classic, mia and should not be used if hypoglycemia
severe GH deficiency and normal GH secretion is (or asthma) is already present). As mentioned,
blurry as our classic tests have proven less the measurement of a single sample for basal GH
80
concentrations is useless in the diagnosis of GH
deficiency but may be helpful in GH resistance.
Secretagogues invoked in the testing for GH
deficiency are given early in the morning after an
overnight fast (hypoglycemic patients should not
be forced to fast unobserved, so the test must be
modified!). Two tests are usually performed
because 30–50 % of normal children can fail to
increase GH concentration after one test; how-
ever, two tests yield a false positive (failure of a
normal child to reach the normal limit of serum
GH) more than 10 % of the time. Hypothyroid
individuals will not respond normally to GH
secretagogues, and hypothyroidism is much more
common than GH deficiency; thyroid status must
be tested before GH testing.
Several pharmacologic tests are commonly
invoked as secretagogues. L-Dopa is used in doses
of 125 mg for body weight up to 15 kg, 250 mg
for weight up to 35 kg, and 500 mg for body
weight over 35 kg; samples are taken at 0, 30, 60,
and 90 min. Nausea and vomiting are possible
side effects for a few hours after administration.
Clonidine in a dose of 0.1–0.15 mg/m2 can be
given and samples obtained at the same time
sequenced; side effects are possible hypotension
and lethargy for several hours, so we prefer the
lower range of dosage. Since it may be dangerous
to have emesis while sleeping, usually the L-dopa
test is performed before the clonidine test.
Intravenous arginine infusion of 0.5 g/kg body
weight up to 20 g over a 20-min period can be
given with samples taken at the same time peri-
ods as mentioned earlier; no side effects are
likely. A glucagon stimulation test may be accom-
plished with the IM administration of a dose of 30
μg/kg glucagon (maximum 1 mg) and collecting
GH samples at 0, 30, 60, 90, 120, 150, and 180
min afterwards; nausea and hyperglycemia are
the side effects. Insulin-induced hypoglycemia
(0.075–0.1 U/kg body weight of insulin given
i.v.) is an effective but extremely dangerous test;
the patient must be shown to have a normal fast-
ing blood sugar just before the test and must not
have a known tendency toward hypoglycemia, a
working i.v. line must be available to infuse dex-
trose should a hypoglycemic seizure occur, and
the patient must be watched carefully by a physi-
5 Disorders of Growth
cian during the test. The patient will be extremely
uncomfortable during the hypoglycemia that
results. Glucose and GH should be measured at 0,
15, 20, 30, 60, and 90 min. Cortisol may be mea-
sured at 60 and 90 min if this test is performed to
test ACTH reserve as well as GH secretion. If
severe hypoglycemia occurs, dextrose must be
administered immediately; no greater concentra-
tion than 25 % dextrose at 1 mL/kg should be
infused so that blood sugar will increase but no
severe change in osmolality will occur. Growth
hormone-releasing factor (GHRH) is not com-
mercially available for testing and offers little
improvement in testing over the other regimens.
(When it was administered in a dose of 5–10 μg/
kg, serum GH concentrations increased in normal
individuals.) GH-deficient patients demonstrate
either no increase in GH or a blunted increase to
secretagogues. Those with a pituitary defect have
no response, whereas those with a hypothalamic
defect may respond partially.
Nonpharmacologic tests are available in addi-
tion to the stimulatory tests. After 10 min of vig-
orous exercise, normal children will increase
their GH in 80 % of trials. Sequential serum
samples may be taken at night in the hope that
the peak that customarily occurs 90 min after the
onset of sleep may be captured, but this method is
expensive and inconvenient. Sampling for GH
levels every 10–15 min for 24 or 12 h has been
suggested as a way to determine whether a nor-
mal circadian rhythm of GH secretion is present;
the facilities for such a study are generally
unavailable.
Due to remarkable lack of reliability in labora-
tory testing of GH secretion, results must be
interpreted in view of anthropomorphic growth
data to make the diagnosis of GH deficiency. The
addition of measurement of IGF-1 improves
accuracy however.
Plasma IGF-1 concentrations must be inter-
preted with caution. Low values may mean mal-
nutrition rather than GH deficiency; in
malnutrition, GH values usually increase, and
IGF-1 values decrease because GH receptors
decrease. In delayed puberty, values are more
appropriate for bone age than for chronologic age
and may be incorrectly interpreted as abnormally
Abnormalities of Growth
low in such a situation; thus a 14-year-old with an
11-year-old bone age who has an IGF-1 value
inappropriate for a 14-year-old but appropriate
for an 11-year-old is likely normal. While IGF-1
assays can be helpful, their accuracy is called into
question. The measurement of IGF-BP3 in addi-
tion to IGF-1 may add accuracy to the diagnosis
of GH deficiency especially in those under 3
years or in malnutrition.
Growth Hormone Treatment of GH Deficiency
and Other Disorders Approved for GH
Treatment
The treatment of GH deficiency is accomplished
by the use of biosynthetic recombinant DNA-
derived GH. Previously, cadaver-donated
pituitary-derived GH was administered, but the
recognition that some batches were contaminated
with the prions of Creutzfeldt–Jakob disease
(CJD) led to the discontinuation of such therapy
in 1983–1985 and the switch to recombinant-
derived GH; it is possible that some children
treated before that date will still develop CJD as
cases were reported as late as 2014. Biosynthetic
GH is available with the 191-amino acid sequence
of the natural GH molecule from many compa-
nies. Daily subcutaneous injections are adminis-
tered in doses starting at about 0.18–0.3 mg/kg/
week given 6 or 7 days/week; about twice this
dose is approved during puberty as there is higher
endogenous GH release during puberty in normal
individuals. Dosage is prescribed related to
weight and titrated to the growth response. The
aim is also to maintain plasma IGF-1 values in
the normal range for safer dosing and to theoreti-
cally reduce the risk of development of neoplasm
or other comorbidities from this mitogenic medi-
cation. IGF-1 values are expressed in terms of Z
scores which indicate the number of standard
deviations above or below the mean. It is sug-
gested that if IGF-1 concentrations are consis-
tently more than a 2.5 z score or SDS above the
mean, GH dose should be decreased.
Syringe-and-needle administration of either
premixed solutions of GH or lyophilized prepara-
tions that must be reconstituted has been replaced
by the use of mechanical pens that use cartridges
of premixed GH, and even needleless devices are
81
available. A new long-acting preparation is said to
be available soon.
GH is presently indicated for GH-deficient
patients, Turner syndrome (see Chaps. 8 and 9),
growth failure of renal insufficiency, Noonan syn-
drome, SHOX gene deletion either in Leri–Weill
syndrome with one missing SHOX allele or
Langer syndrome, SGA, and uncomplicated ISS.
GH is approved for use in children with Prader–
Willi syndrome for short stature, but it is the meta-
bolic effects and improvement of muscle tone in
which it exerts its most important effects; respira-
tory compromise however is a contraindication to
GH therapy as GH can worsen respiratory obstruc-
tion through soft tissue enlargement in these chil-
dren, and only after establishing adequate
respiratory function should GH be initiated in
Prader Wili. Since respiratory fatalities are more
likely in the first 9 months of treatment, it is rec-
ommended that the dose of GH be started at about
½ the standard dose and increased over the first
few months.
GH is used illicitly in numerous ways. Athletes
and weight lifters obtain GH by unscrupulous
providers to increase muscle strength, but no ben-
efit has been proven in these conditions (at least
with standard doses which are likely considerably
lower than illicit doses). GH treatment of adults
with severe GH deficiency is indicated to main-
tain bone density and improve skin, muscle con-
dition mood, and memory. While GH is indicated
in the treatment of adults with bona fide GH defi-
ciency, the use of GH in the general treatment of
aging without a diagnosis of GH deficiency is
used in unscrupulous antiaging clinics. The
Growth Hormone Research Society recently
reviewed all data and stated, “the clinical use of
GH or GHS (growth hormone secretagogues) in
older adults, alone or in combination with testos-
terone, cannot be recommended.”
The FDA approved GH for therapy in children
with ISS, and a height SDS −2.25 (<1.2 %) that is
associated with a growth rate unlikely to permit
attainment of adult height in the normal range, in
pediatric patients whose epiphyses are not closed
and for whom diagnostic evaluation excludes
other causes associated with short stature that
could be observed or treated by other means.
82
Consensus guidelines state that this can be
considered if the height ranges from −2 SDS to
−3 SDS with best effects if GH is started between
5 years and early puberty. Randomized control
studies are scarce, but a recent review summarized
that with a mean age at start of treatment of 10
years, mean duration of GH therapy was 5.4 years
(average duration of treatment 4–7 years); the
mean difference between treated and untreated
children was approximately 5.5 cm (3.5–7.5 cm).
The mean adult height achieved after GH therapy
at conventional dosages was −1.5 SDS. Better
results occurred with early age at onset of ther-
apy, higher GH dose, greater birth length, and
more delay in bone age. Also, children whose
parents were of normal height gained more than
those with familial short stature. The mean adult
height was increased 0.7 SD in treated children.
Often the referral for short stature occurs too late,
when the effect of GH is far less since the bone
age is more advanced. It is important to realize
that with annual costs of $20,000–40,000 per
year for growth hormone, a mean gain of 1 in.
means an expenditure of $52634. Some may
wonder if the child might be happier with the
money rather than the treatment. Indeed there is
preliminary data suggesting that children with
ISS and GHD become progressively less happy
with treatment and clinic visits compared to typi-
cal untreated children.
Complications of GH treatment are rare but
include a tendency toward slipped capital femoral
epiphyses, and patients must be asked about hip
and leg pain or the development of a waddling gait;
the treatment is surgical. Pseudotumor cerebri is
rare but may cause a severe headache along with
papilledema: although it should be reversible, if it
is allowed to continue, impairment or loss of vision
may result from effects on the optic nerve.
Hypothyroidism may develop during GH therapy,
and a free T4 and TSH value should be obtained
annually or if growth rate decreases. Development
of antibodies to GH is less a problem with the use
of human sequence GH but should be considered if
a patient ceases to grow as expected while receiv-
ing therapy with GH. Type 2 diabetes is theoreti-
cally possible due to the insulin resistance caused
by GH therapy but rarely occurs. Indeed, obesity
5 Disorders of Growth
decreases GH levels in basal and stimulated states,
leading to a suggestion of true GH deficiency.
Obesity is related to type 2 diabetes in genetically
susceptible individuals; the evaluation of an obese
patient appearing to have coexisting GH deficiency
and type 2 diabetes may be difficult although most
children with obesity will tend to have taller-than-
average stature so the question may not arise.
GH therapy in Turner syndrome utilizes a
higher dose (0.375 mg/kg/week) than in GH defi-
ciency (up to 0.3 mg/kg/week in prepuberty).
Treatment may be more beneficial if started before
2 years of age. Oxandrolone, a non-aromatizable
androgen (0.05 mg/kg/day), is reported to increase
adult height, but liver function must be monitored
and observation for virilization is necessary
according to a study in toddlers. Concerns arose
that while estradiol administration may improve
age-appropriate appearance, it may decrease adult
height. Data from a multidecade study of low-
dose estrogen started at age 12 combined with GH
started as young as 5 years suggests that this com-
bination may increase growth rate safely. Side
effects of GH therapy are reported at a higher
prevalence in Turner syndrome including type 2
diabetes mellitus and scoliosis, so close observa-
tion is necessary.
There are studies of the use of GnRH agonists
to delay pubertal development and thereby allow
the period of growth to continue; some studies use
combined GH and GnRH. An evidence-based
review found no convincing evidence that this
treatment is effective and it is not recommended.
Aromatase inhibitors stop the conversion of
androgens to estrogens by aromatase, and it is
estrogen that advances bone age and ultimately
causes cessation of growth. Letrozole and anas-
trozole have been successfully used in boys with
constitutional delay to allow a taller adult height
achievement. Testes may become much larger,
and testosterone may rise substantially during
therapy. Side effects are few but may include
abnormalities in the shape of vertebrae.
Theoretically, adult bone density could be
decreased, but there is no proof of this concern at
present. This is not an approved therapy and must
be considered experimental and only to be used in
controlled studies at present.
Abnormalities of Growth
Recently, French researchers released data
from a large ongoing prospective study and
reported increased prevalence of bone cancer and
cardiovascular and CNS vascular disorders in
young adults previously treated with GH as teen-
agers and younger. Review of the records of other
European countries showed no such findings, so
the explanation for this unusual set of data was
not clear, and reanalysis of the statistics indicated
that these conclusions cannot be supported. At
the time of this writing, a second paper from this
group linking GH treatment with hemorrhagic
stroke in early adulthood was released. While it is
considered a good study, methodological issues
are raised, but the cause and effect of GH treat-
ment and stroke remain to be established. It is
recommended that patients and families be noti-
fied of these possibilities as they decide upon
therapy. The FDA is presently investigating these
data, but findings have not changed clinical prac-
tice in the USA and the FDA has not suggested
GH use change from the standard manner.
Controversy exists over the negative psycho-
logical effects of short stature. There is a great
need for robust scientific study of these effects
rather than relying on common stereotypes that
short stature diminishes quality of life. Further, it
is the patients who are brought for evaluation
who are usually studied rather than the children
in the community with short stature who do not
come to medical attention. Nonetheless, psycho-
logical support should be least considered for a
short child whether or not medical therapy is
offered. Parents should be counseled against
thinking that the fact that their child is shorter
than average is a tragedy and that therapy is
required at all costs. In view of the constant bom-
bardment by the media that leadership, friend-
ship, and indeed the company of the opposite sex
require tall stature (at least in boys), some boys
(and some girls) may become depressed; the
most severe of these tendencies are rare, but the
physician must be sensitive to such a possibility.
If the child’s parents are shorter than average and
unhappy about it, they may tend to read into the
child’s future the unpleasant experiences they
had, which may not, after all, directly reflect on
their height. Children should be counseled toward
83
sports that will realistically allow success and
foster self-confidence; for example, soccer is
more appropriate than basketball, and martial arts
classes can lead to greater self-confidence in an
insecure shorter child. The ultimate psychologi-
cal outlook of a short child may result, in large
part, from the manner in which the child was
approached by family, teachers, peers, and physi-
cians during the early years.
Children diagnosed with GH deficiency may
later develop other pituitary deficiencies such as
ACTH deficiency even if it is not found at initial
evaluation. Thus every child with diagnosed GH
deficiency should be monitored at intervals for
ACTH deficiency. Likewise, GH treated children
should be monitored for the development of
hypothyroidism annually.
Other Endocrine Disorders
Other Endocrine or Syndromic
Conditions
Hypothyroidism
Hypothyroidism will decrease the growth rate
and retard skeletal development. Most children
with congenital hypothyroidism will be diag-
nosed with neonatal screening procedures, but
acquired hypothyroidism is still a frequent occur-
rence in later childhood and adolescence (see
Chap. 6). It is quite unfortunate if a hypothyroid
patient who can be easily treated with inexpen-
sive pills is considered inappropriately for GH
therapy, but this author has seen this situation.
Cushing Syndrome
Cushing syndrome refers to excess glucocorti-
coid exposure from endogenous or exogenous
sources. Topical and even inhaled preparations of
glucocorticoid can retard growth and must be
considered a potential cause of decreased growth
(see Chap. 10). The decreased growth in Cushing
syndrome is generally considered due to sup-
pressed growth hormone secretion through
increased somatostatin secretion.
Pseudohypoparathyroidism
Pseudohypoparathyroidism type 1A (#103580
ICD+PSEUDOHYPOPARATHYROIDISM,
84
TYPE IA; PHP1A) with resistance to PTH is
accompanied by Albright’s hereditary osteodys-
trophy, a chubby appearance, short stature, short
fourth metacarpals, round face, and developmen-
tal delay. Hypocalcemia and hyperphosphatemia
can be treated with 1,25 OH vitamin D therapy,
but the poor growth will remain (see Chap. 7).
Some patients demonstrate GHRH resistance.
Rickets
Rickets is making a comeback in the developed
world due to lack of or inconsistent vitamin D
supplementation of breast-fed infants (there is
inadequate vitamin D in breast milk) who are
shielded from sunlight (e.g., in the developing
world due to cultural practices that cover the skin
or the use of sunscreen to avoid skin cancer);
growth is impaired in nutritional rickets.
Hypophosphatemic rickets is associated with
short stature, and GH treatment was investigated
but not shown to be effective to increase growth
(see Chap. 7). The many genetic forms of rickets
are mostly associated with short stature. Return
to metabolic balance in some forms improves
growth rate.
Diabetes Mellitus
Modern treatment of diabetes mellitus offers
excellent control, but not all patients adhere to
recommended treatment. Growth can be affected
by poor control. In the most severe cases, poor
control leads to Mauriac syndrome with atten-
dant short stature, delayed pubertal development,
and hepatomegaly with abnormal liver function
(see Chap. 11).
Diagnosis of Short Stature
As stated above, the following criteria may be
used as indicators of the need for an evaluation
for disorders of growth:
1. Stature <2.25 SD or 1.2 % (the Pediatric
Endocrine Society uses <2 SD below the mean
for age and gender or 2.3 % for ISS, while the
Growth Hormone Research Society uses <3 SD
below the mean)
2. Height velocity <2 SD below mean for bone
age
5 Disorders of Growth
3. Height corrected for midparental height of
<−2 SD or <2.3 % (the Growth Hormone
Research Society uses <1.5 SD)
4. Signs indicative of an intracranial lesion
including a tumor or trauma
5. Signs of multiple pituitary hormone defi-
ciency (MPHD)
6. Neonatal symptoms and signs of GHD
7. A history of central nervous system radiation
A combination of two or more of these charac-
teristics warrants increased concern (Table 5.2).
A full history and physical examination are
essential for the evaluation of short stature to
reveal genetic or nutritional influences or sys-
temic diseases. Interfamilial interactions can be
observed during the interview process to evaluate
the possibility of psychosocial dwarfism. If no
previous height measurements are available, a
history of changes in shoe or clothing size can be
of value to determine whether the child is grow-
ing adequately, although careful follow-up mea-
surements over at least 3 months (and longer if
possible) are necessary for diagnosis.
History and Physical Examination
In many cases, the diagnosis is apparent from the
medical history. The clinician must query for
abnormalities or toxic exposures of pregnancy,
nutritional status during pregnancy, difficulties of
delivery, and degree of prematurity, if any, and
evaluate weight for gestational age (Fig. 5.1).
Determination of age of puberty of parents (men-
arche in mothers and age of physical changes of
puberty or cessation of growth in fathers) or sib-
lings may suggest a tendency toward constitu-
tional delay in growth or adolescence. Family
history of chronic disease, including neurologic or
endocrine conditions, and the child’s history of
symptoms of chronic disease of almost any organ
can be of great importance, as most chronic dis-
eases can decrease growth. Remember that virtu-
ally every page of a textbook of pediatrics discusses
a condition which can impair growth.
Physical examination must be complete to
search for abnormalities of nutrition, chronic
disease, and neurologic problems, especially of
the central nervous system (CNS). Physical
Abnormalities of Growth
Table 5.2 The evaluation of short stature
Test
CBC
ESR, CRP
Chemistry panel (electrolytes, liver enzymes, BUN)
Carotene, folate, tissue trans-glutaminase antibody, or reflexed
celiac panel
Urinalysis
Karyotype, candidate gene analysis, SNP analysis using
microarrays on DNA chips, array-comparative genomic
hybridization (array-CGH), or other genomic techniques
Cranial MRI imaging
Bone age
IGF-1, IGF BP3
Free thyroxine and TSH
Prolactin
BUN blood urea nitrogen, CBC complete blood count, CRP C-reactive protein, ESR erythrocyte sedimentation rate, IGF
BP3 insulin-like growth factor-binding protein 3, MRI magnetic resonance imaging, TSH thyroid-stimulating hormone
examination begins with the accurate measure-
ment of height, weight, head circumference, arm
span, upper-to-lower segment ratio, and vital
signs. Height and height velocity are plotted on
appropriate charts (see Figs. 5.4 and 5.5). It is
essential to always calculate and plot body mass
index (BMI charts found at www.CDC.com; see
Chap. 12); low BMI for age might indicate mal-
nutrition due to chronic disease, whereas elevated
BMI for age might raise a concern since many
children with obesity have increased stature
while endocrine conditions and various syn-
dromes can lead to obesity and short stature. As a
general rule, endocrine problems slowing growth
tend to be found in heavier (but not necessarily
obese) children rather than thin ones with the
possible exception of hyperthyroidism or
untreated type 1 diabetes mellitus. Signs of dis-
ease or syndromes are evaluated. If decreased
85
Rationale
Anemia: nutritional, chronic disease, malignancy
Leukocytosis: inflammation, infection
Leukopenia: bone marrow failure syndromes
Thrombocytopenia: malignancy, infection
Inflammation of infection, inflammatory diseases,
malignancy
Signs of acute or chronic hepatic, renal, adrenal
dysfunction; hydration and acid-base status
Assess malabsorption; detect celiac disease
Signs of renal dysfunction, hydration; renal
tubular acidosis
Evaluate for genetic syndromes
Assesses hypothalamic-pituitary tumors
(craniopharyngioma, glioma, germinoma) or
congenital midline defects
Determine physiologic maturation, and evaluate
height potential
Reflects growth hormone status or nutrition
Detects hypothyroidism
Elevated in hypothalamic dysfunction or
destruction, suppressed in pituitary disease
nutrition appears to be the problem, an endocrine
condition is less likely, and other causes must be
considered.
If no diagnosis is obvious from history or phys-
ical examination, laboratory evaluation is per-
formed. A screening chemistry panel for liver and
kidney function, a bicarbonate and electrolyte
determination to evaluate the possibility of renal
tubular acidosis or a metabolic acidosis syndrome,
a complete blood count with differential, and a uri-
nalysis including microscopic examination may
indicate a problem not obvious from the physical
examination. A free thyroxine determination and
TSH also are obtained to determine whether hypo-
thyroidism is present. A celiac reflexive panel
which ensures adequate IGA to ensure validity of
the test will determine if unexpected celiac disease
is the etiology of the problem; evaluation of caro-
tene or folate for determination of fat absorption
86
may be considered. A sedimentation rate is used
as a general indicator of inflammation. A bone-age
determination will not lead to a diagnosis (although
it may support several potential diagnoses), but
will indicate the amount of remaining growth, in a
general manner. If obesity complicates short stat-
ure and Cushing syndrome is under consideration
(rare), a urinary free cortisol determination is
obtained or an AM plasma or salivary cortisol after
midnight dexamethasone suppression (see Chap.
10). An elevated serum Prl concentration will sug-
gest hypothalamic deficiency and lack of dopa-
mine suppression; if it is low, it will suggest
pituitary disease.
If neurologic symptoms are noted or if a CNS
tumor is in the differential diagnosis, an MRI eval-
uation with gadolinium contrast of the hypotha-
lamic–pituitary area is in order. It is essential that
thin cuts be ordered and taken through the hypo-
thalamic–pituitary area on the MRI so that a small
tumor or congenital abnormality is not missed.
Suspected congenital GH deficiency also
requires an MRI to determine possible CNS
developmental abnormalities. Small or absent
pituitary glands, ectopic pituitary location, and
interruption of the pituitary stalk are found in
some congenital abnormalities associated with
pituitary dysfunction.
Evaluation of GH secretion is usually per-
formed if no other diagnosis is apparent from the
evaluation. As mentioned earlier, IGF-1 determi-
nations are preferred by many pediatric endocri-
nologists rather than GH stimulatory testing.
IGF-1 values must be interpreted by pubertal and
nutritional status and are best expressed in z
scores based upon standard deviations from the
mean; +/- 2 SD are considered within the normal
range. Insurance companies may insist on GH
secretory testing nonetheless. An IGF-1 concen-
tration may be falsely low because of nutritional
deficiency or constitutional delay, but if the
IGF-1 and IGF-BP 3 are normal, classic GH defi-
ciency is less likely. If stimulation is performed,
the diagnosis of classic GH deficiency is rela-
tively straightforward, as GH values will be
lower than the limits stated above. The other,
more subtle conditions of impaired GH secretion
will be more difficult to correctly diagnose.
5 Disorders of Growth
Table 5.3 Etiologies of tall stature
Variations of normal
Constitutional
Genetic
Exogenous obesity
Endocrine disorders
Pituitary gigantism
Sexual precocity
Thyrotoxicosis
Beckwith–Wiedemann syndrome
Infant of a diabetic mother
Nonendocrine disorders
Marfan syndrome
Klinefelter syndrome
XYY syndrome
Cerebral gigantism (Sotos syndrome)
Homocystinuria
Weaver-Smith syndrome
Modified from Styne DM. Growth disorder. In Greenspan
FS, Gardner DG, eds. Basic and clinical endocrinology.
New York: Lange, 2011: with permission
Tall Stature
Nonendocrine Causes of Tall Stature
Constitutional or genetic tall stature is the other side
of the coin from constitutional or genetic short
stature, although it is far more rarely evaluated
(Table 5.3). Patients are taller than average, may
have a moderately advanced bone age but a height
velocity appropriate for bone age, and have no
sign of the disorders described later. Puberty will
begin early in children with constitutional tall
stature, so that adult height will not likely be
above normal range, although height during
childhood was greater than normal. Obesity will
advance bone age and physiologic development
and often leads to tall stature in childhood but does
not translate into a taller adult height.
Genetic tall stature occurs in a family with one
or, more often, two parents taller than the normal
adult range. The child can be expected to reach
a taller-than-average height as an adult. The
adjusted midparental height will help in the eval-
uation of genetic tall stature (Fig. 5.8).
Girls more often will be concerned about
being taller than average than will boys; often
fears are intensified by parental concerns about
Abnormalities of Growth
tall stature and effects on social development.
However, such fears may have decreased in view
of the modern success of tall fashion models,
actresses, and athletes. Thus treatment is rarely
invoked today because of ethical issues, but high-
dose estrogen therapy has been used in the past
and has been effective in slowing longitudinal
growth while advancing puberty, causing a rapid
increase in bone age and thereby limiting adult
height in girls. Because of theoretic risks of high-
dose estrogen therapy—such as thrombotic
effects, the development of ovarian cysts, and
future menstrual disorders—therapy, if ever con-
sidered, is not to be undertaken without a careful
description of the possible side effects. Further,
the child must be included in discussions con-
cerning her adult height. In rare circumstances, a
girl with a predicted height of more than 6 ft,
who is age 10–12 years with a bone age no older
than 10–11 years, may hope to realize a decrease
in her final height of up to 2 in. with the use of
estrogen therapy. As always, a concern for hema-
tologic disorder arises when estrogen is used,
and a search for factor V Leiden deficiency is
appropriate in such therapy. This therapy is not
recommended by the author but is presented for
completeness and for historical interest.
Boys rarely are concerned about excessive
adult height, but testosterone therapy has been
used to precipitate pubertal development and
limit adult height. Such therapy is not recom-
mended either.
Cerebral gigantism (*117550 CEREBRAL
GIGANTISM at 5q35) or Soto syndrome is rec-
ognized by the prominent forehead and sharp
chin, with prognathism, high-arched palate,
down-slanting palpebral fissures, hypertelorism,
strabismus, and nystagmus. Developmental
delay, behavioral problems with expressive diffi-
culties, and possibly seizures are often found. No
evidence is found of GH excess, but bone age is
advanced, and hands and feet are large, with genu
valgum. Rapid growth is most characteristic of
infancy, and height velocity decreases by mid-
childhood or adolescence, leading in many cases
to normal adult stature.
The Weaver syndrome (#277590 WEAVER
SYNDROME) is associated with prenatal as well
87
as postnatal increased stature and advanced bone
age but no acceleration of growth velocity, as seen
in Soto syndrome. It is usually sporadic. Facial fea-
tures include macrocephaly, large bifrontal diame-
ter, flattened occiput, long philtrum, round face in
infancy, retrognathia, prominent chin with central
dimple, large ears, strabismus, hypertelorism, epi-
canthal folds, down-slanting palpebral fissures, and
depressed nasal bridge. Numerous skeletal abnor-
malities include scoliosis, kyphosis, coxa valga,
limited elbow extension, limited knee extension,
flared metaphyses (especially distal femora and
humeri), camptodactyly, broad thumbs, prominent
fingertip pads, large hands, clinodactyly, talipes
equinovarus, calcaneovalgus, metatarsus adductus,
short fourth metatarsals, prominent toe pads, pes
cavus, and overriding toes. Behavior and learning
disorders, seizures and hypotonia, and abnormali-
ties of CNS anatomy occur in some.
Marfan syndrome (#154700 MARFAN
SYNDROME; MFS at 15q21.1) includes dispro-
portionate tall stature with long-bone overgrowth
(dolichostenomelia), arm span exceeding height,
a very low upper-to-lower segment ratio, arach-
nodactyly (or long, thin fingers and toes), hyper-
extensibility of the joints, as well as joint
contractures. Other skeletal anomalies include
scoliosis, kyphoscoliosis, thoracic lordosis, spon-
dylolisthesis, lumbosacral dural ectasia, pectus
excavatum, pectus carinatum, and pectus asym-
metric deformity. Optic anomalies include sub-
luxation of the lens (ectopia lentis) with myopia,
corneal flatness, retinal detachment, iris hypopla-
sia, early glaucoma, early cataracts, and down-
slanting palpebral fissures. In addition, the face is
long and narrow, with dolichocephaly, high-
arched narrow palate, micrognathia, retrognathia,
and crowded teeth. Respiratory findings include
pneumothorax, pulmonary blebs, and, in the worst
cases, emphysema. Cardiac abnormalities include
aortic root dilatation, aortic regurgitation, ascend-
ing aortic aneurysm, aortic dissection, mitral
regurgitation, mitral valve prolapse, congestive
heart failure, pulmonary artery dilatation, tricus-
pid valve prolapse, and premature calcification of
mitral annulus. The skin reveals striae distensae.
The disorder results from a mutation in the fibril-
lin gene.
88
Homocystinuria (*236200 HOMOCYSTINU-
RIA at 21q22.3) is an autosomal dominant
condition with a phenotype somewhat similar
to that of Marfan syndrome including ectopia
lentis. The disorder is owing to mutations in
cystathionine β-synthase, which leads to the
laboratory findings of homocystinuria and methi-
oninuria. Pectus excavatum or carinatum, osteopo-
rosis, biconcave “codfish” vertebrae, kyphoscoliosis,
dolichostenomelia, arachnodactyly, and limited
joint mobility may be found. Mitral valve prolapse
is seen as is an increased risk for myocardial infarc-
tion. Developmental delay, psychiatric disorders,
and seizures are all characteristic of homocystin-
uria. Treatment involves a low-methionine, cystine-
supplemented diet for pyridoxine nonresponders
and pyridoxine supplementation for the roughly
50 % of affected patients who are classified as
pyridoxine responders.
Syndromes with extra Y chromosomes such
as 47XYY or 48XYYY lead to tall stature in
childhood and adult life, without any evidence of
increased GH. Klinefelter syndrome (47XXY)
may be associated with tall stature, but this is not
universal (see Chaps. 8 and 9).
Endocrine Etiologies of Tall Stature
Pituitary gigantism is due to a GH-secreting ade-
noma in childhood; acromegaly occurs with pitu-
itary hypersecretion of GH in an adult. Because
the epiphyses are not closed in an affected child,
height velocity increases, although some of the
coarse facial features of an acromegalic appear-
ance also may be noted. Organomegaly may
occur, and glucose intolerance or frank diabetes
may result. Elevated basal GH concentrations
and IGF-1 and IGF-BP3 levels confirm the diag-
nosis. A pathologic rise in growth hormone after
glucose administration or after TRF administra-
tion is another feature of somatotropic adenomas.
McCune–Albright syndrome may have, as one
feature, pituitary gigantism due to autonomous
GH secretion (see Chap. 9). Likewise, multiple
endocrine neoplasia 1 (MEN 1) may include
excessive GH secretion, and if, as rarely occurs,
it occurs before epiphyseal fusion, pituitary
gigantism will result (see Chap. 10). Treatment is
accomplished by somatostatin analogues, radia-
tion therapy, or surgery, all of which are discussed
5 Disorders of Growth
elsewhere. The criteria for successful treatment
in adults are stringent and are probably the same for
the rare cases of gigantism: normal (age/sex-
adjusted) insulin-like growth factor type 1 (IGF-
1), growth hormone (GH) random (GHr) <1 μg/L,
and a GH nadir (GHn) during oral glucose toler-
ance test (OGTT) of <0.4 μg/L.
Precocious puberty of any etiology increases
growth in childhood, but early epiphyseal closure
and short adult stature will result if untreated (see
Chap. 9).
One remarkable case of estrogen-receptor
defect (#615363 ESTROGEN RESISTANCE;
ESTRR) in a male led to continued growth into
the 25th year, with a bone age delayed so far that
the epiphyses remained open. Lack of estrogen
effect also led to osteoporosis. This case helped
establish the understanding that it is estradiol that
advances bone age and stimulates GH secretion.
A single female case has been identified as well.
Thyrotoxicosis increases height velocity and
skeletal age advancement if left untreated (see
Chap. 6).
Increased insulin can increase growth rate by
cross-reaction with IGF-1 receptors. Infants of
diabetic mothers are large at birth, but postnatal
growth is normal as insulin effects wane. Fetal
hyperinsulinism is the stimulus for the excessive
fetal growth; neonatal hypoglycemia can be a
serious complication, as the high maternal glu-
cose concentration that led to the fetal hyperinsu-
linism is removed at the time of birth, but the
insulin secretion continues for days. Children
with β-cell adenomas could have continued rapid
growth during their hyperinsulinemic state, but
their hypoglycemia will most likely be the clini-
cal condition that brings them to diagnosis and
treatment first (see Chap. 12).
Beckwith–Wiedemann syndrome (#130650
BECKWITH-WIEDEMANN SYNDROME;
BWS imprinting at 11p15.5) presents with large
newborn length and weight, omphalocele (exom-
phalos), and macroglossia. Body size remains
large throughout childhood, with an advanced
bone age. Life-threatening hypoglycemia occurs
because of hyperinsulinism due to pancreatic
hyperplasia. In addition, hemihypertrophy,
diastasis recti, hepatomegaly, and cardiomegaly
are seen. A large fontanelle with a prominent
Suggested Readings
occiput, a metopic ridge, coarse facial features,
and linear ear lobe creases with posterior helical
indentations occur. In addition, fetal adrenocortical
cytomegaly and large kidneys with medullary
dysplasia are found. Cryptorchidism is described,
with a tendency to neoplasia including Wilms
tumor, hepatoblastoma, adrenal carcinoma, and
gonadoblastoma. Beckwith–Wiedemann syn-
drome results from overexpression of the pater-
nally expressed genes or a lack of expression of the
maternally expressed genes within the 11p15
region. Wilms tumor is associated with uniparental
disomies of paternal origin and gain of methylation
at ICR1 (the opposite of hypomethylation at ICR1
found in the Russell–Silver dwarfism above).
Diagnosis and Treatment of Tall
Stature
Generally, the historical and physical manifesta-
tions of the conditions listed earlier are evident
during the history and physical examination.
Pituitary gigantism is associated with an elevated
IGF-1 concentration but only if precocious
puberty is ruled out since during precocious
puberty, IGF-1 concentrations increase higher
than in age-matched controls and may be con-
fused with acromegalic values. Basal GH con-
centration is usually elevated in pituitary
gigantism when compared with the low concen-
trations seen in normal subjects (a rare situation
in which a single GH determination may lead to
a diagnosis). Pituitary gigantism also responds
with GH secretion to agents that normally do not
stimulate GH secretion, agents such as glucose
(normally glucose suppresses GH), gonadotropin-
releasing hormone (GnRH), and thyrotropin-
releasing factor (TRF). Pituitary gigantism may
be treated with transsphenoidal microadenomec-
tomy if the tumor is approached early.
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23. Ranke MB. Treatment of children and adolescents
with idiopathic short stature. Nat Rev Endocrinol.
2013;9(6):325–34.
24. Rogol AD, Hayden GF. Etiologies and early diagnosis
of short stature and growth failure in children and
adolescents. J Pediatr. 2014;164(5 Suppl):S1–14 e16.
25. Eugster EA, Pescovitz OH. Gigantism. J Clin
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ment of the hand and wrist. Stanford, CA: Stanford
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in-children.
 Disorders of the Thyroid Gland
The hormones of the thyroid gland exert impor-
tant effects on growth and development including
early effects on the development of the central
nervous system (CNS), regulation of tempera-
ture, and influences on metabolism. Disorders of
the thyroid gland are common forms of endocrine
disease in childhood, and the primary care pro-
vider will definitely encounter some of these.
Normal Thyroid Physiology
and Anatomy
The production of thyroid hormones by the thyroid
gland is regulated by the hypothalamus and the
pituitary gland (Fig. 6.1). Hypothalamic thyrotropin-
releasing hormone (thyrotropin-releasing factor or
TRF in some publications), a three-amino-acid
peptide, is released from the median eminence into
the pituitary portal circulation. Although TRF has
many functions in the CNS, for our purposes, it
stimulates the pituitary gland to release thyroid-
stimulating hormone (TSH) into the general circu-
lation, where it reaches the thyroid gland and
stimulates the production and release of endoge-
nous thyroid hormones. Thyroid hormones exert
feedback inhibition on the hypothalamic–pituitary
axis and suppress TSH secretion to reach an equi-
librium of euthyroidism. Thyroxine rather than T3
appears to be most important in suppression of
TSH and feedback inhibition. In the absence of
adequate thyroid hormone production and release
© Springer International Publishing Switzerland 2016
D.M. Styne, Pediatric Endocrinology, DOI 10.1007/978-3-319-18371-8_6
6
(primary hypothyroidism), TSH increases. TSH is
released in a pulsatile manner with increased
release at night. Secondary hypothyroidism (inad-
equate or absence of pituitary TSH) and tertiary
hypothyroidism (inadequate or absence of hypo-
thalamic TRF) are differentiated from primary
hypothyroidism by the finding of normal or
decreased serum TSH; in the secondary form,
serum TSH is nondetectable before or after TRF
administration; in the tertiary form, TSH is measur-
able and increases from low levels to an abnor-
mally prolonged elevation after TRF although even
normal responses are reported. In the presence of
autonomous and excessive production of endoge-
nous thyroid hormone (as found in Graves’ dis-
ease) or administration of exogenous thyroid
hormone, the release of TSH is suppressed to non-
measurable levels in sensitive TSH assays.
Thyroid hormones are composed of two tyro-
sine molecules, an α(inner)- and a β(outer)-ring,
and a variable amount of iodine. The inner or
alpha ring is closest to the alanine side chain, and
the outer or beta ring is farthest away. They are
synthesized in the following sequential steps:
1. Active transport of plasma iodide into the thy-
roid follicular cell by the iodine/sodium sym-
porter (or the iodine pump) stimulated by
TSH; thyroglobulin is found in the colloid of
the thyroid gland, and this is the site of organi-
fication of the tyrosine residues attached to
thyroid globulin.
91
92
a Third ventricle
Neuroendocrine
cell nuclei
Superior
hypophyseal
artery
Long portal
vessels
Thryrotrophs
Anterior
pituitary
Hormone
secretion
T4 and T3
Fig. 6.1 The hypothalamic–pituitary–thyroid axis. (a)
Normally a balance exists between thyroid hormones
and thyroid-stimulating hormone (TSH) due to a func-
tioning feedback loop. (b) In primary hypothyroidism,
insufficient thyroid hormones are produced to suppress
TSH to normal. (c) In secondary or tertiary hypothy-
roidism (tertiary hypothyroidism is demonstrated in
this figure; a red X put over the anterior pituitary gland
2. Organification of the tyrosine molecules is
accomplished by the addition of one iodine at
the 3 position [causing the formation of
monoiodotyrosine (MIT)] or two iodines at
the 3 and 5 positions [forming diiodotyrosine
(DIT)] by thyroid peroxidase at the luminal
cell membrane stimulated by TSH. Mature
thyroid hormones are composed of two iodin-
ated tyrosine molecules with an alanine side
chain: the coupling of one DIT with one DIT
to form 3,5,3′,5′-tetraiodothyronine (thyroxine
6 Disorders of the Thyroid Gland
Hypothalamus
TRF secreting cells
Stalk
Inferior
hypophyseal
artery
Posterior
pituitary
Short portal
vessel
TSH
would demonstrate secondary hypothyroidism), insuf-
ficient TSH stimulates the thyroid gland to produce
adequate thyroid hormone. (d) In hyperthyroidism due
to Graves’ disease, the autonomous production of thy-
roid hormone by thyroid-stimulating immunoglobulin
(TSI) and TSH receptor antibody suppresses TSH to
nondetectable levels
or tetraiodothyronine or T4) or one DIT with
one MIT to produce 3,5,3′-triiodothyronine
(triiodothyronine or T3).
3. The release of T4 and T3 from the thyroid gland
is stimulated by TSH which interacts with the
G protein seven-transmembrane domain cellu-
lar membrane receptor causing stimulation of
adenyl cyclase to produce cyclic AMP ulti-
mately causing the protein-mediated release of
thyroid hormones from thyroglobulin and
release of the hormones into the circulation.
Normal Thyroid Physiology and Anatomy
b Third ventricle
Neuroendocrine
cell nuclei
Superior
hypophyseal
artery
Long portal
vessels
Thryrotrophs
Anterior
pituitary
Hormone
secretion
T4 and T3
Fig. 6.1 (continued)
4. TSH stimulates entry of thyroglobulin into the
follicular cell by pleocytosis, where it is
metabolized and iodine is subsequently
released and reused in the process again.
Although both T4 and T3 are released from the
thyroid gland, most of the circulating T3 is
derived from peripheral deiodination of the
β-ring of T4, except in the case of hyperthyroid-
ism, in which excessive T3 secretion from the
thyroid gland may occur. T3 is the metabolically
active form of thyroid hormone. Reverse T3 (RT3)
or 3,3′,5′-triiodothyronine is a metabolically
inert product of the peripheral deiodination of the
α-ring of T4; this form is found in greater amounts
in the fetus or during severe illness.
93
Hypothalamus
TRF secreting cells
Stalk
Inferior
hypophyseal
artery
Posterior
pituitary
Short portal
vessel
TSH
Circulating T4 is bound predominantly to
serum proteins; 75 % is bound to thyroid-binding
globulin (TBG), 20 % to transthyretin (thyroxine-
binding prealbumin or TBPA), and 5 % to albu-
min, with only 0.02–0.06 % present in the
circulation as free thyroxine (FT4); about 0.3 %
of T3 circulates as free T3 (FT3). Free T3 is the
metabolically active form of thyroid hormone,
whereas protein-bound T3 and T4 may be consid-
ered reservoirs of hormone in equilibrium with
the metabolically active free hormone. The thy-
roid binding proteins are affected by genetic con-
ditions, are decreased by androgens, and are
raised by estrogens, thereby changing the total T4
measurement. Thus, free T4 is the preferable
measurement in an accurate assay; there are older
94
c Third ventricle
Neuroendocrine
cell nuclei
Superior
hypophyseal
artery
Long portal
vessels
Thryrotrophs
Anterior
pituitary
Hormone
secretion
T4 and T3
Fig. 6.1 (continued)
methods such as resin T3 uptake (RT3U) to
account for variations in protein binding after
measuring total T4 but they are rarely used now.
T3 enters the cell through thyroid hormone
transporters located in the cell membrane. There
are several types of thyroid hormone transport-
ers including Na+/taurocholate cotransport-
ing polypeptide, the Na+/independent organic
anion transporting polypeptide (OATP) family
operating mainly in the central nervous system,
the heterodimeric L-type amino acid transport-
ers (LAT1, LAT2), and the monocarboxylate
transporter (MCT) family which is widespread
in various organs. The Allan–Herndon–Dudley
syndrome is due to mutations in the monocar-
6 Disorders of the Thyroid Gland
Hypothalamus
TRF secreting cells
Stalk
Inferior
hypophyseal
artery
Posterior
pituitary
Short portal
vessel
TSH
boxylate transporter 8 gene (MCT8) (#300523
ICD+ALLAN-HERNDON-DUDLEY
SYNDROME; AHDS) and is characterized by
low serum-free thyroxine, low serum rT3, but
increased serum triiodothyronine (T3) and normal
or mildly increased thyroid-stimulating hormone
(TSH) along with dysmorphology and profound
mental and muscular developmental delay.
Free T3 binds to nuclear thyroid hormone pro-
tein receptors (TR) that modulate thyroid
hormone-dependent gene expression. There are
two forms of receptors, TRalpha and TRbeta
with two forms of each receptor; the four result-
ing receptors are expressed in different thyroid
responsive tissues in the body. Thyroid hormone
Fetal Thyroid Development in the Newborn 95

d Third ventricle Hypothalamus

Neuroendocrine
cell nuclei TRF secreting cells

Superior
hypophyseal Stalk
artery

Long portal
vessels Inferior
hypophyseal
artery
Thryrotrophs

Anterior Posterior
pituitary pituitary

Short portal
Hormone vessel
secretion

TSH

TSI
TSHR AB

T4 and T3

Fig. 6.1 (continued)

receptors are similar to steroid receptors in Once the DNA/TR/thyroid hormone/coactivator

structure and function and are members of the
steroid hormone superfamily. The receptors are
present either as monomers (TR), heterodimers
with retinoid X receptor (TR/RXR), or homodi-
mers (TR/TR). TR/RXR heterodimers are the
most transcriptionally active complex. In the
absence of hormone, TR exists in a complex with
corepressor proteins binding to hormone response
elements (HREs) in DNA in an inactive state.
Binding of thyroid hormone results in a confor-
mational change in TR which displaces corepres-
sors from the receptor/DNA complex while
adding coactivator proteins to the complex.
complex is formed, RNA polymerase transcribes
DNA into mRNA which leads to translation of
the mRNA on ribosomes and the production of
proteins or peptides predicted by the hormone
that result in changes in cell function.
Fetal Thyroid Development
in the Newborn
The thyroid gland originates from the embryonic
pharyngeal floor between the first and second
pharyngo-bronchial pouch near a site later identi-
96
fied as the foramen cecum, noted after birth as a
pit at the back of the tongue. The normal thyroid
gland descends to the customary location at the
thyroid cartilage anterior to the trachea. In some
cases of congenital hypothyroidism, the thyroid
gland fails to descend far enough (sublingual or
lingual thyroid is the result) or descends too far,
sometimes ending up as far inferior as the medi-
astinum. An ectopic thyroid gland may be too
small or dysplastic to produce adequate thyroid
hormone, resulting in congenital hypothyroid-
ism. A thyroid gland in the normal location also
may be small (thyroid dysplasia or hypoplasia),
or, in the most severe case, absent in athyreosis.
One lobe may be absent, or an extra lobe, the
pyramidal lobe, may develop out of an embry-
onic remnant of the thyroglossal duct cyst, lead-
ing to asymmetry in appearance but possibly
normal function through compensatory hypertro-
phy. Thyroid dysgenesis may occur due to abnor-
malities in the homeobox genes (PAX8, TTF1,
FOXE1 and NKX2-5, which are responsible for
thyroid embryogenesis) in the approximately
2 % of cases that are familial; however, most
cases of thyroid dysgenesis occur sporadically.
A thyroglossal duct cyst connects the foramen
cecum to the final location of the thyroid gland
and may be present after fetal life, sometimes
containing functional thyroid tissue. If a thyro-
glossal duct cyst is removed without insuring the
presence of other thyroid tissue, the child may be
rendered hypothyroid by the surgery.
By 10–11 weeks of gestation, the human thy-
roid gland shows follicular organization and
demonstrates the ability to concentrate iodine. By
this time, TRF is demonstrable in the fetal hypo-
thalamus, and TSH is found in the fetal pituitary
and circulation. The pituitary–hypothalamic por-
tal system is developing around this time and is
mostly mature by 20 weeks’ gestation. Most of
the components of thyroid physiology are in
place by the second half of gestation. Thus, TSH
stimulation of thyroid function begins approxi-
mately midgestation.
Monodeiodination of the inner ring α of
thyroxine leads to reverse T3 (RT3), an inactive
moiety (compared with active T3), and monode-
iodination of the outer ring β of thyroxine leads
6 Disorders of the Thyroid Gland
to the production of T3 the active form of thyroid
hormone. In the fetus, the majority of T4 under-
goes deiodination of the inner ring, leading to the
formation of RT3 (compared with active T3) in
parallel with concentrations of T4 lower than
found in postnatal life. Late in gestation, outer-
ring deiodination of thyroxine increases, forming
more T3, and serum T3 finally begins to increase
as well. At term, fetal TSH and T4 are slightly
higher than those found in normal adult concen-
trations; fetal serum RT3 is markedly higher than
in the adult, and fetal serum T3 is considerably
lower. Thus, the fetus is normally in a relatively
decreased state of thyroid action compared with
the postnatal state.
Serum values of TBG and other thyroid-
binding proteins increase with advancing gesta-
tion, as do other serum proteins.
Serum concentrations of the thyroid hor-
mones found in the fetus reflect maturation of
the fetal thyroid gland, as little of the maternal
thyroid hormones and virtually none of the
maternal TSH cross the placenta. During preg-
nancy hCG will tend to stimulate thyroid func-
tion, and estrogens will likewise raise protein
binding levels increasing total thyroxine.
However, it is estimated that as many as 15 % of
women have subclinical hypothyroidism during
pregnancy. Subclinical hypothyroidism in the
mother can lead to spontaneous abortion, pre-
eclampsia, gestational hypertension, gestational
diabetes, and preterm delivery. A mother on thy-
roxine therapy is estimated to require a 50 %
higher dose during pregnancy. There is evidence,
although it is not found in all studies, that a
mother with inadequately or untreated hypothy-
roidism will have an offspring with slightly
decreased IQ, suggesting the importance of the
small amount of T4 that does cross the placenta
before the fetal thyroid gland matures.
Hypothyroidism in both mother and fetus may
lead to severe developmental delay. If the mother
produces a normal amount of thyroxine, even if
the fetus is profoundly hypothyroid, early treat-
ment after birth will usually allow normal intel-
lectual development demonstrating the
importance of the maternal contribution to thy-
roid physiology.
Laboratory Evaluation
After delivery, serum TSH quickly increases
and peaks at 30 min; T4 is secreted in response
and increases by 24–72 h to values equivalent to
those found in adult hyperthyroidism, with a slow
decrease toward adult normal values over the fol-
lowing weeks, months, and years. Serum T3
exhibits a primary increase in the hours after birth
after the umbilical cord is cut because of increased
outer-ring deiodination of thyroxine and exhibits
a secondary increase at 24–72 h due to the increase
in T4 secretion; RT3 decreases after birth because
of the switch from inner-ring deiodination to
outer-ring deiodination; TBG remains relatively
constant after birth. Localized deiodination in
brown adipose tissue which is present in the neo-
nate but not in any quantity in the adult leads to
localized production of T3 and is felt to enhance
thermogenesis in the newborn after birth.
Laboratory Evaluation
In the past, total serum T4 was the most common
measurement available. However, the total T4
value must be adjusted for the effects of available
serum proteins on total T4 measurement. If thy-
roid-binding proteins are altered by genetic con-
ditions, the total T4 value will change with no
change in the free moiety and without biological
complications. One older method to determine
thyroid-binding proteins invokes the use of a
resin T3 (RT3U) assay which serves as a surro-
gate test for the direct measurement of the protein
effects on total thyroid hormone levels. The total
T4 is multiplied by the RT3U thereby calculating
the free thyroxine index. This complex procedure
is now usually replaced by the direct measure-
ment of FT4 by RIA or more accurately by equi-
librium dialysis methods, although this later
method requires more effort, is more expensive,
and is generally available in national laborato-
ries. Labeled analog or labeled antibody-free T4
assays are more readily available. As always,
technical issues can affect results, so clinical cor-
relation or correlation with TSH values is help-
ful. Thyroid hormone values must be interpreted
by age in childhood, so choice of laboratories
with pediatric standards is essential.
97
Serum thyroglobulin (TBG) assays are
invoked to determine the presence of thyroid tis-
sue as only this organ produces thyroglobulin.
Endogenous Antibodies to TBG however affect
results of TBG determinations.
Ultrasensitive TSH assays are now widely
available to measure TSH accurately to 0.5 mIU/
mL or less. TSH values are dependent upon assay
characteristics, so it is best to use the same assay
sequentially when following a patient over time,
often difficult when the laboratory you are depen-
dent upon in a medical system switches to a
cheaper contracted send-out laboratory or uses a
new assay platform. TSH values also show a
diurnal rhythm of peaks at midnight and nadirs at
noon in most situations. Values vary between
individuals more than values repeatedly taken
from a single individual, so the best comparisons
are in the same assay in the same individual if
treatment is invoked. Lastly, the determination of
the upper limit of normal TSH values in children
may not always be straightforward. Longitudinal
study of children with only slightly elevated TSH
values up to 7.5 mIU/L was followed with a
descent into the normal range or stability with no
evidence of disease in most demonstrating that
normal values for TSH may be higher in children
than adults. Further, values only slightly below
the normal reference interval do not necessarily
indicate hyperthyroidism. As with all laboratory
tests, clinical correlation is necessary in interpret-
ing this test.
A patient with Graves’ disease will have a
value of serum TSH below the normal reference
range (often less than 0.5 mIU/mL) because of
suppression by the autonomous secretion of thy-
roid hormones. A patient with secondary (pitu-
itary defect lacking TSH production) or tertiary
(hypothalamic defect due to lack of TRF produc-
tion) hypothyroidism will have variable results,
whereas a normal adult patient will have a value
between 0.3 and 3.04 mIU/L (check the labora-
tory used for their exact standards for age, or
refer to Chap. 15). In primary hypothyroidism or
compensated hypothyroidism, serum TSH is
elevated. The combination of serum FT4 and
TSH determination will allow the differential
diagnosis of primary from secondary or tertiary
98
hypothyroidism. Differentiation between sec-
ondary hypothyroidism and tertiary hypothy-
roidism is more difficult and may require a
dynamic TRF test. A dose of 200 mg of TRF is
given intravenously (i.v.) and TSH measured at
0, 10, 15, 30, 60, 90, 120, and 180 min (or at
several of these times in some protocols). A nor-
mal response is an increase in TSH to at least
10 mIU/mL after about 15 min; in secondary
hypothyroidism, no increase is seen in TSH, and
in tertiary hypothyroidism, the increase may be
delayed until 60–120 min, and the TSH may
continue to increase during the 180-min period.
The TRF test also may be used in the diagnosis
of hyperthyroidism, as no increase in TSH will
occur after TSH with the autonomous thyroxine
secretion characteristic of Graves’ disease. The
TRF test is rarely invoked in Graves’ disease or
other conditions with the development of newer
laboratory techniques including ultrasensitive
TSH and newer thyroid-stimulating antibody
tests.
Assays for T3 or free T3 are of interest in the
evaluation of hyperthyroidism but not usually
necessary in the diagnosis of hypothyroidism.
Measurement of reverse T3 (RT3) is rarely invoked
except in some cases of nonthyroidal illness.
Imaging of Thyroid
Ultrasonographic scanning of the thyroid gland is
useful to determine the location and size of a thy-
roid gland mass; however, it is not as reliable in
finding ectopic glands in the diagnosis of con-
genital hypothyroidism. A scan may differentiate
cystic from solid masses and the relation of the
mass to neck structures. If a solitary nodule is
solid, it is more likely to be carcinoma than if it is
a simple cyst. Ultrasonography also can be used
to guide a biopsy needle for fine-needle aspira-
tions. However, if a needle biopsy is obtained,
the pathology service must have experience in
accurately interpreting the results. Some suggest
that because excision may be indicated in the
case of single cold nodules in any case, excision
biopsy should be performed for both diagnosis
and treatment of suspected cancer. With features
6 Disorders of the Thyroid Gland
more strongly suggesting a malignancy, surgical
excision biopsy is a better approach.
Radioiodine imaging of a thyroid gland may
be used in the differential diagnosis of nodules of
the thyroid gland to determine whether they are
functional or “hot” compared with nonfunctional
or “cold” nodules. Imaging may be used for the
localization of an ectopic thyroid gland. However,
in a clear case of Hashimoto thyroiditis with clas-
sic history, findings, and laboratory findings, lit-
tle is added by a thyroid scan. Radioiodine or
technetium uptake will be used in some cases in
the diagnosis of Graves’ disease or in preparation
for radioiodine therapy for Graves’ disease or
thyroid carcinoma.
The scanning of a neonate or infant presents
particular problems; the radioiodine tracer, which
is administered orally or by nasogastric (NG)
tube, may be spit up by the infant and may leave
tracts of radioactivity on the skin, falsely suggest-
ing thyroid tissue on imaging. Injectable perchlo-
rate is an alternative tracer which can be given IV.
It is recommended that the child be fed to elimi-
nate tracer uptake in salivary glands and to foster
the onset of sleep during the scan. Further, a neo-
nate suspected of having hypothyroidism may
have no detectable thyroid gland on scan just
after birth, but after months pass, a normal gland
may be detected; this may be due to the transient
presence of thyroid-binding inhibitory immuno-
globulin in the neonatal circulation that was
passed from the mother (if the mother has symp-
tomatic or asymptomatic autoimmune thyroid
disease) to the fetus. Application of iodine-con-
taining cleaning compounds to the skin of the
neonate may cause transient hypothyroidism by
inhibiting neonatal thyroid function. A congeni-
tal iodine-trapping defect (#274400THYROID
DYSHORMONOGENESIS 1; TDH1) will elim-
inate thyroidal uptake of radioiodine and suggest
aplasia but appear the same as these transient
conditions on US and scan. The demonstration of
an ectopic or hypoplastic gland in a neonate on
an acceptable-quality scan, however, is good evi-
dence that the child has a permanent defect in thy-
roid function. In the differential diagnosis of
congenital goiter, perchlorate discharge test may
be used in which radioactive thyroid uptake is
Disorders of the Thyroid Gland
determined and then determined a second time
after administration of potassium perchlorate,
which causes the discharge of nonorganified
iodine; if the turnover of iodine is much higher
with perchlorate than without, an autosomal
recessive enzyme deficiency causing an organifi-
cation defect is present.
An important consideration when performing
radioactive thyroid-uptake determinations for
hyperthyroidism is to measure the uptake early,
such as at 4 h, as well as at 24 h, because a quick
turnover of radioactive iodine, as occurs in
Graves’ disease, may lead to a high uptake at 4 h
but a low uptake at 24 h, so that a sole late scan
may falsely eliminate hyperthyroidism as a diag-
nosis. Scanning can be done with 123I or techne-
tium 99 pertechnetate; the former must be used
before thyroxine is administered (if indicated),
whereas the latter may be used even if thyroxine
has already been administered. The ingestion of
excessive iodine or the use of contrast agents will
decrease the ability to perform a scan with 123I for
a considerable period; in fact the iodine status of
the individual if outside of the normal intake
range can affect the results of the test and iodine
intake is increasing with many foods such as
bread and salt augmented with iodine. A low
iodide diet is characteristically instituted before
radioactive iodine treatment for thyroid carci-
noma to ensure maximal uptake.
Disorders of the Thyroid Gland
Goiter
An enlargement of the thyroid gland is a goiter;
the affected patient may be euthyroid, hypothy-
roid, or hyperthyroid, so the finding of goiter does
not indicate the diagnosis (Table 6.1). A goiter
may be large enough to be visible to the patient or
parent or may be subtle enough to be noted only
on directed physical examination. If the patient
swallows water during the examination, the
mobile nature of the thyroid gland should iden-
tify it as it rises and falls on swallowing.
Examination of the neonate or infant should
99
focus on the detection of soft tissue anterior to the
tracheal cartilage. The size of the thyroid gland
can be estimated as 5 g of thyroid tissue is the
equivalent of a teaspoon size of tissue and 15 g of
a tablespoon. The thyroid gland increases in size
with growth until the teenager reaches a gland
size of about 10 g. The margins of the goiter
should be noted distinctly from the neighboring
sternocleidomastoid muscle, and measurement
should be recorded. The longest diagonal length
of each lobe, the shortest diagonal length of each
lobe, and the height of the isthmus may be
recorded for comparison at future visits to deter-
mine the effect of treatment. Some observers find
it useful to trace the outline of the gland on a
piece of tissue paper and to include it in the
patient’s record for future comparison. An esti-
mation of the percentage the gland appears to be
increased over normal size may be accomplished
(i.e., a slightly or moderatedly enlarged gland
might be 25–50 % increased, whereas an obvi-
ously enlarged gland may be 100 % increased).
While a homogeneous goiter most likely is due to
Hashimoto’s thyroiditis in a child or teenager,
confirmatory tests must be performed.
Ultrasonography may detect fetal goiters. This
could be due to exogenous agents given to the
mother or a metabolic form of hypothyroidism in
the fetus. There are some reported cases of intra-
uterine treatment of such patients with thyroid hor-
mone, but this is not presently standard of care.
The thyroid functional status is next determined
in a patient with a goiter. Most goiters in the neo-
nate will be diagnosed by means of the TSH value
on the newborn screening programs and will be
due to maternal ingestion of a goitrogen [such as
methimazole or propylthiouracil (PTU) for treat-
ment of maternal hyperthyroidism] or an inborn
error of thyroid biosynthesis. The majority of goi-
ters in the late childhood through adolescent years
will be due to euthyroid or hypothyroid Hashimoto
thyroiditis, followed by a lower incidence of
hyperthyroidism due to Graves’ disease. A minor-
ity of indeterminate goiters of mild degree may
persist for years; these may be colloid goiters, a
diagnosis that is established only after all other
diagnoses are eliminated. Colloid goiter occurs
 100

Table 6.1 Etiologies of thyroid enlargement

Disorder Goiter Nodule Free T4 TSH Other features Inheritance
Autoimmune Usually Usually not Usually low but Usually high but Positive antithyroid peroxidase or Autosomal dominant, recessive,
hypothyroidism could be Nl or could be Nl or antithyroglobulin antibodies or sporadic; may be part of
(Hashimoto thyroiditis) high in euthyroid low in euthyroid autoimmune
Hashimoto Hashimoto polyendocrinopathy syndromes
Acute or suppurative One lobe or overall No High transiently Low transiently Painful, may originate through
thyroiditis enlargement at beginning at beginning pyriform sinus, treated with
antibiotics
Subacute thyroiditis Usually No High transiently Low transiently Painful, may be treated with
at beginning at beginning anti-inflammatory agents for pain
but since differentiation between
bacterial and viral infection may be
difficult, antibiotics may be used
Adenoma Yes High if functional Low if functional
or Nl if not or Nl if not
Papillary carcinoma Yes Usually normal Usually normal History of radiation? Sporadic or autosomal
dominant
Follicular carcinoma Yes Usually normal Usually normal History of radiation? Sporadic or autosomal
dominant
6

Medullary carcinoma Yes Normal Normal Calcitonin high in basal, Sporadic or familial medullary
pentagastrin-, or calcium- carcinoma of the thyroid
stimulated state; ret mutation (FMCT) and may be associated
positive even before calcitonin with MEN 2 or MEN 3
increases
FMCT familial medullary carcinoma of the thyroid, MEN multiple endocrine neoplasia
Disorders of the Thyroid Gland
Hypothyroidism
mainly in areas deficient in adequate iodide and is
not accompanied by an elevation in serum antimi-
crosomal or antithyroglobulin antibody levels, nor
is there an alteration in thyroid function from nor-
mal. The thyroid gland slightly increases in size
during puberty, the so-called physiologic goiter of
adolescence, but significant increases in thyroid
size suggest a pathologic process, and evaluation
of goiters is indicated, rather than accepting a goi-
ter as a normal variation.
A solitary nodule in childhood is unusual and
worthy of careful attention and should not simply
be considered a routine goiter. Serious consider-
ation of thyroid cancer must arise if a solitary
nodule is noted (see later). A thyroid scan may be
used to determine whether the nodule is hot and
functional or cold and nonfunctional. A cold nod-
ule is particularly worrisome, as it more likely
indicates neoplasia although functional nodules
can occur in neoplasia (see later).
Hypothyroidism
Congenital Hypothyroidism (CH)
The detection and treatment of neonates with
hypothyroidism should be considered a pediat-
ric emergency (Table 6.2). If therapy is not
begun soon after birth, developmental delay
will result. The goal of treatment is to com-
mence immediately upon diagnosis. Neonatal
hypothyroidism is a relatively common disor-
der, with an incidence close to one in 3,000 live
births. CH is more common in Asian, Native
American, and Hispanic populations, while
Caucasians and African Americans have a lower
prevalence. It is more common in older mothers
and in premature infants.
Because of the difficulty in making a clinical
diagnosis early enough to salvage mental func-
tion based on the history and physical examina-
tion alone, routine neonatal screening has been
instituted in the USA and in most countries. In
fact congenital hypothyroidism is the most com-
mon disease for which neonatal screen is per-
formed. In most cases, samples of blood are
collected from a heel stick, placed on a filter
101
paper, and sent to a centralized laboratory, where
blood is eluted from the paper and analyzed for
concentration of TSH (in some locations T4
might be determined instead). Most screening
programs will report results by age 7 days. The
timing of the screening is important as a sample
should be collected after 24 h, sometimes diffi-
cult with the tendency to early postnatal dis-
charge. A screening test is just that and is not
reliable for diagnosis and therapy without confir-
mation. However, if the TSH value is elevated, a
diagnosis of presumptive hypothyroidism is
made. If the result is indeterminant, the central-
ized laboratory in some states might offer a
repeated sample. However, a high value of TSH
on screening should suggest the wisdom of
immediately obtaining a serum FT4 and TSH by
venipuncture in preparation for instituting ther-
apy rapidly. If the TSH is low, it will not be
detected on TSH-screening programs, and the
diagnosis of secondary or tertiary hypothyroid-
ism will be missed; in most cases, these diagno-
ses are accompanied by other deficits of the
hypothalamus or pituitary, and the diagnosis will
be indicated by these other conditions such as
growth hormone or ACTH deficiency, which
may lead to neonatal hypoglycemia or even
hypoglycemic seizures (see later). Since it is
possible that screening tests may not be per-
formed in a newborn or may not pick up all cases
of congenital hypothyroidism, the clinician
treating newborns must retain a high index of
suspicion for any other signs of hyperthyroidism
that may develop.
It is important to view the normal develop-
mental physiology of the fetus and newborn to
understand the pitfalls of the neonatal screening
program and interpretation of thyroid function in
the days and weeks after birth (read above). To
repeat, after delivery, serum TSH quickly
increases and peaks at 30 min; T4 is secreted in
response and increases by 24–72 h to values
equivalent to those found in adult hyperthyroid-
ism, with a slow decrease toward adult normal
values over the following weeks, months, and
years. Serum T3 exhibits a primary increase in
the hours after birth and exhibits a secondary
increase at 24–72 h due to the increase in T4; RT3
Table 6.2 Etiologies of congenital hypothyroidism
Disorder Subtypes Prevalence Goiter Free T4 TSH Other features Inheritance
Thyroid dysgenesis 1:3,000–5,000 No Low High May be agenesis, hypoplastic, or ectopia Mostly sporadic, but
3 % have gene mutations
Thyroid dyshormonogenesis 1:40,000
Iodine-transport defect Yes Low High Mutation of gene for sodium/iodide AR
symporter. Treated with extra iodide
Organification defect 1:40,000 Yes Low High Mutation of thyroid peroxidase. Positive AR
perchlorate discharge test is diagnostic
Pendred syndrome 1:50,000 Yes Low High Defect in pendrin gene. Deaf mute and AR
positive perchlorate discharge test
Iodotyrosine deiodinase defect Yes Low High High RAIU but early discharge. High serum AR
MIT and DIT
Hypothalamic–pituitary 1:100,00 No Low Low Mostly sporadic but may
abnormality be part of AR multiple
pituitary hormone
deficiency
Familial TSH deficiency No Low Low Abnormal TSH-β gene AR
Pit-1 or Prop-1 gene No Low Low Absence of GH and Prl secretion AR
deficiency
TSH unresponsiveness Rare No Low High Mutation of TSH-receptor gene AR
Transient hypothyroidism 1:40,000
Maternal antibodies blocking No Low High
TSH receptor
Goitrogens (medication such Yes Low High
as maternal PTU or food such
as certain cabbages)
Excess or inadequate iodine, Yes Low High
e.g., endemic cretinism
Thyroid hormone resistance 1:100,000 Yes High High Mutation of thyroid-receptor gene. May be AR, AD. Sporadic
general (TSH may be normal), peripheral,
or pituitary resistance
Thyroglobulin defects 1:40,000 Yes Low High Mutation of TG gene AR
TSH thyroid-stimulating hormone, AR autosomal recessive, AD autosomal dominant, PTU propylthiouracil, RAIU radioactive iodine uptake, MIT monoiodotyrosine, DIT diiodotyro-
sine, GH growth hormone, Prl prolactin (Modified from Fisher DA. The thyroid. In: Rudolph CD, Rudolph AM, eds. Rudolph’s pediatrics. New York: McGraw-Hill; 2002:
2059–2079)
Hypothyroidism
decreases after birth; TBG remains relatively
constant after birth.
It is essential to understand this developmental
physiology to properly understand the diagnosis
of congenital hypothyroidism. A normal child at
term will have serum T4 concentrations in the
adult hyperthyroid range during the 24–72 h after
birth, whereas a child with bona fide hypothyroid-
ism will have serum T4 either below the normal
adult range or in the normal adult range. Healthy
premature babies, their development interrupted
before the normal stage of thyroid physiologic
development at term, have a lower concentration
of T4, and premature babies with respiratory
distress syndrome or others who are small for
gestational age will have T4 values lower than do
normal age-matched premature children.
A late rise in TSH is found in these neonatal con-
ditions which will complicate neonatal screening
tests. Some programs check a second sample in a
few weeks after birth and find an increased inci-
dence of hypothyroidism due to delayed rise in
TSH; this occurs most often in premature infants.
Thus, the gestational age of the neonate, the
clinical condition, and the postnatal age are
important in the interpretation of neonatal
thyroid-screening tests. Age-adjusted normal
ranges for these tests are essential information
from any laboratory testing at these ages and
conditions.
The signs and symptoms of congenital hypo-
thyroidism in its classic form include large
tongue, coarse facies, umbilical hernia, a combi-
nation of lethargy and irritability, poor growth
and weight gain, short extremities with a delayed
or high upper-to-lower-segment ratio, persis-
tently open posterior fontanel, large anterior fon-
tanel, and coarse voice. Further, pericardial
edema can be noted on ultrasound study in infants
left untreated for a prolonged time. However,
these signs and symptoms take weeks to months
to develop, and if suspicion of congenital hypo-
thyroidism were to be triggered by physical stig-
mata alone, the majority of patients would
already have irreversible mental changes before
diagnosis was accomplished and therapy began.
Although features such as prolonged gestation
with large birth weight, persistent jaundice, tem-
103
perature instability, lag in the time of the initial
episode of stooling to more than 20 h after birth,
edema, and hypoactivity and poor feeding can be
seen in hypothyroid patients in the neonatal
period, most or all of these findings could be
signs of other diseases as well and may not sug-
gest the definitive diagnosis to the physician
without the aid of neonatal screening.
Thus neonatal screening programs were estab-
lished to diagnose patients uniformly before
definitive symptoms occur. However, the signs
and symptoms of congenital hypothyroidism
must be kept in mind because the statewide
screening programs are not infallible, and a
patient may miss screening because of home
birth, early discharge from the hospital, long stay
in the neonatal intensive care unit, transfer
between hospitals, or even lost samples. If a sus-
picion exists that a newborn might have hypothy-
roidism, rather than waiting for the neonatal
screening result, standard serum FT4 and TSH
determinations can be requested, and the results
may be available even sooner than those from the
screening program.
Anatomical
The development of the thyroid gland is described
above. The etiology of congenital hypothyroid-
ism is usually anatomical (85 % of cases): thus
athyrosis, hypoplasia of the thyroid gland (half to
one-third of cases), or a lack of descent of the
thyroid gland from its initial site of formation to
its normal mature location (thyroid ectopy or, by
analogy to the term used for lack of descent of the
testes, “cryptothyroidism”) occur. These condi-
tions were generally considered to occur in a spo-
radic pattern, but there are genetic disorders in
1–3 % of cases (#218700 THYROID
DYSGENESIS at 2q12-q14), although there are
usually other findings in these cases with gene
mutations. The presence of thyroglobulin in the
serum indicates the presence of at least some thy-
roid tissue. A 123I thyroid scan is able to demon-
strate ectopy, but an initial finding of athyrosis or
hypoplasia on scan may occur because of mater-
nal blocking antibodies that crossed the placenta
and may falsely suggest a permanent anatomic
abnormality, when a transient condition is
104
actually present (see earlier). Ultrasound exami-
nation of the area will help determine the pres-
ence of thyroid tissue in those infants with TSH
receptor-blocking antibodies (TBA or thyroid-
binding inhibitory immunoglobulin (TBII) which
are passed from the mother who has autoimmune
thyroid disease herself; she may have atrophic
thyroiditis which is characterized by thyroid
autoantibodies, often TSH blocking antibodies,
causing functional hypothyroidism, and absence
of goiter). Ultrasound may indicate the presence
of thyroid tissue when an infant has a genetic
iodine-trapping defect that will interfere with the
demonstration of the tissue on an 123I scan.
Ultrasound is not reliable in seeking ectopic
glands however.
Endemic cretinism is found in areas of iodine
deficiency, but with iodine supplementation of
salt, bread, and other foods, the prevalence has
decreased worldwide, and the condition is virtu-
ally nonexistent in the USA except in households
where alternative food sources are used and the
family avoids supplementation. Nonetheless,
iodine deficiency is still the leading cause of
congenital hypothyroidism worldwide, and it
is all the more tragic because it is easily
preventable.
Severe hypothyroidism at any age can lead to
myxedema, a term derived from mucinous edema
as described in the nineteenth century. Myxedema
is due to protein-bound mucopolysaccharides, hyal-
uronic acid and chondroitin sulfuric acid, in areas of
the skin which leads to a swollen appearance.
Biochemical
Biochemical abnormalities of the thyroid gland
are usually inherited in an autosomal recessive
manner and often involve the development of a
goiter in about 10–15 % of cases of congenital
hypothyroidism. The prevalence of biochemical
congenital hypothyroidism is about 1 in 40,000.
Possible diagnoses in a with goiter include
dyshormonogenesis, such as peroxidase defects or
organification defects (#274500 ICD+THYROID
DYSHORMONOGENESIS 2A; TDH2A due to
mutation in the thyroid peroxidase gene at 2p25)
which may be a part of the Pendred syndrome
6 Disorders of the Thyroid Gland
which includes neurosensory deafness (#274600
ICD+PENDRED SYNDROME; PDS). With a
deiodinase defect (#274800 ICD+THYROID
DYSHORMONOGENESIS 4; TDH4), the indi-
vidual cannot remove iodine from the DIT or MIT
and therefore becomes iodine deficient from
iodine loss in the urine. Other conditions include
thyroglobulin defects causing lack of coupling of
MIT and DIT (#274900 ICD+THYROID
DYSHORMONOGENESIS 5; TDH5) and a
defect in TSH receptors (#275200-
HYPOTHYROIDISM, CONGENITAL,
NONGOITROUS, 1; CHNG). A defect in the
transport of iodine into the thyroid gland due to
mutation in the sodium/iodide symporter which
develops the large gradient between lower extra-
cellular iodine concentrations and higher intracel-
lular concentration of iodine is not always goitrous
(#274400THYROID DYSHORMONOGENESIS
1; TDH1), while defects in hydrogen peroxide
generation (#607200THYROID DYSHOR-
MONOGENESIS 6; TDH6) are not goitrous.
Three forms of resistance to thyroid hormone
are reported all with a defect in the same TSH
receptor beta gene. Generalized (central and
peripheral resistance) to thyroid hormone
(#188570 THYROID HORMONE
RESISTANCE at 3p24.3) is associated with
delayed speech development, attention-deficit/
hyperactivity disorder associated with goiter, but
euthyroid status due to increased secretion of
thyroid hormone. The defect is in the TR beta
receptor, and the inheritance is usually autoso-
mal dominant. Other kindreds have thyroid hor-
mone unresponsiveness or Refetoff syndrome in
an autosomal recessive pattern (#274300
THYROID HORMONE UNRESPONSIVE-
NESS at 3p24.3) in which thyroid hormone and
TSH concentrations are high; the patients are
clinically euthyroid but may have exophthalmos,
deaf–mutism, skeletal abnormalities, and goiter;
there is also a mutation in the gene for the
β-portion of the thyroid hormone receptor in this
syndrome as well as the previous one. Autosomal
dominant selective pituitary resistance to thyroid
hormone (#145650 THYROID HORMONE
RESISTANCE, SELECTIVE PITUITARY;
Hypothyroidism
PRTH) leads to hyperthyroidism since the
elevated thyroid hormone levels do not suppress
TSH secretion from the pituitary gland.
Hypothalamic–Pituitary Abnormalities
Rarely (fewer than 1 in 100,000 live births), isolated
TSH deficiency or secondary hypothyroidism is
found, but multiple pituitary deficiencies accompa-
nying TSH deficiency are found more frequently in
an incidence of 1 in 20,000–30,000. The manifesta-
tions of secondary or tertiary hypothyroidism are
usually milder than primary hypothyroidism. There
are extremely rare familial forms of isolated TSH
deficiency (#275100 ICD+HYPOTHYROIDISM,
CONGENITAL, NONGOITROUS, 4; CHNG4)
due to mutations in TSH beta-subunit or isolated
TRF deficiency (tertiary hypothyroidism)
(%275120THYROTROPIN-RELEASING
HORMONE DEFICIENCY) in the TRF receptor
gene. However, TSH or TRF deficiencies are seen
with other pituitary hormone deficiencies which
will likely manifest the signs that will lead to the
diagnosis such as hypoglycemia, microphallus, or
jaundice. Genetic defects leading to multiple pitu-
itary deficiencies along with TSH deficiency are
found in mutations of Pit-1, Prop-1, HESX1, LHX4,
or other autosomal genes leading to many associ-
ated defects (see Chap. 3).
Thyroid-Binding Globulin Mutations
In several situations, thyroid-binding proteins are
altered and thereby alter the serum T4 and T3 con-
centrations. Decreased TBG, or TBG deficiency
(*314200 THYROXINE-BINDING GLOBULIN
OF SERUM; TBG at Xq22.2), occurs in 1 of
10,000 live births in a sex-linked pattern. The
serum T4 and T3 are decreased, and the serum FT4
is normal, but because serum TSH is normal, the
child will be not detected by the newborn TSH-
screening program. Most children are normal, but
mental retardation also is reported in the litera-
ture. Familial dysalbuminemic hyperthyroxinemia
(FDH) (*145680 HYPERTHYROXINEMIA,
FAMILIAL) leads to increased T4 but a normal
105
serum T3; the free forms of both hormones are
normal, and the patient is asymptomatic.
Children with nephrosis will have massive loss
of thyroid hormone in the urine and thyroid-binding
globulin due to proteinuria. Some studies reported
elevated TSH values which reverted to normal with
resolution of the nephrosis.
Consumptive Hypothyroidism
Neonates may have hemangiomas with excess
type 3 deiodinase activity which decreases the
biological action of thyroxine by conversion to
inactive metabolites including reverse T3 leading
to often severe hypothyroidism and elevated
TSH. There may be a positive neonatal screen
for hypothyroidism. Replacement doses of thy-
roxine are many times higher than expected for
age due to the fact that the enzyme inactivates
the administered thyroxine as well as the endog-
enous thyroxine. Most patients have been
reported with infantile hepatic hemangiomato-
sis, but other tumors may exert the same effects
in older individuals.
Exogenous Agents
External agents administered to the mother can
cause congenital hypothyroidism. Radioactive
iodine mistakenly given to a pregnant woman
with Graves’ disease will immediately cross the
placenta and damage the developing gland; if the
dose is less than therapeutic, total destruction of
the gland may not occur, but neoplasia may fol-
low because of the damage to the fetal thyroid
gland. Methimazole or, now rarely, PTU given to
a pregnant woman with hyperthyroidism also
will cross the placenta and can cause profound
hypothyroidism if the maternal dose is too great;
when the PTU is cleared after delivery, the baby
will recover from the hypothyroidism caused by
this suppression, but the thyroid-stimulating
immunoglobulin that was passed from the mother
via the placenta will begin to exert its effect,
causing transient but potentially clinically rele-
vant hyperthyroidism.
106
Paradoxically, excessive iodine given to the
mother can suppress thyroid gland formation,
as can a deficiency of iodine. Iodine deficiency
is highly prevalent in the world and leads to
goiter, cretinism (this word is not to be used in
discussion with families of course), poor
growth, and hypothyroidism. Cretinism may
present with neurological signs including
developmental delay, mutism, and spasticity or,
with the myxedematous form, with myxedema
and more moderate developmental delay and
growth failure.
Transient Congenital Hypothyroidism
and Variants
Transient congenital hypothyroidism is seen
when mothers are exposed to excess iodine and
antithyroid medications for hyperthyroidism or
transfer antithyroid antibodies to their fetus. Rare
cases of heterozygous mutations in DUOXA2
lead to transient CH.
Transient hyperthyrotropinemia, in which a
child will have normal serum T4 concentrations for
age but a slightly elevated TSH (often in the range
of 20–30 mIU/mL), may be confused with primary
hypothyroidism. The natural history of such
patients is a decrease in the TSH concentrations to
normal by age 1–2 years in the absence of treat-
ment. Children with laboratory values characteris-
tic of transient hyperthyrotropinemia should be
watched for evidence of decreasing thyroid func-
tion in case they have bone fide hypothyroidism,
instead of benign transient hyperthyrotropinemia.
Patients with neonatal hypothyroidism will in some
cases maintain a normal serum T4 concentration at
the time of the newborn screening at the expense of
an elevated TSH via compensated hypothyroidism;
most will be detected, but some will have normal
serum TSH at birth and for some time thereafter
until the inadequate thyroid gland fails. An ectopic
or hypoplastic thyroid gland that, although func-
tional enough at birth to allow a normal newborn
screen, decompensates with time, and true hypo-
thyroidism develops; these cases may present with
apparent transient hyperthyrotropinemia. Thus
elevated serum TSH is a worrisome finding; the
differential diagnosis in this case should be made
by an experienced pediatric endocrinologist.
6 Disorders of the Thyroid Gland
Management of a Positive Neonatal
Screen
With the receipt of a screening test result suggest-
ing congenital hypothyroidism, another set of
serum samples for confirmatory T4 or free T4 and
TSH should be immediately drawn, as the results
of a screening test require proof. If the initial
TSH was quite high, treatment with thyroxine
may be started while awaiting the results of the
confirmatory tests.
A nuclear medicine thyroid scan may be help-
ful if the expertise is available but is subject to
limitations noted above. A large gland on scan
suggests dyshormonogenesis, a small or ectopic
gland an anatomic defect, but an absent gland can
be due to disease such as TSH or TRF deficiency
or iodine symporter mutation but also may be
temporary and due to maternal blocking antibod-
ies. Maternal blocking antibodies are determined
by a thyrotropin binding inhibitory immunoglob-
ulin or TBII assay. Urinary iodine determination
if low indicates iodine deficiency and if high
indicates excess iodine exposure in the mother;
both can cause a positive neonatal screen.
Measurable serum thyroglobulin will indicate
the presence of thyroid tissue, but absence will
indicate the lack of thyroid tissue.
A bone-age determination of the knee and foot
is useful in some cases if the infants is shielded
with lead; the distal femoral epiphysis calcifies at
36 weeks of gestation, the proximal tibial epiphy-
sis at 38 weeks, and the cuboid epiphysis of the
feet at term. Although most newborns don’t
require this confirmation, a bone age of the leg and
foot can be determined at the time of receipt of the
screening results, and the finding of delayed lower
extremity bone age for gestational age may
strengthen the impression of congenital hypothy-
roidism (a hand bone age is not useful at this age).
Patients with congenital hypothyroidism may have
epiphyseal dysgenesis or irregular multifocal cal-
cification on radiograph when the epiphyses do
appear after the institution of treatment.
Treatment of congenital hypothyroidism
should begin immediately after the diagnosis is
established, as long as confirmatory tests beyond
the neonatal screening tests are obtained first. In
those cases in which the screening results show
Hypothyroidism
Table 6.3 General starting doses of thyroxine by age in
micrograms/kg: all must be adjusted by clinical state and
serum thyroxine (and TSH after the newborn period)
Age Doses of thyroxine (μg/kg)
0–3 months 10–15
3–6 months 8–10
6–12 months 6–8
1–5 years 5–6
6–12 years 4–5
>12 years 2–3 (and lower with
completion of pubertal
development)
TSH thyroid-stimulating hormone
From various sources including prescribing information
for levothyroxine (synthroid) from Abbott Laboratories
an extremely high TSH, treatment can be started
even before the confirmatory results return, as it
will be most unlikely that a mistake in diagnosis
has occurred. Presently, recommended dosage of
synthetic thyroxine is 10–15 μg/kg for the new-
born (a dose of 37.5–50 μg is the usual daily dose
in term newborns) and less thereafter, 3–5 μg/kg
until a total dose of 100–150 μg is reached at the
maximum in a teenager (Table 6.3). Thyroxine is
most widely available in tablets and is crushed
and administered in a small amount of formula,
water, or breast milk in the newborn. While fast-
ing is the best time to administer thyroid medi-
cines, this is not possible in the newborn; at least
avoiding extra calcium, iron preparations, or soy
will increase the likelihood that the medication
will be absorbed adequately. The chronologic
relationship of medication to diet should remain
consistent for compatible longitudinal lab results.
Liquid thyroxine is available for parenteral use
but is quite expensive; it has been used rarely for
patients who are unable to take medications
orally. Compounding pharmacies cannot make a
safe suspension that allows the same dosage per
administration, and this method is to be avoided.
T3 is not used for the treatment of hypothyroid-
ism, nor is a combination of T4/T3 as lay websites
may suggest. There is no indication for desic-
cated thyroid pills although naturopaths may sug-
gest it. Children must be followed up carefully,
with determination of thyroxine or free thyroxine
at 2 weekly intervals as treatment starts until
therapeutic range is reached. Continued follow-
107
up of growth rate, serum TSH and thyroxine, or
free thyroxine at frequent intervals is essential to
make sure therapy is continuing and effective
especially in the first 2–3 years. The American
Academy of Pediatrics recommends testing chil-
dren every 2–3 months for the first 6 months, 2–3
months until 3 years old, and 6–12 months there-
after. Lab values should have free T4 or total T4 in
the upper ½ of the range and TSH between 0.3
and 5 (or some say 0.3–2) mIU/mL. There is con-
tinued evaluation of the best dose of thyroxine to
be used and how to monitor the dosage. There are
conflicting reports as to whether slight overtreat-
ment is harmful. Most agree that rapid normal-
ization of free thyroxine values is appropriate.
If a patient with diagnosed primary hypothy-
roidism has not had an elevation of the serum
TSH to abnormally high values during treatment,
which would have demonstrated a permanent
impairment of thyroid function, and has no
known anatomic defect in the thyroid gland, a
careful challenge off medication may be tried, at
age 3 years of age to see if they have a transient
defect. Such a challenge can only be carried out
in those patients that have reliable families and
can be counted on to return for follow-up; if these
criteria are met, thyroxine can be discontinued
for 2–4 weeks, with serum T4 and TSH measured
at 1, 2, 4, and 6 weeks to determine thyroid func-
tion. Most thyroid-dependent brain growth is
completed by 3 years, so that the test is safer at
this age than at an earlier age, but it is not advis-
able to leave a hypothyroid child off thyroxine
for long intervals, even at this age. If elevated
TSH is seen confirming permanent hypothyroid-
ism, the trial off therapy is over and the child
deserves renewed and continued thyroxine ther-
apy; if no elevation of TSH occurs by 6 weeks off
thryoxine, the child is normal.
Neonates with congenital hypothyroidism may
have elevated TSH concentrations for months or
even years after the onset of appropriate therapy
because of a persistent abnormality of feedback
suppression; attempting to suppress these TSH
concentrations to normal levels may lead to exces-
sive thyroxine dosage. Thus the goal of therapy
should be to maintain a normal serum thyroxine
or free thyroxine concentration at the upper half
108
of the normal range for age rather than to suppress
the TSH to normal values for age at this early age.
Significant overtreatment with thyroxine will
cause advancement of the bone age and can lead
to craniosynostosis and can decrease intellectual
attainment. Further, the administration of full
treatment dosages of thyroxine to infants with
congenital hypothyroidism that were untreated for
a period of months may cause the onset of conges-
tive heart failure because of the rapid mobilization
of fluid accumulated during the myxedematous
state; in such children with late onset of therapy, it
is preferable to work up to the full dose over a
period of 7–14 days. Of course, excessively low
dose of thyroxine for a long time may lead to a
poorer CNS result, so this titration of the dose
upward cannot be a prolonged process.
Sick premature infants may have low TSH
and thyroxine values due to their immature devel-
opment. Neonatologists have considered thyroid
supplementation for severely premature infants
with no evidence of thyroid disease other than
these lab values. Clinical studies have not shown
consistent benefit, and this is not recommended
practice. Likewise there is no evidence of benefit
in treating infants with the sick euthyroid syn-
drome of low T4, T3, and TSH with thyroxine.
Patients treated early and appropriately with
thyroxine are likely to have normal intelligence
according to ever accumulating data. Parents should
be reassured about the expected normal outcome as
the institution of neonatal thyroid screening and
neonatal treatment has markedly decreased the
morbidity of this common condition. In only very
rare cases, even if therapy began in the first week of
life, severe intellectual impairment is reported.
The brain is dependent upon the supply of thy-
roxine which is deiodinated locally to produce
T3, so if a fetus is normal even if the mother is
thyroid deficient, the T3 supply to the brain
should be acceptable in most cases. Likewise if a
fetus is hypothyroid and the mother is normal, a
small amount of thyroxine that passes the pla-
centa from mother may provide adequate sub-
strate to allow appropriate levels of T3 in the fetal
brain. However, lack of maternal thyroxine in the
face of fetal hypothyroidism leads to a profound
deficiency of T3 leading to severe developmental
6 Disorders of the Thyroid Gland
delay. Prenatal therapy of fetuses in families
with proven genetic hypothyroidism is reported.
This is presently considered an experimental pro-
cedure. While there is evidence (still controver-
sial) that untreated or poorly treated maternal
hypothyroidism is correlated with lower intelli-
gence in offspring who do not have hypothyroid-
ism, there is no confirmatory evidence of the
benefit of treating the mother with thyroxine
during pregnancy. This is in distinction to the
definite improvement in fetal outcome if iodine
deficiency is treated during pregnancy.
Acquired Hypothyroidism
Acquired hypothyroidism is not a rare disease.
It is estimated that this group of disorders occurs
in over 1 % of school-age children.
Childhood hypothyroidism starting after age
2–3 years does not carry the risk of permanent
mental retardation, as does untreated neonatal
hypothyroidism, but temporary, reversible behav-
ior changes are frequent. Mild congenital abnor-
malities, such as an ectopic thyroid gland, may
first manifest in the childhood period, although
most will have been diagnosed by moderate ele-
vations of the TSH level in the newborn screen-
ing programs. The addition of iodine to food in
the USA has effectively eliminated endemic
iodine-deficient goiter, although children born in
many other countries are still at risk as are those
whose parents insist on “natural” salt or other
foods without iodine added.
Symptoms of classic hypothyroidism include
cold intolerance, constipation, and some weight
gain due to myxedema. In spite of common per-
ceptions that hypothyroidism is responsible for
significant obesity, the weight gain does not
increase to the extent of severe obesity. Skin is
dry, and the hair is brittle and even sparse in
hypothyroidism. Long-standing primary hypo-
thyroidism may lead to enlargement of the pitu-
itary gland due to increased TSH secretion:
erosion of the sella turcica may appear to indicate
the presence of a tumor on radiograph, so thyroid
function should always be evaluated in the face
of such a finding, if otherwise unexplained.
Hypothyroidism
Hypothyroidism causes poor postnatal growth
and results in short stature. Long-bone growth is
diminished, and the upper-to-lower-segment
ratio (see Chap. 5) is decreased for age, leading
to immature proportions. The bone age is delayed,
often significantly. Puberty and menarche is
delayed or absent in teenage patients. Treatment
will increase growth rate to values often higher
than the average for age leading to “catchup
growth.” In addition, treatment of acquired hypo-
thyroidism will advance bone age and, if the
child is old enough, precipitate appropriate
pubertal development. However, if the condition
is untreated for a long period, adult height will be
compromised even with appropriate treatment.
Autoimmune Thyroid Disease:
Hashimotos Thyroiditis
Hashimoto thyroiditis or chronic lymphocytic
thyroiditis or autoimmune thyroid disease
(*140300 HASHIMOTO STRUMA at 8q23-q24)
is responsible for the majority of cases of acquired
hypothyroidism. This autoimmune disorder is
often found in the same family group as Graves’
disease. In Hashimoto thyroiditis, there is forma-
tion of unsuppressed clones of thymus-dependent
lymphocytes directed against the thyroid gland,
causing lymphocytic infiltration of the gland. B
lymphocytes, either through interaction with T
lymphocytes or because of stimulation linked to
the damaged thyroid cells, produce antithyroid
antibodies, antithyroglobulin, or antithyroid per-
oxidase antibodies (previously called antimicro-
somal antibodies) that are characteristic of the
disorder and are a cornerstone of the diagnosis.
Hashimoto thyroiditis is frequently associated
with other disorders. Autoimmune polyglandular
diseases may include Hashimoto thyroiditis:
Type 1 (#240300 ICD+AUTOIMMUNE
POLYENDOCRINE SYNDROME, TYPE I,
WITH OR WITHOUT REVERSIBLE
METAPHYSEAL DYSPLASIA; APS1) may be
inherited in an autosomal dominant or autosomal
recessive manner and consists of two of three
major conditions hypoparathyroidism, Addison’s
disease, and mucocutaneous candidiasis, which
might be the first sign noted. Other findings may
include hypothyroidism, hypogonadism, kerato-
109
conjunctivitis, dental enamel hypoplasia, chronic
active hepatitis, cholelithiasis, asplenia, malab-
sorption, diarrhea, chronic atrophic gastritis,
vitiligo, ectodermal dystrophy, alopecia, insulin-
dependent diabetes mellitus, transient, isolated
hypoaldosteronism, and pernicious anemia.
Type 2 (269200 SCHMIDT SYNDROME)
consists of hypo- or hyperthyroidism, Addison’s
disease, type 1 diabetes mellitus, but not hypo-
parathyroidism nor candidiasis.
Type 3 autoimmune polyendocrinopathy may
be invoked to describe Hashimoto thyroiditis
with one of the other autoimmune endocrine
organ failures with the exception of Addison’s
disease which is not included in type 3. Thus
other features of the type 3 syndrome may include
type 1 diabetes mellitus, celiac disease, hypogo-
nadism, sarcoidosis, Sjogren syndrome rheuma-
toid arthritis, vitiligo, and alopecia.
Clinical characteristics of Hashimoto thyroid-
itis include goiter, minimally to severely elevated
TSH concentrations, and frequently a family his-
tory of thyroid disease. A characteristic pebbly
surface to the gland is felt because of accentua-
tion of the normal follicular structure of the
gland. A positive titer of antithyroid peroxidase
antibodies or antithyroglobulin antibodies or
both are helpful in diagnosis; children more fre-
quently have the former antibodies, whereas
adults more usually have the latter. Lymphocytic
infiltration of the thyroid gland occurs, with the
formation of germinal centers on histologic study
(there is no need to obtain tissue for histology for
diagnosis however). There is no reason to per-
form a thyroid scan or uptake in a well-
documented case of Hashimoto thyroiditis.
Elevated serum TSH and decreased FT4 indi-
cate obvious primary hypothyroidism. Lower but
slightly elevated TSH concentrations with nor-
mal serum FT4 present a problem. As noted
above, TSH values in childhood may be consid-
ered normal by some evidence. Normal children
who have TSH values up to 7.5 mIU/L in a study
with years of follow-up demonstrates no further
elevation in most cases and often decreases to
lower levels in children. However, if the TSH is
definitively elevated, the treatment is clear: the
administration of thyroxine until the TSH is sup-
110
pressed to normal and the serum FT4 increases to
or stays at normal. If the TSH is not elevated and
the goiter is minimal, the patient may be regu-
larly evaluated for further deterioration in thyroid
function during the following months and years.
If the goiter is noticeable, thyroxine may be given
for a period of 3 months to see if the goiter can be
diminished; if the small goiter does not change,
thyroxine may be stopped and the patient fol-
lowed up until the thyroxine treatment may
become definitively necessary.
Rarely children are born with only one lobe of
thyroid gland, usually the left. This tissue may
undergo compensatory hypertrophy, and it has
the usual chance of developing Hashimoto thy-
roiditis, causing a presentation of hypothyroid-
ism with one-sided goiter.
Annual screening is recommended for Down
syndrome, Turner syndrome, and Klinefelter syn-
drome, all of whom are predisposed to the devel-
opment of autoimmune hypothyroidism.
Remarkably, premature sexual development
occurs in some children with untreated primary
hypothyroidism which is identified as the Van
Wyk–Grumbach syndrome; girls have breast
development, and boys have enlargement of tes-
tes and possible slight enlargement of the penis,
but usually don’t demonstrate premature devel-
opment of pubic hair. Galactorrhea may be found
because of increased secretion of prolactin in pri-
mary hypothyroidism, as TRF stimulates prolac-
tin as well as TSH release (see Chap. 9a).
Other Causes for Acquired
Hypothyroidism
Other causes for acquired hypothyroidism
include a thyroglossal duct cyst (188455
THYROGLOSSAL DUCT CYST, FAMILIAL)
for the rare genetic form in the midline of the
neck. While usually non or poorly functional, it
may contain the only functioning thyroid tissue
available to the patient; if any midline congenital
defect of the neck is removed surgically, it may
contain a thyroglossal duct cyst; the patient must
be evaluated for the development of hypothyroid-
ism, or, alternatively, the patient should have a
thyroid scan to confirm the presence of remaining
thyroid tissue which will function after the cyst is
6 Disorders of the Thyroid Gland
removed. Internationally, iodine deficiency is the
most common cause of acquired hypothyroidism
as endemic cretinism (above). Excess iodine
intake (e.g., from kelp given by a naturopath,
medications containing iodine, radiographic
dyes, and/or topical from antisepsis therapy such
as Betadine for an open umbilical wound) may
suppress thyroid function and temporarily lead to
hypothyroidism, but will later escape due to the
Wolff–Chaikoff effect. Certain drugs impair thy-
roid function such as lithium which can cause
hypothyroidism and goiter or amiodarone which
may cause either hypothyroidism or hyperthy-
roidism. Infiltrative disease from Langerhans cell
histiocytosis or lymphoma or hemochromatosis
due to iron infiltration of the thyroid gland due to
transfusions for thalassemia or cystinosis may
cause primary hypothyroidism. Infiltrative dis-
eases such as lymphoma and Hodgkin’s disease
and their treatment can affect thyroid function as
rarely can a teratoma. Treatment for hyperthy-
roidism (e.g., surgery or radiation) even if ini-
tially leading to euthyroid status will often later
lead to hypothyroidism. A liver hemangioma caus-
ing elevated activity of type 3 deiodinase that pref-
erentially converts T4 to reverse T3 and T3 to T2,
thereby decreasing available thyroid function, will
lead to acquired hypothyroidism; sometimes the
hypothyroidism is diagnosed first and leads to the
diagnosis of the hemangioma. Some hemangioma
are reported to shrink with glucocorticoid therapy
resolving the inactivation of thyroid hormone.
With improvement in oncology care, more
and more children survive cancer. If there was
radiation to the head and neck, hypothyroidism
may develop in close to one-third, and all are at
risk for the development of thyroid carcinoma.
Chemotherapy may affect thyroid function as
may infiltrative conditions such as Hodgkin’s
disease. Thus, laboratory testing with free T4 and
TSH is indicated and ultrasonography to detect
the formation of nodules.
Any disease of the hypothalamic–pituitary
area may decrease TSH secretion, leading to sec-
ondary or tertiary hypothyroidism (see Chap. 3).
Abnormalities of TBG may be congenital (as
above), but also may be acquired. Thus, increased
TBG binding of thyroid hormones occurs with
Hypothyroidism
estrogen treatment or pregnancy or is the result of
an inherited condition; decreased TBG binding
of thyroid hormones occurs with androgen ther-
apy, protein-losing conditions, and an X-linked
genetic condition (see earlier). If free T4 is nor-
mal, thyroxine therapy may not be needed. There
is significant and sometimes contradictory litera-
ture of the effects of antiepileptic drugs including
phenytoin (Dilantin), phenobarbital, valproate,
carbamazepine, oxcarbazepine, and levetirace-
tam; there are reported changes in thyroid func-
tion in some but no definite evidence that
thyroxine therapy is necessary just due to the
medication use. Clinical correlation is necessary.
Euthyroid Sick Syndrome
Euthyroid sick syndrome presents with abnor-
mal thyroid laboratory findings in an individ-
ual with nonthyroidal illness without any
disorder of the hypothalamic pituitary thyroid
axis. After the illness resolves the laboratory
tests revert to normal. Characteristically
decreased serum T3 and serum T4 with possibly
low TSH is found with elevated reverse T3 as is
found in the fetus; some call this the low T3
syndrome. Thyroid treatment is usually not
necessary in this condition since the condition
resolves with treatment of the underlying
disorder.
Diagnosis of Hypothyroidism
Diagnostic techniques are outlined above in indi-
vidual disorders. It is important for the provider
to realize that there is a normal variation in thy-
roid function tests which extend beyond the labo-
ratory reference intervals in some cases and to be
aware that subtle changes from the laboratory
standards may not be grounds for treatment.
Likewise some individuals in the population have
antithyroid antibodies with no apparent disease
and no need for treatment. Details of diagnosis
are found above for various conditions.
Treatment of Hypothyroidism
Acquired hypothyroidism is treated with thyrox-
ine in a variable dose, depending on age and based
111
on weight, up to a maximum of 100–150 μg (see
Table 6.3); older children require less thyroxine
per kilogram body weight than is used in a neo-
nate with hypothyroidism. Unlike some neonates
with congenital hypothyroidism, older children
can safely have the dose titrated until the serum
TSH is suppressed to normal. In the most severe
cases with severe myxedema or even pericardial
effusion, the dose must be slowly increased.
Pseudotumor cerebri is rarely encountered after
the initiation of treatment in severe cases and
sometimes even before treatment commences. No
proven advantage is found in T3 or T4/T3 nor des-
iccated thyroid treatment over thyroxine treat-
ment. Treatment with thyroxine should return the
child to the baseline state. Thus if the child was
hyperactive before hypothyroidism developed,
treatment may return the child to hyperactivity
and school work may suffer. Parents must know
this in advance and understand the treatment is
necessary and support in school must follow.
Parents must understand that once the diagnosis
of acquired hypothyroidism is established, the
treatment will likely be lifelong.
The half-life of thyroxine is 5–7 days.
Stabilization after initiation of thyroxine treat-
ment or a dose change usually takes 5–6 weeks to
occur, so in most cases laboratory tests should be
timed to this interval. T3 is not usually used for
therapy; the half-life of T3 is only 1 day. This can
be used to advantage when a nuclear medicine
scan has to be performed. The patient can be
switched to T3 for 4–6 weeks and the T3 discon-
tinued the day before the scan is performed; this
avoids unnecessary malaise of the hypothyroid
state which would last 6 weeks if T4 was discon-
tinued without any thyroid hormone replacement
while waiting for the scan.
Overtreatment is detrimental as is lack of
treatment. Excessive thyroxine dosage can
advance bone age and lead to decreased intellec-
tual development. Even normal doses of thyrox-
ine have been reported to rarely cause
pseudotumor cerebri in children.
In the absence of diagnosed hypothyroidism,
thyroxine is not to be used as a “weight loss drug.”
112 6 Disorders of the Thyroid Gland

Hyperthyroidism may be required for the 12 weeks or so until the

Neonatal Hyperthyroidism
Maternal thyroid-stimulating immunoglobulins
freely pass the placenta and can have significant
effects on the fetus. These antibodies may last for
years in the mother after she has been treated for
hyperthyroidism and may affect her fetus even
though she is asymptomatic due to surgery or
radioactive iodine therapy administered years
earlier. Only a minority of offspring of a mother
with Graves’ disease will have signs of hyperthy-
roidism. Fetal hyperthyroidism may be indicated
by tachycardia and IUGR on ultrasound. Maternal
hyperthyroidism requires referral to a high-risk
obstetrics center with appropriate therapy for the
mother. If the maternal dose of antithyroid medi-
cation is excessive, the child may be born pro-
foundly hypothyroid, with goiter, and can even
have severe respiratory insufficiency because of
pressure on the trachea exerted by the large goi-
ter. At birth an infant of maternal hyperthyroid-
ism may have a positive screen for congenital
hypothyroidism if the mother was treated with
PTU or methimazole that pass through the pla-
centa to the child. After the medication effect is
eliminated in a few days, neonatal hyperthyroid-
ism may develop. If there are extreme manifesta-
tions in some, mortality is possible. The newborn
may develop goiter, tachycardia, elevated blood
pressure, failure to gain weight, flushing, and
even exophthalmos. Congestive heart failure due
to supraventricular tachycardia and hepato-
splenomegaly may occur. Methimazole therapy
stimulatory antibodies decrease. In addition,
Lugol solution may be given to inhibit thyroxine
secretion and glucocorticoids may be given in
high dosage to limit T4 and T3 conversion.
Once thyroid levels decrease the child is sus-
ceptible to the effects of hypothyroidism on brain
development due to overtreatment with thyroid
lowering agents. Close monitoring and augmenta-
tion of low serum T4 with thyroxine as necessary
during this period and the antithyroid medications
should be weaned down as soon as feasible.
Mothers with hyperthyroidism may take
methimazole while breast-feeding. Current guide-
lines suggest that the amount of methimazole in
the breast milk is too low to cause significant
effects as long as the mother’s dose is no more
than 20 mg per day. It is suggested that she take
the medication immediately after breast-feeding.
However if the child has any suggestion of liver
disease or blood dyscrasia, evaluation is war-
ranted since these can be caused by methimazole
in rare cases.
Older Children
Hyperthyroidism in pediatrics is usually due to
Graves’ disease (#275000 GRAVES DISEASE),
an autoimmune disease that may coexist with
Hashimoto thyroiditis (Table 6.4). The incidence
of Graves’ disease is lower than Hashimoto thy-
roiditis in childhood, about 1:10,000 for Graves’
disease. Girls are more often affected than boys
(5:1) with Graves’ disease. Human leukocyte
antigen (HLA)-DR3 and HLA-B8 predispose

Table 6.4 Etiologies of hyperthyroidism

Disorder Free T4 TSH RAI uptake Other features
Autoimmune Graves’ disease High Low Early elevation Thyroid-stimulating immunoglobulin
or TSH receptor antibodies positive
TSH-secreting pituitary tumor High High NA Look for pituitary tumor on MRI
Pituitary T3 resistance High High NA Increased TSH is secreted because of
resistance to T3 feedback
Nodular hyperthyroidism High Low Hot nodule (nodule takes RAI uptake demonstrates the activity
up 123I, but the rest of the of the nodule
thyroid gland does not)
TSH receptor-activating High Low NA Could be isolated or part of the
mutations McCune–Albright syndrome
RAI radioactive iodine, SH thyroid-stimulating hormone, MRI magnetic resonance imaging, NA not applicable
Hypothyroidism
Caucasians to Graves’ disease. The peak age at
onset is near adolescence. Thyroid-stimulating
hormone receptor antibodies (TR-Ab) and
thyroid-stimulatory immunoglobulin (TSI) (vari-
ous laboratories use various abbreviations for this
same test or similar ones, so check with the labo-
ratories for the tests offered; most commercial
tests do not differentiate between stimulating
(TRS-Ab), neutral, and blocking antibodies
(TRB-Ab)) are directed toward the TSH receptor,
leading to autonomous thyroid function and
hyperthyroidism with suppression of TSH. Other
antibodies displace TSH from the TSH receptor
but do not stimulate the thyroid gland (these are
thyroid-binding inhibiting immunoglobulins
(TBIIs); these vary as TBII from patients with
Hashimoto thyroiditis decrease thyroid function,
while TBII in Graves’ disease sometimes block
the stimulatory antibodies and sometimes do
not). T3 is produced more efficiently in Graves’
disease than in the normal state, and both T4 and
T3 exceed the TBG capacity, so that FT4 and FT3
increase. In some cases, the T4 is normal, but the
T3 is elevated; in the diagnosis of hyperthyroid-
ism, both should be measured, as both must be
suppressed during therapy. Serum TSH is sup-
pressed in Graves’ disease because of the autono-
mous formation of thyroid hormones.
Weakness, increased pulse rate, emotional
lability or other behavior changes (sometimes to
the point of apparent psychiatric disease and
remarkable personality changes to the point of
engaging in illegal activity out of character for
the patient), hyperactivity, and lack of attention
span, weight loss, and diarrhea are characteristic
findings. Subtle or significant goiter may be
found, possibly with a bruit over the thyroid
gland. Exophthalmos may occur because of infil-
tration of glycosaminoglycan in the posterior
area of the orbit. Increased autonomic tone can
cause lid retraction and “stare.” These two
ophthalmologic conditions may at first look simi-
lar but should be noted separately. Pretibial myx-
edema, sometimes called Graves’ disease
myopathy or peau d’orange (orange peel) skin,
presents as a waxy, discolored induration of the
skin on the anterior aspect of the lower legs in
some patients, although it is more common in
113
affected adults (this is not to be confused with the
myxedema of profound hypothyroidism, which
shares a term, but means protein-bound muco-
polysaccharides deposition in areas of the skin
which leads to a swollen appearance). Signs of
Graves’ disease also include systolic hyperten-
sion and velvety (smooth) and moist skin. Deep
tendon reflexes are brisk, even to the point of clo-
nus especially in the ankle jerks. Supraventricular
tachycardia may be a presenting symptom and
lead to an admission to a pediatric ICU before the
diagnosis of hyperthyroidism is considered or
established.
Before establishing a diagnosis of Graves’
disease, it is important to consider factitious
hyperthyroidism. Thyroid hormone is readily
available in the medicine cabinet of many (often
middle-aged individuals) some diagnosed with
bona fide hypothyroidism and others erroneously
diagnosed as such. The wide availability of thy-
roxine may lead to toxic ingestion of parent’s
thyroxine by an infant or even Munchausen’s by
proxy by the administration of thyroxine to a
child.
A hot nodule rarely may be active enough to
cause hyperthyroidism in a child.
Hamburger thyrotoxicosis is due to ingestion
of ground beef in which the bovine thyroid asso-
ciated with neck muscles was included in the
serving.
Diagnosis
Laboratory findings in hyperthyroidism are ele-
vated serum T4 and T3 (both in either the total or
free determination) with nondetectable or sup-
pressed TSH. If the TSH is not suppressed, the
patient may have a TSH-secreting condition as
the etiology for hyperthyroidism, an exception-
ally rare occurrence in pediatrics. A positive
TSH receptor antibody or TSI titer may be
found (but check with the specific laboratory
for the designation of this test, as noted earlier).
Often positive titers of antithyroglobulin and
antimicrosomal antibodies are seen; if the titers
of antimicrosomal and antithyroglobulin anti-
bodies are very elevated, the patient may have
the hyperthyroid phase of Hashimoto thyroid-
itis in which preformed thyroid hormone is
114
released (often called Hashitoxicosis), which
may be short lived and not require a permanent
type of treatment; thus follow-up is very impor-
tant. Thyroid growth-stimulating antibodies
and thyrotropin receptor-blocking antibodies
are found, as well as lymphocytic infiltration of
the thyroid gland.
It is usually not necessary to perform a thyroid
scan or uptake if the constellation of symptoms
and laboratory results are classic. If, however, a
scan is used, an early (4-h) determination of
uptake should be made before turnover of the
radioactive tracer occurs in this condition of
increased thyroid metabolism. The results of a
RAI scan in hyperthyroidism will be increased
uptake, while in Hashitoxicosis uptake will be
decreased.
A complete blood count (CBC) is obtained
to detect changes in the white blood cell
(WBC) count due to the hyperthyroid state; the
WBC count may already be decreased in
untreated hyperthyroidism or may be decreased
later by medical therapy for hyperthyroidism.
Liver function should be evaluated before
starting the thyroid medication: for reference
ALT > 25U/L (boys) and > 22U/L (girls) are
considered normal but higher levels may be
found in untreated hyperthyroidism.
Propylthiouracil (PTU) is no longer used on a
regular basis in pediatrics but in rare occasions
might have to be invoked for brief therapy during
preparation for surgery should methimazole
cause undue side effects. Determination of anti-
nuclear antibody (ANA) titers should be obtained
if PTU is to be used as treatment to ensure that a
positive antibody determination, a finding some-
times reported in the untreated hyperthyroidism,
is not present before medication is given; PTU
may seriously affect liver function or cause a
lupus-like syndrome and carries a black box
warning from the FDA.
Some children will have elevated thyroid lev-
els without symptoms of hyperthyroidism, which
is described as subclinical hyperthyroidism. This
may persist for years before Graves’ disease
develops, and therapy may not be necessary in
the initial stage. Some may normalize.
6 Disorders of the Thyroid Gland
Treatment of Hyperthyroidism
There is a chance of remission in children and
adolescents with Graves’ disease. The likelihood
of remission increases with milder abnormalities
of laboratory tests at presentation, resolution of
the hyperthyroid state within 3 months of starting
treatment, and older age at onset. About 20 %
of affected children go into remission for every
2 years of treatment, but the rate of remission pla-
teaus in about 8–10 years with a total of about
50–75 % achieving a remission overall in various
series. Three types of treatment for hyperthyroid-
ism are used: medication, radiation therapy, and
surgery.
Knowing the factors which enhance the
likelihood remission help determine whether a
progression to permanent therapy such as surgery
or radiation is best if medication is being consid-
ered for the first treatment modality.
Medication
Methimazole is the only medical therapy now rec-
ommended for children and adolescents in the
USA. Methimazole blocks organification of iodine
and decreases T4 to T3 conversion. PTU, previ-
ously recommended, now has a black box warning
that it should not be given to children (nor adults)
due to risk for liver cirrhosis which may lead to the
ultimate need for a liver transplant. Methimazole
is given in doses of 0.2–0.5 mg/kg per day (the
widest reported range for dosage of methimazole
is 0.1–1.0 mg/kg per day) which usually comes
out to 15–45 mg/day for a teenager. It is generally
divided into 2–3 doses per day, but some will
achieve control with a dose given once or twice per
day. The aim is to cause a sufficient suppression of
the autonomous thyroid function to bring about a
euthyroid state; this suppression of the thyroid
gland is not a cure of the disease but rather a con-
trol of the condition. The patient is followed up for
shrinkage of the goiter, an essential finding if
remission is to be expected. Guidelines suggest the
use of medication for only 1 year, but in practice
many continue for multiple years before consider-
ing a permanent type of therapy.
Side effects occur 5–20 % of the time during
such medical therapy. Serious side effects of
Hypothyroidism
methimazole are not common but can be life-
threatening; granulocytopenia or agranulocytosis
is dose dependent and usually is found in the first
100 days of use: if fever, sore throat, or general ill
feelings arise, a CBC must be checked before
administering more methimazole. Stevens–
Johnson syndrome or other rashes are reported.
Arthralgia may occur and reversible cholestasis
is a risk so warnings for development of jaundice
are indicated. Mild peroxidase–antineutrophil
cytoplasmic autoantibodies (ANCA)-associated
vasculitis may occur later well, but the side
effects noted above generally occur before 1 year
treatment.
PTU was known to cause lupus-like syndrome
and hepatitis possibly leading to cirrhosis, but the
switch to the use of methimazole has lessened
such risks.
These drugs should be discontinued if serious
side effects develop, and alternative methods of
therapy should be used which include surgery
and radioactive therapy. Lack of compliance, a
common condition in the adolescent age group,
also is an indication for surgical or radioiodine
therapy. Short-term carefully monitored use of
PTU may be considered if severe reaction to
methimazole occurs.
Propranolol (2–3 mg/kg/day or 5–10 mg every
6 h as a starting dose) can control symptoms of
hyperthyroidism while awaiting another mode of
therapy to exert its effects and is useful in short-
term situations such as in preparation for surgery
or in the face of thyroid storm; side effects of pro-
pranolol on respiratory (bronchospasm) or circu-
latory (hypotension) function are possible, so
patients must be chosen for this medication care-
fully in case they have asthma or another condi-
tion in which propranolol is contraindicated.
Studies have shown propranolol to be helpful for
long-term management in adults, but it has not
generally been used as such in children.
Definitive types of therapy are surgery or
radioactive iodine treatment. With successful
treatment of hyperthyroidism even without
affecting the parathyroid glands, the child may
experience “hungry bone syndrome” and a ten-
dency toward hypocalcemia for months after
115
therapy, and thus calcium and vitamin D moni-
toring and if necessary treatment are in order.
Surgery
Total or near total thyroidectomy is an alternative
therapy, but subtotal thyroidectomy is associated
with a higher recurrence rate. An experienced
high-volume thyroid surgeon (30 cases per year)
should perform the operation so that complica-
tions will be unlikely; there is a 30 % complica-
tion rate in children in general, but if a high-volume
pediatric thyroid surgeon is used, the rate
decreases to 4 % in a recent study. Recurrent
laryngeal nerve paralysis is an unusual but possi-
ble complication. Transient hypocalcemia can
follow thyroidectomy because of postoperative
edema of the parathyroid glands, or the condition
could be permanent if the parathyroid glands are
removed along with the thyroid tissue. Thyroid
storm could develop rarely during thyroid sur-
gery. Preparation for surgery involves the use of
medical management to control the hyperthyroid
state. Some use supersaturated iodine solution
(Lugol’s, 8 drops per day) for the 10 days before
surgery; the iodine will reduce the blood supply to
the gland. Iodine has only a temporary effect in
suppressing thyroxine secretion from the hyper-
thyroid gland; escape usually will occur after 2–4
weeks (the Wolff–Chaikoff effect), so the surgery
should be set soon after starting iodine treatment.
Although the surgeon may be able to remove the
optimal amount of tissue to allow euthyroid func-
tion after surgery, hypothyroidism may develop in
the years after surgery because of continued scar-
ring and reduced function of the remaining thy-
roid tissue, according to some reports. Thyroid
storm may develop during surgical therapy, espe-
cially in patients not yet under control, so pro-
pranolol therapy may be needed.
Nuclear Medicine Therapy
Radioactive iodine (131I; RAI) therapy has been
used in hyperthyroidism for more than 50 years
and has proved safe in studies of adolescents who
received this therapy. No thyroid cancers have
been detected if the dose of radioactivity is calcu-
lated to destroy all thyroid tissues. However,
116
there are reports of the development of secondary
cancers in the tissue surrounding the thyroid
gland four to five decades after radioactive iodine
therapy, and this factor must be considered when
considering radioactive iodine therapy. No effects
on offspring of adults previously treated with
RAI are noted unless of course it is administered
during pregnancy. Although no documentation of
statistically increased risk is found, some still
consider it ill advised to administer RAI to
younger children for a potentially reversible con-
dition. The Pediatric Endocrine Society sug-
gested that 131I therapy may be beneficially used
in younger patients, but it is more commonly
used now in adolescents. As one dose of RAI
may not cure the patient especially if the dose is
inappropriately low, another dose may be neces-
sary. Thyroid storm could occur during RAI treat-
ment, especially in patients not yet under control,
so propranolol therapy may be needed here as
well.
Female patients of reproductive age must be
warned about the risks to a fetus of Graves’ dis-
ease itself and of the effect of medical therapy for
the condition. Radiotherapy for hyperthyroidism
must not be administered if the patient was
pregnant.
Treatment of neonatal Graves is detailed
above.
Hyperthyroidism rarely occurs because of a
thyroid adenoma (hot nodule) or carcinoma, sub-
acute thyroiditis, or suppurative thyroiditis. These
possibilities are covered elsewhere in this chapter.
Two rare instances occur when hyperthyroid-
ism might be found with elevated serum TSH
values. Selective pituitary resistance to thyroxine
(145650 HYPERTHYROIDISM, FAMILIAL,
DUE TO INAPPROPRIATE THYROTROPIN
SECRETION, autosomal dominant) leads to lack
of feedback inhibition to T3 feedback, so TSH
increases, and hyperthyroidism results, as the rest
of the body can respond to the increased secre-
tion of thyroid hormone even if the pituitary
gland cannot. Further, a rare TSH-secreting pitu-
itary tumor might cause hyperthyroidism with
elevated serum TSH and FT4.
Hyperthyroidism may be caused by muta-
tions of the TSH receptor (#609152
6 Disorders of the Thyroid Gland
HYPERTHYROIDISM, NONAUTOIMMUNE),
so that constitutive activation leads to uncon-
trolled thyroid hormone secretion. Findings
include low birth weight, tachycardia, advanced
bone age, delayed motor development, delayed
speech development, mental retardation, sleep
difficulties, hyperactivity with laboratory find-
ings of decreased TSH, and increased free T4.
They will have no exophthalmos nor pretibial
myxedema.
The McCune–Albright syndrome may dem-
onstrate autonomous thyroid function because of
mutations of the G protein (see Chap. 8).
Thyroid Storm
Thyroid storm is a rare complication in children
and adolescents. Thyroid storm may present with
acute onset of hyperthermia and tachycardia in a
patient with underlying hyperthyroidism.
Precipitating factors include surgery, infection,
pregnancy, and diabetic ketoacidosis. It may
occur during surgical or radioiodine therapy for
hyperthyroidism. Symptoms include high fever,
sweating, tachycardia, and reduced mental state
ranging from confusion to coma. Immediate ther-
apy is indicated for this severe condition.
Propranolol (1–3 mg/kg orally per day, divided
into a dose every 6 h as a starting dose) can con-
trol some symptoms of thyroid storm. Propranolol
may be given intravenously at a dose of 0.01 mg/
kg up to a total of 5 mg at a rate of less than 1 mg/
minute, but an intraatrial pacing catheter is a nec-
essary precaution because of the risk of serious
bradycardia. Dexamethasone in a dose of 1–2 mg
every 6 h can reduce serum T3. Lugol’s solution
of concentrated iodine can be given orally if the
patient is conscious to decrease the release of
thyroid hormone from the thyroid gland; intrave-
nous NaI in a dose of 1–2 g/day divided into 1/2
dose ever 12 hours may be given if the patient is
adult sized and is unconscious. A cooling blanket
can help control the hyperpyrexia. Methimazole
will not take effect for several days, but to plan
for the possibly extended course of the disorder,
20–30 mg can be given every 6 h (by slurry, if
necessary) in larger children. Fluid management
must be observed, and if tachycardia causes heart
failure, digitalis may be necessary.
Hypothyroidism
Thyroid Hormone Overdose
A toddler or older child may ingest excessive
amounts of an adult’s thyroid hormone.
Alternatively, there is the possibility that
Munchausen’s by proxy may be considered in
which the dose is purposefully administered.
Close to one-third of the reported cases of thy-
roxine overdose in the USA in 2008 were in the
pediatric age group. Thyroxine takes several days
to exert its effect due to its 5–7-day half-life, so
the presentation may be delayed after the expo-
sure. Triiodothyronine however is more rapid
acting, and the effects will occur similar. The pre-
sentation of thyroid hormone excess is similar to
that of hyperthyroidism or thyroid storm. Thus,
the patient will manifest gastrointestinal symp-
toms including abdominal pain, nausea and vom-
iting, diarrhea or anorexia, nervous system
findings including anxiousness, tremor, increased
deep tendon reflexes, confusion, psychosis, or
even seizure. Adrenergic effects of thyroid hor-
mone overdose include rapid pulse, palpitations,
sweating, hypertension or hypotension, and ele-
vated temperature. Because of the increased met-
abolic rate in hyperthyroidism, adrenal
insufficiency may develop more easily if the
patient is already developing autoimmune
Addison’s disease. Long-term exposure to ele-
vated doses of thyroxine will increase symptom-
atology, and in addition to advanced bone age
and craniosynostosis in younger children, weight
loss may occur and the patient may progress to
coma. An EKG in an individual with excessive
thyroxine ingestion will likely show supraven-
tricular tachycardia.
Neoplasms
A single firm nodule of the thyroid gland is a
more ominous finding in a child than is multiple
nodular goiter. The majority of solitary lesions
will be benign, but carcinoma is possible. Lack
of concentration of 123I on thyroid scan (a cold
nodule) increases the likelihood of carcinoma as
functioning nodule (warm or hot nodule) has a
117
lower likelihood of malignancy. Ultrasonographic
evidence that the nodule is a cyst makes it less
likely to be malignant, but carcinomas may be
found in the walls of thyroid cysts, and the solid
portion of a cyst is a target for diagnostic fine-
needle aspiration. The presence of enlarged
anterior cervical lymph nodes, metastases on
chest radiograph, or hoarseness all make the
likelihood greater that the single thyroid nodule
is malignant.
Carcinomas of the thyroid gland are rare in
childhood (these constitute less than 1 % of child-
hood cancers and less than 10 % of all thyroid
cancers), but certain historic features increase the
likelihood of a thyroid mass being malignant.
Children with thyroid Ca have a good prognosis
for survival in spite of a higher risk of recurrence
than in adults even if metastases may be discov-
ered at presentation. A history of low level irra-
diation of the thyroid gland (e.g., inadvertently
while treating acne, enlarged thymus, or ring-
worm, as was done in the past, or due to a nuclear
accident, as in Chernobyl) at a young age is sig-
nificant, and if the irradiation was done for the
therapy of another cancer (e.g., at the time of
bone marrow transplant), the risk is higher. The
risk of cancer is greatest if radiation occurs dur-
ing early childhood, but thyroid tumors appear
even decades after irradiation. The local radiation
used for the treatment of Graves’ disease does
not appear to cause thyroid carcinoma, as it elim-
inates all of the thyroid follicular cells as it con-
trols Graves’ disease. Indeed, there is no record
of thyroid cancer developing in children treated
with ablative doses of radioactive iodine for
Graves’ disease. However, a 50-year follow-up
of pediatric patients treated with radiation doses
similar to that used for Graves’ disease shows
increased risk of carcinoma in the tissue sur-
rounding the thyroid that was irradiated but not in
thyroid tissue itself as it was eliminated. Staging
in children according to adult standards is not as
helpful as in adults to predict future complica-
tions. Likewise while adult nodules are biopsied
when they reach 1 cm in diameter in most cases,
in children biopsy should occur when nodules are
0.5 cm.
118
Many areas and cell types of the thyroid
gland may undergo neoplastic degeneration. A
survey between 1973 and 2004 of children with
thyroid carcinoma in the USA revealed that
83 % had papillary carcinoma, 9.5 % had fol-
licular carcinoma, and 5 % had medullary
carcinoma.
Medullary Carcinoma
of the Thyroid (MCT)
Medullary carcinoma of the thyroid (MCT) arises
from parafollicular C cells and is most often
found in the MEN 2 syndrome (see Chap. 10)
(#171400 MULTIPLE ENDOCRINE
NEOPLASIA, TYPE II; MEN 2) at 10q11.2 or
(#162300 MULTIPLE ENDOCRINE
NEOPLASIA, TYPE IIB; MEN 2B at 10q11.2)
as almost all cases of MEN 2 are associated with
MCT. C-cell hyperplasia may precede develop-
ment of medullary carcinoma of the thyroid.
Isolated MCT can occur in an autosomal domi-
nant condition (#155240 MEDULLARY
THYROID CARCINOMA, FAMILIAL; MTC at
1q21-q22, 10q11.2). Germ cell-line mutations in
the ret oncogene, a proto-oncogene with a tyro-
sine kinase domain on chromosome 10q11.2, are
demonstrated in patients with MCT with or with-
out MEN 2. Prophylactic thyroidectomy is rec-
ommended by 10 years or earlier in affected
patients with appropriate ret mutations.
Epithelial-Derived Differentiated
Thyroid Cancer (DTC)
Epithelial-derived differentiated thyroid cancer
(DTC) includes papillary thyroid carcinoma
(PTC) and follicular thyroid carcinoma (FTC).
The age-adjusted annual incidence is 0.54 cases
per 100,000 children or adolescents, 1 per
1,000,000 at 10 years of age, 1 per 200,000 from
10 to 14 years of age, and 1 per 75 at 15–19 years.
Seventy percent of children present with local
metastases and 15 % with distant metastases,
usually in the lungs. Distant metastases will not
likely appear on standard imaging but are seen on
RAI scans. Recurrence rates up to 30 % are found
as long as 20 years later.
6 Disorders of the Thyroid Gland
Familial Nonmedullary Thyroid Carcinoma
Familial occurrence of papillary or follicular Ca
is recognized in families with 3 or more members
with DTC. Screening of family members at 18
years of age is recommended.
Papillary Carcinoma
Papillary carcinoma may demonstrate enlarged
lymph nodes as well as a thyroid nodule. This
may be associated with Gardner syndrome
(*175100 ADENOMATOUS POLYPOSIS OF
THE COLON; APC at any of 5q21-q22, 1p34.3-
1p32.1), which is transmitted in an autosomal
dominant pattern and includes disorders of mul-
tiple systems including colonic polyps and other
neoplasias; follow-up is necessary in case thyroid
carcinoma develops in a patient diagnosed with
Gardner syndrome. Autosomal dominant forms
of papillary carcinoma exist (#188550 THYROID
CARCINOMA, PAPILLARY associated with
any of 17q23-q24, 14q, 10q21, 10q11.2, 8p22-
p21.3, 1p13, 7q32-q34 loci). Abnormalities in
the ret or trk oncogenes may be found in papil-
lary Ca.
Follicular Thyroid Carcinoma
Follicular thyroid carcinoma is usually found in a
sporadic pattern but may be an autosomal dominant
condition (188470 THYROID CARCINOMA,
FOLLICULAR; FTC at 10q23.31). This neoplasm
is found less frequently in children than the other
two types listed.
Diagnosis
The steps involved in the diagnosis of a solitary
nodule are determination of function by labora-
tory evaluation, radioiodine scan, and either nee-
dle biopsy or open surgical biopsy and excision.
Determination of free T4 and TSH can be helpful;
if thyroid hormone is elevated and TSH sup-
pressed, there may be a hyperfunctioning nodule.
Evaluation of the appearance by ultrasound scan
may help determine if there is carcinoma; irregu-
lar borders, heterogeneous densities, and micro-
calcifications are indicators of greater likelihood
of cancer.
Hypothyroidism
Fine-needle aspiration under ultrasound guid-
ance is indicated in suspicious nodules 0.5–1 cm
according to some authorities. FNA is useful in
evaluation of lymph nodes since metastases to
lymph nodes is common and presurgical knowl-
edge of metastases will help surgical planning.
Needle biopsy is safe and has a low level of
false-negative results, but the experience of the
local pathologists in performing and reading nee-
dle biopsy specimens is important in making the
choice. Even if a needle biopsy suggests a benign
or indeterminate diagnosis, if the nodule fails to
shrink on suppressive thyroxine therapy or grows
over the ensuing months, it may require open
excisional biopsy as well. In the absence of expe-
rienced clinical help in the procedure of needle
biopsy or in a situation heavily suggestive of a
malignant diagnosis, open excisional biopsy is
best. Only 60 % of samples obtained through
fine-needle aspiration in childhood are diagnos-
tic. New molecular biology techniques offer the
promise of improved diagnosis and ultimately
improved prediction of prognosis in children
with thyroid cancer.
Measurement of calcitonin in the basal or cal-
cium or pentagastrin-stimulated (it is difficult to
get pentagastrin at the time of this writing) state
is indicated if there is suspicion of MCT or the
finding of a first-degree relative with a ret muta-
tion. Evaluation for pheochromocytoma in
affected individuals is important (see Chap. 10).
Treatment of Thyroid Carcinoma
Surgery
Total or near total thyroidectomy is performed if
papillary or follicular carcinoma is found to min-
imize remaining neoplastic tissue. Treatment by
a high-volume surgeon (more than 30 thyroid Ca
surgeries per year) is important due to the high
complication rate with such a diagnosis; even an
experienced surgeon experiences a 15 % compli-
cation rate including recurrent laryngeal nerve
damage, hypoparathyroidism, hemorrhage, and
infection, and children under 6 years are most
susceptible to complications. Surgery is usually
the course of treatment for hyperfunctioning nod-
ules as they rarely regress spontaneously.
119
Radiation
Outcome studies support the use of radioactive
ablation (131I using ablative dosage) of remaining
tissue or metastases after surgery in children;
there is a 20–30 % recurrence rate if both modali-
ties of therapy are not combined. Decades of
study suggested the safety of this modality for
children as young as 5 years. However, recent
longer-term follow-up data demonstrated an
increased risk of secondary carcinoma four to
five decades later in tissues near the original thy-
roid, but not in the thyroid bed. Thus, concern for
secondary malignancies after successful RAI
therapy arise; studies in children are sparse, and
details are missing in many long-term follow-
ups, so firm conclusions are not available. There
is the confounding factor that having thyroid Ca
predisposes a patient to risk for secondary malig-
nancies which makes interpretation of studies on
the issues of secondary malignancies after RAI
treatment more difficult. In addition to reproduc-
tive risks, there is a risk of pulmonary fibrosis
(for those with lung metastases). There are also
risks to family members, especially in children at
the home, exposed to radiation-treated children
if they return home in the days after administra-
tion of RAI therapy before the radiation has
passed out of their body.
Preparation for RAI treatment includes main-
taining a low iodine diet and avoiding iodine-
containing soaps or medication (e.g., contrast,
amiodarone) for 1 month. Low urinary iodine
excretion is a sign that the patient has successfully
diminished or eliminated iodine from their diet.
The patient may be rendered hypothyroid by
withdrawing T4 for 4 weeks before the radioactive
dose is to be administered so that the thyroid
gland will avidly take up iodine due to the ele-
vated TSH caused by the cessation of T4 replace-
ment. Alternatively switching to T3 replacement
for the 4 weeks before RAI treatment and, because
of the short half-life of T3, stopping the T3 just the
day before treatment will allow patients to elimi-
nate the symptoms of hypothyroidism that would
have occurred if 4 weeks passed without any thy-
roid hormone. This method of using T3 prior to
treatment will not suppress the thyroid tissue’s
avidity for iodine uptake for successful treatment.
120
The patient must not be constipated or retained
iodine will affect the GI tract. At the time of RAI
administration recombinant human TSH (rTSH)
may be invoked to further ensure that the thyroid
takes at the radioactive iodine, but this treatment
is not FDA approved for children and is extremely
expensive.
Suppression of remaining tissue by replace-
ment therapy with thyroxine administration is
carried out thereafter. This raises the risk of
effects on behavior and growth as suppressive
doses of thyroxine are higher than replacement
dose. Serum thyroglobulin determination will
indicate if there is any remaining thyroid tissue
(normal or neoplastic) but cannot be performed if
there are thyroglobulin antibodies present. If thy-
roglobulin antibodies exist, they may be mea-
sured at intervals as reduction of thyroid/tumor
tissue will lower the antibody level. Follow-up
highly by sensitive US scans are preferred over
RAI scans to minimize further radiation exposure.
Recombinant human TSH may be used to stimu-
late the remaining thyroid tissue before radioac-
tive iodine scans are performed. Treatment of
metastases that take up iodine may be accom-
plished by large doses of radioiodine.
Painful Thyroid Glands
Tenderness of the thyroid gland may indicate a
viral infection (subacute thyroiditis) or a bacte-
rial infection (suppurative thyroiditis). Either of
these conditions will be accompanied by an ele-
vated erythrocyte sedimentation rate. Subacute
thyroiditis also called de Quervain thyroiditis
may follow a viral illness such as mumps. The
course usually includes a phase of hyperthyroid-
ism due to release of preformed thyroid hormone;
during this phase the RAI uptake is decreased,
due to damage to the thyroid gland. The course of
the viral illness may last 6–9 months and then
spontaneously improve. Suppurative thyroiditis
might be accompanied by fever, sore throat,
hoarseness, or dysphagia, most of which are
absent in subacute disease. It is important to
search for a pyriform sinus fistula by barium
swallow, which may play a role in the etiology of
6 Disorders of the Thyroid Gland
suppurative thyroiditis. The viral condition is
accompanied by a lymphocytosis on CBC, and
the bacterial form, by an elevated WBC count,
with a “shift to the left.” Bacterial infections are
treated with appropriate antibiotics, and viral
infections, with anti-inflammatory medications
until inflammation resolves.
Hyperfunctioning Nodule
Hyperfunctioning nodules may lead to symptoms
of hyperthyroidism. They may be solitary or mul-
tiple. A RAI scan will demonstrate one or more
“hot” nodules that take up tracers, while the rest
of the thyroid is “cold” and does not. Due to the
concern that the hot thyroid tissue will take up
high levels of radioactivity but the cold regions
will have lower levels and the concern of the
effect of nonablative radioactivity exposure in the
cold tissue in younger children, a surgical
approach is usually preferred.
Further Reading
1. Rivkees SA. Chapter 12—thyroid disorders in chil-
dren and adolescents. In: Sperling MA, editor.
Pediatric endocrinology. Philadelphia, PA: Elsevier;
2014. 4th ed; 2014. p. 444–470.
2. Vliet GV, Deladoëy J. Chapter 7—disorders of the
thyroid in the newborn and infant. In: Sperling MA,
editor. Pediatric endocrinology. Philadelphia, PA:
Elsevier; 2014. 4th ed; 2014. p. 186–208.
3. Leger J, Gelwane G, Kaguelidou F, Benmerad M,
Alberti C. Positive impact of long-term antithyroid
drug treatment on the outcome of children with
Graves’ disease: national long-term cohort study.
J Clin Endocrinol Metab. 2012;97(1):110–9.
4. Bahn RS, Burch HB, Cooper DS, Garber JR,
Greenlee MC, Klein I, Laurberg P, McDougall IR,
Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan
MN. Hyperthyroidism and other causes of thyro-
toxicosis: management guidelines of the American
Thyroid Association and American Association of
Clinical Endocrinologists. Endocr Pract. 2011;
17(3):456–520.
5. De Vries L, Bulvik S, Phillip M. Chronic autoimmune
thyroiditis in children and adolescents: at presentation
and during long-term follow-up. Arch Dis Child.
2009;94(1):33–7.
6. American Academy of Pediatrics, Rose SR, Section
on Endocrinology and Committee on Genetics,
American Thyroid Association, Brown RS, Public
Health Committee, Lawson Wilkins Pediatric
Endocrine Society, Foley T, Kaplowitz PB, Kaye CI,
Further Reading
Sundararajan S, Varma SK. Update of newborn
screening and therapy for congenital hypothyroidism.
Pediatrics. 2006;117(6):2290–2303.
7. Rivkees SA, Mazzaferri EL, Verburg FA, Reiners C,
Luster M, Breuer CK, Dinauer CA, Udelsman R. The
treatment of differentiated thyroid cancer in children:
emphasis on surgical approach and radioactive iodine
therapy. Endocr Rev. 2011;32(6):798–826.
8. LaFranchi SH. Approach to the diagnosis and treat-
ment of neonatal hypothyroidism. J Clin Endocrinol
Metab. 2011;96(10):2959–67.
9. Ferrara AM, Onigata K, Ercan O, Woodhead H, Weiss
RE, Refetoff S. Homozygous thyroid hormone recep-
tor beta-gene mutations in resistance to thyroid hor-
mone: three new cases and review of the literature.
J Clin Endocrinol Metab. 2012;97(4):1328–36.
10. Rivkees SA. Pediatric Graves’ disease: management
in the post-propylthiouracil Era. Int J Pediatr
Endocrinol. 2014;2014(1):10.
11. Glaser NS, Styne DM. Predicting the likelihood of
remission in children with Graves’ disease: a pro-
spective, multicenter study. Pediatrics. 2008;121(3):
e481–8.
12. Zimmerman D. Thyroid carcinoma in children and
adolescents: diagnostic implications of analysis of
the tumor genome. Curr Opin Pediatr. 2013;25(4):
528–31.
13. Rivkees SA. Pediatric Graves’ disease: controversies
in management. Horm Res Paediatr. 2010;74(5):
305–11.
14. Cunniff C, Frias JL, Kaye C, Moeschler JB, Panny SR,
Trotter TL, Comm G. Health supervision for children
with Down syndrome. Pediatrics. 2001;107(2):442–9.
15. Loomba-Albrecht LA, Bremer AA, Styne DM,
Glaser NS. High frequency of cardiac and behav-
ioral complaints as presenting symptoms of hyper-
thyroidism in children. J Pediatr Endocrinol Metab.
2011;24(3-4):209–13.
121
16. Fu J, Dumitrescu AM. Inherited defects in thyroid
hormone cell-membrane transport and metabolism.
Best Pract Res Clin Endocrinol Metab. 2014;
28(2):189–201.
17. Negro R, Stagnaro-Green A. Diagnosis and manage-
ment of subclinical hypothyroidism in pregnancy.
BMJ. 2014;349:g4929.
18. Luongo C, Trivisano L, Alfano F, Salvatore D. Type 3
deiodinase and consumptive hypothyroidism: a com-
mon mechanism for a rare disease. Front Endocrinol.
2013;4:115.
19. Ortiga-Carvalho TM, Sidhaye AR, Wondisford
FE. Thyroid hormone receptors and resistance to thy-
roid hormone disorders. Nat Rev Endocrinol. 2014;
10(10):582–91.
20. Francis GL, Waguespack SG, Bauer AJ, Angelos P,
Benvenga S, Cerutti JM, Dinauer CA, Hamilton J,
Hay ID, Luster M, Parisi MT, Rachmiel M, Thompson
GB, Yamashita S; American Thyroid Association
Guidelines Task Force. Management Guidelines for
Children with Thyroid Nodules and Differentiated
Thyroid Cancer. Thyroid. 2015;25(7):716–59.
21. Marti JL, Jain KS, Morris LG. Increased risk of sec-
ond primary malignancy in pediatric and young adult
patients treated with radioactive iodine for differenti-
ated thyroid cancer. Thyroid. 2015;25(6):681–7.
22. LaFranchi S. Acquired hypothyroidism in childhood
and adolescence. UpToDate,http://www.uptodate.
com/contents/acquired-hypothyroidism-in-childhood-
and-adolescence
23. LaFranchi S. Clinical features and detection of con-
genital hypothyroidism. http://www.uptodate.com/
contents/clinical-features-and-detection-of-
congenital-hypothyroidism
24. LaFranchi S. Treatment and prognosis of congenital
hypothyroidism. http://www.uptodate.com/contents/
treatment-and-prognosis-of-congenital-hypothyroidism
 Disorders of Calcium Metabolism
and Bone
Calcium is essential for skeletal integrity and
plays an essential role in the function of all of the
living cells of the body. The intracellular and
intravascular concentration of calcium in blood is
maintained within a narrow range. Increases or
decreases in serum and intracellular calcium
concentrations may be caused by a wide range of
etiologies and can lead to profound changes in
organ function.
Calcium Metabolism
Storage and Absorption of Calcium
The majority of the body’s store of calcium resides
in the skeleton, with about 1 % in the recently
deposited bone, a pool that can mobilize more eas-
ily, and only 1 % of the body’s calcium is found in
the serum. Calcium is measured as total calcium,
comprising protein bound and the ionized form.
Ionized calcium, the form that causes physiologic
effects, comprises about 45 % of the total serum
calcium; ionized calcium measurements are now
readily available. Ionized calcium is tightly regu-
lated within a narrow range of values. Of the
remainder, 50 % circulates bound to albumin and
globulin, and the rest is associated with other ions.
Thus, total calcium must be interpreted in light of
the amount of circulating protein, because in states
of low protein total calcium decreases; correction
may be calculated as total serum calcium level
declines by 0.8 mg/dL for every 1 g/dL decrease in
© Springer International Publishing Switzerland 2016
D.M. Styne, Pediatric Endocrinology, DOI 10.1007/978-3-319-18371-8_7
7
serum of albumin under 4 g/dL. Ionized calcium
is affected by pH as alkalosis increases protein
binding limiting ionized calcium which may pre-
cipitate symptoms of hypocalcemia and acidosis
releases calcium from protein binding raising
ionized calcium. Calcium also varies by age
(see Chap. 15). Thus, the physiologic state of
the individual must be considered when inter-
preting either total or ionized calcium.
There are several ions and hormones that
control calcium. Thus, parathyroid hormone,
1,25-dihydroxyvitamin D, and, more likely in
pathologic situations, calcitonin and parathyroid
hormone-related peptide (PTHRP) affect serum
calcium. Plasma phosphate and magnesium also
play an important role in aspects of the regulation
of calcium.
Calcium is taken up from the gastrointestinal
tract by two mechanisms. The paracellular mecha-
nism occurs when calcium is taken up through the
tight junctions between cells and is facilitated by
proteins including claudins. Active transport of
calcium across the gastrointestinal cells from the
lumen is the major process involved in calcium
absorption, and this process can be influenced by
1,25-dihydroxyvitamin D; inability to respond to
1,25-dihydroxyvitamin D leads to hereditary
1α,25(OH)2D-resistant rickets (HVDRR).
The gastrointestinal (GI) tract can increase the
efficiency of calcium absorption by active trans-
port in states of diminished calcium intake
through vitamin D-dependent process. However if
oral intake is less than 200 mg/day, excretion
123
124
from stool exceeds the amount of absorption,
leading to a net loss of calcium which cannot be
remedied by the GI tract. On the other hand the
GI tract limits active calcium absorption if GI
intake increases above 1,000 mg/day, but passive
absorption cannot be limited; thus excessive oral
calcium intake can cause hypercalcemia (e.g., the
milk alkali syndrome). Endocrine factors affect-
ing calcium absorption include growth hormone
and estradiol which increase absorption and thy-
roid hormone and glucocorticoid which decrease
absorption.
About 95 % of calcium that enters the renal
tubule is reabsorbed. Calcium is resorbed in the
renal tubules mainly by passive paracellular pro-
cesses generally similar to those in the gastroin-
testinal tract although active transcellular
resorption occurs as well under the control of
parathyroid hormone. Renal tubular resorption is
affected by dietary intake, physiologic status, and
various genetic conditions. Resorption of cal-
cium is stimulated by parathyroid hormone and
parathyroid hormone-related protein, but gluco-
corticoids and mineralocorticoids decrease
resorption. Increased excretion occurs in states of
increased calcium intake, hypercalcemia (in the
absence of hypercalciuric hypercalcemia), loop
diuretics, and increased plasma volume.
Serum calcium is regulated within close limits
by several hormones that balance GI intake with
urinary or fecal loss; the skeleton serves as a reser-
voir of calcium, so that calcium may be mobilized
when needed or stored if necessary. In disorders of
calcium metabolism, excessive calcium may be
removed from the bone, or, alternatively, defi-
ciency in various factors may impair bone forma-
tion, leading to one of several bone diseases.
Besides increasing bone strength, calcium
plays a major role in cellular function by acting
as an intracellular second messenger as described
in the beta cell, cardiac cells, and other cells else-
where in this book. Calcium plays an essential
role in the secretion of neurotransmitters, nerve
conduction, and muscle function. Hypocalcemia
leads to increased neuromuscular excitability
leading to tremor; paresthesia around the mouth,
fingers, and toes; muscle cramps; tetany; laryngo-
spasm; stridor or seizures; and apnea in neonates
7 Disorders of Calcium Metabolism and Bone
as a result. As a reflection of the central role of
calcium in cardiac cell function, hypocalcemia
can lead to prolongation of the QT interval on an
electrocardiograph.
The Calcium-Sensing Receptor
Maintenance of serum calcium is accomplished
by changes triggered by the calcium-sensing
receptor (CASR (+601199 CALCIUM-SENSING
RECEPTOR; CASR)), a plasma membrane
G-protein-coupled receptor that is expressed in
the parathyroid hormone-producing chief cells of
the parathyroid gland where parathyroid hormone
is produced and released, the cells lining the kid-
ney tubule where calcium is resorbed and the C
cells of the thyroid gland where calcitonin is pro-
duced and released. The CASR can sense small
changes in circulating calcium concentrations,
and genetic alterations in the receptor are respon-
sible for normal variation in serum calcium
ranges as well as several diseases as described
below. The CASR has a “set point” which is the
calcium concentration at which PTH secretion is
half-maximal; if the set point is too high, hyper-
calcemia will result, and if the set point is too
low, hypocalcemia may occur. In the normal state
an increase in serum calcium will stimulate the
CASR to suppress parathyroid hormone secre-
tion and to decrease the resorption of calcium in
the renal tubule. However, mutations can cause
an increase or decrease in sensitivity of CaSR
leading to hypo- and hypercalcemia respectively.
An example is familial hypocalciuric hypercalce-
mia in which a decrease of sensitivity of the
calcium-sensing receptor leads to hypercalcemia
and retention of calcium in the urine. Other tis-
sues express CASR demonstrating a remarkable
range of effects changes in serum calcium may
bring about.
Phosphate
Phosphorus in the form of phosphate is another
major component of bone but also plays an
important role in cell function throughout the
Calcium Metabolism
body involved in such processes as membrane
receptor activation and in the formation of high-
energy compounds. About 80 % of phosphate is
found in bone, 9 % in skeletal muscle, 10 % in
the viscera, and only about 0.5 % in extracellular
fluid in phospholipids, phosphate esters, and free
inorganic phosphate, the latter being the common
measurement. Serum phosphate varies with age
far more than serum calcium; for example, con-
centrations in premature infants are above
6.4 mg/dL, in children are 4.2–6.4 mg/dL, and in
older teenagers are 2.2–4.3 mg/dL.
Phosphate is absorbed in the small bowel
mainly by active processes directly stimulated by
1,25-dihydroxyvitamin D and therefore indi-
rectly stimulated by hypocalcemia and parathy-
roid hormone. In states of phosphate deficiency a
low phosphate level stimulates the production of
more 1,25-dihydroxyvitamin D and thereby
increases phosphate absorption.
Phosphorus with calcium forms the hydroxy-
apatite molecules (Ca10(PO4)10(OH)2) which are
responsible for the strength of bone and make up
85 % of skeletal weight. As serum calcium rises
phosphate decreases and vice versa; the product of
calcium times phosphorus in a normal state is 30.
If the product rises above 30, ectopic calcification
may occur. Phosphate is absorbed in a process
similar to calcium with both active and passive
transport. About 30 % of phosphate absorption is
passive. Phosphate is widely available in food,
and passive absorption is proportional to the
amount of intake. Active intestinal phosphate
absorption is increased by 1,25-dihydroxy-
vitamin D. The kidney is the organ that is mostly
responsible for the regulation of phosphate.
Phosphorus is resorbed in the kidney tubules by an
active process which is increased by hypophos-
phatemia but decreased by hyperphosphatemia
and parathyroid hormone and parathyroid hor-
mone-related protein. A hallmark of the hypo-
parathyroid state is elevated serum phosphate due
to increased resorption.
Fibroblast growth factor 23 (FGF23) is a
member of the phosphatonin family which
decreases phosphate resorption in the renal tubule
and inhibits 1-α-hydroxylase, thereby decreasing
the formation of 1,25-dihydroxyvitamin D
125
(or calcitriol) and decreases PTH secretion.
Secretion of FGF23 is normally inhibited by
hypophosphatemia. FGF23 is coded by the
phosphate regulating endopeptidase homolog,
X-linked, gene (PHEX). Hypophosphatemic
rickets is characterized by elevations of FGF23
due to inactivating mutations in PHEX. New
clinical research studies are attempting to treat
the condition by utilizing antibodies to FGF23.
FGF23 can be measured in commercial laborato-
ries; the assays are more accurate in elevated
states than reduced states of FGF23. FGF23 is
also elevated in the tumoral calcinosis syndrome
which is likely a cause of the abnormal phosphate
metabolism in that condition.
Phosphate can shift from extracellular to intra-
cellular locations in many conditions, and this
may present as hypophosphatemia. Insulin treat-
ment of diabetic ketoacidosis is one example of
this phenomenon and is also found in the refeed-
ing syndrome, e.g., after treatment of anorexia
nervosa and hungry bones syndrome noted below.
Respiratory alkalosis is also associated with intra-
cellular shift of phosphate.
Since phosphate is mainly an intracellular ion,
evaluation of the true state of phosphate abun-
dance is difficult due to variation throughout the
day in serum samples. Tubular reabsorption of
phosphate can be carried out on a 3-h timed urine
collection for phosphate and creatinine matched
with serum values of phosphate and creatinine
after an 8-h fast. The percent tubular reabsorption
of phosphate is calculated, and if it is high in
times of hyperphosphatemia or low in times of
hypophosphatemia, it indicates a disorder of the
proximal tubule. Excessive FGF23 will cause low
1,25-dihydroxyvitamin D and low percentage
reabsorption of phosphate, while diminished
FGF23 will cause increase in the reabsorption of
phosphate and 1,25-dihydroxyvitamin D.
Magnesium
Magnesium is necessary in adequate quantities to
allow the secretion of parathyroid hormone and
for its interaction with the parathyroid hormone
receptor. Only about 1 % of the body’s magnesium
126
stores are extracellular. About 30 % of magnesium
in the circulation is protein bound with the rest
being free of protein. Thus, hypomagnesemia is a
cause of the hypoparathyroid state and hypocal-
cemia; if this is the etiology of hypocalcemia,
repletion of magnesium will cure it. The absorp-
tion of magnesium in the gastrointestinal tract
occurs generally by passive mechanisms although
there is an active component which if altered by
loss of function of the transporter can lead to sec-
ondary hypocalcemia. The active resorption of
magnesium in the renal tubule is stimulated by
PTH and inhibited by hypermagnesemia and
hypercalcemia. When magnesium stores are low,
renal resorption increases. Hypomagnesemia
may occur because of lack of absorption or due to
renal leaks of magnesium. Some causes of sec-
ondary hypomagnesemia are Bartter syndrome,
renal tubular acidosis, acute renal failure, chronic
inflammatory bowel disease, or postsurgical
intestinal resection. Evaluating a spot magne-
sium-to-creatine ratio in urine will determine
whether it is due to a renal leak if the ratio is high
or magnesium depletion if the ratio is low.
Hypermagnesemia will also suppress parathy-
roid hormone secretion.
Parathyroid Hormone
and Parathyroid Hormone-Related
Protein
Parathyroid hormone (PTH) is a polypeptide pro-
duced in the chief cells of the four parathyroid
glands formed by the third and fourth pharyngeal
arches; a fifth parathyroid gland may be located
within the thyroid gland in some individuals (but
some people have as many as seven).
PTH is synthesized as a larger prehormone
that is metabolized to the mature 1–84 parathy-
roid molecule. The active portion of parathyroid
hormone is in the first 34 amino acids in the N or
amino terminal region. Soon after secretion the
parathyroid hormone molecule is cleaved into
C-terminal and N-terminal moieties. There are
various assays for PTH; the amino terminus
assay measures the biologically active form that
has a shorter half-life, while the C terminal assay
7 Disorders of Calcium Metabolism and Bone
measures the various inactive forms of PTH that
have a longer half-life. Unfortunately because
parathyroid hormone is secreted intact and as the
inactive carboxy terminus of PTH as well, assays
must be highly specific to measure the active
parathyroid hormone in the circulation. In fact
the lack of specificity of various assays leads to
significant differences in values, especially in the
presence of renal disease where the terminal mol-
ecules are present in higher concentrations; it is
important to know the characteristics of the assay
being used and what it actually measures.
The CSAR stimulates increased production
and secretion of PTH when it senses a low calcium
concentration and inhibits the process when cal-
cium concentration is high. High serum phosphate
enhances secretion of PTH, while high 1,25-dihy-
droxyvitamin D decreases secretion of PTH.
Parathyroid hormone interacts with its seven-
transmembrane domain G-protein-coupled type 1
receptor, type 1 PTH/PTHrP which is found in the
kidney and on osteoblasts but also on other tissues.
Parathyroid hormone interacts with its receptor to
stimulate adenyl cyclase, and measurement of
nephrogenic cAMP (by measuring plasma and uri-
nary cAMP) is a measure of parathyroid hormone
activity; in some types of pseudohypoparathyroid-
ism nephrogenic cAMP does not rise after para-
thyroid hormone administration. The effects of
parathyroid hormone or parathyroid hormone-
related protein are inhibiting renal resorption of
phosphate in the proximal tubule of the nephron,
increasing renal resorption of calcium in the distal
tubule, increasing renal 1α-hydroxylation of
25-hydroxyvitamin D which in turn increases
intestinal calcium absorption, and increasing the
intestinal absorption of calcium. PTH mobilizes
calcium and phosphorous from the skeleton by
simulating differentiation of osteoclasts, the cells
that cause bone resorption, from circulating mono-
cytic hemopoietic cells, stimulating bone remodel-
ing, and releasing calcium and phosphorus
hydroxyapatite in the bone.
Parathyroid hormone-related protein
(PTHrP) while important in fetal calcium
metabolism is produced after birth by various
tumors and may serve as a tumor marker for
these conditions. It is not regulated by a
Calcium Metabolism
feedback inhibition as is parathyroid hormone
and therefore is continuously produced. PTHrP
is formed locally in many tissues and acts in a
paracrine manner on nearby tissue, in contrast to
the endocrine action of PTH which acts at a dis-
tance from the parathyroid gland; however if
PTHrP is produced in great enough quantities, it
also acts as an endocrine substance which raises
serum calcium. PTHrP is responsible for the
hypercalcemia of malignancy.
Vitamin D and Its Metabolites (Fig. 7.1)
Vitamin D is responsible for the absorption of
calcium and phosphorus from the GI tract and
assists in the mineralization of the skeleton by pro-
viding calcium and phosphorus to the osteoblasts.
Endogenous vitamin D3 (or cholecalciferol)
can be considered a steroid hormone, which is
produced from 7-dehydrocholesterol, a choles-
terol metabolite, by the effect of sunlight on the
skin, which breaks the beta ring of the cholesterol
molecule, followed by a rearrangement of the
molecule into the characteristic form of cholecal-
ciferol caused by the heat of the body. The pro-
duction of cholecalciferol proceeds faster with a
lighter complexion than in dark-skinned individu-
als so that 10–15 min of midday sun exposure will
be adequate for light-skinned individuals, two to
three times more for dark-skinned individuals and
six to ten times more for very dark-skinned indi-
viduals to produce adequate vitamin D; Winter
sun exposure would be more. The recommenda-
tion to limit sun exposure through the use of sun-
screen or sun avoidance will not allow these
periods of exposure; vitamin D deficiency may
develop without additional supplemental oral
vitamin D intake. While vitamin D might be found
in oily fish, a customary healthy diet does not con-
tain a sufficient amount of vitamin D, and thus
supplementation with vitamin D is necessary fail-
ing adequate sun exposure. Oral vitamin D is gen-
erally found in the form of vitamin D2 or
ergocalciferol derived from plants, while D3 or
cholecalciferol is derived from animal sources.
They both follow the same metabolic pathways.
Vitamin D is absorbed with other fats since it is a
fat-soluble vitamin and is incorporated into
127
chylomicrons which are delivered to the liver. In
the liver 25(OH)vitamin D is synthesized by
25-hydroxylation of either form of vitamin D.
25(OH)vitamin D values reflect the body’s stores
of vitamin D, and measurements are available
clinically. 25(OH)vitamin D is transported to the
glomerulus bound to vitamin D-binding protein
where it is filtered, resorbed, and in the mitochon-
dria undergoes 1α-hydroxylation to form
1,25-dihydroxyvitamin D (or calcitriol), the active
factor in vitamin physiology and the molecule
which can interact with the vitamin D receptor.
Measurement of 1,25-dihydroxyvitamin D does
not reflect body stores and is not as useful as the
measurement of 25(OH)vitamin D with the excep-
tion of certain metabolic conditions such as loss
of function of 1-α-hydroxylase. 1-α-Hydroxylase
is increased if serum Ca and phosphate are low,
thereby increasing the active vitamin D moiety,
and is also increased by parathyroid hormone
(PTH), PTH-related protein (PTHrP), calcitonin,
growth hormone (GH), prolactin, and insulin-like
growth factor (IGF)-1. Increased serum Ca and
phosphorous and 1,25-dihydroxyvitamin D all
decrease the activity of 1-hydroxylase in a nega-
tive-feedback loop. Calcitriol also decreases PTH
synthesis and secretion by negative feedback.
Calcitriol is inactivated in the liver and kidney
and other organs with increased inactivation in
hypercalcemia and hyperphosphatemia and with
increased FGF23. Calcitriol formation is increased
in several granulomatous conditions as noted
below under other causes of hypercalcemia.
Vitamin D deficiency can occur with absence
of adequate vitamin D intake. However, sun
exposure will increase the production of vitamin
D and will mitigate the situation. Cloudy days or
sun exposure through a window will not allow
the skin to produce much vitamin D. However in
the present era of concern over skin cancer due to
sun exposure in children and the recommenda-
tions for the use of sunscreen, sun exposure in
children must necessarily be limited so that oral
vitamin D intake is usually essential. The NIH
does not recommend sun exposure for more than
a few minutes without protection as a manner of
increasing vitamin D.
Vitamin D deficiency can occur with various
gastrointestinal disorders including celiac disease
128 7 Disorders of Calcium Metabolism and Bone

HO
7-Dehydrocholesterol (skin)

Sun + –
light UV Sun avoidance
CH2
HO
Vitamin D3

Liver – Liver disease

25-Hydroxylase Anticonvulsants
Biliary disease

OH

CH2

25-Hydroxyvitamin D

1α -Hydroxylase Aluminum?? Lead??

Low Ca++ –
Renal disease
Low P
+ PTH Vitamin D - dependency rickets
X-linked hypophosphatic rickets
Kidney

OH + Gut
Ca++
+ Ca++
CH2 Maintain normal
blood calcium
HO OH
1,25-Dihydroxyvitamin D3 Ca– Ca++
– Aluminum
+
Ca++
Calcitonin Mineralization
Demineralization
PTH
1,25(OH)2D

Fig. 7.1 The pathway for the regulation of serum cal-
cium and the biosynthesis of 1,25(OH)2 vitamin D
(redrawn from a figure by Chesney R, in Styne DM, ed.
Pediatric endocrinology: House officer series.). The
child exposed to adequate sunlight will convert 7-hydroxy
cholesterol to vitamin D3. With normal liver function and
no exposure to medications that may inhibit the process,
vitamin D is 25-hydroxylated in the liver. An additional
1-hydroxylase step occurs in the kidney to produce the
active moiety 1,25-dihydroxyvitamin D. The location of
parathyroid hormone and vitamin D effects is indicated
along with factors which may inhibit appropriate effects.
Redrawn from an original figure from R. Chesney with
permission

short bowel syndrome, biliary obstruction, and
any cause of fat malabsorption.
Cholecalciferol and ergocalciferol are fat
soluble, so an overdose will exert effects for
months as it is released from fat. Calcitriol is not
fat soluble, so daily dosing or several doses per
day are needed and its effects last only a short
time. It is easier, and cheaper, to treat with chole-
calciferol than calcitriol in vitamin D deficiency
although calcitriol will be necessary in other con-
ditions in which endogenous conversion to
1,25-dihydroxyvitamin D is limited.
In severe vitamin D deficiency when treat-
ment is offered, the patient may experience hypo-
calcemia due to the hungry bone syndrome. Thus,
the bones long deprived of calcium will with
vitamin D treatment avidly take up calcium lead-
ing to lower serum calcium levels. Thus, calcium
Calcium Metabolism
augmentation is necessary. There may be associ-
ated hypophosphatemia, hypomagnesemia, and
hyperkalemia as described below.
Vitamin D is also ingested from various vita-
min D-supplemented dairy products (D2 or ergo-
calciferol is the most common form in food
although D3, cholecalciferol, is also added to
food) or other foods that may already contain
vitamin D (e.g., oily fish such as salmon and cod
liver oil).
1,25-Dihydroxyvitamin D interacts with the
nuclear transcription factor, the vitamin D recep-
tor (VDR), which is a member of the steroid
receptor superfamily. The complex of the vitamin
D molecule and its receptor forms a heterodimer
with the retinoid receptor and binds to a vitamin
D-responsive element in the DNA on a specific
gene which is responsive to vitamin D such as
genes for calcium binding protein or
24-hydroxylase. VDR is expressed throughout
the body but for the purposes of this discussion is
found in the GI tract, the renal tubule, and the
osteoblasts. The vitamin D receptor can reduce
expression of 1α-hydroxylase while increasing
CYP24 which inactivates 1,25-dihydroxy-
vitamin D. Increased expression of the gene for
the VDR occurs with exposure to 1,25-dihydroxy-
vitamin D, while gene expression is decreased by
glucocorticoids. 1,25-Dihydroxyvitamin D
increases absorption of calcium and phosphorous
from the small intestine and assists PTH in the
resorption of bone to increase serum calcium and
by the production of osteoclasts. 1,25-Dihydroxy-
vitamin D also assists in the mineralization of the
skeleton by maintaining serum Ca and PO4 within
appropriate ranges to allow deposition of
hydroxyapatite, the calcium–phosphorus com-
pound which comprises the mineral portion of
bone. In addition, 1,25-dihydroxyvitamin D
increases retention of calcium from the renal
tubule to decrease the loss of calcium in the urine,
while it decreases phosphorus retention from the
nephron. All forms of vitamin D circulate bound
to a vitamin D-binding protein of 52 kDa.
A complex feedback loop is found in this sys-
tem of calcium regulation, as an increase in
serum calcium decreases PTH secretion, which
in turn decreases the 1α-hydroxylation of 25(OH)
129
vitamin D, limiting the production of 1,25(OH)
vitamin D, and both limit further increase in cal-
cium. Further, a decrease in serum calcium trig-
gers a release of PTH, which increases 1,25(OH)
vitamin D production, and both of these factors
increase serum calcium values. Vitamin D recep-
tors in the parathyroid hormone cells and calcitriol
can suppress parathyroid hormone secretion and
also suppresses calcitonin secretions.
The fetus is completely dependent upon the
maternal supply of vitamin D. 25-Hydroxyvitamin
D crosses the placenta, but if the mother is defi-
cient, the infant will be as well.
Calcitonin
Calcitonin is a polypeptide hormone produced by
the parafollicular or C cells of the thyroid gland.
Calcitonin decreases serum calcium by inhibiting
the action of osteoclasts on bone and by restoring
calcium into bone, thus inhibiting the effect of
PTH on bone. Increased calcitonin is secreted at
times of hypercalcemia by signaling through the
CASR, and calcitonin secretion is decreased at
times of hypocalcemia. Calcitonin is a tumor
marker for medullary carcinoma of the thyroid, a
condition for which it is secreted in excess
(see Chap. 10). Remarkably in spite of the biologic
activities detailed above, absence of calcitonin or
increased endogenous levels of calcitonin do not
significantly affect serum calcium levels.
Nonetheless, exogenous calcitonin is used as
therapy for hypercalcemia although this is being
replaced by bisphosphonates in some situations.
Alkaline Phosphatase
Alkaline phosphatases are a family of metalloen-
zymes responsible for catalyzing the hydrolysis
of phosphate esters and are found in the intesti-
nal, placental, and liver isoforms. Post-translation
modification leads to tissue-specific forms found
in bone, liver, and kidney which can be separated
due to their different isoelectric points and heat
stability by a clinical laboratory. The bone form
is secreted by osteoblasts and increases with min-
130
eralization of bones. Total alkaline phosphatase
measurements characteristically reflect the liver
and bone forms. The alkaline phosphatase from
bone rises during childhood growth and roughly
relates to growth rate. But bone-derived alkaline
phosphatase will also increase in diseases of bone
turnover such as rickets, fibrous dysplasia
(including McCune–Albright syndrome), and
juvenile Paget’s disease reflecting bone activity.
Low levels of alkaline phosphatase lead to the
severe crippling conditions hypophosphatasia
due to mutations in the alkaline phosphatase
gene (ALPL) (#241500 ICD+HYPOPHOSPHA
TASIA, INFANTILE) which is autosomal reces-
sive, (#241510 ICD+HYPOPHOSPHATASIA,
CHILDHOOD) which is autosomal recessive,
and (#146300 ICD+HYPOPHOSPHATASIA,
ADULT) which can be autosomal recessive or
autosomal dominant. At the time of this writing
new therapy to replace enzymatic activity is
pending FDA approval for the severe forms.
Markers of bone formation include total and
bone-specific alkaline phosphatase, osteocalcin,
and serum type 1 procollagen. Markers of bone
resorption are urinary hydroxyproline, urinary total
pyridinoline (PYD), urinary free deoxypyridino-
line (DPD), urinary collagen type 1 cross-linked
N-telopeptide (NTX), urinary or serum collagen
type 1 cross-linked C-telopeptide (CTX), bone
sialoprotein (BSP), and tartrate-resistant acid
phosphatase 5b.
Transient hyperphosphatasemia of infancy
and early childhood is a benign condition found
in children under 5 years of age. Bone and liver
alkaline phosphatase isoforms are elevated
although there is no disease in either organ. After
the passage of a few months, alkaline phospha-
tase returns to normal.
Hypocalcemia (Fig. 7.2)
Hypocalcemia can be due to various etiologies
depending upon the age of the child. The signs
and symptoms of hypocalcemia are likewise
dependent on the age of the child. Thus, we will
consider hypocalcemia in the infant and hypocal-
cemia at an older age.
7 Disorders of Calcium Metabolism and Bone
Hypocalcemia in the Infant
Normal term infants have serum Ca greater than
8.5 mg/dL and ionized Ca more than 4.5 mg/dL.
The normal values are controversial in premature
infants, but as a guide, hypocalcemia may be
defined as a serum Ca below as 7.5 mg/dL and
ionized Ca below 4.4 mg/dL(or 1.1 mmol/L) if
birthweight is over 1,500 g and below 7 mg/dL
and ionized Ca below 3.6 mg/dL (0.9 mmol/L) if
birthweight is under 1,500 g. Symptoms of hypo-
calcemia are more nonspecific in newborns than
in older children; poor feeding, emesis, and apnea
may be the only signs. More specific signs of
hypocalcemia that might be found in older infants
include tachycardia, irritability, jitteriness, tetany,
laryngospasm, and seizures.
Early Neonatal Hypocalcemia
For the first few days after birth, the infant will
have difficulty regulating serum calcium. During
this period just after the infant separates from the
maternal calcium supply and the maternal regula-
tion of serum calcium, PTH secretion is often
sluggish, so that transient and mild hypocalcemia
and hyperphosphatemia may result. If the mother
herself has hypercalcemia, the fetus will experi-
ence elevated calcium levels and suppress fetal
parathyroid hormone secretion; after birth there
will be a prolonged period of relative hypopara-
thyroidism while the neonatal parathyroid glands
recover. Further, an infant has a low glomerular
filtration rate that decreases phosphorus excre-
tion and causes increased serum phosphorus,
which further reduces serum calcium. Transient
episodes of low serum calcium during the first 3
days after birth is more common in patients who
are premature, have intrauterine growth retarda-
tion (IUGR) or are small for gestational age
(SGA), have sepsis, have asphyxiation, or are
infants of diabetic mothers (the worse the control
of blood sugar, the lower the Ca in the baby).
This is considered to be early hypocalcemia of
infancy. Cow’s milk contains more phosphorus
than does human milk, even though the calcium
content is higher: the load of oral phosphorus
may enhance the tendency to hypocalcemia of
infancy to symptomatic levels in infants fed with
Hypocalcemia 131

Fig. 7.2 Flow chart of the Low serum Ca

diagnosis of the etiology of
hypocalcemia. Initial
Serum PO4
differentiation between
high serum phosphate
which would suggest a Low High
disorder of parathyroid
hormone action (light gray
arrows) and low serum Serum Alk phos
phosphate which should be
more likely related to an
High Low
abnormality of renal
function open (dashed
dark lines) or vitamin D Serum PTH
stores or action (solid
black line) is a useful to
approach the problem High Low

25 0 H Vitamin D Magnesium

Normal Low Low Normal

Renal Function Vitamin D Hypo- Hypo-

deficiency magnesemia parathyroidism

Normal Abnormal

Pseudohypo- Renal
parathyroidism Disease

cow’s milk formula. This is less common in
breast-fed infants due to the favorable calcium
and phosphorus ratio. Breast milk is a poor source
of vitamin D, especially if the mother has a vita-
min D-deficient diet, and vitamin D deficiency
may occur in an infant because of coexistent vita-
min D deficiency in the mother; this condition is
becoming more common (see below). Thus, early
neonatal hypocalcemia may not occur in breast-
feeding infants, but hypocalcemia and rickets
may develop later unless vitamin D supplementa-
tion of the breast fed neonate is carried out (see
vitamin D deficiency below).
Medications given to the newborn that can
cause hypocalcemia include aminoglycoside
antibiotics, phosphates, citrate, fatty acids, and
bicarbonate.
Late Neonatal Hypocalcemia
If hypocalcemia occurs after 3 days, it is consid-
ered late neonatal hypocalcemia. This may be
due to dietary hyperphosphatemia, which will
lead to low calcium and high phosphorus; low
calcium may trigger PTH secretion and falsely
suggest pseudohypoparathyroidism. Renal dis-
ease may lead to phosphate retention and elevated
parathyroid hormone with the clinical presenta-
tion of reduced renal function. Soy formula or the
early introduction of cereal into the diet leads to
an increased intake of phytates which may lead to
hypocalcemia. Hypomagnesemia will decrease
the secretion of parathyroid hormone leading to
hypocalcemia.
Other causes of hypocalcemia in this period
include hypoparathyroidism. As noted above,
the development of parathyroid function takes a
while after birth, so a transient condition of
hypoparathyroidism can occur. If hypocalcemia
continues, a search for an etiology for decreased
parathyroid hormone secretion or action is war-
ranted. If a chest radiograph shows no thymic
shadow or a cardiac defect of the great vessels is
132
found, the diagnosis of DiGeorge syndrome is
more likely than transient hypocalcemia. The
DiGeorge syndrome (*188400 DIGEORGE
SYNDROME; DGS) results from disordered
development of the third and fourth branchial
pouches and first to fifth branchial arches
derived from neural crest cells. This is usually
found associated with microdeletions of chro-
mosome 22q11.2. This syndrome may be spo-
radic or inherited in an autosomal dominant
pattern and is relatively common with a preva-
lence of 1 in 4,000, similar to congenital hypo-
thyroidism, and is present in 70 % of children
who appeared to have isolated hypoparathyroid-
ism. The classic DiGeorge syndrome combines
hypoparathyroidism with abnormalities of the
aortic arch (such as truncus arteriosus or tetral-
ogy of Fallot) and the thymus (immune defects
related to T-cell defects and disordered cellular
immunity) and impaired cell-mediated immu-
nity. Physical findings include hypertelorism,
short philtrum, micrognathia, malar hypoplasia,
low-set ears, and sometimes cleft palate.
Velocardiofacial syndrome (#192430
VELOCARDIOFACIAL SYNDROME at
22q11.2) has the same gene locus as DiGeorge
syndrome and has, as well, high-arched or sub-
mucous cleft palate, retrognathia, short palpe-
bral fissures, and VSD. The CATCH-22
syndrome is a general term encompassing many
phenotypes caused by mutations at this locus;
this syndrome is composed as a cardiac defect,
abnormal facies, thymic hypoplasia, cleft pal-
ate, and hypocalcemia with deletion at 22q.
Thus, any infant with tetany and hyperphospha-
temia should have evaluation for cardiac and
immune disease at the least, and a genetic screen
should be considered. The hypocalcemia of
DiGeorge syndrome often resolves after infancy
only to recur in some cases at times of rapid
growth of adolescence.
Hypercalciuric hypocalcemia may present in
infancy and is discussed below. There are several
variations of loss-of-function mutations in the
PTH1R. Likewise pseudohypoparathyroidism
may present in an infant and is also discussed
below.
7 Disorders of Calcium Metabolism and Bone
Diagnosis of Infantile Hypocalcemia
As always differential diagnosis starts with a
detailed history. The mother’s nutritional status,
the presence of diabetes, a family history of bone
disease, seizures, kidney stones or other indica-
tions of disorders of calcium metabolism, com-
plications of delivery, and the condition of the
child in the neonatal period all play a role in the
evaluation of the conditions detailed above.
Physical examination will include a search for
dysmorphology and disorders of the extremities
although some of those such as the classic skele-
tal findings of Albright hereditary osteodystrophy
may not develop until later in life. Diagnostic
studies for hypocalcemia of infancy should be
carried before treatment but only if the delay is
judged clinically safe. Thus, obtaining serum
total and ionized calcium, magnesium, phos-
phate, creatinine, 25 OH vitamin D, 1,25-dihy-
droxyvitamin D, PTH (intact), and urinary
calcium and creatinine concentrations is indi-
cated. If diagnosis has not been clarified measur-
ing maternal calcium, phosphorus and PTH level
might be useful. Pseudohypoparathyroidism type
1A may present with associated primary congeni-
tal hypothyroidism and an elevated TSH. The
combination of hypocalcemia and elevated TSH
should point to that possibility. To evaluate the
possibility of DiGeorge syndrome, CBC and
CD4 lymphocyte count are performed. A chest
X-ray to check for a thymic shadow can be done
quickly but may not be completely reliable if the
infant is severely ill. The ultimate diagnostic tool
takes longer, by a fluorescent in situ hybridiza-
tion (FISH) study for a microdeletion of chromo-
some 22q11.2.
Treatment of Newborns
Therapy for asymptomatic hypocalcemia in
infants is usually carried out if the calcium in
the full-term infant is less than 7 mg/dL or in a
premature infant is less than 6 mg/dL, and treat-
ment is provided to those who are symptomatic.
Mild cases might be treated by a change in for-
mula to a low phosphorous formula such as PM
60/40 or one with at least a 4:1 calcium-to-phos-
phorus ratio in addition to oral calcium glubionate
Hypocalcemia
(30–50 mg/kg/day in four divided doses) or calcium
gluconate (500 mg/kg/day in four to six feed-
ings per day). If vitamin D or magnesium is low,
replacement of the deficits is the treatment
modality. Maintenance values of 1,25-dihydroxy-
vitamin D calcium in children with hypopara-
thyroidism range from 20 to 40 ng/kg/day.
With severe symptoms including seizures and
laryngospasm, intravenous (i.v.) 10 % calcium
gluconate (equivalent of 9.3 mg/mL of elemental
calcium) in a dose of 100 mg/kg or 1 mL/kg
infused over 15 min with a total dose no more
than 20 mg of elemental calcium per kilogram is
used. Alternatively, calcium chloride in a dose of
20 mg/kg or 0.2 mL/kg might be substituted with
the same regimen. EKG monitoring for arrhyth-
mias or bradycardia is mandatory at any time i.v.
calcium is administered. If an umbilical venous
catheter is used and the tip is inadvertently is
inserted in the liver, hepatic necrosis may result
from IV calcium administration. A repeated dose
may be administered after 10–15 min if there has
been no response of the symptoms and every 6 h
but only if clinically indicated for continued
hypocalcemia. Maintenance intravenous calcium
is 500 mg/kg/day of 10% calcium gluconate.
Severe hypomagnesemia as etiology for hypo-
parathyroidism is treated with IM injection or a
1–2-h intravenous infusion of 50 % magnesium
sulfate at a dose of 0.1–0.2 mL/kg, again with
careful EKG monitoring. The goal is to achieve a
magnesium level of 1.5 mg/dL.
A decrease in serum ionized Ca2+ leads to the
signs of hypocalcemia: neuromuscular irritability,
causing tetany (heralded by carpopedal spasm,
causing the fingers to extend with ulnar devia-
tion), muscle cramps, weakness, lethargy, pares-
thesias of the extremities, and in the most severe
situation, convulsions and/or laryngospasm (stri-
dor or complete closure of the larynx with the risk
of death) (Table 7.1). Lengthening of the QTc
interval may be seen on the electrocardiogram
(EKG). Although presentation may appear simi-
lar to that of a grand mal seizure, in view of the
tonic/clonic activity, no postictal phase occurs
with the resolution of hypocalcemia.
Hyperventilation causing respiratory alkalosis
will reduce the ionized fraction of calcium by
133
enhanced protein binding of ionized Ca, and this
may precipitate tetany. This situation may occur in
states of anxiety and is treated by rebreathing CO2
(classically from a paper bag) to decrease serum
pH, thereby freeing some calcium from the protein
into the ionized state in the serum. Signs of long-
term hypocalcemia include calcification of the
basal ganglia, cataract formation, and poor tooth
enamel formation. Hypomagnesemia will decrease
PTH secretion and can precipitate a temporary
phase of hypoparathyroidism, which is treated by
remedying the deficit in magnesium rather than by
administration of vitamin D or calcium.
Hypocalcemia in the Child
and Adolescent
The diagnosis of hypocalcemia after infancy is
also based upon age. Normal values will depend
on the laboratory, but one guideline is as follows:
1–5 years the normal range is 9.4–10.8 mg/dL, at
6–12 years it is 9.4–10.2 mg/dL, and up to 20 years
it is 8.8–10.2 mg/dL. On occasion asymptomatic
hypocalcemia may be uncovered, or mild findings
such as muscle soreness or cramps may lead to the
diagnosis. More severe hypocalcemia may be
manifested by three classic physical findings:
1. The Chvostek sign, in which tapping the facial
nerve 0.5–1.0 cm below the zygomatic pro-
cess and 2 cm anterior to the ear lobe causes a
twitch at the angle of the mouth due to con-
traction of the perioral muscles, a demonstra-
tion of muscular irritability. Almost 30 % of
hypocalcemic individuals may not show this
sign however.
2. The Trousseau sign, in which a blood pressure
cuff is inflated at least 15 mmHg above the
systolic blood pressure for 2–5 min; a positive
response is indicated by “main d’accoucheur”
position with flexion of the wrist and metacar-
pophalangeal joints and extension of the inter-
phalangeal joints and adduction of the fingers
due to carpopedal spasm in the arm to which
the cuff was applied. This is reliable in up to
94 % of cases with hypocalcemia. This can be
painful however.
134 7 Disorders of Calcium Metabolism and Bone

Table 7.1 Causes of hypocalcemia

Serum Serum Serum Serum Alkaline
Disorder Ca Ca2+ PO4 PTH phosphatase pH Other features
Vitamin D deficiency Low Low Low High High Nl Serum 25 OH
or Nl or Nl vitamin D low,
1,25(OH2) vitamin
D may be normal
Hyperventilation Nl Low Nl Nl Nl High Cured by
rebreathing
Transient hypocalcemia of Low Low Nl/high Low Nl Nl Made worse with
infancy relative high-phosphorus
to Ca feedings
Congenital Low Low High Low Low Nl May be part of
hypoparathyroidism relative DiGeorge syndrome
to Ca
Autoimmune Low Low High Low Low Nl May be part of
hypoparathyroidism relative autoimmune
to Ca polyendocrinopathy
syndrome, type 1
Pseudohypoparathyroidism Low Low High High Low Nl May be associated
relative with Albright
to Ca hereditary
osteodystrophy
Magnesium deficiency Low Low High Low Low Nl May be part of
relative Barter syndrome,
to Ca malabsorption, or
renal disease
Calcium deficiency Low Low Could be Elevated Elevated Nl Rare in present day
low or except for fad diets,
normal vitamin deficiency
with, possibly, sun
avoidance
Renal disease Low Low High High High Possibly Tests of renal
acidotic function are
abnormal
From: Fisher DA, ed. The Quest Diagnostics Manual: Pediatric endocrinology. San Juan Capistrano: Quest Diagnostics
Incorporated 2000.
PTH parathyroid hormone, Nl normal

3. The peroneal sign, in which a tap on the pero-
neal nerve near the lateral tibial prominence
causes plantar flexion (although tapping any
nerve may lead to contraction of the associ-
ated muscle, other contractions may be more
difficult to demonstrate).
Clinical symptoms of hypocalcemia in the
child include paresthesias, circumoral numb-
ness, muscular cramping, tetany, laryngospasm,
bronchospasm, muscle twitching, carpal–pedal
spasm, and possibly seizures. Lengthening of the
QTc interval may be seen on the electrocardio-
gram (EKG) as well as prominent U-wave,
narrowing of the QRS complex, reduced PR
interval, T wave flattening and inversion and
prolonged ST and ST depression.
Hypoparathyroidism
Hypoparathyroidism is a cause of hypocalcemia.
This is partly due to the lack of parathyroid hor-
mone effect on bones in the maintenance of
serum calcium and partly due to the lack of pro-
duction of calcitriol which is dependent on para-
thyroid hormone action.
While congenital defects of the parathyroid
glands are found in the newborn, some of the
conditions described above may occur at an older
Hypocalcemia
age. However, most cases of hypoparathyroidism
will be due to an autoimmune etiology in child-
hood. Because adrenal insufficiency due to an
autoimmune etiology may accompany autoim-
mune hypoparathyroidism, the clinician must
have a high index of suspicion for adrenal failure
as fatalities have occurred when it is missed.
Autoimmune hypoparathyroidism may occur as
an isolated case or in association with type 1
polyendocrinopathy syndrome, which also
includes chronic mucocutaneous candidiasis and
ectodermal dysplasia (APECED *240300
AUTOIMMUNE POLYENDOCRINOPATHY
SYNDROME, TYPE I). Other associated defects
include Addison’s disease, autoimmune hypergo-
nadotropic hypogonadism, diabetes mellitus type
1, autoimmune disease of the thyroid gland, per-
nicious anemia, vitiligo, alopecia, dental enamel
hypoplasia, keratoconjunctivitis, malabsorption,
chronic active hepatitis, and variable T-cell
defects. A defect in the AIRE gene is seen at
21q22.3 in APECED (see Chap. 10). The
immunodysregulation, polyendocrinopathy,
and enteropathy syndrome (#304790 ICD+
IMMUNODYSREGULATION, POLYENDO-
CRINOPATHY, AND ENTEROPATHY,
X-LINKED; IPEX) is inherited in an X-linked
pattern and is another autoimmune condition
which included hypoparathyroidism in the con-
stellation of disorders. Chronic inflammation of
the GI tract with diarrhea, ileus, and villous atro-
phy combines with eczema and atopic conditions
of the skin, type 1 diabetes mellitus, autoimmune
hypothyroidism, autoimmune hemolytic anemia
and thrombocytopenia, and other types of
immune problems. This condition is caused by an
abnormality of the forkhead box P3 gene
(FOXP3, 300292.0001) and usually leads to
death in infancy or childhood.
Nonautoimmune hypoparathyroidism may
occur sporadically or in autosomal dominant
or autosomal recessive pattern (#146200
HYPOPARATHYROIDISM, FAMILIAL
ISOLATED; FIH at 3q13) due to a mutation in
the PTH gene; patients may have cataracts or
intracerebral calcifications. Hypoparathyroidism
in an X-linked pattern may present in a neonate
(*307700 HYPOPARATHYROIDISM,
135
X-LINKED; HYPX at Xq26–27). Other forms
may be associated with disorders of development
of the parathyroid gland associated with renal
disease and deafness (#146255 HYPOPARA-
THYROIDISM, SENSORI-NEURAL DEAFNESS,
AND RENAL DISEASE; HDR *241400
HYPOPARA-THYROIDISM with sensineural
deafness). The Sanjad–Sakati (*241410
HYPOPARA-THYROIDISM-RETARDATION-
DYSMORPHISM SYNDROME; HRD at
1q42043) syndrome of fetal and postnatal growth
retardation, seizures, developmental delay, and
dysmorphic facial features is associated with
autosomal recessive hypoparathyroidism. The
Kenny–Caffey syndrome (*244460 KENNY-
CAFFEY SYNDROME, TYPE 1; KCS at 1q42–
43) may be inherited in an autosomal dominant,
autosomal recessive, or even X-linked pattern
and includes poor growth, stenosis of the bone
marrow cavity, and thickened tubular cortical
bones. Hypoparathyroidism might occur with
renal dysplasia and deafness (#146255
HYPOPARATHYROIDISM, SENSORI-NEURAL
DEAFNESS, AND RENAL DISEASE; HDRA)
in an autosomal dominant pattern in the rare
Barakat syndrome.
Gain-of-function mutation of the calcium-
sensing receptor (#601198 HYPOCALCEMIA,
AUTOSOMAL DOMINANT 1; HYPOC1) pres-
ents with mild to moderate symptoms of hypocal-
cemia with hypercalciuria and nephrocalcinosis
and/or nephrolithiasis along with calcification of
the basal ganglia. Nephrolithiasis may occur with
calcium oxalate or calcium phosphate kidney
stones. Kidney stones form when the product of
the ions exceeds the solutability factor of the
ions. Homogeneous nucleation occurs when
calcium and oxalate crystals form and then grow
too large and form calcium oxalate stones.
Heterogeneous nucleation occurs when calcium
and phosphorus combine and cause calcium
phosphate nuclei in which calcium oxalate is not
present. Because of the elevated sensitivity of the
calcium-sensing receptor in this condition, para-
thyroid hormone is not detectable or is inappro-
priately low. Children with this condition are
extremely sensitive to vitamin D which in normal
doses will cause hypercalcemia. Treatment has
136
been successful with exogenous parathyroid
hormone.
There are other forms of acquired hypopara-
thyroidism. Hypoparathyroidism may occur from
iron deposition of thalassemia (and its therapy) or
hemochromatosis, copper infiltration from
Wilson disease. Radiation to the thyroid gland
and parathyroid gland area, trauma, or surgery
also may cause acquired hypoparathyroidism.
Surgical hypoparathyroidism may occur after
thyroid surgery. It may be transient because of
inflammation of the area, or it may be permanent
because of the removal of parathyroid tissue
along with the thyroid tissue.
The Diagnosis of Hypoparathyroidism
The diagnosis of hypoparathyroidism rests on
demonstration of decreased serum ionized cal-
cium and increased phosphorus, in the face of
inappropriately decreased serum PTH for the
value of serum calcium. Low serum ionized cal-
cium should, in the normal situation, cause eleva-
tion of serum PTH, and absence of such a response
suggests inadequacy of PTH secretory ability;
complete absence of serum PTH is not necessary
for the diagnosis of hypoparathyroidism. Urinary
calcium excretion is elevated (calcium/creati-
nine ratio greater than 0.2), phosphate excretion
is diminished (tubular reabsorption of phosphate
is greater than 88 %), and cyclic adenosine
monophosphate (cAMP) is low in the urine of
hypoparathyroidism, as PTH normally stimulates
the production of cAMP in the renal tubule.
Hypoparathyroidism as well as pseudohypopara-
thyroidism causes ectopic calcification, particu-
larly intracranial calcification.
Treatment of Hypoparathyroidism
Treatment of hypoparathyroidism must first
address hypocalcemia. For severe symptomatic
hypocalcemia, 10 % calcium gluconate is given
as a dose of 0.5–1 mL/kg infused over 15–20 min
up to a total of 10 mL, given with EKG monitor-
ing (bradycardia and asystole are possible com-
plications of an increase of calcium). The
concentration is decreased to 5% for administra-
tion in some protocols. During the administration
of i.v. calcium, it is important to avoid extravasa-
tion, which may cause severe sloughing of the
7 Disorders of Calcium Metabolism and Bone
skin, possibly requiring plastic surgical repair.
The infusion may be repeated if necessary for the
relief of symptoms but is followed by 10 % i.v.
calcium gluconate at a dose of 500 mg/kg over a
24-h period for neonates and 200 mg/kg for
infants or older subjects. Long-term therapy is
achieved by 1,25(OH)vitamin D (this form elimi-
nates the need for 1-hydroxylation of vitamin D,
which is impaired in hypoparathyroidism) given
at a dose of 20–40 ng/kg/day (calculated as 0.25–
0.75 g twice daily), with oral calcium supple-
mentation adequate to maintain serum ionized
calcium, if necessary. Urine can be tested for
excessive calcium loss by determining urinary
calcium/creatinine ratio (this normally should be
less than 0.2) to evaluate the effects of therapy.
Renal ultrasound examinations are administered
at yearly intervals to search for nephrocalcinosis,
which is a complication of vitamin D therapy.
Phosphorus is restricted in the diet until serum
phosphorus decreases to near-normal levels,
which should occur when serum ionized calcium
approaches normal. Serum ionized calcium
should be measured regularly until stability is
achieved to assure that serum calcium remains in
the normal range. (For a discussion of emergency
treatment of hypocalcemia, see Chap. 14.)
Pseudohypoparathyroidism
Individuals with resistance to PTH have pseudo-
hypoparathyroidism or PHO and have all the
features of hypoparathyroidism except that PTH
is elevated, although it is ineffective in control-
ling calcium values due to abnormalities in the
receptor for PTH rendering it unresponsive. This
condition can occur early in infancy as well as
later in childhood. The phenotype known as
Albright hereditary osteodystrophy (AHO),
which consists of short stature, obesity, round
facies, brachydactyly, and metacarpal or metatar-
sal hypoplasia resulting in shortened forth and
fifth fingers and toes, is found in pseudohypo-
parathyroidism type 1A (#103580 ICD+PSEUD
OHYPOPARATHYROIDISM, TYPE IA;
PHP1A). The condition is due to a loss-of-func-
tion mutation of the Gs-alpha isoform of the
GNAS gene (139320) located at 20q13.32
thereby limiting the effects of parathyroid hor-
mone on its receptor. In an example of parental
Hypocalcemia
imprinting, if the mutated gene is inherited from
the father, AHO results in isolation without
deficient hormone action in a condition known as
pseudopseudohypoparathyroidism (#612463
ICD+ PSEUDOPSEUDOHYPOPARATHYRO
IDISM; PPHP), whereas if the gene is inherited
from the mother, the child has type 1A PHO as
described above also with AHO phenotype.
Urinary cAMP excretion does not increase after
PTH infusion if the defect is generalized (type
1A), and resistance to thyroid-stimulating hor-
mone (TSH), antidiuretic hormone (ADH), and
growth hormone-releasing hormone (GHRH)
may occur in conjunction with type IA PHO with
the phenotype of AHO. Basal ganglia calcifica-
tions are common on radiograph, and subcutane-
ous calcifications occur as well. Other subjects
may have renal unresponsiveness to PTH, but
responsiveness of the skeleton to PTH, leading to
the hyperparathyroid bone disease, osteitis
fibrosa cystica. These subjects have type 1B
pseudohypoparathyroidism (#603233 PSEUDO
HYPOPARATHYROIDISM, TYPE IB at
20q13.3), in which the metabolic findings of
hypoparathyroidism occur, but the general phe-
notype is normal except for the skeleton, and no
mutation is found in the GNAS1 gene. In pseudo-
hypoparathyroidism type II, an autosomal reces-
sive condition (%203330 ICD+PSEUDOHYPO
PARATHYROIDISM, TYPE II; PHP2), eleva-
tion of urinary cAMP response in parathyroid
hormone occurs but is diminished, but renal
phosphate excretion does not respond to PTH and
hyperphosphatemia and hypocalcemia results.
Progressive osseous hyperplasia (#166350
ICD+OSSEOUS HETEROPLASIA, PROGRE-
SSIVE; POH) is an imprinted defect also due to a
mutation resulting in loss of function of the
Gs-alpha isoform of the GNAS gene (139320) on
the paternal allele. This condition presents with
heterotopic bone formation in the dermis (oste-
oma cutis) and subcutaneous fat along with joint
ankyloses and growth retardation of the limbs
affected by heterotopic bone formation. It is
hypothesized that POH is an example of the
extreme presentation of PPHP.
The therapy for pseudohypoparathyroidism
is the same as that for hypoparathyroidism
described earlier.
137
Magnesium Deficiency and Magnesium
Excess
Magnesium deficiency diminishes PTH secretion
as well as PTH-mediated bone resorption. Thus,
signs of magnesium deficiency are those of hypo-
calcemia which usually accompanies magnesium
deficiency. EKG changes of hypomagnesemia
are prolonged QTc interval, atrial and ventricu-
lar ectopy, atrial tachyarrhythmias, and torsades
de pointes.
Magnesium deficiency may be found in the
newborns who are infants of diabetic mothers or
mothers suffering from eclampsia or have mag-
nesium deficiency themselves. Hypomagnesemia
is found in IUGR and prematurity. Nasogastric
suctioning may deplete the child of magnesium.
Treatment with loop diuretics, thiazide diuretics,
various types of antibiotics, gastrointestinal treat-
ments, digitalis, and various anticancer medica-
tions (cisplatin, aminoglycosides) can diminish
urinary magnesium reabsorption and result in
hypomagnesemia. Pancreatitis or malabsorption
disorders including inflammatory bowel disease,
celiac disease, or resection of parts of the GI tract
can also lead to hypomagnesemia.
Magnesium deficiency may result from renal
disease (either with (#248250 ICD+
HYPOMAGNESEMIA 3, RENAL; HOMG3) or
without other tubular defects) or intestinal mal-
absorption which may occur in an autosomal
recessive (#602014 ICD+HYPOMAGNESEMIA
1, INTESTINAL; HOMG1) as well as X-linked
patterns. Bartter syndrome refers to several auto-
somal recessive disorders characterized by
decreased sodium chloride reabsorption in the
thick ascending loop of Henle which leads to salt
wasting; hypokalemic, hypochloremic metabolic
alkalosis; and hypercalciuria with increased
plasma renin activity and hyperactivity of the
renin–angiotensin system with increased plasma
aldosterone; hypomagnesuria is often found as
well. There are antenatal severe forms of Bartter
syndrome (#601678 ICD+BARTTER
SYNDROME, ANTENATAL, TYPE 1) and
(#241200 ICD+ BARTTER SYNDROME,
ANTENATAL, TYPE 2) as well as forms
(#602522 BARTTER SYNDROME, TYPE 4A)
and (#613090 BARTTER SYNDROME,
TYPE 4B) associated with sensorineural deaf-
138
ness. Replacement oral magnesium oxide given
several times daily will reverse hypoparathy-
roidism, hypocalcemia, and tetany, as hypo-
magnesemia resolves. Gitelman’s syndrome
(#263800 ICD+ GITELMAN SYNDROME) is
an autosomal recessive disorder associated
with renal potassium and magnesium wasting
leading to polydipsia with hypomagnesemia,
hypocalciuria, and hypokalemic alkalosis.
Patients may demonstrate generalized muscle
weakness, muscle cramps, tetany, seizures, par-
esthesias, and episodic paralysis after strenu-
ous exercise.
Treatment of hypomagnesemic states is
accomplished by oral or intravenous magnesium
administration. Intravenous or intramuscular
administration of a 50 % magnesium
(MgSO4.7H2O) sulfate at a dose of 0.05–0.2 mL/
kg which provides 2.5–5 mg/kg elemental mag-
nesium can be administered in emergency situa-
tions including convulsions as might be found in
a neonate as long as careful cardiac monitoring
accompanies infusion since the EKG changes of
acute hypermagnesemia include a prolonged PR
interval, increased QRS duration, and increased
QT interval and may lead to complete heart block
and cardiac arrest. Oral therapy may be accom-
plished with 50 % MgSO4.7H2O at a dose of
0.2 mL/kg/day.
Elevated serum magnesium may be asymp-
tomatic or may be associated with central ner-
vous system depression and hypotonia. While
decreased serum magnesium leads to impaired
parathyroid hormone secretion so does exces-
sively elevated magnesium levels. A neonate of a
mother who has been treated with significant
magnesium will itself have hypermagnesemia
and may also suffer from hypocalcemia. Other
sources of excessive magnesium include
administration of IV or oral magnesium products
including antacids or with enemas.
Hypermagnesemia is treated with increased
hydration to excrete the magnesium load, but in
situations of hypocalcemia and hypoparathyroid-
ism, administration of calcium and
1,25-dihydroxyvitamin D may be necessarily on
a temporary basis.
7 Disorders of Calcium Metabolism and Bone
Activating Mutations of the Calcium-
Sensing Receptor
Activating mutations of CaSR factitiously signal a
state of excessive calcium in the absence of excess
calcium which leads to a decrease in parathyroid
hormone secretion and results in mild to moderate
hypocalcemia. (#601198 HYPOCALCEMIA,
AUTOSOMAL DOMINANT 1; HYPOC1) This
condition can lead to calcium deposition in the
kidney and in the central nervous system.
Antibodies directed to the calcium-sensing recep-
tor may produce this same clinical presentation
and may be found in autoimmune hypoparathy-
roidism as an associated finding. Antibodies to the
calcium-sensing receptor may also produce
hypercalcemia.
Hyperphosphatemia
Hyperphosphatemia may occur because of con-
genital defects or acquired conditions. Elevated
phosphorus will tend to complex with calcium
leading to hypocalcemia and ectopic calcium
phosphate crystal deposition and ectopic tissue
mineralization of subcutaneous tissues or of the
juxta-articular muscle. With acute phosphorous
administration either oral, intravenous, or rectal in
the form of enemas, hypocalcemia may be severe
enough to cause positive physical findings.
Familial hypophosphatemic tumoral calcinosis
(#211900 TUMORAL CALCINOSIS,
HYPERPHOSPHATEMIC, FAMILIAL; HFTC)
is an autosomal recessive condition due to
mutations in the UDP-N-acetyl-alpha-D-
galactosamine:polypeptide N-acetylgalactos-
aminyltransferase 3 gene (GALNT3,
601756.0001) (GALNT3), FGF23 gene, or the
klotho gene (KL). Hyperphosphatemia occurs
because of increased tubular resorption of phos-
phate. Variation in findings may occur due to the
different genes involved, but characteristically
there is a normal to elevated serum 1,25-dihy-
droxycholecalciferol, normal serum calcium, and
normal serum PTH. FGF23 is characteristically
low while C-terminal variants of the full PTH mol-
ecule have been found to be high in some patients.
Nephrocalcinosis is likely along with precipitation
of calcium phosphate crystals in subcutaneous
Hypocalcemia
tissue; periarticular calcification; pain in joints
including the hip, elbow, and shoulder due to ecto-
pic calcification; and pain and swelling of long
bones, occur among other findings.
Hypocalcemia may occur during treatment for
neoplasms due to tumor cell lysis. Tumor lysis
syndrome (TLS) includes hyperphosphatemia,
hyperkalemia, hypocalcemia, and hyperuricemia.
Cell destruction from hemolytic anemia or crush
injuries among other causes will lead to a similar
presentation as tumor lysis syndrome.
Rhabdomyolysis can also lead to hyperphosphate-
mia and hyperkalemia; there may be either hyper-
or hypocalcemia encountered in rhabdomyolysis.
Hyperphosphatemia found in chronic kidney
disease may require treatment by phosphate
binding agents. Older agents are calcium- or
aluminum-containing medications, while newer
agents are non-calcium- or aluminum-based
agents (sevelamer hydrochloride compounds and
lanthanum carbonate); they are more expensive,
and while they have theoretical benefits in con-
trolled studies, the data do not yet support their
preferential use.
Ectopic bone formation is different than soft
tissue calcification described above. Ectopic bone
formation may occur due to hereditary conditions
or after surgery or injury. Ectopic bone formation
or heterotopic ossification is the formation of
endochondral bone in soft tissues including mus-
cle, subcutaneous tissue, and fibrous tissue adja-
cent to joints. Hereditary progressive osseous
hyperplasia (#166350 ICD+ OSSEOUS
HETEROPLASIA, PROGRESSIVE; POH) is an
autosomal dominant condition caused by loss-of-
function mutations in the GNAS gene on the
paternal allele which are the same gene defects
found in pseudopseudohypoparathyroidism.
POH may be a condition of the extreme end
of the range of manifestations of pseudo-
pseudohypoparathyroidism.
Diagnosis of Hypocalcemia
The diagnosis of the etiology of hypocalcemia is
accomplished by the measurement of various
minerals, hormones, and often vitamin D. As
139
noted on the flow chart (Fig. 7.2), the level of
phosphorus gives much information, as if it is
high, a deficiency of PTH or an inability to
respond to PTH is likely and if low, a deficiency
of vitamin D or its action is likely. The differen-
tial diagnosis of various forms of pseudohypo-
parathyroidism may require the measurement of
plasma and urinary nephrogenic cAMP. The
diagnostic process may be complex, so refer to
Figs. 7.1 and 7.2 as well as to the descriptions of
the various conditions.
Normal Bone Growth
Bone is a complex organ which is affected by
various endocrine factors but also produces its
own endocrine agents. Bone is not a static organ
but once formed undergoes remodeling through-
out life. Bone is composed of an organic matrix,
osteoid, comprised of protein which is mainly col-
lagen which becomes mineralized with the depo-
sition of calcium, phosphate, and hydroxyapatite.
Bone mineralization begins with the formation
of the anlagen which is a framework of cartilage
upon which the future skeleton will be formed by
a process known as endochondrial ossification.
Chondrocytes progress through sequential stages
of resting, proliferating, and pre-hypertrophic
and hypertrophic growth leading to enlargement
of the anlagen. Hypertrophic chondrocyte cells
toward the center of the cartilage produce colla-
gen X and other factors in the mature extracellular
matrix. Hypertrophic chondrocytes also produce
angiogenesis factors, vascular endothelial growth
factor (VEGF), which promote the development
of blood vessels in the area which subsequently
allow osteoblasts (bone-forming cells) and the
inactive form osteocytes, osteoclasts (resorbing
cells), and hemopoietic cells to establish in the
area. This forms a primary ossification center. The
hypertrophic chondrocytes undergo apoptosis and
are replaced by osteoblasts, formed out of mesen-
chyme, which will add their secretions to the
extracellular matrix and will form trabecular bone.
Trabecular bone is porous and is found in the end
of long bones, in vertebrae, and in flat bones such
as the pelvis. In contrast cortical bone is dense and
140
is found in the shaft of long bones and in the outer
shell around cancellous bone at the end of joints
and the vertebrae. Periosteum covers the outside
surface of long bones except at joints, while end-
osteum coats the inside of long bones. Bone
growth in width occurs at the periosteum.
The extracellular matrix contains a host of
collagen molecules including collagen type I n
which contains α1(I) and α2(I) chains which are
coded by the genes COL1A1 and COL1A2;
mutations in these genes lead to osteogenesis
imperfecta. Mutations of other types of collagen
in the matrix lead to disorders that range in effect
from lethality to dwarfism to early-onset arthritis.
A peripheral tube forms around the central carti-
lage known as the diaphysis area. The primary
ossification center resides within this tube. Bone
marrow is formed centrally with the arrival of the
hemopoietic cells. At the ends of the cartilage,
known as the epiphyses, secondary ossification
centers develop, and the growth plate, which will
later appear as a lucency on radiograph of the
ends of the bone and is responsible for longitudi-
nal bone growth, is established in the epiphysis.
The epiphyses ultimately fuse at the end of nor-
mal growth, a process stimulated by estrogen.
The metaphysis is the area of widening between
the narrow diaphysis and the wider epiphysis.
Further processes of chondrocyte proliferation,
hypertrophy, and apoptosis progress allowing
remodeling and the deposition of calcium, phos-
phate, and hydroxyapatite (Ca10(PO4)6(OH)2)
upon the extracellular matrix which provides
strength and stiffness of bone. The collagen in
bone provides elasticity and decreases the risk
of fracture. Thus, bone demonstrates strength
and a degree of elasticity. Disorders of bone may
arise from defects in calcification or defects in
protein production.
Bone formation in remodeling occurs because
of physical and endocrine factors. Mechanical
loading stimulates skeletal ossification and regu-
lates changes in bone geometry and density. It is
important that children are active for this reason.
Bone formation is enhanced with growth hormone
and the IGF axis as well as thyroid hormone.
While continuous exposure to parathyroid hor-
mone increases bone loss, intermittent exposure
stimulates bone formation.
7 Disorders of Calcium Metabolism and Bone
Osteoblasts as well as other cells produce
receptor activator of nuclear factor kappa-B
ligand (RANKL) which is a member of the tumor
necrosis family of molecules. RANKL is located
on the surface of osteoblasts and interacts with the
osteoclastic receptor activator of nuclear factor
kappa-B (RANK) to stimulate osteoclastic bone
resorption. Osteoprotegerin (OPG) is also a
member of the tumor necrosis factor family and
is a decoy receptor for RANKL and so inhibits
activation of osteoclasts. OPG production is
stimulated by estrogen and by the medication
strontium ranelate. Denosumab is a medication
with a structure similar to OPG which is used to
decrease bone resorption.
On the other hand glucocorticoids increase
bone resorption by stimulating osteoclastogene-
sis and decrease osteoblastic function leading to
a net loss of bone and decrease in bone forma-
tion. Bone resorption is also stimulated by
interleukin(s)-1, -6, and -11 (IL-1, IL-6, IL-11)
and tumor necrosis factor (TNF) alpha and beta
by enhancing osteoclast development; these
agents also inhibit bone formation.
Bone resorption is inhibited with by estrogens
and oral selective estrogen receptor modulators.
Androgens also inhibit bone resorption, and while
direct effects have been demonstrated, most of the
effect appears to be through the aromatization of
testosterone to estrogen. Calcitonin will also
inhibit bone resorption and appears not to have a
major physiologic function in this regard.
Vitamin D and Calcium Deficiency
Hypocalcemia due to calcium deficiency, with or
without rickets, had become uncommon in our era,
but more recently a reappearance of vitamin
D-deficient rickets in breast-fed infants not supple-
mented with vitamin D occurred. This can also
occur in an infant receiving less than 33.8 oz or
about 1 quart of vitamin D-supplemented infant
formula every day. Hypocalcemia of vitamin D
deficiency can present to such a severe degree that
hypocalcemic seizures occur. An infant raised on
an inappropriate fad diet deficient in vitamin D or
calcium or with the substitution of nondairy
creamer for a milk-based formula, a situation that
Hypocalcemia
may arise in families with low income and may be
considered a form of urban kwashiorkor, may
develop hypocalcemia. In cases in which calcium
deficiency is the etiology and not vitamin D defi-
ciency, serum 25-hydroxyvitamin D is normal, but
1,25(OH)2D is either normal or high and PTH val-
ues are high.
Rickets (Table 7.2)
Rickets is a disorder of mineralization compared
to osteoporosis which is a disorder of protein for-
mation. Inadequate vitamin D intake or absorp-
tion during childhood will cause inadequate
absorption of calcium and phosphorus, leading to
hypocalcemia and hypophosphatemia (Table 7.2).
These factors cause increased PTH secretion,
which leads to increased bone turnover and ele-
vated serum alkaline phosphatase activity.
Chondrocytes in the growth plate of long bones
and osteoid, the collagen-containing organic
matrix of the bone trabeculum, fail to mineralize
normally in this situation, causing rickets. Both
rickets and osteomalacia are characterized by
decreased mineralization of osteoid; the former
occurs during periods of growth when there are
open epiphyses, causing abnormal formation of
long bones, ribs, and skull, and the latter occurs
after growth ceases in the adult and leads to a ten-
dency toward fractures. Radiologic evaluation of
the bones shows undermineralization of the
growth plate, an indistinct and ragged metaphysis,
and bowing due to the influence of weight bearing
on bones lacking tensile strength. Rickets is often
divided into calciopenic and phosphopenic rickets
based upon which ion deficit is primary.
Findings in nutritional rickets are often
encountered when the child enters the toddler
stage and include genu valgum (“knock knees”)
or genu varum (“bow leg”) developing after the
child begins walking and usually associated with
pain in ambulation. Bowing of the arms, classic
and often palpable widening of the metaphyses of
the long bones, “rachitic rosary” which appears as
an inverted “V” parallel and lateral to the costal
margins, Harrison grooves or sulci (indentation
of the lower chest wall as a result of softening),
141
frontal bossing, and more rarely craniotabes
(ping-pong ball-like skull which should not be
demonstrated clinically by the examiner) are
found. Appetite is poor, walking is delayed, and
growth is decreased in many affected children.
Radiographic findings of thin bones with cupping
(concave), widening, and irregular “moth-eaten”
appearance of the metaphyses are diagnostic after
the condition is established. Costochondral swell-
ing is noted. Bone density may be decreased. In
those patients with hypocalcemia, all the findings
listed earlier for low calcium may be found.
Nutritional Rickets
Milk and other food products have been fortified
with ergocalciferol in the USA, whereas other
areas of the developed world may provide vita-
min D to children as a capsule, so vitamin
D-deficiency rickets is rare today. However, not
all dairy products are supplemented with vitamin
D, and some children are given milk substitutes
that have no vitamin D; inspection of the package
is necessary to determine the vitamin D content.
Further, fad or well-intentioned but incorrectly
constructed vegetarian/vegan diets may be defi-
cient in vitamin D and require supplementation.
Alternatively, as normal breast milk has less
vitamin D content than recommended for an
infant, especially if the mother herself is vitamin
D deficient, an infant raised on breast milk with-
out vitamin D supplementation may be deficient.
This problem is intensified with the use of sun-
screen, an important measure to decrease the risk
of skin cancer, and is further enhanced in a child
with a dark complexion. There is a resurgence of
rickets in infancy due to these nutritional issues
even in a sunny climate. If an older child is not
exposed to the sun (e.g., because of institutional-
ization or complete swaddling covering the skin),
the conversion of 7-dehydrocholesterol to vita-
min D3 will be limited, and vitamin D deficiency
results. Children with dark skin color living at
northern latitudes, wearing opaque clothes, and
mostly remaining indoors are at particular risk
for developing rickets if not supplemented with
vitamin D.
Fat malabsorption due to a variety of condi-
tions may lead to vitamin D deficiency and
 142

Table 7.2 Types of rickets

Serum Serum Serum Serum
Defect Serum Ca PO4 alk phos 25(OH)D 1,25(OH2)D Serum PTH Other features
Vitamin D deficiency Normal at first, then may Normal High to Low Low to Normal at Was rare in the developed world owing to
rise after parathyroid at first, extremely normal first, then vitamin D supplementation. Now resurging
hormone secretion then low high high due to breast-feeding without adequate
increases vitamin D supplementation. Occurs in fat
malabsorption, deficient maternal vitamin D,
prematurity, sunlight avoidance
Hepatocellular rickets Low Low High Low Low to High
normal
Anticonvulsant-associated Low Low High Low Low to High Due to increased metabolism of 25(OH)D
rickets normal (e.g., from phenobarbital and hydantoins in
addition to lack of sunlight exposure,
usually in a poorly ambulatory individual)
Vitamin D-dependency rickets Low Low or High Normal Low High Requires high doses of vitamin D. AR
7

type 1 or pseudovitamin D- normal inheritance due to a loss-of-function

deficiency rickets mutation of the 1α-hydroxylase gene
Vitamin D-resistant rickets or Low Low High Normal High High Might have alopecia, growth failure, dental
vitamin D-dependency rickets hypoplasia. AR inheritance due to
type 2 loss-of-function mutation of the vitamin D
receptor
X-linked hypophosphatemic Normal Low High Normal Low Nl to high X-linked inheritance due to mutation of
rickets PHEX gene
From: Fisher DA, ed. The Quest Diagnostics Manual: Pediatric endocrinology. San Juan Capistrano: Quest Diagnostics Incorporated 2000
AR autosomal recessive, PTH parathyroid hormone, Nl normal
Disorders of Calcium Metabolism and Bone
Hypocalcemia
rickets. This may occur with disturbance of the
enterohepatic circulation and absence of pancre-
atic enzymes or may follow bariatric surgery.
Patients with cystic fibrosis or short bowel syn-
drome are subject to vitamin D malabsorption. A
calcium-deficient diet or, more rarely, inadequate
dietary phosphate also can lead to rickets. Diets
laden with phytates, found in some cereals, also
will lead to calcium deficiency because they bind
calcium in the GI tract and limit absorption.
There are three phases of vitamin D-deficient
rickets (according to C. Arnaud): at first serum
calcium is low (this phase may be missed at the
onset) which leads to elevation of PTH that raises
serum calcium by mobilization from the bone.
The response to parathyroid hormone ultimately
falters due to a form of PTH resistance, and
serum calcium falls again, while serum phos-
phate rises in the second stage. This is a time in
which hypocalcemic seizures may be manifest.
The hypocalcemic seizures found in rickets may
be accompanied by hyperphosphatemia and ele-
vated PTH falsely suggesting pseudohypopara-
thyroidism. Rising PTH levels finally overcome
the resistance and cause hypophosphatemia with
repletion of serum calcium with further resorp-
tion of bone in the third stage. Alkaline phospha-
tase rises, and the characteristic radiographic
features of rickets begin. If vitamin D is inade-
quate, calcium and phosphorus both fall, while
PTH and alkaline phosphatase rise further and
severe rickets develops. The changes of vitamin
D-deficient rickets can be reversed with vitamin
D treatment.
Gastric bypass surgery is now more frequently
invoked in the treatment of severe obesity in
adolescence. The side effects of gastric bypass
surgery can be vitamin D deficiency and meta-
bolic bone disease. This may be due to malab-
sorption, dumping syndrome, or absence of
pancreatic enzyme or interruption of the entero-
pathic circulation depending upon the surgical
procedure invoked.
Hepatocellular Rickets
Liver diseases such as biliary atresia, neonatal
hepatitis, some hereditary liver diseases, and,
rarely, cystic fibrosis cause several difficulties with
143
vitamin D metabolism: (a) fat malabsorption due
to inadequate bile salt in the small intestine
decreases absorption of the fat-soluble vitamin
D; (b) hepatic 25-hydroxylation may be
decreased; and (c) because vitamin D is excreted
in bile, the enterohepatic circulation of vitamin D
may be interrupted. Therapy with 1,000–2,000 IU
(25–50 μg) of vitamin D daily may cure this form
of rickets, but the use of oral 25(OH)D may be
necessary to treat children with biliary atresia.
Exposure to the sun may be beneficial in such
patients as well but this should not be excessive as
noted elsewhere.
Renal Osteodystrophy
In significant renal disease, impaired 1-hydroxyl-
ation of 25 OH vitamin D will lead to the hypo-
calcemia that triggers PTH secretion causing
secondary hyperparathyroidism. The PTH will
increase remodeling of the bone, and serum alka-
line phosphatase will rise. The serum phosphorus
remains elevated because of decreased urinary
excretion caused by the renal disease. Thus, renal
osteodystrophy results in osteitis fibrosa cystica
caused by secondary hyperparathyroidism, as
well as renal rickets or osteomalacia due to bone
undermineralization. Bowing of the lower
extremities, bone pain, and myopathy may occur.
Parathyroid hormone values are increased due to
elevated serum phosphorus. Therapy involves
1,25-dihydroxyvitamin D, which increases serum
ionized Ca2+, which in turn decreases PTH
secretion. Oral calcium carbonate is given with
meals to block intestinal phosphate absorption,
and a low-phosphate diet is recommended.
Phosphate binding agents may be necessary in
secondary hyperparathyroidism of renal disease
and are mentioned below in hyperphosphatemia.
Because renal disease may be subtle in some
cases, evaluation of renal function is important in
the evaluation of hypocalcemia.
Anticonvulsant-Associated Rickets
or Hypocalcemia
Anticonvulsants such as phenobarbital and
hydantoins speed the metabolism of 25(OH)D to
more inactive metabolites. Because some
children taking these substances may be
144
institutionalized, a decreased intake of dairy
products fortified with vitamin D also may occur,
as well as reduced sunlight exposure. These com-
bined effects may lead to rickets or hypocalce-
mia. This complication is unusual in ambulatory
children receiving anticonvulsants.
Treatment with 800 IU (20 μg) of vitamin D
daily is appropriate to correct hypocalcemia and
hypophosphatemia in these children, especially if
adequate calcium intake is assured.
Rickets of Prematurity
Very low birth weight preterm infants have not
received the normal third trimester placental
transfer of calcium (150 mg/kg body weight/day)
or phosphate (75 mg/kg/day), and after birth,
their intestine may not be adequate to absorb cal-
cium to replace the interrupted placental func-
tion. Further, diminished 25-hydroxylation
occurs because of liver immaturity, even if the
mother was supplemented with vitamin D and the
infant is not deficient in vitamin D. Hypocalcemia,
hypophosphatemia, elevated alkaline phospha-
tase activity, rib and limb fractures, and rachitic
changes at the diaphyses and metaphyses of long
bones will result. Serum concentrations of
1,25(OH)2D are extremely high as a compensa-
tory mechanism, exceeding 120 pg/mL (normal
values are 15–90 pg/mL depending upon age);
these elevated values of 1,25-dihydroxyvitamin
D do not indicate that the defect is resolving
however as 25-hydroxy-vitamin D levels indi-
cate vitamin D stores, while 1,25-dihydroxyvi-
tamin D levels do not. If the infants also have
bronchopulmonary dysplasia and are receiving
long-term loop diuretic therapy, they will lose
more calcium through hypercalciuria.
Treatment consists of the use of calcium and
phosphate supplements in the infant’s milk, the
use of high-mineral formulas, and additional
vitamin D administration.
Genetic Causes of Rickets
Defects in Vitamin D Production or Action
1α-hydroxylation deficiency rickets (*264700
PSEUDOVITAMIN D DEFICIENCY RICKETS
at 12q14), also called vitamin D-dependency
rickets type 1 and pseudovitamin D-deficiency
7 Disorders of Calcium Metabolism and Bone
rickets, leads to the inability to produce
1,25(OH)2D by 1-hydroxylation. This condition
may be noted clinically at age 12–16 weeks and
is inherited in an autosomal recessive pattern.
Besides nondetectable or decreased serum cal-
citriol, there will also be hypophosphatemia,
increased serum PTH, increased serum alkaline
phosphatase, and generalized aminoaciduria.
Patients with this condition require very large
doses of vitamin D (200,000–1,000,000 IU
daily) or physiologic doses (0.5–1.0 μg) of
1,25(OH)2D to cure the rickets. The levels of
25(OH)D are normal or high and of 1,25(OH)2D
are low; the latter do not increase during treatment
with vitamin D.
Vitamin D-dependency rickets, type 2 (#277440
VITAMIN D-DEPENDENT RICKETS, TYPE
2A; VDDR2A at 12q12-q14O) or vitamin D-
resistant rickets is inherited in an autosomal reces-
sive pattern and is due to inactivating mutation of
the vitamin D receptor, leading to a defect in the
binding of 1,25(OH)2D to its nuclear receptor.
These patients have an extremely elevated serum
concentration of 1,25(OH)2D (exceeding 150 pg/
mL; normal, 15–90 pg/mL depending upon age),
but endogenous 1,25(OH)2D and normal doses
of exogenous 1,25(OH)2D are ineffective.
Treatment often requires remarkably high doses of
1,25(OH)2D, in excess of 10 μg/day.
Additional features include cyst of the skin
and alopecia sparing the eyebrows. Patients have
hypotonia and difficultly in walking as well as
delayed motor development, and seizures may
occur due to hypocalcemia. There is secondary
hyperparathyroidism which leads to hypophos-
phatemia and increased serum alkaline phospha-
tase levels, but since vitamin D receptors are
inactive, there is hypocalcemia. Patients also may
be found with delayed tooth eruption and enamel
hypoplasia with early onset of dental caries.
Rickets, hypocalcemia, enamel hypoplasia,
and signs of secondary hyperparathyroidism are
seen in these children as are short stature and
total alopecia.
Hypophosphatemic Rickets
Hypophosphatemia characteristically is due to
renal phosphate wasting. There are often no
symptoms of hypophosphatemia but occasionally
Hypocalcemia
patients complain of weakness, bone pain, rhab-
domyolysis, and altered mental state. However,
the secondary effects of hypophosphatemia
involve disorders of bone mineralization. The
most common form of inherited rickets in the
developed world is X-linked hypophosphatemic
rickets (*307800 HYPOPHOSPHATEMIA,
X-LINKED at Xp22.2-p22.1), an X-linked domi-
nant condition found in hemizygous males and
heterozygous females. Affected children have a
reduction in the amount of phosphate reabsorbed
in the nephron and lose considerable phosphate in
their urine. A reduction in the serum value of
1,25(OH)2D also occurs. Affected children have
hypophosphatemia, causing insufficient mineral-
ization of the bone, even though their serum cal-
cium is normal. By the time the child begins to
walk, bowing of the lower extremities is seen, but
unlike those with other forms of rickets, affected
children do not have tetany, myopathy, a rachitic
rosary, or secondary hyperparathyroidism.
These children have inadequate dental enamel
and dental cysts leading to frequent tooth decay.
Other physical features include midfacial hypo-
plasia and frontal bossing. The disorder is usu-
ally due to a mutation in the PHEX gene on
Xp22.1.p leading to elevations of FGF23.
Treatment involves oral phosphate supplements
in up to five divided doses to attempt to maintain
serum phosphate values within normal limits
most of the day, although oral phosphate can
precipitate diarrhea. Children with X-linked
hypophosphatemic rickets have a decreased
ability to produce 1,25-dihydroxyvitamin D2 to
an incomplete defect in the regulation of
25-hydroxyvitamin D-1-alpha-hydroxylase
activity. In states of hypophosphatemia
1,25-dihydroxyvitamin D should increase but is
inappropriately normal in X-linked hypophos-
phatemic rickets. Increased levels of parathy-
roid hormone do not overcome this block, but
there is a normal response to calcitonin admin-
istration in clinical studies, but calcitonin is not
currently used for therapy. 1,25(OH)2D is admin-
istered in doses of 0.25–0.75 μg every 12 h, as
the patients have inadequate amounts of serum
1,25(OH)2D for the degree of hypophosphate-
mia. Some clinical studies used GH treatment in
affected subjects, but there was no effect on
145
adult height. Clinical studies have just begun on
FGF23 with as a treatment for X-linked hypo-
phosphatemic rickets.
There are autosomal recessive forms of hypo-
phosphatemic rickets due to other gene defects
(#241520 ICD+ HYPOPHOSPHATEMIC
RICKETS, AUTOSOMAL RECESSIVE, 1;
ARHR1 due to a homozygous mutation in the
DMP1 gene at 4q21.) which may include nerve
deafness in the constellation of symptoms and
autosomal recessive forms without nerve deaf-
ness (#613312 HYPOPHOSPHATEMIC
RICKETS, AUTOSOMAL RECESSIVE, 2;
ARHR2- due to a homozygous mutation in the
ENPP1 gene at 6q 23.2) and autosomal dominant
forms (#193100 ICD+ HYPOPHOSPHATEMIC
RICKETS, AUTOSOMAL DOMINANT;
ADHR due to a mutation in the FGF23 gene at
12p13) of hypophosphatemic rickets in addition
to the more frequent X-linked dominant form.
Treatment of hypophosphatemic rickets aims
to promote bone healing clinically and on radio-
graphs and reduction of alkaline phosphatase to
normal levels. Phosphate is administered in mul-
tiple daily doses since values drop quickly after
ingestion. Sixty mg/kg/day is the usual dose for
younger children and 40 mg/kg/day for adoles-
cents. Gastrointestinal distress or diarrhea may
result. Measuring urinary phosphorus is a way of
checking compliance as it will rise with treat-
ment even further than the baseline state in this
condition but will not rise if the child is not tak-
ing phosphate. Due to impairment of 1 alpha
hydroxylase, 1,25-dihydroxyvitamin D is admin-
istered in doses of 0.5–1 μg/day until the pubertal
growth spurt when a dose of 0.5–1.5 μg/day
might be necessary. Monitoring urinary calcium
is necessary to avoid the development of hyper-
calciuria which may be accompanied by nephro-
calcinosis. A urinary calcium/creatinine ratio
should be less than 0.35 mg/mg creatinine in
toddlers and less than 5 mg/kg of body weight
per day in older children. Ultrasonography to
determine if there is nephrocalcinosis is carried
out every year or 2. It is also recommended to
supplement with ergocalciferol or cholecalciferol
to raise 25-hydroxy-vitamin D levels to normal.
A rare paraneoplastic condition which
presents with biochemical findings similar to
146
hypophosphatemic rickets is oncogenic osteoma-
lacia. This condition is usually associated with a
phosphaturic mesenchymal tumor, mixed con-
nective tissue variant, which can rarely occur at
any age and gender and often is undiscovered for
years due to the small size of the tumor. FGF23 is
elevated, and phosphaturia occurs and ultimately
rickets.
The bone cyst found in McCune–Albright
syndrome may lead to elevated FGF23. This can
lead to hypophosphatemic rickets or osteomala-
cia. Thus, phosphate levels must be evaluated in
patients with McCune–Albright syndrome espe-
cially before treatment of bone cysts.
Bisphosphonates are invoked as experimental
treatment for McCune–Albright syndrome but
are not proven to be beneficial as yet; if used dur-
ing hypophosphatemic conditions, phosphate
would be expected to drop further causing
increased complication.
Renal Tubular Acidosis
Proximal renal tubular acidosis is due to inability
to resorb bicarbonate in the renal tubule and is
often associated with the Fanconi syndrome (in
which glucose, amino acids, uric acid, and phos-
phate are also not reabsorbed). Elevated parathy-
roid hormone may lead to secondary Fanconi
syndrome with a mild acidosis in vitamin
D-deficient rickets before treatment with vitamin
D; this situation may falsely suggest primary renal
tubular acidosis. Distal renal tubular acidosis is
associated with an inability to acidify urine. These
patients present a manner similar to vitamin
D-deficient rickets except that in this case there is
hypercalciuria which may lead to nephrocalcino-
sis and renal failure. Treatment with vitamin D
will worsen the situation by increasing hypercalci-
uria, but treatment with bicarbonate will help
remedy this situation.
Diagnosis of Rickets
The differential diagnosis of rickets is made by
measuring serum Ca, PO4, and increased alkaline
phosphatase determinations, as well as serum
25-hydroxyvitamin D. Parathyroid hormone is
elevated in many of the stages of rickets. Albumin
and creatinine are also useful measurements as
7 Disorders of Calcium Metabolism and Bone
are the urinary fractional excretion, tubular
resorption, and tubular threshold for phosphate.
Treatment of Vitamin D Deficiency
(Table 7.3)
There is controversy but for children a serum
25(OH)D value is considered normal if D ≥20 ng/
mL (50 nmol/L), while 15–<20 ng/mL (37.5 and
50 nmol/L) is vitamin D insufficiency and
≤15 ng/mL (37.5 nmol/L) is vitamin D defi-
ciency; a reasonable goal in children is attain-
ment of 20–30 ng/mL, but these values may be
revised as research continues into the optimal
dose. Obese children tend to have a lower value
of vitamin D, but it is not clear what are the clini-
cal implications of these lower levels or whether
the vitamin D is sequestered in fat. The Institute of
Medicine of the USA recommends 400 IUs of
vitamin D to be administered to infants up to 1
year of age and due to a high prevalence of sub-
clinical vitamin D deficiency which is heralded
by increased parathyroid hormone values in the
USA has increased recommendations to 600 IU/
day between the ages 1 and 18 years. These dos-
ages are used for maintenance rather than treat-
ment of deficiency. Treatment of vitamin
D-deficient children with ergocalciferol at
3,000 U daily for infants less than 6 months and
6,000 U daily for age 6 months to 12 years for 6
weeks is usually curative, although additional
calcium intake may be required. In cases of mal-
absorption due to gastrointestinal disease (cystic
fibrosis, short bowel syndrome, post-pediatric
surgery), increased doses of vitamin D are needed
with careful monitoring to avoid overtreatment.
Excessive vitamin D intake leads to hypervita-
minosis D, and hypercalcemia may develop, and
since vitamin D is fat soluble, it will take weeks
or months (6 months or even more) to return to
normal stores; thus monitoring of 25-hydroxy-
vitamin D levels is important during treat-
ment. There are reports of hypervitaminosis D in
children treated within the recommended guide-
lines; thus every child must be individualized by
monitoring vitamin D, alkaline phosphatase, and
PTH values to determine whether the deficiency
is repleted. To avoid overtreatment, monitoring
of serum calcium and urinary calcium which rises
Hypercalcemia 147

Table 7.3 Calcium and vitamin D dietary reference intakes by life stage
Calcium Vitamin D
RDA (mg/day) RDA (IU/day) Serum 25OHD
(intake that covers (intake that covers level (ng/mL)
Life-stage group (age needs of ≥97.5 % of UL needs of ≥97.5 % (corresponding
and gender) population) (mg/day)a of population) to the RDA)b UL (IU/day)a
1–3 years (M + F) 700 2,500 600 20 2,500
4–8 years (M + F) 1,000 2,500 600 20 3,000
9–13 years (M + F) 1,300 3,000 600 20 4,000
14–18 years (M + F) 1,300 3,000 600 20 4,000
19–30 years (M + F) 1,000 2,500 600 20 4,000
31–50 years (M + F) 1,000 2,500 600 20 4,000
51–70 years (M) 1,000 2,000 600 20 4,000
51–70 years (F) 1,200 2,000 600 20 4,000
71+ years (M + F) 1,200 2,000 800 20 4,000
Pregnant or lactating (F)
14–18 years 1,300 3,000 600 20 4,000
19–50 years 1,000 2,500 600 20 4,000
Infants
0–6 months (M + F) 200c 1,000 400c 20 1,000
6–12 months (M + F) 260c 1,500 400c 20 1,500
Data from Dietary reference intakes for calcium and vitamin D,National Academies Press, 2010. Used with
permission
M male, F female
EARs for calcium were 500 mg/day for ages 1–3 (M + F), 800 mg/day for ages 4–8 and 19–50 (M + F) and ages 51–70
(M), 1,000 mg/day for ages 51–70 (F) and 71+ (M + F), and 1,100 mg/day for ages 9–18 (M + F). EAR for vitamin D
was 400 IU/day for all life-stage groups
a
UL indicates level above which there is risk of adverse events. The UL is not intended as a target intake (no consistent
evidence of greater benefit at intake levels above the RDA)
b
Measures of serum 25OHD levels corresponding to the RDA and covering the requirements of at least 97.5 % of the
population
c
Reflects AI reference value rather than RDA. RDAs have not been established for infants

in hypervitaminosis D is helpful. Use of must be carried out to make sure overtreatment

1,25-dihydroxyvitamin D is not recommended in
states of vitamin D deficiency. One reason is that
it would do nothing to replete the stores of the
body’s vitamin D. Secondly, if vitamin D treat-
ment is offered in vitamin D-deficiency rickets,
serum 1,25-dihydroxyvitamin D levels rise to
supraphysiologic levels which would not occur
with the replacement of 1,25-dihydroxyvitamin
D in standard doses itself.
If compliance appears likely to be a problem,
“stoss” therapy may be invoked; this is one large
single dose of 150,000–600,000 units of vitamin D
given every 3 months as an oral dose divided
throughout 1 day or single intramuscular injection
(IM injection is not available at the time of this
writing in the USA however). Again monitoring
does not occur.
In some cases the rickets is so severe that
orthopedic surgery is required to correct the
abnormalities.
Dihydrotachysterol is a vitamin D molecule
that requires metabolism by the liver but not the
kidney. Thus, it may be preferred in situations of
renal disease, and its rapid onset of action is also
beneficial.
Hypercalcemia
Hypercalcemic symptoms usually occur when
calcium levels are greater than 12 mg/dL, but
the definition of hypercalcemia is a calcium
148 7 Disorders of Calcium Metabolism and Bone

Table 7.4 Causes of hypercalcemia

Serum Serum Alk 25(OH) 1,25(OH)
Condition Ca PO4 phos PTH vitamin D vitamin D Other features
Primary High Low High High Normal Nl or high
hyperparathyroidism for Ca
Familial High Normal, Normal Normal Normal Normal Urine Ca is low. Usually
hypocalciuric high, or or high or high benign but in homozygosity,
hypercalcemia low profound hypercalcemia
and diffuse
hyperparathyroidism
develops as above. AD
inheritance
Hypercalcemia of High Nl or High Low Normal Nl Due to secretion of PTHrP,
malignancy low which creates a state of
hyperparathyroidism
Hypervitaminosis D High Nl or Nl or Low High Nl or high Due to overtreatment or fad
low low megavitamin diets
Renal insufficiency Low Nl or Nl or High Normal Decreased Could lead to tertiary
and secondary high high autonomous (or tertiary)
hyperparathyroidism hyperparathyroidism
Increased High Normal Normal Normal Normal High Occurs in granulomatous
1α-hydroxylation of disease and neoplasms
25 OH vitamin D (lymphomas)
Immobilization High Normal High Nl Nl Nl
hypercalcemia to low
Hyperthyroidism High Nl/high Low Nl Nl or low
Adrenal High Nl Low Nl Nl or low
insufficiency
Thiazide diuretics High Nl Low Nl Nl or low Urine Ca is low
Hypervitaminosis A High Nl Low Nl Nl or low
Modified from: Fisher DA, ed. The Quest Diagnostics Manual: Pediatric endocrinology. San Juan Capistrano: Quest
Diagnostics Incorporated 2000 with permission
Nl normal, PTHrP parathyroid hormone-related peptide

level above the age-related normal range for the
laboratory which usually means above 10.8–
11.3 mg/dL (Table 7.4). Lethargy, weakness,
inability to concentrate, and depression may
develop. Many patients have nausea, vomiting,
anorexia, constipation, and weight loss; the neo-
nate may manifest gastroesophageal reflux, leth-
argy, decreased weight gain, and lack of growth
in length. Because a high extracellular calcium
concentration impairs the capacity of the distal
tubule of the nephron to respond to ADH, hyper-
calcemic patients have polyuria and an inability
to concentrate the urine; dehydration and azote-
mia may result as well as nephrolithiasis, neph-
rocalcinosis, and calciuria. Signs on physical
examination may include band keratopathy of
the medial and lateral margins of the cornea
(nonpurulent conjunctivitis), shortening of the
QT/QTc due to shortening of the ST interval on
EKG recording, and extremely wide QRS, low R
wave, disappearance of p waves and tall peaking
T waves. In addition, hypertension, hypercalci-
uria and nephrolithiasis, pancreatitis, and peptic
ulcer disease. Hypercalcemia also may lead to
hypertension. If serum calcium increases to more
than 16 mg/dL, stupor and coma may occur.
Many nutritional and maternal causes of
hypercalcemia are seen in the newborn. Thus,
excessive administration of calcium or, con-
versely, inadequate administration of phosphorus,
as well as excessive vitamin D administration
directly to the child or, rarely, through the moth-
er’s breast milk, causes elevation of serum Ca.
Subcutaneous fat necrosis due to birth trauma or
Hypercalcemia
birth asphyxia elevates serum Ca due to the
1-hydroxylase activity of macrophages.
Primary Hyperparathyroidism
Hyperparathyroidism can lead to hypercalcemia,
but this condition is rarer in children than in the
adult. Hypercalciuria occurs with hyperparathy-
roidism mainly due to the hypercalcemia and
may lead to nephrolithiasis and even renal fail-
ure. Bone pain, muscle aches, and arthropathy
are reported in pediatric series.
Hyperparathyroidism may occur because of an
adenoma of one or more of the parathyroid glands
or because of mutations in the calcium-sensing
receptor. Hyperparathyroidism might be an iso-
lated finding in a sporadic or autosomal dominant
pattern (#145000 HYPERPARATHYROIDISM 1;
HRPT1) or can be found in the multiple endocrine
neoplasia syndromes (MEN 1, MEN 2). However,
since hyperparathyroidism may be the first mani-
festation of multiple endocrine neoplasia syn-
dromes 1 and 2A, it is incumbent upon the
treating physician to eliminate the diagnosis of
multiple endocrine neoplasia type I before
assuming the patient has isolated hyperparathy-
roidism (see Chap. 14).
Transient hyperparathyroidism in the neonate
may occur if the mother has hypoparathyroid-
ism. Maternal hypocalcemia causes increased
fetal PTH secretion to maintain a normal fetal
serum calcium, but PTH secretion continues into
the newborn period and causes elevated serum
Ca in the newborn for a few days to weeks.
Increased bone remodeling may be found since
the condition was active during fetal period.
Primary hyperparathyroidism causes increased
absorption of ingested calcium and increased
release of calcium from mobilized bone as well
as increased urinary excretion of phosphorus and
calcium. Thus hypercalcemia and hypophospha-
temia occur, and, ultimately, nephrocalcinosis
develops. Mild hypercalcemia leads to constipa-
tion and polyuria, whereas in those with more
may include significant hypercalcemia, manifes-
tations, arrhythmia, hypotonia to the level of
respiratory compromise. Bone pain; subperiosteal
149
bone resorption, mainly of the distal phalanges;
osteitis fibrosa; fractures of the ribs and other
bones; peptic ulcer; and hypertension are found
in affected children. Because PTH stimulates the
synthesis of 1,25(OH)2D by 1-hydroxylation,
serum 1,25(OH)2D is elevated but not
25-hydroxyvitamin D as would occur in vitamin
D toxicity. This diagnosis is made if serum ion-
ized calcium is elevated with inappropriately
increased serum PTH, as PTH should be sup-
pressed to nondetectable levels in a normal
patient with elevated serum calcium.
In the postoperative state after parathyroidec-
tomy, the patient may experience hypocalcemia of
the “hungry bone’s syndrome.” The resorption of
the bones caused by elevated parathyroid hor-
mone abruptly ceases, and the bones then avidly
take up calcium lowering serum calcium levels.
The calcium must be replaced by oral or intrave-
nous method in the immediate period after such
surgery. The accompanying hypo-phosphatemia
should however not be treated as administration of
phosphate will lower calcium further. Associated
with these changes are hypomagnesemia which
should be replaced and hyperkalemia which might
also have to be addressed. As stated above, hungry
bone syndrome is also found in replacement of
vitamin D after severe vitamin D deficiency.
Familial Hypocalciuric Hypercalcemia
Familial hypocalciuric hypercalcemia (FHH
#145980 HYPOCALCIURIC HYPER-
CALCEMIA, FAMILIAL, TYPE I; HHC1 at
3q13.3-q21) or (FHH) is an autosomal dominant
condition due to inactivating mutation of the
CaSR which leads to a higher set point of the
receptor in the parathyroid cells. Elevated
calcium values are seen by the sensor as normal,
and these inappropriately elevated values are
maintained by increased PTH secretion, so that
an equilibrium is reached at a higher than nor-
mal range of serum calcium (11–12 mg/dL is
common) and ionized calcium. Parathyroid
hormone is either elevated or inappropriately
normal for the degree of hypercalcemia.
Hypercalcemia, hypermagnesemia, hypocalciuria,
150
and hypophosphatemia are found. Usually no
symptoms occur, but conditions due to the ele-
vated calcium including pancreatitis and choleli-
thiasis are found in some subjects. This condition
may lead to inappropriate diagnosis of hyper-
parathyroidism and an inappropriate removal of
the parathyroid glands; the diagnosis may be
made in patients with a family pattern of elevated
serum calcium in the face of decreased urinary
calcium excretion. Affected patients will not
respond to a low-Ca diet, for they will mobilize
bone calcium to make up for the deficit and incur
more skeletal complications.
In contrast to heterozygous FHH which
requires no parathyroidectomy, homozygosity or
compound heterozygousity of the inactivating
mutation of the CaSR leads to profound and
potentially fatal hypercalcemia (14–20 mg/dL) in
a condition known as neonatal severe hyperpara-
thyroidism (#239200 HYPERPARAT
HYROIDISM, NEONATAL SEVERE; NSHPT)
in which parathyroid hormone is extremely ele-
vated in spite of the severe hypercalcemia.
Neonatal severe hyperparathyroidism does
require parathyroidectomy and may respond to
the use of bisphosphonates as calcium-lowering
agents in preparation for surgery (see below).
Urinary calcium is inappropriately low (less than
4 mg/kg/day), and the calcium/creatinine ratio is
usually less than 0.10 in spite of the level of
hypercalcemia. Severe bone resorption, frac-
tures, and rachitic changes may be seen in those
who survive the neonatal period.
Hyperparathyroidism may be due to adeno-
mas or hyperplasia of the chief cells.
Hyperparathyroidism might rarely be associated
with multiple ossifying fibromas of the maxilla
and mandible (#145001 HYPERPARATHY
ROIDISM 2; HRPT2) which may also occur
with renal carcinoma or Wilms tumor, thyroid
carcinoma, and parathyroid carcinoma.
Some infants with mild disease have remission
or a mild course, but the usual treatment for a
parathyroid adenoma is surgical extirpation.
If hyperplasia of multiple glands is found, all of
the glands may be removed, with a fraction of
one reimplanted in the forearm, where it can
be surgically reduced in size if hypercalcemia
continues or recurs.
7 Disorders of Calcium Metabolism and Bone
Miscellaneous Causes
Hypercalcemia of Malignancy
Hypercalcemia may be caused by elevation of
PTHrP in patients with malignancy. This may be
found in children with leukemia, lymphoma,
rhabdomyosarcoma, Ewing sarcoma, and other
neoplasms. The treatment of the underlying
malignancy usually reverses hypercalcemia.
Other Endocrine Disorders Causing
Hypercalcemia
Hyperthyroidism leads to active bone turnover
and enhanced resorption, causing mild hypercal-
cemia. Adrenal insufficiency allows increased
intestinal calcium absorption and may lead to
hypercalcemia. Replacement with glucocorti-
coids will reverse hypercalcemia in adrenal
insufficiency.
Drug-Induced Hypercalcemia
Thiazide diuretics are natriuretic but not calci-
uretic and cause diminished urinary calcium
excretion and so may cause mild hypercalcemia.
They are used in conditions prone to developing
urinary calcium stones.
Hypervitaminosis D may occur if excess vita-
mins are given to a child in the therapy for a hypo-
calcemic disorders or in a mistaken confidence in
megavitamin therapy. Fat-soluble vitamin D [ergo-
calciferol (vitamin D2) or cholecalciferol (vitamin
D3)] are stored for months in fat tissue, so an over-
dose is quite long lasting. However 1,25(OH)2D is
short acting, so that excessive dosage can be
quickly corrected. A discussion when to use either
medication is noted above. Individual monitor-
ing must be carried out with the use of ergocalcif-
erol or cholecalciferol as vitamin D toxicity has
been reported in children who were treated with
standard recommended doses. Glucocorticoids
(prednisone at 1–2 mg/kg/day) may be used to
reduce intestinal calcium absorption in the condi-
tion. Children in England at the end of World War
II frequently manifested hypercalcemia, appar-
ently because of excess vitamin D intake.
Hypervitaminosis A increases bone resorption
causing hypercalcemia and may occur with mega-
vitamin therapy. Usually vitamin A excess is found
with vitamin D excess if caused by fad diets.
Hypercalcemia
Milk Alkali Syndrome and Hypercalcemia
of Renal Insufficiency
Excessive ingestion of calcium usually in the
form of calcium carbonate is linked to this hyper-
calcemic condition which can lead to renal fail-
ure. Originally described with the use of calcium
and absorbable alkali for the treatment peptic
ulcers, it may now occur due to excess of calcium
intake for supplementation of dietary sources.
Individuals with renal insufficiency may
have hyperphosphatemia, hypocalcemia,
decreased 1,25(OH)D production, and therefore
increased PTH secretion, causing secondary
hyperparathyroidism. This may become autono-
mous (tertiary hyperparathyroidism). Thus,
even when calcium increases, it does not sup-
press PTH secretion. Calcium carbonate, lac-
tate, or bicarbonate intake given to block
intestinal phosphate accumulation in chronic
renal insufficiency may lead to a form of the
milk alkali syndrome, which includes hypercal-
cemia, hypocalciuria, alkalosis, and all the clini-
cal signs and symptoms of hypercalcemia.
Chronic hyperphosphatemia will cause second-
ary hyperparathyroidism.
Granulomatous Disease
Disorders that demonstrate increased
1α-hydroxylation of 25(OH)vitamin D which
forms increased 1,25(OH)2D include granuloma-
tous disease (sarcoid, eosinophilic granuloma)
or various infectious causing granulomas
including tuberculosis, histoplasmosis, coccidioi-
domycosis, leprosy, or HIV and neoplasms
(lymphomas, dysgerminomas). Enzyme activity
is reportedly increased in monocytes in these
conditions. Affected patients can experience
hyperabsorption of dietary calcium and subse-
quent hypercalcemia. Sarcoid patients also may
become hypercalcemic with small doses of vita-
min D. With increased sun exposure, hypercalce-
mia is worse in sarcoidosis as serum 25(OH)D
increases. Glucocorticoid treatment may be used
to reduce intestinal calcium absorption, reduce
serum calcium values, and decrease 1,25(OH)2D
values.
Hypercalcemia can also be found in cases of
inflammatory bowel disease.
151
Immobilization Hypercalcemia
A child (or more usually an adolescent) who is
immobilized, usually from a fracture and trac-
tion, will have enhanced bone resorption and
diminished bone formation, which may lead to
immobilization hypercalcemia. Intramuscular
calcitonin (50–200 U) will block bone resorption,
although ambulation is the best treatment.
Williams Syndrome
Williams syndrome, now more frequently termed
Williams–Beuren syndrome (#194050
WILLIAMS-BEUREN SYNDROME; WBS at
7q11.2), is a sporadic and contiguous gene dele-
tion syndrome consisting of short stature and
developmental delay, supravalvular aortic steno-
sis, pulmonary arterial stenosis, and a pathogno-
monic facial appearance; it is due to a mutation in
the gene for elastin. “Elfin facies,” consisting of a
small head, protuberant ears, a cupid’s bow lip
with short philtrum, peg-like teeth, blue iris with
whitish flecking, and frequent caries, is the clas-
sic phenotype. Subjects are hyperactive, with
what is described as a “cocktail party patter” per-
sonality. They appear brighter than their full IQ
scores would suggest, as they have a great dis-
crepancy between their verbal and mathematics
performance on testing. They are said to have
increased musical abilities on many instruments.
About 20 % of these children have hypercalce-
mia, hypercalciuria, nephrocalcinosis, and even
renal impairment; the cause appears related to
abnormalities of the Williams syndrome tran-
scription factor (WSTF) encoded by BAZ1B
(*605681 BROMODOMAIN ADJACENT TO
ZINC FINGER DOMAIN, 1B; BAZ1B) which
leads to increased production and decreased deg-
radation of calcitriol. A low-calcium diet or the
use of glucocorticoids to block intestinal calcium
transport may be indicated in those affected with
hypercalcemia, but calcium levels tend to
normalize with the passage of a few years.
Idiopathic hypercalcemia of infancy (143880
HYPERCALCEMIA, IDIOPATHIC, OF
INFANCY) is a rare and usually self-limited con-
dition that may represent a component of Williams
syndrome. Usually normal serum 1,25(OH)2D
and 25(OH)D values are found. A low-calcium
152
diet or glucocorticoid treatment may be pre-
scribed, but most children are asymptomatic.
Fat necrosis with local dystrophic calcifica-
tion occurs in sick term or preterm infants who
have had trauma, cold exposure, or hypoxia. Fat
necrosis may lead to hypercalcemia due to the
1-hydroxylase activity of macrophages and can
persist for several days to weeks, but generally
resolves sooner without sequelae. Fat necrosis
may occur later in life as well.
Other Causes of Hypercalcemia
Various endocrine causes of hypercalcemia include
hyperthyroidism and glucocorticoid deficiency.
While pheochromocytoma can occur along with
hyperparathyroidism in multiple endocrine neo-
plasia type 2A, 2B, pheochromocytoma by itself
can produce parathyroid hormone-related protein
which may lead in rare cases to hypercalcemia.
Thiazide diuretics limit the excretion of calcium
in the urine and thereby can raise calcium levels and
serum. Hypercalcemia can result from hypervita-
minosis A or the use of retinoic acid. Treatment
with lithium can increase parathyroid hormone to a
small degree leading to hypercalcemia.
Treatment of Hypercalcemia
The therapy for nonsymptomatic hypercalcemia
allows time for mild measures such as increasing
hydration, decreasing calcium in oral intake, and
limiting vitamin D intake including multivita-
mins. Acute severe hypercalcemia is treated first
with hydration with sodium chloride-containing
fluid until fluid volume is restored and only then
the use of a loop diuretic, furosemide (1 mg/kg/
dose given slowly intravenously is one option),
which will increase urinary calcium excretion,
may be added. It is extremely important to deter-
mine the state of hydration before the use of the
loop diuretic as dehydration may precede the use
of the diuretic and the diuretic will simply worsen
it. Treatment of dehydration is essential in the
treatment of hypercalcemia. Likewise long-term
use of loop diuretics may lead to nephrocalcino-
sis. Thiazide is not used as a diuretic since it will
limit calcium excretion and increase serum cal-
cium. In addition, sodium sulfate and sodium
7 Disorders of Calcium Metabolism and Bone
phosphate are administered during therapy. Oral
phosphate may be administered to bind calcium
in the intestine, but may result in diarrhea.
Bisphosphonates (described below) may be used
to lower serum calcium and a dose of 0.5–1 mg/
kg/dose by intravenous infusion over 4–6 h with
careful monitoring of serum calcium. Calcitonin
(2–4 U/kg/injection every 6–12 h) may be used to
lower serum calcium but is not a long-term agent
since tachyphylaxis develops in a few days. Oral
glucocorticoids decrease calcium absorption
from the intestines and may be used in severe
cases of increased vitamin D or 1,25-dihy-
droxyvitamin D but will not be helpful in hyper-
parathyroidism. Glucocorticoids also increase
urinary calcium excretion in addition to increased
uric acid excretion so glucocorticoid therapy can
lead to nephrolithiasis and nephrocalcinosis.
Ketoconazole is used as a therapy for fungal dis-
ease but inhibits the formation of 1,25-dihy-
droxyvitamin D as well as general steroid
formation; if this agent is used for states of exces-
sive calcitriol formation, careful monitoring for
adrenal insufficiency is essential. Dialysis is
sometimes invoked in very severe hypercalce-
mia. Of course treatment of surgically correct-
able conditions such as hyperparathyroidism or
parathyroid adenoma is another step. (For a dis-
cussion of the emergency treatment of hypercal-
cemia, see Chap. 15.)
Information on a treatment that should not be
used in childhood: [Phenylalkylamines (cinacal-
cet) are calcimimetic agents which have been
used in adults to stimulate the calcium-sensing
receptor and thereby decrease parathyroid hor-
mone secretion. However, the FDA has elimi-
nated the use of this substance in children pending
an investigation into its safety.]
Evaluation of Hypercalcemia
Family history is important to determine if multi-
ple endocrine neoplasia as or other genetic condi-
tions such as FHH are considerations. Maternal
health, diet, and complications of birth are like-
wise important as noted above. Evaluation of
symptoms of hypercalcemia may be negative
in mild cases of hypercalcemia. Laboratory
Hypercalcemia
evaluation may require multiple measurements of
calcium and multiple determinations of parathy-
roid hormone due to variation in laboratory tech-
niques and results. An elevated serum protein will
increase total serum calcium without parathyroid
disease. Hyperparathyroidism may cause skeletal
abnormalities even though calcium and parathy-
roid hormone levels are still in normal range but
are in inappropriate relation to each other. Urinary
calcium excretion must be determined. Skeletal
evaluation is performed to look for changes caused
by hyperparathyroidism. Imaging of the parathy-
roid glands is done with ultrasound, MRI or CT, or
sestamibi (methoxyisobutylisonitrile) scans which
will indicate parathyroid gland activity.
Osteoporosis
A peak increment of bone mineral accrual occurs
in infancy and in late adolescence. The adolescent
accrual occurs after peak growth rate, and it may
be this imbalance of bone size to mineral content
that causes the increased prevalence of fractures
in close to 5 % of normal adolescent boys. A low
impact fracture (sometimes called a pathologic
fracture) is defined as a fracture which occurs at a
vertical distance less than the standing height of
the individual. While a low impact fracture might
occur in the long bones, spinal fractures are other
indicators of pathologic fractures.
Low bone mass is inherited in a genetic pattern;
40–60 % of bone mass is determined by heredity.
However, children and adolescents can modify
their bone mass by a non-genetic manner. Activity
leading to weight bearing increases bone mass,
and adequate calcium, phosphorus, and vitamin
D intake likewise improve bone health.
Inadequate calcium and vitamin D intake is
endemic in youth in the USA which increases the
likelihood of bone disease. Further, ingestion of
carbonated beverages limits calcium-containing
dairy-product ingestion, limits calcium absorption
because of the phosphate content of the beverages,
and at least in females causes decreased bone
mass. Smoking decreases bone mass. Anorexia
nervosa has many effects not the least of which is
decreased bone mineral density; the female ath-
letic triad likewise encompasses this finding (see
Chap. 9). Obesity, while increasing weight bear-
ing, does not increase bone mass in the normal
153
relationship and can lead to increased prevalence
of pathologic conditions such as slipped capital
femoral epiphyses, Blount’s disease, and fractures.
Immobilization reduces the ability of bone to
reach normal density, and even the limited activity
of children in our modern society has an effect of
decreasing bone strength.
Any hypogonadal condition will also decrease
bone mineral acquisition and increase fracture
risk. Excess thyroxine or PTH administration
cause decreased bone density. Glucocorticoid
treatment in excess of physiologic amounts can
stimulate osteoclasts and inhibit osteoblasts. Any
of the conditions mentioned in this text that lead
to those endocrine abnormalities must be consid-
ered a risk factor for diminished bone density.
Likewise chronic diseases often associated with
increased inflammation as well as leukemia and
other cancers are associated with low bone density.
Immobilization may lead to hypercalcemia but
may also lead to decreased bone density.
Since much of the determination of bone den-
sity is genetic, those with a genetic background
suggesting susceptibility to osteoporosis may
already have more fragile bones at the time of
puberty. Idiopathic juvenile osteoporosis is rare
and may be isolated or found in autosomal reces-
sive pattern (259750 OSTEOPOROSIS,
JUVENILE). The condition appears a few years
before pubertal development, but some subjects
appear to resolve with the progression of puberty.
In affected children extremity fractures due to
osteoporosis will cause the expected local pain and
swelling; vertebral fractures, in addition, will
diminish height. This condition must be differenti-
ated from mild osteogenesis imperfect (see below).
Newborns are susceptible to decreased bone
density based on gestational age and nutritional
status as well as the mothers’ nutritional status and
especially her vitamin D stores. Three-fourths
of the bone calcium content is accrued in the last
trimester, so premature infants are deprived of
much of this mineral. Further, abnormal GI func-
tion and absorption due to many disorders will
limit calcium, phosphorus, and vitamin D intake.
A limitation exists to the amount of calcium and
phosphorus that can be infused in total parenteral
nutrition, leading to greater risk of decreased bone
in subjects receiving such support.
154
Many chronic diseases will decrease bone den-
sity leading to secondary osteoporosis. Celiac dis-
ease is quite common and affects growth as well
as bone density as will other types of gastrointesti-
nal disease and renal disease. Celiac disease will
impair absorption of vitamin D.
Bone density and mineralization are important
concepts in the evaluation of rickets and osteopo-
rosis. Bone mineralization refers to the addition of
mineral, calcium phosphorus, and other minerals
into the bone matrix. Bone density refers to the
ratio of bone mass to volume and is expressed as
grams over centimeters cubed. Dual X-ray absorp-
tiometry (DEXA) measures areal density which is
not true density since it is expressed as grams per
centimeter squared representing the area under
evaluation. Quantitative computed tomography
(QTC) measures actual volumetric bone density.
The terms relating to bone evaluation are BMDtotal
which is the mineral density within the bone under
the periosteal envelope and/or articular surfaces,
BMDcompartment which is the mass of mineral
per unit volume of trabecular or cortical bone, and
BMDmaterial which is the degree of mineraliza-
tion of the organic bone matrix.
Bone density evaluations are generally carried
out by DEXA scan in children as the radiation
exposure is quite low and the information can
be related to fracture risk. DEXA measures the
BMDtotal and bone mineral content (BMC), but
results are for areal rather than the volumetric
results and the results vary by bone size (thin
versus thick bone structure). Determination of
volumetric bone density (three-dimensional) is
superior to determination of areal bone density
(only two-dimensional), as thicker bones have
higher calcium content but may not be any denser
than smaller bones. Areal bone density is not as
closely related to fracture risk as volumetric bone
density. Adjustment for bone size is accom-
plished by expressing bone mineral apparent
density (BMAD) or estimated volumetric bone
density. DEXA cannot differentiate trabecular
versus cortical bone. Bone density that is deter-
mined by DEXA scan in children should be
expressed in Z-scores which are age and gender
adjusted (and ethnic group standards are also
available) as opposed to T-scores which are
7 Disorders of Calcium Metabolism and Bone
adjusted for young adults of 21 years. If the
T-score is reported and used for diagnosis, every
young child will automatically have osteoporosis.
Many inappropriate referrals are made because
of the use of the T-score rather than the Z-score.
In the adult terms indicating bone mineral con-
tent are osteopenia (−1.1 to 2.4 SD below the
mean) and osteoporosis (−2.5 SD or more)
which is a more severe decrease in mineral con-
tent raising the likelihood of pathologic fractures.
In childhood and adolescence the term osteopo-
rosis might be used for a child with low bone
mass (−2 standard deviations for age, sexual mat-
uration, and gender) who has had a low impact
fracture but more appropriately the terms low
bone density or mass are applied in pediatrics.
There are other methods of determining bone
density. Volumetric bone density can be evalu-
ated by qCT techniques, but they require a higher
dose of radiation, the CT scanner necessary to
perform the test is not readily available, and there
are limited standards for pediatrics. This tech-
nique is used in research studies however. MRI is
used in research studies and offers potential for
measuring volumetric bone density in differenti-
ating from cortical to trabecular bone. Qualitative
ultrasound is a technique that requires no ionized
radiation, but standards are not readily available
for children nor are clinical correlations.
Evaluation of the etiology of diminished bone
density will start with family history of osteopo-
rosis or pathologic fractures and continue with
nutritional history of the child. Evaluation for
coexisting conditions such as anorexia nervosa or
other chronic conditions is important. Physical
examination will include determination of height
in standard deviations or percentiles for age,
growth rate, and nutritional status by BMI.
Evaluation for a chronic disease or congenital
conditions is important. Laboratory evaluation
includes measurement of serum calcium and ion-
ized calcium, phosphate, magnesium, alkaline
phosphatase, PTH, 25(OH)vitamin D, 1,25(OH)2
vitamin D, creatinine, and urinary calcium and
creatinine. In appropriate cases based on history,
serum thyroxine and glucocorticoids and gonadal
steroids are useful. A reflexive panel for celiac
disease may be indicated.
Hypercalcemia
Treatment includes ensuring that normal vita-
min D levels and intake are present; that calcium
intake is at least at the recommended level for age,
if not more than recommended for basal levels;
and that physical activity is fostered as tolerated.
Oral calcium citrate is a useful form of calcium
treatment or replacement; foods containing cal-
cium in appreciable degrees include dairy prod-
ucts (cheese, yogurt, milk); sardines; dark leafy
greens including spinach, kale, turnips, and col-
lard greens; cereals fortified with calcium includ-
ing Total, Raisin Bran, and Corn Flakes; soy milk
fortified with calcium (which does not include all
soy milk); and breads, grains, and waffles enriched
with calcium. Precipitating factors such as gluco-
corticoid therapy must be minimized in an attempt
to balance the beneficial effects of these medica-
tions on the disease under treatment with the
adverse effects of the medication on bones.
There are no medications approved in child-
hood for the treatment of low bone mass.
Bisphosphonates are agents used in adults to
impede osteoclast function and inhibit bone
resorption but are not approved for children. While
they have been successfully used in osteogenesis
imperfecta, there are reports of successful treat-
ment in osteopenia in selected children with
increased bone resorption. After the first use of
bisphosphonates an acute phase reaction occurs
which appears to be an episode of infection with
vomiting and possibly a rash. Treatment leads to
higher density of the bone that is improved by the
treatment interspersed with lower density of the
osteoporotic bone leading to a fragility at these
junction sites which may lead to fracture. Some
suggest that the agents be used regularly once
started until bone growth ceases. There is hypocal-
cemia initially which leads to rebound hyperpara-
thyroidism and increasing 1,25-dihydroxyvitamin
D. It is generally suggested that the patient be
admitted for the 3 days of treatment for close
observation but many are treated in the outpatient
setting. Zoledronate is an agent offering a simpler
plan of treatment and is gaining favor over pami-
dronate in children. There are reports of bisphos-
phonate-related osteonecrosis of the jaw or
BRONJ in adults, but the most recent review
reports none in children. Nonetheless data are
155
scarce and the agents have not been used for very
long. Therefore, it is recommended to perform any
necessary dental work before the use of bisphos-
phonates if possible, and of course prevention of
dental disease is essential if the use of bisphospho-
nates is being considered. In view of the long-term
side effects of bisphosphonates in the long term, as
they are stored in the bone for many years, they are
best used under the guidance of clinical studies in
experienced centers.
Osteopenia of the Premature Infant
Since the fetus requires calcium and phosphorus
during pregnancy, premature infants do not
receive this supply of the minerals necessary for
bone development. Even recognizing this fact, it
has been difficult to supplement premature
infants with enough calcium and phosphorus to
equal the supply they would have received in
utero. Some medications for use in the premature
infant also interfere with a bone development.
Metabolic bone disease of prematurity is the term
used to indicate these problems in premature
infants which may progress to the development
of rickets. Risks of fractures are high as 30 % of
premature infants weighing less than 1,500 g suf-
fer fractures. Elevated alkaline phosphatase and
decreasing phosphorous have generally been
used as an indicator of risk of osteopenia and
rickets in the premature infant.
Long-term parenteral nutrition can lead to
metabolic bone disease leading to osteopenia
and progressive liver disease while leading to
jaundice and failure to thrive. Elevated alkaline
phosphatase in these conditions is frequently
related to the bone disease.
Osteogenesis Imperfecta
Osteogenesis imperfecta is a group of condi-
tions characterized by increased fragility of
bones and multiple fractures. They range in
severity from mild to fatal. At the time of this
writing there are 15 variations of osteogenesis
imperfecta listed on Online Mendelian
Inheritance in Man. The numbering system is
based upon the date of the first report of the con-
dition; this discussion will focus on the first
three types as examples of the conditions which
156
are inherited in an autosomal dominant pattern.
Osteogenesis imperfecta type 1 (#166200
Osteogenesis imperfecta, type I) presents with
relatively mild osteopenia with a variable degree
of fractures which usually improves at puberty.
Wormian bones are intra-sutural bones found in
the skull sutures and are present in this condi-
tion. Blue sclera, thin skin, and easy bruising are
characteristics on physical examination with the
stature lower than expected for the family. Mitral
valve prolapse is also found. This condition may
be confused with idiopathic juvenile osteoporo-
sis. Osteogenesis imperfecta type II (#166210
OSTEOGENESIS IMPERFECTA, TYPE II) is
extremely severe usually leading to perinatal
death; the child has fractures present at birth.
Blue sclera and wormian bones are present. The
condition is due to mutation in the collagen I,
alpha-1 polypeptide gene. Osteogenesis imper-
fecta type III (#259420 ICD+OSTEOGENESIS
IMPERFECTA, TYPE III) also presents with
prenatal fractures with more severe fractures
continuing after birth; the blue sclera noted at
birth turns white with age.
Increased Bone Mass Osteopetrosis
Decreased osteoclast function results in a group of
eight congenital disorders known as osteopetrosis.
Autosomal recessive osteopetrosis (#259700
OSTEOPETROSIS, AUTOSOMAL RECESSIVE
1; OPTB1) also called malignant form of osteopo-
rosis is due to homozygous or compound hetero-
zygous mutation in the osteoclast-specific
TCIRG1 subunit of the vacuolar proton
pump while (#259710 OSTEOPETROSIS,
AUTOSOMAL RECESSIVE 2; OPTB2) is
caused by a mutation in the TNFSF11 gene.
Physical findings listed on OMIM involve multi-
ple organs and relate to the effects of increased
bone mass on skeletal integrity and stability func-
tion of nerves or bone marrow trapped within the
increasing bone mass. Thus, physical findings
include frontal bossing; facial paralysis; deafness;
blindness; extraocular muscle paralysis; nystag-
mus; optic atrophy; dental caries; distorted pri-
mary molars; hepatomegaly; splenomegaly;
uniformly dense skeleton; pathologic fractures;
bone-within-bone radiographic appearance; thick,
7 Disorders of Calcium Metabolism and Bone
dense skull; narrowness of neural and vascular
foramina; sandwich appearance of vertebral bod-
ies; coxa vara; splayed metaphyses; hydrocepha-
lus; seizures (tetany); cranial nerve palsies;
pancytopenia; anemia; and extramedullary hema-
topoiesis. Autosomal dominant osteoporosis
(#166600 OSTEOPETROSIS, AUTOSOMAL
DOMINANT 2; OPTA2) is due to a mutation in
the chloride channel 7 gene (CLCN7). Bone mar-
row transplants have been helpful in some forms
of osteopetrosis, and calcitonin has also been used
with some success.
Nonaccidental Bone Injuries
The question may arise as to whether a fracture is
nonaccidental or whether it is caused by osteopo-
rosis, osteogenesis imperfecta, rickets, hypo-
phosphatasia, or other types of metabolic bone
disease in forensic cases. Due to the serious legal
implications in the consideration of nonacciden-
tal injuries, it is best to involve an expert in the
field in a discussion with the child’s provider and
radiologist. Many cases arise before the child is
ambulatory which raises index of suspicion of
how a fracture can occur when the child has little
mobility. Often a skeletal survey will be carried
out to look for nonapparent fractures or meta-
bolic disease. Sometimes a skeletal survey or a
specific radiograph will be repeated in a few
weeks to see if any evidence of healing might
occur suggesting the recency of the event.
Nuclear imaging of the bones is sometimes car-
ried out because there is increased specificity for
fractures with this method than with a skeletal
survey. This is a situation where an expert opin-
ion is necessary.
Aluminum Toxicity
Aluminum (Al) is found in parenteral nutrition
components including additives for calcium and
phosphate, and premature infants are particularly
liable to toxicity. While the FDA recommends a
maximum exposure of 5 μg/kg of aluminum, the
date of manufacturer of the nutrition formula related
to the data of administration may cause significant
changes in content leading to excessive dosing.
Suggested Readings
Aluminum toxicity leads to central nervous system
changes and decreased mineralization of bone as
well as liver damage.
Suggested Readings
1. Shaw N. A practical approach to hypocalcaemia in
children. Endocr Dev. 2009;16:73–92.
2. Root AW, Diamond Jr FB. Chapter 18—Disorders of
mineral homeostasis in children and adolescents. In:
Sperling MA, editor. Pediatric endocrinology. 4th ed.
Philadelphia, PA: Elsevier; 2014. p. 734–845.
3. Root AW. Chapter 8—Disorders of calcium and phos-
phorus homeostasis in the newborn and infant. In:
Sperling MA, editor. Pediatric endocrinology. 4th ed.
Philadelphia, PA: Elsevier; 2014. p. 209–276.
4. Lips P. Vitamin D, physiology. Prog Biophys Mol
Biol. 2006;92(1):4–8.
5. Allgrove J. Physiology of calcium, phosphate and
magnesium. Endocr Dev. 2009;16:8–31.
6. Allgrove J. A practical approach to rickets. Endocr
Dev. 2009;16:115–32.
7. Linglart A, Biosse-Duplan M, Briot K, Chaussain C,
Esterle L, Guillaume-Czitrom S, Kamenicky P,
Nevoux J, Prie D, Rothenbuhler A, Wicart P, Harvengt
P. Therapeutic management of hypophosphatemic
rickets from infancy to adulthood. Endocr Connect.
2014;3(1):R13–30.
8. Winzenberg T, Jones G. Vitamin D and bone health in
childhood and adolescence. Calcif Tissue Int.
2013;92(2):140–50.
9. Crabtree N, Ward K. Bone densitometry: current status
and future perspectives. Endocr Dev. 2009;16:58–72.
10. Bergwitz C, Juppner H. Disorders of phosphate
homeostasis and tissue mineralisation. Endocr Dev.
2009;16:133–56.
11. Davies JH. A practical approach to problems of
hypercalcaemia. Endocr Dev. 2009;16:93–114.
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12. Bhatt RN, Hibbert SA, Munns CF. The use of bisphos-
phonates in children: review of the literature and
guidelines for dental management. Aust Dent
J. 2014;59(1):9–19.
13. Misra M, Pacaud D, Petryk A, Collett-Solberg PF,
Kappy M, Drug and Therapeutics Committee of the
Lawson Wilkins Pediatric Endocrine Society. Vitamin D
deficiency in children and its management: review of
current knowledge and recommendations. Pediatrics.
2008;122(2):398–417.
14. Abrams SA, Committee on Nutrition. Calcium and
vitamin D requirements of enterally a preterm infants.
Pediatrics. 2013;131(5):e1676–83.
15. Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon
PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC,
Gallo RL, Jones G, Kovacs CS, Mayne ST, Rosen CJ,
Shapses SA. The 2011 report on dietary reference
intakes for calcium and vitamin D from the Institute
of Medicine: what clinicians need to know. J Clin
Endocrinol Metab. 2011;96(1):53–8.
16. Lui JC, Nilsson O, Baron J. Recent research on the
growth plate: recent insights into the regulation of the
growth plate. J Mol Endocrinol. 2014;53(1):T1–9.
17. Wit JM, Camacho-Hubner C. Endocrine regulation
of longitudinal bone growth. Endocr Dev. 2011;
21:30–41.
18. Misra M. Vitamin D insufficiency and deficiency in
children and adolescents. UpToDate; 2014
19. Carpenter T. Overview of rickets in children.
UpToDate; 2014.
20. Carpenter T. Overview of rickets in children. http://
www.uptodate.com/contents/overview-of-rickets-
in-children.
21. Carpenter T. Treatment of calcipenic rickets in children.
http://www.uptodate.com/contents/etiology-and-
treatment-of-calcipenic-rickets-in-children.
22. Scheinman SJ, Drezner MK. Hereditary hypophos-
phatemic rickets and tumor-induced osteomalacia.
http://www.uptodate.com/contents/hereditary-
hypophosphatemic-rickets-and-tumor-induced-osteo-
malacia.
 Disorders of Sexual Differentiation
The appearance of ambiguous genitalia in a new-
born can present a biological and psychological
emergency: the former because of possible electro-
lyte and glucocorticoid abnormalities and the latter
because of the distress the parents will experience.
This is a condition in which experience and careful
consideration are essential; immediate consultation
with a pediatric endocrinologist at the least or better
yet consultation with a team established for the eval-
uation and treatment of a child with a disorder of
sexual differentiation (usually composed of endo-
crinologist, geneticist, psychologist, surgeon/urolo-
gist, and ethicist) is recommended before making a
diagnosis, assigning sex of rearing, or embarking
upon a treatment plan. Much has changed in the
management of this condition with recent insights
derived from long-term patient observations.
Indeed, the classifications of intersex conditions
presented in this chapter were only developed
approximately a decade ago with the input of
patients and families as well as providers. These
new terms replace the terms that will be found in
older textbooks which may lead to some confusion.
In this chapter, we will use the new terminology
while on occasion referring to the old ones in case
the reader needs to cross-reference older articles.
Normal Sexual Differentiation
Normal sexual differentiation is based on geno-
type, which will determine gonadal sex, which
leads to phenotypic sexual differentiation, and
© Springer International Publishing Switzerland 2016
D.M. Styne, Pediatric Endocrinology, DOI 10.1007/978-3-319-18371-8_8
8
which determines social sexual role. If a gene
mutation or exposure to an endocrine disrupting
substance occurs, this normal progression may
not occur, and a disorder of sexual differentiation
(DSD) condition will lead to the phenotype of
ambiguous genitalia.
Genotype
Genotype or chromosomal sex is 46, XY for a
male and 46, XX for a female (Fig. 8.1). The Lyon
hypothesis stated that one of the X chromosomes
in a female is inactivated so that only one dose of
each gene on the X chromosome is active. It is
now established that inactivation does not occur
on the entire X chromosome, as some genes
remain active and are required for normal sexual
differentiation. This “relatively” inactivated X
chromosome appears as a Barr body at the periph-
ery of the nuclear envelope on a Giemsa-stained
preparation of cells scraped from the buccal
mucosa. Patients will have one fewer inactivated
X chromosome (and one fewer Barr body) than
the number of X chromosomes, so that those with
more than two X chromosomes will have more
than one Barr body (e.g., a patient with 48XXXY
will have two Barr bodies) and those with only
one X chromosome (45X Turner syndrome) will
have no Barr body. You may encounter Barr bod-
ies mentioned in the literature (and that is why it
is included in this chapter); we do not recommend
this test be performed for clinical diagnosis as few
159
160 8 Disorders of Sexual Differentiation

Fig. 8.1 Genes found on the X chromosome of importance to sexual differentiation. From Grumbach and Conte in
Williams textbook of endocrinology 10th edition 2002. Used with permission

laboratories are capable of staining buccal smears
in a reliable manner and few physicians have
enough experience to interpret the buccal smear
results appropriately. Thus, a karyotype determi-
nation is the only accurate method to determining
chromosomal sex. However, the determination of
chromosomal sex does not itself determine the
management of the child as many more consider-
ations must be taken into consideration.
The Y chromosome contains the SRY gene,
which directs the differentiation of the bipotential
gonad in the early fetus into a testis. Active genes
on portions of the distal arms of the Y chromo-
somes, the pseudoautosomal regions, can undergo
meiotic recombination with the corresponding dis-
tal pseudoautosomal areas of the X chromosome.
The SRY gene is located proximal to the boundary
of the pseudoautosomal region of Y chromosome.
The translocation of the SRY to an X chromosome
can cause an XX individual, who inherited one
normal X chromosome from the mother and one X
chromosome which now has an SRY gene from
the father, to develop testicular tissue; this is the
origin of an XX male, an individual who would
demonstrate many characteristics that would be
found in a 47XXY male with Klinefelter’s syn-
drome. The SRY also can be transferred to an auto-
some, allowing an XX phenotypic male to result
Normal Sexual Differentiation 161

Fig. 8.2 The major

steps and genes and
INTERMEDIATE
hormones involved in
MESODERM
gonadal sexual
differentiation SF-1
WT-1

PLACENTA
UROGENITAL
RIDGE
Y chromosome X chromosome
PAR SOX9

SRY
BIPOTENTIAL
GONAD

Duplication of Ovarian
DAX-1 or WNT-4 genes

SOX9
hCG WNT-4
Leydig SOX9 OVARY
cells
TESTIS
FEMALE SEXUAL
Sertoli Steroidogenic DEVELOPMENT
cells genes
SF-1 SOX-9
WT-1 AMH gene SF-1

Testosterone Support of
AMH wolffian ducts
5 Androgen
AMH Receptor reductase receptors

Dihydrotestosterone Masculinization
of external
Regression of genitalia
MuIlerian ducts
MALE SEXUAL DEVELOPMENT

from this anomaly. Alternatively, 46, XY pheno-
typic females lack testicular development because
of the loss of SRY from the Y chromosome inher-
ited from the father. Other autosomal genes deter-
mine sexual differentiation; abnormalities of these
regions also may lead to disorders of sexual dif-
ferentiation (Fig. 8.2).
Gonadal Sex
Gonadal sex is determined by the presence or
absence of the SRY. There are genes that cause
the indifferent gonad to develop into an ovary in
the absence of SRY, including Wnt4 and Bmp2,
so that ovarian development is no longer consid-
ered a passive process and the development of a
testis an active process as was the case in the
past. Abnormalities in the genes causing testicu-
lar development in a 46, XY individual character-
istically lead to ambiguous genitalia or sex
reversal, while abnormalities in the genes caus-
ing ovarian development of a 46, XX individual
usually manifest later in life as absent or delayed
menarche or premature menopause. Dysgenetic
testicular development leads to a risk for neopla-
sia and might be found, for example, in an indi-
vidual with an apparent 45X karyotype with
mosaicism for a small number of 46, XY cells.
Fluorescence in situ hybridization probes for the
162
Y chromosome are used to determine if an indi-
vidual has a Y cell line indicating the presence of
dysgenetic testicular tissue that may become neo-
plastic even though the gonad was expected to be
a streak gonad comprised only of fibrous tissue.
If there is only one X chromosome and no SRY,
the gonad will develop into an ovary during the
fetal period and the ovary will contain ova. The
ova, however, will atrophy in the absence of a
second normal X chromosome, and the ovary
will degenerate into the “streak gonad” character-
istic of Turner syndrome. Many other genes are
involved in the creation of the gonad, so this
schema must be considered a simple summary.
The steroid metabolism of the gonad involves
several enzymes in the conversion of cholesterol
into androgens or estrogens; many of these enzymes
also are important in the biosynthetic activities of
the adrenal gland, so that a genetic defect in an
enzyme may affect both gonadal and adrenal func-
tion. Figure 8.3 demonstrates the steroid molecules,
the enzymes involved and the names of the genes
that identify them. Steroid determinations and
genetic probes in clinical or research laboratories
will detect these enzymatic defects.
Primordial germ cells develop in the primary
ectoderm and migrate to the dorsal wall of the
yolk sac. By the fifth to sixth week the primordial
germ cells migrate to the midgut and hind gut. By
the seventh and eighth week they have migrated
through the dorsal mesentery into the gonadal
ridges formed near the nephrotic cord where by
the ninth week they colonize their respective tes-
tes or ovaries. Thereafter with appropriate genetic
composition, they will differentiate into oogonia
in the fetal ovary or spermatocytes in the fetal tes-
tis. Meiosis is the process of cell division in germ
cells that leads to the development of haploid
cells which can become oogonia or spermato-
cytes. Germ cells in the ovary immediately begin
meiosis as they develop into oogonia, but germ
cells in the testes become quiescent until meiosis
begins in the peripubertal period.
Phenotypic Sex
Phenotypic sexual development involves the inter-
nal ducts and external genital appearance. The
8 Disorders of Sexual Differentiation
development of these two areas is based on the
effect, or lack thereof, of androgens and proteins.
Internal sexual ducts (Fig. 8.4) start as bipo-
tential, but one set develops and the other degen-
erates as sex is determined. Internal genital ducts
are masculine if derived from the Wolffian ducts
or feminine if derived from the Müllerian ducts.
In the presence of the testicular peptide product
derived from the Sertoli cells, anti-Müllerian
hormone (AMH or MIF for Mullerian Duct
Inhibitory Factor), a member of the TGF-beta
superfamily, the Müllerian ducts will atrophy
through paracrine action of AMH; in the absence
of AMH, the uterus, oviducts, and the upper two-
thirds of the vagina will develop spontaneously
into a basic form. Gonadal development in 46, XY
DSD (previously termed male pseudohermaphro-
ditism) may lead to more Leydig cell function
and testosterone production than AMH produc-
tion, and some level of Müllerian development
may occur in a genetic male with impaired AMH
production due to dysgenetic testes in these
cases. In the presence of high local concentra-
tions of testosterone, the Wolffian ducts will
develop into the rete testes, efferent ducts, epi-
didymis, vas deferens, and seminal vesicles
through paracrine action of the testosterone. As
the testosterone and AMH will come from a tes-
tis, a unilateral testis in ovotesticular DSD (previ-
ously termed true hermaphroditism) could
produce Müllerian regression and Wolffian dif-
ferentiation on the ipsilateral side, whereas a con-
tralateral ovary could allow the development of
contralateral oviduct and a hemiuterus. Thus in a
ovotesticular DSD, one side of the internal sexual
ducts may appear similar to male ducts and the
other to female ducts.
External genitalia (Fig. 8.5) are bipotential
until 8 weeks of gestation. Without the presence
of characteristic male concentrations of andro-
gens, the genital tubercle will become a clitoris,
the urogenital folds will become the labia minora,
and the labia majora will form from the labio-
scrotal swelling. In the presence of systemic cir-
culating testosterone, which is locally converted
into dihydrotestosterone (DHT or 5a-androstane-
17b-ol-3-one) by the 5α-reductase enzyme in the
sexual skin, and in the presence of normal andro-
gen receptors (ARs), a boy will be virilized into a
Normal Sexual Differentiation 163

Fig. 8.3 Normal steroid

physiology in the adrenal
gland and the gonads as
described in the text.
Enzymes are noted in blue;
major products are noted in
red. The pathways most
prominent in the gonads are
on the right with some of the
steps also found in the zona
fasciculata of the adrenal
gland

classic male appearance. With DHT, the genital
tubercle will differentiate into a penis, the uro-
genital slit will form a penile urethra, and fusion
of the labioscrotal folds will produce a scrotum.
The fetal testes must be functional to allow
these steps of virilization to progress. In the first
trimester, maternal human chorionic gonadotro-
pin (hCG) stimulates the LH/hCG receptor on the
fetal testes to produce the testosterone necessary
for male development, as fetal gonadotropins are
not yet secreted from the fetal pituitary gland in
substantial amounts. During the last two trimes-
ters as hCG wanes, fetal pituitary LH is secreted
in the greater amounts that are necessary to stim-
ulate testicular activity and cause further normal
growth of the penis; if the fetal pituitary gland
cannot produce luteinizing hormone (LH), the
penis will be normally shaped (because of early
164
Fig. 8.4 A schematic depiction of the development of the internal sexual ducts when testosterone exerts or does not
exert its normal effects (Adapted from an original figure of Dr. J. Wilson with permission)
hCG stimulation of the fetal testosterone produc-
tion) but small because of lack of the enlargement
that only occurs if stimulated by fetal LH; with-
out fetal LH the penile length will likely be less
than 2.0 cm (which is −2.5 SD from the mean)
and is called a microphallus, as compared with an
average normal length of 3.5 cm at term.
Some of the enzymes involved in the produc-
tion of sex steroids on the same as found in the
adrenal gland as described in Chap. 10. The zona
fasciculata of the adrenal gland produces sex ste-
roids, but some of the steps are only found or
more active in the testes and ovaries (Fig. 8.3).
Disorders of the normal steroid biosynthetic
pathway are described below.
Any interruption of the normal progression
toward masculine development in a 46, XY
fetus will result in the development of some
degree of ambiguous genitalia. Any exposure to
androgens at a sensitive time in development
will cause a 46, XX fetus to virilize to some
degree also causing ambiguous genitalia. If the
8 Disorders of Sexual Differentiation
female is exposed to the androgen after 8 weeks
and before 13 weeks of gestation, the vaginal
opening may fuse posteriorly to become slit-
like, and the urogenital slit may enclose at least
part of the urethra; androgen exposure after 13
weeks of gestation will only enlarge the length
and thickness of the phallic structure, causing
clitoromegaly without affecting the vaginal
opening. Average term penile size is 3.5 (gently
stretched) × 1 cm and clitoral size is about
4 mm × 3 mm. Thus, the appearance of the geni-
talia at birth reveals much about the physiology
of the fetus.
The anogenital distance measures from the pos-
terior of the scrotum of the male or of the posterior
fourchette of the female to the center of the anus.
The distance is related to androgen exposure as the
distance is longer in males (19.81/−6.1 mm) than
in females (9.11/−2.8 mm). Lengthening of the
anogenital distance in girls occurs with excessive
androgen exposure, and shortening of the anogeni-
tal distance in boys occurs with inadequate andro-
Normal Sexual Differentiation 165

Fig. 8.5 A schematic depiction

of the changes to the external
genitalia of the developing fetus Genital
when testosterone is converted to fold
DHT by interaction with the Genital
androgen receptor. On the left in swelling
a normal male. Male develop- INDIFFERENT
ment can only proceed with the Genital STAGES
presence of adequate amounts of tubercle
dihydrotestosterone (DHT) and
normal androgen receptors.
Female development in the
absence of DHT is presented on
the right (Adapted from an MALE FEMALE
original figure by Dr. J. Wilson
with permission)
Glans Glans

Urethral
Fused groove
genital folds
Anus Anus
Urethral
groove
Labia minora
Labia majora
Scrotum

Prepuce

Body of
penis Clitoris
Urethral oritice
Scrotal Hymen
raphe

gen production or in the presence of endocrine
disruptors which lessen androgen effects.
Social Gender
Gender development may be thought to consist
of (a) gender identity, the experience of one’s self
as female or male; (b) gender role, the behavior
that identifies to others or self whether one is
male or female; (c) sexual orientation, the choice
of gender of sexual partners; and (d) the desire
and capacity for parenting.
The classic view has been that gender identity
is determined mainly by the surroundings of the
growing child, but because the physical appear-
ance of the child influences those interacting with
the child, gender identity is also affected by phys-
ical sexual differentiation. Interactions with fam-
ily and peers will teach the child how to act within
the expected gender role. However, a growing
body of research demonstrates effects of prenatal
166
androgen exposure on subsequent gender devel-
opment, although human beings retain plasticity
to allow some alteration to the effects of prenatal
androgen exposures. For example, a girl exposed
to prenatal androgens, because of virilizing CAH,
if raised socially as a girl, will have a normal
female gender identity but may demonstrate some
male tendencies in play behavior and reasoning
and/or a male tendency in gender role. Conversely,
males who are exposed to prenatal androgens but
have inadequate male external genitalia and are
therefore raised as females may choose a male
gender identity spontaneously in later childhood
or adolescence. Thus, in cases of 46, XY DSD,
described later, decisions on sex of rearing are
difficult, and recommendations are presently con-
troversial and undergoing reconsideration. Patient
groups have been forceful in suggesting that gen-
der assignment and surgical reconstruction should
await such time as the child can decide; others
believe that this is unworkable, and gender should
be assigned in an unambiguous manner early. All
would agree that parents must be involved and
that the best understanding of the biology of the
condition must be considered. It has been consid-
ered difficult to institute change of gender suc-
cessfully after age 18 months (except for the case
of 5α-reductase deficiency discussed later), and
concern remains over the psychological effects of
spontaneous or guided change in gender identity
later in life. Legal issues arise in considerations of
gonadectomy in affected children before the age
of consent and advocacy groups have brought suit
for their assertions that gonadectomy have been
improperly performed in young children. For all
of these complexities the DSD team described at
the beginning of this chapter, usually found in
children’s hospitals or university centers, should
be consulted. Gonadectomy for other causes than
neoplasia should not occur without consideration
of the future social and legal considerations.
Disorders of Sexual Differentiation
The present term for what was previously called
an “intersex condition” is a disorder of sexual dif-
ferentiation or DSD.
8 Disorders of Sexual Differentiation
46, XX DSD: Conditions Causing
Genetic Females to Become Virilized
(Previously Called Female
Pseudohermaphroditism)
These 46, XX patients are exposed to excessive
amounts of androgen which can be converted to
DHT during fetal life causing virilization of
external genitalia. In the absence of anti-
Müllerian hormone (since there is no testis nor
Sertoli cells), internal ducts will be derived from
Müllerian ducts and will be female ducts includ-
ing ovaducts and uterus leading to the possibility
of fertility.
Congenital adrenal hyperplasia is detailed
below since the most common ones present with
ambiguous genitalia. The basis of steroidogene-
sis is discussed in Chap. 10, and aspects of adre-
nal insufficiency are found there as well.
Virilizing Congenital Adrenal
Hyperplasia
An abnormality in any of the enzymes involved in
the production of cortisol will, in the absence of
feedback inhibition, allow increased adrenocorti-
cotropic hormone (ACTH) secretion. The adrenal
glands, unable to produce the glucocorticoid end
product, cortisol, which would ordinarily suppress
ACTH, will become hyperplastic. Depending on
the enzyme affected, the adrenal gland may make
extremely increased androgens which will cause
virilization of a female fetus. Alternatively, a
defective enzyme which is essential for testoster-
one production will cause inadequate virilization
in a male. A defect of an enzyme in the pathway
involved in the production of aldosterone will
cause sodium loss and the retention of potassium,
leading to hyponatremia and hyperkalemia, possi-
bly to a life-threatening extent although some of
these salt-losing conditions do not demonstrate
ambiguous genitalia (see Table 8.1).
21-Hydroxylase Deficiency (*201910
ADRENAL HYPERPLASIA, CONGENITAL,
DUE TO 21-HYDROXYLASE DEFICIENCY)
21-Hydroxylase deficiency, the most common
type of CAH, is the most common cause of
ambiguous genitalia and virilization in a
Disorders of Sexual Differentiation
Table 8.1 Differential diagnosis of adrenal enzyme effects
Newborn
Deficiency Phenotype
StAR (also known as lipoid Infantile female
congenital adrenal hyperplasia)
3β-Hydroxylase (3βHSD) Ambiguous in XY
Female or ambiguous in XX
17α-Hydroxylase (P450c17) Infantile female
11β-Hydroxylase (P450c11β) Male in XY
Ambiguous in XX
21-Hydroxylase (P450c21) Male in XY
Ambiguous in XX
18-Hydroxylase (P450c11AS) Normal
newborn female, and the nonclassic type of
21-hydroxylase deficiency is the most common
type of genetic disease in human beings.
21-Hydroxylase deficiency CAH is best consid-
ered as a spectrum of diseases ranging from the
mild nonclassic or cryptic form to the simple vir-
ilizing form to the salt-wasting form. The
21-hydroxylase enzyme is a P450-class enzyme
with the gene (denoted as cpy 21A2) located on
chromosome 6 (6p21.1) in proximity to the
human leukocyte antigen (HLA) locus adjacent
to the genes for the fourth component of comple-
ment. Progesterone is 21-hydroxylated into
deoxycorticosterone (DOC) in the pathway
toward the production of aldosterone and
17-hydroxyprogesterone [17(OH)progesterone],
or 17OHP is 21-hydroxylated to 11-deoxycorti-
sol in the pathway toward cortisol. Thus because
the production of cortisol is diminished due to a
defect in the 21-hydroxylation step, ACTH
increases and stimulates the production of prod-
ucts of the adrenal gland proximal to this defect:
the main product is 17(OH)progesterone and its
precursors. Elevated 17-hydroxyprogesterone
concentrations may be converted into testoster-
one by either of two metabolic pathways. In the
classic pathway conversion of 17-hydroxypro-
gesterone to androstenedione and testosterone,
dihydrotestosterone occurs by 17,20 lyase
enzyme activity which is inefficient. Recently,
the more efficient “backdoor” pathway which
causes the conversion of 17-hydroxyprogester-
one to androstenedione through 5 alpha reductase
167
Postnatal Salt losing=+
Virilization Hypertension=*
− +
+ +
+ +
− *
+ *
+ *
+ +(50 %)
+ +(50 %)
− +
type 2 and aldo-keto reductase subfamily 1C and
subsequent conversion to androstanediol and
dihydrotestosterone by 17-beta hydroxysteroid
dehydrogenase type VI was described. This new
understanding suggested there may be better
markers for the control of congenital adrenal
hyperplasia than 17-hydroxyprogesterone and
that improved treatments may be developed. All
patients with 21-hydroxylase deficiency have
elevated 17-hydroxyprogesterone at diagnosis in
the basal state in the congenital (severe) form or
after ACTH stimulation in the late-onset (non-
classic or cryptic) form discussed later.
Classical CAH condition occurs in about 1 in
15,000 births. About 50 % of patients with the
congenital form have clinical salt loss and hyper-
kalemia because of impaired production of
DOC. Within one family, if a proband has salt los-
ing, other affected children also will be salt losers;
further, the affected children within one family
will share the same HLA types, allowing a possi-
bility of prenatal diagnosis of future pregnancies.
Females with 21-hydroxylase deficiency will be
virilized in utero due to elevated androgens that
reach the externa genitalia by classic endocrine
mechanisms, demonstrating any variation of clitor-
omegaly, posterior fusion of the labia majora some-
times into the appearance of an “empty scrotal
sack,” and lack of formation of the vaginal vesicular
septum, causing a urogenital sinus. Thus, a 46 XX
female will have an appearance on the continuum
from ambiguous genitalia to “male with unde-
scended testes.” However, the internal ducts remain
168
female in the absence of AMH or local paracrine
exposure to high concentrations of androgens
which require a testes to be present and functional.
Exposure to prenatal androgens characteristic of
CAH is reported to exert an effect on behavior as
girls as those with CAH exhibiting more male like
play and behavior than their unaffected sisters. A
male infant with 21-hydroxylase deficiency will not
appear obviously abnormal and may not be diag-
nosed until a metabolic emergency occurs, which is
why newborn screening for 21-hydroxylase defi-
ciency is so important. On the contrary, a girl with
ambiguous genitalia will usually receive immediate
attention because of more immediate diagnosis
caused by the appearance of ambiguous genitalia.
Newborn screening programs in most
locations regularly include detection of
17-hydroxyprogesterone values on their panel to
ensure early treatment of 21-hydroxylase defi-
ciency. However, premature infants will not yet
have appropriate development of the definitive
zone of the adrenal gland so that 3-beta-hydroxys-
teroid dehydrogenase and 11-beta-hydroxylase
activity are not active to the levels that occur at
term, because premature infants do not have the
characteristic postnatal decrease in activity of the
fetal zone of the adrenal gland. Thus premature
infants may have a positive newborn screen or an
indeterminate value of 17-hydroxyprogesterone
leading to the necessity of secondary screening. If
the child being evaluated is a premature infant
with a normal female phenotype without clitoral
enlargement nor partial fusion of the vaginal open-
ing, it is virtually impossible that the child would
have classic virilizing 21-hydroxylase deficiency,
thus indicating that the screen was a false positive.
A normal-appearing phenotypic male however
will have no visual signs to indicate whether the
positive newborn screen is a false-positive or a
true diagnostic finding. Premature infants with
false-positive neonatal screens for 21-hydroxylase
deficiency will with the passage of time develop
normal enzyme function and the abnormal values
will decrease.
In the salt-losing form of 21-hydroxylase
deficiency, salt wasting does not manifest until
after several days of age. Likewise, hypoglyce-
mia does not always develop in the immediate
neonatal period but may take a day or two to
8 Disorders of Sexual Differentiation
appear. Thus, in these days of short-stay deliver-
ies, a patient may actually be discharged from
the hospital before biochemical complications
develop. The initial signs of electrolyte distur-
bance may be vomiting and may appear as a
case of viral gastroenteritis on casual evaluation.
Boys who look normal may be mistakenly diag-
nosed as having pyloric stenosis and even
undergo unnecessary GI surgery which may be
fatal due to untreated adrenal insufficiency; one
diagnostic difference is that patients with
21-hydroxylase deficiency have high potassium
concentrations and often acidosis, whereas those
with pyloric stenosis have low potassium and
metabolic alkalosis. If untreated, salt loss can
lead to sodium values in the 110 mEq/L or lower
range and elevated potassium to the range
greater than 9.5 mEq/L by age 3–4 weeks if the
child survives that long without therapy.
Vomiting can lead to weight loss, so that body
weight decreases to a point lower than birth
weight. Simple virilized patients have no obvi-
ous salt loss but may have more subtle decreases
in total body sodium leading to elevated plasma
renin activity (PRA), suggesting the need for
extra salt or mineralocorticoid therapy in spite
of the absence of the clear diagnosis of salt-los-
ing adrenal hyperplasia.
Skin pigmentation may darken in flexural
surfaces, on the areola, or generally, a band of
pigment may occur at the gumline while the
patient is untreated because of extremely
increased ACTH secretion, but this pigmenta-
tion will not occur until after the immediate
neonatal period. Androgen secretion will lead
to peripheral sexual precocity in affected chil-
dren who survive the neonatal period in the
untreated state, with the appearance of pubic
hair, clitoral or penile enlargement, acne, deep-
ening of the voice, muscular development, and
rapid growth. Aromatization of the androgens
to estrogens will advance bone age over the
months and years after birth. Therefore,
although the child will be large for age, the
rapid bone-age advancement will later lead to
early epiphyseal fusion, and short adult stature
will result. The testes will not initially enlarge
in affected boys because they are not stimulated
by gonadotropin secretion since the virilization
Disorders of Sexual Differentiation
is caused by the androgens and precursors of
the adrenal gland. Elevated androgens will also
cause maturation of the hypothalamic–pituitary–
gonadal axis. When glucocorticoid treatment is
administered and adrenal androgen secretion
decreases, the adrenal androgens that were sup-
pressing gonadotropin secretion diminish, and
true central precocious puberty may develop
(with pubertal testicular enlargement then
developing in boys). This secondary complica-
tion will further compromise adult height by
causing bone-age advancement; central preco-
cious puberty after exposure to excess andro-
gens can be treated with gonadotropin-releasing
hormone (GnRH) analogs, as can any other
cause of central precocious puberty (see Chap. 9).
Testicular enlargement may also occur because
of enlargement of testicular adrenal rest tissue
(TART) which refers to embryonic adrenal tis-
sue remaining in the testes which can be stimu-
lated by ACTH. This condition previously was
thought to occur in poorly treated patients, but
it is now apparent that all boys with congenital
adrenal hyperplasia are susceptible to the devel-
opment of TART. Long-term studies indicate
that TART tissue may become neoplastic, so
male patients should be followed up carefully.
There are various terms used in the literature
for the mildest types of 21-hydroxylase defi-
ciency: nonclassical, cryptic, or late-onset
21-hydroxylase deficiency. We will use the term
nonclassical 21-hydroxylase deficiency which is
characterized by normal phenotype at birth, and
therefore this is not considered 46, XX DSD
(i.e., no clitoromegaly nor posterior vaginal
fusion occurs in girls), with androgenic effects
only occurring years after birth, in childhood,
adolescence, or young adulthood. The serum
17-hydroxyprogesterone and other adrenal
androgen concentrations may be elevated in the
basal state but definitely will be elevated after
ACTH stimulation, but they will be not as high as
found in the congenital form of CAH. Female
patients may complain of increasing facial or
body hair, and menstrual abnormalities may
occur. The incidence varies in ethnic groups, with
an incidence of 1:1000 in the general Caucasian
population and as much as 1:50–27 in Ashkenazi
169
Jewish women, making this disorder the most
common genetic disease in human beings.
Nonclassical congenital adrenal hyperplasia
presents in a very similar manner to PCOS as
described in Chap. 9. The nonclassical congenital
adrenal hyperplasia is a disorder solely of the
adrenal glands and not the ovaries. Polycystic
ovarian disease is mainly based in the ovaries,
and each condition requires different treatment.
We will use the term cryptic 21-hydroxylase defi-
ciency for patients with laboratory values identi-
cal to those found in patients with the late-onset
form, but without virilization: cryptic 21-hydrox-
ylase deficiency appears to be a variant of the
late-onset form.
Diagnoses
The diagnosis of 21-hydroxylase deficiency is made
by the elevation of serum 17-hydroxyprogesterone
concentrations, the precursor of the enzyme that is
deficient, in the basal state or 60 min after 250 mg
synthetic ACTH (1–24 ACTH or Cortrosyn) given
intravenously. Note that the low-dose ACTH stimu-
lation test mentioned in Chap. 10 is not appropriate
for this diagnostic activity. Serum concentrations of
17-hydroxyprogesterone are elevated in cord blood
of normal infants compared to blood samples sev-
eral days later because of the activity of the fetal
adrenal zone at that early stage as well as contribu-
tions from the mother’s steroid metabolism.
However, 17-hydroxyprogesterone values decrease
to levels of 100–200 ng/dL within 24 h after birth.
A neonate with classic 21-hydroxylase deficiency
will have concentration of 17-hydroxyprogesterone
in the 5,000–10,000 ng/dL range or higher, allow-
ing differentiation from normal infants. However,
due to widespread neonatal screening using sensi-
tive techniques, some children with nonclassical
CAH may be discovered at birth. Methods of
screening for 21-hydroxylase deficiency in heel-
stick samples taken after birth are instituted in the
newborn screening programs of all states. As stated
above, false-positive screens are common in prema-
ture infants due to the immature state which allows
continued fetal adrenal zone function for a period
after birth in contrast to term baby when the fetal
adrenal zone rapidly decreases. Prenatal diagnosis
is available for 21-hydroxylase deficiency by mea-
170
suring amniotic fluid steroid metabolite values or by
matching the HLA type of the fetus under consider-
ation (taken from amniocentesis or chorionic villus)
to an affected proband sibling of known HLA type
or by restriction fragment length polymorphism
analysis of fetal tissue. Recent techniques are devel-
oped to allow diagnosis on the scarce fetal blood
cells that enter the maternal circulation. A mother
with a proband with 21-OH CAH who is pregnant
again may be treated with glucocorticoids that pass
the placenta to decrease virilization of a potentially
affected female fetus. Prenatal treatment involves
the use of dexamethasone as cortisol and predniso-
lone are deactivated by the placenta as they are con-
verted to inactive cortisone and prednisone by 1
beta HSD 2.
If the chorionic villus sample determines the
fetus is male or if endocrine testing of amniotic
fluid shows the fetus is not affected, glucocorti-
coid therapy is stopped. Each parent is heterozy-
gous for the CAH gene; there is a one in four
chance of an offspring having homozygous con-
genital adrenal hyperplasia, and of those one will
be a female who can be viralized; thus there is a
one in eight risk of a treatable prenatal condition.
Thus, seven of eight fetuses are unnecessarily
treated with glucocorticoids for 8–12 weeks of
gestation and are subjected to potential risk from
this treatment. Fetal treatment with glucocorticoid
administered to the mother may diminish viriliza-
tion of affected females but is still considered
experimental therapy. While some reports suggest
this is safe therapy, there are cautions as orofacial
clefts, decreased birth weight, poorer verbal
working memory, and poorer self-perception and
scholastic and social competence are also
reported, and it is cautioned that this treatment be
carried out in controlled studies with experienced
practitioners of the method if at all.
The risk of cleft palate due to fetal glucocorti-
coid excess adds further caution when consider-
ing this method.
Older methods of diagnosis, now superseded,
include analysis of a 24-h urine collection for
17-ketosteroid as a reflection of adrenal androgen
secretion (primarily DHEA or dehydroepiandros-
terone). Difficulties occur if a full 24-h collection
is not obtained; we have seen patients mistakenly
8 Disorders of Sexual Differentiation
considered normal on the basis of a 3-h collection
that was fallaciously low because of low volume
and inadequate time of collection. A 24-h urinary
pregnanetriol determination, a reflection of
17-hydroxyprogesterone secretion, has the same
reliance on a full 24-h urine collection.
Diagnosis in the newborn rests upon analysis
of a serum sample for 17-hydroxyprogesterone
as well as other metabolites of the adrenal gland;
laboratories experienced with pediatric endocrine
practice will treat the situation as a medical emer-
gency and analyze the blood within a day or two.
These experienced laboratories will make deter-
mination on small samples of blood that are
appropriate in a newborn rather than the large
samples requested when diagnosing a young
adult with hirsutism. A panel of precursors to
various causes of intersex can be carried out on
very small samples in national laboratories with
pediatric standards. New highly sensitive analy-
ses of urinary metabolites of adrenal androgens
are becoming available on spot collections and
may further simplify diagnosis.
As salt loss is not usually seen in a salt-
losing patient until after about age 5 days, vigi-
lance must not be relaxed until days to weeks of
carefully observing the patient’s electrolyte sta-
tus pass. Since hemolysis is possible from a
heelstick sample which will raise the potassium
value, a carefully collected venous sample
should be obtained if questions of hyperkale-
mia rise. A plasma renin activity (PRA) should
be obtained to confirm salt loss, but the result of
this test may not be available for several days,
and immediate diagnosis cannot therefore rest
on this test. Plasma renin activity values must
be correlated with age in the laboratory with
pediatric standards as the values are higher in
children than adults.
If an ultrasound examination in a newborn
with ambiguous genitalia reveals a uterus, the
patient will most likely be 46, XX DSD and
therefore will most likely be a female with
21-hydroxylase deficiency based upon probabil-
ity. However, it is essential to confirm the diagno-
sis and not simply guess based on the prevalence
of 21-hydroxylase CAH as other diagnoses
remain possible. A vesicovaginogram with careful
Disorders of Sexual Differentiation
technique, using a rubber dam to contain the radi-
opaque dye, will reveal the anatomy of the
internal vaginal structures and whether absence
of the vesicovaginal septum is causing the devel-
opment of a urogenital sinus.
Radiological evidence in the evaluation of
21-hydroxylase deficiency which is untreated for
a longer time will include an advanced bone age
(a simple virilized child may survive this long if
no serious stresses encountered, but a child who
is salt losing will become profoundly ill before
this age). An enlarging pituitary contour (due to
basophil hyperplasia) on MRI or erosion of the
sella turcica will develop lateral skull radiograph
if the patient is un- or undertreated for years.
Genetic testing for 21-hydroxylase deficiency
is available in commercial laboratories. The
functional gene for 21-hydroxylase is CYP 21A2
but there is an inactive pseudo-gene, CYP 21
A1P which is about 98 % identical to the func-
tional gene. 95 % of cases of 21-hydroxylase
deficiency are accounted for by about 11 muta-
tions, and rather than sequencing the entire gene,
targeted analysis of these mutations can be car-
ried out. Genetic analysis is not usually necessary
to identify an individual with 21-hydroxylase
deficiency as biochemical testing will usually
suffice, but it is a means of determining whether
a fetus may be carrying the mutation present in
an affected family once the proband has been
identified.
For the differential diagnosis of adrenal
enzyme defects, see Table 8.1.
Treatment
Virilizing 21-hydroxylase deficiency is treated
with glucocorticoid replacement, and the most
common approach is the use of natural com-
pounds such as hydrocortisone (cortisol).
Because an adrenal, testicular, or ovarian tumor
may cause virilization in a child and because
some metabolites are common to the adrenal
gland and the gonads, the suppression of the
offending androgens by glucocorticoid therapy is
by itself a diagnostic test for the presence of an
enzyme defect rather than a neoplasm. While
there is good evidence that once per day dexa-
methasone treatment is compatible with normal
171
growth, at the time of this writing this approach is
not widely practiced in growing children and is
not included in the current guidelines. However,
synthetic glucocorticoids such as prednisone,
prednisolone, or dexamethasone have their place
in the treatment of older individuals once growth
ceases. The dose of hydrocortisone is variable
among individuals, but for an initial dose,
13–15 mg/m2 or more of cortisol is useful (The
ultimate dose may be greater than the normal
secretory rate of cortisol, because the goal is not
simply to replace the adrenal cortisol production
but also to suppress abnormal product formation,
and adrenal production is elevated even more due
to the adrenal hyperplasia). Once control occurs
and adrenal hyperplasia is reduced, lower doses
may be invoked based upon growth, steroid val-
ues, and bone-age advancement in laboratory
testing. Oral Cortef is usually administered in
doses every 8 h. The dose should be titrated to the
child as noted later. Some recommend that the
greater portion of the dose be given at bedtime so
the early-morning peak of ACTH will be sup-
pressed and less androgen will be secreted, but
there is little evidence that one method is better
than the other (this is the reverse of the schedule
for the treatment of adrenal insufficiency without
CAH; see Chap. 10). There is no place for solu-
tions of hydrocortisone made up by a compound-
ing pharmacy as the variation in the daily dose
will be far too great to allow careful treatment. If
an emergency arises, intravenous or intramuscu-
lar hydrocortisone hemisuccinate (Solu-Cortef)
is used. Intramuscular cortisone acetate takes
hours to initiate effect and is not an appropriate
medication to use in an emergency.
Many methods are proposed to best follow the
efficacy of treatment but the oldest, that of atten-
tion to growth rate and bone age, often are the final
measures of adequacy of treatment; if the dose of
glucocorticoid is too low, the growth rate is exces-
sive because of the resulting elevated androgens,
whereas too much glucocorticoid quickly sup-
presses growth rate and may cause excessive
weight gain. Bone-age advancement is usually
determined yearly; an increase of 1 year of bone
age for each year of chronologic age is ideal.
Serum 17-hydroxyprogesterone measured at a set
172
time in the day after a dose of glucocorticoid (usu-
ally 2 h after the morning dose in one scheme or at
8:00 a.m. before the morning dose in another
scheme) and testosterone (measured in sensitive
HPLC MS/MS assays) and androstenedione con-
centrations are frequently used to monitor therapy;
a 17-hydroxyprogesterone concentration value
will remain above normal in most cases, but should
be well below the untreated state, and age- and
sex-appropriate testosterone or androstenedione
concentration are the goals. Salivary steroid deter-
minations have been used successfully to study
some patients but are not presently in general use.
Mineralocorticoid therapy is administered to
salt-losing patients in the form of
9-fluorohydrocortisone (Florinef) at 0.05–
0.15 mg/day orally. Exogenous mineralocorti-
coids cause the retention of sodium and excretion
of potassium at the distal tubule level of the kid-
ney to remedy the lack of endogenous mineralo-
corticoid. Extra salt also may be administered at
a dose of approximately 1–2 g/day of sodium
chloride divided into several feedings, which
equals 17–34 mEq of Na, since breast milk and
formula have relatively low sodium content; the
parents may be given a few test tubes marked at
the height 1–2 g of table salt would reach, so that
they may measure the correct amount for the
child. Alternatively, a salt tablet can be newly
mixed with water or formula and administered in
appropriate milliequivalent dosage. Blood pres-
sure can rise high enough to cause hypertensive
encephalopathy if too much salt or mineralocorti-
coid is given, whereas too little will precipitate
hyponatremia and hyperkalemia and possibly
hypotension. Inadequate mineralocorticoid also
can be considered a stress and cause elevation of
ACTH and therefore cause increasing androgen
concentrations. In such a situation, where the
body interprets salt loss as stress, misinterpreta-
tion of the androgen levels may suggest the need
for additional glucocorticoid, which would lead
to growth suppression; if appropriate mineralo-
corticoid is given instead, the androgens will
decrease, and growth will normalize. If control is
poor and bone-age advancement leads to a very
short predicted adult height, growth hormone has
been reported to increase adult height but this is
not an FDA approved use of GH.
8 Disorders of Sexual Differentiation
At times of stress, glucocorticoid therapy must
be increased two- to threefold. Usually this will be
necessary when an infectious illness causes a
fever higher than 38.5 °C or 101.3 °F. Current
guidelines do not recommend stress therapy for
minor illnesses such as URIs, athletic activities, or
emotional stress. If the patient is vomiting and
cannot retain oral medications, the patient should
be evaluated at the office or emergency room, but
on the way if the child appears in extremis, hydro-
cortisone-sodium succinate (Solucortef) can be
given, intramuscularly or, in case of emergencies
causing shock and poor perfusion, intravenously.
A dose of 25–50 mg of hydrocortisone-sodium
succinate for a child younger than 5 years and a
dose of 50–100 mg for an older child will be an
appropriate initial dose for most emergencies. Too
much glucocorticoid in an emergency is not going
to cause a problem, whereas inadequate dosage
may be ineffectual in reversing the effects of adre-
nal insufficiency and shock.
Patients with 21-hydroxylase deficiency require
special preparation for surgery to avoid precipitat-
ing an acute adrenal crisis. A dose of hydrocorti-
sone-sodium succinate of 25–100 mg (depending
on patient size) is given at the time of induction of
anesthesia, and an infusion of the glucocorticoid is
maintained during the procedure, or boluses are
given every 4–6 h to ensure a daily dose in excess
of 45 mg/m2, more than triple the secretory rate of
the adrenal glands. This high-dose glucocorticoid
therapy is maintained during surgery and in case
of complications, but in most cases, the dose can
be quickly tapered over the several days postoper-
atively. Because of the risks of hyponatremia and
hypoglycemia, normal saline is infused during the
operation and as needed thereafter in a preparation
with dextrose in 5–10 % concentrations as no
intravenous florinef is available.
Patients with 21-hydroxylase deficiency pur-
sue activities in most ways as any other child, but
because they may develop complications of
minor illnesses quite easily, they must be observed
closely during illnesses. Frequent complications
include hypoglycemia and hyponatremia in salt
losers; any patient with 21-hydroxylase defi-
ciency seen with acute illness must be considered
to have hypoglycemia and hyponatremia until
proven otherwise, and initial fluid management
Disorders of Sexual Differentiation
must include dextrose and salt. We strongly sug-
gest that patients with 21-hydroxylase deficiency
wear an identification bracelet or necklace
(MedAlert or equivalent) and that they or their
parents carry an identifying letter of emergency
procedures from their doctor in case they require
emergency treatment from an institution not
familiar with this diagnosis. Unfortunately, the
parents must be very assertive as we know of
informed parents trying to inform emergency
room physicians of the treatment the child should
receive but they are dismissed out of hand by the
emergency room staff. To anticipate emergencies,
it is recommended that all children who leave the
parents for any period of time have a bracelet or
necklace stating that they have congenital adrenal
hyperplasia steroid dependent or perhaps better
“Addison’s disease” which is a term more easily
recognized than congenital adrenal hyperplasia in
an emergency department and may lead to less
confusion. The treatment of hypoadrenal shock
and hyponatremia is detailed in Chap. 14.
Surgical correction of ambiguous genitalia is a
highly specialized area. Exogenous genitalia are
ranked by Prader scores ranging from 1 (mild) to
5 (severe) virilization, and the scores generally
track the severity of the enzymatic defect and the
degree of salt losing. Clitoromegally may be so
severe with a score of 4–5 to require surgery, but
more often parents now wait for the child to “grow
into” the size of the clitoris. However, a urogenital
sinus with vagina and bladder with abnormal
anatomy predispose to urinary tract infections, so
imaging is needed to determine if repairs are
required to limit this possibility. As stated above
advocacy groups have promoted their strong feel-
ings about the surgical treatment of children with
congenital adrenal hyperplasia and other disor-
ders with ambiguous genitalia. Hence, consulta-
tion with experienced pediatric endocrinologists
or DSD treatment groups is strongly advised.
Teenagers with congenital adrenal hyperplasia
(or other chronic diseases) need plans for transi-
tion to adult care. The team approach that is so
important in the care for children with congenital
adrenal hyperplasia may be more difficult to find
in the adult internal medicine setting (discussed
in Chap. 11 regarding transition in diabetes care).
Nonetheless, considering who will take care of
173
the child as an adult and informing the family and
teenager about this years before the transition is
quite important. Treatment of congenital adrenal
hyperplasia of the severe form must continue
through life.
Nonclassical CAH Treatment
Nonclassical CAH is not a condition with DSD
and is discussed in Chap. 9. Treatment of the
nonclassical type of CAH may be continued in
women who experience hirsutism and infertility.
Treatment of males may not be necessary in the
adult years according to current guidelines.
Fertility in CAH
In males with CAH the fertility rate is reduced
compared with the normal population, the most
frequent cause being testicular adrenal rest tumors.
Development and growth of these tumors was
assumed to be ACTH-dependent, and it was previ-
ously thought that undertreatment plays an impor-
tant role. It is now noted these adrenal rests may
increase even if treatment is optimal and that
surgical intervention may be considered, but there
is presently no clear indication as to whether
treatment will affect fertility. Fertility outcomes in
females with CAH depends on their presentation;
classic salt-wasting-type CAH leads to the greatest
degree of problems with fertility. There is a rela-
tionship to the degree of adrenal suppression and
the age of menarche and regularity of the menstrual
cycle. Progesterone and 17-OH-progesterone have
to be well regulated in addition to adrenal andro-
gens to achieve normal ovulatory cycles. In fact it
is reported that an important reflection of the
degree of control is reflected in the regularity of
menstrual cycles. Polycystic ovarian syndrome,
ovarian adrenal rest tumors, as well as the success
of genital surgery and psychological factors that
occur from the regular clinic visits and genital
exams the woman has experienced in her child-
hood exert influence on fertility. While fertility or
desire for fertility is an issue for the adult years of
a woman with congenital adrenal hyperplasia, the
roots of infertility are found during the pediatric
years and the treating physician should be aware
of these issues.
Genetic counseling is essential in this and
other genetic conditions. The person with con-
174
genital adrenal hyperplasia who has a partner
sharing the for congenital adrenal hyperplasia
has a one in four chance of having an affected
child and a one in four chance of having a com-
pletely unaffected child with a two in four chance
of having a child who is a carrier of the condition.
But genetics is more complex than a simple
mathematical schema, hence the recommenda-
tion for genetic counseling.
11-Hydroxylase Deficiency
11-Hydroxylase deficiency (*202010 ADRENAL
HYPERPLASIA, CONGENITAL, DUE TO
11-β-HYDROXYLASE DEFICIENCY CYP11B1
At 8q21–q22) leads to virilization, salt retention,
hypokalemia, and hypertension; the enzymatic
block leads to excessive 11-deoxycortisol (com-
pound S) and deoxycorticosterone (DOC, a
potent mineralocorticoid) production, and,
because ACTH is elevated in the absence of
adequate cortisol and because no defect occurs
in the formation of androgens, serum androgens
as well as precursors such as 17OHP also are
elevated. Glucocorticoid therapy is necessary to
stop virilization and reduce salt retention and
hypertension. Conversely, mineralocorticoid is
not used in this condition, as this is a disorder
with excessive mineralocorticoid production.
While diagnosis of girls will usually occur in the
neonatal period due to their ambiguous genitalia,
those with less severe defects and boys will come
to diagnosis later in childhood due to precocious
male pubertal development and hypertension.
The phenotype of this condition is similar to
21-hydroxylase deficiency. There is a late-onset
form of 11-hydroxylase deficiency.
3-Hydroxysteroid Dehydrogenase
Deficiency
(*201810 ADRENAL HYPERPLASIA II at
1p13.1) causes salt loss and virilization in
genetic females but inadequate virilization in
genetic males, because DHEA is a weak andro-
gen and the only androgen made in the affected
males. This condition in genetic females does
not cause such severe virilization as in 21-hydrox-
ylase deficiency, and genetic males are less viril-
ized than the normal male phenotype and usually
8 Disorders of Sexual Differentiation
present with tertiary hypospadias. The enzyme
deficiency causes a decrease of glucocorticoid
and mineralocorticoid production but an increase
in dehydroepiandrosterone and its sulfate
(DHEA and DHEAS). As dehydroepiandros-
terone is measured as ketosteroid in the urine,
elevated 24-h urinary ketosteroids, an older test
not used now, will be positive in this condition.
There will be elevated values of androstenedione
and T concentrations. Due to peripheral conver-
sion, 17-hydroxyprogesterone rises and may
lead to a positive CAH screen, but the
17-hydroxypregnenolone/17OHP ratio in the
basal state or after an ACTH stimulation test (a
rise to more than 100 nmol/l or 3,300 ng/dl) is
diagnostic. Treatment is the same as with salt-
losing 21-hydroxylase deficiency, but the presen-
tation may be much more catastrophic in the
newborn due to more severe glucocorticoid and
mineralocorticoid deficiencies.
Maternal Sex Steroid Ingestion or
Androgen-Producing Conditions
Maternal ingestion of progestins of androgen deri-
vation between 8 and 12 of gestation may cause
46, XX DSD. Diethylstilbestrol (DES) ingestion is
no longer recommended for preventing spontane-
ous abortion (it was not effective for this use) since
1971 due to its effects on Müllerian duct deriva-
tives leading to clear cell adenocarcinoma of the
uterus and vagina in the daughters of treated
women. In the sons of treated women DES is
linked to undescended testes, development of cysts
of the epididymis, and inflammation of the testes.
Other exposures to exogenous androgens may
also virilize the female fetus. If mothers have
androgen-producing tumors of adrenal or ovary,
the androgens will be passed to the fetus; much
of the androgen will be aromatized by the pla-
centa to estrogen but not necessarily all.
Other Causes of 46, XX DSD
P450-Oxidoreductase Deficiency
There are also other causes of 46, XX DSD
such as P450-oxidoreductase deficiency
(PORD) which may be found in the Antley–
Bixler syndrome (#201750 ANTLEY-BIXLER
Disorders of Sexual Differentiation
SYNDROME WITH GENITAL ANOMALIES
AND DISORDERED STEROIDOGENESIS;
ABS1) due to mutations in the cytochrome
P450 oxidoreductase gene (POR, 124015.0001)
leading to fetal adrenal androgen excess and
ambiguous genitalia in both boys and girls and
the potential for a host of congenital abnormali-
ties in other organ systems. Antley–Bixler syndrome
type 2 has no genital anomalies (#207410 ICD +
ANTLEY-BIXLER SYNDROME WITHOUT
GENITAL ANOMALIES OR DISORDERED
STEROIDOGENESIS; ABS2) is caused by
mutation in the fibroblast growth factor receptor
gene, FGFR2, and presents with craniosynostosis,
radiohumeral synostosis, midface hypoplasia,
choanal stenosis or atresia, and multiple joint con-
tractures without steroid abnormalities.
Aromatase Deficiency and Estrogen
Receptor Deficiency
A loss-of-function mutation in the gene coding
for aromatase (#613546AROMATASE
DEFICIENCY) eliminates the conversion of
androgens of estrogen and leads to virilization in
a pregnant woman and virilization to some degree
in the 46, XX offspring. This is an autosomal
recessive condition.
There are two patients reported with the estro-
gen receptor deficiency (#615363 ESTROGEN
RESISTANCE; ESTRR) in an apparent autoso-
mal recessive pattern. A 46, XY individual with
absent estrogen receptors will look normal at birth
but with the absence of estrogen will not have nor-
mal bone-age advancement nor epiphyseal fusion
and will grow to a tall stature and have remark-
ably decreased bone density. The female patient
as well as the male patient had elevated levels of
estrogen but she also had delayed bone-age devel-
opment and no sign of pubertal development.
Mayer–Rokitansky–Küster–Hauser
Syndrome
Mayer–Rokitansky–Küster–Hauser syndrome
(%277000 MAYER-ROKITANSKY-KUSTER-
HAUSER SYNDROME) is an autosomal domi-
nant condition in a 46, XX individual in which
there is absence of Müllerian duct derivatives
175
leading to absence or severe hypoplasia of the
upper two-thirds of the vagina and the absence of
the uterus in the presence of normal ovarian func-
tion but primary amenorrhea. There are associ-
ated cervicothoracic somite anomalies, unilateral
renal agenesis, and conductive deafness in some
cases. Müllerian aplasia and hyperandrogenism
(158330 MULLERIAN APLASIA AND
HYPERANDROGENISM) are to be differentiated
from androgen resistance; in this case the external
genitalia will appear to be phenotypically female
in a 46, XY individual, but the internal ducts will
reveal the absence of Müllerian duct derivatives
due to the production of Müllerian duct inhibitory
factor and the Wolffian ducts will be absent due to
lack of local androgen effect. Thus, testes will be
present internally, and the patient will present as a
phenotypic female with primary amenorrhea.
46, XX Gonadal Dysgenesis
46, XX gonadal dysgenesis (#233300 OVARIAN
DYSGENESIS 1; ODG1) has the phenotype of
an immature female with internal Müllerian
ducts. The individual has streak ovaries, histo-
logically fibrous tissue, and elevated gonadotro-
pin levels. There is no production of estrogen nor
inhibin. The condition may be sporadic or follow
an autosomal recessive pattern with deafness
(*233400 GONADAL DYSGENESIS, XX
TYPE, WITH DEAFNESS).
46, XY DSD: Disorders Causing
Inadequate Virilization of a Genetic
Male (Previously Called Male
Pseudohermaphroditism)
An inability to produce testosterone, an inability
to convert testosterone to DHT in the sexual skin,
or a resistance to androgen action all can cause
46, XY DSD. These are the patients in whom the
most uncertainty arises over gender of rearing.
Testicular enzyme deficiencies include some dis-
orders in which the same enzymes are deficient in
the testes as in the adrenal glands. AMH defi-
ciency will occur in 46, XY DSD conditions with
abnormal Sertoli cell function which occurs
176
when the testes are dysgenetic, but when there
are only mutations of the enzymes important in
the production of androgens AMH is normal.
46, XY DSD with Enzymatic Deficiencies
Involving the Gonads and the Adrenal
Glands
Smith–Lemli–Opitz Syndrome
(#270400 SLOS) is caused by a deficiency of
7-dehydrocholesterol reductase (*602858
7-DEHYDROCHOLESTEROL REDUCTASE;
DHCR7) leading to deficient steroid produc-
tion including androgens and in some cases
mineralocorticoids. There are multiple dys-
morphic features often associated with devel-
opmental delay, but 46, XY DSD is a frequent
phenotype although some 46, XY patients look
so much like a phenotypic female that diagno-
sis may be long delayed.
StAR Deficiency
StAR (steroid acute regulatory protein) assists
the entry of cholesterol into the gonadal or adre-
nal cell mitochondria for steroid synthesis.
StAR deficiency (#201710 LIPOID
CONGENITAL ADRENAL HYPERPLASIA at
8p11.2) eliminates the production of all adrenal
and gonadal steroid production, and large, lipid-
laden adrenal glands develop, which may inferi-
orly displace the kidneys (the condition is also
called lipoid adrenal hyperplasia). In the com-
plete form, all 46, XX and 46, XY individuals
will have a normal female phenotype at birth.
The Leydig cells in males will be destroyed by
the lipoid deposition, while the Sertoli cells will
still produce Müllerian duct inhibitory factor
so that the female genital phenotype will be
accompanied by absence of Müllerian ducts.
Remarkably the ovaries in females are not stim-
ulated until puberty so that at the age of puberty
sufficient estradiol is produced independent of
StAR to allow feminization and even anovula-
tory cycles. Genetic males however will have no
progression of secondary sexual development at
puberty and will remain with an infantile female
phenotype. Incomplete or late-onset forms of
StAR deficiency have various clinical presenta-
8 Disorders of Sexual Differentiation
tions including adolescent or adult adrenal fail-
ure. Profound Addisonian crisis will occur by
5–7 days after birth because of the complete
absence of mineralocorticoids and glucocorti-
coids. Replacement steroid treatment is the
same as for salt-losing 21-hydroxylase defi-
ciency, with the exception that glucocorticoid
replacement dosage may be lower due to the
lack of necessity to suppress androgenic sub-
stances produced by the adrenal glands of the
21-hydroxylase-deficient patient. The condition
is found in an autosomal recessive pattern and is
most common in Korea, Japan, Switzerland, and
some Arab populations.
Recently, patients were found with 20–22 des-
molase deficiency (#613743ADRENAL
INSUFFICIENCY, CONGENITAL, WITH
46, XY SEX REVERSAL, PARTIAL OR
COMPLETE) that had a presentation similar to
StAR deficiency with the exception of absence of
lipoid deposition in the adrenal glands.
3-Hydroxysteroid Dehydrogenase
Deficiency
As described above, 3-hydroxysteroid dehy-
drogenase deficiency (*201810 ADRENAL
HYPERPLASIA II at 1p13.1) in 46, XX DSD
causes salt loss (in most) and inadequate virilization
in genetic males. The phenotype is micropenis,
perineal hypospadias, bifid scrotum, and a blind
vaginal pouch with gynecomastia often developing
at puberty in males. Diagnosis is made by elevated
pregnenolone, 17a-hydroxypregnenolone, DHEA,
and DHEA-sulfate (DHEAS) and elevation of the
17OHPreg:17OHP ratio.
17α-Hydroxylase Deficiency
17α-Hydroxylase deficiency (*202110
ADRENAL HYPERPLASIA, CONGENITAL,
DUE TO 17-α-HYDROXYLASE DEFICIENCY
at 10q24.3) eliminates the 17-hydroxylation of
progesterone and pregnenolone and interferes with
the production of both cortisol and sex steroids;
46, XX and 46, XY patients cannot produce corti-
sol or androgens or estrogens but make excessive
mineralocorticoid in the form of desoxycorticoste-
rone. The defect is in CPY17, which codes for
both the 17α-hydroxylase and 17,20-lyase
Disorders of Sexual Differentiation
enzymes. Phenotype is of an immature female in
the complete form, but some incompletely affected
males may have ambiguous genitalia. Thus, hyper-
tension, hypokalemia, and elevated serum proges-
terone, pregnenolone, corticosterone, and DOC
but decreased PRA, 17-hydroxyprogesterone, and
aldosterone in an immature female phenotype are
the clinical cornerstones of diagnosis. Primary
amenorrhea in a phenotypic female may be the
presentation if the subject is first diagnosed in ado-
lescence. 46, XX patients will have an immature
female phenotype at birth and develop hypergo-
nadotropic hypogonadism at puberty.
46, XY DSD with Other Enzyme
Deficiencies Involving the Testes But
Not the Adrenal Gland
17,20-Lyase or Desmolase Deficiency
17,20-Lyase or desmolase deficiency (*202110
ADRENAL HYPERPLASIA, CONGENITAL,
DUE TO 17α-HYDROXYLASE DEFICIENCY
at 10q24.3) results from a mutation in the CPY17
gene, which causes 17α-hydroxylase deficiency
and lack of conversion of 17-hydroxyprogesterone
to androstenedione and also 17-hydroxypregnen-
olone to dehydroepiandrosterone and thereby
limits the production of testosterone. The CPY17
gene codes for the enzyme that catalyzes the
17-hydroxylation of pregnenolone and progester-
one, so that deficiency of this action leads to
46, XY DSD with decreased 17 OHP values. The
phenotype is infantile female or ambiguous geni-
talia with micropenis, perineoscrotal hypospa-
dias, and cryptorchidism or “labial” or inguinal
testes. Gynecomastia can occur at puberty and
some virilization may occur at puberty.
17β-Hydroxysteroid Dehydrogenase Type 3
17β-Hydroxysteroid dehydrogenase type 3 (17β
HSD3 or 17β-hydroxysteroid oxidoreductase
deficiency or 17β-ketosteroid reductase defi-
ciency) (#264300 17β-HYDROXYSTEROID
DEHYDROGENASE III DEFICIENCY at 9q22)
interferes with the conversion of androstenedione
to testosterone and estrone to estradiol. The phe-
notype is infantile female or some degree of
ambiguous genitalia. Internal ducts are Wolffian,
177
albeit undeveloped due to low local testosterone,
and because of the presence of Müllerian duct
inhibitory factor from the fetal testes, Müllerian
ducts regress. The upper 2/3 of the vagina is
absent (since it is a Müllerian derivative), and the
testes are internal or “labial”; patients have had
“hernias” repaired that contained the testes with-
out the correct diagnosis being made before sur-
gery. Gynecomastia or some virilization may
occur at the time of puberty.
46, XY DSD with Disorders
of Androgen Action
5α-Reductase Deficiency
5α-Reductase deficiency (defect in SRDA2, the
steroid 5α-reductase enzyme gene *264600
PSEUDOVAGINAL PERINEOSCROTAL
HYPOSPADIAS; PPSH at 2p23) eliminates the
conversion of testosterone to DHT in the sexual
skin, thereby causing the formation of chordee
(ventral binding of the phallus by attached skin);
small phallic structure; hypospadias; bifid scro-
tum, usually with undescended testes; and a uro-
genital sinus; this is described as pseudovaginal
perineoscrotal hypospadias. The production of
AMH ensures the absence of Müllerian deriva-
tives, but the presence of testosterone in high
concentrations internally supports the develop-
ment of Wolffian structures. At puberty, possibly
because of increasing production of testosterone
or to the effects of steroid 5α-RD type 1, encoded
by the SRD5A1 gene, which is active during
puberty and normal SRDA type 1 activity located
in the liver and other nonsexual skin, DHT-
dependent effects such as enlargement of the
penis, descent of the testes are possible (within
the limitations of the anatomy), and pigmentation
of the scrotum occurs, as well as increased mus-
cle mass and deepening of the voice. No acne or
male pattern recession of hair occurs, however, as
they are dihydrotestosterone dependent. Most
remarkably, affected patients from the Dominican
Republic are initially raised as girls, but at the
time of puberty and thereafter are considered
male in social contexts. This phenomenon has
been considered an example of the plasticity of
human gender roles, but the children are usually
178
known to have the condition in early life (known
as heuvodoces for the descent of testes at
puberty), so the situation may not be soley due to
an isolated change in gender. The condition is
also found in Papua New Guinea, the individuals
are known as kwalatmala, and affected subjects
also change gender role at puberty from female to
male. It is also reported more frequently in Saudi
Arabia, but patients are found elsewhere as well.
Most are raised as boys with reasonable adult
adjustment to their lives according to the largest
series of follow-up. Diagnosis is established by
measuring the testosterone to dihydrotestoster-
one ratio in the basal state or after hCG stimula-
tion. The testosterone to dihydrotestosterone
ratio should be less than 10:1.
Androgen Insensitivity
The complete syndrome of androgen insensitiv-
ity (previously called testicular feminization;
#300068 ANDROGEN INSENSITIVITY
SYNDROME; AIS at Xq11-q12) results from a
loss-of-function mutation in the androgen recep-
tor gene (AR) on the X chromosome in an
X-linked recessive pattern. Complete androgen
insensitivity is not actually seen as ambiguous
genitalia, because in the absence of testosterone
action, the phenotype is infantile female. This
condition is found in a prevalence of about
1:20,000–60,000. Internal ducts are hypoplastic
Wolffian ducts. The vaginal pouch is blind
because of the absence of the upper two-thirds of
the vagina, normally derived from Müllerian ele-
ments, which atrophies because of the normal
testicular production of AMH, and the uterus and
oviducts are likewise absent due to AMH. In the
newborn period there may be an inguinal hernia
in a phenotypic girl with masses representing the
gonads. At puberty, the unopposed estradiol
causes normal feminization, but the lack of
androgen action eliminates the development of
pubic and axillary hair. The defect is character-
ized by a decrease in the testosterone and DHT
receptor numbers or a postreceptor defect.
Patients usually have an unambiguous female
gender role and are raised as females, so decision
on sex of rearing is not an issue in the newborn
period. Diagnosis is often made in an adolescent
8 Disorders of Sexual Differentiation
female, often tall, with amenorrhea and no pubic
or axillary hair. Thus, a phenotypic female being
evaluated for primary amenorrhea will be
shocked to be told that she has a 46, XY karyo-
type during her adolescence or young adult years
when told in an ill-advised manner: The diagnos-
tician must be aware of such an outcome before
addressing the issue with the patient and temper
the discussion in a sensitive manner.
LH is usually elevated due to resistance to
negative feedback from testosterone. AMH is
normal as the defect is not in the gonads.
The incomplete syndrome of androgen insen-
sitivity is due to a less severe deficiency or less
severe defect in the AR. Phenotype may be nor-
mal male (with the only abnormality being infer-
tility), may be an underdeveloped male with
small but normally formed phallus, or may be
ambiguous. Internal female ducts disappear due
to normal production of AMH, while male ducts
also degenerate due to lack of normal androgen
action. At puberty, some degree of gynecomastia
over the usual amount found in puberty in a nor-
mal genetic male may be noted, and some pubic
and axillary hair development should occur.
Serum LH and testosterone concentrations are
above normal. These patients experience some
androgen effect in utero, and reports, albeit lim-
ited, indicate 10–15 % may experience gender
dysphoria and chose to change gender either
female to male or male to female; the majority
do stay in their initially assigned gender how-
ever. Sex assignment requires the most careful
consideration and discussion with the parents.
Unresponsiveness to hCG and LH
Unresponsiveness to hCG and LH (*152790
LUTEINIZING HORMONE/CHORIOGO
NADOTROPIN RECEPTOR; LHCGR at 2p21) is
associated with low testosterone production and
ambiguous genitalia, because in the absence of LH/
hCG receptors, no Leydig cell testosterone produc-
tion can occur. Presentation is phenotypic female if
complete, but partial absence of LH/CGR allows
some degree of virilization. Diagnosis is accom-
plished by showing no substantial rise in testoster-
one after hCG administration. Sisters of affected
patients may be infertile.
Disorders of Sexual Differentiation
Persistent Müllerian Duct Syndrome
Mutations limiting or decreasing the production
of Müllerian duct inhibitory factor, AMH, or its
receptor (#261550 PERSISTENT MULLERIAN
DUCT SYNDROME, TYPES I AND II; PMDS)
are associated with bilateral cryptorchidism in
boys or inguinal uterus and fallopian tubes in
girls and are inherited in an autosomal recessive
pattern with male sex limitation.
46, XX Testicular DSD
An individual with 46, XX karyotype may
develop testicular tissue if the SRY gene is trans-
located to another chromosome even if there is
no Y chromosome (#400045 46, XX SEX
REVERSAL 1; SRXX1). Thus, the SRY gene
might be found on X chromosome due to recom-
bination or on an autosome. An individual with
two X chromosomes and an SRY gene may
resemble the phenotype of Klinefelter’s syn-
drome. Some 46, XX individuals with reportedly
normal male genitalia or soft testes are found
with mutations the involving the sox 3 gene
(#300833 46, XX SEX REVERSAL 3; SRXX3).
Anorchia or the Testicular Regression
Syndrome
In the testicular regression syndrome a 46, XY
individual is found to have no gonads and a small
but normal scrotum with otherwise normal exter-
nal genitalia (%273250 ICD + TESTICULAR
REGRESSION SYNDROME; TRS). While this
is discussed in Chap. 9, on occasion the individ-
ual may have ambiguous genitalia.
Penile Agenesis
Penile agenesis is a rare sporadic condition which
occurs with abnormalities of development of the
caudal structures in some cases. Thus, it may be
found with imperforate anus, absent raphe of the
scrotum, and renal defects, often severe. Penile
aplasia may also occur as an isolated defect in the
development of the genital tubercle. Complete
penile aplasia will not occur with endocrine dis-
orders causing decreased biosynthesis or biologi-
cal effect of androgen. Penile aplasia is not to be
confused with microphallus in which a perfectly
formed but extremely small penis is present
179
which can occur with endocrine disorders includ-
ing growth hormone deficiency, gonadotropin
deficiency, and other conditions described in this
chapter and Chap. 9.
A notable case of penile ablation due to
complications of circumcision demonstrates
the virilizing effect of prenatal androgens on
central nervous system function; the child was
sex reversed to a female gender since there was
no penis but after maturation the individual
self-reverted back to a male gender identity.
Thus, the decision on sex assignment cannot be
based on anatomy alone but must include the
prenatal exposure to androgens the child might
experience. The situation again relies upon a
multiple disciplinary team management as
described below.
Gonadal DSD
Ovotesticular DSD
Rare patients with both testicular and ovarian tis-
sue have ovotesticular DSD (previously called
true hermaphroditism). The tissue is more often
combined in ovotestes on at least one side rather
than a normal ovary on one side and a normal
testes on the other. Because of variable produc-
tion of AMH (Müllerian duct inhibitory factor)
and local and systemic testosterone, the internal
ducts and external genitalia will be quite variable
among individuals. Thus, part of a uterus may be
present on one side, with some male ducts on the
contralateral side.
The patients most commonly have a 46, XX
karyotype, with the SRY present on some chro-
mosomes (but there is no Y chromosome). Other
cases may have the karyotype of 46, XX/46, XY
chimeras or 46, XY individuals with a presumed
46, XX cell line in the gonads.
Fertility has rarely been described in ovotes-
ticular DSD, but the ovarian tissue can rarely pro-
duce some feminization at puberty. Conversely,
the dysgenetic testicular tissue can undergo
malignant degeneration and should be removed.
Because of concerns over the difficulty of plastic
reconstruction of the phallus, most patients are
raised as girls.
180
46, XY Gonadal Dysgenesis
46, XY gonadal dysgenesis (#400044 46, XY
SEX REVERSAL 1; SRXY) or Swyer syndrome
may result in an immature female phenotype if
the dysgenesis is complete or ambiguous genita-
lia if functional Leydig cells remain from the
dysgenetic testes. Internal duct formation will
depend on the amount of AMH produced from
the dysgenetic testes. The etiology may be abnor-
malities of SRY function, autosomal mutations,
or duplication of the Dosage Sensitive Sex rever-
sal (DSS) locus on the X chromosome. Some
older individuals may appear to be tall females,
while others may virilize due to incomplete dys-
genesis of the testis. In a remarkable case, an
individual with 46, XY gonadal dysgenesis gave
birth to a phenotypic female with SRY +46, XY
gonadal dysgenesis suggesting that mothers of
children with Swyer syndrome should all be
checked for the presence of Y chromosome mate-
rial. The condition may be sporadic or follow
X-linked male limited (*306100 GONADAL
DYSGENESIS, XY FEMALE TYPE; GDXY),
autosomal dominant, or autosomal recessive pat-
terns. The dysgenetic testes have a 20- to 46-fold
increased potential for neoplastic formation and
must be removed. If an affected subject feminizes
at puberty, the cause might be estrogen formation
from a gonadoblastoma formed within the dysge-
netic testes and is a sign of concern rather than
optimism mistakenly thinking that there is func-
tional ovarian tissue.
Classic 45X Turner presents with normal female
genitalia phenotype and is discussed in Chap. 9.
However, mosaic Turner syndrome with 46, XY/45
XO karyotype or variants on this mosaic karyotype
may present with ambiguous genitalia due to the
presence of dysgenetic testicular tissue which may
become neoplastic and must be removed.
Klinefelter’s syndrome is a disorder of gonadal
development but does not present with ambigu-
ous genitalia and is discussed in Chap. 9.
The differentiation of anorchia from cryptor-
chidism is discussed in Chap. 9.
Endocrine Disruptors
Endocrine disruptors are also discussed in Chap. 9.
8 Disorders of Sexual Differentiation
A higher rate of hypospadias in Danish new-
borns and smaller testes with lower serum inhibin
B, compared with Finish infants, suggested that
environmental agents played a role in the differ-
ence. This and a high frequency of reproductive
problems among adult Danish men, including
impaired semen quality, testicular cancer, and
increased rate of infantile testicular cancer in a
pattern that is attributed to environmental disrup-
tors, are described as the testicular dysgenesis
syndrome (TDS). There may be a genetic compo-
nent to susceptibility to the TDS based upon
GWAS analysis indicating a gene X environment
basis for the disorder.
The Diagnosis and Treatment
of Ambiguous Genitalia
A provider who cares for newborns will rarely
have to manage a child with ambiguous genitalia
but must always be prepared for that situation.
This requires an understanding of the psycholog-
ical dimensions that will be encountered as well
as knowledge of the biochemistry that can cause
this presentation. While this chapter provides a
basic outline of the physiology of sexual devel-
opment and the more common conditions that
occur, it cannot provide the experience necessary
to successfully bring the family through the situ-
ation. While diagnosis is outlined below, it can-
not be overemphasized how important it is to
immediately obtain a consultation with a pediat-
ric endocrinologist even over the phone before
entering into detailed discussions with the family
and embarking upon the diagnostic procedures.
The following paragraphs outline the approach
but cannot cover every eventuality nor provide
the reader with full guidance on how to navigate
the subtleties of family discussions with parents
who do not yet know whether they are going to
raise a boy or girl. In the suggested reading sec-
tion is a paper in which senior pediatric endocri-
nologists provide advice on the approach to the
infant with ambiguous genitalia that will enhance
the reader’s understanding.
Ambiguous genitalia in a neonate must be
treated with urgency and consideration. No sug-
gestion of gender must be made to the parents
The Diagnosis and Treatment of Ambiguous Genitalia 181

until a diagnosis or plan of treatment is estab-
lished. It is appropriate to talk about “the baby”
instead of “he” or “she,” to not have the hospital
print a card having any suggestion of gender on it,
and to speak of “the gonads” rather than testes or
ovaries. Never say that the baby is “partially girl
and partially boy.” The parents can be told that the
baby has an anatomic problem, that the external
genitalia are “unfinished,” and that it is up to the
medical providers, by the way of tests, to deter-
mine the diagnosis baby and to confer with the
parents as to assigning gender. Even if the physi-
cian has a “gut” feeling about the outcome of the
diagnosis, the risks of incorrect assignment of
diagnosis are great, and it is best to support the
obviously concerned parents without giving them
false direction.
Steps in the diagnostic process will vary,
depending on whether the baby has palpable
gonads or whether no gonads are palpable (see
Figs. 8.6 and 8.7). Although a list of appropriate
steps exists, it must be emphasized that in this
situation, the help of an expert consultant or DSD
committee is necessary. The vagaries of the inter-
pretation of the tests could allow an incorrect
diagnosis. There is a recent increasing reliance
upon genetic diagnosis in cases of ambiguous
genitalia, and genomic methods are becoming
easier to order, are less expensive, and have faster
turnaround time. Thus, the classic steroid methods
on these figures may be soon superseded in some
conditions. Ratios of the various steroid metabo-
lites provide further assistance in the diagnosis,
and standard values for these ratios are available

XX Karyotype XY

Present Absent Present

Low Normal Low

High Normal Low Normal High Normal

Combined 17α−ΟΗ Androstenedione

Salt Losing 17OH Pregnenolone deficiency/17,20
lyase deficiency Testosterone
Low
with hypertension
Normal to Low Normal
Isolated
Moerate Elevation 17,20
No Yes Androstenedione
lyase
DHEAS T/DHT deficiency
P450 Aromatase Normal or CPY17
deficiency or moderate
High
elevation
11 Deoxycortisol High High Normal

Response to
High Normal Testosterone
or normal
receptor
3β-HSD2 Deficiency

Abnormal Normal
11β OH deficiency/ 46, XX DSD
P450c11 deficiency Maternal androgens 5α
with hypertension Ovotesticular DSD Reductase
deficiency
21-OH or P450c21 21-OH or P450c21
Deficiency Virilizing Deficiency salt losing
17-oxidoreductase deficiency Partial androgen 46, XY DSD
or 17βHSD-3 deficiency resistance

Fig. 8.6 Diagnostic algorithm for a patient with ambigu- that play a role in diagnosis, so this is only a basic guide.
ous genitalia in which no gonad palpable; this is not ade- Likewise, new genetic tests can assist in diagnosis and
quate for final diagnosis in many cases. There are many should be investigated on the GeneTests website or other
more considerations based upon ratios of steroid moieties genomic information sources
182 8 Disorders of Sexual Differentiation

Karyotype
XY XO/XY XX,XY,
XX XX/XY

Present Absent Absent Present Present

Mullerian Duct
on Imaging

AMH Low Normal Normal Variable Low Low

17OHP Normal Low Normal High

P450 Oxidoreductase
Combined 17α-OH Testosterone deficiency Ovotesticular
Ovotesticular DSD deficiency/17,20 DSD
lyase deficiency 46, XY DSD
with hypertension
Low Normal

T/DHT
17β-HDS3
deficiency High Normal

5α reductase Response to
deficiency testosterone or
Receptor Assay

Normal Low

Partial Androgen
Ovotesticular DSD
resistance
46, XY DSD

Fig. 8.7 Diagnostic algorithm for a patient with ambigu- ratios of steroid moieties that play a role in diagnosis so
ous genitalia in which gonads (possibly inguinal) are pal- this is only a basic guide. Likewise, new genetic tests can
pable; this is not adequate for final diagnosis in many assist in diagnosis and should be investigated on the
cases. There are many more considerations based upon GeneTests website or other genomic information sources

from the several national endocrine laboratories
identified in Chap. 16 to assess the clinician.
Medical history is important as in all diagno-
ses in pediatric endocrinology. Gestational age,
birth weight, and maternal exposures are of great
importance. Special attention is directed to deter-
mine if the mother has signs of androgen secre-
tion or had ingestion of virilizing drugs. The
mother must be queried for a history of
unexplained deaths in the family (which would
suggest CAH). Determination of consanguinity
is important in the search for autosomal recessive
conditions. Toxin exposures in the environment
due to the location of the child’s home or employ-
ment of the parents or other family members who
might bring toxins into the house, for example,
agricultural workers might work among pesti-
cides or other agrichemicals.
A phenotypic male must be examined for
phallic size (gently stretched length and width
eliminating the foreskin), chordee or the binding
of the phallic structure ventrally, the appearance
of hypospadias, underdevelopment of a scrotum,
and palpation for its contents. If testes cannot be
palpated or measured, a careful examination of
the inguinal area must be performed with lubri-
cant or soap to smoothly bring the examining
finger down the inguinal area to see if it can
move a gonad that is high in the canal into the
scrotum. In a girl the clitoral size is measured in
width and length eliminating any redundant skin
of a clitoral hood and inspecting for scrotaliza-
tion of the labia (rugation and pigmentation of
the skin to look like a scrotum), the appearance
an “uninhabited” scrotum, or presence of palpa-
ble masses in the “labial” area. Labial masses
The Diagnosis and Treatment of Ambiguous Genitalia
might be testes, ovaries, or even a uterus. An
examination for asymmetry is essential.
Imaging studies are the tests with the quickest
results and may be done soon after a DSD is con-
sidered. An ultrasound performed by an
experienced radiologist will search for uterus,
ovaries, vaginal appearance and oviducts, and
other Müllerian structures in a phenotypic female
or one with ambiguous genitalia. It must be
emphasized that the radiologist must be experi-
enced as we have received reports of absence of
ovaries and uterus in a female child with viriliz-
ing 21-hydroxylase CAH who unequivocally had
them. Also the presence of gonads and their
architecture and texture may indicate whether
testicular, ovarian, or ovotesticular tissue is pres-
ent. MRI is sometimes indicated to provide infor-
mation on structures. Contrast studies of the
vaginal opening and urinary tract will reveal
sinus formation. In an older child, a bone-age
examination as a reflection of androgen effect is
useful. Cystoscopy may visualize the anatomy,
but in some cases laparoscopy is to be performed
for definitive diagnosis and treatment.
Laboratory determinations will be directed
toward the possible diagnoses considered.
Screening for 21-hydroxylase deficiency congen-
ital adrenal hyperplasia is universal at birth in the
USA, but results may take 7 days to return which
may be too late for safely initiating treatment if
the child has salt-losing tendencies. Likewise, a
screening test is inadequate for diagnosis, so if
there is a high suspicion of 21-hydroxylase con-
genital adrenal hyperplasia, venous sampling for
confirmatory laboratory tests must be performed.
In most cases karyotype analysis should be per-
formed as an emergency procedure (laboratories
will rush the process in most cases). (As noted,
no reliance should be put on a buccal smear.) We
must emphasize again that the karyotype will not
define the diagnosis but will assist in the determi-
nation of the diagnosis.
Anti-Müllerian hormone (AMH) will reflect
the presence and function of sertoli cell and will
partially indicate the state of functioning of the
testicular tissue: AMH will be decreased or vari-
able in syndromes with testicular dysgenesis. An
ultrasound of the internal structures can be help-
183
ful with an ultrasonographer who has experience
with newborns; we have seen cases in which a
completely erroneous reading upset the family
and incorrectly directed the clinician’s efforts.
Serum androgen metabolite determinations
should be ordered, including at least 17-OH-
progesterone, androstenedione, DHEAS, testos-
terone, and DHT. In all cases the laboratory must
have pediatric standards, and the methods must
be sensitive and specific; for T and DHT the
HPLC/tandem mass spectroscopy method in a
laboratory with pediatric standards is essential.
Thus, with AMH and ultrasound indicating ser-
toli function and testosterone indicating Leydig
cell function, the defect can be better deter-
mined: e.g., both are low in testicular dysgenesis
and low T and normal AMH are found in Leydig
cell dysfunction due to enzymatic defect.
National laboratories can run panels, e.g., CAH
panel, for most or all of these appropriate tests
for DSD on small samples in neonates and chil-
dren, so do not draw the large samples that your
local laboratory may think are necessary without
checking with the sendout lab. The serum tests
will be done as an emergency if one of the few
national laboratories experienced in pediatric
endocrine testing is used as they understand the
importance of this process. Serum LH and folli-
cle-stimulating hormone (FSH), if markedly
elevated to the castrate range, may suggest dys-
genetic gonads; sensitive pediatric assays are
necessary if low values are to be correctly
assessed. It is important to note that gonadotro-
pins may peak spontaneously in the neonatal
period and the months thereafter (the minipu-
berty of infancy) and confuse the issue. Urinary
collections for 17-ketosteroid and pregnanetriol
are difficult because of the requirement of a 24-h
collection and are no longer used.
The diagnosis may be clear from the results,
although an anxious several-day wait for the
values will ensue, in even the best situations. If
a question remains whether there is a function-
ing testis or what is the activity of 5α-reductase,
an hCG stimulation test should be performed.
There are several protocols for the hCG test as
noted in Chap. 9. A single dose of 1,500 IU i.m.
hCG is administered in one diagnostic schema,
184
and baseline sample and 72-h serum sample for
levels of LH, FSH, testosterone, inhibin B, and
AMH are measured. If the testosterone result
after 72 h is a level 2–20 times higher than base-
line in infants, the result is normal. If the other
androgen metabolites of interest rise according
to laboratory standards, an enzymatic defect is
eliminated. If the patient is in mid-childhood or
older, one injection of hCG may not be adequate
to stimulate the quiescent Leydig cells. Thus,
hCG is given three times per week on alternate
days for 2 weeks, and then measurement of
serum testosterone (or other appropriate andro-
gens or precursors) is performed 24 h after the
last injection of hCG to determine whether tes-
tosterone secretion can be induced over this lon-
ger period of hCG administration. Serum levels
of DHT as well as testosterone should be mea-
sured if a reflection of the activity of 5α-reductase
is desired. As another effect of the injections, if
undescended testes are present, the testes may
descend into the scrotum if the inguinal ring is
not definitively too small to allow the passage.
If there is a question of testosterone responsive-
ness of the phallus, 3 months of testosterone
administration should be performed (as noted in
Chap. 9). Blood or buccal smear for gene analy-
sis or sexual skin biopsy for androgen receptors
or 5α-reductase activity may be sent to a labora-
tory which performs such testing (see
GeneTests), but not all mutations will be
detected; reported positive mutations range for
28–90 % depending upon the investigator and
sporadic versus familial cases.
Serum electrolytes and plasma renin activity
should be monitored in conditions being consid-
ered with salt wasting. As stated above it may
take several days after birth for hyponatremia
and hyperkalemia to develop.
Genetic testing for karyotype and fluorescent
in situ hybridization for Y chromosome material
or SRY will help in many cases and is available
commercially. Genetic testing for specific diag-
noses may be possible: The GeneTests website
lists tests and laboratories as well as indications
for testing. Since new tests are becoming avail-
able almost weekly, look at that website for
extremely useful information on the possibility
of testing and the location of the laboratories.
8 Disorders of Sexual Differentiation
Unfortunately even with new syndromes
being discovered regularly, not all children will
receive a specific diagnosis.
Treatment
The treatment is tempered to the biological
condition and the potential effects of androgens
on the CNS and is best planned with a multidis-
ciplinary team. General discussions of treatment
for congenital adrenal hyperplasia are noted
above in the section regarding 21-hydroxylase
deficiency. For those conditions that will not
allow maturation at the time of puberty treat-
ment, follow the plan presented for hypergo-
nadotropic hypogonadism in Chap. 9. As
emphasized above a transition team for the care
of the individual as the teenage years are reached
is extremely important. The wisdom of interna-
tional senior pediatric endocrinologists is pre-
sented in the Wilson reference in the Suggested
Reading section.
The Decision of Sex of Rearing
There are many considerations to determine the
sex of rearing of the child with ambiguous geni-
talia. The discussion below is general and cannot
be used as a guide book for an individual child.
Added to the considerations below are legal con-
siderations. Removal of the gonad in a child that
occurs before informed consent can be given has
many implications. Advocacy groups have
brought suit against treating physicians who per-
formed gonadectomy or other types of recon-
structive surgery in children with DSD. This field
is constantly evolving, and before any surgical
interventions are done, the advice of the DSD
team as described below and a careful consider-
ation of all ethical and legal issues are essential.
The decision about sex of rearing in a patient
with ambiguous genitalia depends on the diagno-
sis and on the wishes and outlook of the family.
One consideration is to retain fertility, if possible.
For example, in 21-OH deficiency CAH in a
46, XX individual fertility will usually be possi-
ble with appropriate treatment, but it is important
The Decision of Sex of Rearing
to note that there is a decreased interest in child-
bearing by affected females with 21-OH defi-
ciency, so in some cases, the preservation of
fertility will not be important to an individual
(although this knowledge may be clear only in
retrospect). Another consideration is to ensure
that the external genitalia can be made compati-
ble with the sex of rearing. However, an overrid-
ing issue is the effects of androgens on the fetal
brain as the individual grows which may make,
for example, a 46, XY individual with incom-
plete androgen resistance who was raised as a
female may experience gender dysphoria and
wish a male role even though the child’s anatomy
led to a decision to raise the child as a girl:
Likewise such an individual raised as a boy on
occasion may wish to decide to become a female.
The parents must be able to cope with the deci-
sion reached, but it may be difficult in some cul-
tures that prize a son to raise a child with 46, XY
DSD as a daughter no matter what the anatomy
may be. On the other hand, some cultures look
with disfavor on a daughter who is infertile.
Pediatric surgical or pediatric urological pro-
cedures, performed by an experienced surgeon,
are required if anatomic modification is consid-
ered for any patient with ambiguous genitalia. In
46, XX DSD, the decision will usually be to raise
the child as a girl to preserve fertility in spite of
uncertainty over the later desires over child bear-
ing. Most of these patients will have an enlarged
clitoris, usually too much to appear as a normal
variation, although there will be relative shrink-
age with time and suppressive treatment. In many
cases the decision will be to let the child “grow
into” the clitoris rather than intervene with sur-
gery. Should a decision be made for modification,
the procedure of choice is clitoral recession with
preservation of the glans and the nerve supply, in
contrast to more severe procedures including cli-
torectomy as performed in past decades. Clitoral
recession, if indicated, may be performed by age
1 year to avoid the child being noticeably differ-
ent from peers in the eyes of babysitters or child-
care workers, since the child may not always be in
the presence of the parents after the first months.
The vagina may require enlargement, and the pos-
terior fusion opened in some cases with reevalua-
tion at the time of puberty due to subsequent
185
scarring. If there is a urogenital sinus, the internal
anatomy will have to be repaired as well to
decrease the risk of urinary tract infections. The
vaginal procedures may be carried out in stages,
with the final steps done at the time of puberty.
Patients with complete androgen insensitivity
have a good outcome being raised as females, and
there is no consideration of sex reversal in these
patients. 46, XY DSD have usually been raised as
infertile females, except for 5α-reductase defi-
ciency, when male gender role is the usual out-
come after puberty. Those 46, XY DSD with
severe testicular enzyme defects or dysgenetic
testes will usually have mainly female phenotypes
and can never make adequate testosterone,
whereas those with partial androgen resistance
will be unlikely to respond adequately to testoster-
one. Reconstruction of the phallus may be practi-
cally difficult if there is no response to androgen.
In all cases of 46, XY DSD, the testes will be
undescended or partially descended and will be
subject to an increased risk of testicular neoplasm
in a location where they cannot be regularly
examined. If there are dysgenetic testes, the risk
rises higher. Thus, orchiectomy has been sug-
gested in these conditions, again after careful
consideration.
In 5α-reductase deficiency, a potential for fer-
tility as a male remains, although reports do not
suggest it is very likely; patients have usually
been raised as males after correction of the chor-
dee and hypospadias, and the testes are brought
to at least the lower inguinal canal where they
can be regularly evaluated in case neoplastic
change were to occur. In 46Y DSD raised as a
male, hypospadias repair may be indicated early
to allow him to urinate standing.
In the syndrome of complete androgen resis-
tance (or testicular feminization in the past), the
testes will induce feminization at the time of
puberty and are often left in until that time; in the
absence of androgen effect there is a lower risk of
cancer in these patients before puberty. The
increased psychological difficulty of explaining
the need for a gonadectomy to a teenage child will
be encountered if both explanation of her condition
to the child and the orchiectomy is delayed. Again,
careful consideration of ethical and legal consider-
ations are important if that is the decision.
186
If the penis of a boy with microphallus is
responsive to testosterone, the child can usually
be raised as a male if that is the decision. Patients
with congenital hypopituitarism and microphallus
will usually be able to achieve fertility with appro-
priate therapy and are not considered for sex
reversal (see Chap. 9).
A question under constant consideration is the
decision of sex of rearing in a child with partial
androgen insensitivity or with an anatomic defect
that makes a male gender assignment far more
difficult. In the past, these patients were raised as
girls. However, increasing evidence indicates that
exposure of the prenatal brain to androgens may
cause a tendency to a male gender role, making it
more controversial to raise such affected children
in a female gender, without regard for the possi-
bility of reconstructive surgery creating an ade-
quate penis. Published cases relate how subjects
were assigned to a female gender but self-reas-
signed to male gender in the prepubertal or the
pubertal period. Again, the recommendation is to
consult with a pediatric endocrinologist or DSD
team to assist in deciding on the sex of rearing
until this situation is better understood.
Multidisciplinary Team
Management
If at all possible, a child with DSD requiring con-
sideration of gender assignment should be
referred to an institution with an experienced
DSD management team, usually located at major
academic medical centers. The composition may
vary but ideally this team will have a pediatric
endocrinologist, pediatric geneticist, pediatric
urologist or surgeon, a psychiatrist or psycholo-
gist with experience in this area, and a legal and a
bioethics expert to navigate the thorny issues of
parental versus infant rights and informed con-
sent. The experience of the medical team cannot
be overestimated in importance.
Unfortunately results of the management of
the some conditions, particularly 46, XY DSD,
cannot be predicted. The social/psychological
outcome depends not just on medical acumen but
the capability of the caregivers and the individu-
al’s response to the condition.
8 Disorders of Sexual Differentiation
Youth with Gender Dysphoria
There is accumulating experience in the appro-
priate treatment of youth with gender dysphoria
to improve quality of life. This is not considered
a disorder of sexual differentiation, and few
affected individuals themselves have a
DSD. While sex of rearing is assigned at birth or
soon thereafter, gender identity takes many more
years to develop, and there may be incongruence.
There are various terms in use by various organi-
zations to define an individual who has a gender
identity different than their sex of rearing with
gender dysphoria being favored. A person with
gender dysphoria is said to have a marked incon-
gruence between the assigned gender and the
experienced or expressed gender of at least
6-month duration. Sexual orientation or identity
relates to the choice of the gender of a partner and
may be heterosexual, homosexual, or bisexual,
and any of these occur in gender-conforming per-
sons as well as gender dysphoric individuals.
Teams with experience in counseling and treating
youth with gender dysphoria are still rare but are
developing at major medical centers across the
world. Guidelines for their care are available
from various international organizations includ-
ing the Endocrine Society and are presented in
the suggested readings.
Suggested Readings
1. Rosenthal SM. Approach to the patient: transgender
youth: endocrine considerations. J Clin Endocrinol
Metab. 2014.
2. Miller WL, Flück CE. Chapter 13 - Adrenal cortex
and its disorders. In: Sperling MA, editor. Pediatric
endocrinology. 4th ed. Philadelphia, PA: Elsevier;
2014. p. 471–532.e471.
3. Witchel SF, Lee PA. Chapter 5 - Ambiguous genitalia.
In: Sperling MA, editor. Pediatric endocrinology. 4th
ed. Philadelphia, PA: Elsevier; 2014. p. 107–156.
e101.
4. Ostrer H. Disorders of sex development (DSDs): an
update. J Clin Endocrinol Metab. 2014;99(5):1503–9.
5. Vidal I, Gorduza DB, Haraux E, Gay CL, Chatelain P,
Nicolino M, Mure PY, Mouriquand P. Surgical options
in disorders of sex development (dsd) with ambiguous
genitalia. Best Pract Res Clin Endocrinol Metab.
2010;24(2):311–24.
6. Lee PA, Houk CP. Key discussions from the Working
Party on Disorders of Sex Development (DSD) evalu-
Suggested Readings
ation, Foundation Merieux, Annecy, France, March
14-17, 2012. Int J Pediatr Endocrinol. 2013;2013(1):12.
7. Hughes IA, Nihoul-Fekete C, Thomas B, Cohen-
Kettenis PT. Consequences of the ESPE/LWPES
guidelines for diagnosis and treatment of disorders of
sex development. Best Pract Res Clin Endocrinol
Metab. 2007;21(3):351–65.
8. Douglas G, Axelrad ME, Brandt ML, Crabtree E,
Dietrich JE, French S, Gunn S, Karaviti L, Lopez ME,
Macias CG, McCullough LB, Suresh D, Sutton
VR. Consensus in guidelines for evaluation of DSD
by the Texas Children’s Hospital Multidisciplinary
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 Disorders of Puberty
Normal Pubertal Development
Puberty should not be considered as a single event
but rather a continuous process in which the hypo-
thalamic–pituitary–gonadal axis develops from
the infantile stage to maturity. This is just one part
of the continuum of reproductive function that
begins during fetal life and ends in senescence.
The age of puberty is, in large degree (50–80 %),
determined by genetic factors, but environmental
factors can alter this target. The increasing preva-
lence of obesity has been one factor postulated to
decrease the age of menarche in recent years.
Physical Development (Fig. 9.1)
Physical development of puberty can be denoted
in an objective manner by sexual maturation rat-
ings (SMR) which are commonly called Tanner
stages in honor of the British physician who
developed these standards. It is important to
objectively describe the age of puberty in a devel-
oping child so that changes can be appropriately
noted in case the process starts too early, pro-
gresses too quickly, or does not start at all. It is
best to separate the stages between pubic hair
development and other aspects of puberty
(Tables 9.1 and 9.2).
Breast tissue is evolved from apocrine glands
and consists of epithelial cells forming the ductal
network of the gland, adipocytes surrounding the
© Springer International Publishing Switzerland 2016
D.M. Styne, Pediatric Endocrinology, DOI 10.1007/978-3-319-18371-8_9
9
ducts producing the fat pad, endothelial cells of
the blood vessels, as well as fibroblasts. Estrogen
stimulates the pubertal development of the breast.
Prolactin in adequate amounts can stimulate lac-
tation of the breast, while galactorrhea is a patho-
logic lactation due to abnormal elevation of
prolactin secretion.
It is important to note that both boys and girls
can achieve fertility before physical maturity is
reached.
In addition to these standard stages of puberty
classically related in textbooks of pediatrics, it is
important to note that the appearance of axillary
hair, facial hair, comedones, acne, and axillary
odor are other aspects of pubertal development
which should be noted in the patient’s record. In
addition, although rarely stated in print, the change
in appearance of the face is striking so that young
children with precocious puberty may have faces
that more clearly resemble a face of a teenager.
The appearance of the vaginal mucosa
changes during puberty; the vaginal mucosa
becomes cornified (keratinified) by estrogen
effect. The pubertal vaginal mucosa is reddish
(but not bright red as might be found with an
infection) and progresses to a duller pinkish
color with clear or slightly whitish discharge
(not as might appear in an infection, however)
occurring due to estrogen stimulation. Uterine
volume and ovarian size change with pubertal
development and sonographic standards are
available; uterine volume greater than 1.8 mL
and ovarian volume greater than 1.2 mL occur
189
 A Breast Development and Pubic Hair B Genital Development and Pubic Hair
Breast Pubic hair

Stage 1 Stage 1 Stage 1

Stage 2 Stage 2 Stage 2

Stage 3 Stage 3 Stage 3

Stage 4 Stage 4 Stage 4

Stage 5 Stage 5 Stage 5

Fig. 9.1 (a) Breast development. Stage B1, prepubertal,
elevation of the papilla only. Stage B2, breast buds visible
or palpable with enlargement of the areola. Stage B3, fur-
ther enlargement of the breast and areola with no separa-
tion of their contours. Stage B4, projection of areola and
papilla to form a secondary mount over the rest of the
breast. Stage B5, mature breast with projection of papilla
only. Appearance of pubic and labial hair among girls.
Stage PH1, prepubertal, no pubic hair. Stage PH2, sparse
growth of long, straight, or slightly curly minimally pig-
mented hair, mainly on labia. Stage PH3, considerably
darker and coarser hair spreading over mons pubis.
Normal Pubertal Development 191

Table 9.1 Hormone values in sensitive pediatric assays in puberty

Tanner Boys Girls
Testosterone Estradiol DHEAS
Stage LH (IU/L) FSH (IU/L) (ng/dL) DHEAS (g/dL) LH (IU/L) FSH (IU/L) (pg/mL) (g/dL)
I ≤0.52 <3.0 <5 <89 <0.15 0.50–4.50 <16 <46
II <1.76 0.30–4.00 <167 <81 <2.91 0.40–6.50 <65 15–113
III <4.06 0.30–4.00 21–719 22–126 <7.01 0.40–6.50 <142 42–162
IV 0.06–4.77 0.40–7.40 25–912 33–177 0.10–14.7 0.80–8.50 <283 42–241
V 0.06–4.77 0.40–7.40 110–975 110–510 0.10–14.7 0.80–8.50 See below 45–320
Values according to Quest Diagnostics, 2010; other laboratories will return other standards. Methods used are Estradiol,
ultrasensitive, LCMSMS, in cycling females: follicular stage 39–375 pg/mL, midcycle stage 94–762 pg/mL, luteal stage
48–440 pg/mL; LH-pediatric is an immunometric (sandwich) electrochemiluminescent (ECL) ultrasensitive assay. FSH-
pediatric is an immunometric (sandwich) chemiluminescent ultrasensitive ELISA (C-ELISA) assay. Testosterone is a
tandem mass spectrometry assay; estradiol, ultrasensitive, is a tandem mass spectrometry assay, and DHEA-S is a com-
petitive chemiluminescent immunoassay

in central precocious puberty (CPP) or normal
puberty. An experienced sonographer can
determine whether the uterus and ovaries are
manifesting pubertal stages of development, but
one without experience in pediatrics may erro-
neously report worrisome results.
Age at Onset of Puberty
The age of menarche is more easily determined
than any other aspect of pubertal development,
and most historical records show that the age of
menarche decreased over the last several hundred
years (secular trend) to reach a relatively stable
point in the mid-twentieth century. Recently, there
is evidence of a decrease in age of menarche once
again, and this is often attributed to the obesity
epidemic in childhood. Other theories would sug-
gest that environmental toxins affect the age of
menarche as well. African-American girls develop
earlier than Caucasian girls with Hispanic girls
being in between. It is presently accepted that
Caucasian girls may enter puberty following their
seventh birthday and African-American girls after
their sixth birthday without apparent disease but
often with excessive weight. However, it is essen-
tial that anyone evaluating a girl showing pubertal
development before these lower ages makes cer-
tain that there is neither neurological or other cen-
tral nervous system problem nor any premature
primary adrenal or ovarian activity (including a
tumor) causing this early development. The aver-
age age of onset of puberty in girls in the USA is
approximately 10 years, and the mean age of
menarche in the USA is about 12.9 years for
Caucasian girls and 12.3 years for African-
American girls. Late onset of puberty in girls is
denoted by lack of secondary sexual development
by 13 years of age. The accepted lower average
age of onset of puberty in boys has not yet changed
from 9 years in the USA in spite of the obesity
epidemic, although recent data shows that over-
weight boys begin puberty earlier than lean boys
but obese boys may be delayed. The upper age of
normal pubertal development of boys is 14 years
of age. A recent study of American boys between
10 and 16 years of age showed that the mean ages
for onset of Tanner 2 genital development for non-
Hispanic white was 10.14, African American was

Fig. 9.1 (continued) Stage PH4, thick adult-type hair that
does not yet spread to the medial surface of the thighs. Stage
PH5, hair is adult type and is distributed in the classic inverse
triangle. (b) Genital development and pubic hair growth
among boys. Stage G1, prepubertal. Stage G2, enlargement
of testis to >2.5 cm, appearance of scrotal reddening, and
increase in rugations. Stage G3, increase in length and to a
lesser extent breadth of penis, with further growth of testes.
Stage G4, further increase in size of penis and testes and
darkening of scrotal skin. Stage G5, adult genitalia. Stage
P1, preadolescent, no pubic hair. Stage P2, sparse growth of
slightly pigmented, slightly curved pubic hair, mainly at the
base of the penis. Stage P3, thicker curlier hair spread later-
ally. Stage P4, adult-type hair that does not yet spread to
medial thighs. Stage P5, adult-type hair spread to medial
thighs (Descriptions from Tanner, Growth at Adolescence,
1962, Oxford, Blackwell Scientific Publications). Adapted
from N Engl J Med 2008;358:2366–2377
192 9 Disorders of Puberty

Table 9.2 Causes and classification of delayed puberty Table 9.2 (continued)
Idiopathic (constitutional) delay in growth and puberty Functional gonadotropin deficiency
Hypogonadotropic hypogonadism: delayed puberty Anorexia nervosa
related to gonadotropin deficiency Bulimia
CNS disorders Psychogenic amenorrhea
Tumor Impaired puberty and delayed menarche in
Craniopharyngioma female athletes and ballet dancers (female athlete
Germinoma triad)
Other germ cell tumors Hypergonadotropic hypogonadism: delayed puberty
Hypothalamic and optic glioma related to gonadal failure
Astrocytoma Girls
Pituitary tumor Syndrome of gonadal dysgenesis (Turner
syndrome) and its variants
Other causes
XX and XY gonadal dysgenesis
Langerhans histiocytosis
Familial and sporadic XX gonadal dysgenesis
Granulomatous and postinfectious lesions of and its variants
the CNS
Other forms of primary ovarian failure:
Vascular abnormalities of the CNS Premature menopause
Radiation therapy Radiation therapy
Congenital malformations especially Chemotherapy
associated with craniofacial anomalies
Autoimmune oophoritis
Head trauma
Resistant ovary
CNS surgery
Galactosemia
Hydrocephalus
Glycoprotein syndrome type 1
Isolated gonadotropin deficiency
FSH receptor gene mutators
With hyposmia or anosmia: Kallmann syndrome
LH–hCG resistance
Without anosmia
Noonan or pseudo-Turner syndrome
Congenital adrenal hypoplasia (DAXI mutation)
Polycystic ovarian disease
Isolated LH deficiency
Boys
Isolated FSH deficiency
Syndrome of seminiferous tubular dysgenesis and
Idiopathic and genetic forms of multiple pituitary its variants (Klinefelter syndrome)
hormone deficiencies
Other forms of primary testicular failure
Other endocrine causes of delayed puberty
Chemotherapy
Hypothyroidism
Radiation therapy
Diabetes mellitus (poorly controlled)
Testicular biosynthetic defects
Cushing disease
Sertoli-only syndrome
Hyperprolactinemia
LH resistance
Miscellaneous disorders
Anorchism and cryptorchidism
Chronic systemic disease and malnutrition
CNS central nervous system, LH luteinizing hormone,
Marijuana use
FSH follicle-stimulating hormone, hCG human chorionic
Gaucher disease gonadotropin
Prader–Willi syndrome
Laurence–Moon and Bardet–Biedl syndromes
Sickle cell disease 9.14, and Hispanic boys was 10.04 years, and for
Cystic fibrosis stage 2 pubic hair, 11.47, 10.25, and 11.43 years,
Acquired immunodeficiency syndrome respectively. Mean years for achieving testicular
Chronic gastroenteric disease volumes of >3 mL were 9.95 for white, 9.71 for
Chronic renal disease African American, and 9.63 for Hispanic boys,
Malnutrition and for >4 mL were 11.46, 11.75, and 11.29
(continued) respectively. For girls, the NHANES III US
The Endocrine Changes of Puberty
national study showed the mean ages for onset of
stage 2 breast development were 9.5 years for
African Americans, 9.8 years for Mexican
Americans, and 10.4 years for white Americans,
whereas the onset of stage 2 pubic hair occurred at
10.4 years for white Americans, 9.4 years for
African Americans, and 10.6 years for Mexican
Americans. Secondary sexual development char-
acteristically spans a period of 4 years from begin-
ning to reaching stage 5.
Ages of Pubertal Stages and Duration
The Pubertal Growth Spurt
The greatest growth period in a child’s life occurs
during fetal development (one cell to 7 lb in 9
months!), but there are other growth spurts that
are apparent after birth. Increased growth is noted
during the first few years in the infant–child
growth spurt between 1½ and 3 years. The sec-
ond greatest growth velocity after birth is noted
during the pubertal growth spurt. During this
period, girls may gain 25 cm and boys 28 cm.
Girls’ pubertal growth spurts occur about 2 years
earlier than boys and girls gain less stature during
the spurt than boys, and this accounts to the aver-
age difference in adult height between men and
women of about 5 in. in the USA.
The control of the pubertal growth spurt
depends on numerous factors, including estrogen,
growth hormone, insulin-like growth factors, thy-
roid hormone, and adequate nutrition. In both
boys and girls, it is estrogen, either directly
secreted as in girls or converted from testosterone
in boys, that is responsible for the increase in
growth hormone and IGF 1 during the pubertal
growth spurt and is linked to the increase in height
velocity. Estrogen is also responsible for the
advancement of bone age that ultimately leads to
epiphyseal fusion and cessation of growth.
The pubertal growth spurt is an early event in
female puberty, and upon attainment of men-
arche, relatively limited growth is left for a girl.
The pubertal growth spurt, however, is a later
event in the puberty of boys. Thus, if a boy com-
plains of short stature but has not yet entered
pubertal development and has no other disorder,
193
it is likely that the boy will still have significant
growth left. Alternatively, if he has advanced
pubertal development, he probably has relatively
little growth left.
Skeletal Development and Bone
Mineral Density
While it is an imperfect method, bone-age deter-
mination gives us a general indication of how
much more growth is available and is often
invoked to predict adult height. As with ultraso-
nography of the uterus and ovaries, experience is
extremely important in the accurate interpretation
of bone-age development. See Chap. 5 for more
discussion on bone-age assessment.
The fastest accrual of bone density occurs dur-
ing infancy and puberty. In America, relatively few
teenagers get adequate vitamin D or calcium intake
and therefore are at risk for decreased bone den-
sity, leading to osteopenia or even osteoporosis. A
current theory holds that it is possible to achieve
normal bone density later in life by increasing cal-
cium intake after these crucial time periods,
assuming that the individual does not have a
genetic tendency toward osteoporosis. However, it
is quite important to ensure adequate vitamin D
and calcium intake as a step to guard against
decreased bone density during childhood and
puberty and this simple step is often overlooked.
The Endocrine Changes of Puberty
Gonadotropin-releasing hormone (GnRH) is
released in pulsatile fashion from the hypothala-
mus into the hypophysiotropic portal system to
reach the anterior pituitary which leads to pulsatile
release of gonadotropins, LH and FSH, from the
pituitary gland. If, however, GnRH is infused in a
constant manner, the pituitary gonadotrophs will
cease to respond to it, receptors for GnRH will
decrease, and LH and FSH will fall. This phenom-
enon is used in the treatment of CPP where long-
acting GnRH analogues act similar to a constant
infusion of GnRH and thereby cause cessation of
the pubertal level of gonadotropin secretion.
194
While GnRH is one key in the control of
puberty, another peptide, kisspeptin, plays an
important role. Kisspeptin is secreted from
“KNDy” neurons in the arcuate nucleus that
secrete neurokinin B and dynorphin as well.
Kisspeptin interacts with its receptor, KISSR
(previously called GRP-54), to stimulate GnRH
secretion. Mutation of the receptor or absence of
kisspeptin protein will both eliminate pubertal
development and reproduction. Alternatively, an
excess of kisspeptin or a stimulatory mutation of
GRP-54 will cause precocious puberty.
Pituitary follicle-stimulating hormone stimu-
lates the follicles of the ovary to produce estrogen
and the seminiferous tubules of the testes to sup-
port sperm development. Luteinizing hormone
has less effect on the female ovary until ovulation
occurs, at which time it stimulates the luteiniza-
tion of the follicle into the corpus luteum. In a boy,
luteinizing hormone stimulates the Leydig cells to
produce testosterone. The Sertoli cells of the tes-
tes and the follicles of the ovaries also produce the
protein hormone inhibin which, in addition to sex
steroids, exerts a feedback inhibitory effect on LH
and FSH secretion. The inhibin molecule has a
beta subunit termed activin; activin stimulates the
synthesis and release of FSH from the pituitary
gland. Follistatin, produced in the pituitary gland,
inhibits the activin effect by binding to the activin
receptor. The testes likewise produce anti-Mülle-
rian hormone (AMH, sometimes called Müllerian
duct inhibitory factor or MIF; see sexual differen-
tiation Chap. 8). Measurement of the protein prod-
ucts of the gonads is useful to determine the
presence or absence of gonads and may assist in
the differentiation of constitutional delay in
puberty (CDP) from idiopathic hypogonado-
tropic hypogonadism (IHH). Gonadotropin
secretion is very high in primary gonadal failure
due to the absence of inhibin as well as the
absence of sex steroids so that there is diminished
negative feedback inhibition occurring.
Hypothalamic GnRH begins to stimulate pitu-
itary LH and FSH release in the fetus. By midg-
estation when the hypothalamic pituitary portal
system is functional and hypothalamic GnRH
can reach the pituitary gland, LH and FSH con-
centrations are extremely high. As fetal develop-
ment progresses, higher central nervous system
9 Disorders of Puberty
centers inhibit the unbridled release of GnRH
and LH and FSH likewise decrease. In the male
fetus, testosterone secretion is stimulated first by
placental human chorionic gonadotropin (hCG).
hCG levels fall by week 20 and thereafter fetal
pituitary luteinizing hormone secretion stimu-
lates the fetal testis. Normal penile development
requires hCG and a functional testes early in
development, but if there is no pituitary LH avail-
able by midgestation, the penis, although perfectly
formed, will not enlarge to normal size and a new-
born boy with gonadotropin deficiency will have a
microphallus (or a phallus length more than 2.5
SD below the mean which is less than 2.0 cm in
stretched length (although some sources state less
than 2.5 cm defines microphallus)). A microphal-
lus will also be narrower than a normal penis.
After birth, when the newborn infant is
released from the inhibitory effects of high con-
centrations of maternal estrogen, pulses of pitu-
itary LH and FSH increase in amplitude and
frequency, leading to pulses of steroid secretion
from the gonads. Infantile testosterone concen-
trations can peak as high as 150 ng/dL during this
“mini-puberty of infancy,” a clearly mid-pubertal
level in normal boys. Girls likewise have elevated
peak levels of estradiol that can bring about
breast development soon after birth. Thus, gonad-
otropin values reach pubertal levels during the
first months and years after birth, and sex steroid
secretion in both boys and girls can episodically
reach values as high as those found during
puberty; this makes the diagnosis of precocious
puberty in infancy all the more difficult.
The juvenile pause (childhood phase of
decreased endocrine activity after the mini-
puberty of infancy) that follows infancy is char-
acterized by low activity of the hypothalamic
GnRH secretion and low levels of LH and FSH
secretion. Thus childhood gonadotropin secre-
tion is also pulsatile, but the amplitude is quite
low. If the child has no functional gonads, such as
is found in Turner syndrome, gonadotropin con-
centrations rise higher than normal, although
they do not rise as high as the levels found later in
Turner syndrome during the pubertal age range.
This indicates that intrinsic CNS inhibition is
active during the childhood juvenile pause with
feedback inhibition by sex steroids and inhibin
The Endocrine Changes of Puberty
active at a high level; the strength of the feedback
inhibition decreases just before and continues
during the pubertal period allowing gonadotro-
pins and sex steroids to rise to pubertal levels.
The control of the intrinsic CNS inhibitory
process suppressing GnRH secretion appears
mediated by various CNS peptides including
gamma-amino butyric acid (GABA), an inhibitory
neuropeptide. The recent discovery of MKRN3 a
paternally expressed maternally imprinted gene,
as a putative “brake” on the endocrine control of
puberty provides another clue as to the control
of the onset of puberty as inactivating mutations of
MKRN3 lead to familial CPP.
Gonadarche (Fig. 9.2a)
Gonadarche denotes the reawakening of the
gonad at the time of pubertal development after
the juvenile pause due to stimulation by increas-
ing amplitude and frequency of GnRH pulses,
leading to increased pulsatile pituitary gonado-
tropin secretion. Gonadotropin secretion is prom-
inent in the fetus once hypothalamic pituitary
portal system develops by midgestation.
Unrestrained gonadotropin secretion leads to
stimulation of fetal testosterone secretion in the
male. During gestation the fetal adrenal zone of
the adrenal gland produces DHEA which is
metabolized by the placenta to produce estriol
and other estrogens which are present in high
concentrations. The placenta likewise produces
large amounts of progestin; this would suppress
maternal gonadotropins inhibiting ovulation
during pregnancy. Progestin also supports the
continuation of the pregnancy by supporting
the endometrium and suppressing myometrial
contractility during gestation. As gestation pro-
gresses, inhibitory substances including gamma-
aminobutyric acid (GABA) and possibly the
products of the gene MKRN3 suppress central
nervous system stimulation of gonadotropin
secretion. Soon after birth and the removal of the
suppressive action of maternal estrogen, gonado-
tropins peak once again and remain elevated for
months after birth in both boys and girls. The
male infant will experience the mini-puberty of
infancy due to this gonadotropin secretion stimu-
195
lating testosterone secretion. Likewise elevated
gonadotropin levels will stimulate infantile ova-
ries for a period of months after birth. At the age
of onset of puberty decreased inhibition of GnRH
secretion by higher central nervous system
(decreased inhibition by GABA and MRKN3 is a
major mechanism) and decreased sensitivity to
negative feedback inhibition by sex steroids and
inhibin allow increased GnRH secretion into the
pituitary portal circulation. Thus, to a degree
puberty might conceptually be considered to be a
condition which is held back from a younger
child until the higher level inhibition is with-
drawn. Congenital defects of the hypothalamus,
CNS surgery, or injury to the hypothalamus can
release this inhibition and bring about CPP. After
the inhibition of puberty during the juvenile
pause, at the time of peripubertal period or the
onset of puberty there is an increase in stimula-
tory peptides such as kisspeptin and glutamate
which increase GnRH secretion in turn.
Plasma gonadotropins first rise at night in a
diurnal rhythm in the peripubertal period, the
period just before physical development begins,
and during later periods of pubertal development,
they rise during the day as well until there is no
longer any diurnal variation; adults follow this
pattern of relatively equal secretion during day
and night. Clinically it would be better to measure
gonadotropin secretion in the middle of the night
to determine if puberty has begun but practicality
necessitates measurement during clinic hours.
The episodic increased amplitudes of LH and
FSH secretion are followed within a few hours by
increased sex steroid secretion which leads over
time to the physical changes of puberty described
above.
Due to the increase in gonadotropin levels the
gonads secrete their respective sex steroids. The
ovary secretes estrogens and the testis secretes
testosterone either of which brings about the
physical changes of pubertal development. In the
female estrogen secretion leads to breast devel-
opment while adrenarche (described below) with
rising adrenal androgens lead to axillary and pubic
hair development as well as acne. In the male tes-
tes enlarge as a reflection of increased seminifer-
ous tubular development and to a lesser extent
Leydig cell development. The testes produce
196 9 Disorders of Puberty

a Third ventricle Hypothalamus

Neuroendocrine
cell nuclei

GnRH secreting cells

Superior
hypophyseal Stalk
artery

Long portal
vessels Inferior
hypophyseal
artery
LH and FSH
–
Secreting cells

Anterior Posterior
pituitary pituitary

Hormone Short portal

secretion vessel

+ LH and FSH

Testosterone Estrogen
and inhibin and inhibin

Testes Ovary

Fig. 9.2 (a) The normal physiologic state of gonadotro-
pin-releasing hormone episodically stimulating pituitary
gonadotropins to stimulate the gonads to release sex ste-
roids which exert negative feedback on the pituitary and
hypothalamus to reach an equilibrium. The negative feed-
back equilibrium will be set at a higher sensitivity in
childhood and a lower sensitivity during puberty. The
gonads also make a protein hormone, inhibin, which
exerts negative feedback inhibition but is not shown in the
diagram. (b) Hypogonadotropic hypogonadism in which
the hypothalamus does not produce gonadotropin-releasing
hormone (top “X” indicating tertiary hypogonadotropic
hypogonadism) or the pituitary gland does not release
gonadotropins (lower “X” indicating secondary hypogo-
nadotropic hypogonadism) so that the gonads do not
secrete their steroid hormones. (c) Hypergonadotropic
hypogonadism in which the gonads do not produce sex
steroids nor inhibin leading to extremely elevated levels
of LH and FSH due to the lack of feedback inhibition

mainly testosterone but produces a small amount
of dihydrotestosterone and DHEA. Testosterone
circulates with albumin (38 % roughly) or sex
hormone-binding globulin (60 %) leaving 2 % as
free testosterone which can diffuse into the tis-
sues. Sex hormone-binding globulin is increased
by estrogens and decreased by androgens.
Besides androgens, the testis also produces estro-
gens. Estrogen receptors are present in the male
epididymis and spermatic ducts and apparently
play a prominent role in maintaining fertility. The
majority of estrogen in the circulation in males
The Endocrine Changes of Puberty 197

b Third ventricle Hypothalamus

Neuroendocrine
cell nuclei

GnRH secreting cells

Superior
hypophyseal Stalk
artery

Long portal
vessels Inferior
hypophyseal
artery
LH and FSH

Secreting cells

Anterior Posterior
pituitary pituitary

Hormone Short portal

secretion vessel

LH and FSH

Testosterone Estrogen
and inhibin and inhibin

Fig. 9.2 (continued)

however is produced by aromatase acting on cir- single-androgen receptor to combine with

culating testosterone. Testosterone and dihy-
drotestosterone binds to the androgen receptor
which is coded on the X chromosome.
Dihydrotestosterone binds more avidly to the
receptors than testosterone which accounts for its
increased potency. This receptor like other ste-
roid receptors is a member of the steroid–thyroid
hormone nuclear superfamily, found in the cyto-
plasm, and associated with several heat-shock
proteins and immunophilins. When testosterone
or dihydrotestosterone binds to the receptor, it
dissociates heat-shock proteins from the complex
of the androgen dimerized receptors allowing a
another receptor molecule; thus, androgen and its
receptor translocate into the nucleus, binding to
DNA and ultimately transcription and protein
formation of androgen action occur.
Antiandrogens compete with androgen bind-
ing to the androgen receptor. Cyproterone acetate
is a steroid molecule that acts as an antiandrogen
while flutamide, bicalutamide, and nilutamide
are nonsteroidal antiandrogen antagonists. Anti-
antigens are used in girls with hirsutism or in
conditions such as premature Leydig cell and
germ cell maturation in boys to decrease andro-
gen effects if the source of androgens cannot be
198 9 Disorders of Puberty

c Third ventricle Hypothalamus

Neuroendocrine
cell nuclei

GnRH secreting cells

Superior
hypophyseal Stalk
artery

Long portal
vessels Inferior
hypophyseal
artery
LH and FSH

Secreting cells

Anterior Posterior
pituitary pituitary

Hormone Short portal

secretion vessel

LH and FSH

Testosterone Estrogen
and inhibin and inhibin

Fig. 9.2 (continued)

removed. Antiandrogens have been used in con-
junction with glucocorticoids in the treatment of
virilizing CAH. Antiandrogens are teratogenic.
Estrogen is produced by the granulosa cells of
the ovarian follicles while progesterone and
androgens are produced by the theca cells which
lack aromatase that could convert such androgen
precursors into estrogens. The ovaries secrete
one-third of woman’s testosterone production,
the other two-thirds being produced from periph-
eral conversion from precursors. About 80 % of
circulating estradiol comes from the ovary with
the rest from peripheral effects of the aromatase
enzyme. Circulating estradiol is bound to sex
hormone-binding globulin (38 %) and albumin
(60 %) with about 2 % circulating his free estra-
diol. Estradiol is either directly conjugated or
converted into estrogens and then conjugated
before excretion in the urine.
Estrogens stimulate mammary gland develop-
ment in puberty. Estradiol also has effects on
fluid balance as it lowers the point at which argi-
nine vasopressin is secreted and at which thirst
arises and increases sodium resorption in the kid-
ney, thereby increasing plasma volume.
Selective estrogen receptor modulators
(SERMs) block estrogen effects to a different
degree in different tissues. Because estrogen
The Endocrine Changes of Puberty
advances bone age and causes epiphyseal fusion,
various approaches to delay the effects of estro-
gen on these processes are utilized in clinical
studies. Thus tamoxifen, ormeloxifene, and ral-
oxifene act as antagonists on bone (also act as
antagonists at breasts and uterus). Clomiphene
acts as an estrogen antagonist on the hypothala-
mus but also exerts some estrogen effects; it can
be used to stimulate secretion of LH and FSH by
blocking estrogen negative feedback inhibition
on the hypothalamic–pituitary axis. Aromatase
inhibitors stop the production of estrogen from
androgens and have been invoked to block the
effect of estrogen on bone maturation in order to
increase adult height.
Progesterone is the product of the theca cells
of the luteinizing follicle during the luteal
phase of the menstrual period. It is also a mol-
ecule important in the metabolic production of
other steroid molecules including cortisol, min-
eralocorticoids, and androgens. Progesterone is
also a product of the testes, is a precursor in the
biosynthesis of testosterone, and also has
effects on spermatogenesis and Sertoli cell
function.
Progesterone acts on its receptor (PR, also
known as NR3C3 or nuclear receptor subfamily 3,
group C, member 3), in a manner similar to other
steroid hormones such as estrogen described above.
Progesterone increases plasma volume by
increasing protein retention in the intravascular
space. Progesterone does not appear to exert the
same effect on lowering the threshold for thirst
and vasopressin secretion as estrogen. The combi-
nation of some progesterone forms and estrogens
in an oral contraceptive limits fluid retention.
Progestin androgenic activity varies with prep-
aration. Low androgen is found in norgestimate,
desogestrel, norethindrone 0.4–0.5 mg, and
drospirenone; moderate androgen is found in levo-
norgestrel triphasic, norethindrone acetate 1.0 mg,
norethindrone 1.0 mg, and ethynodiol diacetate
1.0 mg; and high androgen is found in norgestrel
0.3 mg, norethindrone acetate 1.5–2.5 mg, and
levonorgestrel 0.15 mg.
Androstenedione is a precursor of androgens
in the adrenal glands, testes, and ovaries. In nor-
mal women there is an equal production of
199
androstenedione and testosterone from the ova-
ries and the adrenal glands. Androstenedione can
be converted to testosterone by many cells in the
body. In the theca cells androstenedione produc-
tion is under the control of LH; androstenedione
is converted to estrogen in neighboring granu-
losa cells under the control of FSH. But in poly-
cystic ovarian syndrome, there is predominant
secretion of androstenedione from the ovaries.
17-Hydroxyprogesterone, a precursor of andro-
gens, is produced by theta cells of the ovary during
the luteal phase and the Leydig cells of the testes.
The majority of dihydrotestosterone is pro-
duced by peripheral conversion by 5-alpha-hydrox-
ylase of testosterone usually in localized tissue.
Testosterone production in the testes leads to
enlargement of the phallus. Conversion of testos-
terone to the highly potent androgen dihydrotestos-
terone usually locally leads to the production of
pubic and axillary hair and male pattern baldness
as well as prostate growth. Testosterone is metabo-
lized by oxidation, reduction, hydroxylation, and
finally conjugation but may be excreted in the urine
as other steroid hormones are.
Severely decreased weight is incompatible
with menarche or even pubertal development due
to decreased secretion of GnRH and therefore of
LH and FSH. There has been considerable specu-
lation as what factor may cause low weight to
lead to decreased gonadotropin secretion. Leptin,
the hormone released by adipose tissue (see
Chap. 13), appears to be a factor which is neces-
sary, but not sufficient, for pubertal development.
In the absence of leptin effects, in the rare indi-
viduals who are deficient in leptin production
(#614962 LEPTIN DEFICIENCY; LEPD) or in
leptin receptors (#614963 LEPTIN RECEPTOR
DEFICIENCY), puberty does not occur demon-
strating the importance of leptin in the pubertal
process. Both of these are autosomal recessive
conditions. When leptin is administered in leptin
deficiency, puberty will progress if the subject is
of pubertal age or bone age is appropriate for
pubertal development: Leptin will not cause chil-
dren to advance into puberty in isolation.
Stress suppresses gonadotropin secretion.
This may be one mechanism of hypothalamic
amenorrhea.
200
Spermarche
Spermarche is the first appearance of sperm,
noted in first morning urine specimen in clinical
studies, and occurs at a mean chronologic age of
13.3–16 years depending upon the study, and at a
mean pubic hair stage 2–3. However, spermarche
may be found in normal boys with bilateral tes-
ticular volumes of only 3 mL and no physical
signs of puberty.
Adrenarche
Adrenarche denotes the increase in adrenal
androgens that occur prior to the appearance of
pubic hair which is called pubarche; adrenal
androgen values rise before gonadotropin secre-
tion increases. Adrenarche only occurs in human
beings and our closest primate relatives. There is
an increase in the size of the zona reticularis
associated with the increase in dehydroepian-
drosterone, dehydroepiandrosterone sulfate, and
androstenedione secretion, the major androgens
of the adrenal. These are weak androgens that are
converted to more potent androgens such as
testosterone which itself can be converted by
5-alpha-hydroxylase to dihydrotestosterone.
Adrenal androgens also can be converted to
estrogens of various potencies by the enzyme
aromatase. Adrenal androgens circulate primar-
ily bound to albumin with a smaller contribution
from sex hormone-binding globulin. In addition
to the appearance of pubic hair, there is a change
in complexion with the onset of comedones or
acneiform lesions and increased axillary hair;
adrenal androgens may rise early in the condition
premature adrenarche; often growth rate increases
slightly, although not as much as found in preco-
cious puberty, and bone age may be slightly
advanced over the normal 2 standard deviation
variation. Adult height is characteristically
reported as normal even with some advancement
in bone age. Alternatively, the absence of adrenal
androgens leads to a diminished development of
pubic and axillary hair, but the androgen produc-
tion of the testes and the ovaries lessens that
affect. Adrenal androgen deficiency may occur
9 Disorders of Puberty
because of ACTH deficiency or alternatively due
to enzymatic defects blocking androgen produc-
tion (see Chap. 8). In general, adrenal androgens
are not used for therapy in pediatric or adolescent
patients, but DHEA is available for treatment
should there be a complaint about inadequate
sexual hair development.
Adrenarche characteristically is described as
an event that occurs at 6 and 8 years of age;
increasing secretion of adrenal androgens actu-
ally starts around 3 years of age and progresses
from there. Premature adrenarche is usually
characterized as onset of pubic hair before 6–8
years of age and exaggerated adrenarche is used
as the term if androgen values are higher than
characteristically found in the more common
form of premature adrenarche.
There is usually coordination between gonad-
arche and adrenarche, but the control for each is
distinct and either can occur first at the time of
puberty. If the rise in adrenal androgens occurs
earlier than in the normal progression, premature
adrenarche and subsequent premature pubarche
occur. The age of classic premature adrenarche
described in the medical literature may overlap
an age that is now considered within the normal
limits of the onset of pubertal development, so
confusion may occur as to whether an individual
has normal or premature adrenarche.
Pediatric Sex Steroid
and Gonadotropin\Assays
Assays aimed toward the adult population gener-
ally are calibrated to indicate if LH and FSH are
very high, as found in postmenopausal women,
and whether testosterone is as high as in a normal
adult male or low as found in testicular failure.
Specialized pediatric assays are necessary if one
is to know the true values of sex steroids and
gonadotropins in childhood or during pubertal
development. Thus, testosterone should be mea-
sured by HPLC tandem mass spectroscopy which
usually is carried out in a national lab (since the
equipment is extremely expensive) which has
pediatric standards. This assay is more expensive
than the standard adult testosterone assay but is
The Endocrine Changes of Puberty
the commercial assay that is valid in childhood
and in women as well. If a sample is subject to
extraction and chromatography and then mea-
sured in a radioimmunoassay, valid values for
evaluation of puberty will result, but this modi-
fied radioimmunoassay is not available in most
laboratories without personally requesting the
special steps to be carried out. It is possible to
measure free testosterone which is not bound to
sex hormone-binding globulin in bioavailable
testosterone assay; bioavailable or bioactive tes-
tosterone assays are useful in the evaluation of
virilizing disorders in girls and women. Estradiol
is best measured in the HPLC tandem mass spec-
troscopy system as well. LH and FSH should be
measured in a highly sensitive immunometric
assay and interpreted with pediatric standards,
again characteristically requiring a national send-
out laboratory. There is virtually no useful infor-
mation if the standard LH and FSH assay is
carried out in many disorders of puberty since
they are far too insensitive to accurately deter-
mine childhood values; they could be used in
gonadal failure such as in a pubertal aged girl
with Turner syndrome or a late pubertal boy with
Klinefelter syndrome, but not in the normal child
or one with a more subtle problem.
As pubertal development begins, a larger store
of gonadotropins develops in the pituitary gonad-
otrope cells. Stimulation of the pituitary gonado-
trophs with GnRH, or more recently with GnRH
agonists which are more readily available, allows
determination of maximal gonadotropin secre-
tion, an important diagnostic criterion for the
onset of puberty. However, the highly sensitive
pediatric LH and FSH assays can be used on sin-
gle, unstimulated blood samples to determine the
onset of puberty, sometime eliminating the need
for a GnRH stimulation study to determine the
presence or absence of pubertal gonadotropin
values. Pediatric ultrasensitive gonadotropin and
sex steroid determinations are capable of demon-
strating increasing values before physical puber-
tal development is detected.
In boys, an 8:00 a.m. serum testosterone value
of 20 ng/dL, or 0.7 nmol/L, has been shown to
herald the onset of male pubertal development
within the next 12 months, a finding useful in the
201
diagnosis of the impending onset of puberty in
constitutional delay in puberty.
More than 97 % of sex steroids are non-
covalently bound to sex hormone-binding globulin
(SHBG), sometimes denoted testosterone-binding
globulin (TEBG). Estrogen stimulates a rise in
SHBG, which has the effect of increasing the
protein-binding of testosterone so that a given
level of testosterone has less biological effect in
girls with higher SHBG. Androgens in boys,
however, decrease SHBG, thereby allowing more
unbound and therefore more active testosterone to
circulate in a manner which increases androgen
effect in a boy as pubertal development progresses.
The girl who has increased androgen levels due to
polycystic ovarian syndrome will have decreased
SHBG which likewise will increase the effects of
her androgen levels.
Inhibin B rises as Sertoli cells mature during
puberty. Conversely AMH decreases in concert
with the rise in inhibin as the Sertoli cells mature.
Both can yield important information in the
evaluation of puberty or disorders of sexual
differentiation.
Ovulation and Menarche
The last stage in hypothalamic–pituitary devel-
opment is the onset of positive feedback, leading
to ovulation and menarche. While in prepuberty a
small amount of estrogen will suppress LH and
FSH secretion, after midpuberty, estrogen in the
appropriate amount at the appropriate time in the
menstrual cycle can stimulate gonadotropin
release. Thus, as puberty progresses increasing
estrogen secretion from the ovary occurs as feed-
back inhibition of estrogen on gonadotropin
secretion decreases. Primordial follicles are the
fundamental reproductive units that comprise the
pool of resting oocytes. Primary follicle develop-
ment is the first stage of follicular growth.
Primary follicles differ from primordial follicles
in several ways as the oocyte begins to grow.
As growth progresses, the zona pellucida is
formed and the secondary follicle develops which
includes attainment of maximal oocyte growth,
proliferation of granulosa cells, and acquisition
202
of theca cells. The tertiary follicle enters the early
antral phase characterized by the formation of an
antrum or cavity in the follicle. The antral fluid
contains steroids, proteins, electrolytes, proteo-
glycans, and an ultrafiltrate that forms from dif-
fusion through the basal lamina. Other changes in
this phase include further theca cell differentia-
tion. Subpopulations of thecal interstitial cells
develop within the theca interna, acquire LH
receptors, and are capable of steroidogenesis.
The granulosa cells begin to differentiate into
distinct cell layers. The dominant follicle develops
which is able to increase estrogen secretion
during the follicular phase or proliferative phase
of the menstrual cycle to exert positive feedback
on the hypothalamus leading to the midcycle LH
surge that brings about ovulation. Once ovulation
occurs, LH causes luteinization of the granulosa
cells of the follicle leading to a rise in progester-
one as well as estrogen during the luteal or secre-
tory phase. Finally, estrogen falls again along
with progesterone and the menstrual cycle occurs.
During the follicular phase the uterus builds up
by proliferation and differentiation of the endo-
metrium until the functional layer is shed and
menstrual flow occurs. However, even if the mid-
cycle surge of gonadotropins is present, ovula-
tion may not occur during the first menstrual
cycles; 85–90 % of menstrual cycles are anovula-
tory in the first year after menarche, about 60 %
in the third year after menarche, and about 25 %
in the fifth year after menarche. Menstrual irregu-
larities in normal girls appear to be relatively
minor as menstrual length variation is 21–45
days in 75 % of girls during the first menstrual
year, but this variation decreases to about 5 % by
the third menstrual year.
Recently revised definitions of abnormal uter-
ine bleeding state that secondary amenorrhea
occurs when no menstrual cycle appears in a
period of over 90 days after menarche, and oligo-
menorrhea occurs when there are fewer than four
periods in the year (average cycle length 90 days)
in the first year after menarche, fewer than six
periods in the year (average cycle length 60 days)
in the second year after menarche, and fewer than
eight periods per year (average cycle length 45
days) during the third to fifth year after men-
arche. Abnormal uterine bleeding occurs when
9 Disorders of Puberty
menstrual bleeding occurs more than every 21
days or lasts more than 7 days or soaks more than
one pad or tampon every 1–2 h. Minor irregulari-
ties of the menstrual cycle are usually due to
abnormal hypothalamic pituitary ovarian func-
tion and often resolve while more serious and
long-lasting complications require evaluation
and treatment. The high prevalence of anovula-
tory periods after menarche may be due to unrec-
ognized PCOS in some individuals rather than a
normal developmental phenomenon. It is recom-
mended that significant menstrual irregularity be
evaluated if it persists over 1 year and especially
that is associated with other pathologic findings
such as galactorrhea or hirsutism. However, some
of the first cycles after menarche may be ovula-
tory, and fertility is possible in the first cycle.
Just as in boys, girls are reproductively mature
prior to physical maturity; girls may become fer-
tile and even pregnant prior to physical or emo-
tional maturity.
Miscellaneous Metabolic Changes
The rise of sex steroid concentrations at the
onset of puberty is either directly or indirectly
associated with many changes in other labora-
tory values. In boys, the hematocrit rises. In
both boys and girls high-density lipoprotein
(HDL) concentrations rise and alkaline phos-
phatase rises during the pubertal growth spurt
(often this rise is incorrectly interpreted as evi-
dence for a prostatic tumor or liver abnormal-
ity). Serum IGF-I concentrations rise with the
growth spurt. Prostate-specific antigen (PSA) is
measurable after the onset of puberty in boys and
may provide another biochemical indication of
pubertal onset.
Abnormalities of Puberty
Delayed Puberty
If a girl does not begin any aspect of pubertal
development by 13 years, or a boy by 14, the
diagnosis is delayed puberty (some consider
boys delayed if no signs appear by 13.5 years).
Abnormalities of Puberty
Table 9.3 Differential diagnosis of delayed puberty
Serum Serum gonadal
Condition gonadotropins steroids
Constitutional delay Prepubertal Low
in growth and (low)
adolescence
Hypogonadotropic Prepubertal Low
hypogonadism (low)
Hypergonadotropic Elevated Low
hypogonadism
This can be an example of normal variation, such
as constitutional delay in puberty, or a serious
condition, such as gonadotropin deficiency due to
a central nervous system tumor. Thus the etiol-
ogy of delayed puberty is always worth serious
consideration. The clinician must determine
which patient and parents need reassurance and
which need testing to determine if a serious con-
dition is present (Table 9.3).
Constitutional Delay in Puberty
(See Chap. 5)
CDP is usually accompanied by constitutional
delay in growth in childhood. These are children,
more frequently boys, who tend to be thin and
who have a physiologic delay in all measurable
aspects of growth, but not in mental develop-
ment. Thus, CBC, alkaline phosphatase, and
other biological measures that change with
pubertal development are characteristic of a
young child. The bone age is delayed as well, and
the height age (the height age is the chronologic
age at which the child’s height is equal to the 50th
percentile on the growth chart) is delayed for age
but generally appropriate for the bone age (the
bone age has significant limitations in accuracy,
however). These children have plasma gonado-
tropin and sex steroid values characteristic of
younger children and a phenotype more appro-
priate for a younger child. Sometimes watchful
waiting is necessary for years after the first evalu-
ation until pubertal development proceeds in the
natural history of the condition, but almost all
subjects begin pubertal development by 18
years of age. Delayed adrenarche and gonad-
arche are often found together in constitutional
203
Miscellaneous
Patient usually has short stature for chronologic age but
appropriate height and growth rate for bone age. Both
adrenarche and gonadarche are delayed.
Patient may have anosmia (Kallmann syndrome) or other
associated pituitary hormone deficiencies. If gonadotropin
deficiency is isolated, the patient usually has normal height
and growth rate but lacks a pubertal growth spurt.
Adrenarche may occur at a normal stage in spite of absent
gonadarche (serum DHEAS may be pubertal).
Patient may have abnormal karyotype and stigmas of
Turner syndrome or Klinefelter syndrome.
delay, although the rule is not constant for all.
Unlike patients with Kallmann syndrome
(below), the sense of smell is normal and there is
no increased incidence of cryptorchidism nor
microphallus. The condition has a strong family
pattern as 50–75 % of patients have a family
history of the same.
There is no definitive diagnostic test to estab-
lish constitutional delay or to separate it from
hypogonadotropic hypogonadism although the
finding of a value of inhibin B >35 pg/mL in one
study supported the diagnosis of CDP while in
another study inhibin B <111 pg/mL with basal
LH <0.3 IU/L was highly diagnostic for
IHH. Standards for the inhibin assay vary with
the method and laboratory, so a distinct cutoff is
not yet established in this diagnostic situation.
Clearly the history and physical findings must
be considered as a whole and elimination of
other pathologic conditions must occur before
accepting the diagnosis; this is a diagnosis of
exclusion.
Hypogonadotropic Hypogonadism
(Fig. 9.2b) (#146110)
Hypogonadotropic hypogonadism (HH) may be
due to a genetic defect in gonadotropin secretion, a
developmental defect, a tumor, or other CNS abnor-
malities. Individuals will characteristically grow
normally at first in isolated hypogonadotropic
hypogonadism (IHH), but will have no pubertal
growth spurt due to the lack of the rising sex ste-
roids in puberty. If growth hormone is affected as
well as gonadotropin secretion with multiple pitu-
itary deficiencies, the child will have a decreased
growth rate during childhood and puberty.
204
Isolated Hypogonadotropic
Hypogonadism
Patients with IHH characteristically grow normally
during childhood but, with the absent pubertal
growth spurt, fall behind the height of typical
subjects. Since they have a delay in epiphyseal
fusion, they may continue to grow to a taller adult
height. The individual may develop eunuchoid
proportions consisting of long legs and arms and
an upper-to-lower segment ratio well below 0.9,
the value ordinarily normal for adults. IHH may
be a congenital defect, sometimes related to a
defined mutation. However, acquired gonadotro-
pin deficiency is an ominous sign and could be an
indication of a central nervous system tumor.
There is a continuum in the manifestation of
gonadotropin deficiency ranging from complete
absence of puberty to delay in puberty extending
to reproductive defects alone. Most recently, it
was determined that 10–20 % of patients with
proven genetic defects who would be expected to
have permanent hypogonadotropic hypogonad-
ism can recover function and demonstrate normal
reproductive hormone secretion; thus continued
evaluation is required after the initial diagnosis is
made. Within any given family, there may be indi-
viduals with constitutional delay and other rela-
tions with Kallmann syndrome demonstrating the
overlapping nature of conditions causing hypogo-
nadotropic hypogonadism.
Kallmann Syndrome (KS)
KS is the most common genetic form of IHH. KS
in the classic form manifests with an impaired
sense of smell (hyposmia or anosmia) and gonad-
otropin deficiency. However, there is great genetic
heterogeneity, and within a given family, some
patients may have a normal sense of smell with no
reproductive hormone function, while others may
have a normal sense of smell with reproductive
ability. The classic X-linked Kallmann syndrome
(308700 Kallmann syndrome 1; Kal1 at Xp22.3)
is due to impaired migration of GnRH neurons
from the anterior region of the embryonic nose
(the olfactory or cribriform plate) to the normal
location of GnRH neurons in the medial basal
hypothalamus, above the pituitary portal system,
by about 20 weeks of gestation. The mutation of
9 Disorders of Puberty
the KAL1 gene leads to abnormalities in the pro-
duction of anosmin, which is a neural cell adhe-
sion molecule that is responsible for this normal
migration of the involved cells. Autosomal domi-
nant Kallmann syndrome 2 (*147950, KAL2) is
associated with defects of the midline such as
cleft palate, neurosensory hearing loss, and
extremity movements known as synkinesia; it is
due to mutation in the fibroblast growth factor
receptor 1 gene (FGR1 gene). Kallmann syn-
drome 3 (*244200; KAL3) manifests with mid-
line defects such as cleft palate or lip as well as
unilateral renal agenesis; it is due to a mutation in
the G protein-coupled prokineticin receptor-2
gene or its receptor and is thought to be an autoso-
mal dominant condition. The CHARGE syn-
drome (#214800 ICD+CHARGE SYNDROME
consisting of colobomata, heart anomalies, cho-
anal atresia, retardation, genital and ear anoma-
lies) includes IHH and hyposmia and is caused by
mutations in the CHD7 gene and is inherited in an
autosomal dominant pattern; patients with
CHARGE syndrome should be evaluated for
hypogonadotropic hypogonadism, especially if
there is deafness and hypoplasia of the semicircu-
lar canals. An ever-increasing number of genes are
associated with KS and IHH in an oligogenetic
manner indicating that inheritance occurs in a
more complicated manner than in simple
Mendelian patterns; these oligogenic patterns may
explain why several affected members of the same
family may have different clinical characteristics.
Loss-of-function mutations of the KISS1R
previously known as GRP54 (#614837
HYPOGONADOTROPIC HYPOGONADISM 8
WITH OR WITHOUT ANOSMIA; HH8), the G
protein-coupled receptor 54 for kisspeptin, lead to
hypothalamic hypogonadism. Although rare, these
patients have been instrumental in understanding
the kisspeptin–GnRH axis. Loss-of-function
mutations in the GNRH-receptor gene have been
noted for several years (#228300 FERTILE
EUNUCH SYNDROME), but more recently
mutations in the GNRH gene (#614841
HYPOGONADOTROPIC HYPOGONADISM
12 WITH OR WITHOUT ANOSMIA; HH12)
have been discovered and linked to hypothalamic
hypogonadism. Mutations of the DAX gene
Abnormalities of Puberty
(#300200 ICD+ADRENAL HYPOPLASIA,
CONGENITAL; AHC) are associated with hypo-
gonadotropic hypogonadism, adrenal hypoplasia,
glycerol kinase deficiency, and muscular dystro-
phy. Normally, there are beta and alpha subunits
to the FSH and LH molecules, the alpha subunit
being common to all pituitary-glycoprotein
hormones while the beta subunit confirms speci-
ficity of action. Rarely mutations of FSH beta
gene (#229070 FOLLICLE-STIMULATING
HORMONE DEFICIENCY, ISOLATED) or
mutations of the LH beta gene (*152780 lutein-
izing hormone, beta-polypeptide) are reported in
which there is no production of intact FSH or LH
molecules. Without the FSH beta gene, sper-
matogenesis cannot progress while without the
LH beta gene, Leydig cell stimulation will not
occur and the patient may have the phenotype of
the “fertile eunuch syndrome” in which there is
lack of physical evidence of testosterone action
while the seminiferous tubules enlarge and sper-
matozoa can develop.
Other mutations more rarely causing hypotha-
lamic hypogonadism without anosmia include the
steroidogenic factor 1 (SF1) as well as TAC3,
TACR3, CHD7, and NELF. Commercial labora-
tories are now able to probe for mutations in many
of these genes.
Mutations in the LH receptor manifest in a
phenotypic male with micropenis, or ambiguous
genitalia, or even an XY phenotypic female
(#238320 ICD+LEYDIG CELL HYPOPLASIA,
TYPE I); this is discussed in Chap. 8.
Abnormalities of the Central Nervous
System
These conditions are prime examples of why the
diagnosis of the etiology of delayed puberty must
be carefully established; if untreated, many of
these conditions can be fatal.
Central Nervous System Tumors
(Many of these are discussed in Chap. 3)
The secretion of any hypothalamic pituitary
hormone can be affected by tumors of the CNS.
Thus late onset of gonadotropin deficiency, as
opposed to congenital gonadotropin deficiency,
is an ominous sign since the clinical findings may
205
indicate a tumor. If both anterior and posterior
pituitary deficiencies are noted, a central nervous
system tumor should be even more highly
suspected.
To reemphasize, late onset of growth failure
or a cessation of pubertal development that has
already started is of great concern.
Autoimmune or Lymphocytic
Hypophysitis
Autoimmune hypophysitis is rarely reported in
childhood. It may involve lymphocytic infiltra-
tion of the pituitary gland. It presents as a pitu-
itary mass associated with hypopituitarism.
Hypogonadotropic hypogonadism is one possi-
ble outcome.
Craniopharyngiomas are tumors of Rathke’s
pouch originating in the pituitary stalk. Spread to
the suprasellar region or even the sella turcica is
possible. Peak incidence is between 6 and 14
years of age. Patients may be symptomatic with
complaints of headache, visual loss, polyuria,
and polydipsia. Signs on physical exam may be
either short stature or cessation of previously nor-
mal growth, findings of hypothyroidism, and
sexual infantilism. Papilledema or optic atrophy
(not congenital optic dysplasia) might be found
as well. On occasion, slow-developing cranio-
pharyngiomas are diagnosed during evaluation of
other conditions. For instance, pituitary calcifica-
tions may be found on a radiograph taken during
orthodontic evaluation. CT scans will show flecks
of calcium within the tuber cinereum in more
than 80 % of cases. MRI scans before and after
gadolinium will define the shape and size of the
tumor better although it will not show calcifica-
tion without modification. This tumor might be
cystic, and the sella turcica may be eroded by
expansion of the tumor. Transsphenoidal micro-
surgery can be used for extirpation if the tumor
is intracellular. Larger tumors that cannot be
completely removed by this method may be
treated with craniotomy and radiation as the
tumors are radiosensitive. However, late effects of
radiation are possible with CNS irradiation, such
as secondary tumors of local tissue.
Other tumors of the central nervous system
reside outside of the sella turcica such as
206
germinomas of the pineal, which by their mass
may lead to HH; since they secrete hCG which
acts as LH, they may cause peripheral precocious
puberty in males but not females. Astrocytomas
and gliomas (which may or may not be associ-
ated with neurofibromatosis) are other CNS
tumors that may cause HH.
Intracellular adenomas are rare, but they may
impair pituitary function. Most do not secrete
hormones in childhood, but prolactinomas, which
are rare in childhood, will manifest galactorrhea
as a diagnostic characteristic of this prolactin–
secreting tumor. Hyperprolactinemia may delay
puberty or cause amenorrhea.
Histiocytosis X may be associated with diabe-
tes insipidus, but other hypothalamic hormones
may also be deficient and HH can occur.
Granulomas of tuberculosis sarcoidosis, postin-
fectious inflammation, or vascular lesions of the
central nervous system can impair hypothalamic
pituitary function. CNS trauma due to accidents,
child abuse, or surgery for tumors near the area
can also affect hypothalamic pituitary gonadal
function. Hydrocephalus can cause GnRH defi-
ciency as may any other etiology of increased
intracranial pressure, such as a subarachnoid cyst.
Congenital Defects of the CNS
(See Chap. 3)
Congenital defects of the CNS are characteristi-
cally found in the neonatal period or soon there-
after. They may be associated with single
hypothalamic–pituitary defects or more com-
monly multiple deficiencies.
Septo-optic Dysplasia
Septo-optic dysplasia (SOD), or the appearance
of small, pale optic discs, is associated with
impaired vision ranging from mild defects to
blindness and is often found with horizontal or
pendular (to and fro) nystagmus. Optic hypopla-
sia is to be differentiated from optic atrophy
which may be an ominous sign of a tumor causing
the degeneration of a previously normally formed
optic disc. About 50 % of patients with optic dys-
plasia have absence of the septum pellucidum
and a diagnosis of SOD. SOD may be the result
of a mutation in the homeobox gene HESX
9 Disorders of Puberty
(#1182238 septo-optic dysplasia). SOD is com-
patible with normal pituitary function in some
patients, but deficiencies should be considered in
all. SOD can also cause CPP.
Other midline defects of the central nervous
system associated with pituitary deficiencies
range from a simple cleft palate (6 % have growth
hormone deficiency) up to holoprosencephaly.
Hypogonadotropic Hypogonadism
Following Irradiation
Oncofertility is a new field growing out of the
increasing number of cancer survivors with
infertility following successful treatment of their
cancer. Radiation treatment may cause growth
hormone deficiency or gonadotropin deficiency
but also, when used to treat a central nervous sys-
tem tumor, may lead to a combination of preco-
cious puberty and growth hormone deficiency.
The growth hormone deficiency will not be dem-
onstrated by extremely slow growth if the puberty
is progressing rapidly as the sex steroid secretion
stimulates growth masking the GH deficiency
(read below).
Idiopathic Hypopituitarism
The most frequent pituitary hormone defect with
hypothalamic deficiency is growth hormone defi-
ciency, but gonadotropin deficiency follows in
prevalence. If both growth hormone and gonado-
tropin function are deficient, accurate diagnosis
may be difficult. Growth hormone deficiency
itself can delay puberty which, of course, would
also be found in gonadotropin deficiency. While
hypopituitarism is usually sporadic, familial
hypopituitarism may be found in X-linked
(*3120000 panhypopituitarism) and autosomal
recessive pattern (#262600 pituitary dwarfism
III) and may be found with diabetes insipidus
(241540 hypopituitarism, congenital, with cen-
tral diabetes insipidus). Mutation in the pituitary
paired-like homeodomain transcription factor
(PROP1 #262600 PITUITARY HORMONE
DEFICIENCY, COMBINED, 2; CPHD2) causes
hypopituitarism with absence of PRL, LH, FSH,
GH, or TSH. However, patients with mutations of
another related transcription factor
POU1 (#613038 PITUITARY HORMONE
Abnormalities of Puberty
DEFICIENCY, COMBINED, 1; CPHD1) lack
GH, prolactin, and TSH but retain ACTH and
gonadotropin function (ACTH deficiency may
develop later however).
Boys with congenital hypopituitarism might
present at first with microphallus, a normal-
appearing penis which, however, is less than
2 cm (2.5 cm in some sources) in stretched
length at birth. Associated growth hormone or
ACTH deficiencies might occur and lead to
hypoglycemic seizures. Thus, hypoglycemia and
microphallus in a newborn boy should cause
consideration of congenital hypopituitarism,
especially if pendular nystagmus occurs in addi-
tion as an indication of SOD. Microphallus can
be treated with low-dose testosterone therapy
(25 mg intramuscularly of testosterone enan-
thate every month for three doses) to enlarge the
penis without causing undue advancement of the
bone age. Sex reversal should not be considered
in boys with congenital hypopituitarism and
microphallus since the penis will grow with tes-
tosterone therapy and the outcome is good. The
clinician must be aware that, later in life, obese
boys are often referred for microphallus when, in
fact, their penis is normal in width as well as
length but is buried in fat; in these cases, the width
of the penis should be a good indication of whether
the penis is normal even if it is mostly hidden.
Females with congenital hypopituitarism have
normal genitalia at birth but like boys may have
pendular nystagmus and hypoglycemic seizures.
Syndromes Associated
with Hypogonadotropic Hypogonadism
Prader–Willi syndrome (#176270) includes fetal
and infantile hypotonia, short stature, obesity,
lack of satiety, as well as almond-shaped eyes
and characteristic facies. Hands and feet are
small (acromicia). The children are developmen-
tally delayed, and microphallus and undescended
testes in boys and delayed menarche in girls are
often found. While this is usually associated with
short stature, some children are normal or tall in
childhood. The etiology of this condition is a
microdeletion of 15q11 in about 70 % of patients
which can be confirmed with fluorescent in situ
hybridization (FISH); maternal disomy of the
207
SNRPN gene may be found in other affected
patients (see growth Chap. 5 for more).
Laurence–Moon syndrome (*245800
Laurence–Moon) and Bardet–Biedl (#209900
Bardet–Biedl syndrome) syndrome share some
features and were considered separate entities
but are now combined into the Bardet–Biedl
syndrome with an autosomal recessive pattern
of inheritance. Obesity, short stature, develop-
mental delay, and retinitis pigmentosum can be
associated with hypogonadotropic hypogonad-
ism or hypergonadotropic hypogonadism as
well. Spastic paraplegia, polydactyly, and other
features noted in Chap. 5 are found.
Weight Loss and Chronic Disease
Weight loss due to chronic disease, malnutrition,
and even dieting to less than 80 % of ideal weight
can cause hypogonadotropic hypogonadism. A host
of diseases affecting nutrition including poorly
treated diabetes mellitus, gastrointestinal disorders
causing malabsorption or celiac disease, connec-
tive tissue disorders, among others can cause
delayed puberty. Anorexia nervosa is a psychiatric
disorder characterized by a distorted body image,
obsessive fear of obesity, and food avoidance that
can cause severe self-induced weight loss, primary
or secondary amenorrhea in affected females,
widespread endocrine disorders, and even death as
this condition has a higher mortality rate than any
other psychiatric diagnosis (mortality rate is approx-
imately 15 %). Specific diagnostic details are pro-
vided in the Diagnostic and Statistical Manual of
Mental Disorders, fifth edition [DSM-V], criteria
of the American Psychiatric Association. The onset
of puberty may be delayed in the most seriously
affected younger subjects. Osteopenia or osteoporo-
sis is a consequence of estrogen deficiency. Weight
loss causes reversion of gonadotropin secretion pat-
terns to prepubertal low-amplitude pulsatile secre-
tion and many months may pass before hormonal
function is regained with weight gain. Even after
weight gain, however, amenorrhea may persist, pos-
sibly related to the psychiatric disease itself.
Bulimia nervosa is a syndrome of binge eating
and purging. Evidence of this condition, besides
purging behaviors, includes frequent trips to the
bathroom after meals, evidence of vomiting in
208
the presence of laxative, or diuretic packaging in
personal spaces like under beds. Affected patients
often have severe, rigid exercise episodes.
Vomiting may lead to unusual swelling of the
cheeks and jaw area due to parotid irritation and
there may be calluses on the palms (Russell sign)
or knuckles as evidence of self-induced vomit-
ing. Teeth may be stained from the effects of the
acid in the vomitus. Growth may be impaired and
bone density may be decreased. Like anorexia
nervosa this syndrome can be fatal.
The female athlete triad incorporates the fea-
tures of decreased bone density and menstrual
abnormalities with energy intake out of balance
with energy expenditure; recent recommenda-
tions suggest referring instead to “Relative
Energy Deficiency in Sport” (RED-S) which
encompasses the condition in boys as well and
directs attention to the basic etiology. These girls
are characteristically thin; however, athletic
amenorrhea may also occur in heavier girls who
exercise excessively when athletic amenorrhea is
found in swimmers or ice skaters. Decreased
activity in these heavier girls allows the resump-
tion of normal pubertal development and menses
without necessarily an increase in weight.
Hypothyroidism will inhibit the onset of
puberty and menses or, if it occurs after the onset
of puberty, will stop the progression of puberty.
Primary hypothyroidism may be associated with
galactorrhea due to elevated prolactin as well as
elevated TSH, both due to increased TRF secre-
tion. Sometimes, severe primary hypothyroidism
is associated with some features of precocious
puberty in the Van Wyk–Grumbach syndrome
due to stimulation of the gonads by extremely
high TSH values which allows cross-reaction
with gonadotropin receptors.
Hypergonadotropic Hypogonadism
(Fig. 9.2c)
Hypergonadotropic hypogonadism is due to
primary gonadal failure. Serum gonadotropins
are elevated because of lack of feedback inhibi-
tion from steroid or inhibin secretion from the
abnormal gonads. Most patients have a karyo-
type abnormality or a history of prior chemo-
therapy or radiotherapy. The congenital defects
9 Disorders of Puberty
causing disorders of sexual differentiation are
also discussed in Chap. 6.
Disorders of the Ovaries
Turner Syndrome
The Turner syndrome of gonadal dysgenesis is
the most common form of primary gonadal fail-
ure in a female phenotype; the prevalence is
between 1:2,000 and 1:5,000 live phenotypic
female births. Turner syndrome is caused by a
loss or abnormality of one X chromosome or a
portion of it. It is estimated that the 45X karyo-
type occurs in 1 of 15 spontaneous abortions and
that 99.9 % of 45X fetuses do not survive longer
than 28 weeks of gestation. Classic cases of
Turner syndrome have a 45X karyotype. There is
no Barr body found on buccal smear after Giemsa
staining (this test has been replaced by karyotype
determination; Barr body determination should
no longer be used for diagnosis because of lack
of reliability). Physical features of Turner syn-
drome include short stature (average adult height
is 143 cm), streak gonads (a normal complement
of ova is present at birth, but accelerated oocyte
apoptosis occurs in the postnatal period), sexual
infantilism, and a female phenotype. Other find-
ings include down-turned edges of the mouth
(leading to a “fish-mouth appearance”) with ret-
rognathia and high-arched palate, ptosis and epi-
canthal folds, broad shield-like chest, the
appearance of wide-spaced and hypoplastic
poorly pigmented nipples, short webbed neck
with low hairline, short fourth metacarpals,
Madelung abnormality of the wrist (radial short-
ening and bowing with dorsal subluxation of the
distal ulna and limited rotation), wide-carrying
angle of the arms (cubitus valgus), knock-knee
appearance (genu valgum), multiple nevi, spoon-
shaped (hyperconvex) hypoplastic nails, and
lymphedema of the extremities, particularly in
infancy. At birth, many patients have lymph-
edema of the extremities and loose skin folds
around the neck, which later transform into the
classic webbed neck and also account for the
low-set ears; this newborn appearance of new-
born Turner syndrome is the Bonnevie–Ullrich
syndrome. A tendency exists toward keloid
Abnormalities of Puberty
formation, which can complicate attempts to
correct the webbed neck surgically. A girl with
Turner syndrome may not manifest all the physi-
cal findings and may appear as an average short
girl, so a high index of suspicion in any short girl
without a diagnosis is indicated; rarely girls with
taller familial heights will not even be short and
hypogonadism will be the indicator. Turner syn-
drome is considered a gonadal disorder of sexual
differentiation (DSD).
The SHOX gene (*312865 SHORT STATURE
HOMEOBOX; SHOX at Xpter-p22.32) on the
short arm of the X chromosome near the pseudo-
autosomal region is absent on the aberrant or
absent X chromosome; this gene is related to the
short stature of Turner syndrome and gives rise to
the Madelung deformity of the wrist; absence of
the SHOX gene is a cause of short stature in other
children without Turner syndrome (see Chap. 5).
The genes determining ovarian development are
also located on the X chromosome. In addition to
the abnormalities of the wrist, girls with Turner
syndrome are predisposed toward kyphoscoliosis
and osteopenia.
Patients with the 45X karyotype usually have
normal intelligence but may perform poorly on
tests of visual–spatial perception and demonstrate
other defects in memory and executive function;
other karyotypes may be associated with defects in
intelligence. Frequent episodes of otitis media in
childhood may lead to conductive hearing loss,
although sensorineural hearing loss is possible, as
well. Abnormalities of the shape of the kidneys
(e.g., horseshoe kidneys or duplications) may lead
to frequent urinary tract infections in those with
abnormal kidney function, so ultrasound evalua-
tion of kidneys is indicated. Left-sided heart anom-
alies (such as coarctation of the aorta often first
noted due to hypertension soon after birth or bicus-
pid aortic valve) are common. Affected girls
require cardiac evaluation for heart defects and
appropriate follow-up care. Even normotensive
patients require regular screening for aortic dilation
every 5–10 years as adults. Increased incidence of
Hashimoto thyroiditis, celiac disease, type 1 diabe-
tes, and insulin insensitivity are other features.
Variants of Turner syndrome occur with
abnormal X chromosome or mosaicism (e.g.,
209
XO/XX). Such patients may have some gonadal
function and a more typical female phenotype.
Other variants of Turner syndrome include
patients with mosaicism involving the Y chromo-
some, such as XO/XY. A FISH probe for Y chro-
mosome material should be performed if this
situation is suspected. These patients may have
dysgenetic testes rather than streak gonads and
are at risk for the development of gonadoblastoma
or malignant degeneration of the gonad, so gonad-
ectomy is indicated. Gonadoblastomas may
secrete estrogen falsely suggesting residual ovar-
ian function. Phenotype may be infantile female
to ambiguous genitalia or phenotypic male.
Growth hormone (GH) treatment is approved
for Turner syndrome; treatment increases stature in
Turner syndrome above the average adult height of
143 cm often to 152 cm or more. The age to initiate
estrogen replacement is controversial; if it is
offered too early and in high dosage, it will
decrease the adult height, while late start may
intensify psychological problems. Recent evidence
shows that low doses of estrogen offered at the
average age of puberty will not affect height when
used in conjunction with GH (see growth Chap. 5).
Other Forms of Primary Ovarian Failure
Ovarian failure can occur with chemotherapy for
malignant disease. If the ovaries are not shielded
or surgically moved out of the path of a beam of
abdominal/pelvic radiation therapy, failure may
occur.
FSH receptor mutations (#233300 OVARIAN
DYSGENESIS 1; ODG1) can occur in a pheno-
typically female individual who does not develop
secondary sexual characteristics at puberty and
does not menstruate. There are bilateral “streak
gonads,” consisting of fibrous tissue and variable
amounts of wavy ovarian stroma. Affected
females have a uterus and fallopian tubes and
external genitalia are infantile female.
Galactosemia (*606999 GALACTOSE-1-
PHOSPHATE URIDYLYLTRANSFERASE;
GALT) presents after neonatal galactose inges-
tion with jaundice, hepatosplenomegaly, hepato-
cellular insufficiency, hypoglycemia, renal
tubular dysfunction, muscle hypotonia, sepsis,
tendency toward E. coli sepsis, growth failure,
210
feeding dysfunction, and cataract. Long-term
complications include mental retardation, verbal
dyspraxia, motor abnormalities, and hypergonad-
otropic hypogonadism in females only.
Galactosemia screening is performed at birth in
most countries.
Premature menopause has also been described in
otherwise healthy girls owing to the presence of anti-
ovarian antibodies. Patients with Addison disease
may have autoimmune oophoritis as well as adrenal
failure. Polyglandular autoimmune syndromes 1
(#240300 AUTOIMMUNE POLYENDOCRINE
SYNDROME, TYPE I; APS1) and 2 (%269200
AUTOIMMUNE POLYENDOCRINE
SYNDROME, TYPE II; APS2) combine various
auto endocrine organ failure and premature ovarian
failure can occur as well.
A sex steroid biosynthetic defect due to 17-alpha-
hydroxylase deficiency (P450c17) (#202110
ADRENAL HYPERPLASIA, CONGENITAL,
DUE TO 17-ALPHA-HYDROXYLASE
DEFICIENCY) is manifested as sexual infantilism
and primary amenorrhea in a phenotypic female
(regardless of genotype since testes and ovaries can-
not produce sex steroids) with hypertension and
hypokalemic alkalosis (see Chap. 8 on sexual dif-
ferentiation). Carriers of the FMR1 gene responsi-
ble for fragile X syndrome are susceptible to
premature ovarian failure.
Infectious Oophoritis
Infectious oophoritis may be caused by gonor-
rhea or chlamydia. This is an ascending infection
from the lower reproductive tract.
Primary Amenorrhea Associated
with Normal Secondary Sexual
Development
A structural anomaly of the uterus or vagina
interfering with the onset of menses in spite of
normal endocrine milieu will present with pri-
mary amenorrhea in the presence of normal
breast and pubic hair development. A transverse
vaginal septum, an imperforate hymen, or the
Rokitansky–Kuster–Hauser syndrome (%277000
MAYER–ROKITANSKY–KUSTER–HAUSER
SYNDROME) of congenital absence of the vagina
combined with abnormal development of the uterus
9 Disorders of Puberty
or absence of the uterine cervix in the presence of a
functional uterus may present in this way.
46,XY and XX DSD
46,XY disorder of sexual development (DSD),
previously called male pseudohermaphroditism,
is an alternative cause of primary amenorrhea if a
patient has achieved thelarche. The syndrome of
complete androgen resistance leads to female
external genitalia and phenotype without axillary
or pubic hair development in the presence of
pubertal breast development (androgen resis-
tance or the syndrome of testicular feminization;
see Chap. 8 and below).
XX and XY gonadal dysgenesis may be spo-
radic or familial. Stature is normal, and pheno-
type is sexually infantile female in the XX form
(*233400 GONADAL DYSGENESIS, XX
TYPE, WITH DEAFNESS) or may be ambigu-
ous in the XY form (*306100 GONADAL
DYSGENESIS, XY FEMALE TYPE; GDXY).
A FISH probe for Y chromosome material
should be performed if this situation is sus-
pected. Patients with an XY karyotype should
undergo gonadectomy because of potential neo-
plastic degeneration of the dysgenetic testes
(see Chap. 8).
Disorders of the Testes
Klinefelter Syndrome
Klinefelter syndrome, or seminiferous tubular
dysgenesis, is the most common cause of testicular
failure, with a prevalence of 1 in 500–1,000 males.
Because of variable Leydig cell function, serum
testosterone levels in the adult patients vary from
low to close to normal. Therefore, the age of onset
of puberty may be normal, but secondary sexual
changes do not progress to the adult stage. In
puberty or in the adult, testes are firm and grow no
longer than 3.5 cm, with histologic changes of
hyalinization and fibrosis of the seminiferous
tubules progressing with pubertal development.
Seminiferous tubular function is invariably
affected, and impaired spermatogenesis is the rule;
microsurgery may allow the removal of a few
remaining normal spermatozoa to allow assisted
fertility in adults.
Abnormalities of Puberty
Even before the onset of puberty, testes are
small and the upper-to-lower segment ratio is
decreased for age, although arm span is not
greater than height as is found in patients with
eunuchoid proportions, and these body propor-
tions persist into adulthood. Stature is often taller
than average in Klinefelter syndrome.
Serum gonadotropin concentrations may be
measured at the upper limit of the normal range
or slightly above this limit during childhood.
Serum LH and especially FSH are elevated to
castrate levels after pubertal age due to decreased
testosterone and/or inhibin production from the
affected testes. Gynecomastia is common, and
breast cancer may develop (a 20-fold increased
risk over a nonaffected male). Germ cell tumors
of the mediastinum also are more likely in
affected males.
Some patients come to evaluation because of
personality disorders and learning disability in
the prepubertal age range. A verbal IQ dispropor-
tionately lower than performance IQ and expres-
sive developmental defects in speech and
language are found. A tendency toward explosive
outbursts and difficulty in controlling anger are
seen, even though the individuals otherwise tend
to be passive. Thus the diagnosis should always
be entertained in a child with any of these person-
ality or learning problems; since karyotype deter-
mination is often invoked in the diagnosis of
learning difficulties, the diagnosis of Klinefelter
syndrome is occurring at younger and younger
ages. Further, the use of amniocentesis for other
indications allows prenatal diagnosis of
Klinefelter syndrome as well.
Klinefelter syndrome results from nondisjunc-
tion of the sex chromosomes. It is more common
with advanced maternal age. The karyotype is clas-
sically 47,XXY; we do not recommend obtaining a
buccal smear, although it would be positive in con-
trast to a 46,XY male in which a buccal smear is
negative. Variants of Klinefelter syndrome are
reported, with mosaicism such as in XX/XXY,
XXYY, XXXY, and XXXXY karyotypes. Other
patients are reported with features similar to those
of Klinefelter syndrome but with an XX karyotype
(XX males); in these cases, transfer of the SRY
from the Y to the X chromosome is the cause
(see Chap. 8 on sexual differentiation).
211
46,XY DSD
LH receptor mutation leads to lack of testosterone
production. Two types are noted. Type I (#238320
LEYDIG CELL HYPOPLASIA, TYPE I and II),
complete inactivation of LHCGR, demonstrates
complete 46,XY DSD (formerly male pseudoher-
maphroditism), low testosterone and high LH lev-
els, total lack of responsiveness to LH/CG challenge,
phenotype of an immature female with lack of
breast development, and absent development of
secondary male sex characteristics. Type II, due to
partial inactivation of the gene, leads to patients in a
spectrum from micropenis to severe hypospadias.
Females with inactivating mutations in the LHCGR
gene display defective follicular development and
ovulation, amenorrhea, and infertility.
Complete androgen insensitivity syndrome
(#300068 ANDROGEN INSENSITIVITY
SYNDROME; AIS) presents as a 46,XY pheno-
typic female with amenorrhea and absence of
pubic and axillary hair. This condition follows an
X-linked inheritance pattern. Partial androgen
insensitivity syndrome (#312300 ANDROGEN
INSENSITIVITY, PARTIAL; PAIS) manifests as
46,XY DSD with 46,XY karyotype, ambiguous
genitalia with hypospadias, hypogonadism,
gynecomastia, and infertility in an X-linked
recessive pattern.
Noonan syndrome (#163950 NOONAN
SYNDROME 1; NS1 12q24.1) (previously termed
pseudo-Turner syndrome or male Turner syn-
drome) is a dominantly inherited condition which
has no biological relationship to Turner syndrome
in spite of sharing some physical features with
Turner syndrome (such as webbed neck, ptosis,
short stature, wide-carrying angle, and lymph-
edema), as well as features different from those of
Turner syndrome (such as normal karyotype, trian-
gle-shaped face, pectus excavatum, right-sided
heart disease in contrast to left-sided heart disease
in Turner syndrome, and, more commonly, devel-
opmental delay). Affected boys may have unde-
scended, often impaired, testes. Growth hormone is
approved for treatment of short stature in this con-
dition (see growth Chap. 5). Genetic diagnosis is
available with mutations at PTN11 mutations on
12q24.1 found in some patients. Some reports link
this mutation with a decreased response to GH but
recent reports question this finding.
212
Radiation and Chemotherapy Damage
Survival is now possible in a wide range of child-
hood cancers. However, radiation therapy to the
area of the gonads or chemotherapy may dimin-
ish or limit gonadal function. Elevated gonado-
tropins suggest the diagnosis of gonadal failure,
and this may be noted only after a period of fol-
low-up. Methods to preserve fertility in children
treated for cancer are under investigation in the
field of oncofertility and some show promise for
future fertility. Recent concepts consider quality
of remaining germ cells rather than quantity.
Spermatogonia have been recovered from radia-
tion- or chemotherapy-damaged testes or ovaries.
Anorchia and Cryptorchidism
Cryptorchidism refers to unilateral or bilateral
undescended testes and must be differentiated
from anorchia, which is the complete absence of
both testes in a phenontypic male. Anorchia is
also known as the testicular regression syndrome.
While the testes develop in the abdominal cavity,
by month 7 of gestation they usually descend into
the scrotum. The peptide hormone insulin-like 3
(INSL3) is expressed at high levels in fetal Leydig
cells and interacts with the relaxin family peptide
receptor 2 (RXFP2) to promote the testicular
descent. INSL3 also plays a role in adult fertility.
More than 97 % of term and 79 % of premature
infant boys have descent of the testes. By age 9
months, 99.2 % of testes are descended, with little
progress thereafter. Thus by age 9–12 months,
most testes that will descend spontaneously will
have done so. Lack of descent is associated with a
tenfold increase in neoplasia, and the inability to
examine undescended testes for neoplastic
changes makes the situation worrisome. Thus, by
age 1 year, all undescended testes should undergo
orchiopexy or, if abnormal, orchiectomy. Although
an increase in the incidence of carcinoma is noted
if the testes are left in their undescended position,
there is evidence that undescended testes have an
intrinsic problem, as one-third of carcinomas
develop in cryptorchid testes after orchiopexy, and
20 % of cryptorchid patients have carcinoma in
the contralateral descended testes. Unilateral
anorchia may lead to compensatory hypertrophy
of the contralateral testes.
9 Disorders of Puberty
It is important to differentiate bilateral crypt-
orchidism from anorchia. In anorchia, the testes
were present during fetal life to allow the devel-
opment of a normal male phenotype including a
normal penis and normal Wolffian duct struc-
tures, but the testes atrophied, possibly because
of vascular insufficiency subsequent to genital
development leaving the scrotum small and
“uninhibited.” A sequence of evaluations may
determine whether bilateral cryptorchidism or
anorchia is present. Ultrasound examination in
experienced hands can reveal the presence of the
testes, but lack of visualization may not be defini-
tive proof of absence of the testes. Elevation of
gonadotropins above the normal for age indicates
lack of functioning of testicular tissue. Detection
of inhibin or AMF indicates the presence of tes-
ticular tissue and can help to eliminate the diag-
nosis of anorchia; inhibin B values more than 3
standard deviations below the mean are compati-
ble with anorchia.
Stimulation tests have been evaluated for use
in cryptorchidism in Prader–Willi syndrome; the
protocol may be repeated in a patient with bilat-
eral undescended testes without Prader–Willi
syndrome. The administration of a single dose of
1,500 IU i.m. hCG is administered in one diag-
nostic schema for the Prader–Willi syndrome,
and baseline and 72 h afterwards serum levels of
LH, FSH, testosterone, inhibin B, and AMH are
measured. The result is normal when the maxi-
mum testosterone level after 72 h is 2–20 times
higher than baseline in infants aged 3–12 months
and 5–10 times higher, between 2.5 and
9.0 nmol/L, in infants aged 1–4 years. If no
increase in testosterone can be induced with one
to six injections of hCG, the patient may have no
Leydig cells and therefore has anorchia.
There are studies of longer-term administra-
tion of hCG or GnRH to foster descent of testes
in boys with variable results. Administration of
an hCG dose, 250 IU for infants aged 3–12
months of age and 500 IU IM for infants aged
1–4 years, twice a week for 6 weeks led to a
descent of testes in 62 % who had a positive stim-
ulation test and 23 % of the testes reached a sta-
ble scrotal position. GnRH or GnRH agonist has
been used to promote testicular descent in some
Abnormalities of Puberty
studies. It has been suggested that hCG and
GnRH caused descent of undescended testes only
in cases of retractable or “yo-yo” testes, which
travel up and down in the canal at various times
and there is no situation in which surgery might
not be indicated in the first place.
If no indication of testicular function is found
and then if no descent of the testes can be brought
about, the question of exploratory surgery arises.
Exploratory surgery, which may lead either to
orchiopexy if normal testicular tissue is found or
to a diagnosis of anorchia if no testes are found,
may be indicated. However, a recent study stated
that there is a high degree of concordance of
endocrine testing indicating anorchia with surgi-
cal findings and suggested that exploratory sur-
gery may not be necessary if the endocrine tests
all point to anorchia. If there is evidence of tes-
ticular tissue by endocrine testing or by descent
after hCG stimulation or if the cryptorchidism is
unilateral, orchiopexy is indicated by age 1 year;
further testicular damage will occur if the testes
are left in their warmer, intraabdominal location.
The findings of abnormal development of gen-
italia in boys, risk of low sperm count, and sus-
ceptibility to testicular cancer as adults is
postulated to be related to fetal exposure to toxins
which are suspected to cause prenatal disruption
of normal testis differentiation, the testicular dys-
genesis syndrome (TDS).
A higher rate of hypospadias in Danish new-
borns and smaller testes with lower serum inhibin
B compared with Finnish infants suggested that
environmental agents played a role in the differ-
ence. This and a high frequency of reproductive
problems among adult Danish men, including
impaired semen quality, testicular cancer, and
increased rate of infantile testicular cancer in a
pattern that is attributed to environmental disrup-
tors is described in the TDS. There may be a
genetic component to susceptibility to the TDS
based upon GWAS analysis indicating a gene X
environment basis for the disorder.
Orchitis
Orchitis denotes an inflammation causing swell-
ing of one or both of the testicles which may be
caused by an infection from many different types
213
of bacteria and viruses. The most common cause
of orchitis has been a viral infection with the
mumps virus. It most often occurs in boys after
puberty. Orchitis usually develops 4–6 days after
the mumps begins. Because of childhood vacci-
nations, mumps is now rare in the USA. Orchitis
may also occur because of infections with sexu-
ally transmitted diseases including gonorrhea and
Chlamydia.
Differential Diagnosis of Delayed
Puberty (Fig. 9.3)
If the onset of puberty is delayed according to
the guidelines above, determination as to whether
the patient has primary gonadal disease and
hypergonadotropic hypogonadism or hypotha-
lamic–pituitary disease and hypogonadotropic
hypogonadism is the first step (Fig. 9.2). If the
gonadotropins are high and there is no contribu-
tory history such as surgery, radio or chemother-
apy, or autoimmune disease, consideration
should be given toward a diagnosis that might be
confirmed by karyotype, such as Turner syn-
drome or Klinefelter syndrome or their variants,
even if the physical examination does clearly
suggest these possibilities.
Differentiation between temporary constitu-
tional delay in puberty and hypogonadotropic
hypogonadism is difficult as both conditions have
low serum gonadotropin values. First consider-
ation is always to rule out a CNS tumor or other
serious conditions; complete neurologic evalua-
tion is performed and MRI considered if no other
diagnosis or chronic disease is established. If
midline abnormalities are present or anosmia is
present, the diagnosis is likely to be hypogonado-
tropic hypogonadism. If a compelling family
history is found of delayed but ultimately sponta-
neous puberty (e.g., the father shaved later than
his peers or mother’s menarche was delayed) and
there are no historical or physical findings of con-
cern, the diagnosis is likely to be constitutional
delay in puberty. The presence of increased
serum gonadotropin values into the pubertal
range on third-generation assays, a pubertal
response of LH after GnRH agonist, or increasing
a.m. serum testosterone values above 20 ng/dL
(a morning serum testosterone concentration
214 9 Disorders of Puberty

a Serum gonadotropins elevated

Yes Low

Karyotype Height and growth pattern

Abnormal Normal
Short for chronological Normal until Late-onset growth failure
age, but appropriate absence of
height for bone age growth spurt ? Signs of increased intracranial
pressure, ? Vision abnormalities,
Sense of smell ? Diabetes insipidus
Anosmia or No Yes
Normal hyposmia
Cranial MRI
Abnormal
Normal

47XXY-Klinefelter Primary testicular Constitutional Isolated Kallmann Consider CNS tumor

syndrome, 45XO- failure delay in growth gonadotropin syndrome malnutrition, chronic
Turner syndrome, Primary ovarian and puberty deficiency disease, Continued
Other failure hypothyroidism, surveillance
celiac disease

b Karyotype

Normal 46XX

Anatomic defect
of genital tract

Yes No
46XY 45XO or variant
Cranial MRI

Abnormal Normal

Syndrome of 45XO-Turner syndrome, Define defect, e.g., Cerebral Functional abnormality of

androgen or other variant (rare imperforate hymen neoplasm pulsatile LH release
resistance presentation in view of
normal secondary sexual
development, however)

Fig. 9.3 (a) Evaluation of absence of secondary sexual Cuttler L. Normal pubertal development. In: Rudolph CD,
development among boys at 14 years and girls at 13 years. Rudolph AM, eds. Rudolph’s Pediatrics. New York:
(b) Evaluation of primary amenorrhea with normal sec- McGraw-Hill, 2002:2093–2105, with permission)
ondary sexual development (revised from Styne DM,

over 20 ng/dL (0.7 mmol/L) indicates the likeli-
hood of pubertal development within 12 months)
or an inhibin B value over 111 pg/mL (in an alter-
native assay and study, the cutoff would be over
35 pg/mL) suggest that secondary sexual devel-
opment will occur. A rise in nighttime peaks of
gonadotropins is helpful but cumbersome to
obtain.
Other strategies to differentiate CDG from HH
have been attempted: for example, in some reports
an increase in adrenal androgens and the appear-
ance of pubic hair without signs of gonadarche are
reported at the usual age of puberty in hypogonad-
otropic hypogonadism, while a delay occurs in the
increase in adrenal androgens along with a delay
in the appearance of all signs of secondary sexual
development in constitutional delay in puberty.
Unfortunately, watchful waiting remains the main
method of diagnosing the etiology of delayed
puberty: if a patient has not gone through the
changes of puberty spontaneously by age 18–19
years, it is unlikely that he or she will do so.
The differential diagnosis of primary amenor-
rhea with normal secondary sexual development
Abnormalities of Puberty
may encompass the realm of chromosome anom-
alies, anatomic defects, or endocrine defects
noted in this chapter. Historical and physical fea-
tures may point the way to possible diagnosis;
Fig. 9.3 demonstrates the reasoning that may be
used, based on the results of a karyotype determi-
nation after initial evaluation is complete.
Treatment of Delayed Puberty
While psychological effects are caused by
delayed puberty due to an immature appearance,
short stature appears to affect subjects more. As a
general rule, boys are more distressed than girls.
Psychological status should be investigated and
support offered if necessary.
Sex steroid administration is used to promote
pubertal development in hypogonadotropic hypo-
gonadism and also is useful temporarily in
selected cases of constitutional delay. If the dif-
ference between the two cannot be established, 3
months of low-dose sex steroid therapy can be
used in patients feeling the pressure of an imma-
ture appearance who are not comforted by the
thought of “waiting for nature to take its course.”
The goal is to cause some progression of second-
ary sexual development without advancing bone
age and decreasing adult height.
Individuals with hypogonadotropic hypogo-
nadism have a risk of decreased bone density as
adults. Since most teenagers do not get recom-
mended doses of calcium or vitamin D, encour-
aging adequate replacement is always wise.
While genetics affects adult bone density signifi-
cantly, administration of calcium and vitamin D
according to daily recommendation and sex ste-
roids when appropriate may allow a closer
approximation of the normal curve of bone den-
sity with age.
After age 14 years (the upper age at onset of
normal pubertal development), boys with HH
may be given 50 mg of testosterone enanthate
intramuscularly every month for 3 months.
Testosterone may be administered by skin
patches or by the daily use of gel (however nei-
ther approved by the FDA for those under 16
years) if the patient wishes to avoid injections.
Since testosterone enanthate lasts for a month,
daily treatment lowers the risk of long-term
215
complications if an overdose occurs. The gel
must not touch other children in the house
directly or by clothes or towels or they also may
become virilized. No appropriate oral prepara-
tion of testosterone is available or safe, as oral
methyl testosterone may cause liver damage.
If no sign of spontaneous puberty occurs in the
3 months after the treatment ceases, another
course of testosterone can be offered after the
interval. Patients with known hypogonadotropic
hypogonadism will have to receive testosterone
therapy continuously in increasing doses until
the final dose of 200–400 mg/month is reached
over a 6–12-month period. Lower doses may be
given every 2 weeks rather than larger doses
every 3–4 weeks to minimize psychological
effects of the waxing and waning testosterone
concentrations as higher doses are reached.
Some men may require hCG injections in addi-
tion to testosterone to promote pubic hair devel-
opment and to achieve a more normal adult
appearance. Investigation into the use of LH and
FSH rather than androgen replacement for boys
is under investigation as a more physiologic
manner of promoting maturation of the testes
than sex steroid replacement. Replacement with
DHEA is a method sometimes used to increase
pubic hair development.
Patients with GH deficiency who have been
treated with GH regularly since an early age usu-
ally can receive the sex steroid treatment regimen
described earlier. If they remain quite short or
have not been treated long before the teenage
years, testosterone therapy may be withheld for a
while or started at a lower dosage to ensure that
maximal growth is reached before epiphyseal
fusion eliminates the ability to respond to GH.
While investigators have used GnRH analogue to
delay the progression or onset of puberty to allow
increased growth on GH as an experimental
therapy, efficacy is not supported.
Aromatase inhibitors inhibit the conversion of
androgens to estrogens, and since it is estrogen
that advances bone age and ultimately causes ces-
sation of growth, this was found to increase adult
height. Thus, letrozole and anastrozole have been
successfully used in boys with constitutional
delay to allow achievement of a taller adult height.
216
Testes may become much larger than typical and
plasma testosterone rises substantially during
therapy. Side effects are reportedly rare but may
include abnormalities in the shape of vertebrae.
Theoretically adult bone density could be
decreased with the use of aromatase inhibitors,
but there is no proof of this concern at present.
This is not an FDA-approved therapy and must be
considered experimental and is only used in con-
trolled studies at present.
Girls with delayed puberty may be treated
with low-dose estrogen therapy at 13 years if
CDP is suspected or earlier for HH or ovarian
failure. While oral therapy with ethinyl estradiol
or conjugated estrogens has been the classic
approach, there is concern about the nonphysio-
logical manner of administration and the meta-
bolic effects of oral estrogen first passing through
the liver before reaching the true target tissue of
the breast and uterus. If oral therapy is to be used,
17-beta estrogen is considered more physiologic
than ethinyl estradiol. Topical estrogen therapy is
now preferred as it may carry less risk than oral
estrogen therapy of hypertension, gallstones,
increased fat mass, decreased insulin sensitivity,
and increased triglycerides (topical estrogen does
not, however, increase HDL cholesterol and
decrease low-density lipoprotein [LDL] cholesterol,
as does oral estrogen). Estrogen-impregnated
patches are available for topical treatment but are
not FDA approved in children. 17-Beta estradiol
patches (0.025 mg/patch; Vivelle Dot matrix
patch) may be cut into fragments the size of
one-eighth to one-fourth of a patch fragment to
initiate pubertal development with more physio-
logic estrogen values. After several months,
and after the appearance of breakthrough bleed-
ing, estrogen is given only on days 1–21 of the
month. Withdrawal bleeding should then occur
regularly each month after the end of the estrogen
administration.
Because of the concern over an increase in
uterine carcinoma with exogenous estrogen
treatment, it is recommended that a girl taking
estrogens have a pelvic examination yearly. Girls
and parents must be warned about increased risk of
breast cancer with estrogen therapy, especially in
those with a family history of this disease. Those
9 Disorders of Puberty
with a family history of venous embolism may
be at increased risk by estrogen therapy; testing
for factor V Leiden may be performed (this is
not a standard recommendation for all subjects
with out such a history at this time). Similar to the
case in boys with respect to testosterone therapy,
girls with GH deficiency should not receive long-
term or higher-dose estrogen therapy until growth
rate is normalized by GH administration.
A progestational agent such as medroxypro-
gesterone acetate (5 mg) is given on days 12–21
of the cycle after breakthrough bleeding begins to
achieve a more normal endocrine milieu and to
decrease the risk of uterine neoplasia from the
estrogen itself.
Patients with Turner syndrome (the syndrome
of gonadal dysgenesis) can benefit from the treat-
ment of their growth deficiency. Growth rate can
be increased in Turner syndrome with adminis-
tration of GH with a resulting increase in adult
height. The addition of oxandrolone, a weak
oral androgen, is reported to increase the effect
of GH on growth. Side effects of oxandrolone
include pubic hair development, enlargement of
the clitoris, and lowering of the voice, so this
agent is added only after the age of onset of nor-
mal puberty, if at all. Previously girls with Turner
syndrome were not given estrogens until the late
teenage years for fear of decreasing their adult
height by advancement of their bone age; now,
low-dose estrogens are started earlier to allow
secondary sexual development at an appropriate
age, such as 13 years, and to reduce psychoso-
cial pressure and some studies suggest that it can
be started even earlier. The combination of GH
and estrogen has not increased adult height more
than GH alone in studies when the estrogen is
started early.
The infertility of Turner syndrome has also
been addressed. With the appropriate endocrine
support, a donated ovum may be fertilized, by
using the technique of in vitro fertilization, and
transferred to a subject with Turner syndrome,
but this method has great risk. Affected individu-
als may be able to maintain a pregnancy with
appropriate endocrine support to term and give
birth. There is risk of uterine rupture in this situ-
ation, and there a 2 % mortality rate is reported,
Abnormalities of Puberty
so this course is not a standard of care. Of course,
adoption is a well-recognized option for any
individual who wishes to be a parent whether
infertile or not.
Sexual Precocity (Table 9.4)
Sexual precocity in a boy is the development of
secondary sexual characteristics before age
9 years. In the past the accepted onset of preco-
cious puberty was before 8 years of age in girls,
but the obesity epidemic and other implicated fac-
tors convinced most authorities that the age should
be set lower. The age of diagnosis remains contro-
versial in girls, but the Pediatric Endocrine
Society presently states that when a girl has signs
of puberty before her seventh birthday if
Caucasian or sixth if African American, the girl
has precocious puberty. Further analysis sug-
gested that these early limits of normal puberty
are best applied to girls who are overweight or
Table 9.4 Causes and classification of sexual precocity
Central (or complete) isosexual precocious puberty
(GnRH-dependent sexual precocity or premature
activation of the hypothalamic pulse generator)
Familial or constitutional central precocious puberty
Idiopathic true precocious puberty
CNS tumors
Hamartoma of the tuber cinereum
Optic glioma associated with neurofibromatosis
type 1 or isolated
Hypothalamic astrocytoma
Craniopharyngioma
Ependymoma
Other CNS disorders
Encephalitis
Static encephalopathy
Brain abscess
Sarcoid or tubercular granuloma
Head trauma
CNS surgery
Hydrocephalus
Arachnoid cyst
Myelomeningocele
Vascular lesion
(continued)
217
Table 9.4 (continued)
Cranial irradiation
True precocious puberty after late therapy for
congenital virilizing adrenal hyperplasia or other
previous chronic exposure to sex steroids
Peripheral (or incomplete) isosexual precocity
(hypothalamic GnRH independent)
Isosexual precocity
Boys
Gonadotropin-secreting tumors
hCG-secreting CNS tumor (e.g.,
chorioepithelioma, germinoma, teratoma)
hCG-secreting tumors outside the CNS
(hepatoma, teratoma, choriocarcinoma)
Increased androgen secretion by adrenal gland or
testis
Congenital adrenal hyperplasia (CYP21 and
CYP11B1 deficiencies)
Virilizing adrenal neoplasm
Leydig cell adenoma
Familial testotoxicosis (sex-limited autosomal
dominant pituitary gonadotropin-independent
precocious Leydig cell and germ cell maturation)
Cortisol resistance syndrome
Girls
Ovarian cyst
Estrogen-secreting ovarian or adrenal neoplasm
Peutz–Jeghers syndrome
Severe primary hypothyroidism
Both sexes
McCune–Albright syndrome
Iatrogenic or exogenous sexual precocity
(including unintentional exposure to estrogens in
food, drugs, or cosmetics or to topical androgens
used by male members of the household)
Contrasexual precocity
Boys
Estrogen-secreting adrenal or testicular tumor
Exposure to exogenous estrogen
Girls
Androgen-secreting adrenal or ovarian tumor
Late-onset CAH
Exogenous androgen exposure (e.g., due to
fathers’ improper use of topical testosterone)
Variations of pubertal development
Premature thelarche
Premature isolated menarche
Premature adrenarche
Adolescent gynecomastia of boys
CNS central nervous system, hCG human chorionic
gonadotropin, GnRH gonadotropin-releasing hormone
218
obese as normal pubertal development is rarer
at those ages in girls within the normal range of
weight. However, any girl with the onset of
puberty before 8 years must be considered with a
high index of suspicion for a disease as the etiol-
ogy so as not to miss subtle findings of a condition
such as a brain tumor. A careful search for historical
or physical features of organic disease must occur
before a girl with puberty earlier than 8 years is
considered normal. The child must have abso-
lutely no sign of central nervous system disorder
or other conditions that might trigger pathologic
precocious puberty. A girl who proceeds rapidly
through puberty, who has menarche before age 9
years, or has neurological signs or other findings
of disease accompanying such early puberty must
not be considered normal before a complete eval-
uation is completed. Thus, in any case in which
concern arises, investigation for a disorder that
might be causing precocious puberty is war-
ranted, rather than simply relying on the age cri-
teria stated earlier.
If the etiology of early puberty is the premature
maturation of the hypothalamic–pituitary axis, the
condition is denoted as central, complete, or true
precocious puberty (CPP), which is a pituitary
gonadotropin-dependent condition; if the etiol-
ogy is autonomous secretion of sex steroids in
boys or girls or autonomous secretion of hCG in
boys, the condition is peripheral precocious
puberty (or incomplete precocious puberty or
pseudo-precocious puberty), a pituitary
gonadotropin-independent condition. If the puber-
tal development is appropriate for sex but early it is
isosexual precocity and if virilization occurs in
girls or feminization in boys, it is contrasexual
precocity. Patients of all categories will have rapid
growth and skeletal maturation and, without treat-
ment, may fulfill the paradox of the tall child who
ceases growing early because of premature epiphy-
seal fusion and becomes a short adult.
Central (Complete or True) Precocious
Puberty (Fig. 9.4a)
The onset of puberty occurring close to, but
below, the lower age limits of normal pubertal
development, without evidence of an organic dis-
order, may possibly be a normal variant. A family
tendency toward this situation will assist in estab-
9 Disorders of Puberty
lishing the diagnosis although careful genetic
evaluation of family patterns suggests that the
occurrence of early puberty is often not reported
accurately. While slightly early puberty might be
the mirror image of constitutional delay in
puberty, in which there is a family tendency in
normal subjects toward delayed onset of puberty,
in either case a deviation from the normal limits
of age of onset of puberty is not to be taken
lightly and must be considered a disorder until
adequate evidence proves it to be a normal varia-
tion. To consider a child who starts pubertal
development slightly below the normal age
guidelines as having a constitutional tendency,
no signs of neurologic or other serious diseases
must be present, and the sequence of events and
progression must be the same as in normal
puberty. With the recent finding of a familial
nature of CPP in more subjects, these borderline
cases may be manifestation of these genetic
variants.
Idiopathic Central Precocious Puberty
If no tumor or other definitive diagnosis is found,
and if no family tendency exists, the diagnosis of
exclusion is idiopathic CPP. These patients mani-
fest all of the endocrine findings of normal
puberty, albeit at an earlier age. Their progress
may be normal and continuous or slow and wax-
ing and waning. Boys with this condition will first
demonstrate symmetrical and progressive testicu-
lar enlargement, just as found in normal puberty.
Girls are brought to evaluation for idiopathic pre-
cocious puberty more often than boys in the USA,
partially due to differing parental concerns about
the social effects on girls of early pubertal devel-
opment compared with boys.
Gain-of-Function Mutations
in the Kisspeptin Axis
Inactivating mutations in the KISS1R cause
hypogonadotropic hypogonadism, but an auto-
somal dominant KISS1R mutation is associated
with CPP due to prolonged action of the
receptor compared to wild type (#176400
PRECOCIOUS PUBERTY, CENTRAL).
Likewise mutation in the KISS gene which
codes for kisspeptin has been found in three
children with precocious puberty. One of the
Abnormalities of Puberty 219

a Third ventricle Hypothalamus

Neuroendocrine
cell nuclei

GnRH secreting cells

Superior
hypophyseal Stalk
artery

Long portal
vessels Inferior
hypophyseal
artery
LH and FSH

Secreting cells

Anterior Posterior
pituitary pituitary

Hormone Short portal

secretion vessel

LH and FSH

Testosterone Estrogen
and inhibin and inhibin

Testes Ovary

Fig. 9.4 (a) Central precocious puberty in which
increased GnRH stimulates the anterior pituitary gland to
increase secretion of LH and FSH which stimulate the
gonads. While sex steroid secretion increases and causes
the physical changes of puberty, the steroids are unable to
exert feedback inhibition to decrease the GnRH secretion.
(b) Peripheral precocious puberty in which the gonads
autonomously secrete their respective sex steroids to
cause secondary sexual development. In this case the
increased sex steroids do suppress GnRH secretion, but
since GnRH is not involved in the etiology of this condi-
tion, puberty progresses

mutations appears to lead to prolonged survival
and activity of kisspeptin from degradation.
MKRN3
Recently loss-of-function mutations of MKRN3,
an imprinted gene located on the long arm of
chromosome 15q11.2, in children with CPP led to
the consideration that this gene and its product,
makorin ring finger protein 3, is an important
inhibitor of pubertal development during the
juvenile pause (#615346 PRECOCIOUS
PUBERTY, CENTRAL, 2; CPPB2). All of the
children, mostly girls, inherited their mutation
from their fathers as the maternal allele of this
gene is silenced by methylation, a case of monoal-
lelic expression. The familial nature of the condi-
220 9 Disorders of Puberty

b Third ventricle Hypothalamus

Neuroendocrine
cell nuclei

GnRH secreting cells

Superior
hypophyseal Stalk
artery

Long portal
vessels Inferior
hypophyseal
artery
LH and FSH

Secreting cells

Anterior Posterior
pituitary pituitary

Hormone Short portal

secretion vessel

LH and FSH

Testosterone Estrogen
and inhibin and inhibin

Testes Ovary

Fig. 9.4 (continued)

tion was not always apparent until careful
determination of family history was taken. Some
affected girls began puberty between 6 and 9
years of age providing another reason that CPP
below 8 years in girls may not be idiopathic.
Treatment with GnRH agonist appears effective
in most cases.
Central Nervous System Disorders
CPP occurs more often in girls than in boys.
However, CNS tumors are found more often in
boys with precocious puberty than in girls. In all
cases of CPP, a CNS tumor must be considered
first as the etiology, especially in boys; idiopathic
conditions are diagnoses of exclusion.
Hamartomas of the tuber cinereum are con-
genital conditions composed of ectopic hypotha-
lamic tissue and usually contain GnRH in their
neurons. They function as a supplemental hypo-
thalamus that operates outside of the normal
inhibitory effects of the CNS on GnRH secretion.
They have characteristic locations and appear-
ances on MRI, so biopsy is rarely necessary.
They are not neoplasms and do not enlarge.
Abnormalities of Puberty
Because of their sensitive location, hamartomas
of the tuber cinereum are rarely amenable to sur-
gical removal: medical therapy with GnRH ago-
nists is the treatment of choice for this form of
precocious puberty. However, because intracta-
ble gelastic (laughing) or other types of epilepsy
may accompany the hamartoma, surgical treat-
ment may be directed to the epilepsy but is rarely
used solely for precocious puberty.
Ominous CNS tumors include germinomas
often located in the pineal gland. Germinomas
may secrete hCG and cause incomplete preco-
cious puberty in boys (see later) or may activate
the entire hypothalamic–pituitary axis and cause
central precocious puberty. Germinomas are
radiation sensitive. Other CNS tumors causing
precocious puberty (or delayed puberty depend-
ing upon the location) are astrocytomas and
ependymomas; gliomas of the optic nerve or
hypothalamus may be isolated or part of neurofi-
bromatosis. See Chaps. 3 and 5 for more discus-
sion of these CNS tumors that also affect growth.
Delayed rather than precocious puberty may
be the outcome of tumors or injuries of the CNS,
depending upon the location in the hypothala-
mus. Posterior hypothalamic locations of central
nervous system are the ones most likely to cause
precocious puberty.
Other CNS causes of true precocious puberty
include space-occupying lesions or etiologies of
increased intracranial pressure, including granu-
lomas, suprasellar arachnoid cysts, hydrocepha-
lus, or head trauma including birth trauma.
Precocious puberty may be associated with cere-
bral palsy and other intellectual defects.
Other Causes of CPP
Severe hypothyroidism can cause delayed
puberty or, paradoxically, precocious puberty:
the latter, known as the Van Wyck–Grumbach
syndrome, appears due to cross-reaction with the
elevated TSH concentrations interacting with the
FSH receptors. Any virilizing condition, when
resolved, can trigger true precocious puberty,
presumably because of maturation of the hypo-
thalamic–pituitary axis. This may occur after glu-
cocorticoid treatment is initiated for
long-untreated virilizing congenital adrenal
221
hyperplasia (CAH), after the removal of an adre-
nal androgen-secreting tumor, and after androgen
therapy for various disorders, such as anemia.
Peripheral Precocious Puberty
and Exogenous Sex Steroids (Fig. 9.4b)
Unregulated sex steroid secretion is the major
cause of peripheral precocious puberty in girls
and in boys, although boys with tumors secreting
hCG will also have peripheral precocious puberty
as the hCG stimulates the testes. The only sites
that can secrete sex steroids in an unregulated
manner in disease are the adrenal glands and the
gonads.
Girls
Peripheral isosexual precocious puberty may
develop in girls because of ovarian or adrenal
secretion of, or ingestion of or exposure to, estro-
gen. Serum gonadotropins are suppressed, whereas
serum estradiol concentrations are elevated.
Ovarian follicular cysts can secrete enough
estrogen to cause breast development, and when
the cyst resolves, withdrawal bleeding can occur.
Usually cysts are small and limited in effect, but
some can secrete enough estrogen to cause serum
estradiol concentrations to increase as high as
those found in tumors. Cysts may occur only
once, but recurrent cysts are possible. Surgical
intervention is rarely indicated for simple cysts.
Estrogen-secreting tumors include granulosa
cell tumors (the most common), gonadoblasto-
mas (which can arise in streak gonads of gonadal
dysgenesis), lipoid tumors, and ovarian carcino-
mas. The majority of granulosa cell tumors can
be palpated by bimanual examination.
Exogenous estrogen exposure may occur
through diet (chicken necks, beef, or veal have
contained estrogen because of improper com-
mercial estrogen treatment to enhance growth
of the animals), by ingestion of medications
that may include estrogen (perhaps given to
mother or grandmother), or even by skin
absorption after contact with estrogen-contain-
ing cosmetics or hair cream or lotions (laven-
der or tea tree oil has been implicated after
dermal application and some hair pomades
contain sex steroids).
222
Boys
Boys can develop incomplete isosexual preco-
cious puberty either by autonomous secretion or
ingestion of sex steroids or by tumor production
of hCG, which will cause testosterone secretion
from Leydig cells due to hCG interacting with
the LH receptors. hCG production causes no
endocrine or physical effects in girls. Serum LH
and the LH response to GnRH will be sup-
pressed because of autonomous testosterone
secretion in peripheral gonadotropin-independent
precocious puberty.
Androgen secretion may occur due to
21-hydroxylase or 11-hydroxylase deficiency
CAH, adrenal carcinomas, and interstitial cell
tumors of the testes. A Leydig cell tumor is seen
with irregular enlargement of one or both testes.
With adrenal hyperplasia, the testes will usually be
of prepubertal size in younger boys since the
androgen emanates from the adrenal glands.
However, a testicular adrenal rest tumor composed
of ACTH-responsive tissue located in the testes, a
common but ectopic location for adrenal tissue
originating in fetal life, may enlarge later in
CAH; this is denoted as testicular adrenal rest tis-
sue, or TART (see Chap. 6).
Premature Leydig and germinal cell maturation
or male limited precocious puberty (#176410
PRECOCIOUS PUBERTY, MALE-LIMITED at
2p21) is a rare condition but is instructive in the
understanding of puberty, as it results from a unique
error of biology. A mutation in the seven-trans-
membrane domain of the LH receptor causes the
LH receptor to be constitutively activated so that
testosterone is produced even in the absence of
LH. Affected boys demonstrate androgen effects at
an early age, and often a family history of affected
fathers or uncles is found in this male limited auto-
somal dominant disorder. Remarkably, at the time
of normal puberty, these boys switch from periph-
eral gonadotropin-independent precocious puberty
to normal GnRH-dependent pubertal physiology
that ultimately can lead to fertility; indeed central
precocious puberty can follow suppression of the
autonomous phase of testosterone secretion.
Treatment may be effective with an antiandrogen
such as flutamide or nialamide and an aromatase
inhibitor such as letrozole in decreasing the effects
of androgen secretion early in life. When CPP
9 Disorders of Puberty
develops following successful treatment of the ear-
lier peripheral PP, GnRH agonist is then effective
in the CPP phase.
If hCG stimulates the testes to produce testos-
terone, the testes will be slightly enlarged (more
than 2.5 cm) but will not be as large as found in
true precocious puberty, because the seminifer-
ous tubules, which are normally responsive to
FSH, will not increase to pubertal size since no
increased FSH secretion occurs. hCG-secreting
tumors include hepatomas, hepatoblastomas,
teratomas or chorioepitheliomas of the gonads,
mediastinum, and retroperitoneum, as well as
germinomas of the pineal gland. A hepatoblas-
toma may quickly prove to be fatal after the
diagnosis of precocious puberty is made.
The McCune–Albright syndrome (#174800
MCCUNE–ALBRIGHT SYNDROME; MAS at
20q13.2) involves the triad of café au lait spots,
fibrous dysplasia of the long bones (cysts are nota-
ble on radiograph or bone scan, and pathologic
fractures are found), and either central or incom-
plete precocious puberty. Other forms of increased
endocrine activity such as Cushing syndrome,
hyperthyroidism, pituitary gigantism, and hypo-
phosphatemic rickets are found in McCune–
Albright syndrome. The wide-ranging effects of
this condition occur because of somatic mutations
in the Gα-stimulatory protein of the adenyl cyclase
pathway. Thus the LH receptor and other mem-
brane-based protein hormone receptors are con-
stitutively activated by the Gα-stimulatory
protein and always functioning, even in the
absence of the stimulatory ligand. Multiple
tissues (e.g., skin, bone, Leydig cells, follicular
cells, thyroid cells, adrenal cortical cells, and
pituitary cells) are activated in a random distribu-
tion in the body due to somatic mutations.
Contrasexual Precocity: Feminization
in Boys and Virilization in Girls
Boys
Feminization in a boy before the age of puberty
is rare. Rarely, an estrogen-secreting adrenal
adenoma or a chorionepithelioma causes gyne-
comastia. The treatment of adenomas or carci-
noma of the ovary, testis, or adrenal gland is
surgical correction.
Abnormalities of Puberty
Aromatase Excess Syndrome
Gynecomastia in prepubertal boys can be caused
by increased extraglandular aromatization of
C19 steroids of adrenal origin, such as andro-
stenedione, and subsequent increased extraglan-
dular estrogen production in sporadic or familial
cases. The autosomal dominant form leads to
excess estrogen synthesis from C19 precursors
due to aromatase overexpression, especially in fat
and skin; it is a consequence of gain-of-function
mutations of CYP19, the gene that encodes aro-
matase, resulting from a chromosome arrange-
ment that gives rise to a cryptic promoter.
Feminizing Testicular Tumors
Feminizing testicular tumors may cause gyneco-
mastia in boys younger than 6 years of age who
have the Peutz–Jeghers syndrome. Aromatase is
absent or is present in barely detectable amounts in
prepubertal testes, but maximal amounts appear in
late puberty. In normal testes, aromatase is pre-
dominantly present in the Leydig cells, but in tes-
ticular tumors of Sertoli cells or Leydig cells
(e.g., associated with the Peutz–Jeghers syn-
drome), the Sertoli cells of the tumor express aro-
matase. Both testes may be enlarged, and the
histology indicates sex cord or Sertoli cell tumors
that form annular tubules and often have areas of
calcification; increased estradiol secretion is
noted in the basal state, and a further rise occurs
after hCG administration. Sonography or MRI of
the testes may be useful in making the diagnosis.
Prepubertal gynecomastia can also be caused
by neurofibromatosis.
Girls
Adrenal Causes of Virilization
Virilization in a girl indicates serious organic dis-
ease except for premature adrenarche which leads
to only modest androgen effects. CAH resulting
from 21-hydroxylase or 11β-hydroxylase defi-
ciency or from androgen-producing tumors of the
adrenal can cause virilization. Nonclassic or late-
onset forms of CAH do not demonstrate ambigu-
ous genitalia, but there is evidence of androgen
effect in prepuberty or the teenage years. 3β-HSD/
Δ4,5-isomerase deficiency is a rare type of CAH
characterized by elevated levels of Δ5-17P
223
(17-hydroxypregnenolone), DHEA, and DHEAS,
as well as decreased secretion of aldosterone and
cortisol in the severe form. Severely affected
patients have mineralocorticoid and glucocorti-
coid deficiencies and may die in infancy. Excess
adrenal androgens lead to virilization in utero and
to ambiguous external genitalia, including clitoral
enlargement in females with continued viriliza-
tion after birth. Milder forms of this disorder can
cause hirsutism in women. Women with a 46,XY
phenotype and incomplete forms of androgen
resistance syndrome or 17β-HSD type 3 defi-
ciency may have virilization as well as breast
development at the time of expected puberty.
Aromatase deficiency due to mutations in the
CYP19 gene, which encodes aromatase, is associ-
ated with intrauterine masculinization of the
external genitalia in affected 46,XX individuals
and also with progressive virilization, lack of
female secondary sex characteristics, multicystic
ovaries at the age of puberty, tall stature, and
osteopenia.
Cushing syndrome resulting from adrenal car-
cinoma usually manifests as growth failure with
or without virilization, obesity, and moon facies;
striae may not appear until months to years later.
Syndrome of Glucocorticoid Resistance
The syndrome of glucocorticoid resistance has
variable manifestations. Some patients demon-
strate hyperandrogenic signs such as acne, hir-
sutism, male-type baldness, menstrual
irregularities, and oligoanovulation and infertil-
ity. Dexamethasone decreases the excessive
adrenal androgen secretion, virilization, and
advancing bone age found in general glucocorti-
coid resistance.
Virilizing Ovarian Tumors
Arrhenoblastoma, also called Sertoli tumor of the
ovary, is the most common virilizing ovarian
tumor, but it is rare in children. Somatic missense
mutations affecting the RNase IIIb domain of
DICER1 that alter DICER1 function in a manner
that perturbation of microRNA processing may
be oncogenic are common in these nonepithelial
ovarian tumors. Lipoid-cell tumors of the ovary
and gonadoblastomas of the ovary are even more
unusual sources of androgens.
224
Endocrine Disruption in Puberty
There are rising concerns that endocrine disrupting
chemicals (EDCs), defined as “an exogenous
substance that causes adverse health effects in an
intact organism, or its progeny, secondary to
changes in endocrine function,” exert many
effects on growth and development of children
including pubertal development. Far more con-
clusive evidence of an adverse effect of EDCs
comes from animal rather than human studies,
and some of the data on human beings derives
from industrial accidents and very-high-level
exposure rather than the lower level exposures
most individuals experience, so EDCs must be
studied in more detail in human beings.
Nonetheless, there is a significant concern that
the exposure of the fetus or developing child to
the multitude of industrial chemicals in the envi-
ronment either delay or advance pubertal devel-
opment. Parents will often ask about these issues
Legislatures have acted in some states to try to
decrease chemical exposures. University centers
are studying this issue and developing guidelines
to help parents avoid toxic exposures.
Variations of Early Pubertal
Development
Premature Thelarche
Premature thelarche is a benign condition of
unilateral or bilateral breast development, usu-
ally in a girl younger than 3 years. Minimal or
no other signs of estrogen effect are present (i.e.,
no dulling of the vaginal mucosa, little areolar
(nipple) development or pigmentation, and no
increase in growth rate). Serum estradiol values
are prepubertal, as the follicular cyst thought to
cause this condition is often spontaneously
resorbed by the time the patient comes to evalu-
ation. Some evidence exists that FSH is higher
in premature thelarche than in age-matched chil-
dren without thelarche, but the serum LH and
the LH response to GnRH are prepubertal. Some
children with central precocious puberty may at
the beginning of this condition appearing very
much as if they have premature thelarche. Thus,
9 Disorders of Puberty
it is important to continue to observe children
with premature thelarche over time. Exaggerated
thelarche is found in girls with premature thelar-
che with some advancement of the bone age and
increase in growth rate.
Premature Adrenarche
Premature adrenarche is a benign self-limited
appearance of a small amount of pubic hair, com-
edones, axillary hair, or odor, which usually
occurs after age 6 years. The normal increase in
adrenal androgens, including DHEA and its sul-
fate (DHEAS), occurs earlier in this condition
than in an unaffected child, and the pubic hair
then follows the increase in DHEAS. Thus a
6–8-year-old with Tanner stage 2–3 pubic hair
may have a DHEAS value characteristic of a
12–13-year-old. The rest of pubertal develop-
ment, such as testicular development in a boy or
breast development in a girl, will occur at a nor-
mal age. A slight increase in growth rate may be
noted, along with a slight advancement of bone
age, but neither should be pronounced, or a more
serious virilizing disorder is likely.
Late-onset CAH may have an initial appear-
ance indistinguishable from that of premature
adrenarche. Thus clinical follow-up is indicated,
even if it appears that the child has the benign
condition, premature adrenarche. If any doubt
exists that the condition seems to be more severe
than premature adrenarche, or if a family history
of the same condition is found, testing for CAH is
indicated by using basal adrenal metabolite eval-
uation as well as measurement after ACTH stim-
ulation (see Chaps. 10 and 15). Polycystic ovarian
syndrome (PCOS) also appears in some cases
similar to premature adrenarche. A history of
SGA birth may precede the onset of premature
adrenarche. (PCOS is discussed in Chap. 13)
An adrenal tumor or other more serious form
of virilization must manifest limited virilization in
its earlier stages and may be mistaken for
premature adrenarche, so follow-up of premature
adrenarche, although usually benign, is indicated.
Gynecomastia
Gynecomastia is the appearance of breast devel-
opment in a male. Physiologic or pubertal gyne-
Endocrine Disruption in Puberty
comastia is a variation of normal that is seen in a
boy who, usually, has reached Tanner stage 2–3
pubertal development. In the majority of cases,
the condition disappears within 1–3 years, but in
some cases, it may last longer and require surgi-
cal removal. The longer the tissue remains, the
more likely it will not spontaneously resolve,
because scar tissue ultimately develops in the
breast tissue. Obese subjects may have a reduc-
tion in this glandular tissue or its prominence by
reducing their weight. Thinner boys with several
years of gynecomastia may require surgery to
resolve the condition.
Pathologic gynecomastia will occur in
Klinefelter syndrome; breast cancer may develop
in the tissue affected by gynecomastia in
Klinefelter syndrome. Gynecomastia is also a
feature of Reifenstein syndrome (#312300
REIFENSTEIN SYNDROME), or any form of
partial androgen resistance, as well as in rare pre-
pubertal boys with 11β-hydroxylase deficiency
(*202010 ADRENAL HYPERPLASIA,
CONGENITAL, DUE TO 11β-HYDROXYLASE
DEFICIENCY at 8q21) or aromatase excess syn-
drome (139300 GYNECOMASTIA,
HEREDITARY). Medical therapy has been tried
without success in gynecomastia, so surgery is
the only present treatment for persistent gyneco-
mastia. Prepubertal gynecomastia indicates
exposure to or pathologic secretion of estrogen
and must be carefully investigated.
Macroorchidism
Macroorchidism is defined as testes twice the
normal size for age without androgenization. It is
a rare manifestation of the McCune–Albright
syndrome and an occasional finding in prepuber-
tal boys with long-standing primary hypothy-
roidism. In the McCune–Albright syndrome, an
activating mutation in the Gsα gene primarily
expressed in the Sertoli cell can cause macroor-
chidism due to Sertoli cell proliferation and
hyperfunction with increased concentration of
serum inhibin B and AMH; there may be no
increase in testosterone levels due to absence of
Leydig cell hyperplasia, elevated gonadotropins,
225
or signs of puberty. Testicular adrenal rests (TART)
in CAH can cause bilateral macroorchidism as can
lymphoma. Macroorchidism is a feature of severe
aromatase deficiency in young male adults and in
men with an FSH-secreting pituitary macroade-
noma. Bilateral megalotestis (testicular volume,
26 mL) in adults can occur as a normal variant.
Testes will enlarge during treatment with aroma-
tase inhibitors.
The fragile X syndrome is associated with
developmental delay, a long face and large prom-
inent ears, and macroorchidism in 80 % of
affected pubertal boys. The enlarged testes are
caused by increased interstitial volume and
excessive connective tissue, including increased
peritubular collagen fibers, rather than by an
increase in the seminiferous tubules. Enlargement
of the testes is demonstrable in the prepubertal
period in most patients with fragile X syndrome,
but the onset of true macroorchidism (>4 cm)
occurs only in the later prepubertal period.
Differential Diagnosis of Precocious
Puberty
A girl with early-onset breast development may
have premature thelarche (usually with more sub-
tle breast development) or estrogen secretion due
to peripheral precocious puberty or gonadotropin-
stimulated estrogen secretion due to central preco-
cious puberty if thelarche is more substantial.
However, if a girl has early breast development and
an appropriate stage of pubic hair development for
the degree of breast development, she probably has
CPP, as no other condition is likely to produce both
estrogen and androgen in balanced amounts
(Fig. 9.4a). A boy who shows signs of virilization
with symmetrically enlarging testes of homoge-
neous appearance and consistency to palpation is
likely to have CPP: bilateral testicular tumors are
alternative etiologies of enlarging testes, but it is
unlikely that they will be symmetrical and homo-
geneous and have regular surfaces. Gonadotropin-
independent Leydig and germ cell maturation
leads to a small degree of enlargement of testes
since the seminiferous tubules are not as affected
as Leydig cells, but the testes do not reach full
226
pubertal size. If the testes are not enlarging even
though the patient exhibits androgen effects, an
adrenal source of androgen products must be sus-
pected, such as an adrenal tumor or adrenal enzyme
defect, or exogenous androgens as the etiology.
If significant isosexual pubertal development is
noted (breast development in a girl or virilization
in a boy), determination of sex steroid and serum
gonadotropin concentration (in modern, sensitive
pediatric assays) is performed. Serum gonadotro-
pin concentrations and GnRH agonist-stimulated
LH and FSH will reveal pubertal values in CPP,
but the LH values will be prepubertal in preco-
cious adrenarche or in precocious thelarche (see
Fig. 9.5). If the diagnosis is CPP, a search for a
CNS abnormality is indicated, and an MRI is per-
formed to determine whether a hamartoma of the
tuber cinereum or an expanding neoplasm is pres-
ent. Boys more often than girls will have a brain
tumor as the cause of their true precocious puberty
(Table 9.5).
If sex steroids are elevated but gonadotropins
are suppressed, autonomous sex steroid secretion
is likely to be found. If beta hCG is elevated, an
hCG-secreting tumor is suggested as modern
beta hCG assays do not cross-react with LH. An
MRI is invoked to search for liver, CNS, medias-
tinum, or other locations for the hCG-secreting
tumor. Alternatively, exogenous sex steroids can
cause these laboratory findings.
Treatment of Precocious Puberty
Gonadotropin-releasing hormone analogues
(GnRH-As) are extremely potent versions of
GnRH which have an extended time of action.
These agents cause downregulation of GnRH
receptors, such as would occur during a constant
GnRH infusion, thereby decreasing episodic
Fig. 9.5 (continued) before 7 years among white girls
and 6 years among African-American girls (revised
from Styne DM, Cuttler L. Normal pubertal develop-
ment. In: Rudolph CD, Rudolph AM, eds. Rudolph’s
Pediatrics. New York: McGraw-Hill, 2002:2093–2105,
with permission). (c) Diagnostic algorithm for pubic
hair before 7 years among white girls and 6 years among
9 Disorders of Puberty
gonadotropin release. When GnRH-A sup-
presses gonadotropin secretion, sex steroid
secretion decreases, the rate of bone-age
advancement decreases, as does the rate of rapid
growth, and the height prognosis of treated
patients improves if treatment is started early,
usually before 6 years. The effects are revers-
ible, as those patients whose therapy is discon-
tinued increase gonadotropin secretion to
pubertal values, following the same pattern as is
usually found in the early stages of normal
puberty, and fertility is reported in adult life.
GnRH-As are commercially approved for the
treatment of central precocious puberty in the
form of monthly or three-monthly injections,
daily injections, and yearly surgical implants.
GnRH agonist therapy is not necessary to ensure
an adequate adult height in a patient who has
slowly progressive or waxing and waning preco-
cious puberty that commences at an age only
slightly younger than the normal age at the onset
of puberty. Further, GnRH agonist treatment of
puberty with the onset after 6 years of age is less
likely to increase adult height.
Testolactone and letrozole are aromatase inhib-
itors that stop estradiol and estrone biosynthesis.
These added to antiandrogens such as flutamide or
nilutamide are used in McCune–Albright syn-
drome in boys with peripheral precocious puberty
and in familial gonadotropin-independent Leydig
cell and germ cell maturation to decrease viriliza-
tion. Ketoconazole, an antifungal agent, causes a
17–20 lyase block in the testosterone biosynthetic
pathway and has been used to decrease testoster-
one secretion in familial gonadotropin-
independent Leydig cell and germ cell maturation;
adrenal suppression is a side effect of such treat-
ment and adds to the risk of treatment.
Peripheral precocious puberty can be followed
by true precocious puberty after treatment if the
African-American girls. DHEAS dehydroepiandrostene-
dione sulfate, 17α-OHP 17α-hydroxyprogesterone,
GnRHA gonadotropin-releasing hormone agonist
(reprinted from Styne DM, Cuttler L. Normal pubertal
development. In: Rudolph CD, Rudolph AM, eds.
Rudolph’s Pediatrics. New York: McGraw-Hill,
2002:2093–2105, with permission)
Endocrine Disruption in Puberty 227

a Possibility of exogenous
androgens or hCG
Yes No

Testicular size

Longest diameter < 2.5 cm Longest diameter > 2.5 cm

Adrenal etiology Serum hCG elevated

Yes No
Asymmetrical
17OHP DHEAS Cortisol elevated, ACTH Serum LH suppressed enlargement
elevated elevated elevated, no signs of
Yes No (Basal LH or LH
Cushing syndrome
response to
GnRHA is pubertal)
Exogenous P450C21 Adrenal Glucocorticoid hCG Testotoxicosis or True precocious Testicular tumor or
androgen or deficiency virilizing resistance secreting other autonomous puberty adrenal rest with CAH
hCG exposure tumor or tumor testosterone
late-onset secreting lesion
3β HD of testes
deficiency

b Basal or GnRHA
stimulated levels of
LH are pubertal
Yes No

Central Serum estradiol

precocious puberty at pubertal levels
No Yes

Cranial MRI
Ultrasound of
uterus and ovary
Normal Abnormal Normal Abnormal

Cafe au lait spots

No Yes

Idiopathic Hamartoma of tuber Premature Consider: Estrogen-secreting Ovarian cyst McCune−Albright

precocious cinereum, CNS thelarche adrenal neoplasm, extrinsic or tumor syndrome
puberty tumor, or other lesion estrogen exposure

c
DHEAS above prepubertal levels
Yes No

Basal or ACTH-stimulated
17-OHP levels elevated
Yes No

Free testosterone
level increased
Yes No

Cortisol and ACTH

levels elevated
Yes No

Virilizing Late-onset P450021 Virilizing Cushing syndrome Premature

adrenal deficiency ovarian or glucocorticoid adrenarche
tumor neoplasm resistance

Fig. 9.5 (a) Diagnostic algorithm for precocious Rudolph CD, Rudolph AM, eds. Rudolph’s Pediatrics.
puberty among boys before age 9 years (revised from New York: McGraw-Hill, 2002:2093–2105, with per-
Styne DM, Cuttler L. Normal pubertal development. In: mission). (b) Diagnostic algorithm for breast development
228 9 Disorders of Puberty

Table 9.5 Differential diagnosis of precocious puberty

LH response to Serum sex
Serum gonadotropin GnRH or GnRH steroid
concentrations agonist concentrations Gonadal size Miscellaneous
Central (complete or true) precocious puberty
Pubertal Pubertal pattern Pubertal values Normal pubertal MRI scan of head to
enlargement of rule out a central
gonads in males nervous system tumor,
hamartoma, or other
central nervous system
lesion
Incomplete precocious puberty
Males
Chorionic gonadotropin- High basal hCG or High or Slight to moderate Hepatic tumor must be
secreting tumor, high LH that does not rise pubertal values enlargement of considered. MRI scan
hCG (or LH in cross- with GnRH, but gonads of head if hCG-
reactive assay), positive β-LH is low and secreting central
pregnancy test, but β-LH does not rise nervous system tumor
(specific assay) is low suspected. LH assay
may measure hCG, so
both results may be
high while β-hCG is
high and β-LH, in an
assay which does not
detect hCG, is low
Leydig cell tumor, Prepubertal or Extremely high Irregular asymmetric
prepubertal suppressed pattern testosterone enlargement of testes
(gonadotropins low)
Familial gonadotropin- Prepubertal or Pubertal or Testes longer than Found in sex-limited
prepubertal independent suppressed pattern higher values 2.5 cm but smaller dominant patterns
sexual precocity with than expected for
premature Leydig and stage of pubertal
germ cell maturation development
prepubertal (low)
Females
Granulosa cell tumor Prepubertal or Extremely high Ovarian enlargement Granulosa cell tumor
prepubertal (follicular suppressed pattern estradiol on physical, CT, is usually palpable on
cysts may have similar MRI, or sonographic rectal examination
presentation) examination
Follicular cyst Prepubertal or High to Cysts may be visible Withdrawal bleeding
prepubertal suppressed pattern of extremely high on sonogram may occur when
gonadotropins are low LH secretion. FSH estradiol estrogen levels
secretion may rise decrease. Cysts may
above normal range recur

condition has been uncontrolled for a long period
and the sex steroids have exerted a maturational
effect on the hypothalamic–pituitary axis. In this
situation GnRH-A might be effective even though
it was not effective during the peripheral preco-
cious puberty portion of the condition.
Psychological support is helpful to both child
and parents. Their larger size may make children
with precocious puberty the center of unwanted
attention. Children with true precocious puberty,
if intellectually and socially appropriate, may be
able to accept accelerated school placement so
Polycystic Ovarian Syndrome
that they can be placed in a class with children
whose size is closer to their own. Girls with pre-
mature menstrual periods should be prepared for
the event before menarche and supported through
this difficult time. Of further concern is the pos-
sibility that the patient could be the target of sex-
ual abuse, with the additional element of potential
fertility. Boys with precocious puberty and high
testosterone values will be prone to aggressive
activity and may masturbate publicly, but are
unlikely to seek out sexual activity in the absence
of social maturation. In some cases, the treating
physician can help the family through this stress-
ful time, but psychological counseling should be
considered in the more significant cases.
Early menarche is associated with a higher
risk of breast cancer; thus, affected girls should
be counseled as adults about screening for this
disease.
A discussion of transgender youth is beyond
the scope of this volume, but it should be men-
tioned that delaying puberty in these patients
while psychological counseling and determina-
tion of the ultimate course of therapy is proceed-
ing may be accomplished using GnRH agonists
(see Chap. 8).
Polycystic Ovarian Syndrome
Polycystic ovarian syndrome is the most common
reproductive disorder with a prevalence of 4–10 %
of the female population depending upon diagnos-
tic criteria used. Polycystic ovarian syndrome is
the most common form of normal gonadotrophic
anovulation. PCOS has long been known to inter-
fere with reproduction and menstrual periods and
known to cause the disheartening appearance of
severe acne and hirsutism. More recently PCOS
has been recognized as the metabolic syndrome of
women based upon an insulin-resistant state, car-
rying a risk of dyslipidemia leading to cardiovas-
cular disease, insulin resistance and type 2
diabetes, and other associated manifestations of
the insulin resistance including obstructive sleep
apnea and hypertension. Obesity is extremely
229
common in PCOS in the USA but less common in
PCOS in other countries suggesting an environ-
mental influence on the development of obesity
related to PCOS. PCOS is found in familial pat-
terns and the unaffected sisters and even the broth-
ers of the affected individuals have endocrine
manifestations of hyperandrogenism. A correlation
of low birth weight and the development of
polycystic ovarian syndrome has been reported.
Premature adrenarche is felt to be harbinger in
some girls of the development of PCOS, but this is
not universal.
There are various criteria for the diagnosis
of polycystic ovarian syndrome, but they are
validated in adults in most cases. The Rotterdam
criteria for polycystic ovarian syndrome are in
common use and include evaluation for the
presence of polycystic ovarian appearance on
ultrasound examination. This consideration is
more difficult to establish in teenagers as a
transvaginal ultrasound may not be appropriate
and the obesity often found in polycystic ovar-
ian syndrome decreases the accuracy of a trans-
abdominal ultrasound. The Endocrine Society
has provided guidelines for the diagnosis of
polycystic ovarian syndrome in teenage girls.
According to the guidelines, diagnosis of PCOS
in an adolescent girl is made if there is clinical
and/or biochemical evidence of hyperandrogen-
ism (after exclusion of other pathologies) in the
presence of persistent oligomenorrhea. Since
there is such a high rate of irregularity in men-
strual periods or anovulatory periods soon after
menarche and since there are multiple ovarian
cysts in normal pubertal girls, anovulatory
symptoms and evidence of polycystic ovaries
are not appropriate criteria themselves in teen-
age girls although they are more compelling at
older ages. About two-thirds of girls with poly-
cystic ovarian syndrome have menstrual disor-
ders ranging from primary amenorrhea to
secondary amenorrhea to dysfunctional uterine
bleeding. Acne is so common in teenagers that
it cannot be used by itself as a criteria. However,
about 60 % of girls with polycystic ovarian
syndrome have hirsutism.
230
Measurement of anti-Müllerian hormone has
been suggested as helpful in the diagnosis as
elevated levels are found in the offspring of
PCOS mothers and in affected women. AMH is
a reflection of the increased number of follicles
usually found in PCOS. Normal ovarian histol-
ogy is more likely related to an adrenal source
of androgens. Further some but not all patients
with PCOS have elevated LH/FSH ratios.
While excess androgens can cause hirsutism,
acne vulgaris, and male pattern alopecia, there is a
wide variety of responses in individuals to similar
levels of androgen. Pilosebaceous units respond
differentially to various doses of androgen expo-
sure depending upon the location of the unit.
Sebaceous cells can metabolize dehydroepian-
drosterone (DHEA) in a stepwise process to
androstenedione, testosterone, and dihydrotestos-
terone (DHT) and thus can be considered intra-
crine cells which convert a prohormone, DHEA,
into a potent hormone, DHT. The hair follicle has
its base a dermal papilla while closer to the skin
are sebaceous glands. The dermal papilla has
enzymes that can produce dihydrotestosterone and
in the presence of IGF 1 hair growth progresses.
Growth hormone is required to produce sexual
hair demonstrating the interaction between andro-
gens and the growth hormone-IGF 1 system.
Idiopathic hirsutism is not related to androgens,
and the etiology of hair growth is not yet clear for
this condition.
Other conditions may have some presenting
symptoms similar to polycystic ovarian syn-
drome. Nonclassic congenital adrenal hyperpla-
sia, most frequently 21-hydroxylase deficiency,
will lead to hirsutism and irregular menses. The
differential diagnosis is confused by the finding of
elevated adrenal androgens in 20–30 % of patients
with PCOS suggesting in some patients a com-
mon disorder of ovaries and adrenals. Further thy-
roid disease may cause irregular menstrual periods
and weight gain, and hyperprolactinemia may
cause irregular periods. These conditions are
discussed in other chapters and should be elimi-
nated before the diagnosis of polycystic ovarian
syndrome is established.
Because polycystic ovarian syndrome is an
insulin-resistant condition and often occurs in the
9 Disorders of Puberty
presence of obesity, girls diagnosed with poly-
cystic ovarian syndrome should be evaluated
for type 2 diabetes; a 2-h glucose tolerance test
and/or a hemoglobin A1c determination are sug-
gested as described in Chap. 11. Because poly-
cystic ovarian syndrome should be considered
the metabolic syndrome of women, screening for
cardiovascular risk factors should be carried out;
family history of cardiovascular disease, strokes
or early deaths, cigarette smoking, hypertension,
dyslipidemia, obstructive sleep apnea, and type 2
diabetes are all risks for cardiovascular disease in
polycystic ovarian syndrome.
Treatment of polycystic ovarian syndrome in
adolescents depends upon the aspect to be
targeted. Obesity should always be treated by
lifestyle modification as the first modality. In the
treatment of acne, hirsutism, and anovulation,
contraceptives should be invoked. The Endocrine
Society could find no basis to recommend one
hormonal contraceptive preparation over
another. Metformin will be indicated in the
presence of type 2 diabetes and may be used (off
label) in prediabetes but also may have a small
but beneficial effect on decreasing weight gain
in some individuals. Small studies suggest that
metformin works better in adolescents than
adults in polycystic ovarian syndrome.
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 Disorders of the Adrenal Gland
Disorders of the adrenal gland can lead to effects
as disparate as abnormal sexual differentiation,
decreased or increased growth velocity, and life-
threatening endocrine emergencies. Diseases can
arise from abnormalities within the adrenal gland
itself, from abnormalities in the control of the
adrenal gland, or from exposure to the exogenous
steroid compounds, even if these are prescribed
for the appropriate treatment of diseases. This
chapter does not discuss congenital adrenal
hyperplasia which is found in Chap. 8.
Normal Adrenal Gland Physiology
The paired adrenal glands sit above the kidney
(which accounts for their archaic name, the supra-
renal glands) and are composed of two major
components derived from different embryonic tis-
sues, the cortex and the medulla (Fig. 10.1). The
adrenal cortex is derived from mesenchyme and
produces steroid compounds synthesized from
the cholesterol molecule; the adrenal medulla is
derived from neural crest tissue and produces
catecholamines.
The median eminence of the hypothalamus
secretes corticotrophin-releasing factor (CRF), a
41-amino-acid peptide that stimulates the release
of adrenocorticotropic hormone (ACTH) from
the anterior pituitary gland.
The adrenal gland histology and function
change considerably between fetal life and child-
hood. The fetal adrenal gland is larger in relation
© Springer International Publishing Switzerland 2016
D.M. Styne, Pediatric Endocrinology, DOI 10.1007/978-3-319-18371-8_10
10
to the body than is true after birth. The fetal adre-
nal gland has a definitive zone in the cortex which
produces glucocorticoid and mineralocorticoid
and a larger fetal zone internally. The fetal zone
lacks 3-beta hydroxysteroid dehydrogenase and
thus produces large quantities of dehydroepian-
drosterone (DHEA) and its sulfate. The steroid
precursors produced by the fetal adrenal zone,
DHEA and variants, are utilized by the placenta to
produce estrogens, estrone, estradiol, estriol, and
estetrol. The level of maternal estrone is an indi-
cator of the health of the fetus. In anencephaly in
which fetal ACTH is extremely decreased and the
fetal adrenal zone is not stimulated, estrone levels
decrease in mother’s samples. Maternal glucocor-
ticoid production increases during pregnancy,
but the placenta through the action of 11-beta-
hydroxysteroid dehydrogenase-1 (11β-HSD1)
inactivates maternal hydrocortisone into the inac-
tive form cortisone. Treatment of mothers with
betamethasone to enhance fetal lung maturation
has not to date been proven to lead to long-term
neurologic or other effects although long-term
studies are ongoing to study the issue. Repeated
courses are recommended in some cases, and
there is some evidence of an increase in congeni-
tal defects, but these are not universal findings.
The premature baby will retain fetal adrenal
function longer than the term baby, and false pos-
itives in the newborn screening test for congeni-
tal adrenal hyperplasia can occur because of this
immaturity. The definitive zone of the fetal adre-
nal develops into the three zones of the mature
233
234 10 Disorders of the Adrenal Gland

Third ventricle Hypothalamus

Neuroendocrine
cell nuclei

CRF secreting cells

Superior
hypophyseal
artery
Stalk

Long portal
vessels
Inferior
Adrenocorticotrophs hypophyseal
artery

Secreting cells

Anterior Posterior
pituitary pituitary

Hormone Short portal

secretion vessel
Glomerulosa
ACTH
Fasciculata

Reticularis

Medulla

Aldosterone Cortisol Androgens Catecholamines

Fig. 10.1 Normal adrenal gland physiology in which
corticotropin-releasing hormone (CRH) from the hypo-
thalamus reaches the pituitary gland through the hypo-
physiotropic portal system to cause ACTH secretion.
ACTH interacts with its receptors on the adrenal glands
to produce cortisol and androgens. Cortisol exerts gluco-
corticoid effects and provides feedback inhibition on the
pituitary gland and hypothalamus to suppress CRH and
ACTH secretion until a normal equilibrium is reached

adrenal gland cortex: the zona glomerulosa, zona
fasciculata, and the zona reticularis going from
the outer most cortex toward the medulla. The
zona glomerulosa predominantly produces min-
eralocorticoids, the zona fasciculata glucocorti-
coids, and the zona reticularis adrenal androgens
although there is overlap between the zones.
The periventricular nucleus of the hypothala-
mus produces and secretes corticotrophin-
releasing factor (CRF) which stimulates the
pituitary production and secretion of adrenocor-
ticotropin or ACTH. Both CRF and vasopressin
are secreted at times of stress and both can
stimulate ACTH secretion. The stress response
Normal Adrenal Gland Physiology
characteristically relates to physical or meta-
bolic stress. Psychological stress can also trig-
ger ACTH release. Other factors enhancing
ACTH secretion are hemorrhagic shock and
hypovolemia. The hypothalamic–pituitary axis
response to stress is essential in insuring appro-
priate cardiovascular response to angiotensin II
and catecholamines and on the other hand inhib-
iting excessive activation of the immune sys-
tem. Inflammatory cytokines including IL-1β,
IL-6, and TNF mediate the adrenal response to
stress in part due to intraadrenal direct stimula-
tion of glucocorticoid production and in part
due to stimulation of CRF and ACTH secretion.
Glucocorticoids are effective in suppressing the
proinflammatory cytokine response characteris-
tic of autoimmune, inflammatory, and allergic
diseases by directly inhibiting the activity of
activated T cells, monocytes, and macrophages
and by decreasing the production of proinflam-
matory cytokines. The lytic effects of glucocor-
ticoids are used in the treatment of leukemia and
other tumors. However, in sepsis and various
other forms of stress, there can be a disassocia-
tion from appropriate adrenal stimulation lead-
ing to critical illness-related corticosteroid
insufficiency (CIRCI) of the HPA axis.
Corticotropin or ACTH is cleaved from the pre-
cursor molecule, pro-opiomelanocortin (POMC),
which also plays a role in appetite regulation
(see Chap. 13), after posttranslational modifica-
tions. ACTH is released in a pulsatile manner with
a diurnal variation of increased values prior to
awakening in the morning which is controlled by
a biological “clock” in the suprachiasmatic
nucleus (SCN) of the ventral hypothalamus.
Other products of the cleavage of POMC that
exert effects on the central nervous system and
elsewhere in the body include α-melanotropin
(α-melanocyte-stimulating hormone, or α-MSH)
which causes pigmentation characteristic of states
where there is increased ACTH secretion,
β-melanotropin (β-MSH), N-terminal peptide of
pro-opiomelanocortin (NPP, or pro-γ-MSH),
γ-melanotropin (γ-MSH), corticotropin-like inter-
mediate peptide (CLIP), β-lipotropin (β-LPH),
lipotropin gamma (γ-LPH), β-endorphin, and
[Met]enkephalin. TNF-α and IL-1β are inflamma-
tory cytokines that increase ACTH secretion; there
235
are saturable transporters that can bring them
across the blood brain barrier.
ACTH is a polypeptide hormone which acts
through a G protein seven-transmembrane domain
receptor, the MC2R receptor. ACTH stimulates
the uptake of LDL cholesterol into the adrenal
gland, to a smaller extent the production of choles-
terol, and ultimately the production of glucocorti-
coids in the zona fasciculate through several steps
(Fig. 10.2). ACTH causes cholesterol esters to be
converted to free cholesterol by cholesterol ester
hydrolase and enables their transport into the mito-
chondria by its effect on the steroidogenic acute
regulatory protein (StAR). Within the mitochon-
dria the side-chain cleavage enzyme (P450 SCC)
converts cholesterol to pregnenolone which is con-
verted to progesterone by 3-beta hydroxysteroid
dehydrogenase. Progesterone is 17-hydroxylated
by 17,20-lyase (P450 C17) and the resulting
17-hydroxyprogesterone is the precursor to
21-hydroxylase (P4 50 C 21). 17-OHP is extremely
elevated in 21-hydroxylase deficiency congenital
adrenal hyperplasia leading to the diagnosis of the
condition. 17-Hydroxyprogesterone is 21-hydrox-
ylated to produce 11-deoxycortisol. Finally
11-deoxycortisol, also known as compound S, is
11-beta hydroxylated (P4 50 C11 beta) to produce
cortisol (also called compound F or hydrocorti-
sone). Cortisol through negative feedback inhibi-
tion of the central nervous system (CNS) reduces
the secretion of CRF and therefore ACTH until
equilibrium is reached.
Cortisol is a glucocorticoid that stimulates
gluconeogenesis, maintains blood pressure, and
affects mood. The secretory rate of cortisol var-
ies depending upon the method of measure-
ment. Stable isotope-dilution technique
employing high-performance liquid chromatog-
raphy–mass spectrometry revealed a secretory
rate of 6.8 ± 1.9 mg/m2/day, while the use of
stable isotope dilution using gas chromatogra-
phy–negative ion chemical ionization mass
spectrometry revealed a secretory rate of
4.8 ± 0.6 mg/m2/24 h in male children and
4.4 ± 0.5 mg/m2/24 h in female children. Presently
most clinicians utilize a normal secretory rate of
6–8 mg/m2/day as a starting point for replacement
therapy and stress dosing with adjustments made
upon the patient’s response: oral glucocorticoid
236 10 Disorders of the Adrenal Gland

Cholesterol
P450SCC
Δ5
Pregnenolone

3β-HSD
P450c17
Progesterone (17α-OH)

P450c17
(17α-OH) Δ5 17-OH
Pregnenolone
P450c17
17-OH (17,20 lyase)
Progesterone
P450c21
P450c21 (21-OH)
(21-OH) 17βHSD-111
Dehydroepiandrosterone Androstenediol
(DHEA)
Deoxycortico-
Sterone 3β-HSD
(DOC) 17βHSD-111
Deoxycortisol (S) Δ4
P450c11β P450c11 Androstenedione Testosterone
(11β-OH) (11β-OH)
P450aro P450aro 5α-
P450c11 AS reductase
(18-OH) Cortisol (tissue)
Estrone Estradiol
17βHSD-1

Corticosterone (B)
Dihydrotestosterone
P450c11 AS
(18-OH)

18-OH Corticosterone
P450c11 AS
(18-oxidase)

Aldosterone

Mineralocorticoid Glucocorticoid Sex steroids

Zona glomerulosa Zona fasciculata Zona reticularis

Fig. 10.2 Normal adrenal gland physiology as gland in which much of the activity that occurs is noted
described in the text. Enzymes are noted in blue, major in bold at the bottom
products are noted in red, and the zone of the adrenal

dosage is about double these values. Most but
not all studies show that increased BMI and
waist–hip ratio and increased visceral fat
increase the ACTH response to stimulatory test-
ing and increase AM cortisol and urinary free
cortisol.
Steroid and thyroid receptors are members of
a “superfamily” including receptors for steroid
hormones (hydrophobic molecules) as well as
thyroid hormones, fatty acids, prostaglandins,
and leukotrienes (see Fig. 1.5). Unbound
glucocorticoid receptors (GR) reside in the
Normal Adrenal Gland Physiology
cytosol in complexes with various proteins
including heat-shock protein 90 (hsp90), heat
shock protein 70 (hsp70), and FKBP52 (FK506-
binding protein 52). Cortisol passively enters the
cells where it binds to the glucocorticoid receptor
(GR) also known as NR3C1 (nuclear receptor
subfamily 3, group C, member 1) releasing the
hsps. The cortisol–receptor complex homodi-
merizes and translocates through active trans-
port to the nucleus, where it binds to
DNA-responsive elements to activate gene tran-
scription in a process known as transactivation.
In other cells the cortisol–receptor complex can
further complex with other transcription factors to
suppress the expression of genes that ordinarily
are unregulated by these transcription factors in a
process known as transrepression.
Cortisol has many metabolic actions in the
body. Cortisol enhances gluconeogenesis and
inhibits production of interleukin (IL) 12, inter-
feron (IFN)-gamma, IFN-alpha, and tumor-
necrosis factor (TNF)-alpha by antigen-presenting
cells (APCs) and T helper (Th)1 cells, while
upregulating IL-4, IL-10, and IL-13 by Th2 cells.
Cortisol enhances glycogenolysis by activating
glycogen phosphorylase, so that epinephrine can
exert its effect on glycogenolysis. Chronic expo-
sure to elevated cortisol as in Cushing syndrome
leads to proteolysis and muscle wasting and
weakness and a decrease in bone formation.
Excess cortisol will inhibit wound healing due to
effects on connective tissue.
Cortisol is metabolized in the liver by reduc-
tion to cortisone, oxidization to 17-ketosteroids,
or hydroxylation to 6-beta-hydroxycortisol. The
metabolites are excreted in the urine as they
become water soluble by conjugation with sul-
fate or glucuronic acid. Metabolism is increased
with elevated thyroid hormone. The kidney also
metabolizes cortisol with 11-beta-hydroxysteroid
dehydrogenase type 2 which converts cortisol to
cortisone. Urinary 17-hydroxycorticosteroids
(17-OHCS) measure both cortisol and its urinary
metabolites.
Each of these enzymatic processes can fail
due to loss-of-function mutations leading to
various types of congenital adrenal hyperplasia.
The lack of cortisol feedback to the hypothalamus
237
and pituitary from these conditions leads to
increased ACTH which causes the adrenal gland
to produce excessive amounts of products
through the remaining operative pathways which
in the most common forms of CAH is androgens
which virilize a female fetus. Congenital adrenal
hyperplasia is named for the large size of the
adrenal glands which occurs because of the
excessive stimulation of ACTH. Even though the
glands are hyperplastic in congenital adrenal
hyperplasia, they do not produce cortisol, unlike
the bilateral adrenal hyperplasia of Cushing dis-
ease. It is important not to confuse the adrenal
hyperplasia of Cushing disease with congenital
adrenal hyperplasia.
Cortisol circulates mostly (80–90 %) protein
bound to cortisol-binding globulin (CBG or trans-
cortin), which serves as a reservoir to smooth out
the peaks and valleys of cortisol secretion. While
cortisol binds to CBG, synthetic glucocorticoids
such as prednisolone or dexamethasone bind
poorly to CBG partially explaining their increased
potency. If excess glucocorticoid is produced, as
in Cushing disease, free cortisol will overwhelm
the available CBG causing increasing free cortisol
levels bringing about excessive glucocorticoid
effects and spillover into the urine as urinary free
cortisol. Like TeBG, CBG increases with
increasing estrogen and decreases with increas-
ing androgen. Autosomal dominant or autoso-
mal recessive CBG deficiency (#611489
CORTICOSTEROID-BINDING GLOBULIN
DEFICIENCY) may be asymptomatic as free
cortisol remains normal, but complaints of fatigue
or hypotension are reported.
The weak adrenal androgen, dehydroepian-
drosterone (DHEA), is produced in the zona retic-
ularis. Production is dependent on the presence of
ACTH, as without ACTH no significant amount
of adrenal androgens will be produced. But DHEA
is produced in increased quantities at the time of
normal puberty; this is not related to a change in
ACTH secretion. The control of this increase in
adrenal secretion, known as adrenarche, is poorly
characterized but does not occur in the absence of
ACTH. It is possible that some undiscovered pitu-
itary hormone or intra-adrenal processes mediate
adrenarche. DHEA is produced from ∆5 17-OH
238
pregnenolone by the 17,20-lyase activity of P450
C17. DHEA serves as a precursor for the more
potent androgens androstenedione, androstene-
diol, and ultimately testosterone from peripheral
conversion (see Chap. 9). These androgens can be
aromatized to estrogen in the periphery. DHEA is
weakly bound to sex hormone binding while
DHEAS is not bound to that protein.
Aldosterone, the main mineralocorticoid of the
adrenal cortex, under normal physiologic condi-
tions is regulated by the renin–angiotensin axis
and less by ACTH. If there is ACTH deficiency as
in secondary or tertiary adrenal insufficiency,
mineralocorticoid function will still remain nor-
mal. However, mineralocorticoids can be secreted
in response to abnormally high concentrations of
ACTH, as found in ectopic ACTH-secreting
tumors. Likewise vasopressin not only stimulates
ACTH secretion but may also exert a brief stimu-
lation of aldosterone secretion. With lowered total
body sodium or hypotension or just simply stand-
ing up, renin, an enzyme produced in the juxta-
glomerular apparatus of the kidney, acts on
angiotensinogen to form angiotensin I; angioten-
sin I is transformed by the converting enzyme of
blood and lung to form the octapeptide, angioten-
sin II. Angiotensin II (and its metabolite angioten-
sin III) stimulates aldosterone production and
secretion from the zona glomerulosa of the adre-
nal cortex. Elevated potassium will also stimulate
aldosterone production.
Aldosterone circulates with about 67 % bound
(17 % bound to transcortin and 47 % to albumin)
with remaining 36 % circulating as free hormone.
Like cortisol, aldosterone is metabolized in the
liver by reduction, oxidization, and hydroxyl-
ation with the major urinary metabolite being
tetrahydroaldosterone glucuronide. Metabolism
is decreased in liver disease.
Similar to cortisol, aldosterone passively
enters the cells where it binds to the aldosterone
receptor or nuclear receptor subfamily 3, group C,
member 2 (NR3C2). The aldosterone–receptor
complex homodimerizes and translocates through
active transport to the nucleus, where it binds to
DNA-responsive elements to activate gene tran-
scription in a process known as transactivation.
Aldosterone interacts with its specific aldoste-
rone receptor or nuclear receptor subfamily 3,
10 Disorders of the Adrenal Gland
group C, member 2 (NR3C2) in a manner similar
to cortisol mostly in the kidney collecting ducts
but has effects on the colon and skin to a minor
degree. Cortisol can interact with the aldosterone
receptor and excessive cortisol exerts a mineralo-
corticoid effect. This effect is decreased by local
conversion of cortisol to the inactive molecule cor-
tisone by 11-beta-hydroxysteroid dehydrogenase 2
decreasing the effect of cortisol on aldosterone-
sensitive tissue.
Aldosterone interacts with its receptor to stim-
ulate the active reabsorption of sodium and chlo-
ride from the proximal convoluted tubule and
excretion of K by the sodium–potassium-
activated adenosine triphosphatase pump (Na(+)–
K(+)-ATPase; Na(+)–K+ pump), as, to a lesser
extent, does its precursor, deoxycorticosterone
(DOC), another potent mineralocorticoid. When
DOC is produced in excess, as in 17-OH defi-
ciency congenital adrenal hyperplasia (CAH), an
increased mineralocorticoid effect will be noted,
but renin will be suppressed, as will aldosterone.
The serum concentrations of sodium and potas-
sium reveal much about mineralocorticoid func-
tion: without mineralocorticoid effect, serum
sodium decreases and serum potassium increases,
whereas in states of excess mineralocorticoid, total
body sodium increases, serum sodium increases to
high normal, and blood pressure increases while
potassium decreases. DOC also is produced in the
zona fasciculata, an ACTH-responsive region of
the adrenal gland that produces mainly cortisol.
Thus, when ACTH is extremely elevated, as found
in ectopic ACTH syndrome, as indicated above,
mineralocorticoid increases and causes hypokale-
mia, possibly with alkalosis, and increased blood
pressure because of sodium retention. The new-
born is relatively insensitive to aldosterone.
Hyponatremia and hyperkalemia due to salt-
losing congenital adrenal hyperplasia do not
develop until 3–5 days after birth which may relate
to the lack of necessity for aldosterone action to
maintain normal sodium and potassium during
these first several days.
Serum ACTH normally increases in the morn-
ing before awakening, at about 4:00–6:00 a.m., in
a person on a customary daily schedule, and serum
cortisol increases in a couple of hours thereafter in
response. Serum concentrations of both ACTH
Measurement of Steroids
and cortisol decrease in the afternoon and evening
as part of the normal circadian rhythm of adrenal
activity. The circadian rhythm of ACTH and corti-
sol is not present in the newborn. It generally takes
up to 7–8 weeks for the normal circadian rhythm
to develop. If an individual changes to a different
sleep–wake cycle than they are used to, there will
be a disorder in the circadian rhythm; after a period
of approximately 21 days, the circadian rhythm
will adjust to the new schedule; thus, a person
waking at night and sleeping during the day will
have the peak of ACTH and cortisol phase shifted
to increase just before awakening at night. The
delay in this adjustment however can lead to physi-
ologic stress in the body; it is likely one of the rea-
sons for “jet lag.”
Because ACTH concentrations vary consider-
ably due to the episodic nature of ACTH secretion,
a single-serum ACTH determination may not be a
valid reflection of the ACTH–cortisol axis. Serum
cortisol concentrations also rise episodically but
are more stable than those of ACTH because of
protein binding of cortisol by CBG and other pro-
teins. Cortisol can be quickly elevated by stress;
unless serum samples for cortisol are obtained
under relaxed conditions or unobtrusively obtained
through an indwelling intravenous catheter, a high
value may be specious. Serum cortisol concentra-
tions, when abnormally elevated for the time of
day, can be considered a reflection of stress or
excessive secretion (as might be seen in Cushing
disease) and the difference between the two is of
great importance. Thus, in Cushing disease evening
cortisol levels may match morning cortisol levels
leading to an overall increase in cortisol effect.
Measurement of Steroids
There are various methods available to measure
steroids in urine and plasma. Radioimmunoassays
are subject to cross-reaction between various ste-
roid molecules which can change results. Thus
the most accurate method of determining steroid
levels in the plasma is the use of high-performance
liquid chromatography (HPLC)/tandem mass
spectroscopy (MS/MS) which is a more expen-
sive method usually available only in national
laboratories but is a much more specific method.
239
It is essential that the values determined by any
method be referenced to standards for the age of
the child. Since not all laboratories have pediatric
standards, it is important to choose a laboratory
that does have standards for the correct age of
your patient. Thus it is generally necessary to
send samples for analysis to larger national labo-
ratories that have the correct techniques and the
correct pediatric standards.
A urinary free cortisol determination is quite
specific for cortisol. Alternative methods measure
17-hydroxycorticosteroid (17-OHCS) which is a
metabolite of cortisol. Normal urinary free corti-
sol is 11 ± 5 mg/m2/day and clearly relates to
body size. An older test, 17-ketogenic steroids, is
rarely invoked nowadays as an indication of uri-
nary glucocorticoid metabolites. Urinary metab-
olites of DHEA and DHEAS are measured as
17-ketosteroids (17 KS). Thus 17-ketosteroids
measure urinary adrenal androgens but do not
measure the more potent testosterone.
Measurement of ACTH presents technical
problems and should be carried out in a reliable
laboratory. Plasma needs to be handled in a sensi-
tive manner and kept cold.
ACTH-stimulation tests are used to determine
adrenal secretory ability and to diagnose congen-
ital adrenal hyperplasia. The standard tests utilize
a sample 30 and 60 min after the intravenous
infusion of synthetic ACTH (1–24). The standard
dose is 15 μg/kg in children up to 2 years of age
and 0.25 mg for children older than 2 years, but
these are maximal doses and it is suggested that
these high doses do not reveal whether the adre-
nal glands can actually mount increased secre-
tory response during stress. A lower dose is
suggested to be better able to determine whether
the adrenal gland is likely to function adequately
in emergency situations. Thus a 1 μg dose is sug-
gested to evaluate the adrenal gland response to
determine if cortisol secretion will rise in stressful
situations or whether exogenous glucocorticoids
should be administered at times of stress. While
there is controversy over the ideal peak of corti-
sol after ACTH stimulation to eliminate risk of
adrenal insufficiency, a peak value of 18–20 μg/dl is
usually considered adequate. There remains con-
troversy over whether the high or low dose ACTH
test is the superior method.
240
Other methods may be invoked to determine
pituitary or adrenal secretory ability. Insulin-
induced hypoglycemia is a dangerous test but
when carefully performed can indicate the ability
of the pituitary gland to secrete adequate ACTH
and the adrenal gland to respond by increasing
cortisol secretion. Insulin-induced hypoglycemia
is considered the “gold standard” for determining
growth hormone secretory ability as well.
Metyrapone blocks 11-hydroxylase and tempo-
rarily renders the adrenal gland incapable of pro-
ducing cortisol leading to an increase in ACTH
due to the decrease in negative feedback inhibi-
tion by cortisol. A rise in 11-deoxycortisol, the
precursor to the block induced by metyrapone,
indicates pituitary ACTH secretory ability; this
test cannot be utilized in primary adrenal failure
since the adrenal gland will not be able to secrete
11-deoxycortisol.
Disorders of the Adrenal Cortex
Hypoadrenal States
The most common causes of decreased cortisol
production are the congenital adrenal hyperplasia
(CAH) syndromes discussed in Chap. 8. In these
conditions, ACTH is elevated due to reduced pro-
duction of cortisol and the ensuing lack of nega-
tive feedback inhibition on ACTH secretion.
Increased cortisol secretion does not occur in
response to the elevated ACTH because of enzy-
matic defects in the adrenal gland which interfere
with the production of cortisol and abnormalities
of adrenal sex steroids and/or mineralocorticoids
occur.
Addison’s Disease (Fig. 10.3)
Addison’s disease is a complete primary adrenal
gland failure, and an affected patient exhibits the
results of glucocorticoid and mineralocorticoid
deficiency. Addison’s disease is rare in pediat-
rics, but the same findings may be found in some
salt-losing forms of CAH or other congenital
defects of the adrenal gland. Because Addison’s
disease is well known and the details of congeni-
tal adrenal hyperplasia are less known, it can be
10 Disorders of the Adrenal Gland
helpful for the parents of a child with congenital
adrenal hyperplasia whenever they need to visit
an emergency department to tell emergency
providers that the child has Addison’s disease to
ensure appropriate treatment. Tuberculous infec-
tion of the adrenal gland was more common in
previous generations and gave rise to most of the
earlier reports of Addison’s disease. Autoimmune
disease is responsible for the majority of cases of
Addison’s disease at present, and often other
associated autoimmune disorders are found as
autoimmune polyendocrinopathy syndromes
(see below). Antibodies to adrenal enzymes
(antibodies to P450c2, the most commonly posi-
tive, or P450scc and P450c17 are tested) are
measurable. Because Addison’s disease causes
progressive destruction of the adrenal gland,
some function may be retained and a patient may
present with glucocorticoid deficiency and only
later develop mineralocorticoid deficiency or
more rarely mineralocorticoid precedes gluco-
corticoid deficiency.
Autoimmune Polyglandular
Endocrinopathy
Type 1 autoimmune polyglandular syndrome
(*240300 AUTOIMMUNE POLYEN-
DOCRINOPATHY SYNDROME, TYPE I)
includes Addison’s disease as well as hypopara-
thyroidism, pernicious anemia, hypoparathy-
roidism, hypogonadism, and type IA diabetes
mellitus and may include autoimmune pituitary
defects. This condition is also known as autoim-
mune polyendocrinopathy-candidiasis-
ectodermal dysplasia (APECED). Chronic muco-
cutaneous candidiasis may be a helpful physical
finding as it is often the first condition noted.
Other findings may be found in the gastrointesti-
nal system (diarrhea or chronic atrophic gastritis)
and integument (vitiligo and alopecia). Antibodies
related to the affected organ system may be
detected in the blood. APECED is caused by
mutations in the “autoimmune regulator” (AIR)
gene. Type I autoimmune polyglandular syn-
drome is characteristically inherited in an autoso-
mal recessive manner, but there are reports of
autosomal dominant inheritance. Adrenal insuffi-
ciency itself can cause elevated TSH suggesting
Disorders of the Adrenal Cortex 241

Third ventricle Hypothalamus

Neuroendocrine
cell nuclei

CRF secreting cells

Superior
hypophyseal
artery
Stalk

Long portal
vessels
Inferior
Adrenocorticotrophs hypophyseal
artery

Secreting cells

Anterior Posterior
pituitary pituitary

Hormone Short portal

secretion vessel
Glomerulosa
ACTH
Fasciculata

Reticularis

Medulla

Aldosterone Cortisol Androgens Catecholamines

Fig. 10.3 The hypothalamic–pituitary–adrenal axis in secretion. ACTH rises in the presence of low values of
primary adrenal failure. In the absence of cortisol produc- cortisol establishing the diagnosis of primary adrenal
tion, there is no feedback inhibition on CRF or ACTH insufficiency

hypothyroidism, but this finding resolves with glu-
cocorticoid therapy; this may make the evaluation
of autoimmune disease more complex.
Type 2 autoimmune polyglandular syndrome
(269200 SCHMIDT SYNDROME), or Schmidt
syndrome, is usually found in middle-aged
women and includes thyroiditis and/or diabetes
mellitus type 1 A and, later, ovarian failure, in
addition to adrenal insufficiency. Other findings
may include alopecia, ophthalmologic findings
(cataracts, keratoconjunctivitis, band keratopathy),
chronic candidiasis of mucosa, skin, and nails,
candidal granuloma, thymoma, thymic dysplasia,
T-lymphocyte deficiency, hypothyroidism,
hyperthyroidism, type IA diabetes mellitus, type
2 diabetes, pernicious anemia, myxedema, tetany
242
and seizures, laryngitis, chronic pulmonary
disease, pancreatic insufficiency, steatorrhea,
chronic hepatitis, cirrhosis, splenic agenesis, and
iron-deficiency anemia. Hypoparathyroidism is
not part of the syndrome. While candidiasis is not
classically described as part of type II autoim-
mune polyglandular syndrome, OMIM lists can-
didiasis as an association in this condition.
Inheritance varies and may be autosomal reces-
sive, autosomal dominant, or multifactorial. A
relation is seen to human leukocyte antigen (HLA)
type DR32 and DR4 and type II autoimmune
polyglandular syndrome.
Type III autoimmune polyglandular syndrome
involves autoimmune hypothyroidism and possibly
type 1 diabetes but not usually adrenal disease.
Wolman Disease
A rare form of mutation of the gene for choles-
terol esterase that limits cholesterol entry into the
steroidogenic pathways is described. Wolman
disease (*278000 WOLMAN DISEASE 10q24-
q25 or primary xanthomatosis) is an autosomal
dominant disorder of adrenal insufficiency that
manifests with vomiting, diarrhea, steatorrhea,
hepatosplenomegaly, hepatic fibrosis, esophageal
varices, and intestinal malabsorption. The condi-
tion leads to cholesterol and triglyceride accumu-
lation in all cells of the body and is ultimately
fatal although bone marrow transplantation has
shown promise in treatment of some. Diffuse par-
ticulate adrenal calcifications are seen on radio-
graph. Laboratory evaluation reveals acid
cholesteryl ester hydrolase deficiency, foam cell
infiltration in the bone marrow as well as dissem-
inated in other organs, vacuolated blood lympho-
cytes, and normal or moderately elevated plasma
lipids with hypercholesterolemia. There are xan-
thomatous changes in the liver, adrenal, spleen,
lymph nodes, bone marrow, small intestine,
lungs, and thymus and slight changes in skin,
retina, and CNS.
Adrenoleukodystrophy
Adrenoleukodystrophy, called bronze Schilder
disease in the past (*300100 ADRENOLEU-
KODYSTROPHY; ALD at Xq28), is an X-linked
disorder that combines degeneration of the white
matter of the brain (causing CNS changes, ulti-
10 Disorders of the Adrenal Gland
mately leading to dementia) with glucocorticoid
deficiency; some individuals also demonstrate
mineralocorticoid deficiency. Blindness, hyper-
pigmentation, degenerative neurologic disorder,
slurred speech, spastic paraplegia, and peripheral
neuropathy are seen; ultimately impotence and
sphincter disturbances develop as well as limb
and truncal ataxia. Primary adrenal failure and
gonadal failure develop in childhood in the usual
presentation of the more severe childhood or
cerebral form while the milder form develops in
adults, termed adrenomyeloneuropathy. Elevated
long-chain fatty acids are found in plasma, fibro-
blasts, amniocytes, and chorionic villi because of
peroxisomal lignoceroyl-coenzyme A (CoA)
ligase deficiency due to mutations in the ATP-
binding cassette, subfamily D, member 1 gene
(ABCD1). On radiographic examination, atrophy
of pons and cerebellum are seen on CT scan. A
defect in the metabolism of very-long-chain fatty
acids is noted, and serum hexacosanoic acid
(c26) is elevated, leading to an abnormally high
ratio of c26/c22 fatty acids. Newborn screening
programs increasingly test for this condition.
This condition must always be in the differential
diagnosis of non-autoimmune adrenal failure.
Congenital Adrenal Hypoplasia or AHC
AHC (*300200 ADRENAL HYPOPLASIA,
CONGENITAL; AHC at Xp21.3-p21.2) may
cause an Addison-like condition, occurring in an
X-linked pattern, with histologic findings of cyto-
megaly; this may be accompanied by hypogonad-
otropic hypogonadism. The X-linked form is due
to mutations in the NR0B1 gene encoding DAX-1
gene and may occur with glycerol kinase defi-
ciency, ornithine transcarbamylase (OTC) defi-
ciency, and muscular dystrophy. An autosomal
pattern of inheritance is described as well (202150
ADRENAL HYPOPLASIA, CONGENITAL,
WITH ABSENT PITUITARY LUTEINIZING
HORMONE), which is associated with the
appearance of a miniature adult cortex and com-
plete lack of the fetal cortex at birth; this also is
associated with the absence of pituitary LH.
Patients have findings of adrenal insufficiency
including glucocorticoid deficiency and miner-
alocorticoid deficiency. Treatment is accom-
plished with replacement of both hormones.
Disorders of the Adrenal Cortex
Congenital Unresponsiveness to ACTH
Congenital unresponsiveness to ACTH is due to
homozygous or compound heterozygous muta-
tion in the gene encoding melanocortin-2 receptor
(MC2R; 607397), which is also the adrenocorti-
cotropin receptor (ACTHR) and presents with
glucocorticoid deficiency but not mineralocorti-
coid deficiency. This receptor is a G protein-cou-
pled cell membrane receptor which exerts effects
through the activation of adenyl cyclase which
leads to increased synthesis of cAMP (see
Chap. 1, Fig. 1.4). This may be found in an auto-
somal recessive pattern in familial glucocorticoid
deficiency type I (#202200 GLUCOCORTICOID
DEFICIENCY 1; GCCD). Familial glucocorti-
coid deficiency type 2 is due to a mutation in the
melanocortin-2 receptor accessory protein or
MRAP also in an autosomal recessive pattern
(#607398 GLUCOCORTICOID DEFICIENCY
2; GCCD2). Symptoms are those of glucocorti-
coid insufficiency without abnormal electrolytes
or dehydration; due to elevated ACTH levels,
hyperpigmentation is prominent. Familial gluco-
corticoid deficiency may combine with alacrima,
achalasia, and autonomic symptoms to cause
Allgrove syndrome (#231550 ACHALASIA-
ADDISONIANISM-ALACRIMA
SYNDROME; AAA at 12q13) due to a mutation
in the ALADIN gene (*605378 ALADIN;
AAAS) in an autosomal recessive pattern. Some
individuals with Allgrove syndrome also demon-
strate mineralocorticoid deficiency.
Secondary or Tertiary Adrenal
Insufficiency (Fig. 10.4)
ACTH deficiency from the pituitary gland or
corticotropin-releasing factor deficiency from the
hypothalamus will lead to glucocorticoid defi-
ciency and androgen deficiency of the adrenal
gland but not mineralocorticoid deficiency. Any
of the tumors noted in Chaps. 3, 5, and 9 can
cause these problems although growth hormone
and other pituitary hormones are usually affected
more frequently than ACTH. Because of coexist-
ing thyrotropin-releasing factor or TSH defi-
ciency due to such tumors, treatment of the
hypothyroidism may bring about adrenal crisis
due to unrecognized deficiency of ACTH or
243
corticotropin-releasing factor; when any form of
hypothyroidism is diagnosed, there must be
consideration of associated glucocorticoid
deficiency.
Congenital defects of pituitary development
lead to multiple pituitary hormone deficiencies
which can include ACTH deficiency as noted in
Chap. 3. Isolated ACTH deficiency is exceed-
ingly rare but reported in an autosomal recessive
pattern (#201400 ICD+ ACTH DEFICIENCY,
ISOLATED; IAD). Another rare condition mani-
festing glucocorticoid deficiency is pro-
opiomelanocortin deficiency (#609734
PRO-OPIOMELANOCORTIN DEFICIENCY)
which is characterized by pale skin color and red
hair associated with insatiable appetite and
remarkable early-onset weight gain. POMC is the
precursor of ACTH and is also an important factor
in the control of appetite as described in Chap. 13.
Proprotein convertase 1/3 deficiency (*162150
PROPROTEIN CONVERTASE, SUBTILISIN/
KEXIN-TYPE, 1; PCSK1), likewise another
rare disorder, leads to early-onset and severe
obesity, but because the processing of POMC is
abnormal, adrenal insufficiency or ACTH defi-
ciency can occur.
Miscellaneous
Adrenal hemorrhage in the newborn may lead to
calcifications within the adrenal gland and a flank
mass and if severe and widespread leads to com-
promise of adrenal function. Cysts and tumors of
the adrenal cortex and medulla also may lead to
calcifications within the adrenal gland. The
Waterhouse–Friderichsen syndrome of adrenal
hemorrhage associated with meningococcemia
or other types of bacterial sepsis is rare but devas-
tating, leading to shock and, if untreated, death.
Meningococcemia is often associated with men-
ingitis. Smith–Lemli–Opitz syndrome (270400
ICD+ SMITH-LEMLI-OPITZ SYNDROME;
SLOS) is a dysmorphic condition which is some-
times associated with adrenal insufficiency due
to mutations in the delta-7-dehydrocholesterol
reductase gene; ambiguous genitalia and cryptor-
chidism may be found in the male as well.
HIV infection can cause adrenal dysfunction
up to adrenal insufficiency by direct glandular
244 10 Disorders of the Adrenal Gland

Third ventricle Hypothalamus

Neuroendocrine
cell nuclei

CRF secreting cells

Superior
hypophyseal
artery
Stalk

Long portal
vessels
Inferior
Adrenocorticotrophs hypophyseal
artery

Secreting cells

Anterior Posterior
pituitary pituitary

Hormone Short portal

secretion vessel
Glomerulosa
ACTH
Fasciculata

Reticularis

Medulla

Aldosterone Cortisol Androgens Catecholamines

Fig. 10.4 The hypothalamic–pituitary–adrenal axis in
secondary (shown here) or tertiary adrenal failure. In the
absence of ACTH, there is no stimulation of the adrenal
gland to produce cortisol and thus ACTH and cortisol val-
ues are both low in secondary hypocortisolism. The same
will happen if there is an absence of CRF in tertiary
hypercortisolism when low ACTH and cortisol values will
result (tertiary hypercortisolism is not demonstrated on
the slide but would be represented by an X over the hypo-
thalamus rather than over the pituitary gland)

invasion by infectious organisms, infiltrate or Symptoms of Adrenal Insufficiency

inflammation associated with chronic viral infec-
tion, or drug effects.
Chemotherapy often includes the use of
prednisone or dexamethasone, both of which can
cause ACTH suppression leading to secondary
adrenal insufficiency.
Acute adrenal crisis may be the first indication
that the child has adrenal insufficiency and may
be fatal if not appropriately treated with correct
fluids, corticosteroids, and glucose. In primary
adrenal gland failure there is characteristically
loss of glucocorticoid and mineralocorticoid
Disorders of the Adrenal Cortex
function. However, acute adrenal crisis may
alternatively occur with abrupt discontinuation of
chronic glucocorticoid therapy (10–14 days can
establish adrenal suppression) without involve-
ment of mineralocorticoid deficiency. Symptoms
of acute adrenal insufficiency include hypoglyce-
mic seizures, abdominal pain, fever, vomiting,
acidemia, hypotensive shock and death, and if it
occurs with mineralocorticoid failure there will be
hyponatremia, hyperkalemia, and hypochloremia.
Symptoms of chronic glucocorticoid deficiency
include weight loss or lack of adequate weight
gain, weakness and lethargy, fatigue, hypoglyce-
mia, and anorexia, whereas mineralocorticoid
deficiency is heralded by hyponatremia with
hyperkalemia, hypotension, low-voltage electro-
cardiogram (ECG) with small heart on radio-
graph, tachycardia, and acidosis.
Glucocorticoid deficiency may lead to an
inability to excrete a water load indicated by a
decrease in urine output, thereby lowering serum
sodium and osmolality by dilutional effects even
without mineralocorticoid deficiency.
ACTH rises in primary adrenal failure and
metabolism of ACTH to melanocortin leads to
hyperpigmentation of exposed skin, especially of
flexural or injured surfaces, as well as hyperpig-
mentation of the gum line. Monilial lesions of the
skin or nails will occur in the syndromes associ-
ated with mucocutaneous candidiasis and adrenal
insufficiency, which combines an immune defect
with an autoimmune disorder of the adrenal
glands. Salt craving may be noted on questioning
if mineralocorticoids are affected as the child may
add a remarkable amount of salt to his or her
food. In mineralocorticoid deficiency, postural
hypotension or an increase in pulse rate on
standing may be seen; a decrease of blood pres-
sure of 10 mmHg or an increase in pulse rate of
20 is considered significant (autonomic dys-
function is a relatively common cause of pos-
tural hypotension while mineralocorticoid
deficiency is much more rare).
Administration of fluid volume and glucose is
a necessary therapy along with glucocorticoid
replacement. Serum sodium will be low, and
serum potassium will be high if mineralocorti-
coid secretion is low; replacement of sodium and
mineralocorticoid is an appropriate therapy.
245
Glucose/insulin infusions or oral potassium-
retaining resin may be used to bring about a rapid
decrease in extremely elevated serum K if ECG
changes (peaked T waves) suggest such severe
hyperkalemia.
Deficiency of pituitary ACTH (secondary
adrenal insufficiency) or hypothalamic CRF (ter-
tiary adrenal insufficiency) may occur from a
congenital defect or a hypothalamic–pituitary
tumor; usually an associated deficiency of other
anterior pituitary hormones is noted (see Chap.
3). Vasopressin deficiency may accompany the
ACTH deficiency and diabetes insipidus may be
masked due to the inability to excrete a water
load due to glucocorticoid deficiency as described
above. Thus with glucocorticoid treatment,
diabetes insipidus might develop clinically.
Mineralocorticoid function should be normal in
secondary or tertiary adrenal insufficiency.
Diagnosis of Hypoadrenal States
Laboratory evaluation of primary adrenal failure
will demonstrate elevated ACTH concentrations
at any time of the day. Serum cortisol measures
CBG-bound cortisol and free cortisol. Decreased
cortisol concentrations when measured in the
morning hours (because values are already low in
the evening, measurement then may not
differentiate between normal and abnormal val-
ues) (Fig. 10.2) suggest deficient glucocorticoid
secretion. Reduced cortisol reserve is noted on
ACTH-stimulation testing or insulin-induced
hypoglycemia (we do not recommend insulin-
induced hypoglycemia testing if the physician has
no previous experience in performing this danger-
ous test in children). The ACTH test is accom-
plished by the administration of 0.25 mg of
intravenous (i.v.) synthetic 1–24 ACTH, or in the
low-dose test 1 μg of synthetic 1–24 ACTH, at or
before 8 a.m. and measuring cortisol at 0, 30 and
60 min; a value over 18–20 μg/dL is considered
normal. The metyrapone test is used more rarely
than an ACTH-stimulation test. Metyrapone
administration leads to an 11-OH block so that, in
a normal subject, cortisol decreases while ACTH
and 11-OH deoxycorticosterone increase (as do
urinary 17-OH corticosteroids), indicating normal
ACTH reserve. Thus an 8 a.m. serum cortisol,
11-deoxycortisol, and ACTH are determined, and
246 10 Disorders of the Adrenal Gland

a 24-h urine for 17-OHCS is collected the day
before and the day after the metyrapone is given;
a fourfold increase in 11-deoxycortisol or a 70 %
increase in urinary 17-OHCS is a normal response.
Metyrapone is given in a dose of 300 mg/m2 every
4 h for a total of six doses over a 24-h period, but
a total dose should be no more than 3 g.
Alternatively, older children are given 30 mg/kg
at midnight (with food), and a blood sample is
taken the morning before the metyrapone and the
morning after.
Other signs of autoimmune phenomena, such
as Hashimoto thyroiditis or diabetes mellitus,
may be found if an autoimmune polyglandular
syndrome is suspected. Antibodies to the thyroid,
the pancreas, or the ovaries may be obtained in
such a situation.
Treatment of Hypoadrenal States
Note: There is a well-known effect of immunosup-
pression caused by glucocorticoids, but in gluco-
corticoid deficiency states, it is essential that the
glucocorticoids are administered in the recom-
mended doses to replace the deficit or to treat a
stressful situation including infections. In these
situations, there should be no immunosuppres-
sive effect from glucocorticoid administered for
these reasons but if they are not administered to
replace the deficit shock due to acute adrenal
insufficiency may occur.
If adrenal function is inadequate, the goal is
the replacement of glucocorticoid, or if necessary
mineralocorticoid, in physiologic dosage (see
Chap. 14 for more discussion of acute adrenal
insufficiency). This is difficult in view of the
episodic secretion of cortisol and circadian varia-
tion, so only a few doses per day of replacement
glucocorticoids are used. In general, natural
glucocorticoid, cortisol or hydrocortisone, is
preferable during the growing years, but the more
potent, longer lasting glucocorticoids, such as
prednisone, are used after growth has ceased,
mainly because of the ability to cut dosage to
twice per day, or dexamethasone can be used
which can be given once per day. Table 10.1
shows the difference in potency of various prepa-
rations as to glucocorticoid or mineralocorticoid
effects. Note that prednisone must be converted
to prednisolone, and cortisone must be converted
by 11-beta HSD1 to cortisol for biologic activity,
and these medications are therefore given in rela-
tively higher dosage than the more active forms.
Prednisone and cortisol should not be used for
emergency treatment because of the lag in time
for the conversion to be carried out. The secre-
tory rate of cortisol is usually accepted to be
6–8 mg/m2 (see discussion above for details).
Because oral absorption is half the parenteral
absorption, the rate is doubled and administered
orally three times per day, with most given in the
morning, unless the problem is virilizing CAH,
when the time of administration may change
(see Chap. 8). Thus for a 1-m2 child, the oral dose
would be 12–14 mg, but because 5- or 10-mg tab-
lets are the only available oral form, 15 mg is
used, with 5 mg t.i.d. or 10 mg by giving 2.5 mg
in the morning, 2.5 mg in the early afternoon, and
5 mg at bedtime. Suspensions made by com-
pounding pharmacy should not be used for treat-
ment due to irregularity of the amount of
glucocorticoid in each dose. However, smaller
doses for infants may be carefully prepared at

Table 10.1 Glucocorticoid preparations and relative glucocorticoid and mineralocorticoid effect
Glucocorticoid effect (based Mineralocorticoid effect
on anti-inflammatory effect with [fludrocortisone Time of biologic
cortisol = 1.0) (Florinef) = 1.0] action (h)
Cortisol (hydrocortisone) 1 0.005 8
Cortisone 0.8 0.005 8
Prednisone 4 0 18
Prednisolone 4–5 0 16–36
6α-Methylprednisolone 5–8 0 16–36 est
Dexamethasone 27–66 0 36–54
9α-Fluorocortisone 15 1
Disorders of the Adrenal Cortex
home by adding a half of a 5-mg tablet to a given
amount of water or formula before each dose and
calculating the amount of the suspension to be
administered which will yield the desired dose
after shaking it to briefly resuspend it. The cor-
rect dosage cannot be measured by laboratory
methods, but if the child feels well, vital signs are
normal and the child is not gaining excessive
weight, nor is demonstrating a decreasing growth
rate, the dosage is likely to be appropriate (see
Chap. 8 for dosage in virilizing CAH). In times
of stress, fever, surgery, or accidents (but not usu-
ally psychological stress), the dose is doubled or
tripled until the condition is resolved. At times of
severe stress (severe accident or shock) or a sur-
gical procedure when the child is not able to take
medication orally, injectable glucocorticoid in
the form of Solu-Cortef in a Redivial© that com-
bines diluent and powdered medication in one
action of a rubber stopper is easiest to use; gener-
alized doses are 25 mg for infants, 50 mg for
smaller children, and 100 mg for adolescents to
be given immediately upon noting the severe
condition and certainly before the child is taken
to the emergency department (ED) at times of
emergency. No danger occurs in giving one dose
of the medication inappropriately, but not giving
the dose when needed can be serious or fatal.
Intramuscular (i.m.) cortisone takes hours to work
and should never be used as emergency treatment.
The child should wear a MedAlert bracelet or
necklace stating the steroid dependence and a let-
ter, telling any ED doctor the problem, should be
carried at all times if possible. In the ED, sugar,
fluid, glucocorticoid, and if salt losing is part of
the problem, NaCl and mineralocorticoid are
given immediately. As stated above the letter or
MedAlert bracelet might state Addison’s disease
even if the child has salt-losing congenital adrenal
hyperplasia for ease of communication.
When there is salt losing, mineralocorticoid is
given as 9α-fluorohydrocortisone, or Florinef
which allows salt retention. Dosage is meant to
keep body sodium in an adequate range, so the
plasma renin activity (PRA) is kept in the normal
range; Florinef is increased if PRA is too high
and decreased if PRA is too low or if blood pres-
sure rises too high. Florinef is given once or twice
per day. Oral sodium supplementation may be
247
needed to keep the Florinef dose in the 0.05 to
0.15 mg/day range. Usually older children will
self-select the correct amount of salt to meet their
needs, but infants may need added salt. Sodium
chloride or table salt is given as measured by the
teaspoon or by a test tube marked to hold 1 g or
more. Salt tablets are available which often con-
tain 1 mg each and a solution might be made in
which the salt tablet or portion of it is dissolved in
water or formula and a calculated amount to
deliver the required dose be given to the infant.
Note that cortisol and cortisone have some miner-
alocorticoid effect (Table 10.1), whereas the
more potent glucocorticoids do not; if switching
from one preparation to the other, watch for a
change in sodium balance or adjust/add miner-
alocorticoid to the regimen. Shock is a real pos-
sibility if mineralocorticoid deficiency or sodium
deficiency develops.
It is imperative that if hypothyroidism and glu-
cocorticoid deficiency coexist, the glucocorticoid
be instituted before thyroid hormone, or the mini-
mal glucocorticoid that may be present endoge-
nously will be more rapidly metabolized, leading
to acute glucocorticoid-deficient crisis.
Glucocorticoid Withdrawal
Iatrogenic glucocorticoid deficiency is caused by
the abrupt discontinuation of glucocorticoids
after adrenal suppression. This may occur after
therapy for a glucocorticoid-responsive disease
or after the removal of a glucocorticoid-secreting
adrenal tumor or condition, such as one causing
Cushing syndrome. Generally, more than
10–14 days of glucocorticoid therapy will lead to
suppression of endogenous ACTH secretion and,
with increased use, some degree of atrophy of the
adrenal gland. This process must be reversed
before the individual is able to mount a response
to stress. Depending on the dose, potency of the
glucocorticoid, and length of therapy, it may take
months for ACTH to increase and more months
for cortisol to follow suit. Nighttime administra-
tion of exogenous glucocorticoid is more likely
to affect the peak of ACTH secretion and cause
longer suppression, whereas every-other-day
glucocorticoid administration has less effect.
The tolerance of a patient for glucocorticoid
discontinuation is difficult to define, but it is prudent
248
to wean the child off slowly rather than cutting
the therapy immediately if any question of adre-
nal suppression is seen. Symptoms of the steroid-
withdrawal syndrome that occurs if weaning is
too rapid include headache, myalgia, arthralgia,
and fever, although patients receiving glucocorti-
coids for specific diseases may experience resur-
gence of symptoms of those diseases and confuse
the situation. Many schemas exist for weaning an
individual off glucocorticoids; the following is
only one possibility. The dose of glucocorticoid
may be decreased 25 % per week until the physi-
ologic range is reached at which time weaning
slows considerably until the glucocorticoid is
discontinued. Normal endogenous production is
about 6–8 mg/m2/day (see discussion above), but
oral medication is only 50 % absorbed, and so the
physiologic ranges start at double this secretory
rate. For example, for a child taking 20–30 mg of
prednisone divided into two doses per day (which
is equivalent in bioactivity to about 120–160 mg
of cortisol) for more than 1 month, the dose may
be cut to 15 mg of prednisone for 1 week, to
10 mg for 1 week, to 5 mg for 2 weeks, and then
switched to 20 mg of hydrocortisone (divided
into two doses per day) for 1 week and 10 mg for
1 week, and then the medication may be given
only in the morning until the a.m. cortisol (mea-
sured before the cortisol dose) is demonstrated to
be greater than 10 μg/dL. With long term sup-
pression weaning must proceed slower. An a.m.
serum cortisol greater than 15–20 μg/dL indi-
cates adequate basal adrenal function, but the
subject may not yet have adequate reserves of
ACTH for stress. Thus an ACTH-stimulation test
using 0.25 mg i.m. or i.v. cosyntropin or, a 1 μg
intravenous low-dose test, with a measurement of
serum cortisol in 60 min greater than 20 μg/dL
indicates good reserve. A stress dosage of gluco-
corticoids (2–3 times normal basal secretion of
8 mg/m2/day given parenterally if the child can-
not swallow or is vomiting or orally at double this
dose) must be administered if the child has an ill-
ness or accident or if surgery is required before
adrenal reserve returns (see Chap. 8 concerning
CAH). It is useful for the child to wear a MedAlert
bracelet to notify the emergency staff of reduced
adrenal reserve should an emergency room visit
be required.
10 Disorders of the Adrenal Gland
Aldosterone Insufficiency
or Resistance
The production of aldosterone may be impaired in
11-beta hydroxylase deficiency congenital adrenal
hyperplasia or primary adrenal failure. ACTH defi-
ciency will not cause aldosterone deficiency.
Resistance to aldosterone occurs in the new-
born demonstrated by elevated plasma aldoste-
rone levels and a tendency toward hyperkalemia
and hyponatremia which resolve several days
after birth. Alternatively, resistance may be due
to pseudohypoaldosteronism (#177735 PSEUDO
HYPOALDOSTERONISM, TYPE I, AUTOSO
MAL DOMINANT; PHA1A) due to mutations in
the aldosterone receptor (a member of the nuclear
receptor subfamily 3, group C, member 2 gene
(NR3C2)) found in autosomal dominant pattern.
Clinical features include dehydration although
some patients are asymptomatic. Laboratory
findings include metabolic acidosis with hypona-
tremia, hyperkalemia, increased serum aldoste-
rone, and increased plasma renin activity.
Treatment is accomplished with sodium chlo-
ride administration.
A group of five conditions compromise pseudo-
hypoaldosteronism type II; (%145260 ICD+
PSEUDOHYPOALDOSTERONISM, TYPE IIA;
PHA2A) is due to mutations on chromosome
1q31-q42, PHA2B, due to mutations on the WNK4
gene on chromosome 17q21, PHA2C due to
mutations on the WNK1 gene on chromosome
12p13, PHA2D due to mutations on the KLHL3
gene on chromosome 5q31, and PHA2E due to
mutations in the CUL3 gene on chromosome 2q36.
Administration of Florinef should cause reso-
lution of hyponatremia and hyperkalemia in
aldosterone deficiency but not in aldosterone
resistance. Administration of sodium chloride as
used in salt-losing congenital adrenal hyperplasia
will help resolve the electrolyte abnormalities in
pseudohypoaldosteronism.
Adrenal Calcifications
Adrenal calcifications may be asymptomatic or
may be associated with pathological states.
Thus Addison’s disease; adrenal hemorrhage;
Disorders of the Adrenal Cortex
Waterhouse-Friderichsen syndrome; tumors
including neuroblastoma, pheochromocytoma,
adrenal adenoma, or carcinoma; and infections
including TB and Wolman disease may have
associated adrenal calcification.
Hyperadrenal States
Cushing Syndrome
Cushing syndrome refers to the general class of
disorders with increased glucocorticoid effect,
including those due to exogenous glucocorticoid
intake. The specific causes of endogenous hyper-
cortisolism include conditions secondary to
increased pituitary ACTH secretion (only this
form is termed Cushing disease), ectopic ACTH
secretion, autonomous cortisol secretion by the
adrenal gland, or glucocorticoid therapy be it
oral, parenteral, inhaled, or dermal. Before age
7 years, the usual cause of Cushing syndrome is
an adrenal tumor, whereas thereafter, increased
pituitary ACTH secretion characteristic of
Cushing disease becomes a more common etiol-
ogy. Hypercortisolism has wide-ranging effects
on the body, including decreased growth rate;
weight gain in a general truncal or centripetal
pattern, leading to the characteristic buffalo hump
of excessive adipose deposition on the back and a
characteristic round face (moon facies); muscle
weakness, especially in the distal regions, lead-
ing to thinning of the extremities while weight
gain progresses; thinning of the skin, leading to
purple striae (or the so-called cigarette paper skin
referring to the extreme thinness of the skin that
leads to the visibility of the underlying capillar-
ies); hypertension; fatigue; and insulin resistance.
Osteopenia or osteoporosis can lead to multiple
fractures of the spine and other bones. Acne and
hirsutism as well as delayed puberty are often
found in older children. Because the mineralo-
corticoid receptors respond to cortisol especially
in severely elevated levels, an excess of cortisol
leads to salt retention and hypertension (although
such activity is usually minimized by the
11β-hydroxylation by 11-beta HSD2 of excess
cortisol to cortisone, which is inactive). If the
cause of the excess glucocorticoid is excess
ACTH, hyperpigmentation will be found, as
249
described earlier for Addison’s disease. Delay in
diagnosis is frequent with subtle symptoms preced-
ing the diagnosis by years.
Cushing Disease: Hypercortisolism
due to Increased ACTH Secretion
(Fig. 10.5)
An abnormal regulation of the pituitary–adrenal
axis leads to the specific diagnosis of Cushing
disease (called bilateral adrenal hyperplasia,
because of the enlarged appearance of both adre-
nal glands, even though the etiology is in the
hypothalamic–pituitary axis; this should not be
confused with congenital adrenal hyperplasia).
The original report by Cushing describes a patient
with a basophilic adenoma and physical signs of
hypercortisolism, but it was not until 50 years
later that the primary importance of the pituitary
microadenomas in these patients was proven.
The fact that about 20 % of patients appropriately
treated with pituitary microadenomectomy have
recurrences indicates that basic hypersecretion of
hypothalamic CRF may be the etiologic agent for
a minority of patients with Cushing disease.
Cushing disease in childhood first manifests
with growth failure and weight gain in the truncal or
centripetal pattern, with thin and weak extremities.
Other features may include the classic cushingoid
appearance of a buffalo hump of adipose tissue on
the back of the neck; purple striae of the trunk due
to thinning of the skin and exposure of the capillar-
ies; sometimes, but not invariably, pigmentation of
the flexural surfaces and gums; lack of energy; and
the early appearance of acne or pubic hair due to
increased DHEA secretion because of increased
ACTH stimulation. Excess glucocorticoids cause
protein catabolism and results in muscle wasting
and weakness. The personality of patients with
Cushing disease may be abnormal, and some
describe the children as obsessive. The diastolic and
systolic blood pressure may be elevated.
Because of the small size of the usual lesion,
usually less than 10 mm, neurologic symptoms or
signs are not found in Cushing disease unless the
mass has progressed markedly. Contrast-enhanced
MRI in some cases may indicate the location of
the microadenoma but is not always success-
ful. Indeed, unless the surgeon has great experi-
ence in individual detection of the microadenoma
250 10 Disorders of the Adrenal Gland

Third ventricle Hypothalamus

Neuroendocrine
cell nuclei

CRF-secreting cells

Superior
hypophyseal
artery
Stalk

Long portal
vessels
Inferior
Adrenocorticotrophs hypophyseal
artery

Secreting cells

Anterior Posterior
pituitary pituitary

Hormone Short portal

secretion vessel
Glomerulosa
+ ACTH
Fasciculata

Reticularis

Medulla

Aldosterone Cortisol Androgens Catecholamines

Fig. 10.5 Endocrine changes of Cushing disease due to values in the presence of elevated cortisol values. ACTH-
increased ACTH secretion escaping from feedback inhibi- secreting pituitary adenomas or ectopic production of
tion leading to inappropriately normal or elevated ACTH ACTH will present in a similar manner

of Cushing disease and the subtle changes in
appearance between the microadenoma and nor-
mal pituitary tissue may be missed. The majority
of patients successfully treated with removal of
the microadenoma of the pituitary gland ulti-
mately regain normal diurnal variation of cortisol
and ACTH and the growth hormone deficiency
that may accompany the microadenoma usually
resolves although it may take months to years.
Microadenomectomy may have to be repeated
and may ultimately fail in some patients.
Hypophysectomy may be required leading to
hypopituitarism, but these deficiencies can be
treated. Irradiation of the pituitary gland is an
alternative approach and may also lead to hypopi-
tuitarism in subsequent years.
Medical treatments are available. Metyrapone
will lead to only a temporary suppression of adrenal
Disorders of the Adrenal Cortex 251

production of glucocorticoids while ortho,para- pigmentation is known as Nelson syndrome which

DDD (mitotane) leads to a more permanent sup-
pression of adrenal function although substantial
side effects limit its usefulness in children. If the
adrenal glands are removed in an attempt to treat the
disease without successful removal of the etiology
which is the increase in ACTH secretion, enlarge-
ment of the unsuppressed pituitary gland leads to
pressure effects on the surrounding tissue, including
the optic chiasm; this in addition to extreme hyper-
is more often found in adults than children.
Cushing Syndrome due to Autonomous
Cortisol Secretion (Fig. 10.6)
Nodular Adrenal Hyperplasia or Adrenal
Tumors
Under the age of 7 years adrenal tumors take
precedence in the etiology of Cushing syndrome

Third ventricle Hypothalamus

Neuroendocrine
cell nuclei

CRF-secreting cells

Superior
hypophyseal
artery
Stalk

Long portal
vessels
Inferior
Adrenocorticotrophs hypophyseal
artery

Secreting cells

Anterior Posterior
pituitary pituitary

Hormone Short portal

secretion vessel
Glomerulosa
ACTH
Fasciculata

Reticularis

Medulla

Aldosterone Cortisol Androgens Catecholamines

Fig. 10.6 Endocrine changes of Cushing syndrome due to autonomous production of cortisol. Elevated cortisol secretion
exerts negative feedback inhibition on the hypothalamic pituitary axis leading to low ACTH values
252
while over 7 years Cushing disease is more
frequent.
Autonomous cortisol secretion may be seen in
adrenal carcinoma or in single or multiple autono-
mous nodules of the adrenal gland(s). Adenomas
or carcinomas of the adrenal glands may be found
in conditions of asymmetry such as the Beckwith–
Wiedemann syndrome (see Chap. 12). A carci-
noma of the adrenal gland often is difficult to
differentiate from a benign tumor of the gland;
pathologic criteria are available, but often, clini-
cal observation is necessary to define the differ-
ence between a carcinoma and an adenoma.
Carcinomas of the adrenal gland may have defects
in 3β-hydroxylase and secrete large amounts of
DHEA as well as cortisol, leading to a greater
amount of virilization than found with the other
causes of Cushing syndrome such as adrenal ade-
nomas which tend to produce only glucocorti-
coids. Testosterone may be produced directly by
such tumors, and severe virilization has been
seen; the differential diagnosis should include vir-
ilizing ovarian tumors in girls. Because the natu-
ral history of any condition will start with subtle
signs, apparent premature adrenarche without
other definitive signs of virilization may be the
first indication of the presence of an adrenal tumor
and demonstrates the importance of follow-up
even in apparently benign conditions. Feminizing
tumors of the adrenal gland have been rarely
reported in childhood. The treatment of adrenal
tumors is surgical removal although suppression
of the steroid production with the ortho,para-
DDD (mitotane) has been used when surgery was
ineffective in removing all traces of the tumor.
Nodular adrenal hyperplasia is characterized
by areas of active autonomously secreting adre-
nal tissue in an ACTH-independent manner inter-
spersed with areas of quiescent gland on
histologic examination which is due to feedback
inhibition of ACTH secretion by the secretion of
cortisol from the active nodules. The macronodu-
lar form may be associated with McCune–
Albright syndrome (see Chap. 9) in association
with other hyperactive endocrine conditions,
polyostotic fibrous dysplasia, and café au lait
spots of the skin or may be found in multiple
endocrine neoplasia type I (MEN 1).
10 Disorders of the Adrenal Gland
There are two micronodular types of nodular
adrenal hyperplasia, primary pigmented nodular
adrenocortical disease (PPNAD) or isolated
micronodular adrenocortical disease. PPNAD
(10489 PIGMENTED NODULAR
ADRENOCORTICAL DISEASE, PRIMARY, 1;
PPNAD) is characterized histologically by pig-
mented nodules in the adrenal cortex which
secrete glucocorticoids and androgens; these
tumors remarkably increase glucocorticoid
secretion in response to a high-dose
dexamethasone-suppression test while in the nor-
mal situation dexamethasone administration
should suppress glucocorticoid secretion. The
clinical findings of Cushing syndrome will
develop. PPAND is usually found as part of the
Carney complex (#160980 CARNEY COMPLEX,
TYPE 1; CNC10). The Carney complex is an
autosomal dominant multiple endocrine neopla-
sia condition with many physical manifestations
of the eye (conjunctival and scleral pigmenta-
tion), the heart (atrial or ventricular myxoma
with congenital heart failure), the skin (numerous
pigmented nevi, sometimes blue, and lentigines),
hirsutism and red hair, and a tendency to a host of
neoplasias including subcutaneous tumors, Sertoli
cell tumors, mammary ductal fibroadenomas,
Schwannomas, thyroid carcinomas, and pheo-
chromocytomas. Pituitary adenomas will usually
secrete growth hormone and can cause gigantism
in younger individual or acromegaly in older indi-
viduals while prolactin secretion and galactorrhea
may also occur. Differentiated thyroid carcinoma
is associated with the Carney complex as are cal-
cified Sertoli cell tumors of the Leydig cells which
may be indicated by the development of gyneco-
mastia. The Carney complex is found with muta-
tions in the cAMP-dependent protein kinase,
regulatory, type I, alpha gene.
Ectopic ACTH Secretion
Ectopic secretion of ACTH is exceedingly rare in
childhood but has been reported in Wilms tumors
and in islet cell carcinoma of the pancreas. Serum
ACTH values may exceed 1,000 pg/mL, although
modest elevations may be seen at first. The excep-
tional elevations can stimulate mineralocorticoid
production, although mineralocorticoids are not
Disorders of the Adrenal Cortex 253

Poor growth with weight gain

Evaluate as described in Chapter 4 for hypothyroidism, Chapter 5 for growth hormone deficiency, Chapter 7 for pseudohypoparathyroidism

Exogenous source of glucocorticoids by mouth, skin or respiratory system

No Yes

Obtain 24 hour urinary free cortisol or Overnight dexamethasone suppression test

AM cortisol not suppressed AM cortisol suppressed

Elevated Normal two times Exogenous Cushing syndrome

Serum ACTH Cushing disease/syndrome unlikely

common obesity possible

Extremely high High or AM range values Low

found in the PM

Perform high dose Adrenal adenoma or

dexamethasone suppression test carcinoma possible

Not suppressed Suppressed

Exotopic ACTH Cushing disease possible

secretion possible

Fig. 10.7 The evaluation of hypercortisolism

normally very responsive to ACTH in the physio-
logic state, leading to salt retention and potassium
excretion; hypertension, hypokalemic alkalosis,
and subsequent muscle weakness will result. It is
rare to see such excess mineralocorticoid produc-
tion in Cushing disease.
Differential Diagnosis of Cushing Disease
Serum ACTH is not necessarily strikingly ele-
vated in Cushing disease; the finding of a concen-
tration of ACTH more characteristic of the
morning (higher) in the afternoon (i.e., ACTH
concentration is too high for the time of day)
associated with a value of cortisol also too high
for the afternoon or evening is suggestive of
abnormality in the regulation of the ACTH–
cortisol axis (Fig. 10.3). It must be remembered,
however, that stress or even depression will ele-
vate both ACTH and cortisol levels, will be asso-
ciated with aberrant diurnal rhythms, and can
falsely suggest Cushing disease. Pseudocushing
syndrome denotes a situation with many or most
symptoms and signs of Cushing disease, but they
are secondary to other conditions including
severe emotional or pathophysiological stress,
depression, panic disorders, and psychosis as
well as alcoholism or alcohol withdrawal. As
most patients with Cushing disease are obese, the
differential diagnosis is often between exogenous
obesity and Cushing disease (Fig. 10.7).
Urinary metabolites of cortisol are measured as
17-hydroxycorticosteroids (17-OHCS) which
measure both cortisol and its urinary metabolites
and the more specific urinary free cortisol measur-
ing only free cortisol. Normal urinary free cortisol
is 11 ± 5 mg/m2/day. The urinary 17-OHCs and
urinary free cortisol may be elevated for age in
exogenous obesity because of the changes in glu-
cocorticoid metabolism brought about by obesity,
thereby confusing the diagnosis in an obese indi-
vidual, but in Cushing disease, the values will be
higher when corrected for body surface area than
those found in obesity (24-h urinary 17-OHCs
greater than 4.5 mg/m2 and urinary free cortisol
greater than 70 g/m2 are highly suggestive of
hypercortisolism). The great variations in urinary
values from day to day and the difficulty in col-
lecting a full 24-h sample of urine in childhood
mandate that at least two baseline urine collections
are evaluated and collected for glucocorticoid
determinations. The collection should be standard-
ized by creatinine determination.
A midnight blood sample for cortisol in a nor-
mal individual should reveal a value lower than
2 μg/L in the resting individuals in whom an IV
catheter has already been placed so as not to
254
disturb the patient; if the patient awakens, corti-
sol will rise and the diagnosis will still be uncer-
tain. An overnight dexamethasone-suppression
test may be used to screen patients for Cushing
disease, but this test has a high incidence of
false-positive results, although the rate of false
negatives is low; 1 mg of dexamethasone
(0.3 mg/m2 or 15 μg/kg body weight is used for
smaller children) is given orally at midnight, and
a serum sample is analyzed for cortisol at 8:00–
9:00 a.m. the next morning. In presumptive
Cushing disease, plasma cortisol will not be sup-
pressed below 1.8 mg/dL, whereas in exogenous
obesity, the values decrease below 1.8 mg/dL
which is a negative test. If the results are nega-
tive, Cushing disease is unlikely, but if the results
are positive, the following tests are considered.
Salivary cortisol may replace plasma cortisol
measurements in this test.
The classic tests for the differential diagnosis
of Cushing syndrome are the classic dexametha-
sone-suppression tests. In any test requiring
urinary collections, two baseline 24-h urinary
collections are required and the collection is best
carried out in a clinical research unit if possible
due to the vagaries of collection at home. To
insure complete collection, results are character-
istically expressed per gram creatinine. The
low-dose dexamethasone-suppression test uses
1.25 mg/m2/24 h or 30 μg/kg/dose up to 0.5 mg per
dose given as four doses per day for 2 days; if the
urinary 17-OHCs on the second day of the test
decrease 50 % from the two baseline collections
(or if the 17-OHCs are less than 1 mg/m2 and the
urine free cortisol less than 25 μg/m2), the patient
is likely to have exogenous obesity because
they are easily suppressible. It is useful to collect
serum ACTH and cortisol concentrations early in
the morning (6–8 a.m.) and at night (best at mid-
night but could be as early as 8 p.m.) during the
baseline and dexamethasone-suppression phases
of the test to see if serum values also are affected
(e.g., if the cortisol is suppressed to less than
1.8 μg/dL and the ACTH to less than 25 pg/mL);
triplicate sampling is recommended for the
ACTH and cortisol samples because of pulsatile
secretion. Since it will take a while to receive the
results of a low-dose test, the high-dose dexa-
methasone test is usually carried out immediately
10 Disorders of the Adrenal Gland
following the low-dose test, thereby eliminating
the need for 48 h of baseline urine collection
once again. The high-dose dexamethasone-
suppression test is performed to differentiate
between Cushing disease and Cushing syndrome
from other causes. In the high-dose dexameth-
asone-suppression test, 3.75 mg/m2/24 h or
120 μg/kg/dose of dexamethasone (maximum 2
mg/dose) is given as four doses a day for 2 days,
and urinary 17-OHC excretion on the second day
is compared with the two baseline collections; in
Cushing disease, complete suppression of uri-
nary 17-OHCs (<1 mg/kg creatinine) and free
cortisol will occur, whereas in the ectopic ACTH
syndrome or with autonomous cortisol secretion,
no suppression will be seen over baseline levels.
Remarkably in PPNAD there may be a paradoxi-
cal increase in cortisol secretion after high-dose
suppression as noted above.
Ovine CRF infusion is reported as a useful
measure for the differential diagnosis between
Cushing syndrome and Cushing disease as a cor-
tisol value >1.4 μg/dL following a low dose
dexamethasone suppression test as described
above indicates the diagnosis of Cushing syn-
drome and should lead to further evaluation.
However, severe obesity alters results and may
limit the utility of this test. A patient with auton-
omous cortisol secretion will have low basal
ACTH values, a value over 29 pg/mL leads to
the diagnosis of ACTH dependent Cushing syn-
drome. A patient with ACTH dependent Cushing
syndrome will not have an increase in ACTH
with CRF administration. A patient with ectopic
ACTH secretion will have a high basal ACTH
concentration and will not have an increase in
ACTH with CRF, whereas a patient with Cushing
disease will have a large increase in ACTH,
demonstrating the CRF-responsive nature of the
microadenoma.
Salivary cortisol reflects the free cortisol
moiety in plasma and is becoming more popular
in the evaluation of cortisol secretion in chil-
dren. Samples can be collected by spit or by
swabs. Results can be affected by oral intake,
oral bleeding, tooth brushing, and other daily
activities, so the patient must be carefully pre-
pared for the collection. This salivary method
has generally been used for late-night collections
Disorders of the Adrenal Cortex
or overnight dexamethasone-suppression test-
ing. Duplicate samples are suggested to increase
accuracy.
Invasive sampling procedures more often are
applied in adult patients than in children; if the
technical expertise is available, however, these
techniques may be applied in pediatrics. Adrenal
venous sampling for cortisol or other adrenal
gland metabolites is difficult in children, but this
technique may be used in older teenagers to further
evaluate patients suspected to have an adrenal
etiology of Cushing syndrome and can indicate
whether a unilateral adrenal tumor is responsible
for the cortisol secretion. For the evaluation of
Cushing disease, petrosal sinus sampling for
ACTH may indicate the side and location of a
pituitary or extrapituitary source for the ACTH to
narrow the surgical approach necessary for treat-
ment. These highly technical procedures should
only be carried out by experienced hands.
Noninvasive radiologic procedures meet with
mixed success, especially in the CNS. CT scan-
ning or MRI with gadolinium of the pituitary
region may not be helpful because of the small
size of some microadenomas, and the presence of
silent adenomas in many normal individuals may
confuse the issue. The adrenal glands may both
appear enlarged on abdominal CT scans in
Cushing disease, whereas a solitary nodule or
tumor or nodular adrenal hyperplasia may be
identified on high-quality CT scans or MRI. The
presence of an abnormality on imaging may be
helpful in pointing to a disorder, but imaging is
not an acceptable way to eliminate a disorder.
Newer techniques of imaging such as fluorine-18
fluorodeoxyglucose PET combined with CT may
add useful information. Exploratory laparotomy
may yet be required to localize the tumor.
Treatment of Cushing Syndrome
If the diagnosis of Cushing disease is established,
the treatment may be medical, radiotherapy, or sur-
gery. Transsphenoidal microadenomectomy is a
useful method of curing the patient of the microad-
enoma that causes the problem and leaving the rest
of the pituitary gland intact. Experience with this
particular tumor is essential if the surgeon is going
to remove the appropriate part of the gland.
Recurrence is possible, but reoperation can be per-
255
formed if necessary. In the right hands, this proce-
dure is the treatment of choice. Removal of the
basophil adenoma secreting ACTH usually leaves
the remaining quiescent basophils which do not
secrete ACTH. It may take months, up to 18, for the
basophils to recover normal ACTH secretion, and
the secondary adrenal insufficiency must be treated
with glucocorticoid replacement therapy until then.
Previous studies demonstrated the utility of
o,p′-DDD, an adrenolytic agent, to diminish
adrenal function, but other methods have sup-
planted its use in all but inoperable patients.
Metyrapone, an 11-hydroxylase inhibitor, has
been used with some temporary success, but
ACTH levels will soon increase and overwhelm
the block in cortisol production, leading to
renewed symptoms of hypercortisolism.
Mifepristone is a glucocorticoid receptor antago-
nist which is used for inoperable Cushing syn-
drome but it is not approved for pediatric use.
Radiotherapy has been used in some series, but
the risk of hypopituitarism developing after
radiotherapy has led most clinicians to use other
methods of treatment. Bilateral adrenalectomy
will cure the hypercortisolism but leave the pitu-
itary tumor. After a period, the hypersecretory
pituitary tumor, released from the suppressive
effects of hypercortisolism, may grow and secrete
increasing amounts of ACTH: hyperpigmenta-
tion and an enlarging pituitary tumor of Nelson
syndrome result. Of course, if the adrenal glands
are removed, both glucocorticoids and mineralo-
corticoids will have to be replaced for the life-
span of the patient.
The aim of treatment of autonomous adrenal
tumors and ectopic ACTH-secreting tumors is to
eradicate the offending neoplasm. If the ectopic
ACTH-secreting tumor is inoperable, an adrenal
blocking agent or bilateral adrenalectomy is used
to control the hypercortisolism.
The goal of medical treatment of Cushing syn-
drome after the correction of the hypercortisolism
is the replacement of glucocorticoids in appropri-
ate dose to mimic normal adrenal secretion and to
avoid the suppression of statural growth. In the
months after the removal of the microadenoma
of Cushing disease, the remaining suppressed
corticotrophs will not function, and replacement
glucocorticoid therapy will be required. The initial
256
dose of cortisol will have to be relatively high, or
the patient may experience the malaise and leth-
argy characteristic of glucocorticoid withdrawal.
If adequate cortisol is not supplied after surgery,
the child might also go into the shock of acute
adrenal insufficiency. Although the desired dose
of hydrocortisone is approximately 6–8 mg/m2
parenterally or double that dose orally, the initial
dose may have to be twice or more for several
weeks, with gradual weaning to the lower dose as
necessary (see earlier). After 9–18 months, normal
adrenal function will return in the majority of
cases of Cushing disease treated with transsphe-
noidal microadenomectomy. Adrenal suppression
is also described above.
A recent study evaluated growth after treat-
ment of Cushing disease versus autonomous
glucocorticoid-secreting adrenal nodules. The
results showed greater growth after the removal of
nodules than the removal of the pituitary microad-
enomas of Cushing disease partially because
Cushing disease occurs in older children, partially
because the androgen secretion which may
accompany Cushing disease is usually absent in
autonomous glucocorticoid-secreting nodules,
and partially because of the higher prevalence of
vertebral fractures in Cushing disease due to
osteopenia. While the removal of microadenomas
of the pituitary is usually quite successful, growth
hormone deficiency can occur and further add to
the discrepancy in growth between the two types
of conditions.
Hypertension due to Adrenal Disease
Primary Hyperaldosteronism
Primary hyperaldosteronism (or Conn syndrome)
is usually unilateral. With this condition serum or
urinary aldosterone is elevated, plasma renin
activity is low, and potassium is elevated with
hypokalemic alkalosis, hypertension (due to
sodium retention), and polyuria. Aldosterone is
elevated due to autonomous production from the
adrenal gland rather than by stimulation by
angiotensin II and PRA is suppressed. Plasma
aldosterone concentration rises in normal sub-
10 Disorders of the Adrenal Gland
jects when standing for 4 h but decreases in adre-
nal adenomas since this condition is usually not
controlled by the stimulation of angiotensin as in
the normal situation; however, some adenomas
are indeed responsive to angiotensins, so the test
is not completely reliable. Selective venous sam-
pling will indicate unilateral or bilateral disease,
but the technique is quite difficult especially in
children. Imaging by an adrenal iodocholesterol
(NP-59) scan with dexamethasone suppression or
CT and MRI has been useful in localizing the
lesion. Treatment is sometimes accomplished by
high doses of spironolactone but usually by adre-
nal surgery especially if the disease is unilateral.
It is essential to eliminate secondary hyperaldo-
steronism before initiating treatment. Aldosterone
will rise when blood volume is depleted due to
fluid loss or blood loss, sodium is depleted, or
potassium is elevated whether due to disease or
with the treatment of a condition by medication.
Familial hyperaldosteronism (*605635
HYPERALDOSTERONISM, FAMILIAL, TYPE
II) is due to an adrenal adenoma, bilateral adrenal
hyperplasia, or both. It is not treatable with dexa-
methasone as are the following conditions.
Hypertensive Conditions Treated
with Glucocorticoids
Glucocorticoid-suppressible hyperaldosteronism
(#103900 #103900 ICD+ GLUCOCORTICOID-
REMEDIABLE ALDOSTERONISM; GRA
or HYPERALDOSTERONISM, FAMILIAL,
TYPE I at 8q21) is a rare autosomal dominant
condition due to fusion of the cytochrome P450,
subfamily XIB, polypeptide 1 gene (CYP11B1,
610613), and the cytochrome P450, subfamily
XIB, polypeptide 2 gene (CYP11B2, 124080)
leading to elevated aldosterone production; the
increased production of aldosterone is not
caused by a plasma renin activity as PRA levels
are suppressed. There is an associated increase
in 18-oxocortisol and 18-hydroxycortisol.
Hypertension with low potassium results, but this
condition is treated with glucocorticoid adminis-
tration. 17α-Hydroxylase deficiency (*202110
ADRENAL HYPERPLASIA, CONGENITAL,
DUE TO 17α-HYDROXYLASE DEFICIENCY)
Adrenal Medulla
and 11β-hydroxylase deficiency (*202010
ADRENAL HYPERPLASIA, CONGENITAL,
DUE TO 11β-HYDROXYLASE DEFICIENCY)
congenital adrenal hyperplasia both produce a
hypertensive state (see earlier in Chap. 8).
11-Hydroxysteroid dehydrogenase deficiency
interrupts the normal conversion of cortisol to
cortisone by 11-hydroxysteroid dehydrogenase
(218030 CORTISOL 11β-KETOREDUCTASE
DEFICIENCY at 16q22) and leads to apparent
mineralocorticoid excess caused by the excess
mineralocorticoid effect exerted by cortisol.
The condition may be noted at birth and require
glucocorticoid administration to decrease cortisol
production and mineralocorticoid antagonism by
the use of spironolactone. Alternatively, the con-
dition may be an acquired defect due to licorice
ingestion (natural licorice such as found in
Europe, not the red candy ropes more prevalent
in the USA); the treatment is to discontinue lico-
rice. Natural licorice as found in Europe, Asia,
and Africa exerts both mineralocorticoid proper-
ties and glucocorticoid properties by inactivating
11-beta-hydroxysteroid dehydrogenase (type 2)
which would ordinarily convert active cortisol to
inactive cortisone, thereby leading to increased
cortisol effect.
Familial Glucocorticoid Resistance
Familial glucocorticoid resistance (#615962
GLUCOCORTICOID RESISTANCE, GENERA-
LIZED) is an autosomal dominant condition due
to abnormality of the glucocorticoid receptor
caused by a mutation in the nuclear receptor sub-
family 3, group C, member 1 gene (NR3C1).
Glucocorticoid values are quite high, but these
levels do not cause findings of excessive gluco-
corticoids such as found in Cushing syndrome.
Since glucocorticoids cannot exert feedback to
suppress ACTH secretion due to glucocorticoid
resistance, patients have increased products of the
adrenal gland and the other steroids have working
receptors. Thus findings of hypermineralocorti-
coidism and virilization may result. Treatment is
accomplished by increased doses of dexametha-
sone and if necessary treatment of the hyperten-
sion with spironolactone.
257
Bartter Syndrome
Bartter syndrome refers to several autosomal
recessive disorders characterized by decreased
sodium chloride reabsorption in the thick ascend-
ing loop of Henle which leads to salt wasting,
hypokalemia, hypochloremic metabolic alkalo-
sis, and hypercalciuria with increased plasma
renin activity and hyperactivity of the renin–
angiotensin system with increased plasma aldo-
sterone; hypomagnesuria is often found as well.
There are antenatal severe forms of Bartter syn-
drome (#601678 ICD+ BARTTER SYNDROME,
ANTENATAL, TYPE 1) (#241200 ICD+
BARTTER SYNDROME, ANTENATAL, TYPE
2) as well as forms (#602522 BARTTER
SYNDROME, TYPE 4A) (#613090 BARTTER
SYNDROME, TYPE 4B) associated with senso-
rineural deafness.
Gitelman’s Syndrome
Gitelman’s syndrome (#263800 ICD+
GITELMAN SYNDROME) is an autosomal
recessive disorder due to mutation in the thiazide-
sensitive NaCl cotransporter (SLC12A3). This
condition is associated with renal potassium and
magnesium wasting with increased plasma renin
activity resulting in polydipsia, hypomagnese-
mia, hypocalciuria, and hypokalemic alkalosis.
Patients may demonstrate generalized muscle
weakness, muscle cramps, tetany, seizures, par-
esthesias, and episodic paralysis after strenuous
exercise.
Adrenal Medulla
Normal Physiology
The adrenal medulla is derived from neuroecto-
derm and produces catecholamines in the chro-
maffin cells. Chromaffin cells also are located in
the sympathetic ganglion and the organ of
Zuckerkandl (anterior to the aorta), and although
the extraadrenal chromaffin cells mostly regress
in the postnatal period, they remain a potential
site of tumor formation and must be considered
in the diagnostic process.
258
The catecholamine biosynthetic pathway pro-
ceeds from L-tyrosine to L-Dopa (via tyrosine
hydroxylase) to dopamine (via aromatic-L-amino
acid decarboxylase) to norepinephrine (via dopa-
mine β-hydroxylase) to epinephrine [via phenyl-
ethanolamine-N-methyltransferase (PMNT)].
The last step occurs only in a specific sympa-
thetic nervous tissue, the adrenal medulla; the
high concentration of cortisol in the blood supply
to the adrenal medulla induces PMNT and
accounts for the transformation of significant
amounts of norepinephrine into epinephrine in
this location but not in other chromaffin tissues.
Conversely in primary adrenal failure when there
is no high concentration of cortisol reaching the
blood supply of the medulla, epinephrine produc-
tion decreases. Since adrenal failure can lead to
hypoglycemia and since it is the catecholamines
of the adrenal medulla that produce the adrener-
gic symptoms of hypoglycemia, a person may
experience low blood sugar without realizing it
as a form of hypoglycemia unresponsiveness.
Catecholamines are metabolized by monoamine
oxidase (MAO) and catechol-O-methyltransferase
(COMT). Vanillylmandelic acid (VMA) and
homovanillic acid (HVA) are deaminated metab-
olites of catecholamines and are measured when
excessive catecholamine production is suspected,
or where metabolism of catecholamines also is
high, such as in neuroblastoma. Epinephrine and
norepinephrine mediate their actions through
alpha and beta receptors, while dopamine medi-
ates its action through a family of “D receptors”
such as the D2 receptors in the lactotrophs which
when activated suppress prolactin secretion.
Disorders of the Adrenal Medulla
Pheochromocytoma
Pheochromocytomas are derived from the chro-
maffin cells of the adrenal medulla; tumors of the
extraadrenal chromaffin cells are considered as
paragangliomas. Pheochromocytomas are rare in
childhood but represent a curable cause of hyper-
tension and must be considered in the differential
diagnosis of high blood pressure. Familial cases
may be inherited in an autosomal dominant pat-
10 Disorders of the Adrenal Gland
tern (#171300 PHEOCHROMOCYTOMA at
11q23, 1p). They are a component of the multiple
endocrine neoplasia syndromes (see below), neu-
rofibromatosis (*162200 NEUROFIBROM
ATOSIS, TYPE I; NF1 at 17q11.2), and von
Hippel–Lindau disease (*193300 VON HIPPEL-
LANDAU SYNDROME; VHL at 3p26-p25) and
may develop before or after other components of
the syndromes are noted.
Characteristic signs and symptoms of pheo-
chromocytomas include hypertension (more
often constant than episodic in children com-
pared with adults), weight loss, headache, vom-
iting, and, more rarely in childhood than in
adults, paroxysmal episodes of tachycardia,
flushing, sweating, palpitations, or anxiety.
Postural hypotension due to volume depletion
may occur. Diagnosis is made by the demonstra-
tion of elevated plasma or 24-h urinary fraction-
ated metanephrines, which include metanephrine
and normetanephrine, about fourfold higher than
the upper limits of normal range. Various drugs
interfere with this testing including acetamino-
phen, tricyclic antidepressants, phenoxybenza-
mine, and decongestants. HVA and VMA
excretion in spot urine collection remain helpful
in the diagnosis of neuroblastoma but have been
replaced in the diagnosis of pheochromocytoma
or paragangliomas by fractionated urine or
plasma catecholamines. Supine measurements of
plasma metanephrines are helpful if pheochro-
mocytoma is suspected, but standing measure-
ments are higher normally; if the sample was
collected in a previously inserted intravenous
line, stress will not affect the value nor lead to a
false positive. Plasma catecholamine concentra-
tions may not add any information to the urinary
collections, which serve as a reflection of the
integrated catecholamine production over the
previous day. Tumors secreting norepinephrine
and normetanephrine are more likely associated
with paragangliomas while tumors secreting epi-
nephrine or normetanephrine are more likely to
be pheochromocytomas. Provocative pharmaco-
logic tests are no longer used in the diagnosis of
pheochromocytoma or paragangliomas because
of the danger of precipitating a hypertensive cri-
sis and because of the specificity of the plasma
Adrenal Medulla
and urine collections. Dopamine-secreting
tumors are quite rare, but in the clinical situation
where biochemical indicators of pheochromocy-
toma or paragangliomas are negative but one of
these two tumors is suspected, determination of
dopamine and HVA can be helpful.
An adrenal pheochromocytoma may be
located with abdominal CT scanning or with
MRI. To ascertain function, scintiscanning with
the synthetic catecholamine precursor, 131I-meta-
iodobenzylguanidine, which is concentrated by
chromaffin tissue, and single-photon emission
computed tomography (SPECT)/CT are used. If
imaging techniques fail, selective venous cathe-
terization and analysis of catecholamine efflux
may narrow the search for the tumor but only in
older teenagers as such sampling is virtually
impossible in small children.
Surgery to remove the tumor is the treatment
of choice for pheochromocytoma, but the patient
must be prepared for surgery and for invasive
radiologic studies by adrenergic blockade.
Medical management and surgical treatment of
these conditions are fraught with risk and only an
experienced team should consider approaching a
child affected by these tumors. The following is a
summary of the very complex process. Alpha-
adrenergic block should be administered before
β-adrenergic blockade. Phenoxybenzamine is
given orally (5–10 mg every 12 h, with increas-
ing dosage until high blood pressure is con-
trolled) for long-term therapy; i.v. or i.m.
phentolamine (1 mg per dose) is used for hyper-
tensive crises that may occur while the phenoxy-
benzamine block is being established. β-Blockade
by propranolol (5–10 mg given 3–4 times per day
orally for larger children) is added when the heart
rate increases as the α-adrenergic blockade is
being established; propranolol may cause para-
doxical hypertension if given before the
α-adrenergic block is established. If this therapy
is ineffective, α-methyltyrosine (a tyrosine
hydroxylase inhibitor) can be started at 5–10 mg/
kg/day, given four times per day. Nitroprusside is
used as a vasodilator during surgical hyperten-
sion. Surgical preparation also includes adminis-
tration of salt to repair the plasma volume, which
is invariably low.
259
Multiple Endocrine Neoplasia
Multiple Endocrine Neoplasia Syndromes
Multiple endocrine neoplasia syndrome type 1
(# 131100. MULTIPLE ENDOCRINE
NEOPLASIA, TYPE I; MEN1; caused by muta-
tion in the MENEN gene at 11q13) sometimes
called Wermer syndrome occurs in a dominant
pattern although 10 % of patients have new muta-
tions. MEN type I comprises hyperparathyroid-
ism (tumors are often found in all four parathyroid
glands and the parathyroid hormone (PTH) will
be inappropriately elevated in view of the
increased serum calcium), pituitary adenomas
(increased GH secretion causes elevated serum
insulin-like growth factor (IGF)-1 and acromegaly;
increased prolactin causes galactorrhea), pancre-
atic islet cell tumors (hypoglycemia due to insu-
lin from the beta cells), and duodenal tumors
ulcers caused by (gastrin from the alpha cells of
the pancreas or the G cells of the stomach or duo-
denum) as well as skin, adrenocortical, carcinoid,
and central nervous system tumors. Thus hyper-
calcemia, hyperprolactinemia, GH excess, and
hypoglycemia may result. Usually pheochromo-
cytomas are not included in MEN type 1, but
families rarely are reported with only pheochro-
mocytoma and islet cell pancreatic tumors found
in a complex. This disorder usually is rare in chil-
dren, but the prevalence rises in older teenagers
until the majority of patients present as adults.
However, a child in a family with a diagnosis of
this condition can be monitored and tested at a
younger age. Manifestations have rarely been
reported as young as 5 years of age. The syn-
drome is due to loss-of-function mutations in the
MENEN tumor-suppressor gene.
Hyperparathyroidism will present in the usual
manner with elevated serum PTH and calcium,
decreased serum phosphorus, and decreased bone
density. Localization may occur with a sestamibi
scan and treatment is accomplished by removal
of the parathyroid glands.
The gastrointestinal tumors of MEN type I
are now termed gastroenteropancreatic-neuro-
endocrine tumors or GEP-NETs subdivided into
carcinoid GEP-NET tumors that arise in the
lungs, GI tract, or thymus, while when they arise
260
in the pancreas, the GEP-NETs are termed pan-
creatic NETs or pNETs. Gastrinomas in the duo-
denum lead to the Zollinger–Ellison syndrome
of peptic ulcers. Insulinomas of the pancreas
present and are treated in the manner noted in
Chap. 12. Glucagonomas raise blood sugar, so
patient presents with what appears to be mild
diabetes. The pituitary tumors occur at a younger
age than many of the other manifestations of
MEN1 and can secrete in decreasing order pro-
lactin, growth hormone, and ACTH. The adrenal
cortical tumors of MEN1 are often nonfunc-
tional. Genetic testing of first-degree relatives
of index cases of MEN1 is recommended after
genetic counseling. With a positive genetic diag-
nosis, screening for the individual components is
performed regularly.
Multiple endocrine neoplasia type 4 (#610755
MULTIPLE ENDOCRINE NEOPLASIA, TYPE
IV; MEN4) presents a manner similar to MEN1
and genetic testing should be carried out for this
variant if the patient has findings of MEN 1, but
genetic test for this condition is negative.
MEN type 2A (#171400 MULTIPLE
ENDOCRINE NEOPLASIA, TYPE II; MEN
2-associated mutations in the RET protoonco-
gene at 10q11.2) is an autosomal dominant con-
dition which frequently has manifestations in the
pediatric age group. Genetic testing for the muta-
tion in the RET gene is readily available and indi-
cated in all first-degree relatives of a proband.
Because of the association with medullary carci-
noma of the thyroid which often occurs earlier
and metastasizes at a younger age than is found
in sporadic medullary carcinoma of the thyroid,
children with positive genetic testing for MEN
2A should undergo prophylactic thyroidectomy.
Pheochromocytoma is usually found in older
patients, but it has been reported in children and
some recommend screening children with a posi-
tive genetic test for MEN 2A starting at age 5.
Parathyroid hyperplasia of MEN2 is almost uni-
versally found in adults with MEN 2A. The pheo-
chromocytomas are usually located in the adrenal
gland and may be bilateral or multicentric
(see Chap. 14 for a discussion of the emergency
management of pheochromocytoma).
MEN type 2B (#162300 MULTIPLE
ENDOCRINE NEOPLASIA, TYPE IIB; MEN
10 Disorders of the Adrenal Gland
2B-associated mutations in the RET protoonco-
gene at 10q11.2) in contrast to the autosomal
dominant pattern of MEN 2A occurs usually with
spontaneous mutations. Development of medul-
lary carcinoma of the thyroid is universal in the
syndrome while about half of the affected patients
develop pheochromocytoma. MEN 2B is associ-
ated with clear physical findings of skin and gen-
eral body habitus. Ganglioneuromas of the lips
and tongue are distinctive but can also occur on
the conjunctiva, gastrointestinal tract, and urinary
tract. Failure to thrive in infancy occurs as well as
megacolon, colonic diverticulosis, constipation,
and diarrhea related to the GI ganglioneuroma.
There is a marfanoid habitus with lax joints,
kyphosis, scoliosis, and lordosis as well as
hypotonia and developmental delay. Skin mani-
festations also include flushing. The physical
findings should cause the physician to obtain
genetic testing and to search for occult pheochro-
mocytomas and medullary carcinomas. The med-
ullary carcinoma of the thyroid in this condition
often occurs at a younger age and is far more
aggressive than found in MEN2A.
An experienced thyroid surgeon (a high-
volume surgeon usually carries out 30 thyroidec-
tomies per year) must perform the thyroidectomy
in children with various forms of MEN with MCT.
Von Hippel–Lindau disease (*193300 VON
HIPPEL-LINDAU SYNDROME; VHL at 3p26-
p25, 11q13) is an autosomal dominant condition
caused by a mutation in the von Hippel–Lindau
gene (VHL). Pheochromocytomas or gangliomas
may develop at a very young age. Adenocarcinoma
of the ampulla of Vater and pancreatic NETs and
pancreatic carcinoma are also associated with the
condition. Hemangioblastomatosis of the retina,
cerebellum, and spinal cord are frequently found
in the syndrome. The condition is divided into
four subtypes of which three have pheochromo-
cytoma and one has renal carcinoma.
Neuroblastoma
Neuroblastomas are malignant tumors derived from
neural crest and are associated with excessive pro-
duction of catecholamines; in spite of this, they rarely
are seen with clinical symptoms of catecholamine
excess (probably because of catecholamine catabo-
lism within the tumor), although a minority may have
Suggested Reading
hypertension. They often are diagnosed from their
size or the presence of metastases and have a high
incidence of spontaneous regression. Urinary norepi-
nephrine (not epinephrine), VMA, and particularly
HVA and dopamine are excreted in increased
amounts in neuroblastoma. Ganglioneuromas are
benign, mature forms of neuroblastomas derived
from sympathetic ganglion cells; usually silent with
respect to endocrine function, they may manifest
some of the signs of pheochromocytoma.
Neuroblastoma is a finding in the Beckwith–
Wiedemann syndrome (#130650 ICD+
BECKWITH-WIEDEMANN SYNDROME;
BWS). It usually occurs in a sporadic manner due to
mutation in the imprinted gene at 11p15.5.
Neurofibromatosis type I (#162200 ICD+
NEUROFIBROMATOSIS, TYPE I; NF1) is caused
by mutation in the tumor–suppressor neurofibromin
gene (NF1) on chromosome 17. This condition is
associated with abnormalities of growth and puberty
(see Chaps. 5 and 9) and more rarely will be associ-
ated with a pheochromocytoma. Physical findings
are café au lait spots and axillary freckling of the
skin, Lisch nodules of the iris, and neurofibromas
and gliomas and the complications they cause.
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2. Martucci VL, Pacak K. Pheochromocytoma and para-
ganglioma: diagnosis, genetics, management, and
treatment. Curr Probl Cancer. 2014;38(1):7–41.
3. Miller WL, Flück CE. Chapter 13 - Adrenal cortex
and its disorders. In: Sperling MA, editor. Pediatric
endocrinology. 4th ed. Philadelphia, PA: Elsevier;
2014. p. 471–532.
4. Miller WL. Steroid hormone synthesis in mitochon-
dria. Mol Cell Endocrinol. 2013;379(1-2):62–73.
5. Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle
TW, Merke DP, Meyer-Bahlburg HF, Miller WL,
Montori VM, Oberfield SE, Ritzen M, White PC.
Congenital adrenal hyperplasia due to steroid
21-hydroxylase deficiency: an Endocrine Society
clinical practice guideline. J Clin Endocrinol Metab.
2010;95(9):4133–60.
6. Santos L. Stress response in critical illness. Curr Probl
Pediatr Adolesc Health Care. 2013;43(10):264–72.
7. Charmandari E, Kino T, Chrousos GP. Primary gener-
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(Chrousos syndrome) and hypersensitivity. Endocr
Dev. 2013;24:67–85.
8. Stratakis CA. Cushing syndrome in pediatrics.
Endocrinol Metab Clin North Am. 2012;41(4):793–803.
9. Simonetti GD, Mohaupt MG, Bianchetti MG.
Monogenic forms of hypertension. Eur J Pediatr.
2012;171(10):1433–9.
10. Auchus RJ. The physiology and biochemistry of
adrenarche. Endocr Dev. 2011;20:20–7.
11. Brown RJ, Kelly MH, Collins MT. Cushing syndrome
in the McCune-Albright syndrome. J Clin Endocrinol
Metab. 2010;95(4):1508–15.
12. Vehaskari VM. Heritable forms of hypertension.
Pediatr Nephrol. 2009;24(10):1929–37.
13. Oskis A, Loveday C, Hucklebridge F, Thorn L,
Clow A. Diurnal patterns of salivary cortisol across
the adolescent period in healthy females.
Psychoneuroendocrinology. 2009;34(3):307–16.
14. Waguespack SG, Ying AK. Chapter 14 -
Pheochromocytoma and multiple endocrine neoplasia
syndromes. In: Sperling MA, editor. Pediatric endocri-
nology. 4th ed. Philadelphia, PA: Elsevier; 2014.
p. 533–568.
15. Monticone S, Auchus RJ, Rainey WE. Adrenal disor-
ders in pregnancy. Nat Rev Endocrinol. 2012;8(11):
668–78.
16. Moisiadis VG, Matthews SG. Glucocorticoids and
fetal programming part 2: mechanisms. Nat Rev
Endocrinol. 2014;10(7):403–11.
17. Moisiadis VG, Matthews SG. Glucocorticoids and
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Obstet Gynecol. 2013;208(5):354–9.
19. Gamble KL, Berry R, Frank SJ, Young ME. Circadian
clock control of endocrine factors. Nat Rev
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20. Nieman LK, Biller BM, Findling JW, Murad MH,
Newell-Price J, Savage MO, Tabarin A; Endocrine
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Endocrine Society Clinical Practice Guideline. J Clin
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21. Donohoue P. Diagnosis of adrenal insufficiency in
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of-adrenal-insufficiency-in-children.
22 Donohoue P. Causes and clinical manifestations of
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 Diabetes Mellitus
Diabetes mellitus (DM) is the second most
common chronic disease of childhood (if you do
not count obesity, asthma is the most common)
and is characterized by elevated blood glucose
caused by inadequate insulin production or insu-
lin action that leads to disordered carbohydrate,
lipid, and protein metabolism. This may derive
from inadequate insulin secretion (the basic
defect in type 1 DM or T1DM), from inadequate
insulin action, or both (both defects occur in type
2 DM or T2DM). Variations are found on these
two themes with some overlap in the presentation
of type 1 diabetes and type 2 diabetes. Until the
last decades, type 1 DM was the most common
diagnosis in subjects younger than 18 years with
new-onset DM, but now type 2 is becoming more
prevalent and the incidence of T2DM exceeds the
incidence of type 1 DM in American Indian
teenagers with the prevalence in other ethnic
groups exceeding Caucasians rising. The differ-
entiation between the two is not always straight-
forward in the young patient (Table 11.1). Recent
statistics from four geographic areas of the USA
demonstrated a prevalence of type 1 diabetes in
children of 1.93 per 1,000 with a rise of about
20 % in the preceding decade. A more recent
study of commercially insured patients in the US
found a 57 % increase in the prevalence of type 1
diabetes mellitus between 2002–2013 to 2.82
cases per 1,000. The prevalence of type 2 diabe-
tes in children was 0.46 per 1,000 with a rise of
30 % in the preceding decade.
© Springer International Publishing Switzerland 2016
D.M. Styne, Pediatric Endocrinology, DOI 10.1007/978-3-319-18371-8_11
11
Diabetes requires more of a patient or family
than most other chronic conditions and will often
exert significant psychosocial stressors to all
involved. This is a chronic condition in which
everyday attention must be directed to (1) count-
ing the carbohydrate composition of diet, (2) esti-
mating how much activity the child may engage
in, (3) measuring and correcting the finger stick
blood sugar values at least four times a day, and
(4) calculating and administering the correct insu-
lin dosage usually at least four times a day. All this
must be done without the child considering him-
self or herself “sick” as a child with diabetes really
should be considered as a healthy person who has
to take care of his or her condition. The require-
ments of care may be difficult for some families to
carry out as it requires some mathematical ability
and understanding treatment concepts so they can
make medical decisions in the care of the child on
their own on a day-to-day basis. Divorce and sepa-
ration of parents is frequent in the present world;
communication between parents who are no lon-
ger together must remain seamless for the sake of
the child, but communication does not always
continue in this manner. The pressures of the daily
treatment regimen may lead to rebellion in teen-
age patients, and they may ignore the disease or
may not be truthful in relating to parents or physi-
cians how they are treating themselves every day.
The treating physician has to be aware of all these
issues and support the child and family as he or
she addresses the complexities of this condition.
263
 264

Table 11.1 Differential points between various common types of diabetes mellitus
Islet cell
antibodies,
insulin antibodies, Clinical characteristics or
Disorder Ketosis Insulin C-peptide GAD 65 antibody Inheritance Defect habitus
Type 1 Yes Low Low Positive Usually sporadic Autoimmune; Thin with weight loss but
diabetes beta cell failure during this obesity
mellitus epidemic may be heavy
Type 2 Sometimes Normal Normal Negative Familial Inherited insulin Overweight, possibly with
diabetes to high to high resistance and beta recent weight loss
mellitus cell failure worsened
with obesity
Atypical or Sometimes Normal Normal Negative Autosomal Mutation in the paired Occurs in African
ketosis prone to high to high dominant box gene 4 (PAX4) Americans
diabetes
mellitus or
Flatbush
Diabetes
MODY No Normal Normal Negative Autosomal At least 10 different Occurs before age 20 year
to high to high dominant genetic mutations Usually mild
hyperglycemia
MODY maturity-onset diabetes of the young
There are many more forms of Diabetes listed in the journal Diabetes Care and other sources
11
Diabetes Mellitus
Insulin Biosynthesis and Action 265

Insulin Biosynthesis and Action glucokinase is a rate-limiting step in the pro-

Insulin is synthesized by the beta cells of the islets
of Langerhans as proinsulin which is a single-
chain polypeptide. The C-peptide or connecting
peptide is cleaved off of proinsulin leading to the
two chains connected by two disulfide bridges of
the mature insulin molecule. The C-peptide is
produced only in the pancreas and is present in the
circulation only when endogenous insulin is
secreted. Thus it is a marker for endogenous insu-
lin but not exogenous insulin. C-peptide may be
measured to indicate endogenous insulin secre-
tion in a state in which exogenous insulin is still
present in the circulation; C-peptide will be absent
during surreptitious administration of insulin in
Munchausen by proxy.
Glucose enters the beta cell by action of the
glut 2 transporter and is then phosphorylated by
glucokinase upon entry (see Fig. 11.1). Since
cess that leads to insulin secretion, it is
described as the “sensor” for glucose in the beta
cell. Glucokinase activity leads next to an
increase in the ratio of ATP/ADP which acti-
vates the sulfonylurea receptor (SUR)-Kir6
(inward-rectifying potassium channel) complex
of the adenosine triphosphate-regulated potas-
sium channel KATP. Loss-of-function mutations
of the KATP complex are responsible for hyper-
insulinemic hypoglycemia in infancy as
described in Chap. 12 while gain-of-function
mutations lead to neonatal diabetes mellitus
and decreased insulin secretion described
below. An inactivating mutation in glucokinase
is responsible for maturity-onset diabetes of the
young, or MODY type 3 (also known as mono-
genetic diabetes type 3), which leads to a higher
threshold for insulin release and therefore rela-
tively mild hyperglycemia.

ATP-sensitive K+ channel
Ca2+
K+ Voltage
dependent
Ca2+ channel
SUR1
Depolarization
2+
Mitochondria Ca
6. R
KU
2

ATP/ADP↑ cAMP
Nucleus

Islet
Pyruvate transcription
factors
Glucose-6-phosphate
Glucokinase
Glucose
Secretory
granules Insulin

Glucose

GLUT2

Fig. 11.1 The beta cell and its components. The ATP-
sensitive K+ channel (KATP) is the site of action of sulfo-
nylureas which close the channel to cause insulin secretion
and of diazoxide which opens the channel to suppress
insulin secretion. Mutations in this area are responsible
for some forms of hyperinsulinemic hypoglycemia of the
newborn. The GLUT 2 transporter allows glucose to enter
the beta cell where it interacts with glucokinase to produce
glucose-6-phosphate. Glucose-6-phosphate can be metab-
olized during glycolysis leading to increased ATP which
enhances insulin secretion through the ATP-sensitive K+
channel. Thus glucokinase gene acts as the glucose sensor
of the beta cell and plays a major role in determining how
much insulin is released in response to glucose levels in
the normal condition. Mutations in the glucokinase can
lead to hypoglycemia or hyperglycemia
266
Insulin secretion in response to elevated
glucose is biphasic. The first phase of insulin
secretion after glucose stimulation is brief lasting
for 2–5 min followed by a nadir at approximately
15 min. The second phase of insulin secretion
occurs in about 2–3 h. Many studies aiming to
predict the onset of diabetes implicate a decrease
in the first phase of insulin secretion as an initial
defect indicating the development of diabetes.
Insulin interacts with its membrane-bound
receptor which is composed of four subunits and
is similar in structure to the IGF 1 receptor. A
series of intracellular events follow when insulin
interacts with its receptor, some of which are
affected by mutations which render the insulin
receptor inactive. The intracellular processes
which occur after insulin or IGF 1 attach to their
respective receptors differ at physiologic levels.
However, there can be cross stimulation of either
receptor at times of increased insulin or IGF 1
secretion. Insulin increases glucose uptake by
adipose tissue and muscle directly through GLUT
4 and into liver by more indirect manner as there
is no GLUT 4 on liver cell membranes. Insulin
stimulates the production of glycogen in liver and
muscle and protein synthesis in muscle by the
uptake of amino acids and stimulates lipid syn-
thesis through the uptake of triglycerides into
adipose tissue and liver.
In the fed state insulin rises due to oral glucose
intake, while in the fasted state insulin secretion
decreases, but secretion of glucagon, growth hor-
mone, cortisol, and epinephrine, which are con-
sidered counterregulatory hormones that oppose
insulin action, rise. A discussion of the fed and
fasted states is found in Chap. 12.
Glucagon
While the action of insulin can be considered
anabolic in view of its effect of increasing glyco-
gen stores in muscle and liver and lipids in adi-
pose tissue as well as enhancing the entrance of
nutrients into insulin-responsive tissues, gluca-
gon can be considered a catabolic agent by
enhancement of glycogenolysis. Glucagon stim-
ulates gluconeogenesis which also increases glu-
11 Diabetes Mellitus
cose in the bloodstream. Insulin and glucagon are
normally in balance to maintain normal blood
sugar, but secretion is disordered in the hypergly-
cemia of diabetes. Glucagons, GLP 1 and GLP 2,
are derived from preproglucagon encoded by the
preproglucagon gene which is expressed in the
central nervous system, intestinal L-cells, and
pancreatic alpha cells. Posttranslational cleavage
of preproglucagon leads to the production of
mature glucagon in the alpha cells or GLP 1 and
2 in other cells depending upon which prohor-
mone convertases (PC) are present. Glucagon
receptors are seven-transmembrane G-protein-
coupled receptors (see Fig. 1.4). When glucagon
couples with its receptor, activation of cAMP
occurs ultimately simulating the effects of gluca-
gon noted above.
Most glucagon is produced and secreted by
the alpha cells of the islets of Langerhans. GTP-
dependent potassium channels are triggered to
release glucagon at low levels of glucose by acti-
vation of the GTP-dependent potassium (KTP)
channels similar to those found in the beta cell.
Glucagon secretion is also stimulated by amino
acids, gastrin, and CCK in states of stress and
during starvation and exercise. Cortisol and
growth hormone excess are associated with ele-
vated serum glucagon. The secretion of glucagon
is inhibited by elevated blood sugar concentra-
tions, GLP 1, free fatty acids, ketone bodies,
insulin, and, as stated above, somatostatin, an
agent secreted from the delta cells with far-
reaching effects including suppression of gluca-
gon release.
Glucagon secretion is impaired in the early
stages of the development of diabetes leading to
a greater likelihood of hypoglycemia during
attempts to achieve “tight control.” Secretion of
insulin from the beta cell may be a prerequisite
for local control of glucagon secretion. This may
be a reason for the increased sensitivity to hypo-
glycemia as glucagon does not respond to low
blood sugar when hypoglycemia occurs in the
early stages of diabetes. However, glucagon is
elevated in other phases of the natural history of
diabetes. Glucagon is one of the factors that
enhance the development of diabetic ketoacido-
sis (DKA) in the absence of insulin and promote
Other GI Hormones
the development of ketone bodies. In states of
hypoglycemia in individuals with diabetes, glu-
cagon is one of the factors that promote rebound
hyperglycemia in the Somogyi effect, but in other
individuals with diabetes and hypoglycemic
unresponsiveness, the glucagon response to
hypoglycemia which would ordinarily increase
glucose levels is sometimes defective. Since glu-
cagon promotes hyperglycemia, increased atten-
tion is now devoted to glucagon as a target for
treatment of diabetes.
A glucagonoma is a rare finding in multiple
endocrine neoplasia syndrome type I.
Other GI Hormones
There are other significant influences on insulin
secretion in addition to the effect of glucose.
Insulin secretion is greater when glucose is
administered orally due to the effects of incretins,
hormones released from the gastrointestinal tract.
It is estimated that incretin action causes 50–65 %
of the total insulin release that occurs in response
to a meal. The incretin family includes glucose-
dependent insulinotropic polypeptide (GIP also
known as gastric inhibitory peptide) and
glucagon-like peptide (GLP noted above) which
stimulate glucose-dependent insulin release
following oral ingestion. Glucagon-like peptide
1 is produced in the intestinal L cells of the ileum
and colon by cleavage from the proglucagon
molecule by prohormone convertase PC1/3; thus
the same gene codes for both glucagon and
glucagon-like peptide. GLP 1 is low in the fasting
state but rises after ingestion of food mainly stim-
ulated by glucose and fat. GLP 1 exerts its effect
by binding to a G-protein-coupled receptor on
the cell membrane of the pancreatic islets and
also has effects on the central and peripheral ner-
vous system, gastrointestinal tract, cardiovascu-
lar system, kidney, and lung. The effects of GLP
1 on the pancreas include enhancing secretion of
insulin and somatostatin and decreasing secretion
of glucagon while enhancing beta cell prolifera-
tion. GLP 1 decreases gastric emptying time and
thereby brings about a sense of fullness. GLP 1 is
also produced in the nucleus tractus solitarii of
267
the medulla oblongata and GLP 1 also exerts
neurological effects by decreasing appetite, food
intake, and water intake and increasing satiety.
GLP 1 is rapidly inactivated by cleavage at the
N-terminus by dipeptidyl peptidase-4 (DPP-4).
GLP 1 agonists are used in the treatment of type
2 diabetes in the adult to utilize the endocrine
effects of GLP 1 with the additional benefit of an
extended period of activity. Likewise therapeutic
agents that inhibit DPP-4 and that serve as ago-
nists for incretins are used to improve glucose
control, but these are not approved for children.
GIP (gastric inhibitory peptide or glucose-
dependent insulinotropic polypeptide) stimu-
lates insulin secretion in response to glucose.
GIP is a 42-amino-acid polypeptide produced by
the K cells in the duodenum, proximal jejunum,
and other areas of the small intestine.
Carbohydrates and fats are the major nutrient
stimulants for GIP secretion. GIP interacts with a
seven-transmembrane G-protein‐coupled recep-
tor similar to that for GLP 1 and glucagon.
Receptors are distributed in the pancreatic islets,
stomach, brain, pituitary gland, lung, heart, and
vascular endothelium. Remarkably rare cases of
food-dependent Cushing disease appear related
to overexpression of GIP receptors in the adrenal
gland which are found in unilateral adrenal
adenoma or bilateral macronodular adrenal
hyperplasia.
Amlyn is a polypeptide secreted by the pan-
creas along with insulin and has complementary
effects on insulin. Amlyn slows gastric emptying,
regulates postprandial glucagon, and reduces
food intake in a similar manner to GLP 1 but does
not stimulate the secretion of insulin. Pramlintide
is an analog of amlyn which is available for the
treatment of adults with type 1 diabetes, but treat-
ment with the native molecule produces amyloid
fibrils which are harmful to the beta cell.
Pramlintide is not approved for children.
Ghrelin is an appetite-stimulating hormone
(orexigenic) which is produced in several loca-
tions in the body mainly on the gastrointestinal
tract and also influences growth hormone secre-
tion via the growth hormone secretagogue
receptor (GHS-R). Ghrelin is also found in the
pancreas and appears to be involved in diabetes,
268
but its role and action are controversial at pres-
ent. Ghrelin appears to suppress insulin secre-
tion and may be a diabetogenic factor.
Patients with severe lipodystrophy do not
produce leptin, the satiety hormone that origi-
nates from adipose tissue. These patients have
severe insulin resistance and long-term leptin
treatment increases insulin sensitivity and thereby
improves glucose levels and plasma triglycer-
ides. Leptin increases insulin sensitivity and
decreases insulin resistance. Leptin improves
blood sugar in type 1 and type 2 diabetes in ani-
mal models by suppressing the hypothalamic–
pituitary–adrenal axis, and this action may be
studied in the future in human beings as well.
Somatostatin (also known as somatotropin
release-inhibiting factor (SRIF) or SS) is present
in a 14-amino acid peptide or a 28-amino acid
peptide depending upon cleavage of the pre-
prohormone. Somatostatin is produced in various
sites including the delta islets of Langerhans of
the pancreas. Somatostatin exerts actions
throughout the body in addition to hypothalamic
somatostatin’s action of suppressing growth
hormone secretion from the pituitary gland; thus
somatostatin suppresses the release of insulin,
glucagon, gastrin, cholecystokinin (CCK), vaso-
active intestinal peptide (VIP), gastric inhibitory
polypeptide (GIP), secretin, motilin, and entero-
glucagon. Somatostatin interacts with one of its
five different G-protein-coupled receptors which
cause differing effects. Thus, GH secretion is
suppressed by SSTR2 and 5, insulin secretion
is suppressed by SSTR5, and glucagon secretion
is suppressed by SSTR2. The SSTR2 receptor
also affects the immune responses. Various
tumors express differing somatostatin receptors;
GH-secreting pituitary adenomas usually express
SSTR2 and SSTR5, prolactinomas express
SSTR1 and SSTR5, ACTH-secreting adenomas
express SSTR5 with a lower abundance of
SSTR2 (low number), and gastroenteropancre-
atic (GEP) neuroendocrine tumors usually
express SSTR2 but others as well. The different
expression of receptors in various tumors is
important for therapy; octapeptide somatostatin
analogs, for example octreotide and lanreotide,
decrease growth hormone and IGF 1 in only
11 Diabetes Mellitus
60–70 % of acromegalic patients leading to the
need for the development of new medications
more specific to the type of receptor expressed on
a given tumor. Since insulin secretion is sup-
pressed by somatostatin produced by the delta
cells of the pancreatic islets, long-acting agonists
of somatostatin are used in the treatment of some
forms of neonatal hyperinsulinemic hypoglyce-
mia. Radiolabeled somatostatin analogs
(indium-111 (111In)-labeled pentetreotide) are
used to identify tumors with somatostatin recep-
tors in adrenal medullary tumors (NEP tumors
including pheochromocytoma, neuroblastoma,
ganglioneuroma, paraganglioma) or the GI tract
such as gastroenteropancreatic neuroendocrine
tumors (carcinoid, gastrinoma, glucagonoma,
vasoactive intestinal polypeptide-secreting tumor,
pancreatic polypeptide-secreting tumor) and the
CNS (using technetium 99m depreotide [99mTc
depreotide], DTPA) for pituitary and extra sellar
tumors. Excessive somatostatin secretion is found
in somatostatinomas, rare tumors of the D cells of
the islets of Langerhans which may be found in
neurofibromatosis type I, multiple endocrine neo-
plasia type I, or isolated occurrence. They may be
asymptomatic, but some of the patients manifest
the somatostatinoma syndrome which includes
diabetes, gallstones, and steatorrhoea. The find-
ings of the syndrome might also be found with
treatment with somatostatin analogues.
Adiponectin appears to protect against adverse
metabolic effects of obesity. Adiponectin
increases sensitivity to insulin from a decrease in
hepatic gluconeogenesis and increases glucose
transport into muscles as well as increases energy
consumption and fat oxidation in various sites.
Tumor necrosis factor alpha (TNF alpha) is a
pro-inflammatory cytokine that appears to play a
role in the development of both type 1 and type 2
diabetes. Modulation of TNF alpha expression in
animals can decrease the development of dia-
betes. Other inflammatory cytokines that appear
to play a role in the development of type 1 and
type 2 diabetes are interleukin (IL)-1β, the IL-6
family of cytokines, and IL-18.
Pancreatic polypeptide (PP) secretion from
pancreatic peptide-releasing cells (PP or F cells)
of the islet of Langerhans increases during fasting,
Other GI Hormones
exercise, and hypoglycemia but is also stimulated
after protein, fat, and glucose ingestion. Pancreatic
polypeptide secretion is decreased by somatosta-
tin, glucagon, and intravenous glucose. PP is
increased in pancreatic tumors also secreting insu-
lin and glucagon, gastrinomas, and Verner–
Morrison syndrome (VIPoma); PP is used as a
marker for these tumors, now more commonly
known as gastroenteropancreatic neuroendocrine
tumors (NET), when found with MEN1 or alone.
Vasoactive intestinal polypeptide (VIP) is a
28-amino acid peptide found mostly in neurons in
the GI tract and the CNS among other sites. VIP
interacts with its G-protein-coupled receptor on the
cell membrane. VIP has many physiologic effects
as a neurotransmitter and neuromodulator includ-
ing affecting secretion and absorption in the GI
tract, bicarbonate and fluid secretion from the bile
duct, relaxing smooth muscle of the esophagus,
and inducing vasodilation. Because of its anti-
inflammatory anti-immunologic features, it may
prove a therapeutic option for many conditions
including type 1 diabetes mellitus. A VIPoma
causes extremely high-volume diarrhea sometimes
known as pancreatic cholera, and measurement of
VIP levels will help in the differential diagnosis of
this presentation. Radio imaging of VIP receptors
can be used to diagnose VIP-secreting tumors, pan-
creatic adenocarcinoma, and carcinoid tumors.
Patients with Hirschsprung’s disease or achalasia
appeared to have decreased VIP-containing cells
and the GI tract.
Serotonin (5-hydroxytryptamine, or 5-HT) is
mainly produced in the enterochromaffin cells of
the GI tract but also synthesized in serotonergic
neurons of the CNS. In the GI tract it regulates
intestinal movement and in the central nervous
system it regulates mood, appetite, and sleep.
Serotonin also has a role in hemostasis and clot-
ting when it is taken up by platelets. Serotonin is
metabolized to 5-HIAA mostly by the liver. The
carcinoid syndrome is caused by an excess of
serotonin and is characterized by flushing and
diarrhea and may be mistaken for a VIPoma
although the diarrhea is less severe in carcinoid
syndrome; the classic symptoms of carcinoid
syndrome appear most closely related to meta-
static carcinoid tumors in the GI tract. Carcinoid
269
tumors occur with multiple endocrine neoplasia
syndrome type I although more rarely than the
other classically described tumors.
Gastrin stimulates gastric acid secretion from
the parietal cells of the stomach and increases
gastric motility. Gastrin is released from G cells
in the pyloric antrum of the stomach or more
rarely in the duodenum and pancreas.
Parasympathetic nervous stimulation leads to the
release of gastrin-releasing peptide from the
vagus nerve which innervates the G cells.
Ingestion of amino acids into the stomach stimu-
lates the release of gastrin and bombesin also
stimulates gastrin release. While in the normal
state gastrin is secreted from the stomach, tumors
secreting gastrin are usually found in the pan-
creas or small intestine. Excessive gastrin pro-
duction is found in the neuroendocrine tumors
(NETs), gastrinoma which may occur in isolation
or with multiple endocrine neoplasia type I
(MEN1): gastrinomas are the most common pan-
creatic tumors found in MEN1. Gastrinomas
cause the Zollinger–Ellison syndrome which
includes hypersecretion of gastric acid and ulcer-
ation of the duodenum or jejunum. Clinical find-
ings in gastrinomas include abdominal pain and
heartburn. Weight loss occurs due to the GI
symptoms; associated diarrhea might suggest
VIPomas or carcinoid syndrome. Diagnosis is
accomplished by an elevated gastrin concentra-
tion during gastric acid secretion, by stimulation
of gastrin secretion, or by functional studies of
gastric acid secretion.
Chromogranin A is found in large dense core
vesicles in neuroendocrine cells and is cosecreted
with peptide hormones so that it serves as a
marker for various neuroendocrine neoplasms.
Thus elevated Chromogranin A is found in carci-
noid tumors, islet cell tumors, pheochromocy-
toma, pituitary tumors, and medullary thyroid
carcinoma; elevated values are likewise found in
hyperparathyroidism and hyperthyroidism.
Activation of beta 2 adrenergic receptors stim-
ulates insulin secretion while blockade of these
receptors decreases secretion. Activation of alpha
adrenergic receptors decreases insulin secretion
and blockade of alpha adrenergic receptors
increases secretion.
270
Activation of the vagus nerve stimulates
insulin secretion.
Adiponectin is a cytokine which decreases in
obesity and increases with healthy weight.
Diabetes Mellitus
Absence of insulin or insulin action leads to dia-
betes in all of its forms. Lack of insulin action
causes a catabolic state because of decreased
entry of glucose into many cell types such as
muscle and adipose tissue through glut trans-
porters which require insulin for their action (sg.
GLUT4). There is subsequent impairment of
cellular action in these cells but not in the central
nervous system as the glut 1 transporter of the
CNS requires no insulin to allow the entry of glu-
cose. (See Chap. 12 for discussion of normal glu-
cose metabolism.) In the absence of insulin effect
glucose rises since it cannot enter the cells
responsive to insulin. The renal threshold for glu-
cosuria in most people is 180 mg/dL, and as glu-
cose rises above this level, glucosuria begins and
increases leading to an osmotic diuresis with loss
of the calories ingested. This causes the classic
findings of polyuria leading to dehydration with
the individual development of polydipsia.
Proteolysis and glycogenolysis proceed with
resulting weight loss. The absence of insulin in
the portal circulation eliminates the inhibition of
the hepatic acyl carnitine cycle and thereby
allows the production of ketone bodies (acetoac-
etate, acetone, and hydroxybutyrate). Elevated
ketone bodies lead to acidosis and cause shallow
rapid breaths in a hyperventilation condition
known as “Kussmaul breathing” which occurs in
an attempt to eliminate carbon dioxide and
oppose the metabolic acidosis. The presence of
ketone bodies will be noted on the breath as a
“fruity” smell, in the blood as ketonemia, and in
the urine as ketonuria.
Counterregulatory hormones (epinephrine,
glucagon, growth hormone, and cortisol) stimu-
late gluconeogenesis, further increasing serum
glucose and worsening the problem. In the most
severe state of DM, DKA develops, with poten-
tially fatal consequences, as described later.
11 Diabetes Mellitus
The prevalence of T1DM is 1.93/1,000 and of
T2DM is 0.24/1,000 and the SEARCH for
Diabetes in Youth study from the CDC and NIH
reported in 2014 that over 191,000 children in the
USA have diabetes mellitus. The highest preva-
lence of type 1 diabetes is found in Finland with
the lowest in Venezuela. The prevalence in non-
Hispanic white youth is 1 in 370, in non-Hispanic
black youth is 1 in 438, and Asian/Pacific Islander
is 1 in 1,250. Of newly diagnosed cases of diabe-
tes mellitus, T2DM is found in non-Hispanic
whites in 5.5 % of cases, in non-Hispanic black
in 37.6 %, in Hispanic in 35.2 %, in Asian/Pacific
Islander in 34.2 %, and American Indian youth in
80 % of cases. There is an increase in the preva-
lence of type 1 diabetes of approximately 3 % per
year in most countries including the USA. The
incidence of diabetes mellitus is 28.1 per 100,000
per year. Every year over 18,000 children develop
T1DM while over 5,000 develop T2DM.
Type 1 Diabetes Mellitus
Type 1 diabetes develops by destruction of the
beta cells of the islets of Langerhans (apoptosis)
of the beta cells. Type 2 diabetes involves both
apoptosis of the beta cells, initially to a lesser
degree, and insulin resistance. The pancreas
contains about one million islet clusters known
as the islets of Langerhans scattered throughout
the pancreas and each of these islets comprises
1–2,000 beta cells. The islets are surrounded by
exocrine cells of the pancreas and ducts filled
with proteolytic enzymes which can destroy the
islets after death or during pancreatic biopsy.
Islets are too small to image by available tech-
niques, and thus postmortem studies are the main
method of describing the degeneration of islets
cells during the progression of type 1 diabetes.
Histologic studies reveal that CD8 T cells, cyto-
toxic T cells, play a major role in the develop-
ment of insulinitis that occurs during the β-cell
destruction found in type 1 diabetes. Macrophage
infiltration of the islets cells apparently also plays
a role. There is evidence that preproinsulin-
specific CTL clones can kill β-cells. A prominent
feature of type 1A diabetes is the presence of
Type 1 Diabetes Mellitus
autoantibodies to pancreatic beta cell antigens
including glutamic acid decarboxylase 65
(GAD65), insulin, IA-2 (islet cell-associated
phosphorylase), and ZnT8 (zinc transporter
molecules). Detection of these antibodies assists
in the classification of the type of diabetes an
individual may have and assists in the prediction
of the development of type 1 diabetes in clinical
studies in a first-degree relation to a proband with
diabetes who is presently euglycemic. However,
type 1B diabetes (or idiopathic DM) has no circu-
lating antibodies measurable. The report of a
patient with X-linked agammaglobulinemia who
can make no antibodies but nonetheless devel-
oped type 1B diabetes emphasizes that antibody
formation is not a necessary step in the develop-
ment of diabetes mellitus. In contrast to beta cell
destruction which is characteristic of diabetes,
alpha cells which produce and secrete glucagon
remain as do delta cells which produce and
secrete somatostatin.
Type 1 diabetes mellitus (*222100 DIABETES
MELLITUS, INSULIN-DEPENDENT; IDDM),
previously called juvenile-onset diabetes melli-
tus, is a state of insulin deficiency requiring insu-
lin replacement for therapy; this condition cannot
be treated with oral hypoglycemic agents. This
classification is divided into type 1A diabetes of
autoimmune basis which occurs in an individual
with a genetic susceptibility who encounters an
environmental stress and represents the majority
of cases. Type 2B diabetes has similar findings,
but no laboratory tests support an autoimmune
basis. In this chapter we will refer to type 1 diabe-
tes mellitus but will usually be directing com-
ments to type 1A diabetes.
Type 1 DM does not only occur in childhood
as half of the cases are diagnosed in the adult.
There is a 50 % concordance rate of type 1 dia-
betes mellitus in monozygotic twins, indicating
that environmental effects are of importance in
addition to genetic factors or the concordance
would be 100 %; 100 % is the approximate con-
cordance rate of type 2 diabetes mellitus in
monozygotic twins demonstrating the stronger
genetic tendency of this condition. Relationships
exist between the likelihood of developing type
1 diabetes mellitus and the human leukocyte
271
antigen (HLA) haplotype coded on chromosome
6 with a two- to threefold increased risk in indi-
viduals with the HLA DR3 or DR4 haplotype
and a five- to sevenfold increase in risk with both
haplotypes in the same person. Type 1 DM is
100 times more frequent in those with a missing
aspartic acid at position 57 in the DQ β chain
than when there is an arginine at position 52 of
the DQ α chain. The risk of onset of type 1 dia-
betes mellitus in nonidentical siblings is 1 % if
they share no HLA D haplotype, 5–7 % if they
share one haplotype, and 12–20 % if they share
both haplotypes. Other HLA allele haplotypes
reduce the likelihood of the onset of type 1 DM;
for example an aspartic acid at position 57 in a
heterozygous pattern (non-Asp/Asp) decreases
the risk. For Caucasian children, a 6 % risk exists
for a sibling of an affected proband to develop
type 1 DM if the proband is younger than 10
years, and a 3 % risk if the proband is older than
10 years. Further, a 2–5 % risk of type 1 DM is
found in an offspring of a diabetic parent, the
higher risk occurring if the father is affected. A
full explanation of the genetic basis for type 1
diabetes eludes us but it is clear that a genetic
predisposition modified by an environmental
exposure is the etiology.
Many environmental factors are suspected to
play a role in the onset of type 1 DM. The onset
of type 1 DM is more frequent in Fall and Winter
in either hemisphere (suggesting a link to viral
infections, which are more prevalent then) but
can occur all year. The link to viral infections is
suggestive, but the only definitive link of type 1
diabetes with viral infection is with congenital
rubella. Besides viral infections, other factors
such as environmental chemical substances are
considered as a trigger for type 1 diabetes in sus-
ceptible individuals. However, there is no con-
clusive information at present of what exposure
is important, and it is impossible to avoid expo-
sures that are linked to the development of type 1
DM. Several ongoing studies on cohorts starting
at birth aim to determine environmental factors
that might be involved in the development of
T1DM. Other research studies first-degree rela-
tions of probands with T1DM to determine
potential etiologies and determine if it is possible
272
to delay or eliminate the development of T1DM
in those individuals.
As noted, type 1-A diabetes is the specific
diagnosis given to the autoimmune form of type
1 diabetes which is the form most often encoun-
tered. About 90 % of individuals with type 1 DM
have positive diabetes-related antibodies con-
comitant with the discovery of clinical hypergly-
cemia. Glutamic acid decarboxylase 65 (GAD
65) converts glutamate to GABA which is found
in the nerves terminating at the beta cell and anti-
bodies to GAD 65 are commonly found in type
1A diabetes mellitus as are antibodies to insulin,
islet cells, IA-2 (islet cell-associated phosphor-
ylase), and ZnT8 (zinc transporter molecules).
Since an increase in the titer of these antibodies
precedes the onset of clinical type 1 DM by
months to years, it has become clear that a
sequence of beta cell destruction ultimately leads
to the clinical picture that we recognize as type 1
DM. Months pass after exposure to the initial
factors that start the process in a susceptible
patient until the beta cell function is reduced by
80 % to about 20 % of normal levels, which is the
degree of impairment that leads to clinical mani-
festations of diabetes. An intercurrent infection
or other acute stress may precipitate the onset of
type 1 DM or DKA after a period of subclinical
impairment of beta cell activity is determined.
The autoimmune basis of type 1 DM also
predisposes the affected individual to other
autoimmune diseases including Hashimoto thyroid-
itis, autoimmune Addison’s disease, autoimmune
ovarian disease, and celiac disease. Type 1 DM
may be included in autoimmune polyendocri-
nopathy syndrome 2 (269200 SCHMIDT
SYNDROME), which may include candidiasis
along with impairment of endocrine glands (see
Chap. 10). Autoimmune polyendocrinopathy
syndrome #3 may include type 1 diabetes along
with Hashimoto thyroiditis.
The increase in such antibodies is utilized in
clinical research studies of first-degree relatives
of a proband to predict the onset of clinical DM,
especially if the antibody titer is combined with a
measure of impaired beta cell function. If three
antibodies are present in the relative, there is a
high likelihood of the development of diabetes
within 5 years.
11 Diabetes Mellitus
After the onset of clinical type 1 DM and the
start of therapy, there is often a “honeymoon
period” of recovered beta cell function and
decreased insulin requirements, which may,
incorrectly, suggest cure of the disease process
and may last months to a year or more. Clinical
trials of immunosuppressive therapy to lengthen
the honeymoon period and other studies have
been undertaken to determine how to avoid the
development of type 1 DM.
Clinical Presentation of Diabetes
Mellitus
Polyuria, polydipsia, and weight loss with dehy-
dration are the classic findings of all types of DM
and may be noted, usually in retrospect, for sev-
eral weeks before presentation. If the family or
physicians are attuned to the findings, the diagno-
sis might be made before the development of the
DKA that is the inevitable consequence of severe
untreated insulin deficiency; diabetes is so com-
mon in the present era that a relative will often
measure the blood sugar of an ill child in the
home, leading to the discovery of hyperglycemia.
Thus serum glucose might be moderately ele-
vated at presentation (e.g., 200–300 mg/dL)
without the presence of substantial serum ketones
or decreased mentation, or conversely, the serum
glucose might be severely elevated at presenta-
tion (700 mg/dL or more) with severe ketoacido-
sis (pH decreased to 6.9 or lower) and stupor or
coma, all depending on when the natural course
of the disorder is interrupted with medical evalu-
ation and care. About 25 % of subjects are seen in
clinically apparent DKA at the onset of the con-
dition, as described later.
In the presentation of T1DM in this obesity
epidemic, the classic thin appearance of
new-onset T1DM may not occur. In some cases
unexplained weight loss is viewed as a positive
sign in a child with obesity when in fact it is an
early manifestation of developing diabetes melli-
tus. The abdominal pain and nausea and vomiting
characteristic of DKA might instead be mistaken
for a gastrointestinal disorder. The rapid
Kussmaul breathing might be mistaken for respi-
ratory disease. The obtundation that may develop
Type 1 Diabetes Mellitus 273

may be mistaken for substance abuse. Glycosuria symptoms noted earlier, with repetition of these
might be mistaken as a sign of a reduced renal laboratory findings on at least a second occasion.
threshold for glycosuria (because some otherwise If frank DKA is found, the diagnosis requires no
normal individuals do have a renal threshold as further blood sugar confirmation. It must be noted
low as 150 mg/dL) or as the presence of renal that even a fasting blood sugar (BS) of 126 mg/dL
tubular disease. Diabetes is a relatively common is outside of the normal range which extends only
disorder and must always be kept in mind in the to 100 mg/dL; a fasting blood sugar of 100–125 is
evaluation of the child showing these various considered “impaired fasting glucose” and a 2-h
symptoms and signs. An elevated blood sugar postprandial value of 140–200 is considered
sometimes occurs with glycosuria in the presence “impaired glucose tolerance” and either or both
of severe infection or trauma, but the findings indicate the development of prediabetes. The
remit along with the primary illness. In some ADA has recently established a hemoglobin A1c
cases these children will indeed develop bona ≥6.5 % as a diagnostic criteria for diabetes and
fide diabetes later and should be watched espe- prediabetes (5.7–6.4 %). However, hemoglobin
cially if there is a family history of diabetes; type A1c values tend to be variable in teenagers in chil-
2 diabetes is more commonly found in multiple dren and many caring for children use the hemo-
members of the family than type 1 diabetes as is globin A1c as supportive information rather than a
monogenetic diabetes (maturity-onset diabetes of tool for the definitive diagnosis (Table 11.3).
young, or MODY). The finding of the “shift to An elevated titer of antibodies to islet cells,
left” in the blood count which is characteristic of insulin, or GAD 65 is found in the serum in 90 %
DKA may be interpreted as an isolated infection. of cases of type 1 diabetes. Urine analysis will be
Since many children with bona fide new-onset
diabetes mellitus will present with infections that
hastened the onset of the clinical presentation, the Table 11.2 Glucose tolerance test after 1.75 g/kg carbo-
hydrate load (75 g maximum)
clinician must be careful to differentiate between
the two situations. Condition Baseline 1h 2h 3h
If diabetes is considered and glycosuria and/or Normala <110 <200 <140 <130
an elevated finger stick blood sugar is determined Insulin 9 51 37 20
(mU/mL)
by glucometer, it is never appropriate to send a
C-peptide 1.3 3.3 3.0 2.0
confirmatory laboratory glucose determination (ng/mL)
which cannot return on the same day; the author Impaired 110–125 140–199
has seen cases in which this sequence has occurred glucose
over a 3-day weekend so that when the glucose tolerancea
value, well above 200 mg/dL, returned days later Diabetes ≥126 ≥200 ≥200 ≥200
mellitusa
from the laboratory, the child was already in the
a
intensive care unit being treated for DKA. If dia- Blood glucose in mg/dL
betes is considered as the diagnosis, further diag-
nostic activities must occur immediately. Table 11.3 HgbA1c compared with average blood sugar
Laboratory evaluation will reveal elevated HgbA1c (%) Average blood sugar (mg/dL)
serum glucose in diabetes mellitus in the presence 4 60
of polyuria and polydipsia and a glucose tolerance 5 90
test (GTT) is not required in this situation 6 120
(Table 11.2 has standards for GTT for use in other 7 150
circumstances for completeness but is rarely uti- 8 180
lized). The diagnosis, according to the American 9 210
Diabetes Association, specifically requires a fast- 10 240
ing blood glucose equal to or greater than 126 mg/ 11 270
dL or a random (or casual) blood glucose greater 12 300
than 200 mg/dL, with the presence of the 13 330
274
positive for glucose, as the elevation of blood
glucose will exceed the renal threshold of
180 mg/dL that allows glucose excretion into the
urine; however, glycosuria also can occur in
nondiabetic conditions such as a genetic decrease
of the renal threshold for glucose, diseases that
affect the renal tubule, times of severe illness and
stress, and even on occasion after excessive
ingestion of sugar. Positive urine or blood ketone
bodies (acetoacetate, acetone, hydroxybutyrate)
will develop in the absence of insulin, but ketone
bodies also may be found at presentation in chil-
dren with type 2 DM, making differentiation
between the two types difficult. Because of the
elevated serum glucose, the serum sodium will
be low, because of loss of sodium due to osmotic
diuresis and because a 1.6-mEq/L decrease in
serum sodium concentration is found for every
increase in serum glucose of 100 mg/dL. Insulin
deficiency leads to elevation of serum triglycer-
ide and cholesterol, sometimes to a remarkable
degree of over 1,000 mg/dL and several 100 mg/
dL, respectively. These lipid abnormalities may
precipitate pancreatitis. The percentage of hemo-
globin A1c (HgbA1c) demonstrates the degree to
which glucose is nonreversibly bound to Hgb and
provides a window into the length of time the
child has been hyperglycemic.
Diabetic Ketoacidosis
DKA may be the presenting condition at diagno-
sis of diabetes. Risk factors for the development
of DKA are age under 5 years, lower socioeco-
nomic and educational status, and lack of access
to medical care. But DKA is not limited to the
first episode in a previously undiagnosed patient,
as DKA may develop in any patient who does not
adequately care for the condition or misses sev-
eral insulin injections.
While DKA is known to be related to T1DM,
DKA may likewise occur in type 2 diabetes in
children in contrast to the absence of DKA in most
adults with type 2 diabetes. DKA may be defined
as a condition where the glucose is greater than
200 mg/dL, there is ketonemia determined by a
serum beta-OH butyrate greater than 4 mEq/L or
ketones strongly positive by Ketostix measure-
ment at a greater than 1:2 dilution of serum,
11 Diabetes Mellitus
ketonuria with urinary ketones present, usually
“large,” along with acidosis defined as venous
blood gas pH less than or equal to 7.30 and bicar-
bonate equal to 15 mEq/L or less. The level of aci-
dosis defines the severity of diabetes so that mild
DKA is characterized by venous pH of 7.2–7.3 or
HCO3 10–15 mEq/L, moderate DKA as pH 7.1–
7.2 or HCO3 5–10 mEq/L, and severe DKA as pH
<7.1 or HCO3 less than or equal to 5 mEq/L
(Table 11.4). Besides the usual symptoms of poly-
dipsia and polyuria, weight loss may accelerate
because of fluid losses caused by osmotic diuresis
and vomiting. Abdominal pain is common, some-
times suggesting the incorrect diagnosis of acute
abdomen. Patients at presentation usually have
severe elevation of blood glucose, metabolic aci-
dosis with ketone bodies in blood and urine, and
dehydration with urinary sodium and potassium
loss. Dehydration causes increased serum creati-
nine and blood urea nitrogen (BUN; factitious
elevation of creatinine may also occur because of
cross-reaction of acetoacetate in the creatinine
assay) and raises blood sugar even more.
Dehydration increases acidosis. The respiration
rate is increased to counteract the metabolic acido-
sis, and the ketonemia adds a “fruity” aroma to the
breath; deep-“sighing” Kussmaul respiration is the
term used to describe the rapid but shallow respi-
rations. A patient with type 1 DM might certainly
have intercurrent pneumonia, but Kussmaul respi-
ration does not by itself indicate pneumonia; con-
versely, the state of dehydration may minimize the
signs of pneumonia, so consideration for this pos-
sible coexisting condition must occur during eval-
uation of DKA. Indeed, infection may be present
and may have been the precipitating factor to
cause worsening of the diabetic condition, so the
possibility of infection must be considered in all
cases of DKA. Even if no infection is present, the
white cell count is often elevated in DKA, with a
marked shift to the left and prevalence of band
forms of white blood cells (WBCs), related to the
elevation of glucocorticoids during stress.
Metabolic acidosis may be demonstrated if the
anion gap (calculated as [Na+–(HCO3− + Cl−)]) is
increased above the normal limit of
14 mEq/L. Tachycardia is common. The patient
may be confused, stuporous, or in frank comma.
Type 1 Diabetes Mellitus 275

Table 11.4 The treatment of DKA as carried out at UC must be modified along with medication doses as needed
Davis Medical Center developed by the pediatric endo- by the clinical situation encountered
crine, PICU and ED teams; this is only a guideline that
Diabetic treatment plan, pediatrics
Standard admission orders for PICU
1. Admit to PICU
2. Initiate diabetes education
3. Diet: NPO
4. Activity as tolerated
5. I & O and daily weight
6. Lab work:
ABG or VBG gas with electrolytes on admission and then q 3 h
BMP with calcium, phosphate, magnesium on admission and q. 6 h
Amylase and lipase on admission
Blood glucose monitoring q 1 h until i.v. insulin is discontinued
Check urine ketones every void once subcutaneous insulin started
7. Administer O2 to keep O2 saturation >95 % if necessary
8. IV fluids:
Calculations:
Deficit: Assume 7 % dehydrated; weight (kg) × 70 = (a) _____mL
Remaining deficit; subtract all boluses given: (a) − bolus IVF = (b) _____mL
Replace remaining deficit over 48 h: (b)/48 h = (c) _____mL/h
Maintenance IVF: (d) _____mL/h
Total IVF (maintenance + remaining deficit): (c) + (d) = _______mL/h
Serum glucose >250 mg/dL
Normal saline with 20 mEq KCl and 20 mEq KPO4 at total IVF rate
Serum glucose <250 mg/dL
D10 ½ normal saline with 20 mEq KCl and 20 mEq KPO4 at ½ total IVF rate plus ½ normal saline with 20 mEq
KCl and 20 mEq KPO4 at ½ total IVF rate to make D5 ½ NS with 20 mEq KCl and 20 mEq KPO4 at total IVF rate
(Note: there is controversy over whether normal saline should be used in almost all situations including this. You
must use clinical judgment in the condition of the patient to decide on this issue)
9. If urine output not >1 mL/kg/h or serum K >5.0, call MD immediately
10. Regular human insulin continuous infusion at 0.1 U/kg/h
11. Once insulin infusion is begun, call MD if serum glucose is <150 mg/dL or >250 mg/dL
12. Acetaminophen 15 mg/kg = _________ q 4 h PO/PR PRN temperature >38.0 or headache
13. VS, neuro checks, and cardiac monitoring q 1 h while on i.v. insulin, then per unit routine. If GCS < 13 or if
patient c/o headache, neuro checks q ½ h and call MD
14. If it is anticipated that the patient will be transitioned to SC insulin in a.m., please order an UNLIMITED ADA
breakfast
15. When patient is transitioned to SC insulin, home glucose monitor may be used for blood glucose testing
Note: If the patient has known diabetes and is on an insulin pump, the pump should be disconnected and the infusion
set removed. The parents should be instructed to bring a new infusion set to the hospital the following day so that the
pump can be restarted after the patient recovers from DKA

DKA may be the first presentation of diabetes
in an individual. Sometimes the child has visited
doctor within the previous week or two and the
more subtle symptoms were not identified as
indicative of diabetes and no diagnostic tests
were performed. DKA presenting after the diag-
nosis of diabetes however is frequently due to
missed insulin injections, sometimes purpose-
fully. Teenage girls may note that they are gain-
ing weight on insulin therapy and wish to lose
276
weight by omitting the insulin. Teenagers may
act out by skipping their insulin injections or not
attending to their insulin pump appropriately.
DKA may occur with unrecognized insulin pump
infusion malfunction, usually due to the infusion
set being kinked or clogged or having fallen out
of the skin without being noticed.
However, DKA may also occur because of
severe intercurrent illness. Most families edu-
cated in diabetes management can treat mild to
moderate ketonemia at home with appropriate
fluid and insulin management as long as the
child can drink and eat, but if the child has severe
diarrhea or severe vomiting, a visit to the emer-
gency department or admission to the inpatient
ward is likely to be necessary. All children with
diabetes should receive a yearly influenza vac-
cine injection (not nasal spray which is not
approved for diabetes); influenza infection will
very likely lead to hospitalization and need for
intravenous fluids. Present recommendations
suggest that every child with diabetes who is
over 2 years old should get pneumococcal immu-
nization as well.
The life-threatening complication, cerebral
edema (CE), occurs in about 1 in 100 cases of
DKA, more often in younger patients, and may
occur during the hospitalization at which the ini-
tial diagnosis of type 1 DM is made. Mortality is
reported in 20–40 % of cases, and neurologic
sequelae in survivors are reported to be about
25 %. A recent study of 6,000 cases of DKA indi-
cated that CE is more common in patients having
the lowest serum bicarbonate levels, in patients
who received bicarbonate administration, in
those with the youngest ages, in those with the
longest duration of symptoms and in those with
the highest severity of symptoms, in those with
higher BUN, and in those without the normal
increase in serum Na during therapy. CE may
present with a depressed sensorium from 12 up to
24 h after presentation of DKA and after initial
improvement of symptoms. However, many
patients with any degree of DKA have some
degree of brain swelling (which can be demon-
strated on magnetic resonance imaging (MRI)) as
a manifestation of subclinical cerebral edema,
but the clinical manifestations of CE, including
cerebellar tonsillar herniation and subsequent
11 Diabetes Mellitus
respiratory arrest, are the most extreme presenta-
tions. A patient who appears to be improving but
deteriorates, or who develops a headache during
the improvement phase, or younger children who
develop uncharacteristic behavior such as crying,
blinking, or restlessness may be developing clini-
cally relevant CE. Early signs of increased intra-
cranial pressure include (a) altered mental status/
headache with decreased papillary response to
light, (b) bradycardia, (c) hypertension, and (d)
irregular respiration, usually developing later in
the course. Treatment must be rapid and may
include hyperventilation, mannitol infusion
(0.25–1 mg/kg i.v., given over 20 min every
2–4 h), and possibly glucocorticoid administra-
tion, although the glucocorticoid may itself
increase blood glucose values. Hypertonic 3 %
saline has been used less frequently in a dose of
5–10 mL/kg over 30 min, but there are few stud-
ies of this approach. Elevation of the head may
help. Central nervous system (CNS) imaging is
the direct proof of the condition and should be
performed if imaging can be carried out while the
subject is carefully observed and emergency ther-
apy is available. Neurosurgical consult is manda-
tory, as cranial decompression may be necessary.
The cause of CE is in dispute, and the classic
view that an excessive rate of rehydration is the
primary cause leading to cerebral edema is not
supported by recent data. However, careful atten-
tion to the rate and composition of fluid replace-
ment in diabetic ketoacidosis by following
established guidelines is a prudent measure.
Other possible complications of DKA include
the development of thrombosis or pulmonary
embolism and renal insufficiency due to throm-
bosis of major vessels. Thus although the treating
physician must endeavor to moderate fluid
administration so as not to increase the likelihood
of CE, fluid must be adequate to avoid these com-
plications of severe dehydration.
Total body potassium loss may not be directly
reflected in serum levels of potassium as potas-
sium is an intracellular ion. Thus hyperkalemia
or hypokalemia may occur during DKA or dur-
ing its treatment. EKG monitoring therefore is
important during evaluation and treatment of
DKA as T waves are peaked in hyperkalemia and
low in hypokalemia with U waves appearing.
Type 1 Diabetes Mellitus
Monitoring and Treatment of Diabetic
Ketoacidosis (Table 11.4)
DKA is a life-threatening emergency that requires
close monitoring to be carried out in a pediatric
intensive care unit, whenever possible. Patients
from smaller communities are often transported
to such centers by air or ambulance for this care.
Alternatively pediatric intensivist or pediatric
emergency department physicians can provide
guidance to rural providers via telemedicine from
major medical centers. A recent consensus con-
ference of the international Society for Pediatric
and Adolescent Diabetes developed evidence-
based guidelines for DKA which are summarized
below:
Standard evaluation by the pediatric advanced
life support guidelines is carried out with deter-
mination of blood gas, ketones, CBC, metabolic
panel and state of dehydration, state of conscious-
ness, and the establishment of two i.v. lines.
Fluid replacement should be the first treat-
ment but complete replacement should occur
slowly over 36–48 h.
Monitoring for the development of cerebral
edema includes observation for the development
mOsm / L = 2 ´ serum sodium ( mEq / L ) + éë blood glucose ( mg / dL ) / 18 ùû .
This equation indicates that an increase in
blood glucose of 180 mg/dL causes an increase in
osmolality of 10 mOsm/L. Thus DKA is a condi-
tion of hypertonic dehydration, and osmolality is
elevated at presentation.
Treatment of DKA involves fluid and electro-
lyte resuscitation along with insulin administra-
tion. Careful attention to laboratory data and fluid
administration is accomplished with a flow sheet
kept up to date at all times; such a flow chart is
not an option. The concern that excess fluid
administration may predispose to complications
must be balanced by the possibility that the
dehydration at the time of presentation may cause
ischemia of kidney, brain, or other organs. Thus
any guideline for therapy must be modified by
the clinical condition of the patient.
277
of headache, bradycardia, change in neurological
status including such findings as restlessness,
irritability, increased drowsiness, incontinence,
and the development of specific neurological
signs such as cranial nerve palsies, rising blood
pressure, and decreased oxygen saturation.
Because of the potential development of cere-
bral edema, hypertonic (3 %) saline and mannitol
must be kept at hand and used should cerebral
edema develop.
Vital signs and mental status are checked
hourly in affected patients. Blood glucose is mea-
sured hourly; a true laboratory value is best, but a
bedside glucometer is frequently used.
Glucometers must be tested for accuracy, and the
age of the sensor strips used on the device must
be checked for expiration dates to make sure that
they are not too old, which would make them
more likely to report incorrect values. As BS val-
ues descend to the normal range, the glucometer
becomes less accurate, and laboratory confirma-
tion of glucose values becomes even more impor-
tant. Serum electrolytes are measured every 4 h.
Serum osmolality is measured in the laboratory,
but in the interim may be roughly estimated as
The amount of fluid loss in DKA is estimated
according to customary clinical findings. Severe
cases are usually associated with fluid loss equiv-
alent to 10–15 % of body weight, but the standard
presentation is more likely 7 % dehydration.
Clinical signs of dehydration are as follows: 5 %,
normal skin turgor, moist buccal mucosa, tears
present, and pulse regular; 10 %, skin dry, and
tenting of skin possible, buccal mucosa, dry eyes,
deep set, tears decreased, irritability noted, and
pulse increased; and 15 %, clammy skin, parched
buccal mucosa, eyes sunken, no tears, lethargy
noted, and pulse rapid. Because of the osmotic
diuresis, urine output is not a reliable indicator of
hydration.
Most recommend that normal saline solu-
tions be used in the initial phases of rehydration,
278
and there is increasing evidence that hypotonic
fluid leads to complications in many types of
dehydration including DKA. Fluid should be
replaced slowly, over a 36–48-h period, accord-
ing to most recommendations, with half given
over the first 12 h, and the rest, over the remain-
ing 24–36 h. Initial resuscitation may be offered
as a bolus of normal saline at 5–10 mL/kg if sig-
nificant dehydration is detected by abnormal
mEq of sodium required = éëconcentration desired ( mEq / L ) - concentration present ( mEq / L ) ùû
´ 0.6 - 0.7 ´ body weight in kilograms
One half of this deficit is given in the first 12 h
and the rest in the next 24–36 h. An additional
20–40 mEq/L of sodium is added for daily
maintenance.
Potassium deficit is present in all presenta-
tions of DKA. While potassium is mainly an
intracellular ion, a serum potassium value that is
normal indicates a moderate deficit in total body
potassium, whereas a low value indicates a serve
deficit, and even an elevated value is associated
with a mild potassium deficit. Potassium deficit
will increase with saline administration and
expansion of extracellular volume. As acidosis is
corrected, or if alkalosis develops, the potassium
will leave the intracellular space in exchange for
hydrogen, a trend that intensifies with the
glucose and insulin administration in the course
of the treatment. Careful attention to potassium
balance is essential. Although laboratory evalua-
tion is essential, the electrocardiogram (EKG)
offers some information, as peaked T waves are
seen in hyperkalemia, whereas U waves are seen
in hypokalemia along with low T waves.
Potassium can be replaced, once urinary output is
established, by 20–40 mEq/L given slowly in the
replacement fluid. EKG monitoring is essential,
as an excessive amount or speed of potassium
administration may be fatal because of the devel-
opment of arrhythmias. Because Cl may itself
cause acidosis, potassium is best given half as
potassium acetate and half as potassium phos-
phate, with the proviso that phosphate infusion is
best used only when phosphate is low, because in
excess, phosphate can reduce calcium.
11 Diabetes Mellitus
vital signs [low blood pressure (BP), rapid
pulse, and delayed capillary filling], and this
bolus may be repeated if indicators suggest the
need for more immediate fluid replacement. If
the patient is in shock, blood or plasma expand-
ers may be used according to customary inten-
sive care protocols.
Sodium deficits develop with DKA and are
calculated as
Acidosis is almost always corrected by fluid
and insulin administration in DKA. Thus added
bicarbonate is not indicated in most cases, even
with significant acidosis; indeed, added bicar-
bonate is associated with an increased likelihood
of the onset of cerebral edema and may paradoxi-
cally cause cerebral acidosis. While some author-
ities recommend the use of 40 mEq/m2 of
bicarbonate if the pH is 7.1 and 80 mEq/m2 if the
pH is less than 7.0, this chapter does not advo-
cate routine bicarbonate administration. For
completeness only we include the formula to cal-
culate bicarbonate deficit as (12 − observed bicar-
bonate value) × 0.6 body weight (kg), and the
administration is performed as 1–2 mEq/kg over
a 2-h period or slower.
Insulin therapy for DKA is generally adminis-
tered as an i.v. infusion at a rate of 0.05–0.1 U/
kg/h, with the lower dose range usually achieving
a more desirable slower decrease in blood glu-
cose. We do not advocate administration of a
bolus of i.v. insulin initially to saturate sites on
the infusion set, as was the course in the past. The
goal of insulin therapy is a decrease of blood glu-
cose of about 50–100 mg/dL/h. Correction of
blood glucose may precede correction of acid–
base balance. In this situation, it is important to
continue insulin administration until acidosis is
eliminated. Although no dextrose is given in i.v.
fluids at first, as the blood glucose is already
elevated, when blood glucose decreases to about
300–200 mg/dL, dextrose (usually as D5–10 %
in saline) is added to allow the safe, continued
administration of insulin, which will serve to
Type 1 Diabetes Mellitus
eliminate ketone bodies while minimizing the
likelihood of hypoglycemia.
Intravenous insulin is now always administered
in DKA as recombinant DNA-derived regular
human insulin. IV insulin is administered via a
“Y” connector piggybacked onto the other fluids
being administered. Insulin is usually mixed as
50 U into a 250-mL bottle of saline, yielding 1 U
insulin/5mL of saline. The desired hourly units of
insulin will be delivered by the number of millili-
ters determined by multiplying the units by 5 (e.g.,
2 U/h is given as 10 mL/h insulin solution). The
insulin infusion is usually continued until urine
ketone bodies are absent, which is often past the
persistence of hyperglycemia. This stage usually is
reached at the time that the child will be able to
tolerate oral feedings. This is the time to consider
switching to subcutaneous insulin administration,
but the switch must be coordinated or a delay in
administering subcutaneous insulin after discon-
tinuing the i.v. infusion will allow the blood sugar
to rise again to dangerous levels.
Close monitoring of mental status, vital signs,
peripheral perfusion, and serum sodium and
potassium is important through the course.
Evaluation of magnesium and phosphorus is also
indicated initially, and if abnormal, at intervals
thereafter (magnesium deficiency may cause
potassium loss in the urine). All the abnormal
measurements should improve in a continuous
pattern; if sodium decreases rather than increases,
excess free water administration may be the
cause; falling serum sodium is a risk factor for
the development of cerebral edema.
Improvement should be continuous. Thus
deteriorating status may be due to worsening
or unresolved acidosis, uncorrected or devel-
oping hypokalemia, hypoglycemia, hypoten-
sion, untreated infection, or CE.
Onset Without DKA
With increased education of the population, some
patients are diagnosed at earlier stages of the dis-
ease and do not have DKA. BS might be only in
the range of 200–300 mg per deciliter. These
patients might be educated in the outpatient
environment if adequate and trained staff is
available to administer such education. This is
appropriate only if ketosis is absent or minimal
279
and if glucose is only moderately elevated. It is
important but sometimes difficult to differentiate
this situation from type 2 DM described later.
Parents will not be in the best emotional condi-
tion to learn of the care of the child with diabetes
and outpatient management may be efficient but
inappropriate for some situations.
Transitioning to the Long-Term
Management of Diabetes Mellitus
Type 1
Once the diagnosis of diabetes mellitus is estab-
lished, the chronic care phase begins. While the
physiology is well understood and excellent treat-
ment is available, success in chronic daily care still
may be difficult. Successful control of diabetes in
the younger child requires an attentive family
which is able to deal with the calculations neces-
sary in determining carbohydrate content of food
and insulin dosage. Parenting style becomes para-
mount. In the soon-to-be-independent teenager the
cooperation of the patient with the treatment plan
becomes the central focus. Families and patients
vary widely and the treating team must have expe-
rience in dealing with the psychological overlay of
daily care of this chronic condition.
It is important to impress upon the child and
family that the child should no longer be consid-
ered “sick” once a stable biochemical milieu has
been established. Parents must be told that the
condition is not preventable and that it is “not
their fault” by their parenting nor their genes. The
well-treated child will have few limitations on
their daily life and can look forward to a long life
span. With poor care the opposite may be true.
The state-of-the-art care for diabetes in child-
hood and adolescence is provided by a team of
providers including diabetes nurse educators,
dietitians, social workers and psychologists, as
well as the treating physician. Such a team may
not be available in smaller distant locations, but
satellite clinics are often available at a distance
from university centers or children’s hospitals.
Likewise telemedicine treatment can be provided
anywhere in the world if a receiving site is avail-
able that can connect with the transmitting team.
At initial presentation, the family will be
distraught over the new lifelong diagnosis, and it
is necessary to take clues from them as to when
280 11 Diabetes Mellitus

they can be receptive to education about this dis- Table 11.5 Carbohydrate content of selected common
foods
ease. After the resolution of hyperglycemia and
ketonemia/acidosis, the major reason for a patient Starches Amount Carb (g)
to remain in the hospital is lack of ability to carry Bread, white or wheat 1 slice (1 oz) 15
out BS monitoring, insulin administration, treat- Hamburger or hot dog bun 1 bun 20
ment of hypoglycemia, or dietary planning, and Bagel 1 (Deli style) 60–70
the key to these accomplishments is family edu- Doughnut 1 medium 25
cation toward the understanding of these “sur- Pancake or waffle, frozen 1 small 15
vival” skills. In those families that cannot accept Tortilla, corn, 6″ 1.2 oz, each 10
teaching nor understand the teaching provided to Saltine 1 cracker 2
them, a lengthened hospitalization will result. It Oatmeal 1 cup (cooked) 30
Rice, white or brown 1 cup (cooked) 45
is important to involve the patient and family in
Spaghetti 1 cup (cooked) 40
the process of monitoring BS by home glucome-
Corn ½ cup 15
ter and the measurement and administration of
Potatoes
insulin as soon as they are able to accept teaching
Plain, baked Small (3 oz) 15
in the difficult time after the diagnosis. This early
French fries
education may shorten the hospital stay.
McDonald’s Small 25
Refried beans 1 cup 40
Apple
Dietary Management Small 4 oz 15
Medium 6 oz 25
The patient and family must understand appro- Large 8 oz 35
priate dietary management of diabetes, although Grapes 15 pieces 15
it will take some time before this becomes second Strawberries 1 cup (sliced) 10
nature. A dietician is expert in teaching these Apple juice 4 oz (½ cup) 15
skills and should be consulted early in the educa- Whole, low fat or skim 8 oz (1 cup) 12
tional process. The dietary treatment of children Yogurt (plain) 8 oz (1 cup) 12–14
with type 1 diabetes does not limit specific items Table sugar 1 Tbsp 15
as long as the insulin administered is appropriate Ketchup 1 Tbsp/1 pkt 5
for the carbohydrate load. However, an American Spaghetti sauce ½ cup 10
Diabetes Association (ADA) diet provides New York-style pizza 1 slice 45
healthy guidelines as a goal for the diet and con- Note: Exerpts accessed from the website of the Naomi
sists of 45–60 % of total calories from carbohy- Berrie Diabetes Center of Columbia University Medical
drates, 30 % from fat with less than 10 % Center (http://www.nbdiabetes.org/diabetes-faqs)
saturated fat, and 10–20 % calories from protein.
Birthday cake is not to be a staple of the diet, but
on occasion, it can be eaten with insulin cover- Table 11.5 contains a few examples of carbohy-
age, especially in the MDI regimen below. Total drate content of common foods for basic carbo-
recommended calories vary by age and size of hydrate counting.
the child. The family must learn carbohydrate
counting, a skill that will be especially important
if MDI or insulin pump is considered. Type 2 Preparation for Discharge
diabetes does require a carbohydrate-controlled
diet avoiding concentrated carbohydrates and The basic “survival skills” are learned before dis-
this difference between T1DM and T2DM may charge from the initial hospitalization so that the
become an issue in the family when relatives with patient can measure BS by glucometer, measure
type 2 diabetes try to apply their dietary approach insulin from the bottle or pen, administer the
to diet to children with type 1 diabetes mellitus. injection, use emergency measures including
Type 1 Diabetes Mellitus
intramuscular glucagon injection for hypoglyce-
mia, and choose a reasonable diet. The patient
must recognize the signs of hypoglycemia or
impending DKA and the steps necessary to reach
the doctor for advice (not an easy task in a large
medical center) and understand that therapy will
change if an intercurrent illness occurs. Although
the basics of adjustment of insulin may be taught
in the hospital, in this age of mandatory rapid
discharges (mandated by funding agencies rather
than medical judgment), usually inadequate time
is available to teach this all in detail and families
can be overwhelmed with too much information
too soon. Thus after discharge, the family/patient
will call the physician daily for a few days or
weeks to discuss the correct dose of insulin and
explain why it was adjusted as such. This educa-
tional process aids the family in achieving inde-
pendence in understanding the therapy of
diabetes. In time the family and patient who have
observed the response to therapy will offer sug-
gestions for management that may be supported
by the team when deciding on change in therapy.
Hospitalization does not have to continue until
blood sugar control is optimal. Because the
patient will be more active at home than in the
hospital and glucose values will therefore likely
decrease from values seen in the hospital, BS values
do not have to be completely normalized before
discharge. It is not necessary to expect the family
and child to have a complete understanding of the
biology of diabetes before discharge. An under-
standing of the more complex details of the disor-
der will develop during the month that follows
the outpatient-management phase.
Home Measurement by Glucometer
No matter which schema is followed, careful
attention to BS monitoring is essential, at least
before breakfast, lunch, and dinner, and before
the bedtime snack. Home measurement of BS
by glucometer has revolutionized the ability of
family and patient to control BS closely.
Many different glucometers are available for
measurement of BS from drops of blood from the
finger, and all have various advantages and draw-
backs. Most have memories, but electronic memo-
281
ries do not replace the maintenance of a
meticulous record book, which assists the
patient and physician’s review of BS control.
Most glucometer memories can be downloaded
to a computer or uploaded to web-based programs
for the generation of BS versus time-of-day
graphs and other useful analytic information.
These can be used in the clinic or e-mailed to the
provider in between clinic visits. Nonetheless, all
too often, the family brings in a glucometer that
was not set to the correct day and time and there-
fore cannot be interpreted, or they forget the glu-
cometer completely, leading to a wasted visit. If
they keep a record book, they are involved in the
process of monitoring and have a second source
of historical blood glucose data. Although glu-
cometers may have memory of the measurements
over the previous month or more, observation of
the patterns of BS changes is essential if a patient
is to learn how to make adjustments of insulin
doses and to guard against a dead battery falsify-
ing or emptying the glucometer’s memory.
Another reason to keep a written record is that
some patients use multiple glucometers or may
not care for the device correctly: if the glucome-
ter does not have the date or time set (perhaps
because of battery change or dropping the
device), the memory on the glucometer will be
useless, as it will not be possible to determine
when any glucose value occurred.
Families may believe that the child’s report of
the blood sugar is “okay” when in fact it either
has not been taken or is abnormally high or low.
The parents must see the actual numbers in the
glucometer on a regular basis to avoid a tendency
of many pediatric patients to “forget” to measure
blood sugar and report otherwise. Sometimes
pediatric patients will falsify blood sugar mea-
surements by using control solution rather than
their own blood. The patient may lick their finger
before testing which factitiously lowers blood
sugars as well. Others, usually teenagers, may
measure their blood sugar for a week or 2 before
the outpatient visit having rarely done so in the
weeks and months before the visit in an attempt
to show compliance. It is important to look at a
long history of blood sugar management mea-
surement rather than just the last 2 weeks before
the visit.
282 11 Diabetes Mellitus

Some glucometers are able to test blood
ketone levels. This is a more sensitive indication
of impending ketosis and is be helpful in
management.
Subcutaneous Insulin Management
Once BS is brought close to normal values, aci-
dosis is resolved, and the patient is able to toler-
ate oral feedings, it is time to switch to
subcutaneous insulin. Many approaches are used
for insulin therapy, and more than one type of
insulin and type of device are available for
administration (Fig. 11.2, Table 11.6). When the
i.v. insulin is discontinued, the insulin effect will
be quickly eliminated. Thus subcutaneous short-
acting insulin must be given before discontinuing
i.v. insulin to allow it to exert its effect while the
i.v. insulin effect wanes. If the child has been
receiving i.v. insulin for several days and the BS
has stabilized on oral intake, the total sum of
insulin that was infused over the previous 24 h is
used as an initial estimate of the dose of insulin to
be given by subcutaneous injections over the next
24 h. The total daily dose of insulin tends to
average between 0.5 and 1 U/kg/day; usually the
lower range is used at first for safety, although
significant variations are found to this number as
the course of the disease advances.
Two Dose Per Day Regimen
Historically management has involved two injec-
tions per day, each consisting of a moderate-

Three Methods of Administration of Subcutaneous Insulin

Multiple
Dose
Injections
Relative Action of Insulin

Ly Ly Ly Ly Ly Gl

3 Doses
per day

R+
NPH R NPH

2 Doses
per day

12 8 12 6 10 12
AM R+ AM PM R+ PM PM AM
NPH NPH
7:30AM 9:45AM 3:30PM 9:30PM
Breakfast Snack Lunch Snack Dinner Snack

Time of Day

Fig. 11.2 Three methods of administration of subcutane-
ous insulin. The curves represent the usual period of action
of each insulin preparation with the more heavily shaded
“tail” demonstrating the variable time until activity ceases.
Ly lysproinsulin although insulin aspartate is similar in
time of action, R regular insulin although fast acting insu-
lin might be used instead of regular in the 2 or 3 doses per
day schemas, Gl glargine insulin (the action of glargine is
indicated by the light grey area on the top panel)
Type 1 Diabetes Mellitus 283

Table 11.6 Actions of commercially available insulin morning and a dose of very-short-acting insulin,
preparations
lispro, glulisine or aspartate insulin, given before
Onset Peak Duration every meal or substantial snack by using a set
Preparation of action activity of action (h)
ratio of insulin-to-carbohydrate intake (e.g.,
Aspart 10–20 min 40–50 min 3 (to 5)
0.5–2 U insulin per 15 g of carbohydrate). The
Lispro 15–30 min 30–90 min 3 (to 5)
long-acting insulin may be considered to be the
Apidra 20–30 min 30–90 min 1–2.5
insulin that covers the needs of a patient who is
Regular 30–60 min 2–5 h 5–8
not eating and having stable activity per day; thus
NPH 1–2 h 4–12 h 18–24
it is insulin which covers the requirements for
Glargine 1h None 24
simple existence. In a noncompliant patient who
Detemir 1–2 h 6–8 h 24
misses insulin injections if they at least take one
long-acting insulin injection per day, the likeli-
hood of admission for DKA is considerably
acting (e.g., NPH) and a short-acting (e.g., decreased even if they missed many short-acting
aspartate insulin) insulin preparation. The insulin insulin injections. The rapid-acting insulin
dose may be estimated as two-thirds of total daily attends to the carbohydrates ingested and cor-
dose before breakfast and one-third of the total rects abnormal blood sugar values, an insulin that
daily dose of insulin given before dinner, with treats all the variation in living that occurs daily.
one-third of each dose given as rapid-acting and A dietician is essential in calculating this ratio of
two-thirds given as NPH insulin. Two injections insulin-to-carbohydrate intake. The patient or
per day management is a compromise, as the child family must count carbohydrates in each meal
is obliged to eat a meal containing a predictable consumed, so education is complex for MDI. The
carbohydrate content on a strict schedule to main- short-acting insulin is adjusted both on the basis
tain BS while the short- and moderate-acting of the carbohydrates to be consumed (determined
insulins exert their effects; skipping a meal will by carbohydrate counting) and the BS at the time
cause hypoglycemia as no carbohydrate peak of injection (determined by glucometer)
occurs at the time of the expected peak of the (Table 11.7). When the blood sugar is elevated or
action of the moderately acting insulin already decreased compared to normal, the insulin dose
given, whereas excessive carbohydrate intake is raised or lowered by a mathematical calcula-
will cause hyperglycemia. Thus two injections tion noted below. Someone (if the child is too
per day regimens are to be avoided if at all pos- young, some responsible adult) must be able to
sible. Some families are not capable or willing to calculate insulin doses at midday or at snack time
give a third noon injection or a fourth bedtime and administer the insulin while the child is away
injection of long-acting insulin, and the two dose from home. In this regimen, the child has a more
per day regimen is sometimes reluctantly accepted. flexible schedule, whereby meals might be
There are premixed insulins with 30 % short- delayed, extra snacks might be more easily
acting and 70 % moderate-acting insulin in the vial added, or meals may even be missed (this, of
or pen cartridge, but these are hard to adjust appro- course, is not a recommended action). Short-
priately in a child. Multiple-dose injection is a acting insulin may be given by the classic syringe
better schema for all children when possible. and needle with a bottle of insulin or by a more
convenient cartridge-and-pen system in which
Multiple Dose Injection Regimen the dose is dialed in and the insulin administered.
A much improved technique is the multiple dose Insulin vials or pens are usually kept at room
injection (MDI) regimen, sometimes known as temperature, where they are stable for 30 days.
basal bolus regimen, which involves the admin- The first step in preparing an individual who
istration of a long-acting insulin (glargine or was treated with two doses a day to multiple-dose
detemir insulin, which exerts a stable effect over injection is to determine the total insulin
the 24 h after an injection) every evening or requirements that the child has been using for the
284 11 Diabetes Mellitus

Table 11.7 Typical algorithm for short-term insulin cor- sleep period (BS should be measured at 3 a.m. on
rection (sliding scale)
a couple of occasions to be sure), the a.m. BS
For an average child over 10 years value will generally determine whether the dose
qAC of long-acting insulin is appropriate. If the BS
Blood glucose 151–200 Add 1 U Novolog stays stable between a normal premeal determi-
201–250 Add 2 U nation and the value 2 h later, the short-acting
251–300 Add 3 U insulin dose per a given serving of carbohydrates
301–350 Add 4 U is appropriate. If the premeal BS is too high, but
>350 Add 5 U and the calculated dose of additional short-acting
measure urinary
ketone insulin is able to decrease the BS value 2 h later
qHS to a desirable level, the sliding-scale dosage to
Blood glucose 201–250 Add 1 U Novolog control elevated blood sugars is appropriate.
251–300 Add 2 U Insulin is injected subcutaneously and is usu-
301–350 Add 3 U ally injected in the triceps area, the thighs, the
>350 Add 4 U and abdomen, or the lateral, upper buttocks and the
measure urinary injection sites must be changed regularly, or lipo-
ketone hypertrophy may develop, a “lump” under the
For an average child 4–10 years skin that will make the time of absorption vary
qAC from injection to injection and lead to unstable
Blood glucose 151–200 Add ½ U control. More rarely, insulin injections may lead
Novolog
to lipoatrophy and a depression occurs near the
201–250 Add 1 U
injection sites; cromolyn sodium ointment some-
251–300 Add 1.5 U
times is used to resolve this complication.
301–350 Add 2 U
>350 Add 2.5 U and
Pattern adjustments are taught to the family
measure urinary and child to allow them to respond to abnormal
ketones BS values with a change in insulin administra-
qHS tion. Thus they are instructed that the long-acting
Blood glucose 201–250 Add ½ U insulin should remain stable unless a need for
Novolog changing the dose is demonstrated by an aberrant
251–300 Add 1 U pattern of BS over at least 3–5 days. In contrast,
301–350 Add 1.5 U they are taught to change the short-acting insulin
>350 Add 2 U and at the time the injection is given, based on the
measure urinary
ketones concurrent BS.
These are starting doses that must be evaluated in each Thus depending on size and insulin sensitiv-
child after careful monitoring ity, one regimen might be to add 0.5 U starting at
a blood sugar of 151 mg/dL and add another
preceding 24 h. Approximately 40 % of that will 0.5 U for every subsequent elevation of 50 mg/
be long-acting insulin and the rest will be divided dL: e.g., 0.5 U of regular or short-acting insulin
into doses given before meals. A correction fac- to the basal planned dose if BS is greater than
tor is used for two dose per day injection that can 151, 1 U if BS is greater than 201, and 1.5 U if
be retained from the earlier days when it was BS is greater than 251 (Table 11.7). Older and
used for stabilization. All doses are modified larger subjects might get twice these doses, and
with observation of the child with time. empiric adjustment is used to find the best sliding
scale. The rule of 1,500 (some suggest to use
Time of Action of Insulin on Multiple Dose 1,800 when using the most rapid-acting insulin)
Injection Scheme (Tables 11.6) is useful to determine an appropriate sliding
If the patient is using long-acting insulin at scale: divide the total daily dose of insulin on a
bedtime, the BS at bed time is in the normal normal day into 1,500 (or 1,800), and the result is
range, and no hypoglycemia is noted during the the change in BS that might be expected with the
Type 1 Diabetes Mellitus 285

Table 11.8 General guidelines for the adjustment of daily insulin dose (for an average 10-year-old). The chart shows
the last 24-hour history of an example patient
Before breakfast Before lunch Before dinner Bedtime
Blood sugar (mg/dL) 240 260 160 150

Planned fast-acting insulin dose 10 10 10 –

Additional fast-acting insulin 2 3 1 –
on the sliding scale
Long-acting insulin dose – – – 30
(e.g., glargine)
In this case, the 10 U of fast-acting insulin plus 2 U on the sliding scale were not able to cover breakfast and bring down
the prelunch value, but the sugar stayed stable at ~250 mg/dL, so the 12 total units can hold the sugar values and probably
is the correct dose before breakfast with the addition of a sliding scale dose; if the a.m. blood sugar was normal, the lunch
value would likely be as well. Further, because the prebreakfast blood sugar was 240 and the bedtime glargine was 150,
it appears that the nighttime glargine dose was too low. If the pattern is seen over several days and if the blood sugar tested
at 3 a.m. is high, it is safe to add an extra unit or two of glargine insulin to the p.m. dose to bring down the prebreakfast
blood sugar. However, if the 3 a.m. blood sugar is low, the child is experiencing the Somogyi effect which raises the
morning blood sugar; in such a case, without the 3 a.m. value the prebreakfast value will falsely suggest that the nighttime
glargine dose is inadequate. If the breakfast blood sugar is brought down to 100–150 mg/dL by correctly adjusting the
glargine dose, the lunch value may very well follow suit with the new a.m. 12-U dose of fast-acting insulin. Usually it is
best to make just one change at a time and evaluate the results of each change. Although the sliding scale of fast-acting
insulin is designed to be given for changes in blood sugar encountered on a daily basis, a change in the premeal dose of
fast-acting insulin or the dose of glargine is usually not invoked unless a pattern is noted over several days. The adjust-
ments of rapid-acting insulin as described are usually applicable to adjustments in “regular” insulin as well

addition of 1 U of short-acting insulin. Thus if a ment regimen is compromising lifestyle. In gen-

child uses 50 U/day, the addition of 1 U as a slid-
ing scale should reduce the blood glucose level
by 30. One sliding scale may have to be devel-
oped for one meal, and another sliding scale for
another meal. Glucose correction at bedtime usu-
ally starts at a higher level, usually above 201 mg/
dL, to make hypoglycemia during sleep less
likely while all insulin correction during the day
usually occurs at a blood sugar above 151 mg/
dL. All doses are modified with observation of
the child with time.
Computerized Subcutaneous
Insulin Pump
The computerized continuous subcutaneous insu-
lin infusion pump (“insulin pump”) has improved
diabetic management greatly. More and more
patients are being treated by an insulin pump soon
after diagnosis. There are recommendations for
an insulin pump to be invoked when hemoglobin
A1c is high, when there is frequent hypoglycemia
and the blood sugar values are quite variable,
when microvascular complications or risks for
microvascular complications arise, or if the treat-
eral, a patient must be well prepared for the use of
an insulin pump to avoid problems noted below.
An insulin pump is computer controlled, small
(the size of a pager), and contains enough insulin
for 3 days of infusion. It uses short-acting insulin
which through continuous subcutaneous infusion
replaces the long-acting insulin injection of
MDI. The pump does not determine the infusion
rate nor the amount of a bolus of insulin to be
given at mealtimes but rather the pump functions
completely on the understanding of diabetes by
the patient or family and significant adjustments
are necessary. The insulin pump must be pro-
grammed by the family after careful attention to
blood sugars over a portion of the day and the set-
tings changed appropriately. This process must be
repeated several times a year and must be adjusted
as the child grows or enters puberty and insulin
resistance increases. One major advantage of a
continuous subcutaneous insulin infusion pump is
the flexible basal infusion rates. Although a single
injection of glargine or detemir insulin lasts for
24 h exerting a rather stable effect, there is no
way to vary its potency throughout the day.
286
As described below there are variations in basal
insulin requirements over a 24-h period; for
example, the dawn phenomenon described below
leads to requirement for increased insulin before
awakening. A single dose of long-acting insulin
cannot accommodate such changes. Insulin
pumps can change the insulin infusion rate by
half-hour intervals, leading to many possible
changes per day on a preprogrammed schedule.
Most patients use only three to five basal infusion
rates per day, but the numerous possible settings
may be used to improve control. The patient
administers a bolus of short-acting insulin at
mealtimes through the pump replacing the short-
acting injection of MDI, depending on blood glu-
cose values and carbohydrate intake, by ordering
the dose from a touch-pad keyboard on the pump
or by a remote control. The pump has the ability
to infuse a peak bolus, similar to a subcutaneous
injection of insulin, but has advantage of the addi-
tional ability to administer a square or dual wave
of insulin over a longer duration which will help
to control blood sugar which will tend to stay
elevated when fat or protein included in the meal
(e.g., Pizza). Likewise small children may not
always finish their planned meals, and in this case
half of the expected dose of insulin may be admin-
istered just before eating and the rest of the dose
adjusted to the amount of carbohydrate taken in
given soon after eating. This method, like MDI,
allows a more flexible schedule of meals and may
be especially attractive to teenagers. No pump can
decide on the correct dose of insulin itself
(although promising research is aimed at produc-
ing a pump that can do just that).
There are many provisos to successful insulin
pump therapy and serious dangers can arise in
pump therapy if the child and family are unable
to utilize it correctly. The family or child must be
able to count the carbohydrate content of food
and be able to enter it into the pump’s computer
which will calculate the correct dose of insulin
for meal. They must scrupulously monitor BS
values four times or more per day or control will
decline and offer no advantage over injections of
insulin. The infusion set (subcutaneous plastic
tubing) must be changed every 2–3 days, or it
will clog or even become infected, without the
11 Diabetes Mellitus
patient becoming aware of this if blood sugar
monitoring is not frequent. If the tubing is kinked
or clogged or exits the skin, the insulin infusion
may stop unexpectedly. Short-acting insulin is so
quickly cleared from the body that severe insu-
linopenia and even DKA will develop within
hours if the user does not note such problems;
with multiple injection schedules the long-acting
insulin lasts for at least 24 h and offers a longer
margin of safety that cannot be accomplished by
the short-acting insulin pump infusion. The pump
has alarms but cannot detect all problems that
may arise. Thus attention to detail and frequent
BS measurement are even more essential in pump
therapy than in other forms of treatment. We
believe that difficulties in the use of the insulin
pump might be avoided by initially testing the
ability of the patient to use it correctly.
Continuous glucose monitoring is now avail-
able and can be carried out for a period of several
days by using a tiny sensor that is temporarily
implanted in subcutaneous tissue; this process
will alert users to trends in blood sugar control
and impending high or low values serving as an
alarm to dangers. The information can be used to
analyze problems of glucose control or to deter-
mine pattern adjustments to insulin pump ther-
apy. However, the patient cannot use the glucose
reading on the monitor to administer insulin: a
finger stick glucometer is more accurate and must
be used for this purpose. At present one insulin
pump connected to its continuous glucose moni-
tor is able to suspend infusion when the monitor
senses a significant drop in glucose. Another
device is available that can transmit the blood
sugar value determined by the monitor at a dis-
tance to a receiver that might, for example, be
placed next to a parent’s bed should they be con-
cerned about middle-of-the-night hypoglycemia
in a child in another room.
In all regimens, BS is monitored at least four
times per day (before meals and at bedtime,
always before eating), and the insulin dose is
adjusted according to these values. It is important
to wait for 2–3 h after any preceding meal or
snack to obtain a glucometer reading, as it takes
that long to overcome the inevitable peak resulting
from carbohydrate intake. If the patient treats a
Type 1 Diabetes Mellitus
high blood sugar value with insulin less than
2–3 h postprandially, hypoglycemia may result
due to the transient nature of the peak of glucose
measured following a meal. Insulin is not rou-
tinely given outside of the scheduled time unless
the BS is measured very high at alternative times
of the day (e.g., greater than 350) and ketone
bodies appear in the urine.
Initial settings for the insulin infusion rate
are set and then adjusted based upon the needs
of the child after monitoring the results on blood
sugar. The basal infusion rate might be set
according to the long-acting insulin the child
was receiving for a 24-h day and dividing that
by 24 or set the pump to deliver 1/24th of the
child’s dose of long-acting insulin each hour. If
the child has not been on long-acting insulin,
calculate the dose as roughly 40 % of the child’s
weight. The dose of short-acting insulin for each
meal would be the same setting in the pump, as
the child has been using previously for subcuta-
neous insulin before meals. If the child has not
been using subcutaneous insulin prior to the ini-
tiation of the pump, a rule of thumb might be a
dose of insulin of 1 U per 25 g of carbohydrate
for a young child, 1 per 15 g for the several
years before puberty, and 1 per 10 g during
puberty. The correction factor might be ½ U for
every 50 mg/dL elevation starting at 151 mg/dL
blood sugar for young children and 1 U for
every 50 mg/dL in older children as puberty
develops. The correction might start at 201
before bedtime.
These guidelines are general, and individuals
do not follow a simple rule in their response to
calculated insulin dosage. For example, once
stabilized at home after discharge from the hos-
pital, when the child resumes the previous daily
schedule, the insulin dose might be decreased
(10 % or more) as the child will be more active
at home and may plan to participate in exercise,
as the activity will often decrease the blood glu-
cose value and could possibly precipitate hypo-
glycemia; this might occur, for example, twice
per week, if the child has gym class on a twice-
a-week schedule. Alternatively, the family might
have to find empirically the amount of carbohy-
drate needed to maintain the BS during the
287
period of increased activity without a change in
insulin dose; this might be used to good advan-
tage if unplanned activity occurs after insulin
has already been given. In general, blood sugar
drops during exercise and exercise can be a good
treatment if BS is slightly to moderately ele-
vated, but if BS is higher than 350 mg/dL, and
especially if ketones are present, exercise should
be limited or curtailed completely until blood
sugar control is gained by insulin administration.
Exercise during severe hyperglycemia can pre-
cipitate ketonemia and ketonuria. Some children
will increase their BS with exercise, so values
must be checked before, during, and after exer-
cise while determining an individual child’s
response.
Glycosylated Hemoglobin
or Hemoglobin A1c (Table 11.3)
Glucose becomes nonenzymatically bound to
the amino terminus of the β chain of hemoglobin
and measurement of hemoglobin A1c will indi-
cate the average blood sugar over the previous 3
months. The measurement reflects the last 12
weeks of average blood sugar levels with
increased significance given to the values of the
previous 4 weeks. Because the glucose is revers-
ibly bound to hemoglobin for the week before,
the measurement that week plays no role in the
hemoglobin A1c value. The hemoglobin A1c
value is associated with an average blood sugar
concentration. Current guidelines aim for a
hemoglobin A1c value under 7.5 for everyone
under 19 years of age although this is considered
a target fully realizing that less than 25 % of
patients under 19 years of age have reached such
a goal. In fact the target hemoglobin A1c for a
specific child may have to be modified based
upon the circumstances and the abilities of the
family. “Tight control” leading to close to normal
hemoglobin A1c values increases the risk of hypo-
glycemia. Hypoglycemia may be less obvious in
younger children who may not report their symp-
toms. Hypoglycemia may not even be noticed in
those with hypoglycemic unresponsiveness.
288
Other factors must be taken into consideration
when measuring hemoglobin A1c. If hemoglobin-
opathies are being considered in a patient, a
hemoglobin electrophoresis should be carried out
to determine if an abnormal hemoglobin is affect-
ing the hemoglobin A1c value rather than actual
blood sugar effects. Glycosylated albumin, fruc-
tosamine, or total glycohemoglobin by affinity
chromatography might be used as an alternative
measurement of glucose control as these mea-
sures directly relate to the hemoglobin A1c rising
with higher average blood sugar values but are
not affected by abnormal hemoglobin. However,
fructosamine and glycosylated albumin reflect
blood sugar control of the previous 1–2 weeks
rather than the 3 months of hemoglobin A1c.
Alternatively, 1,5-anhydroglucitol is a glucose-
like monosaccharide found in food; intake is bal-
anced with excretion in the normal situation.
However, with hyperglycemia glucose blocks the
reabsorption of 1,5-anhydroglucitol so that val-
ues vary inversely with blood sugar values and
decrease with higher values of hemoglobin A1c;
values reflect control over the last 1 or 2 weeks
before the sample. Hemoglobin A1c can be mea-
sured in minutes by office-based devices;
cross-checking the HgbA1c with the glucose mea-
surements on the glucometer and glucose values
in the record book is a good way to evaluate the
accuracy of the patient’s BS records or recollec-
tion of diabetes management. If, for example, a
teenager has forgotten his or her glucometer and
written records at an office visit but reports that
his or her blood sugar values are always about
150 but hemoglobin A1c measured at the visit is
over 14 indicating an exceptional degree of
hyperglycemia, a discussion should ensue
between the patient and the parents; pediatric
endocrinologist encounter such situations regu-
larly. Thus, a HgbA1c value may lead to a frank
discussion of reasons for poorer control than
expected and reported. It is important to recall
that the HgbA1c is an average, so that near-normal
levels are found with excellent control as well as
with a mixture of high and low values of BS; a
near-normal value does not always indicate
excellent control.
11 Diabetes Mellitus
The Honeymoon Period
Most children with type 1 DM have a period of
resumed insulin secretion and improved control
as the pancreas recovers from glucose toxicity
caused by the extreme elevation of blood sugar.
This temporary recovery of pancreatic function is
known as the “honeymoon period.” Some may
even not require insulin for months at a time; this
period does not define a “cure,” but rather a tem-
porary remission, and parents should not develop
false hope during this period that the disease pro-
cess is over. Immunosuppressive therapy is under
study as a means of prolonging the honeymoon
period.
Beta cell function will decrease due to lipo-
toxicity as well. This may occur only in the pres-
ence of hyperglycemia. Lipotoxicity is usually
discussed in terms of type 2 diabetes. However,
lipid deposition in the beta cell is found in obe-
sity and states of insulin resistance and impairs
pancreatic function as well.
Sick Day Management
Sick day management refers to the changes neces-
sary if there is a likelihood that the child’s intake
will vary from the normal level or if an intercur-
rent infection itself brings about a change in BS
due to the stress of the illness; some children will
have an increase, but some will have a decrease in
BS with infections and values will depend on oral
intake, so no hard and fast rule can be made. A
change in insulin dosage will be determined by
the regimen that the child uses for insulin admin-
istration. In a child taking multiple-dose injec-
tions, the long-acting insulin dose will continue as
it is necessary for basal maintenance of blood
sugar regardless of carbohydrate intake; for short-
term illness, the long-acting insulin dose is usu-
ally not adjusted unless the illness is anticipated to
last for more than a day or 2 but may be reduced
10 % for safety. The short-acting insulin dosage
will be adjusted based upon carbohydrate intake,
so even as the child eats less if the dose is adjusted
appropriately, there should be no problem.
Type 1 Diabetes Mellitus
If the child however is on a two-dose per day
regimen, the NPH insulin dosage is usually dis-
continued since this medication is given in antici-
pation of a meal about 6 h later and during illness
such a meal may be skipped. Thus a child with
the two-dose per day regimen must have more
frequent doses of short-acting insulin that substi-
tutes for the NPH insulin. For patients on an insu-
lin pump, a temporary change in basal infusion
rate may be helpful if trends toward increasing or
decreasing blood sugar values are noted since the
infusion rate is easily changed.
For patients on insulin pump therapy, the
bolus injections will follow carbohydrate intake
and should not present a problem during illness.
Testing for ketone bodies is essential while
the child is ill as the symptoms of illness are
much the same as the symptoms of ketosis.
Testing for ketone bodies must occur whenever
there is abdominal pain, nausea, and/or vomiting
regardless of blood sugar. If this step is elimi-
nated during illness or during an episode of nau-
sea or vomiting, impending DKA may proceed
unnoticed. Testing for urinary or blood ketone
bodies is to be used when blood sugar rises over
350 mg/dL. The presence of ketone bodies will
at the least indicate the need for increased hydra-
tion and will likely be an indication of the need
for increased or more frequent doses of insulin.
Telephone contact is necessary with a provider
at the least during a sick day, if the family has no
experience in sick day management. If the
patient cannot eat or drink, dehydration and sub-
sequent DKA may develop and i.v. fluids become
essential. If the illness involves nausea and vom-
iting and the patient cannot tolerate fluids, the
patient must come to the ED for evaluation; sev-
eral hours’ infusion of fluid may be all that is
required, but hospital admission also may be
necessary. It is not appropriate to give an anti-
emetic [e.g., promethazine (Phenergan)] to a
child with diabetes as an antiemetic may mask
developing diabetic ketoacidosis; the vomiting
may be a sign of DKA rather than, for example,
a viral illness with very different treatment
required. Resolution of high BS and moderate
ketone bodies may decrease the tendency to
vomit, resolving some of the problem.
289
The parents should be taught a general plan
to prepare for a sick day. Blood sugar must be
measured every 2–3 h and urine ketones at least
twice a day on a sick day. The child must be
kept well hydrated. Glucose-containing liquids
may be offered to provide an opportunity to
increase insulin dosage to cover the carbohy-
drates in the liquid and thereby provide another
means for decreasing ketosis. Unless the family
is well versed in sick day management, it is best
to ask them to call the pediatric endocrine team
if ketones in the urine are measured at more
than moderate or if blood ketones are rising. A
value for blood ketones under 0.6 mmol/L is
normal, 0.6–1.5 nmol/L demonstrates rising
ketones which must be monitored further,
1.6–3 nmol/L presents a risk for diabetic keto-
acidosis, and about 3 nmol/L indicates a serious
episode of DKA.
Hypoglycemia
Hypoglycemia is generally defined as blood
sugar under 65 mg/dL, but diabetologists suggest
using a cutoff of 70 mg/dL because it offers a
margin of safety before symptoms occur. In fact
recent guidelines suggest that any blood sugar
low enough to cause significant symptoms might
be defined as hypoglycemia for the individual.
Symptoms of hypoglycemia can be adrenergic
such as sweating, shakiness, pounding heart beat,
or neuroglycopenic such as stupor, irritability,
coma, or seizure. The episodes can be mild or
severe enough to cause death. Hypoglycemia will
occur in all individuals with DM at some point,
and those with good control or those receiving
intensive therapy historically were more likely to
have this complication because their general BS
values will be closer to the low levels characteris-
tic of hypoglycemia; this may no longer be the
case with improved accuracy of glucometers
and the availability of constant glucose monitor-
ing. Parents may be quite concerned about the
occurrence of hypoglycemia and their children
and teenagers may be quite anxious about the
risk for hypoglycemia. However, hyperglycemia
is more damaging than mild hypoglycemia and
290
appropriate control should still be encouraged.
The sensation of low BS might be lost in those
with chronically elevated BS values (hypoglyce-
mic unresponsiveness). Further, more than half
of the episodes of hypoglycemia occur at night;
some children have night terrors as a sign of this
complication, but some have no evidence of
hypoglycemia or progress to seizures without
warning. Middle-of-the-night BS measurements
or a 3-day continuous glucose monitoring session
will help determine if this problem is occurring.
Hypoglycemia can be extremely dangerous in
certain circumstances such as participating in
extreme sports or driving, so preparations that
will avoid hypoglycemia must be in place for
such situations. No teenagers should be allowed
to obtain a driver’s license if they are not care-
fully monitoring their blood sugar and agree to
test their glucose value before driving and agree
to stop the vehicle to retest and treat when symp-
toms occur.
Treatment of hypoglycemia is accomplished
by the administration of simple carbohydrates
(not complex carbohydrates, which will raise the
blood sugar too slowly), but overtreatment may
lead to hyperglycemia and a seesaw effect of BS
values that are too high, leading to another dose
of insulin that drives the value down, requiring
another dose of glucose. Characteristically 15 g
of glucose is given to a child over 5 years of age,
and the blood sugar remeasured in 15 min but
lower doses of glucose will be used in younger
children. If no rise in blood sugar is noted within
10–15 min, another blood sugar is obtained after
more carbohydrate is administered. A serving of
15 g of glucose is approximately the equivalent
of a 4 oz glass of juice or soda, two tablespoons
of raisins, one tablespoon of sugar, honey, or corn
syrup, 8 oz of nonfat or 1 % milk, a few hard can-
dies, or three to four 4-g glucose tablets. Paste
glucose preparations are available as medical
preparations, but cake frosting might well substi-
tute if it is all that is available. These oral glucose
preparations may be absorbed through the buccal
mucosa to a degree if the child is not cooperative
with swallowing. In 15 min, the BS should
increase to more than 100 mg/dL, but if not, the
whole process can be repeated. If the patient is
11 Diabetes Mellitus
not responding to such measures and becomes
insensible, subcutaneous injection of glucagon
(0.02–0.03 or 0.5 mg/kg for children under 12 to
1.0 mg or children over 12 years) must be given
to mobilize glycogen stores in diabetic subjects;
the BS will increase considerably in a short time.
Unfortunately, a glucagon injection may make
the child nauseated and emesis will further
complicate the day’s BS and insulin manage-
ment. All individuals with diabetes must have
easily available glucagon emergency kits that
contain the medication and a syringe and needle
for administration. Intravenous 10 % dextrose in
saline at 2–3 mL/kg will provide emergency
treatment if all else fails.
Hypoglycemia may occur because of inappro-
priate insulin dosing. This may be due to basal or
bolus insulin dosage and the dose may have to be
changed if it was administered as instructed.
Inappropriate carbohydrate counting can also
lead to hypoglycemia and further education
should be invoked. Hypoglycemia may occur
because of increased energy expenditure during
activity and the low blood sugar may not appear
for 8–12 h rather than right after the activity.
Education is important in the prevention of hypo-
glycemia. Anyone caring for the patient at home
or at school must know about the possibility of
hypoglycemia and the treatment for it. A diabetes
alert bracelet is essential to alert any care provider
that the child has diabetes and is subject to
hypoglycemia.
Recurrent hypoglycemia may also be due to
adrenal insufficiency. Type 1A diabetes mellitus
may occur with autoimmune Addison’s disease
in autoimmune polyglandular syndrome number
2 and possibly 3. Therefore evaluation for adre-
nal autoantibodies in patients with progressively
lowering insulin requirements and recurrent
hypoglycemia is in order. Celiac disease may
lead to fluctuating glucose levels as well.
Somogyi Phenomenon
The Somogyi phenomenon occurs when hypo-
glycemia triggers the release of counterregula-
tory hormones that subsequently increase BS;
Type 1 Diabetes Mellitus
thus a low BS at 3 a.m. may cause a rising BS in
the morning. Nightmares, night sweats, and
headaches on awakening may occur in a subject
with the Somogyi phenomenon. It would initially
seem that more insulin is indicated at night
because the a.m. BS is high, but the opposite is
true. Increasing the p.m. dose of intermediate- or
long-acting insulin or increasing overnight basal
infusion from insulin pump would worsen the
situation, because the basic problem is too much
insulin, leading to hypoglycemia.
Dawn Phenomenon
The dawn phenomenon is an increase in blood
glucose in the early morning hours before wak-
ing, due to an elevation of growth hormone and
ACTH/cortisol in the early hours. Alternatively
some children have an antidawn phenomenon in
which the increase in BS occurs just after mid-
night rather than just before waking. Evaluation
of these possibilities requires monitoring BS at
intervals during the night. The 3-day continuous
BS monitoring can help evaluate these various
patterns of blood glucose.
Surgery and Diabetes
If a child is to be kept NPO in preparation for and
during surgery, consideration of insulin manage-
ment is essential. The best management during
surgery would be the intravenous infusion of
insulin and glucose with constant monitoring of
blood sugar and changes in infusion rates as nec-
essary. If surgery is emergent and the patient is
not in metabolic balance, correction of the condi-
tion should be carried out as safety and the situa-
tion dictates. An infusion of 5 % dextrose with
normal saline (there is controversy as to whether
normal saline or hypotonic fluids are best) along
with an i.v. infusion of insulin as is described in
the management of diabetic ketoacidosis may be
carried out. If the procedure is short, a patient on
an insulin pump may receive a customary night-
time infusion rate before surgery and a 10 %
decrease during the surgery. Alternatively a
291
patient on long-acting subcutaneous insulin may
receive a 10–20 % decrease in the customary dose
during surgery. While the patient will be fasting,
rapid-acting insulin will not be necessary, but
insulin coverage of the intravenous glucose may
be calculated at 1 U of insulin for every 4–6 g of
glucose administered. For 5 % dextrose there is
5 mg of glucose per 100 mL. The goal is to
maintain blood sugar in the normal physiologic
range or slightly higher and to avoid ketosis.
Management for a traumatic event might follow
the guidelines for management at surgery.
Diabetes Team Management
The American Diabetes Association and all
authoritative bodies agree that team management
is optimal for close control of diabetes at any age.
Thus a nurse educator, a dietician, and a social
worker or psychologist, in the best of situations,
join the physician. This team approach may only
be available at a larger medical center, which
may be at a distance from the patient. Thus initial
education and quarterly consultations may be
offered, with day-to-day care provided by the
patient’s local physician. In some remote areas,
telemedicine consults are available from major
medical centers, so that advice might be dis-
pensed by two-way television connections if
medical personnel are on site with the patient
who can supply the necessary physical examina-
tions and provide the needed BS values over the
phone, fax, or monitor to the distant consultant.
The aim for older patients is achievement of con-
trol of BS close to the normal range and achieve-
ment of a normal or near-normal value of HgbA1c,
but this is harder although desirable in younger
children and infants. Adolescents and adults are
advised by the ADA to have (a) preprandial BS of
80–120 mg/dL, (b) 2-h postprandial BS of less
than 180 mg/dL, (c) bedtime BS of 100–140 mg/
dL, and (d) HgbA1c of less than 7.5 %.
These values may be difficult to achieve and
are best used as goals rather than expected
accomplishments in all young patients. The goal
of a preprandial BS close to 150 mg/dL may be
appropriate at younger ages to lessen the
292
likelihood of hypoglycemia, fully realizing that
even this relaxed goal might not be reached.
Considerable variation will be found in BS
measurements in children of all ages because of
the lack of precision of glucose management
with present technology, but variations should be
minimized as much as possible.
Children are evaluated as needed for insulin
adjustments and may receive advice over the
phone if they report or fax the BS values to the
physician, but these children should be seen in the
medical office at least quarterly. Subjects’ heights
and weights are tracked to see if normal patterns
are described. Decreased growth may indicate
poor control or the development of hypothyroid-
ism or celiac disease. Decreased BS values and
decreased insulin requirements well after the time
expected to span the honeymoon period might
indicate the development of autoimmune
Addison’s disease. Interphalangeal joints are eval-
uated for contractures that develop after years of
DM. BP is monitored to determine whether
hypertension has developed, possibly because of
kidney damage. All children should be examined
for lipohypertrophy at the sites of insulin injec-
tion, as lack of rotation of sites may predispose to
this complication and lead to irregular absorption
of insulin. Lipoatrophy is rare with the use of
human insulin but was seen more often in the past
with the use of animal insulin. Local reaction to
insulin including erythema, swelling or edema,
warmth, or subcutaneous nodules sometimes
occurs at initial use which usually resolves.
Although untreated type 1 DM leads to weight
loss due to the loss of calories in the urine and cel-
lular starvation, treatment allows weight regain.
However, if a child consumes too many calories
and increases insulin dosage to cover the intake,
obesity may develop. Dietary counseling and
recalculation of insulin dose will help this prob-
lem. Some teenagers may skip or decrease insulin
dose in a misguided attempt to lose weight, with
sometimes tragic consequences.
Every visit the child should have blood pressure
as well as height and weight and BMI determined.
If blood pressure exceeds the 90th percentile for
age, sex, and height, dietary intervention with
increased physical activity should be tried to
11 Diabetes Mellitus
control the blood pressure within 3–6 months.
Pharmacologic treatment is then considered if the
systolic and diastolic blood pressures are consis-
tently above the 95th percentile for age, sex, and
height or consistently over 130/80. If medication
is required, an angiotensin-converting enzyme
(ACE) inhibitor is the first line of treatment for
diabetes. Every year, each child should have
determination of thyroid function (autoimmune
thyroiditis is common in T1DM and may occur at
presentation) by free T4 and thyroid-stimulating
hormone (TSH) if the initial determination at the
time of diagnosis is negative. Fasting lipid deter-
mination is performed after stabilization if the
child is in puberty or at 10 years if there is no fam-
ily history of lipid disorders or at 2–8 years of age
if there is a family history of significant lipid dis-
orders. If a fasting lipid panel is normal, it should
be repeated in 5 years. If a fasting lipid profile is
abnormal, it should be repeated annually to deter-
mine cholesterol and triglycerides (elevated lipid
values occur with poor control). If LDL choles-
terol is over 130 mg/dL and there are risk factors,
and diabetes mellitus type 1 is a risk factor, or
over 160 mg/dL with no risk factors, current rec-
ommendations are to treat with statins (HMG-
CoA reductase inhibitors), but it is essential to
remember that these medications are teratogenic
and girls must not get pregnant while taking
statins. If the lipid level is not abnormal, rescreen-
ing every 5 years is appropriate. Dilated compre-
hensive ophthalmologic examinations are
indicated annually to check for microvascular dis-
ease after the passage of 3–5 years with type 1
DM or at the onset of puberty or 10 years which-
ever is earlier and at diagnosis for type 2 diabetes
in older patients. A celiac reflex panel as evalua-
tion for celiac disease is indicated at diagnosis,
especially if gastrointestinal symptoms, decrease
in growth rate, unexplained hypoglycemia, or
deterioration of blood sugar control, are found
since about 10 % of patients with T1DM have
celiac disease. Vitamin D screening is also recom-
mended in high-risk individuals. Neuropathy and
gastroparesis are rarely seen in the pediatric popu-
lation, but history and physical must be directed
to evaluating these possibilities and sensation and
proprioception should be checked even in the
Diabetes Team Management
young patient. Microalbumin-to-creatinine ratio
determinations are carried out as the patient
reaches the age of 10 years or the start of puberty,
whichever is earlier, or has had diabetes for 5
years to evaluate the possibility of kidney damage
in type 1 diabetes; this is carried out at diagnosis
in patients with type 2 diabetes. If elevated micro-
albumin is confirmed on two additional different
specimens from different days over in 6 months or
if renal function testing shows disease, ACE
inhibitor treatment may slow the progression of
renal disease, but these agents are teratogenic and
cannot be used in pubertal girls without an assur-
ance of abstinence from sexual activity or the use
of birth control. Thus uncontrolled diabetes is
teratogenic as is treatment of hyperlipidemia and
renal disease; a teenage girl must always be coun-
seled on birth control or abstinence.
Dental care must be offered regularly because
of the risk of tooth decay or gum disease interfer-
ing with the control of diabetes and nutrition.
Children with diabetes must be identified in
case they are separated from their guardians at a
time that they may be unresponsive. Although a
bracelet or necklace can be obtained from most
drugstores, the MedAlert system will keep track
of basic medical information and physician’s
phone number and is preferable as a means of
identification.
Summer camps for children with diabetes are
available nationally and are a wonderful way for
patients to meet others with the same problems
and, aside from realizing that they are not unusual
in their condition, to learn ways of dealing with
the disease. Local diabetic groups (lay or medi-
cally based) offer support and information for the
maintenance of good metabolic control.
Iatrogenic or Other Acquired Forms
of Diabetes Mellitus Type 1
Various drugs can precipitate DM, particularly
drugs used in transplantation (such as FK506)
and others used in therapy for cancer (e.g.,
L-asparaginase or prednisone for acute lympho-
cytic leukemia), which complicate the manage-
ment of those serious conditions. The clinical
293
manifestation of DM may wax and wane with the
administration and cessation of the medication.
In some cases, the condition may become
permanent.
Acquired forms of insulin-dependent DM in
children with cystic fibrosis result from the degen-
eration of islet cell pancreatic function leading to
loss of glucagon as well as insulin. Cystic fibrosis-
related diabetes may appear in young patients and
with longer term survival in cystic fibrosis, the
number of subjects with diabetes is increasing. In
this situation, maximal calories are required for
nutrition which has implications for diabetes man-
agement. A team approach involving the pulmon-
ologist, endocrinologist, clinical diabetes educator,
and dietitian is recommended. Evidence-based
consensus statements point out that the diagnosis
is based upon a standard glucose tolerance test as
found in this chapter, although elevated fasting
blood sugar or a 2-h postprandial blood sugar will
also suffice. Annual screening should occur after
10 years of age. Standard self- or family-based
management as is customary in type 1 diabetes
should occur with blood sugar measured at least
three times a day and hemoglobin A1c monitored
quarterly. Insulin is the only appropriate treatment
in that the disease originates from the destruction
of the beta cells. Diabetic complications including
nephropathy and dyslipidemia may occur and
yearly measurement of microalbumin-to-
creatinine ratio in urine should be carried out.
Fasting lipids are measured annually if abnormal
and every 5 years if normal.
Chronic pancreatitis may lead to a picture
condition similar to cystic fibrosis-related diabe-
tes and monitoring should proceed as for T1DM.
Long-Term Complications
Large national or international studies of individ-
uals with diabetes to determine who is likely to
develop complications (e.g., the Diabetes Control
and Complication Trial, DCCT) provided invalu-
able information in determining improved or opti-
mal therapies for diabetes. These pivotal studies
provide evidence-based guidelines for therapy.
When aspects of diabetes care can be determined
from such studies, treatment paradigm should
adhere to them in an evidence-based manner.
294
Nationwide study (DCCT) and international
studies demonstrate a dramatic decrease in com-
plications of type 1 DM with “tight control,”
which involves maintaining the HgbA1c and BS
values close to normal; 99 % of the variation in
risk was attributed to the level of hemoglobin A1c.
The DCCT also showed that poor control during
adolescence leads to increased microvascular
complications even 5–7 years later. Maintaining
blood sugar close to normal does increase the risk
for hypoglycemic reactions, but this may be
minimized by the use of modern monitoring
techniques. The present American Diabetes
Association goal for control of diabetes is a hemo-
globin A1c below 7.5 or any patient under 19 years
of age. This is an evidence-based recommenda-
tion based upon the fact that hyperglycemia will
increase the risk of early complications of diabe-
tes including heart disease and kidney disease.
Microvascular and macrovascular complica-
tions of diabetes in general are related to the
duration of disease and degree of control. The
DCCT, as noted earlier, demonstrated that tight
control with BS close to normal will decrease the
development of these complications and even
reverse them. Long-term complications of diabe-
tes are found in the capillary endothelial cells in
the retina, mesangial cells in the renal glomeru-
lus, and neurons and Schwann cells in peripheral
nerves. These cells cannot reduce the concentra-
tion of glucose within them as other cells in the
body and thus are exposed to high levels of glu-
cose for a longer period than other cells. Damage
to the cells occurs through the polyol pathway.
When glucose concentrations within the cells are
elevated, aldose reductase grows, which would
ordinarily reduce the presence of toxic aldehydes
by conversion to inactive alcohols, in this case
reduction of glucose to sorbitol, which subse-
quently is oxidized to fructose. The aldose reduc-
tase consumes NADPH in this process, thereby
eliminating the production of reduced glutathione,
an important intracellular antioxidant, leaving
the cell exposed to oxidative stress.
Retinopathy develops through changes in the
retinal capillaries and may lead to visual impair-
ment or blindness. Improved control will fore-
stall this complication. Thus ophthalmoscopy
11 Diabetes Mellitus
with dilation or retinal photography is recom-
mended yearly as described on the schedule
above. Nephropathy may develop as puberty pro-
gresses in a child with diabetes or with the
increased duration of the disease. The glomeruli
may become sclerotic after initial thickening of
the basal membrane, so urine evaluation for
microalbumin by urinary microalbumin-to-
creatinine ratio must be carried out yearly after
the onset of puberty. Improved control will delay
or eliminate this complication and even reverse
such changes, but the use of ACE inhibitors will
help limit progression.
Hypertension may develop in a patient with
diabetes usually who is in poor control.
Microalbuminuria might be the first indication of
kidney damage which leads to hypertension or
elevated blood pressure may proceed to microal-
buminuria. Hypertension can lead to increased
risk for cardiovascular events and treatment with
ACE inhibitor is generally suggested as the first-
route therapy. (Hypertension is mentioned in
Chap. 13 as well.)
Neuritis is rare in the initial presentation of
DM but has been reported. Neuropathy in the
extremities is usually but not always found in
adults with diabetes and long-term poor control.
Macrovascular disease of the cardiac vessels is
rare in childhood but will develop with poor con-
trol as the patient ages. This can also be fore-
stalled by good control. Lipid values increase
with poor control, and this factor, genetic tenden-
cies, and the hypertension of kidney disease all
can increase the likelihood of such macrovascu-
lar disease.
Serious infections, including mucormycosis,
are most prevalent in patients with long-term
poor control.
Pancreatitis may lead to diabetes if pancreatic
function is severely affected, but conversely, ele-
vated lipid levels caused by DKA or very poor
control may themselves lead to pancreatitis.
The Mauriac syndrome describes patients
with poorly controlled diabetes mellitus who
develop hepatomegaly and short stature.
Improved care will reverse this situation, but
there is a concern for progression of retinopathy
and complications.
Diabetes Team Management
Poor growth can occur in poorly controlled
diabetes mellitus without the full Mauriac syn-
drome developing. However, celiac disease or
hypothyroidism may likewise lead to poor growth
and must be eliminated as a cause. Poor control
will also lead to delayed puberty and irregular
menstrual periods or amenorrhea.
While no pediatric patient should be smoking
(nor anyone else), individuals with diabetes suf-
fer an increased risk from this habit. Microvascular
complications may increase with smoking and
may also lead to persistent micro- and microalbu-
min area. There is some evidence that smoking
may predispose to the development of type 2
diabetes.
Likewise alcohol is a risk factor in adolescents
with diabetes which may predispose to hypogly-
cemia. If there is prolonged alcohol intake in the
individual with decreased nutritional intake, the
person is in effectively in the fasting state;
glycogen stores will be depleted which tends to
lead to hypoglycemia. Further alcohol ingestion
can interfere with gluconeogenesis since ethanol
is metabolized by alcohol dehydrogenase in the
liver to oxidize to acetaldehyde and acetate which
requires nicotinamide adenine dinucleotide
(NAD) as a cofactor; this limits the abundance of
NAD causing reduced gluconeogenesis and aci-
dosis. Thus alcohol eliminates the second line of
defense against hypoglycemia.
Another complication of diabetes is a risk of
impotence, a discussion that should be held with
noncompliant pubertal boys in hopes that this risk
may motivate them toward better compliance.
Dyslipidemia is common in the presentation
of diabetes. After appropriate control, lipid levels
should return to the baseline for that individual.
With poor control that may not occur. A heart-
healthy diet is always appropriate for someone
with diabetes. Use of medication for hyperlipid-
emia requires specific guidelines and there is
some flux in these guidelines. Treatment for
dyslipidemia is different in diabetes than in the
average individual without a risk. Thus medical
treatment may be considered in a child over
10 years with an LDL cholesterol level unre-
sponsive to lifestyle change over 190 mg/dL
without risk factors, over 160 with a risk factor
295
such as diabetes and over also 130 mg/dL in dia-
betes with additional risk factor(s). Unfortunately
the generally recommended medical treatment,
the use of statins (HMG-CoA reductase inhibi-
tors) as described in Chap. 13, has not been
shown to lower future cardiovascular risk in dia-
betes in children and there are no long-term stud-
ies of their effects in children with or without
diabetes, so even the decision of starting treat-
ment is controversial.
Transition to Adult Care
The care of an adolescent with diabetes involves
increasing the patient’s increased responsibility
for his or her own care and increasing indepen-
dence with parents. This is a stressful time in
many families and conflicts arise as teenagers
will not characteristically follow all care plans.
A nonjudgmental approach with open discussion
is necessary and counseling sometimes must be
invoked during the process.
As reproductive maturity is reached in females
with any type of diabetes, another responsibility
emerges. Diabetes in girls of reproductive age
brings up the questions of complications to
mother and child during pregnancy. Untreated
diabetes is dangerous to a mother and to unborn
fetus. Poorly treated maternal diabetes may lead
to the classic outcome of the infant of the diabetic
mother with high birth weight and tendency to
hypoglycemia, alternatively a small-for-
gestational-age infant who carries metabolic
problems throughout the life or teratogenesis of
the heart and other organs. A macrosomic infant
of a diabetic mother has a risk of shoulder dysto-
cia during delivery and the mother has risk for
undergoing caesarian section. Infants of diabetic
mothers may develop jaundice after birth or
hypocalcemia in addition to the likelihood of
hypoglycemia and hypocalcemia.
In a normal pregnancy there is an increase in
hepatic gluconeogenesis which can be controlled
by increased insulin secretion in a mother
without diabetes but will not be as well controlled
during gestational diabetes. The insulin sensitiv-
ity of a pregnant woman who has progressive
development of insulin resistance due to gesta-
tional diabetes may decrease more than 50 %
296
from the preconception state. Mothers also have
a lower threshold for developing DKA than
before pregnancy. A mother with gestational dia-
betes who has autoantibodies found also in type 1
diabetes may very well be developing type 1 dia-
betes. In the absence of antibodies a woman with
gestational diabetes has a future risk for the
development of type 2 diabetes and/or obesity.
The mother with gestational diabetes carries a
risk for preeclampsia, hypertension, preterm
delivery, miscarriages, stillbirth, perinatal death,
and polyhydramnios. The child carries a risk of
congenital malformations including congenital
heart disease such as tetralogy of Fallot, transpo-
sition of the great arteries, septal defects, and
anomalous pulmonary venous return; central
nervous system and other neural tube defects
including anencephaly, spina bifida, encephalo-
cele, and hydrocephaly; and abnormalities of the
ear including anotia/microtia, orofacial clefts,
limb defects, and defects in the urogenital sys-
tem. Sacral agenesis/caudal dysplasia is more
commonly found in infants of diabetic mothers
compared to the general population. Macrosomia,
small for gestational age, polycythemia, iron
deficiency in developing organs, which may lead
to cardiomyopathy and altered neurodevelop-
ment, hypertension and cardiac hypertrophy due
to catecholamine production, and impaired or
delayed lung maturation may occur. The infant of
a diabetic mother also has a lifelong increased
risk for obesity and type 2 diabetes. Thus coun-
seling all reproductive-age girls in contraceptive
techniques or abstention is essential.
Preconceptional counseling has been demon-
strated to be effective in decreasing complica-
tions and should include discussion with the
mother of potential fetal and maternal complica-
tions, adjusting medications to aim for a hemo-
globin A1c below 6.5 in most cases and
emphasizing the importance of ongoing follow-
up during pregnancy. Since early hyperglycemia
occurs at a time when fetal organs are first devel-
oping, optimal control must be achieved before
pregnancy for optimal outcome. At the first dem-
onstration that a girl with diabetes is pregnant,
transition to a high-risk management team or
specialist in the care of diabetes during preg-
11 Diabetes Mellitus
nancy is appropriate. Careful maintenance of
blood sugar is possible and is required during
pregnancy for a healthy outcome of mother and
child. Of course, institution of healthy manage-
ment techniques for diabetes should occur many
years prior to the pregnancy.
The teenage years also involve other responsi-
bilities of impending young adulthood. Driver’s
license will be sought but cannot be awarded to
someone who does not carefully monitor his or
her blood sugar to make driving safe.
Hypoglycemia is well known to impair judgment
and will render the patient incapable of safely
driving a car. In both cases if noncompliant teen-
agers do not take care of their diabetes or do not
measure their blood sugars to allow them to treat
hypoglycemia or hyperglycemia appropriately,
they are not appropriate candidates for driving.
The driver with diabetes must always measure
blood sugars before turning on the engine to
ensure that BS is in target range. Long-range
drivers require retesting at intervals. There must
be ready supply of glucose available for the driver
especially if they are along vehicle. Because of
the constant risk for auto accidents with or with-
out diabetes the driver should have a MedAlert
bracelet or necklace to indicate the presence of
diabetes in the unfortunate situation should there
be an injury rendering the person incapable of
communicating this fact.
It must be emphasized to the family in patients
who are not complying that there is a significant
ethical risk to an irresponsible teenager driving
with the risk of hypoglycemia and that if stopped
by the authorities the teenager will be considered
“driving under the influence” which is not a sym-
pathetic reception from the police or Highway
Patrol. If fatalities should occur during poorly
controlled diabetes, the charge could very well be
vehicular manslaughter. These unpleasant
thoughts must at least be discussed in some man-
ner to a noncompliant teenager whose parents
plan to offer the car keys. It is the provider’s
responsibility to determine if the teenager is not
responsible enough to drive and if that is the case
to report to state licensing agencies as medical
providers are mandatory reporters. This will lead
to a long delay in regaining a license even if the
Neonatal Diabetes
teenager starts cooperating with diabetic control.
Driver’s licenses in some states require answer-
ing the question “do you have a condition which
will impair your ability to drive the car.” Well-
controlled diabetes might not seem to be such a
condition but poorly controlled diabetes certainly
qualifies.
As the teenage years pass it is important to
prepare an adolescent with diabetes for the next
phase of care which will involve a provider who
cares for adults as they leave the pediatric prac-
tice. The age of transition is dependent upon the
patient and family and their wishes but will
almost always occur by 21 years of age. The tran-
sition is to be planned often in writing and is best
discussed years in advance. An ideal situation
would be a clinic or environment where both
pediatric and adult providers practice side by side
but these are rare. An optimal situation will also
be the identification of the adult provider before
the transition occurs. However, the transition of
care is not always easy as providers for adults
may not accept the insurance plan of the patient.
Teenagers, according to present law, will stay on
the parent’s private insurance plan until 26 years.
The care administered in a provider’s office for
an adult may not include the team-based approach
which is optimal during childhood and adoles-
cent diabetes care. Thus transition is not always
easy process, hence the need to prepare for it long
in advance.
Neonatal Diabetes
Rarely DM is found in the neonate or child up to
6 months of age without laboratory finding of an
autoimmune basis of type 1 DM. This condition
has been called neonatal diabetes mellitus or
monogenetic diabetes of infancy; for this discus-
sion we will call it neonatal diabetes mellitus, or
NDM. Some patients with NDM present between
6 and 12 months of age. Type 1A diabetes melli-
tus is rare under 6 months of age. The etiology of
NDM is found in a family group of at least 20
genetic disorders. Neonatal diabetes was origi-
nally reported with a prevalence of approximately
297
1 in 500,000 but more recently is considered to
be a much more common condition. In some
families adults manifest other diagnoses such as
MODY or type 1 or type 2 diabetes while the
children have NDM. Intrauterine growth restric-
tion and SGA presentation are common in neona-
tal diabetes mellitus. Some forms of neonatal
diabetes can be treated with sulfonylureas after
initial stabilization with insulin which makes the
specific diagnosis important in determining
management. The terminology generally divides
the conditions into transient and permanent
NDM. Not all authorities use this classification as
some of the apparently transient conditions that
last for over 1 year are classified in one schema as
permanent NDM.
Transient Neonatal Diabetes Mellitus
Transient neonatal diabetes mellitus may last for
a few years or remit at puberty. Three genetic
subtypes are noted. Type I transient neonatal dia-
betes (#601410 ICD+DIABETES MELLITUS,
TRANSIENT NEONATAL, 1) presents with
SGA and requires neonatal insulin therapy due to
nonketotic hyperglycemia which usually remits
by 12 weeks of age. Elevated blood sugar may be
noted during intercurrent illnesses thereafter and
between 4 years of age and at puberty type 2 dia-
betes may develop. Type I is due to a mutation in
the imprinted, paternally expressed ZFP57 gene
which lies within the imprinted promoter of
the PLAGL1 gene on chromosome 6q22-q23.
Type II transient neonatal diabetes (#610374
ICD+DIABETES MELLITUS, TRANSIENT
NEONATAL, 2) and type III transient
neonatal diabetes (#610582 ICD+DIABETES
MELLITUS, TRANSIENT NEONATAL, 3) are
due to mutations of the KATP channel of the
β-cell membrane; mutation in the ABCC8 gene
of the Kir6.2 subunits is found in type II which is
found with heterozygous and homozygous inher-
itance and KCNJ11 of the SUR1 subunit is found
in type III which is autosomal dominant. Both
type II and type III transient NDM respond to
oral sulfonylurea therapy.
298
Permanent Neonatal Diabetes
Mellitus
Permanent neonatal diabetes mellitus (#606176
ICD+DIABETES MELLITUS, PERMANENT
NEONATAL; PNDM) may be due to either of
five mutations, but the most common three listed
below are heterozygous autosomal dominant
forms. Activating mutations in the subunits of the
ATP-sensitive potassium (KATP) channel of the
β-cell membrane can be responsible for transient
or permanent neonatal diabetes mellitus. These
include the KCNJ11 gene of the Kir6.2 subunit
which is more common in permanent neonatal
diabetes mellitus or ABCC8 gene of the SUR1
subunit which is more common in transient neo-
natal diabetes. Infants with the KCNJ11 mutation
may have developmental delay due to associated
mutations in their neurons. Those with severe and
developmental delay and epilepsy along with
neonatal diabetes mellitus are considered to
have the DEND syndrome. The diabetes in these
conditions can usually be treated with
sulfonylureas.
Mutations in the proinsulin gene (INS) also
lead to permanent neonatal diabetes, but this
form requires treatment with insulin and not
sulfonylureas.
In addition to the autosomal dominant forms
noted above, autosomal recessive forms are
reported particularly in families with consan-
guineous marriages. While heterozygous muta-
tions in the glucokinase gene lead to MODY type
III, homozygous loss-of-function mutations in
the gene for glucokinase lead to NDM with the
need for lifelong insulin therapy.
Pancreatic agenesis has been related to autoso-
mal recessive homozygous deficiency of PDX1,
which is also the cause of MODY4 (#606392
ICD+MATURITY-ONSET DIABETES OF THE
YOUNG, TYPE 4; MODY4).
Genetic diagnosis is available for NDM and
appears most cost-effective in infants presenting
with diabetes under 6 months of age with the
findings of neonatal diabetes mellitus and no
pancreatic autoantibodies.
11 Diabetes Mellitus
Type 2 Diabetes Mellitus
Type 2 DM is the preferred term for what was pre-
viously called non-insulin-dependent DM (TYPE
2 DIABETES MELLITUS #125853 DIABETES
MELLITUS, NON-INSULIN-DEPENDENT;
NIDDM variously at 20q12-q13.1, 20q12-q13.1,
17q25, 13q34, 11p12-p11.2, 2q32, 2q24.1). Type
2 diabetes is due to a combination of insulin resis-
tance and of impaired first-phase insulin secretion
from the beta cell of the pancreas leading ulti-
mately to more severe insulinopenia. Type 2 DM
was previously considered a disorder of adults,
but American Indian adolescents were reported to
develop this condition over 20 years ago. About
the same time a tenfold increase in type 2 DM was
reported in African-American teenagers and chil-
dren. Now, with the epidemic of childhood obe-
sity across the USA and the associated insulin
resistance, an increase in type 2 DM is found in all
racial/ethnic groups in the USA, but prevalence is
highest in Native American, African-American,
Hispanic-American, and Asian-American teenag-
ers and children, and the condition is appearing
throughout the world in regions where the preva-
lence of obesity is increasing. The prevalence of
type 2 diabetes in adolescence now exceeds the
prevalence of type 1 diabetes in American Indian
teens in the USA. It is more common than type 1
diabetes in children in Hong Kong, Taiwan, and
Japan although children in Asia tend to have
lower BMI associated with the type 2 diabetes
than is found in the USA. This condition has a
stronger genetic pattern than type 1 DM so that
there is usually a family history of type 2 diabetes.
T2DM may be found in children as young as 6
years, although it is most prevalent in the teenage
years when there is a normal physiologic increase
in insulin resistance. In spite of the obesity epi-
demic, type 2 diabetes in childhood and adoles-
cence is not epidemic, with a prevalence of 0.46
per 1,000, but certainly must be considered when
evaluating any child with obesity especially with
symptoms of diabetes.
The physical finding of acanthosis nigricans,
an area of darkened and thickened skin found at
Type 2 Diabetes Mellitus
the back of the neck or in flexural creases, is
physical evidence of insulin resistance. The
description of the later development of diseases
in individuals with impaired fetal growth or
infantile catch-up growth (the Barker hypothesis
or the early life onset of adult disease; see Chap.
5) includes an early development of insulin resis-
tance and type 2 DM. Type 2 DM is found more
frequently in children and teenagers with large
birth weights as well as those with decreased
birth weights.
Unlike classic type 2 DM in adults, children
can develop ketoacidosis presenting in a manner
very similar to type 1 diabetes, confusing the dif-
ferential diagnosis between type 1 DM and type
2 DM. Type 2 diabetes is an insulin-resistant con-
dition and the features of type 2 diabetes are the
same as those of the metabolic syndrome.
Evidence-based guidelines were developed
for type 2 diabetes in pediatrics. Random screen-
ing was not suggested, but when a child with obe-
sity is under evaluation for other comorbidities,
the search for type 2 diabetes is appropriate.
Certain laboratory tests are indicated at the time
of diagnosis of type 2 diabetes and annually
thereafter; these include fasting lipid levels (if
normal initial test screening every 5 years), liver
enzyme determination, urinary microalbumin-to-
creatinine ratio, ophthalmologic examination,
and evaluation for obstructive sleep apnea.
Evaluation for PCOS in girls with suggestive
medical history is also appropriate. Blood pres-
sure must be monitored carefully.
Diagnosis is made in the manner described
above for diabetes with elevated fasting blood
sugars or 2-h postprandial blood sugars on sev-
eral measurements or sometimes in the absence
of symptoms of obvious hyperglycemia but sus-
picion of T2DM by the glucose tolerance test as
described above. The antibodies noted above that
are found in type 1 diabetes should be measured
in apparent type 2 diabetes as they may indicate a
true diagnosis of type 1 diabetes or the risk for
further autoimmune diseases. However, adults
and children with T2DM may have the same anti-
bodies as in type 1 diabetes confusing the issue;
299
some appear to have latent-onset diabetes of the
adult (LADA) or latent-onset diabetes of the
young (LADY) which has an indolent course of
progression to the requirement for insulin ther-
apy. Glucose toxicity occurs at the time of diag-
nosis and in states of hyperglycemia impairs beta
cell function, but some recovery will occur after
euglycemia is established; thus type 1 DM is the
apparent initial diagnosis, but type 2 DM becomes
the favored diagnosis with the passage of time.
Likewise in type 2 diabetes, since lipids are often
extremely elevated at diagnosis, lipotoxicity of
the beta cell also occurs, but recovery will follow
resolution or improvement of hyperlipidemia
with normalizing blood sugars.
The mainstay of therapy for type 2 DM should
be appropriate diet and exercise, and lifestyle
changes leading to weight loss which in some
cases will accomplish better control than the use
of oral medication such as metformin. Adherence
to the Academy of Nutrition and Dietetics’
PEDIATRIC WEIGHT MANAGEMENT
(PWM) GUIDELINE is suggested by the AAP.
However, if the patient is suffering from acute
metabolic derangements, medical therapies for
hyperglycemia are usually needed at first. If there
is no DKA, and if the hemoglobin A1c is below 9,
metformin, a biguanide approved for children
older than 10 years, may be initiated. Metformin
is generally considered safe but can precipitate
lactic acidosis, and a metabolic panel must be
determined to ensure normal function of liver
and kidney before initiating therapy. In addition,
rhabdomyolysis and elevated creatinine kinase
may rarely occur. Since metformin may cause
vitamin B12 (cyanocobalamin or cobalamin) or
folate deficiency, supplementation with these
vitamins is suggested. A dose of 500 mg is used
at first, and if adequate control is not achieved,
the dose may be increased by 500-mg increments
at 1–2-weekly intervals up to a maximum of
2,000 mg divided into two doses per day in larger
children up to a maximum of 2,500 mg/day in
older teens. Abdominal distress may occur with
this therapy but often resolves within a few
weeks; the medication should be offered with
300
meals. Metformin by itself cannot cause hypo-
glycemia since the main action is to decrease
hepatic glucose production but not to increase
insulin secretion. However, if metformin has
been used in a patient treated with insulin, insulin
dosage is decreased as BS decreases with metfor-
min, as unintended hypoglycemia is a possibility
when insulin responsiveness increases.
Insulin is the first line of therapy in a patient
with significant symptoms, if hemoglobin A1c is
over 9, if the blood sugar is ≥250 mg/dL, or in
whom the differential diagnosis between types 1
and 2 is unclear. If the hemoglobin A1c is higher
or symptoms are present after 4 months or if
hemoglobin A1c does not descend to less than 7
on lifestyle or metformin therapy, insulin therapy
is initiated. Sometimes long-acting insulin will
be adequate for initial therapy, but multiple-dose
injection may ultimately be indicated and may be
required for the long term. Blood sugar moni-
toring in the manner described above for type 1
diabetes is carried out in type 2 diabetes on
insulin therapy as well. With successful weight
control, oral hypoglycemic agents and insulin
doses may be decreased or, in some cases,
stopped altogether.
The differential diagnosis between type 1 dia-
betes in the honeymoon phase and type 2 diabe-
tes can be difficult. Patients in the honeymoon
phase of type 1 DM may be able to secrete
endogenous insulin and C-peptide, suggesting
that they have type 2 diabetes further clouding
the differential diagnosis between type 1 and
type 2 DM. In the obesity epidemic one cannot
automatically assume that a child with obesity
has type 2 rather than type 1 diabetes. Likewise
the increased prevalence of type 2 diabetes in
certain racial/ ethnic groups does not mean that
they cannot instead develop type 1 diabetes.
Further, the elevated blood glucose at the time of
diagnosis may exert glucose toxicity on the beta
cells, limiting their ability to secrete insulin to
any appreciable degree, suggesting type 1 diabe-
tes and making the differential diagnosis even
more unclear. Type 2 DM is not an autoimmune
condition, so anti-islet cell, anti-insulin, or anti-
GAD antibodies are classically negative,
11 Diabetes Mellitus
although as stated above they may be negative in
some patients with type 1 DM as well. If the
antibodies are positive and the patient otherwise
appears to have type 2 diabetes, the patient may
have a slowly progressive type 1 diabetes which
at least temporarily does not require insulin
treatment for a year or 2 (latent autoimmune dia-
betes in the young or LADY). Since exogenous
insulin is usually administered in the acute
hyperglycemic phase of any type of diabetes,
insulin assays will be inaccurate if the sample
was taken after insulin therapy because of inter-
ference in the assay by insulin itself or because
of antibodies that may develop against the
administered insulin. Thus measurement of
serum C-peptide cannot clearly separate type 1
and type 2 diabetes at diagnosis but may be use-
ful after disease has been present for at least 1
year when type 1 diabetes patients cease to
secrete insulin in most cases. Observing the
course of the patient is necessary in frequent
cases before the diagnosis is determined.
It is not yet clear what the prognosis and com-
plications of type 2 DM will be in young sub-
jects, but the development of complications
appears to move faster than in younger adults
who have type 2 DM and who have serious and
early complications if control is poor. By exten-
sion, the complications of type 2 diabetes may be
more serious in those adolescents and children
who do not achieve adequate control.
Type 2 diabetes might be found in Turner syn-
drome or Prader–Willi syndrome or any condition
prone to weight gain as described in Chap. 13.
Prevention of type 2 diabetes goes hand in
hand with prevention of obesity, and the approach
to this major public health problem is described
in Chap. 13.
Atypical diabetes mellitus (#612227
ICD+DIABETES MELLITUS, KETOSIS-
PRONE; KPD) or ketosis-prone diabetes some-
times known as Flatbush diabetes often presents
with ketoacidosis but after a short period of insu-
lin treatment may go months to years without the
need for further insulin treatment. Some patients
appear to have a heterozygous and some a homo-
zygous pattern of inheritance.
Type 2 Diabetes Mellitus
Wolfram Syndrome
The Wolfram syndrome (#222300 ICD+
WOLFRAM SYNDROME 1; WFS1) is caused
by homozygous or compound heterozygous
mutation in the gene encoding wolframin (WFS1)
on chromosome 4p. The syndrome combine fea-
tures characterized as DIDMOAD for Diabetes
Insipidus, Diabetes mellitus, Optic Atrophy, and
Deafness, but only insulin-dependent diabetes
mellitus and aggressive optic atrophy are essen-
tial for the establishment of DIDMOAD. Poor
growth in stature, psychiatric disease, severe neu-
rological dysfunction, cardiomyopathy, and geni-
tourinary abnormalities are also described.
Maturity-Onset Diabetes of the Young
or Monogenic Diabetes (Table 11.9)
The group of conditions known as maturity-onset
diabetes of the young (MODY) or monogenetic
diabetes is caused by at least ten different muta-
tions inherited in an autosomal dominant pattern
which usually manifest before adulthood or in
the young adult. They are estimated to account
for less than 1–2 % of cases of diabetes although
it is estimated that 80 % of cases of MODY in
Great Britain remain undiagnosed. The majority
of cases of MODY are types II and III. MODY
type I (#125850 ICD+MATURITY-ONSET
DIABETES OF THE YOUNG, TYPE 1;
MODY1) is caused by a mutation in the gene
encoding hepatocyte nuclear factor-4-alpha
(HNF4A), while MODY type 3 (#600496
ICD+MATURITY-ONSET DIABETES OF THE
YOUNG, TYPE 3; MODY3) is caused by a
mutation in the hepatocyte nuclear factor-1-alpha
gene (142410); some of the manifestations of
both types are similar due to the fact that HNF4-
alpha regulates the expression of HNF1-alpha.
These patients present with an apparently mild
form of type 2 diabetes, but the condition will
worsen over years leading to the need for oral
sulfonylurea therapy to avoid the microvascular
complications that occur in this condition as well
as in type 1 or type 2 diabetes. MODY type III is
associated with elevated HDL cholesterol, while
301
MODY type I has decreased HDL cholesterol.
Mutations of HNF4A also occur in the hyperin-
sulinemic hypoglycemia in infancy (see Chap.
12). About two-thirds of the cases of MODY are
MODY type III. An extremely rare association is
MODY type I found with Fanconi renotubular
syndrome 4 (#616026 FANCONI
RENOTUBULAR SYNDROME 4 WITH
MATURITY-ONSET DIABETES OF THE
YOUNG; FRTS4); remarkably some patients
present with hypoglycemia rather than hypergly-
cemia in this association. MODY type II
(#125851 ICD+MATURITY-ONSET
DIABETES OF THE YOUNG, TYPE 2;
MODY2) is due to a mutation in the glucokinase
gene. This form presents with mild fasting or
postprandial hyperglycemia which may be man-
aged by diet rather than medication. Only 2 %
will require insulin therapy, possibly during preg-
nancy. MODY type V (#137920 ICD+RENAL
CYSTS AND DIABETES SYNDROME;
RCAD) is due to a mutation in the gene encoding
hepatocyte nuclear factor-1-beta (TCF2, or
HNF1B) and combines MODY with cystic dis-
ease of the kidney and often abnormalities of
male or female genitalia. It may be severe enough
to require kidney transplantation. There are other
seven forms of MODY listed in OMIM where
details are available (see Table 11.9).
MODY should be suspected in patients with
diabetes that have none of the antibodies associ-
ated with diabetes, in which diabetes at presenta-
tion is relatively mild, which appears to be
inherited in an autosomal dominant manner.
Mitochondrial Disease and Diabetes
Maternally inherited diabetes and deafness
(MIDD) (#520000 ICD+DIABETES AND
DEAFNESS, MATERNALLY INHERITED;
MIDD) can be caused by mutations in several
different mitochondrial genes: mitochondrial
tRNA-glutamic acid gene (MTTE), mitochon-
drial tRNA-leucine 1 gene (MTTL1), or mito-
chondrial tRNA-lysine gene (MTTK) which
impair beta cell function. The diabetes is similar
to type 2 diabetes in presentation and along with
302 11 Diabetes Mellitus

Table 11.9 Six types of MODY

Condition Gene defect Inheritance Clinical features
MODY 1 #125850 MATURITY- Mutation in the gene Early onset, mild course
ONSET DIABETES OF encoding hepatocyte
THE YOUNG, TYPE I; nuclear factor-4-α
MODY1 (HNF4A; 600281) which
maps to 20q12-q13.1
MODY 2 #125851 MATURITY- Mutation in the gene Early onset, mild course
ONSET DIABETES OF encoding glucokinase common
THE YOUNG, TYPE II; (138079) which maps
MODY2 to 7p13
MODY 3 #600496 MATURITY- Mutation in the hepatocyte Before age 25 years early
ONSET DIABETES OF nuclear factor-1-α gene onset, mild course; insulin
THE YOUNG, TYPE III; (142410), which maps to secretory defect worsens
MODY3 12q34 with age
MODY 4 #606392 MATURITY- Mutation in the IPF1 gene Homozygous infant have
ONSET DIABETES OF (600733) which maps to pancreatic agenesis;
THE YOUNG, TYPE IV; 13q12.2 heterozygous individuals
MODY4 have mild presentation;
rare
MODY 5 #137920 MATURITY- Mutation in the hepatic May have kidney or uterine
ONSET DIABETES OF transcription factor-2 gene defects as well; rare
THE YOUNG TYPE V; (TCF2; 189907), which
MODY5 maps to 17 cen-q21.3.
TYPE V; MODY5
MODY 6/now MATURITY-ONSET Mutation in the Rare, may present with
considered a form of DIABETES OF THE NEUROD1 gene (601724) permanent neonatal
permanent neonatal YOUNG, TYPE VI; MODY6 which maps to 2q31.3 diabetes which may be
diabetes associated with cerebellar
hypoplasia, learning
difficulties, sensorineural
deafness, and visual
impairment

deafness may occur in adulthood. Other features
include findings in the eye (pigmentary retinal
degeneration and macular pattern dystrophy of
the eye retaining normal visual acuity, concentric
narrowing of visual fields, external ophthalmo-
plegia), the heart (cardiomyopathy), and central
nervous system (impaired vestibular function and
dizziness, unsteady gait, seizures, dysarthria).
This diagnosis might be suggested by the physi-
cal findings and a maternal inheritance.
Nonketotic Hyperosmotic Coma
Nonketotic hyperosmolar coma in previous
decades was a condition found in adults which
was also true of type 2 diabetes, but both condi-
tions are now found in pediatrics. Characteristic
findings of nonketotic hyperosmolar coma are
severely elevated blood sugar over 600 mg/dL
and serum osmolality equal to or greater than
350 mOsm/kg; minimal ketosis but the severe
dehydration that results will lead to lactic acido-
sis which in this case may lead to Kussmaul res-
pirations in the absence of ketone bodies. The
arterial PH should be greater than 7.25 or a
venous pH greater than 7.3, with a serum
bicarbonate greater than 15 mEq/dL for this diag-
nosis. Since the patient has type 2 diabetes and
therefore residual insulin activity even though it
is diminished, ketone formation is suppressed
while glucose rises; insulin can suppress ketones
at a lower concentration than required to control
hyperglycemia. Any degree of mental disorder up
to coma and seizures may occur. The treatment is
rehydration similar to the gradual manner
Summary
employed in DKA (above). Serum sodium and
osmolality will decrease during the rehydration
phase. Insulin at approximately ½ the dose used
for DKA may be instituted when blood sugar
ceases to decrease at 50 mg/dL/h.
Summary
We have excellent treatment for diabetes but no
cure for diabetes as yet. At present the use of insu-
lin and high-technology devices are means of
treating diabetes but not of curing diabetes. Many
approaches to finding a cure are under evaluation,
but none has progressed to established care as yet.
Much research is ongoing into the transplantation
of stem cells to develop islet cells or the transplan-
tation of actual islet cells into patients with type 1
DM to allow endogenous production and secre-
tion of insulin in appropriate amounts. Since type
1 diabetes is in most cases immune mediated,
immunomodulatory and anti-inflammatory inter-
ventions are under evaluation internationally.
These techniques for diabetes might be offered in
the future if screening tests suggest a higher risk
for type 1 diabetes or could be utilized after the
diagnosis during the “honeymoon” period when
beta cell function still exists. Beta cells may be
transplanted or stem cells may be transformed
into beta cells to be transplanted into an individual
with existing type 1 diabetes and immunomodula-
tion or anti-inflammatory techniques might be
used to enhance the survival of such beta cells.
Alternatively pancreas transplants or partial pan-
creas transplants might be used in diabetes. An
alternative approach would be the development of
a “smart” insulin pump that can measure blood
sugar and determine appropriate insulin doses
without much intervention from the individual
with diabetes. We are approaching that level as
there is presently a commercial pump which turns
the infusion off when it senses a low blood sugar
but cannot independently manage diabetes. The
goal of continuous blood glucose monitoring by a
miniature device that is linked to the subcutane-
ous insulin infusion pump to form a closed loop
that will function as a replacement pancreas
303
appears ever to come closer. Experimental pro-
grams have accomplished this goal with small
short-term studies and long-term use may follow.
None of these techniques are yet established or
approved by the FDA for children, but many are
promising due to the work of many researchers.
Either the biomechanical or biological approach
will likely markedly improve the health of patients
with T1DM in the foreseeable future. The impor-
tant issue is to ensure that they retain good control
of blood sugar to reduce the development of
comorbidities which will not be reversible even
after we achieve either a cure or improvement in
treatment.
Suggested Readings
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Diabetes Mellitus (T2DM) in children and adoles-
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2. Sperling MA, Tamborlane WV, Battelino T, Weinzimer
SA, Phillip M. Chapter 19—Diabetes mellitus. In:
Sperling MA, editor. Pediatric endocrinology. 4th ed.
Philadelphia, PA: Elsevier; 2014. p. 846–900.
3. Sperling MA. Chapter 9—Neonatal diabetes mellitus.
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12. Glaser NS, Geller DH, Haqq A, Gitelman S, Malloy
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pathophysiological considerations and suggested
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18. Achenbach P, Bonifacio E, Koczwara K, Ziegler
A-G. Natural history of type 1 diabetes. Diabetes.
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19. American Diabetes Association, Lorber D, Anderson J,
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DG, Songer TJ, Yatvin AL. Diabetes and driving.
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21. Dietetics’ AoNa. Pediatric weight management evi-
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Linder B, Divers J,… Study S. f. D. i. Y. Prevalence of
type 1 and type 2 diabetes among children and adoles-
cents from 2001 to 2009. Jama. 2014;311(17):1778–
1786. doi:10.1001/jama.2014.3201
23. Li L, Jick S, Breitenstein S, Michel A. Prevalence of
Diabetes and Diabetic Nephropathy in a Large U.S.
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Diabetes Care. 2015 Dec 17.
24. Levitsky LL, Misra M. Epidemiology, presentation,
and diagnosis of type 1 diabetes mellitus in children
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epidemiology-presentation-and-diagnosis-of-type-
1-diabetes-mellitus-in-children-and-adolescents.
25. Levitsky LL, Misra M. Complications and screening in
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and-screening-in-children-and-adolescents-with-type-
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26. Laffel L, Svoren B. Epidemiology, presentation, and
diagnosis of type 2 diabetes mellitus in children and
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2-diabetes-mellitus-in-children-and-adolescents.
 Hypoglycemia
Symptoms of hypoglycemia may be as vague as
malaise in a child or feeding difficulty in an infant
or as striking and clinically devastating as grand
mal seizures. Conversely, a low blood sugar may
instead be factitious, due to a blood sample stored
too long in a tube without fluoride before analysis
or due to the use of outdated test strips for a glu-
cometer. The signs of hypoglycemia revolve
around changes in central nervous system func-
tion and the autonomic nervous system in the
absence of glucose. Hypoglycemia should always
be confirmed by specific laboratory testing as
vague feelings of hunger may not be associated
with low blood sugar in spite of common wis-
dom. At the time that glucose decreases, a “criti-
cal” blood sample must be obtained (if there is
time to briefly and safely delay treatment) or an
ideal diagnostic opportunity is lost and the diag-
nostic process may become extremely difficult or
expensive.
Normal Carbohydrate Metabolism
The maintenance of normal blood sugar depends
on three basic processes (Fig. 12.1). The intake of
carbohydrates from the gastrointestinal (GI) tract
initiates the fed state. Glycogenolysis, or the release
of glucose from its storage depot, glycogen, is the
initial process in the fasted state. The process of
gluconeogenesis, or the production of glucose from
precursors such as glycerol (derived from fat),
© Springer International Publishing Switzerland 2016
D.M. Styne, Pediatric Endocrinology, DOI 10.1007/978-3-319-18371-8_12
12
amino acids (such as alanine derived from muscle),
and lactate, follows. Anaerobic glycolysis (the
Embden–Meyerhof pathway) in muscle produces
pyruvate, which is then metabolized to lactate or
alanine which are gluconeogenic precursors.
Oxidation of glucose to glycerol-3-phosphate in
adipose tissue can also esterify fatty acids in the
synthesis of triglycerides.
The muscle mass is smaller in children, and
the release of substrates for gluconeogenesis is
more limited. Impairment in production of glu-
cose, even with no change in utilization, will
reduce serum glucose concentration more quickly
in the child than in the adult. The normal glucose
production rate is 8 mg per kilogram per minute
in newborns and infants, 6–8 mg per kilogram
per minute in young children, and 6–8 mg per
kilogram per minute in adolescents as compared
with 1–2 mg/kg/min in the adult. While the treat-
ment of disorders of gluconeogenesis will require
an infusion rate of glucose at the normal produc-
tion rate, since treatment simply needs to replace
the glucose that has not been produced, hyperin-
sulinemic states will require a glucose infusion
rate higher than the normal production rate due to
the fact that the insulin is actively lowering glu-
cose levels. A large portion of the glucose avail-
able in a child is used to provide energy for brain
metabolism. As the brain is much larger in rela-
tion to body size in the infant than in the adult and
consumes relatively more energy, neurologic symp-
toms and signs of hypoglycemia will be manifest
305
306
GH, cortisol
Gluconeogenesis
Glycogen
Liver + Blood
Glucagon
Pancreas
Glucagon
Peripheral
tissues
Fig. 12.1 Features of carbohydrate metabolism with stimulatory (+) and inhibitory pathways (−) indicated. (Adapted from a
drawing in Endocrinology Nakamoto, JM and Mason, PW. San Juan Capistrano; Quest Diagnostics 2012 with permission)
more readily in the hypoglycemic child. Thus for
many reasons, the child is more susceptible to
hypoglycemia and its symptoms than is the adult.
Glucose Regulatory Factors
Concentration of glucose in the serum of normal
subjects is kept remarkably constant by gluco-
regulatory factors. Insulin is secreted from the
beta cells of the pancreatic islets in response to
exogenous glucose, which in turn suppresses
endogenous glucose production by inhibiting
hepatic glycogenolysis and gluconeogenesis (see
Chap. 11 for discussion of influences on insulin
secretion). Insulin is a potent suppressor of
ketone body formation, and as a general rule, if
ketosis is present in hypoglycemia, abnormally
increased insulin secretion is not likely the etiol-
ogy of the hypoglycemia. Further, insulin stimu-
12 Hypoglycemia
Epinephrine
–
+
– glucose
Insulin
+
+
en
og
l yc rgy
G ne
e
lates the storage of glucose as glycogen and
triglycerides as lipids and promotes the uptake of
glucose in many other tissues. Most of the uptake
of glucose occurs via facilitated glucose trans-
porters known as GLUT of which there are 14
types, some of which are insulin sensitive and
some of which do not require insulin for their
action. GLUT 4 is insulin sensitive and is found
in many tissues including skeletal and cardiac
muscle and kidney. Thus insulin decreases blood
sugar by facilitating the transfer of glucose into
cells in these organs through GLUT 4 and by
decreasing the precursors to gluconeogenesis.
Glucose is the major source of energy for the
brain. GLUT 1 does not quite require insulin and
is found at the blood–brain barrier; transport of
glucose into the brain is directly proportional
to glucose levels in the circulation. Due to the
high glucose requirements of the brain, low
plasma glucose concentrations will deprive the
Normal Carbohydrate Metabolism
brain of adequate energy. The brain is able to use
ketone bodies as fuel in the absence of adequate
glucose for at least some of its needs.
Glucagon is produced and released from the
alpha cells of the pancreas and quickly but tran-
siently stimulates hepatic glycogenolysis and
gluconeogenesis and also increases hepatic
ketone production. Glucagon exerts its effect
through a 7-transmembrane G-protein-coupled
receptor. Elevated glucagon levels are found in
some stages of uncontrolled diabetes mellitus
type 1. In contrast to beta cell destruction which
is characteristic of type 1 diabetes, alpha cells
remain as do delta cells which secrete
somatostatin.
Epinephrine from the adrenal medulla can
rapidly stimulate hepatic glycogenolysis and
gluconeogenesis acting through adrenergic G
protein membrane receptors, indirectly affecting
insulin and glucagon as well.
Both the cortisol and growth hormone (GH)
are considered to be counterregulatory hormones
and exert anti-insulin effects by limiting glucose
utilization and increasing glucose production.
GH, however, has an additional early, transient
effect of decreasing serum glucose through the
production and action of the insulin-like growth
factors, although the ultimate effect of GH is to
elevate glucose concentrations (Table 12.1).
The Fed State
After a meal, in the postprandial state, exogenous
glucose is used by, and stored in, tissues, whereas
the mechanism of glucose production, gluconeo-
genesis, is suppressed in normal conditions.
Thus, insulin secretion increases and glucagon
decreases with glucose intake in the fed state.
Insulin is responsible for the storage of glucose
through the production of glycogen mainly in the
liver and muscle, the transport of amino acids,
and incorporation of amino acids into protein in
muscles and lipids into triglycerides in the adi-
pose organ. Insulin suppresses the production of
ketone bodies; ketone bodies are very low or
unmeasurable in blood in the fed state. In fact,
insulin is more efficient at suppressing ketone
formation than it is in decreasing blood sugar.
307
The Fasting State
In the normal fasting state, insulin secretion is
suppressed so that three processes, mostly resid-
ing in the liver, may support energy metabolism:
gluconeogenesis (the aerobic production of glu-
cose from the substrate), glycogenolysis (which
allows the release of glucose from glycogen into
the circulation), and ketogenesis. Glycogenolysis
is stimulated by rising levels of glucagon and epi-
nephrine in the absence of insulin. Glycogenolysis
begins in the fasted state, but glycogen stores are
soon exhausted (after about 4 h in infants and
after 8 h in older subjects). A disorder of glycoge-
nolysis would cause hypoglycemia early in fast-
ing as will a hyperinsulinemic condition. The
next process leading to hypoglycemia if disor-
dered is gluconeogenesis which utilizes amino
acids derived from the breakdown of muscle pro-
tein and lactate from blood cell glycolysis (the
process which converts glucose to lactate). To
preserve muscle protein, hepatic fatty acid oxida-
tion next provides the energy for gluconeogene-
sis. Lipolysis breaks down lipids into triglycerides
which are metabolized into glycerol and free
fatty acids (FFAs). Lipolysis is stimulated by
growth hormone, cortisol, and epinephrine. Fatty
acid oxidation becomes prominent 8–12 h after
fasting in the neonate but only after about 16–24 h
in older children.
The liver is also the site of formation of the
ketone bodies acetoacetate (which is converted
to acetone) and β-hydroxybutyrate from FFAs
through mitochondrial fatty acid oxidation dur-
ing the breakdown of lipids. The ketone bodies
can pass the blood–brain barrier and provide
energy for brain function, albeit limited energy,
and can be used for energy in the skeletal and
cardiac muscle. The production of ketone
bodies by fatty acid oxidation may be viewed as
an adaptive mechanism that spares muscles from
breakdown and the release of amino acids that
would otherwise be used for gluconeogenesis;
likewise, the process preserves glucose to sup-
port brain metabolism and to allow glucose-
dependent metabolism in the red cells. In a
similar manner, the energy needs of some organs
can shift to conserve glucose as the liver, adipose
Table 12.1 Causes of hypoglycemia
Free
Condition Insulin Ketones GH Cortisol Lactate fatty acids GIR Other features
Transient hypoglycemia Low NI or high Appropriate Appropriate NI or high NI or high 6–10 mg/kg/min
of the newborn for BS for BS
Persistent High for glucose Low Appropriate Appropriate Low Low >12–15 mg/kg/min Some defects
hyperinsulinemic value for BS for BS associated with
hypoglycemia of infancy elevated ammonia,
IGF BP1 is low
Beckwith-Wiedemann High for glucose Low Appropriate Appropriate Low Low >12–15 mg/kg/min Organomegaly,
syndrome value for BS for BS elevated IGF-2,
IGF BP1 is low
Beta cell adenoma High for glucose Low Appropriate Appropriate Low Low >12–15 mg/kg/min IGF BP1 is low
value for BS for BS
GH deficiency Nl High Stimulated peak, Nl (if GH High High 6–10 mg/kg/min May have
<10 ng/mL deficiency is findings of SOD
isolated)
ACTH or cortisol Nl High Nl Stimulated peak, High High 6–10 mg/kg/min May have
deficiency <15–18 μcg/mL findings of SOD
Galactosemia Low High Nl Nl High High 6–10 mg/kg/min High galactose
Acyl-CoA Nl Low Nl Nl High High 6–10 mg/kg/min Low carnitine
dehydrogenase,
medium-chain deficiency
Glycogen storage Low High Nl Nl High High 6–10 mg/kg/min Hepatomegally in
disease types 1, 3, 6, 9, 11, 0 type 1, 3, 6, 9, 0
Ketotic hypoglycemia Low High Nl Nl High High 6–10 mg/kg/min Low alanine
(could be GH or cortisol
deficiency)
Hereditary fructose Low High Nl Nl High High 6–10 mg/kg/min Immediately
intolerance precipitated by
fructose intake
Fructose 1-6 Low High Nl Nl High High 6–10 mg/kg/min Not immediately
diphosphatase deficiency precipitated by
fructose intake
but by fasting
Munchausen by proxy High for glucose Low Nl Nl Low Low >12–15 mg/kg/min
with exogenous insulin but C peptide is low until elimination of
administration exogenous insulin
GH growth hormone, Nl normal, ACTH adrenocorticotropic hormone, GIR glucose infusion rate, SOD septo-optic dysplasia
Adapted from a chart in Endocrinology Nakamoto, JM and Mason, PW. San Juan Capistrano; Quest Diagnostics 2012 and Selected Readings
Hypoglycemia
tissue, and muscle can use the β-oxidation of
fatty acids.
In the fasted state, the endocrine milieu main-
tains blood sugar concentration at about 55 mg/
dL: if the blood sugar falls below 55 mg/dL,
endocrine factors attempt to raise blood sugar to
compensate. A “critical sample” will indicate
which hormone concentrations rise appropriately
to increase blood sugar or which are inadequate
to do so (e.g., GH or ACTH deficiency) or if
hyperinsulinism is driving blood sugar down.
The critical sample is described below.
Transition of the Fetus
to Neonatal Life
The fetus is dependent upon maternal supplies of
glucose, and serum levels of glucose in the fetus
vary according to the mother’s levels. Thus a
mother with diabetes who experiences hypogly-
cemia has a fetus who likewise experiences
hypoglycemia, and the opposite occurs when the
mother’s blood sugar is too high. The eight
GLUTs found in the placenta are mostly insulin
independent through most of pregnancy, and thus
the transport of glucose for mother and child
depends upon the concentration gradient rather
than upon insulin levels. When the child is sepa-
rated from the maternal glucose supply at birth,
mobilization of glucose from stored sites must
begin immediately and gluconeogenesis must
commence. During this transitory period, almost
1/3 of appropriate-for-gestational-age newborn
will experience glucose levels less than 50 mg/dL
during the first day of postnatal life in the absence
of disease or symptoms; there is rarely a need to
monitor glucose levels in a normal-term newborn
who had a normal delivery from a healthy mother
according to most authorities. More significant
hypoglycemia in the first 24 h may occur in
small-for-gestational-age infants, premature
babies, babies suffering from neonatal stress or
asphyxia, and of course infants of diabetic moth-
ers or infants with increased insulin secretion. It
is sometimes difficult to determine who is having
transitional mild hypoglycemia in the first 24 h
versus those with a condition requiring treatment.
309
An infant showing signs of hypoglycemia
should have a laboratory glucose determination,
a critical blood sample drawn (see below), and
glucose provided. If there is a medical history or
physical findings suggesting a hypoglycemia
syndrome, this will assist in the diagnosis. The
AGA baby who has prolonged hypoglycemia
after 24 h of age is likely to have a disease as eti-
ology of hypoglycemia.
Hypoglycemia (Table 12.1)
Symptoms of hypoglycemia are due either to
effects of adrenergic and cholinergic agents
(causing sweating, tremulousness, hunger, weak-
ness, and tachycardia) or to central nervous sys-
tem (CNS) manifestations (such as headaches or
reduced mentation, which may extend on a con-
tinuum from drowsiness to coma and seizures).
Even if severe and recurrent hypoglycemia is
ultimately controlled, the patient may still be left
with permanent neurologic impairment such as
developmental delay, memory loss, and seizure
disorders that manifest even when the blood
sugar is normal. Patients taking adrenergic block-
ing agents may not show the initial symptoms of
hypoglycemia in spite of having low blood sugar
concentrations, but still have the potential for
neurologic damage. Symptoms of hypoglycemia
usually begin only when blood sugar decreases
below 55–68 mg/dL, so a value of 55 mg/dl
should trigger an evaluation. Repeated hypogly-
cemia decreases the release of epinephrine from
the adrenal medulla leading to hypoglycemia-
associated autonomic failure (HAAF) and hypo-
glycemic unawareness since the adrenergic
response is one of the features that make a hypo-
glycemic individual realize that he or she is
hypoglycemic. HAAF can occur in repeated
hypoglycemia or in the hypoglycemia that occurs
with the treatment of diabetes mellitus as
described in Chap. 11. The endocrine response to
hypoglycemia might occur at lower glucose level
than 55 mg/dL after repeated episodes of hypo-
glycemia which further complicates the diagno-
sis of the etiology of hyperglycemia since the
secretion of growth hormone and cortisol as
310
counterregulatory hormones will not be triggered
until blood sugar drops below the usual threshold
of hypoglycemia of 55 mg/dL.
The classic method of establishing hypoglyce-
mia invokes Whipple’s triad. Thus the symptoms
or signs of hypoglycemia must occur with a con-
firmed low blood sugar measurement and must
be resolved when the glucose rises. Whipple’s
triad was developed for adults but appears appro-
priate for children and teenagers but not neces-
sarily neonates in whom symptoms are more
subtle. While the threshold 55 mg/dL is appropri-
ate for the diagnosis of hypoglycemia, treatment
should aim to maintain a blood sugar greater than
70 mg/dL.
Various etiologies of hypoglycemia tend to
emerge in a certain chronological order in the
postprandial state after fasting begins, and the
timing of hypoglycemia provides an important
clue to the diagnosis. For example, hypoglycemia
due to fructose intolerance manifests just after
ingesting fructose, and leucine-sensitive hyperin-
sulinism likewise occurs after the ingestion of
leucine. Glycogen storage disease (GSD), in
which there is difficulty in glycogenolysis, mani-
fests in a few hours after eating. After a period of
fasting, other forms of hyperinsulinism or a dis-
order of glycogenolysis will be manifest; next
will appear disorders of gluconeogenesis includ-
ing growth hormone and cortisol deficiency or
fructose-1,6-bisphosphatase deficiency; lastly,
disorders of fatty acid oxidation (acyl-CoA dehy-
drogenase deficiencies) will emerge during a pro-
longed fast.
Hypoglycemia in the Newborn
The definition of hypoglycemia in the newborn
has been controversial, but a plasma glucose less
than 50 mg/dL or, because whole-blood glucose
is 15 % lower than serum or plasma glucose, a
blood glucose less than 43–45 mg/dL may be
used for the diagnosis of hypoglycemia in the
symptomatic neonate in the first 24 h after birth.
Unlike hypoglycemia found in older children or
teenagers, symptoms of hypoglycemia in the
newborn are more generalized and may be subtle.
12 Hypoglycemia
Thus symptoms of hypoglycemia in the newborn
range from grand mal or localized seizures to irri-
tability, hypotonia, lethargy, and difficulty in
feeding, to other rather nonspecific findings, and
to no findings at all because of the immaturity of
the CNS. A high index of suspicion for hypogly-
cemia must be maintained especially with certain
clinical conditions known to be associated more
frequently with hypoglycemia.
The neonate has less tolerance to fasting and
stress than does an older individual because of
limited glycogen or gluconeogenic substrate
availability, and hypoglycemia develops faster in
the newborn. Disorders causing hypoglycemia in
the newborn can be found on a continuum from
decreased ability to stabilize metabolically in the
postnatal period, continuing to hypoglycemia as
a secondary finding associated with other dis-
eases, and ending with disorders in which severe,
unremitting hypoglycemia is the immediate and
primary problem.
Even a normal newborn who has fasted for
6 h has a 10 % chance of having a blood sugar
less than 30 mg/dL and a 30 % chance of devel-
oping a blood sugar less than 50 mg/dL, so tran-
sient hypoglycemia is common. Availability of
ketone bodies as alternative fuel for the CNS
appears to mitigate long-term effects of this
transient hypoglycemia. A neonate who is the
product of a problem pregnancy or delivery is an
even more likely candidate for transient hypo-
glycemia. Thus infants who are premature or
small for gestational age, or who experienced
trauma, asphyxia, or cold exposure at birth,
should be monitored prospectively for the devel-
opment of hypoglycemia. Diseases that have
other significant manifestations may have hypo-
glycemia included in the constellation; frequent
examples include sepsis, postexchange transfu-
sion or erythroblastosis fetalis, congenital heart
disease, or congenital defects of the CNS or
elsewhere. The condition of the mother before
delivery may affect the neonate cell; for exam-
ple, infants of mothers with toxemia, with nar-
cotic addiction, or who are taking oral
hypoglycemic agents or β-adrenergic blockers
are likely candidates for hypoglycemia as are
infants of diabetic mothers.
Hypoglycemia
Hyperinsulinemic Hypoglycemia
in the Newborn
A child who is a term product of a normal deliv-
ery without known complication, fed by 6 h after
birth, should not have persistent hypoglycemia.
However in the presence of excessive insulin
secretion, glucose falls as it is utilized in the met-
abolic processes described above promoted by
insulin. Infants of diabetic mothers have a risk
for hyperinsulinemic hypoglycemia, but it will
be of a transient nature during the first week after
birth. Newborns who are not infants of diabetic
mothers with persistent hypoglycemia after age
2 days and who require more than 10 mg/kg/min
of intravenous glucose to maintain a normal
blood sugar most likely have the hypoglycemia
because of a disorder causing hyperinsulinism of
the newborn and will have a more difficult course
than those with the transient problems mentioned.
Hyperinsulinism may cause devastating hypogly-
cemia in the newborn or older child. Diagnosis is
suspected if any insulin secretion is detected dur-
ing hypoglycemia, a state in which normally no
insulin should be measurable; even low levels of
insulin secretion while the blood sugar is low may
suggest hyperinsulinism. Hyperinsulinism is
especially likely to cause brain damage, as an
absence of glucose as well as lactate and ketone
bodies and found, so that all metabolic fuels for
the brain are unavailable. Absence and suppres-
sion of serum ketone bodies and FFAs are diag-
nostic clues to hyperinsulinism.
Nesidioblastosis was a term classically used to
describe newborns with hyperinsulinemia which
was also called islet cell hyperplasia, islet cell
dysplasia, and islet cell dysmaturity; it represents
the histologic finding of beta cells in the pancre-
atic ductal tissue. Nesidioblastosis was defined as
the development of beta cell islets from pancre-
atic duct tissue, but more recent histologic stud-
ies suggest that this appearance is a normal
variant; some of the patients previously diag-
nosed as having nesidioblastosis may have had
microscopic adenomas that had been missed or a
functional defect that could not be demonstrated
histologically but can now be demonstrated by
molecular probes as noted below.
311
Mothers with permanent or gestational diabetes
mellitus (GDM) who have not maintained eugly-
cemia may have infants who experience intrauter-
ine hyperglycemia, related to maternal blood sugar
concentrations, and who develop beta cell hyper-
plasia in the islets of Langerhans because of this
stimulation by ambient glucose concentrations;
after birth, when removed from the maternal glu-
cose supply, the increased insulin secretion of the
islets will cause minimal to severe hypoglycemia
for hours to a few days after delivery. The IDM,
unless having intrauterine growth restriction
(IUGR) due to even more severe maternal diabe-
tes, has a characteristic appearance of increased
size for gestational age (they are longer as well as
heavier), with extra subcutaneous tissue, a pletho-
ric complexion, and a rather lethargic level of
activity. The hypoglycemia is not solely due to
elevated insulin as they also have decreased gluca-
gon and catecholamine production.
These infants will require a glucose infusion
rate in the range of 10–12 mg per kilogram per
minute and sometimes as high as 15 mg per kilo-
gram per minute. This condition is less frequent if
the mother has excellent blood sugar control dur-
ing pregnancy. Maternal medications including
sulfonylureas, terbutaline, and propranolol can
cross the placenta and cause neonatal hypoglyce-
mia in the newborn. Similarly, infants of mothers
who are not diabetic but were receiving a large
amount of intravenous glucose will have increased
fetal insulin secretion; because the glucose will
abruptly disappear at the time of placental separa-
tion, the child is also at risk for transient hyper-
insulinemic hypoglycemia. In all of these cases,
hypoglycemia should have resolved within a few
days or there will be another diagnosis indicated.
Persistent hyperinsulinemic hypoglycemia in
infancy may occur due to mutations of a variety
of genes causing seven different forms of the
condition. All forms are due to defective feed-
back inhibition of glucose upon insulin secretion
due to mutations in the beta cell; we will consider
five forms here but more may be found in refer-
ences at the end of the chapter or in OMIM. The
etiology of these conditions involves mutations
in the process in which the beta cell senses
312 12 Hypoglycemia

glucose and releases insulin. In the normal situation,
glucose is taken up by the beta cell by the action
of the GLUT2 transporters and phosphorylated
by the enzyme glucokinase. Glucose is oxidized,
and the plasma membrane ATP-dependent potas-
sium (KATP) channel is closed by increased
ATP/ADP ratio which leads to the voltage-
dependent calcium channel to now allow the
influx of calcium into the cell, ultimately leading
to insulin secretion. The KATP channel consists
of a K1-selective pore-forming subunit (Kir6.2)
and a regulatory subunit (SUR-1) and mutations
in either of which occur in persistent hyperinsu-
linemic hypoglycemia in infancy (Fig. 12.2). The
KATP channel is closed by the class of oral dia-
betes medications, sulfonylureas, which stimu-
late insulin secretion and opened by diazoxide
which is used in certain conditions listed below
to suppress insulin secretion. There is heteroge-
neity in these conditions so that some require
pancreatectomy and some respond to diazoxide
with the same gene defect differing in therapeutic
requirements if the inheritance is autosomal
recessive or dominant.
Leucine will also raise the ATP/ADP ratio,
closing the channel and leading to insulin secre-
tion, and mutations may cause leucine-sensitive
hypoglycemia.
The first described form of hyperinsulinemic
hypoglycemia of the newborn (#256450 ICD+
HYPERINSULINEMIC HYPOGLYCEMIA,
FAMILIAL, 1; HHF1) may be inherited in an
autosomal recessive or an autosomal dominant
pattern and results from a mutation in the ATP-
binding cassette, subfamily C, member 8 gene
(ABCC8) which affects the function of the KATP

ATP-sensitive K+ channel
Ca2+
K+ Voltage
dependent
Ca2+ channel
SUR1
Depolarization
Mitochondria Ca2+
6. R
KU
2

ATP/ADP↑ cAMP
Nucleus

Islet
Pyruvate transcription
factors
Glucose-6-phosphate
Glucokinase
Glucose
Secretory
granules Insulin

Glucose

GLUT2

Fig. 12.2 The beta cell and its components. The ATP-
sensitive K+ channel (KATP) is the site of action of sulfo-
nylureas which close the channel to cause insulin secretion
and of diazoxide which opens the channel to suppress
insulin secretion. Mutations in this area are responsible
for some forms of hyperinsulinemic hypoglycemia of the
newborn. The GLUT 2 transporter allows glucose to enter
the beta cell where it interacts with glucokinase to pro-
duce glucose-6-phosphate. Glucose-6-phosphate can be
metabolized during glycolysis leading to increased ATP
which enhances insulin secretion through the ATP-
sensitive K+ channel. Thus glucokinase acts as the
glucose sensor of the beta cell and plays a major role in
determining how much insulin is released in response to
glucose levels in the normal condition. Mutations in
glucokinase can lead to hypoglycemia or hyperglycemia
Hypoglycemia
channel. The patients are large due to the stimula-
tion of the IGF-1 receptors by excessive insulin
during fetal life and later in life may develop
insulin deficiency and diabetes rather than con-
tinuing hyperinsulinism. A single mutation may
exist on the paternal chromosome, with loss of
the normal maternal allele leading to homozy-
gosity for a recessive SUR1 mutation, leading to
focal pancreatic disease. This condition most
often does not respond to diazoxide but may be
amenable to surgical correction without the need
for total pancreatectomy. However, there is a
dominant subtype with normal birth weight
which does respond to diazoxide. The type 2
form (#601820 ICD+ HYPERINSULINEMIC
HYPOGLYCEMIA, FAMILIAL, 2; HHF2) is
due to a mutation in the Kir6.2 subunit of the
potassium inwardly rectifying channel (KATP
channel), subfamily J, member 11 gene (KCNJ11)
which is inherited in an autosomal recessive pat-
tern, and birth weight is usually high. Both homo-
zygous dominant HHF type I and HHF type II are
unlikely to respond to diazoxide therapy since
the site of the defect is where diazoxide exerts its
effect but heterozygous recessive forms may
respond to diazoxide.
Hyperinsulinemic hypoglycemia type 3 is auto-
somal dominant (#602485 HYPERINSU-
LINEMIC HYPOGLYCEMIA, FAMILIAL, 3;
HHF3) and is due to a mutation of the glucokinase
gene. HHF3 may respond to oral diazoxide therapy.
Glutamate dehydrogenase hyperinsulinism or
hyperinsulinemic hypoglycemia type 6 (#606762
HYPERINSULINEMIC HYPOGLYCEMIA,
FAMILIAL, 6 at 10q23.3; HHF6) manifests ele-
vated ammonia levels about 2–5 times the nor-
mal. This condition may be discovered later in
life rather than infancy. The condition is due to
mutations in the glutamate dehydrogenase gene
(GLUD1) which is involved in ammonia metabo-
lism. Leucine activates the enzyme and causes
insulin secretion normally, but in this condition,
inhibition of this process is defective, leading to
excessive insulin secretion. This condition is
inherited in an autosomal dominant pattern con-
dition (although 80 % are new mutations and
appear to be sporadic). Treatment with diazoxide
is often successful in controlling hypoglycemia
313
in the fasting or fed state, and surgery may not be
necessary. Leucine intake must be minimized.
Leucine can also precipitate hyperinsulinemic
hypoglycemia in another condition in an autosomal
dominant pattern (240800 HYPOGLYCEMIA,
LEUCINE-INDUCED) due to mutation in
the ATP-binding cassette, subfamily C, member
8 gene (ABCC8) affecting the SUR-1 subunit.
Hyperinsulinemic hypoglycemia type 7
(#610021 HYPERINSULINEMIC
HYPOGLYCEMIA, FAMILIAL, 7; HHF7)
manifests as hypoglycemia after exercise is due
to elevated pyruvate levels. This condition is due
to mutations in the solute carrier family 16, mem-
ber 1 gene (SLC16A1). The clinical findings are
variable but some patients have been treated suc-
cessfully with partial or total pancreatectomy and
others with diazoxide or by following a sedentary
lifestyle.
The glucose infusion rate required for
successful management of hyperinsulinemic
hypoglycemia most often will be high, e.g., 10 or
12 mg per kilogram per minute, which must be
maintained until success with medical or surgical
therapy is accomplished. Up to 30 % of patients
with hyperinsulinism are reported to have devel-
opmental delay probably related to delay in diag-
nosis and therapy. Patients with autosomal
recessive abnormalities in the KATP channel are
not likely to respond to diazoxide since the KATP
channel is the location of diazoxide action.
However, there are dominantly inherited muta-
tions in the KATP channel (mutations of ABCC8
and KCNJ11) which may respond to diazoxide at
a dose of 5–15 mg/kg/day divided into two or
possibly one dose as indicated above.
Diazoxide was developed to lower blood pres-
sure and also causes fluid retention, so a thiazide
diuretic is sometimes necessary to offset the fluid
retention. Likewise, over long use, diazoxide
increases hair growth to a quite noticeable degree,
particularly on the face. If diazoxide is ineffec-
tive, octreotide may be tried in a dose of 5–20 mg/
kg/day given subcutaneously in divided doses
3–4 times per day or intravenously by a continuous
infusion by pump. Long-acting forms of octreo-
tide such as used in acromegaly are sometimes
effective in older children. Octreotide treatment
314
carries the risk of necrotizing enterocolitis and
development of gall bladder sludge and stones;
ursodiol may be used to control the latter.
Some of the hyperinsulinemic hypoglycemic
syndromes present with focal lesions in the pan-
creas, while others have diffuse pancreatic
involvement. If medication is unsuccessful and
surgery is indicated, it is possible to separate
patients with local lesions that may be amenable
to partial pancreatectomy rather than diffuse
lesions requiring total pancreatectomy by the
use of imaging techniques. While standard
CT scans or MRI imaging will not usually reveal
the focal lesions, positron emission tomogra-
phy (PET) scanning using fluorine-18 L-3,
4-dihydroxyphenylalanine (18F-fluoro-L-DOPA)
tracer takes advantage of the fact that the lesions
take up L-dopa to demonstrate the local lesions.
Hypoglycemia may be caused by the hyper-
insulinism characteristic of the Beckwith–
Wiedemann syndrome (#130650 BECKWITH-
WIEDEMANN SYNDROME; BWS at 11p15.5),
whose features include exomphalos, macroglos-
sia, and gigantism or in the infant, giant syndrome
(large body size and microcephaly but no macro-
glossia or exomphalos).
Beta cell adenomas are extremely rare in
infants and newborns and, although more com-
mon in later childhood, are still rarer than in
adults. Hyperinsulinism of this type may be a
part of multiple endocrine neoplasia type 1 but is
usually found well after the second decade (see
Chap. 10).
Defects in Gluconeogenesis
in the Newborn
Deficiencies of GH and/or adrenocorticotropic
hormone (ACTH) may cause neonatal hypogly-
cemia. In boys, the finding of microphallus (penis
less than 2 cm in length due to gonadotropin and/
or GH deficiency) associated with hypoglycemia
should strongly suggest this diagnosis; visual
impairment and optic hypoplasia also may be
found in septo-optic dysplasia (see Chap. 3).
Virilizing congenital adrenal hyperplasia will
often present with hypoglycemia and cortisol
deficiency but will be indicated by ambiguous
genitalia in girls although boys will appear nor-
12 Hypoglycemia
mal at birth. Adrenal hypoplasia, dysplasia, or
atrophy will not necessarily have diagnostic
physical findings but will lead to hypoglycemia
(see Chap. 3).
Fructose-1,6-bisphosphatase deficiency
(#229700 ICD+ FRUCTOSE-1,6-BISPHOS-
PHATASE DEFICIENCY at 9q22.3) is the result
of a defect in fructose-1-phosphate aldolase,
which utilizes lactate, alanine, glycerol, and oral
fructose for gluconeogenesis. Along with hypo-
glycemia, the newborn infant may have hyper-
ventilation, apnea, seizures and coma,
hepatomegaly, elevated uric acid, and ketosis or
metabolic acidosis. The liver is enlarged as in
GSD type 1, in this condition because of hepatic
steatosis, and differential diagnosis between the
two conditions is through the fed glucagon stimu-
lation test (administration of glucagon after
meal). Signs and symptoms appear with fasting
or illness rather than directly after fructose inges-
tion. A newborn with hypoglycemia after fasting
with lactic acidosis and inadequate rise of blood
sugar to glucagon administration is the classic
presentation. Determination of a mutation in the
fructose-1,6-bisphosphatase gene (FBBP 1) is
diagnostic; minimizing fasting and decreasing
fructose intake as well as avoiding sorbitol is the
management. The condition is autosomal
recessive.
Hereditary fructose intolerance (#229600
ICD+ FRUCTOSE INTOLERANCE,
HEREDITARY) presents with hypoglycemia,
abdominal pain, vomiting, and diarrhea after
exposure to fructose which may first occur after
weaning. The child may demonstrate aversion to
sweet tastes. Laboratory determination reveals
hypoglycemia, and with continued exposure to
fructose, the concentrations of uric acid, lactic
acid, and magnesium rise, while phosphorus,
potassium, and bicarbonate fall. If the fructose
dose increases or exposure continues shock, hep-
atomegaly, hepatic steatosis, and ultimately cir-
rhosis and liver failure occur and later kidney
failure will develop. This is a severe condition
with a potentially fatal outcome. Intravenous glu-
cose is the appropriate early treatment, and
avoidance of all fructose and sorbitol in the diet
is required. It is not recommended that a child
Hypoglycemia
undergoes fructose challenges as the danger is too
great. The disorder is caused by a mutation in the
aldolase B, fructose-bisphosphate gene (ALDOB)
and inheritance is autosomal recessive.
Metabolic abnormalities of branched-chain
amino acids, such as maple syrup urine disease
(*248600 MAPLE SYRUP URINE DISEASE,
TYPE IA at 19q13.1-q13.2), are found in an auto-
somal recessive pattern and characterized by ele-
vated branched-chain amino acids (leucine,
isoleucine, or valine) in serum and urine. In
affected infants, developmental delay, coma, sei-
zures, vomiting, lethargy, elevated serum ammo-
nia, and metabolic acidosis in the presence of
ketotic hypoglycemia will be found. The urine has
the odor of maple syrup (as suggested by the name
of the disorder). Five different forms and degrees
of severity are found, with the basic defect in all
being mutations in the branched-chain α-keto acid
dehydrogenase, E1α subunit gene. Other forms of
maple syrup urine disease are termed type 1B
(*248611) and type 2 (*448610).
Galactosemia (#230400 GALACTOSEMIA at
9p13) is one of the diseases for which generalized
screening is available at birth. Only at the late
stages of the disease in which liver failure devel-
ops is hypoglycemia apparent. The diagnosis will
usually rest on findings other than low blood
sugar such as cataracts, hepatomegaly, decreased
liver function, vomiting, diarrhea, hemolytic ane-
mia, and ultimately ovarian failure in females.
Disorders of organic acid or fatty acid oxida-
tion represent a more common type of disorder
(with a prevalence of one in 9,000–15,000), lead-
ing to fasting hypoglycemia of various degrees
extending to a life-threatening condition. These
disorders limit the production of ketone bodies
during fasting, so they mimic the hypoglycemic
hyperinsulinemic disorders in this regard and
deprive the brain of both glucose and ketone bod-
ies for energy. The conditions are generally the
result of defects in the acyl-CoA system, with
short-, medium-, or long-chain fatty acids
involved in the various classifications. The most
common type is medium-chain acyl-CoA dehy-
drogenase (MCAD) mutations (#201450 ACYL-
CoA DEHYDROGENASE, MEDIUM-CHAIN,
DEFICIENCY OF at 1p31). Hypoglycemia
315
develops in the newborn or infant period, but
sometimes patients are well until several years of
age. Hypoglycemia occurs after prolonged fasts
that may accompany intercurrent illnesses.
Hyperammonemia, hyperuricemia, acidosis, and
elevations of liver enzymes are rarely seen in this
condition. This may present in a similar manner to
Reye syndrome, with disordered mentation and
absent ketone bodies during hypoglycemia.
Plasma carnitine is low, and an increased ratio of
esterified carnitine to free carnitine is found.
Medium-chain dicarboxylic acid should be mea-
sured in the urine to make the specific diagnosis.
Diagnosis can be accomplished through determi-
nation of the types of acyl-carnitine present by
mass spectroscopy, a technique now becoming
more frequently used in newborn screening pro-
grams. Life-threatening emergencies may be
avoided by early diagnosis. The treatment usually
is elimination of fasting for more than a few hours,
6–8 h in infants and 10–12 h for older children.
Primary carnitine deficiency (#212140 ICD+
CARNITINE DEFICIENCY, SYSTEMIC
PRIMARY; CDSP) is due to a loss-of-function
mutation in the solute carrier family 22 (organic
cation transporter), member 5 gene (SLC22A5)
and is inherited in an autosomal recessive pattern.
The form presenting in infancy leads to acute
hypoglycemic episodes without ketosis, while if
the onset is in childhood after 1 year, there is pro-
gressive cardiomyopathy and muscle weakness.
There are numerous other features if the condition
is not treated involving the heart (cardiomegaly,
hypertrophic cardiomyopathy, congestive heart
failure), the liver (hepatomegaly, steatosis), and
the musculoskeletal system (muscle weakness)
which include the following: hypotonia; muscle
biopsy shows lipid deposition; lethargy associated
with hypoglycemia; encephalopathy associated
with hypoglycemia; coma associated with hypo-
glycemia; Reye syndrome; delay in gross motor
development due to weakness; fatty infiltration of
heart muscle; abnormal liver enzymes; increased
urinary carnitine; decreased carnitine in serum,
muscle, heart, and liver; impaired carnitine uptake
in muscle, heart, kidney, fibroblasts, and lympho-
cytes; hyperammonemia; no dicarboxylic acid-
uria; and no ketosis.
316
Hypoglycemia in Older Children
A diagnosis of hypoglycemia in older children
rests upon a higher threshold than during the first
24 h after birth. Hypoglycemia may be diagnosed
at a plasma blood sugar lower than 55 mg/dL
(blood sugar less than 47 mg/dL). However, for
the purposes of treatment, the goal should be
plasma sugar greater than 70 mg/dL (blood sugar
greater than 60 mg/dL).
Some of the same conditions noted under
hypoglycemia of the newborn may be diagnosed
as causes of hypoglycemia in later life. Some of
the conditions described below can present in
newborn in a relatively subtle fashion so that the
diagnosis is initially missed and only diagnosed
later in life as the severity of the hypoglycemia is
noted. The time period between feedings length-
ens with age, leading to more opportunities for
fasting hypoglycemia to present, and the onset of
common illnesses that decrease feeding fre-
quency likewise can precipitate a hypoglycemic
episode. There is however a change in the preva-
lence of the disorders with advancing age. For
example, hyperinsulinism of infancy occurs at a
younger age, while GSD, other than type 1 GSD,
becomes more frequently diagnosed at an older
age, and beta cell adenomas replace most types
of familial hyperinsulinemic hypoglycemia in the
differential diagnosis as children become older.
In all age groups, obtaining the critical sample is
of great importance in the differential diagnosis.
Hyperinsulinism
Hyperinsulinemic hypoglycemia of infancy is
described above. Some patients will present later
in life although they have a congenital defect.
Some will actually have experienced hypoglyce-
mia to an extent which causes brain damage
before the diagnosis is made.
Hyperinsulinism will be more likely the result
of a β-cell adenoma after the newborn period
than of a congenital condition, especially after
age 3 years. This rare but serious condition may
be difficult to diagnose by imaging techniques. It
may be found as one of the manifestations of
MEN type I (Wermer syndrome) (see Chap. 10).
Rapid gastric emptying resulting from the
dumping syndrome after Nissen fundoplication
12 Hypoglycemia
may lead to a sharp increase in serum glucose,
causing release of insulin that subsequently
causes hypoglycemia, but patients will have a
history of GI surgery as an indication of this con-
dition; this occurs more often if the G-tube infu-
sion is administered in boluses rather than
continuously. A dumping syndrome constellation
may be found with the increasing use of gastric
bypass surgery in adolescents with extreme obe-
sity. Dietary measures may be used such as corn-
starch bars which are used in children with
diabetes to slow digestion and maintain blood
sugar. These conditions may be successfully
treated with somatostatin agonists (e.g., octreo-
tide) to suppress insulin secretion or by an alpha
glucosidase inhibitor (acarbose).
Delayed insulin secretion is reported in rare
patients who ultimately develop type 1 diabetes
mellitus. In contrast, “reactive hypoglycemia” is
all too often diagnosed in children who have
unusual behavior or sensations attributed to low
serum glucose but without confirmatory mea-
sured glucose values; sometimes parents pressure
the clinician to make the diagnosis because they
think that they have hypoglycemia themselves
(without laboratory evidence) or because they
have read the latest popular book on the subject.
Insulin resistance can occur because of con-
genital defects or because of acquired conditions
including obesity and polycystic ovarian syn-
drome. While the body is generally resistant to
the extremely high levels of insulin which occur
in insulin resistance, continued secretion of insu-
lin or decreased clearance of insulin from the cir-
culation as blood sugar is falling leads to
hypoglycemia in some patients. Diagnosis will
be made with a prolonged, 5-h, glucose tolerance
test with measurement of glucose and insulin
with each blood sample; accurate results require
that the child has been on a high carbohydrate
diet for at least 3 days before the test. Symptoms
the child may feel are observed and recorded to
see if these symptoms chronologically relate to
any low glucose values detected. If the symptoms
can be reversed with glucose administration, the
condition is more definite. This is the application
of Whipple’s triad.
Congenital hyperinsulinism due to mutations
in the insulin receptor (INSR) can present with a
Hypoglycemia
variety of physical features. The child is charac-
teristically small for gestational age and has
acanthosis nigricans as a manifestation of insulin
resistance. The Donohue syndrome is one exam-
ple of congenital hyperinsulinism (#246200
ICD+ DONOHUE SYNDROME) leading to
postprandial or fasting hypoglycemia. The
patients present with a phenotype of large ears
and “elfin” features leading to the name lepre-
chaunism. Most affected patients die in infancy,
but if they survive, they may develop Leydig cell
hyperplasia, cystic ovaries, and hepatic fibrosis.
Pancreatic beta cell hyperplasia is characteristic.
The Rabson–Mendenhall syndrome (#262190
ICD+ PINEAL HYPERPLASIA, INSULIN-
RESISTANT DIABETES MELLITUS, AND
SOMATIC ABNORMALITIES) combines fast-
ing hypoglycemia with postprandial hyperglyce-
mia and ultimately insulin-resistant diabetes
mellitus as well as an enlarged pineal gland.
Abnormal course facies are found, and enlarged
clitoris or penis and pineal hypertrophy are
reported possibly with precocious puberty. Type
A insulin resistance (#610549 ICD+ DIABETES
MELLITUS, INSULIN-RESISTANT, WITH
ACANTHOSIS NIGRICANS) leads to increased
growth and virilization as well as polycystic ova-
ries. Reactive hypoglycemia has been described
in this condition.
Munchausen by proxy or in the USA more
specifically, “factitious disorder imposed on
another,” involves an adult caregiver who deliber-
ately makes a child sick. In one possible presenta-
tion of this condition, a caregiver injects insulin into
a child, which leads to unexplained hypoglycemia
and/or seizure. Measurement of elevated serum
insulin during hypoglycemia with low C-peptide
indicates that the insulin is from exogenous
sources rather than the patient’s own pancreas
(C-peptide secretion only occurs with endoge-
nous insulin secretion). Absence of hypoglyce-
mia during scrupulous observation of the child,
while eliminating the opportunity for anyone to
administer exogenous insulin, supports this diag-
nosis. Alternatively, a child being given sulfonyl-
ureas will have elevated insulin secretion and
C-peptide secretion and will appear to have an
insulin-secreting condition.
317
Hypoglycemia with Ketosis
Ketotic hypoglycemia classically is seen in a
thin (often male) child of age 18 months to
5 years, who has had a longer-than-average
overnight fast (sometimes this is called the
Saturday night–Sunday morning syndrome
because of the purported late return of parents at
night, causing a delay in breakfast the following
morning due to late awakening and therefore a
prolonged fast for the child). Alternatively, it
may present while the child has an intercurrent
illness that decreases dietary intake. The condi-
tion appears to result from a defect in mobiliza-
tion of alanine for gluconeogenesis or from
decreased muscle mass, as muscles are the major
source of alanine. Affected patients with ketotic
hypoglycemia not secondary to another diagno-
sis tolerate an 18-h fast more poorly than do
typical children. This condition may be a more
exaggerated intolerance to fasting than normal,
as all of the features of ketotic hypoglycemia
will develop in a normal child who is fasted for
an extended period. Normal children can tolerate
a fast lasting for 15 h by 1 year of age, 24 h by
1 year, and 36 h by 5 years without becoming
hypoglycemic.
The term ketotic hypoglycemia is quite gen-
eral and includes many causes of hypoglycemia,
including GH or GH resistance (see Chaps. 3 and
5), but does not include conditions involving
increased insulin secretion. Adrenal failure,
ACTH deficiency, and inappropriately rapid
weaning after post-glucocorticoid therapy all
may lead to hypoglycemia (see Chap. 10). After
reviewing the history of the affected child, it
may become clear that the child had neonatal
hypoglycemia, which apparently resolved after
regular feedings were started. However, the child
may still maintain a tendency toward hypoglyce-
mia after prolonged fasting, which could be a
clue to a deficiency of GH or ACTH. Maple syrup
urine disease is a quite severe defect in the release
of alanine from muscle, owing to a defect in
branched-chain amino acid catabolism (see ear-
lier), which may be first diagnosed after infancy.
Thus all ketotic hypoglycemia is not a benign
variant, and some forms require medical rather
than only dietary management.
318
Several types of GSD cause hypoglycemia,
but hepatomegaly and poor growth might first
bring affected infants to evaluation. GSD type 1
(*232200 GLYCOGEN STORAGE DISEASE I
at 17q21) is the result of a hepatic defect in
glucose-6-phosphatase, the enzyme that converts
glucose-6-phosphate to glucose in the last stage
of gluconeogenesis and glycogenolysis. The con-
dition is divided into types 1A and 1B (#232220
GLYCOGEN STORAGE DISEASE IB at
11q23). Deficiency of this enzyme thus elimi-
nates both processes, which leads not only to
hypoglycemia but also to lactic acidosis and
ketosis, hyperuricemia, hypophosphatemia, and
abnormal platelet adhesiveness. The counterreg-
ulatory hormones rise during hypoglycemia,
including glucagon, growth hormone, and corti-
sol, produce hypertriglyceridemia and hypercho-
lesterolemia, often severe. Presentation of
hypoglycemia with lactic acidosis and ketosis
may occur in the neonatal period or years later
after the development of characteristic growth
failure and hepatomegaly that is the result of gly-
cogen and lipid deposition in the liver, although
liver function usually remains normal. The spleen
is not enlarged, but the kidneys are enlarged
because of glycogen deposition, and renal failure
may develop, but this is not invariable. Type 1B
GSD combines all the features characteristic of
type 1A and, in addition, features neutropenia
and infections that follow (oral and anal lesions
and chronic enteritis). Diagnosis is made by the
administration of glucagon after meal (the fed
glucagon stimulation test) which in a normal
state raises glucose, but with these conditions, no
rise in glucose occurs but lactate rises. Genetic
diagnoses are available. Treatment is frequent or
constant administration of glucose, overnight by
nasogastric tube, as well as the ingestion of
cornstarch to prolong the increase in blood
sugar. The aim is to remedy the lack of available
glucose and to suppress the counterregulatory
hormone secretion that is responsible for many of
the complications.
GSD type 3 (*232400 GLYCOGEN
STORAGE DISEASE III at 1p21) is the result of
a deficiency in amylo-1,6-glucosidase, the deb-
rancher enzyme for glycogenolysis; this is a
milder condition than GSD type 1. Because gluco-
12 Hypoglycemia
neogenesis is functional, the hypoglycemia is less
severe, and many of the complications of GSD 1
are absent. Hepatomegaly does, however, occur
because of increased glycogen stores. Frequent
feeding of glucose or cornstarch is the appropriate
therapy for most of these cases. However, some
children have absence of amylo-1,6-glucosidase
in the muscle as well and have weakness or even
cardiac failure because of this defect; creatinine
kinase is elevated in this condition.
GSD type 6 (*232700 GLYCOGEN
STORAGE DISEASE VI at 14q21-q22) results
from a phosphorylase deficiency and GSD type 9
(#306000 GLYCOGEN STORAGE DISEASE
IXa1; GSD9A1) from liver phosphorylase kinase
(PHK) deficiency; both conditions leading to
diminished glycogen breakdown to free glucose.
Affected patients have hepatomegaly and possi-
bly hypoglycemia, but these are usually milder
conditions than GSD type 1.
GSD 0 (#240600 GLYCOGEN STORAGE
DISEASE 0 at 12p12.2) is a rare condition caused
by hepatic glycogen synthetase deficiency, limit-
ing glycogen synthesis in the liver but not in the
muscle. Thus ketosis and hypoglycemia occur
with fasting, but elevated glucose is found after
eating. The liver is of normal size. This condition
resembles ketotic hypoglycemia in many aspects
but has been reported in only a few individuals.
If a glycogen storage disease is strongly sus-
pected, liver biopsy might be performed for
definitive diagnosis.
Hereditary fructose intolerance is discussed
above.
Other causes of hypoglycemia include mal-
nutrition due to GI disease, diarrhea, or starva-
tion, all of which lead to ketotic hypoglycemia.
Alcohol ingestion or even significant skin expo-
sure to alcohol can interfere with gluconeogen-
esis since ethanol is metabolized by alcohol
dehydrogenase in the liver to oxidize to acetal-
dehyde and acetate which requires nicotinamide
adenine dinucleotide (NAD) as a cofactor limit-
ing gluconeogenesis; this limits the abundance
of NAD causing reduced gluconeogenesis and
acidosis. Ackee fruit ingestion (Jamaican vom-
iting disease), Reye syndrome, or other causes
of hepatic failure and the use of drugs that cause
hypoglycemia as a side effect, such as aspirin or
Hypoglycemia
oral hypoglycemic agents, also may precipitate
hypoglycemia. Propranolol or other β-blocking
agents can cause hypoglycemia, especially after
a fast (e.g., when these agents are used to aug-
ment the response to a GH-provocative test after
an overnight fast), and will also block adrener-
gic symptoms of hypoglycemia. Anorexia ner-
vosa and excessive exercise (not only in an
HHF7) can cause hypoglycemia. As noted ear-
lier, many adults complain of what they call
hypoglycemia and often attribute symptoms in
their children to the same condition. Symptoms
generally occur a few hours after a meal, but
when careful blood glucose measurements are
obtained, low values are rarely found and even
more rarely match the onset of symptoms.
Although a 5-h glucose tolerance test with mea-
surement of glucose and insulin might be con-
sidered, in 25 % of individuals, the blood sugar
decreases during an oral glucose tolerance test
(OGTT) as 10 % of normal adults experience a
blood sugar below 50 mg/dL on the third to fifth
hours of a glucose tolerance test, more if CH2O
loading is not provided for 3 days beforehand,
thus falsely suggesting the diagnosis of hypo-
glycemia. Most experts do not support the exis-
tence of the condition known as reactive
hypoglycemia. Of course, it is harmless to mod-
ify the diet of most children to eat breakfast,
avoid concentrated sugar, and consider a midaft-
ernoon or a midmorning snack (again not exces-
sively sweetened or excessively caloric in this
epidemic of obesity), a measure often suggested
by those who support the diagnosis of reactive
hypoglycemia. If frequent feedings are advised
to avoid factitious hypoglycemia, excessive
caloric intake and obesity might be the result. If
in doubt, rather than supporting an inappropriate
diagnosis, one might discuss with the family that
since simple measures of dietary manipulation
relieve the symptoms, just follow them without
labeling the child. Further, it is important to real-
ize that autonomic dysfunction leading to pos-
tural hypotension and other symptoms may be
the true cause of the symptoms labeled as reac-
tive hypoglycemia. Adequate hydration is usu-
ally suggested as the best treatment for those
conditions.
319
Diagnosis of Hypoglycemia
Medical history for a neonate must include the con-
dition of the mother and whether she had any type
of diabetes or intravenous glucose treatment. The
onset of hypoglycemia in the fasted or fed state is
of importance at any age: Infants will gently have
hypoglycemia in a fasted state (although there are
exceptions as noted above), while older children
may have hypoglycemia in either situation.
Questioning as to whether hypoglycemic agents
are available in the house must be carried out.
A history of prior gastric surgery will also direct
the diagnosis.
Physical examination will aim to discover the
physical findings of an infant of a diabetic mother,
small-for-gestational-age infant, and findings of
Beckwith–Wiedemann syndrome. Midline
defects and microphallus in boys (penis less than
2 cm in length) are indicative of hypopituitarism.
A large liver is compatible with GSD.
Diagnosis of hypoglycemia must involve
measuring blood sugar rather than just assuming
that it is low or relying on a finger-stick glucom-
eter measurement (Fig. 12.3). The method of
measurement of glucose deserves attention due
to several practical issues. As stated above,
,plasma glucose is 10–15 % lower than blood
glucose. Blood samples for a metabolic panel (in
any red top tube) that sit around at room tem-
perature for hours without fluoride in the tube
will have a decrease in blood sugar of 5–7 mg/dL
per hour, and the resulting difference over 2 h
can blur the distinction between normal blood
sugar and hypoglycemia. Tubes containing fluo-
ride (grey top), which stops the metabolism of
glucose by blood cells and allows the storage of
blood for hours without reducing the glucose
concentration, are the best method of collection.
Finger-stick methods of assessing blood glucose
are available by glucometer, but these must be
considered as a guide and not definitive glucose
results. Inadequate sampling or measurements or
out-of-date strips will affect the results.
Glucometers are designed for the management
of diabetes, in whom elevated values are fre-
quent, so they do not reliably measure lower val-
ues. A blood or plasma glucose reading at a
320 12 Hypoglycemia

Diagnostic Schema From Results of Critical Sample

Hypoglycemia

reduced blood sugar (generally less than 50 mg/dl)

historical features such as history of diabetes mellitus under treatment?

No Yes

obtain critical blood sample with glucose, insulin, GH, cortisol, ketone, lactate, pyruvate and other tests consider excess insulin or oral hypoglycemic agents
listed on Table 11.2 IF THIS SAMPLING IS POSSIBLE WITHOUT ENDANGERING THE PATIENT

high for glucose value (FFA will be low suppressed as expected in hypoglycemia (FFA will be high
and elevation of glucose occurs after insulin and no elevation of glucose occurs after glucagon)
glucagon)
ketones
positive negative
c peptide normal
high low low GH elevated deficient FFA transport
ACYL-CoA DEHYDROGENASE,
neonatal period after
GH deficiency cortisol MEDIUM CHAIN AD DEFICIENCY
neonatal
period low normally elevated
infant of ACTH or cortisol deficiency lactate and alanine
diabetic mother exogenous insulin administration low high
Munchausen's by proxy
liver size defect in transient hypoglycemia of infancy
enlarged normal gluconeogenesis
persistent hyperinsulinemic hypoglycemia
islet cell adenoma abnormal glycogenolysis "ketotic early onset after
Beckwith Weideman syndrome phosphorylase deficiency hypoglycemia" onset neonatal/infant period
MEN type I debrancher enzyme deficency
sulfonurea exposure Glycogen storage disease types 1,3,0
fructose 1-6 diphosphatase deficiency alcohol or salicylate intake
hereditary fructose intolerance or Reye syndrome
PEPCK
PC
galactosemia
Glycogen storage disease types 1,3,9,0 eg., glucose 6 phosphase deficiency

Fig. 12.3 Flow chart of the diagnosis of hypoglycemia

licensed laboratory must confirm low blood glu-
cose values below 55–60 mg/dL. Nonetheless, if
used appropriately, with reagents or test strips
that are not outdated, glucometers can be a use-
ful adjunct to diagnosis and follow-up for ade-
quacy of treatment, as long as true laboratory
values are used as well. Methods measuring
reducing substances, such as Clinitest, will mea-
sure other substances, such as galactose, whereas
those using a glucose oxidase technique will be
specific for glucose.
The Critical Sample
When a child has hypoglycemia, a blood sample
should be obtained immediately so that determi-
nations crucial to the diagnosis can be ordered;
this is the “critical” blood sample (Table 12.2) that
is the mainstay of diagnosis. Thus, if BS is
<55 mg/dL, obtain blood for glucose (a true labo-
ratory blood glucose rather than a glucometer
value), insulin (a value of insulin/glucose greater
than 0.3 suggests hyperinsulinism if serum glu-
cose is less than 55 mg/dL, but small increases in
insulin secretion below the detection limit of the
laboratory are still compatible with hyperinsulin-
ism), serum ketones (see below about ketosis),
growth hormone and cortisol (both should rise
with hypoglycemia), lactate (elevation suggests a
defect in hepatic gluconeogenesis such as glucose
6-phosphatase or fructose 1,6-diphosphatase defi-
ciency if ketones are absent or in older children
suggests ethanol ingestion), pyruvate (low pyru-
vate suggests difficulty in mobilizing substrate for
gluconeogenesis) determinations, C peptide (to
separate endogenous versus exogenous insulin
sources), ammonia (elevated in certain hyperinsu-
linemic conditions and along with elevated trans-
aminases in fatty acid oxidation defects), amino
acids, free and bound carnitine (to determine if
there is a defect in mitochondrial beta oxidation),
and, if blood volume allows, free fatty acid (which
are elevated in fatty acid oxidation defects such as
medium-chain AD deficiency but decreased with
increased insulin secretion) determinations, and
extra serum should be frozen for future determi-
nations in case another area of diagnostic inquiry
seems more likely after the initial results are back
(such as IGF-1, IGF-2 which may be produced by
tumors, IGF BP1 which is regulated by insulin
rather than growth hormone and is decreased with
excessive insulin secretion.) Urine should be
obtained for determination of ketonuria at the
same time. The presence of ketone bodies in the
urine or blood at the time of hypoglycemia will
reflect the insulin secretory state; ketotic hypogly-
cemia is virtually incompatible with hyperinsulin-
Hypoglycemia
Table 12.2 The critical blood sample
To be obtained if BS is <50 mg/dL
Glucose
Insulin
Ketones
Growth hormone
Cortisol
Lactate
Alanine
Pyruvate
Also urine organic acids
If possible:
Free fatty acids
C peptide
IGF-1
IGF-11
IGF BP1
Ammonia
Amino acids
Free and bound carnitine
Save as much serum/plasma as possible for future
determinations
IGF insulin-like growth factor
ism but occurs in GH or cortisol deficiency, but
nonketotic hypoglycemia increases the likelihood
that insulin may be the etiologic agent in the con-
dition. Ketosis-accompanying hypoglycemia will
also occur in ketotic hypoglycemia or GSD type
III. Hypoglycemia is diagnosed only if a true
serum/plasma sugar is low or if a glucometer indi-
cates a low blood sugar that is later confirmed
when the laboratory determination returns; if only
symptoms that suggest hypoglycemia are
reported, a diagnosis of true hypoglycemia is not
appropriate until confirmed.
The aim of management of a hypoglycemic
child is to prevent the recurrence of hypoglyce-
mia; if the critical blood sample is missed on pre-
sentation, it may require long periods of
observation before a recurrence allows the
diagnostician to have another chance at diagnosis
with a critical blood sample during another hypo-
glycemic event. Remember that the critical sam-
ple must be processed quickly so that glucose is
not decreased by the metabolic activity of blood
cells in a collection tube in case the blood was
collected without fluoride additives; if the glu-
cose determination is separated into a grey top
321
(or other tube with fluoride) tube initially to stop
metabolism of glucose or if the blood cells are
separated from plasma or serum right away, the
glucose value is more accurate.
After the critical blood sample is drawn, glu-
cose is given to increase the blood sugar; the hypo-
glycemic episode should not be dangerously
prolonged just to obtain blood for the diagnostic
sample, of course. Anticipating the possibility that
hypoglycemia may occur in a predictable situation
will lessen the effort later required for the diagno-
sis and treatment of the condition. Thus patients
with stressful deliveries, with prematurity, or with
IUGR or, conversely, infants with large body size
suspected to be the offspring of a mother with dia-
betes mellitus should have blood sugar monitoring
at frequent intervals during the first 24 h after birth.
In neonates, fasting hypoglycemia most often
occurs, but rarely postprandial hypoglycemia
presents. In older patients, the pattern of hypo-
glycemia is of extreme importance in the differ-
ential diagnosis. Fasting hypoglycemia more
likely will indicate a defect in glucose production
or release, such as a defect in gluconeogenesis or
a GSD, whereas postprandial (or true reactive)
hypoglycemia suggests a hyperinsulinemic state;
overlap occurs, however, as hyperinsulinism will
cause fasting hypoglycemia as well (Table 12.1).
If the critical initial sample is not collected, sev-
eral steps should follow. If the hypoglycemia is not
so severe and urgent, frequent measurement of
blood glucose is made during a 24-h period, before
each meal, and at 1, 2, and 3 h after one or more
meals and also measured in the middle of the
night; this might be called a “nothing tolerance
test.” If the blood sugar is decreased below 55 mg/
dL in any of these samples, as reflected by a finger-
stick glucose method by glucometer, the full set of
critical value tests noted earlier is performed along
with a true laboratory glucose determination, if
possible, before glucose is given to increase the
blood sugar concentration. The critical sample
including an insulin determination should be mea-
sured contemporaneously with a low glucose con-
centration, not sequentially.
If no episode of spontaneous hypoglycemia
occurs, an observed fast should be performed
after a high-carbohydrate diet is given for 3 days
before the beginning of the fast. If the child’s
322
carbohydrate stores are not repleted by the high-
carbohydrate diet, specious hypoglycemia may
occur. The fast should start after a usual over-
night period of sleep (if the child usually goes
without food at night), so that 10–12 h of the rou-
tine fast starts at 7:00–8:00 a.m., a time when the
full hospital staff should be present to handle
potential complications. Finger-stick glucose
determinations by glucometer are made every 2 h
until a tendency is noted for a decrease in glu-
cose. All urine samples are analyzed for ketone
bodies as in ketotic hypoglycemia the appearance
of ketonuria will precede hypoglycemia. At the
time that glucose decreases on the glucometer, a
true laboratory glucose measurement is made at
the same time as the finger-stick sample and the
critical sample obtained. If the fast precipitates
no decrease in glucose by 5:00 p.m. (after
20–22 h), the test can be continued for a full 24 h
in an infant or even 36 h in the older child if ade-
quate staff is available to monitor the child safely.
If the glucose concentration decreases to less
than 55 mg/dL, glucagon is given at a dose of
0.02–0.03 mg/kg to a maximum of 1 mg, and
after 10 min, blood glucose, insulin, lactate, and
pyruvate are measured to see if the child has ade-
quate glycogen stores or if there is an abnormal-
ity in mobilization of glucose. Glucagon should
not, however, be given if hepatomegaly is pres-
ent, as it might worsen metabolic acidosis caused
by a possible gluconeogenic defect. The fast is
usually stopped by 24 (or 36) as hours, and if no
hypoglycemia is demonstrated, it is at least
apparent that the child can tolerate a 24-h fast at
home; such a long fast is not, of course, recom-
mended, but a good margin of error exists if the
child is fed on a reasonable schedule. It should be
clear that if the initial critical sample is obtained
appropriately, this complex diagnostic plan might
often be eliminated altogether.
Various tolerance tests are used in the differ-
ential diagnosis of hypoglycemia. The glucagon
tolerance test (0.3 mg/kg body weight (maximum
dose 500 μg) administration of glucagon intrave-
nously or intramuscularly, with blood glucose,
FFAs, ketones, insulin, and GH determinations
obtained at 0, 5, 15, and 15 min thereafter for 2 h)
determines whether glycogen can be broken
down to supply glucose; in the fed or fasting state,
12 Hypoglycemia
no increase in glucose will be seen in GSD type 1
(glucose-6-phosphatase deficiency), whereas in
ketotic hypoglycemia or GSD type 3, a normal
response will occur in the fed state and a poor
response after a fast. The fructose tolerance test is
no longer recommended to evaluate hereditary
fructose intolerance or 1,6-diphosphatase defi-
ciency as genetic tests are now available.
Some tests cannot be recommended without
prior experience. They are the leucine (orally, dis-
solved in a slurry of CO2-free water administered
through a stomach tube, at 150 mg/kg, or intrave-
nously, 75 mg/kg, and blood obtained for glucose
and insulin at 5, 10, 20, 30, 45, 60, 90, and 120 min
or every 10 min for an hour, respectively) or the
tolbutamide tolerance test (20–30 mg/kg up to 1 g
intravenously and blood sampled at 5, 10, 20, 30,
45, 60, 90, and 120 min) to determine if insulin
secretion is inappropriately high. The tests may be
dangerous, as severe hypoglycemia may be pre-
cipitated by these insulin secretagogues.
The glucose tolerance test (GTT) is rarely
indicated, but if performed to rule out reactive
hypoglycemia, it is important to carry out several
important procedures to ensure that false results
do not confuse the issue: 3 days of high-
carbohydrate diet must be ingested or the response
to the oral glucose load will be falsely abnormal,
even if the patient is normal (this type of prepara-
tion also is important for the other tolerance tests
listed earlier); an insulin determination should
accompany each glucose measurement; the test
should extend for 5 h to look for late hypoglyce-
mia that would be missed on a shorter test; and
the dose of glucose is 1.75 g/kg, as a 20 % solu-
tion. The symptoms manifested by the patient
should be recorded during the test so that any low
blood sugar determinations can be matched with
symptoms of hypoglycemia, making an organic
abnormality more likely. Just as important as
determining that a low blood sugar is associated
with the symptoms is the elimination of the
symptoms with an increase in blood sugar.
Treatment of Hypoglycemia
Treatment of hypoglycemia may be a short-term
initial treatment to correct the specific event or
Hypoglycemia 323

long-term treatment to ensure continuation of a Table 12.3 Treatment of hypoglycemia

normal state: prolonged treatment is best aimed Acute
to achieve a blood sugar value greater than If conscious Oral sugar, cake
60 mg/dL at all times and normal values of frosting or glucose gel,
70–120 mg/dL at least most of the time (Table 12.3; 4 oz juice
see Chap. 15 for discussion of emergency treat- If unconscious i.v. Dextrose bolus,
25 % at 1 mL/kg
ment of hypoglycemia). The initial treatment of
If diabetic or if no i.m. Glucagon, 30 μg/kg
hypoglycemia must be the administration of glu- evidence of GSD and to a maximum of 1 mg
cose sufficient to bring the blood glucose to ade- hepatomegaly
quate levels and to return neurologic function to Chronic
normal but not excessive glucose to cause severely Ketotic hypoglycemia Frequent feedings
increased osmolality. In a child who is only GSD 1 Frequent feedings and
moderately symptomatic, oral glucose is adequate; cornstarch
table sugar, honey (only if the child is older than Hereditary fructose Avoidance of fructose
intolerance
1 year or better yet 2 years and not at risk for infant
Galactosemia Avoidance of galactose
botulism), or jelly can be administered orally or to
Hyperinsulinism Diazoxide, octreotide,
the child’s buccal mucosa if the child is too disori- or pancreatectomy
ented to swallow. For more severe hypoglycemia, Carnitine deficiency Carnitine
intravenous glucose is necessary, but if dextrose MCAD Avoid fasting
in higher concentration (dextrose vials are sup- Long-chain fatty acid Medium-chain fatty
plied as 50 %) is administered, a risk of hyperos- abnormalities acids
molality exists, especially in infants and neonates. GSD glycogen storage disease, MCAD medium-chain
Intravenous D10W is preferable to more concen- acyl CoA dehydrogenase
trated preparation in a dose of 2 mL/kg which is
0.2 g/kg of dextrose over 1 min. Alternatively must be present in the infusion to avoid hypona-
glucose given in 25 % dextrose as a bolus of tremia developing as the hypoglycemia is
1 mL/kg is reasonable. Once the blood sugar repaired. It is useful to calculate the amount of
increases, the child should be observed longer; if glucose in terms of milligrams per kilogram per
the sugar again decreases, a bolus of 5 mL per minute to determine the severity of the hypogly-
kilogram of 10 % dextrose is administered, and if cemia. If 6–8 mg per kilogram per minute of dex-
necessary, an infusion of dextrose, 5–10 %, trose will support the child’s glucose,
should be started; appropriate sodium chloride hyperinsulinism is virtually eliminated.

( Dextrose Concentration in g/dL expressed as an integer) ´ ( mL/hour)

Glucose Infusion Rate (or GIR) in mg/kg/minute =
( Weight in kg ) ´ (6))

If more than 10–12 mg/kg/min of glucose or more
is required repeatedly, the child has severe hypo-
glycemia, most likely due to hyperinsulinism.
Abrupt discontinuation of dextrose support may
lead to rebound hypoglycemia after the normal
increase in insulin secretion caused by dextrose
administration. This rebound condition should not
be confused with bona fide hyperinsulinism. As
transient hypoglycemia resolves, weaning off i.v.
dextrose is followed by frequent oral administra-
tion of glucose-containing substances, as the child
can tolerate under careful observation.
The treatment of several specific diagnoses was
presented earlier. Dietary management is possi-
ble in some conditions.
Frequent carbohydrate feeding is the manage-
ment for uncomplicated ketotic hypoglycemia.
GSD type 1, a gluconeogenic defect, is treated
with frequent carbohydrate feedings, but overnight
blood glucose is supported by uncooked cornstarch
preparation or continuous nasogastric feedings.
Hereditary fructose intolerance or fructose-
1,6-bisphosphatase deficiency mandates avoid-
ance of fructose and sorbitol.
324
Galactosemia mandates avoidance of galac-
tose ingestion.
Fatty oxidation defects, including MCAD,
may respond to a low-fat diet and avoidance of
fasting that might cause lipid breakdown.
In defects of long-chain fatty acid metabolism,
medium-chain triglycerides are administered, and
carbohydrates or glucose given during fasting or
stress that might lead to lipid breakdown.
Carnitine is administered for primary or sec-
ondary carnitine deficiency.
Other measures are used for the management of
severe hypoglycemia. Diazoxide, a benzothiadia-
zine hypotensive agent, in doses of 5–20 mg/kg/
day divided into a dose every 6 h, will suppress
insulin secretion in some cases of hyperinsulinism,
as noted earlier, but will not usually be effective in
β-cell adenomas. A lack of response to diazoxide is
not diagnostic but does suggest the presence of a
β-cell adenoma or one of the hyperinsulinemic
states discussed earlier that will require surgical
removal. Diazoxide has several possible side
effects including hirsutism, water and sodium
retention (may be opposed by the use of hydrochlo-
rothiazide which does not itself cause hypoglyce-
mia mild hyperuricemia, advanced bone age, and
decreased immunoglobulin G and neutrophil num-
bers. Octreotide is a synthetic long-acting soma-
tostatin analogue that will suppress insulin
secretion in some cases. Dosing starts at 5 μg/kg
subcutaneously, titrating the dose to 40 μg/kg/24 h,
divided into six doses per day. Tachyphylaxis is a
possible side effect, as is steatorrhea.
Pancreatectomy is recommended in cases of
hyperinsulinism resistant to diet or medications
and should not be delayed if no other treatment
successfully supports the blood sugar.
Glucocorticoids are also used to increase blood
sugar but should not be used for long-term replace-
ment, except in cases of cortisol or ACTH defi-
ciency, and then only in replacement doses. GH
therapy is offered in cases of GH deficiency. The
most important part of therapy is the rapid institu-
tion of a treatment designed to increase blood
sugar and guard against severe and repetitive hypo-
glycemia and thereby to salvage mental function.
12 Hypoglycemia
Suggested Reading
1. Langdon DR, Stanley CA, Sperling MA. Chapter 21 -
Hypoglycemia in the toddler and child. In: Sperling
MA, editor. Pediatric endocrinology. 4th ed.
Philadelphia, PA: Elsevier; 2014. p. 920–955.e921.
2. De León DD, Thornton PS, Stanley CA, Sperling
MA. Chapter 6 - Hypoglycemia in the newborn and
infant. In: Sperling MA, editor. Pediatric endocrinol-
ogy. 4th ed. Philadelphia, PA: Elsevier; 2014. p. 157–
185.e152.
3. Ly TT, Maahs DM, Rewers A, Dunger D, Oduwole A,
Jones TW. Assessment and management of
hypoglycemia in children and adolescents with diabe-
tes. Pediatr Diabetes. 2014;15 Suppl 20:180–92.
4. Park E, Pearson NM, Pillow MT, Toledo A. Neonatal
endocrine emergencies: a primer for the emergency
physician. Emerg Med Clin North Am. 2014;32(2):
421–35.
5. Tin W. Defining neonatal hypoglycaemia: a continuing
debate. Semin Fetal Neonatal Med. 2014;19(1):27–32.
6. Snider KE, Becker S, Boyajian L, Shyng SL,
MacMullen C, Hughes N, Ganapathy K, Bhatti T,
Stanley CA, Ganguly A. Genotype and phenotype
correlations in 417 children with congenital hyperin-
sulinism. J Clin Endocrinol Metab. 2013;98(2):
E355–63.
7. Lang TF, Hussain K. Pediatric Hypoglycemia. Adv
Clin Chem. 2014;63:211–45.
8. UpToDate Neonatal hypoglycemia Author See Wai
Chan, MD, MPH
9. Sunehag A and Haymond MW. Approach to hypogly-
cemia in infants and children. http://www.uptodate.
com/contents/approach-to-hypoglycemia-in-infantsand-
children.
10. Sunehag A and Haymond MW. Causes of hypoglyce-
mia in infants and children. http://www.uptodate.
com/contents/causes-of-hypoglycemia-in-infantsand-
children.
11. Rozance PJ. Pathogenesis, screening, and diagnosis
of neonatal hypoglycemia. http://www.uptodate.com/
contents/pathogenesis-screening-and-diagnosisof-
neonatal-hypoglycemia.
12. Rozance PJ. Management and outcome of neonatal
hypoglycemia. http://www.uptodate.com/contents/
management-and-outcome-of-neonatal-hypoglycemia.
13. Sunehag A and Haymond MW. Pathogenesis, clinical
features, and diagnosis of persistent hyperinsulinemic
hypoglycemia of infancy. http://www.uptodate. com/
contents/pathogenesis-clinical-features-anddiagnosis-
of-persistent-hyperinsulinemic-hypoglycemia-of-
infancy.
14. Sunehag A and Haymond MW. Treatment and com-
plications of persistent hyperinsulinemic hypoglyce-
mia of infancy. http://www.uptodate.com/contents/
treatment-and-complications-of-persistent-hyperin-
sulinemic-hypoglycemia-of-infancy.
 Obesity
13

young years, American Indians and Hispanics in

Definition the first years have prevalence of obesity close to
18 %. In 2011–2012, 17.7 % of 6- to 11-year-olds
Obesity is the most prevalent nutritional disorder of and 20.5 % of 12- to 19-year-olds were obese.
children in the USA, a remarkable change from the Obesity is higher if the parents have not com-
prominent place of malnutrition due to deficient pleted college in most groups. Waist circumfer-
caloric intake in childhood in the past. Surgeons ence serves as a reflection of visceral adiposity,
General have designated childhood obesity as an and waist circumference has increased faster than
epidemic in the USA. A threefold increase in the BMI over the last decade in children but has also
prevalence of a body mass index (BMI) at or plateaued since 2004.
greater than the 95th percentile for age and gender Overweight is defined as a BMI ≥85th for
in children aged 6–11 years occurred between the ­percentile age and gender and less than 95th per-
National Health and Nutrition Evaluation II (1976– centile. A child less than 2 years of age is obese
1980) and 2004. This trend in most groups has lev- if the weight for recumbent length is greater than
eled off since 2004. At ages 2–19, the prevalence is or equal to the 97.7th percentile of WHO growth
about 17 % (or 12.7 million). standards (charts on CDC website).
Obesity is a striking example of health dispari- A new classification of severe extreme obesity
ties. The prevalence is higher among Hispanic applies to children whose BMI is at or above the
(22.4 %) and non-Hispanic black youth (20.2 %) 99th percentile due to the more severe morbidity
than non-Hispanic white youth (14.1 %) and non-­ and mortality found with this classification. More
Hispanic Asian youth (8.6 %). Obesity in the recently, guidelines recommended the diagnosis of
Asian population in the ages between 5 and 19 severe obesity if a BMI is above 120 % of the 95th
years has increased to 127 % between 1992 and percentile, a BMI is +2.33 standard deviations
2001 which is surprising in a population notable above the mean, or a BMI is greater than 35 kg/m2
for its previous leanness. Obesity increases with (Fig. 13.1). Unfortunately, the classification of
age, but young children are already demonstrating severe obesity is the most rapidly growing classifi-
obesity with a high prevalence: in 2003–2004, the cation in childhood and adolescence and presently
prevalence of obesity in 2–5-year-olds was includes 4–6 % of the population at these ages. We
13.9 % (the prevalence dropped to 8.4 % in 2011– do not use the term “morbid obesity.” We speak of
2012, but there is controversy if this unexpected healthy habits in diet and activity in communica-
drop in the face of no change in other age groups tion with the family and patient rather than the term
across the same time is correct and long lasting or obesity, although “obesity” and “overweight” are
whether it is a short-term variation). Already at used in this chapter as medical terms.

© Springer International Publishing Switzerland 2016 325

D.M. Styne, Pediatric Endocrinology, DOI 10.1007/978-3-319-18371-8_13
326 13 Obesity

2 to 20 years: Boys NAME

Body mass index-for-age percentiles RECORD #

Date Age Weight Stature BMI* Comments

BMI

35

34

33

32

31

30
95
29

BMI 28
90
27 27
26 85 26
25 25
75
24 24

23 23
50
22 22

21 21
25
20 20
10
19 19
5
18 18

17 17

16 16

15 15

14 14

13 13

12 12

kg/m
2
AGE (YEARS) kg/m
2

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Published May 30, 2000 (modified 10/16/00).

SOURCE: Developed by the National Center for Health Statistics in collaboration with
the National Center for Chronic Disease Prevention and Health Promotion (2000).
http://www.cdc.gov/growthcharts

Fig. 13.1 (a) Body mass index-for-age percentiles for girls aged 2–20 years (from http://www.cdc.gov/growthcharts/).
(b) Body mass index-for-­age percentiles for boys aged 2–20 years (from http://www.cdc.gov/growthcharts/)
Definition 327

2 to 20 years: Girls NAME

Body mass index-for-age percentiles RECORD #

Date Age Weight Stature BMI* Comments

BMI

35

97
34

33

32

95
31

30

29

BMI 28
90

27 27
26 85 26
25 25

24 75 24

23 23

22 22
50
21 21

20 20
25
19 19
10
18 18
3
17 17

16 16

15 15

14 14

13 13

12 12

kg/m
2
AGE (YEARS) kg/m
2

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Published May 30, 2000 (modified 10/16/00).

SOURCE: Developed by the National Center for Health Statistics in collaboration with
the National Center for Chronic Disease Prevention and Health Promotion (2000).
http://www.cdc.gov/growthcharts

Fig. 13.1 (continued)
328
The disparities in obesity will translate into the
disparities in morbidity and mortality in adult life.
The economic cost of the epidemic is the sum of
medical care costs, loss of productivity, and of
course the tragedy of chronic disease in an indi-
vidual; the Brookings Institute estimates that if all
the 12.7 million obese US youth became obese
adults the lifetime cost will exceed $1.1 trillion.
Obesity is even affecting national security since
anywhere between 25 and 75 % of youth applying
to the various uniformed services are refused
because they are not in optimal health.
It is of course a mathematical impossibility
for 17 % of a population to be above the 95th
percentile as only 5 % should be above that level.
Presently the CDC is setting normal values for
weight in children by the use of statistics from
decades predating the obesity epidemic. The
CDC weight charts are based upon more than
three-decade-old data although the CDC height
charts derive from more recent data.
Areas of the world previously suffering from
malnutrition are now also manifesting an increas-
ing prevalence of obesity, with the introduction
of a Western (mainly US style) diet and lifestyle.
Type 2 diabetes mellitus is likewise widespread
in these same regions of the world and children
figure prominently in these trends. The preva-
lence of diabetes is predicted to increase by 51 %
worldwide by 2030, with the majority of that
increase occurring in the developing world.
The definition of obesity is an excess of adi-
pose tissue, not just an increase in weight. The
adverse metabolic and psychological effects of
this adipose tissue are of paramount importance,
but the psychological effects of obesity are sub-
stantial as well. Obesity can be expressed as the
percentage of the body consisting of fat. Many
techniques of measurement of body composition
are available: measurement of subscapular skin
thickness (requires special training and is diffi-
cult to reproduce in a clinical office), underwater
weighing (requires a tank of water and other
rarely available materials), bioelectric imped-
ance (easy to perform but sometimes difficult to
standardize at a child’s age and not accurate in
the extreme cases of obesity), dual X-ray absorp-
tiometry (DXA, which is accurate but expen-
sive), or computed tomography (CT) scans
13 Obesity
(highly accurate but expensive and requires
exposure to radiation). To simplify the issue,
anthropologic methods are used in the office set-
ting to express percentage of body fat. In the past,
percentile of weight for age may have been used
to reflect the percentage of body fat, but this is
not helpful in childhood, as it does not take into
consideration the height of the child. Percentile
weight for height is a better indication, but does
not adequately express the relative amount of fat
in the individual, because increased muscle tis-
sue will incorrectly increase the weight for
height. BMI was adopted as the international
standard of adiposity as it is considered to reflect
the percentage of body weight that is fat gener-
ally reliably, and BMI correlates with morbidity
and mortality in adults. BMI is known to be more
accurate in adults than in children, but it is now
the standard of clinical practice in children as
well. BMI should be calculated and interpreted
for every child at every office visit. Electronic
medical record systems often calculate the BMI
automatically, eliminating the need for manual
calculation. If EMR does not have this capability,
there are numerous websites to easily input
height and weight and find the BMI percentage
after input of age and gender as well. Below is
the equation for the calculation of BMI:
BMI in kg / m 2 = weight in kg / height in meters 2
or
703 ´ Weight in pounds ¸ ( Height in inches )
2
The percentile of BMI for age changes by
age in children, so no simple number defines
obesity at all ages, as in adults where a BMI >25
is overweight, >30 is obese, etc. A chart of BMI
versus age from the Centers for Disease Control
(CDC) should be used to evaluate all children
(Fig. 13.1).
Absolute fat mass is relatively constant in
both males and females until just prior to
puberty. During puberty, girls begin gaining sig-
nificantly more fat mass than males and by the
end of puberty have about 5–6 kg more absolute
fat mass, representing an average gain of 1.14 kg
per year.
Etiology of Obesity
The Basic Approach to Childhood Obesity
Prevention
Always Primary
BMI > 85th percentile?
History
Risk factors?
Symptoms of
comorbidities?
Physical
Comorbidities?
Laboratory studies based upon
findings and BMI %
Determine need for weight maintenance or weight loss
Evaluate stage of readiness to change
Use motivational interviewing to
determine appropriate targets for
change behavior
Maintenance!
Fig. 13.2  The Basic Approach to Childhood Obesity
Males do not significantly change their abso-
lute fat mass during their pubertal years. In males,
the net effect of these changes is a decreasing
percent body fat throughout puberty to an adult
value of approximately 13 %. In females, the net
effect of a plateau in fat-free mass and increased
fat mass results in an increasing percent body fat
which averages 25 % in adulthood.
Adults have increased morbidity and mortality
when their BMI increases to more than 25 (clas-
sified as overweight), which is the 85th percentile
of BMI for adults. By extension, a BMI for chil-
dren that is at or above the 85th percentile for age
and gender is considered overweight, whereas at
or above the 95th percentile BMI for age, a child
is considered to be obese (Figs. 13.1 and 13.2).
Normally, an increase in the percentage of
body fat is noted at mid-childhood, called the
329
adiposity rebound. The adiposity rebound is
noted on the BMI chart as an upward curve fol-
lowing the early childhood nadir at about 5–6
years, earlier in girls. An early adiposity rebound
before 4 years or younger increases the likeli-
hood of the development of obesity and meta-
bolic syndrome.
Clinically, a child who is just above the 85th
percentile may not appear to have excessive adi-
pose tissue at casual glance, while in those above
the 95th percentile, excessive adipose tissue
should be more obvious. It is of interest to check
the BMI of the child who appears to be “thin” in
the office setting. In the absence of disease, you
might find that the BMI is actually at the 50th
percentile; we are so used to seeing overweight
and children with obesity in America that an
average child may seem abnormally thin.
Etiology of Obesity
 enetic Factors and the CNS Control
G
of Appetite
Strong genetic and environmental factors affect
obesity, and both factors play a role in the obesity
epidemic. Thus obesity should not simply be
considered a condition of overeating and
­underexercising, although both activities play a
role in the etiology, and both activities must be
changed to control obesity; it is inappropriate and
certainly not clinically helpful to consider obesity
as a simple manner of lack of an individual’s self-­
control. Between 40 and 80 % of the variance in
BMI is determined by genetic factors; greater sim-
ilarity is found in the BMIs of monozygotic twins
than in those of dizygotic twins, and the BMI of an
adopted child relates far better to the BMI of the
biologic parents than to those of the adoptive par-
ents with whom the child was raised.
In spite of this, the loci that are identified to
affect BMI to date have not shown major effects.
Epigenetics refers to the modification of gene
expression by environmental influences, and this
process is certainly demonstrated in the origins
of obesity; when pregnant women have experi-
enced starvation, for example, during famine in
330
World War II, their offspring often have an
increased tendency toward obesity later in life.
Gestational effects are important as a macroso-
mic infant has a higher likelihood of becoming
an obese 10-year-old with insulin resistance.
Further, smaller-birth-­weight infants owing to a
variety of conditions have a tendency to develop
insulin resistance later in life and obesity. Parental
effects may be seen in the case of a child with one
obese parent who has a fivefold increase in the
likelihood of becoming an obese adult, and a
child with two obese parents who has a 12-fold
increased risk.
Single-gene defects account for less than 7 %
of severe obesity but can exert remarkable effects
(see below). The study of individuals with single-­
gene mutations and animal models of obesity has
led to increasing knowledge about the regulation
of appetite.
Several hormones from distal sites act on the
CNS to regulate appetite. Leptin is a peptide hor-
mone produced by adipocytes, and serum levels
of leptin directly correlate with the amount of
adipocytes. Leptin crosses the blood–brain bar-
rier and attaches to a receptor on the melanocor-
tin cells in the arcuate nucleus of the ventromedial
hypothalamus to decrease food intake in an
anorexigenic effect.
Loss-of-function mutations in the leptin gene
or the leptin receptor gene lead to early-onset
progressive obesity and extreme hyperphagia.
Leptin deficiency also eliminates the onset and
progression of puberty. However, when leptin is
administered to leptin-deficient subjects, appetite
decreases to normal levels, weight loss proceeds
while activity levels increase, and if they are of
appropriate age, puberty progresses.
Although the rare mutation in genes for leptin
or for leptin receptors in human beings (only a
few cases of loss-of-function mutations are
reported) leads to early-onset, severe obesity.
Leptin levels are high in most obese human
beings. Because appetite in obese individuals is
not suppressed by these values of leptin, a rela-
tive leptin resistance occurs in human obesity.
Leptin decreases when adipose stores decrease,
and low levels appear to act as a signal to the
organism to increase caloric intake.
13 Obesity
Parenthetically, the anti-inflammatory cyto-
kine adiponectin decreases in obesity with insu-
lin resistance and rises with a healthy weight.
Adiponectin can be seen as an inverse barometer
of the metabolic consequences of obesity.
Ghrelin is a peptide that is released from the
stomach, colon, and small intestine to act as a
signal to the hypothalamus to increase feeding
(orexigenic). Ghrelin acts as a growth hormone
secretagogue through the pituitary gland growth
hormone secretagogue receptor (GHS-R) in the
arcuate nucleus.
Peptide YY (PYY) and glucagon-like peptide
1 (GLP-1) are produced from the intestinal L
cells (or enteroendocrine cell). The PYY crosses
the blood–brain barrier to promote satiety. GLP-1
has numerous effects including inhibition of gas-
tric emptying, promotion of insulin secretion
after eating, and promotion of satiety. The effect
of GLP-1 is utilized in medications known as
incretins in the treatment of type 2 DM, while
inhibition of the enzymes that metabolize GLP-1,
dipeptidyl peptidase-4, or DPP-4 enhances
endogenous GLP-1.
Insulin plays an important role in the metabo-
lism of carbohydrate protein and fat as described
in Chaps. 11 and 12.
Other hormones are produced in the CNS to
regulate eating behavior. Melanocortin cells pro-
duce proopiomelanocortin (POMC) which in
turn is cleaved into various peptides depending
upon the tissue where processing occurs. One
product of POMC is the melanocyte-stimulating
hormone (MSH) which is an anorexigenic hor-
mone (POMC is further described in Chap. 10).
MSH interacts with the MC4 receptor (MC4R)
to decrease appetite and the MC3 receptors
(MC3R) to increase feeding efficiency. Leptin
decreases the production of two factors which
increase caloric intake: (1) agouti-related protein
(AGRP) which blocks the MSH stimulation of
the MC4R and MC3R receptors leading to
decreased satiety and (2) neuropeptide Y which
strongly stimulates appetite. The melanin-con-
centrating hormone (MCH), not to be confused
with the MSH, stimulates food intake.
Monogenetic loss-of-function mutations in
each of these steps have been described in rare
Etiology of Obesity
individuals. A more common single-gene muta-
tion due to early-onset obesity is a loss-of-­function
mutation of the MC4R gene which is found in
2–5 % of the heaviest individuals in several dif-
ferent geographic locations. Patients have pro-
gressive obesity, hyperinsulinism and insulin
resistance, increased lean mass, increased growth,
and advanced bone age. Remarkably, some vari-
ants of the MC4R gene are protective of develop-
ing obesity.
Mutations affecting the cleaving of POMC
lead to early-onset and progressive obesity and
reddish hair due to a lack of MSH and secondary
adrenal insufficiency due to the lack of ACTH.
Prohormone convertase-1 (PC-1) deficiency is a
cause of hypogonadotropic hypogonadism, but
since a mutation affects other preprohormones,
patients are also likely to demonstrate ACTH
deficiency, elevated levels of proinsulin, GI dis-
tress, and obesity. The WAGR syndrome
(#194072 ICD + WILMS TUMOR, ANIRIDIA,
GENITOURINARY ANOMALIES, AND
MENTAL RETARDATION SYNDROME;
WAGR) combines numerous congenital defects
and in some patients, obesity related to decreased
brain-derived neurotrophic factor; thus patients
may have a combination of aniridia, hypospadias,
cryptorchidism, uterine malformations, nephro-
blastoma (Wilms tumor), renal failure, and devel-
opmental delay.
Low dopamine levels, involved in pleasure
sensations, increase appetite, and this pathway is
targeted for the development of medications for
the treatment of obesity which will raise dopami-
nergic effects. Norepinephrine (NE) and sero-
tonin exert suppressive effects on appetite,
which led to the development of medications that
amplify or mimic the action of these two neu-
rotransmitters. Selective serotonin reuptake
inhibitors used in psychiatry have a similar effect.
Phentermine is an NE reuptake inhibitor that is
still in use, but phenylpropanolamine was with-
drawn from the market when it was implicated in
hypertension, stroke, and myocardial infarction.
The widespread use of fenfluramine, a 5-HT
uptake inhibitor, and of dexfenfluramine was
halted because of the increased risk of cardiac
valve abnormalities that accompanied the use of
331
these drugs (a combination of fenfluramine with
phentermine was called fen-phen). Sibutramine,
a serotonin and norepinephrine reuptake inhibi-
tor, has been withdrawn by the FDA due to con-
cern over cardiac side effects.
Endocannabinoids (eCBs) are derivatives of
arachidonic acid (AA) and resemble prostaglan-
dins in structure; these molecules play a role in
reproduction, growth and development, and learn-
ing. The endocannabinoid system not only affects
emotions but also regulates appetite. The eCBs also
affect energy homeostasis and eating behavior by
increasing the palatability of sweet and fatty tastes.
eCBs are elevated during fasting and decrease with
satiety. Antagonists of the eCB system are being
investigated for treatment of obesity.
The vagus nerve senses the fullness of the
stomach and duodenum and acts as a satiety sig-
nal to the central nervous system.
Thus a simplified account of the CNS control
of appetite includes the following steps: (a)
Leptin stimulates production of POMC, (b)
which can be cleaved by enzyme action to MSH,
which in turn (c) interacts with melanocortin 4
receptors (MCR4) to reduce food intake; (d) neu-
ropeptide Y (NPY) is a potent orexigenic (agent
to increase feeding), and (e) AGRP, produced in
the same neuron as NPY, competes with MSH for
the MCR4 and thereby also increases feeding.
Damage to one area of the hypothalamus may
affect these pathways to increase appetite, or
alternatively, damage to other locations of the
CNS will decrease appetite.
Dietary Intake
The treatment of obesity in adults brought about
the development of an exceptional number of
specialty diets. Liquid diets, restrictive diets that
eliminate certain nutrients, and truly bizarre
approaches are provided in the multibillion-dollar
diet book industry. In spite of proliferation of
such plans, the general consensus of available
research is that calories are responsible for the
dietary component of obesity, and it is calories
that should be limited to prevent the development
of obesity or to treat, as long as restriction is not
332
so severe as to interfere with normal growth.
Even a healthy diet can contain too many calories
due to second and third servings. The clinician
should approach the family whenever possible
with the help of a dietitian by analyzing what
they are eating and finding what they might
accept as changes which would benefit the child.
The clinician may have less experience with eth-
nic diets. Nonetheless every ethnic diet, while
sometimes having a tendency toward increased
calories, often can be manipulated to increase
consumption of lower caloric foods. Asian diets
may have excessive rice which increases caloric
intake, but there are also vegetables which can be
stir-fried or, even better, steamed to be part of a
healthy diet. Spanish diets may contain foods
with high carbohydrate content or heavily fried
foods but also contain vegetables and fruit (even
cactus) which can be introduced to the diet in a
healthy manner. The complexities of these issues
point out why the well-trained dietitians familiar
with pediatrics become so important.
Simple approaches to modify diet can be pro-
vided however. Excessive sugar intake is acknowl-
edged as a major threat to health and can be
reduced as a first step. The World Health
Organization recommends decreasing total calo-
ries from added sugars to less than 5 %. The
American Heart Association recommends that no
more than half of a person’s discretionary calorie
allowance (daily “empty calorie” allowance)
should be spent on added sugars. Any type of
sugar-sweetened beverage should be eliminated
from the child’s diet immediately. High-fructose
corn syrup contains a mixture of glucose and fruc-
tose similar to the composition of table sugar
although the formulation does change between
beverages and between companies. High-fructose
corn syrup is now used in a wide variety of foods.
But the endocrine system does not respond to
fructose as it responds to glucose. Fructose inges-
tion does not cause elevated insulin levels or leptin
levels as does glucose, and some authorities feel
that fructose is a bona fide toxin to many meta-
bolic processes. All fructose found in fruit comes
in a package combined with healthy vitamins and
fiber, but when the fruit is mashed into pulp, the
liquid becomes a beverage with a very high calo-
rie content equal to sugar-sweetened beverages.
13 Obesity
Thus elimination of juice from the diet is helpful,
but this suggestion surprises some parents.
Water is the appropriate beverage of older
children as long as there is appropriate intake of
milk to allow calcium and vitamin D intake.
Portion sizes have grown in the USA over the
last decades and so have the plate sizes. It is
important to evaluate the size of portions pro-
vided to a child and emphasize that eating sec-
onds and thirds are certainly not healthy habits
although many children demand these extra serv-
ings. If the child remains hungry after an appro-
priate serving, low- or no-calorie snacks can be
offered such as carrots, celery, or low-calorie
cheese, but a whole new dinner plate full of food
is not appropriate. The MyPlate model will assist
in determining appropriate portion sizes of meal
components (Fig. 13.3).
There is no question that a change in diet in a
child can lead to conflict in some homes which
must be avoided. At times, one parent may be on
board with an appropriate change in diet only to
find that the other refuses to give up his or her
soft drinks or chips or other highly caloric foods
that they think they deserve after working a hard
day. This presents quite a problem with no easy
answer except to suggest that the offending food
substances need to be kept somewhere else
other than the house in which the child lives so
that the stores of these foods will not be available.
A problem that is virtually impossible to address
is the divorced family when one parent is able to
control calories and then the other parent cares
for the child for the weekend and treats him or
her to anything he or she wants. Grandparents
must participate in the approach to weight loss if
they care for the children. Children may go to
their grandparents’ houses before school, and
some may ingest two breakfasts before school
starts: one breakfast at the grandparents’ house
and another breakfast at school. It is clear that the
food environment is a complex issue and innova-
tive solutions are required.
It is virtually impossible to “exercise off a bad
diet.” One children’s meal at a popular fast-food
restaurant might contain 750 calories (some con-
tain over 1,400 calories). The amount of activity
necessary to exercise off that single child’s meal
will exceed 3 h on an exercise bicycle, an
Etiology of Obesity
Fig. 13.3 (a) The MyPlate plate model developed by the
United States Department of Agriculture as a placemat.
(b) The MyPlate model with examples of food and appro-
e­ xpenditure that most providers are unlikely to
accomplish and certainly most children will not.
Eating out frequently is a reliable source of
excess calories; in restaurants, the cost of the
labor is higher than the cost of the food, so man-
agers give larger servings to try to satisfy the cus-
tomer that the meal is worth the cost. Eating out
usually involves increased salt intake, and pro-
cessed foods are common. It is best to counsel the
family to eat at home and to follow healthy habits
they have learned in the clinic.
The type of carbohydrate ingested has effects
on the rise in glucose and insulin in the postpran-
dial state, and these characteristics have been
used to advantage in the development of a
healthy diet. Glycemic index refers to the area
under the curve of glucose values by time after
ingesting a meal of carbohydrates. A high glyce-
mic index meal with carbohydrates that can be
quickly broken down such as bread and rice leads
to a rapid rise in glucose which will trigger a
rapid and elevated rise in insulin which may pro-
333
priate portions as a wall chart. (c) The MyPlate model in
Spanish. Courtesy of Marilyn Townsend UC Davis with
permission
mote increased fat deposition, while a low glyce-
mic index meal such as beans or legumes will
produce a lower peak of glucose and therefore a
lower peak of insulin secretion. In some cases,
the preparation of a food such as potatoes will
influence the glycemic index complicating the
development of a low glycemic index diet; the
glycemic index of a baked potato is 85 and of a
boiled potato is 50. It is evidenced that the low
glycemic index leads to less weight gain in chil-
dren than a high glycemic index meal. The most
recent studies confirm that control of calories is
paramount regardless of glycemic index or load.
Indeed, the diet one can accept and follow is the
one that will exert effects.
There is much benefit from increasing fiber in
the diet of children and adults as present intake is
considerably lower than previous eras. A high-­
fiber diet leads to a lower rise in glucose in the
postprandial state and thereby a lower rise in insu-
lin and a lower degree of lipogenesis. A high-­fiber
diet will slow absorption of triglycerides and
334 13 Obesity

Fig. 13.3 (continued)
Etiology of Obesity 335

Fig. 13.3 (continued)
336
improve fermentation of triglycerides in the lower
gut. In sum, the effect of a high-fiber diet is to
increase insulin sensitivity that will thereby tend to
improve lipid profiles. Fiber also will tend to pro-
mote satiety and tend to decrease caloric intake.
Energy Expenditure
An increase in fat tissue occurs because of
increased caloric intake (by ingestion of food and
drink) or decreased total energy expenditure (TEE).
TEE consists of the sum of (a) basal metabolic rate
(BMR) (resting energy expenditure (REE) is simi-
lar to BMR but is measured in the postabsorptive
state, while basal metabolic rate is measured after
fasting), (b) the thermic effect of feeding, and (c)
nonresting energy expenditure. Nonresting energy
expenditure is composed of exercise and non-exer-
cise activity thermogenesis (NEAT, e.g., fidgeting).
No consistent pattern of decreased basal metabolic
rate accounts for the difference between children
with obesity and those who are not obese in most,
but not all, situations. African-American girls
appear to have a lower basal energy expenditure
than that of girls of other ethnic groups, however.
The balance of caloric intake and expenditure
is remarkably sensitive. An increase of only
36 kcal of intake per day, equivalent to a “pat” of
butter, a change in dietary intake below the limit
of detection in most clinical studies, leads to
13,140 calories per year, while 1 lb of fat equals
3,500 calories of intake; all things being equal, the
metabolic processes vary so much that this equiv-
alency is not strictly accurate but can be used for
illustrative purposes. Obesity is often the result of
a subtle but long-term increase in caloric intake.
Gut Microbiome
There are estimates that an individual has 10–100
times as many microbes in their gut as there are
cells in the body and that the microbiome contains
100 or 1,000 times as many genes as there are
genes in our human genome. The gut microbiome
influences food utilization and regulates aspects
of the intestinal barrier and intestinal immune
13 Obesity
function. The microbiome in turn is influenced by
dietary composition and even exercise. Probiotics
are the beneficial bacteria which are found in fer-
mented foods like yogurt, kefir, cheese, sauer-
kraut, kimchee, and kombucha, among others.
Prebiotics which provide fuel for gut microbes are
the nondigestible carbohydrates found in plant
foods including fruits, vegetables, whole grains,
legumes, nuts, and seeds, among others.
There is evidence that maternal factors during
pregnancy likewise influence the development of
the infant’s microbiome. There is a difference in
the intestinal flora between children born by vag-
inal delivery and those by C-section. Breast milk
contains prebiotics and also probiotics which
introduce and support the beneficial bifidobacte-
ria in the infant’s gut.
There are correlational studies in human
beings showing a difference in the microbiome
in obese and lean children and adults. This,
added to experimental studies in animal models
that provide cause-and-effect data, suggests that
the microbiome may have real importance in the
obesity epidemic and that manipulation of the
microbiome with probiotics might be a future
therapy for obesity.
Although not related to gut flora, neutralizing
antibodies to adenovirus 36 are found in increased
prevalence in obese adults and children although
no cause-and-effect relationship to adenovirus
infection is proven in human beings.
Epigenetics
There is increasing evidence that epigenetics
affects the development of obesity in the child.
While genetic mutations involve changes in the
base sequence of DNA, epigenetics is a revers-
ible process that does not change the base pairs,
but instead, reversibility chemically modifies
DNA or the associated histones. This may occur
by methylation of DNA (addition of methyl
groups to DNA) or posttranslational modification
of histone proteins by methylation or acetylation.
These changes in DNA can progress through
mitotic cell division and can determine whether a
gene is expressed or not expressed at a given time
Etiology of Obesity
development. Epigenetic modification appears to
explain the phenomenon of the early origins of
adult disease often referred to as the Barker
hypothesis. Thus epigenetic modifications of the
fetus by the metabolic milieu of the mother lead
to changes in the metabolism of her child. In fact,
the modification in an ovum in the individual’s
grandmother (where all the mother’s ova are
formed) by changes in the grandmother’s endo-
crine milieu, according to increasing evidence,
can exert effects expressed in the grandchild.
Thus one- or two-generation effects can occur
from, for example, diabetes or obesity in a preg-
nant woman. Epigenetic effects are felt to be
responsible for aspects of obesity, type 2 diabe-
tes, and cardiovascular disease, just to name a
few conditions based in the early environment.
Epigenetic effects can occur because of overnu-
trition, undernutrition, or toxin exposure. There
is a U-shaped curve in which smaller-for-­
gestational-­ age infants (not necessarily classic
SGA weights) or heavier infants (not necessarily
extending into the macrosomic range) develop
insulin resistance and a tendency toward type 2
diabetes and obesity later in childhood and in
adulthood. However, the rate of growth in the
postnatal period also appears to cause epigenetic
modifications in metabolism. Maternal weight
gain also appears to influence the risk of develop-
ment of type 2 diabetes and metabolic syndrome
later in life. Animal data is stronger than human
data, but the diet of the mother, in terms of the
components of carbohydrate and lipid composi-
tion, may also affect metabolic programming of
the fetus. On the positive side, breast-feeding a
macrosomic infant has been shown to lower the
risk for diabetes. While epigenetic modification
can be shown to cause biochemical modifications
of DNA, some of the factors thought to be respon-
sible for epigenetic mechanisms may also be fac-
tors which influence gut biome development.
The Obesogenic Environment
Obesity develops in an individual with a suscepti-
ble genetic makeup who is exposed to an “obeso-
genic” environment, a term that includes a host of
337
environmental factors. The genetic makeup of the
human population cannot have changed over the
last 30 years sufficiently to cause the obesity epi-
demic. Thus environmental factors are considered
a major influence on obesity and are targeted as
modifiable influences. Environmental factors
account for changes in diet and activity which are
the proximate factors that lead to increased weight.
The environment of the home exerts a pro-
found effect. Television watching is an empiri-
cally proven factor in the development of obesity.
The more an individual watches television as an
adult or child, the higher likelihood of develop-
ing obesity. The reasons are not clear, but the
thousands of calories of fast food advertised per
hour during children’s television programs and
the lack of physical activity during the time that
the individual watches television are likely some
of the influences. Television sets are now found
in an increasing percentage of children’s bed-
rooms, and their very presence is associated with
increased obesity rates. Decreasing television
viewing has been linked in experimental studies
to maintaining a more stable BMI during child-
hood. There are other screens than television
screens in the child’s life, and there is evidence
that time spent viewing video games and comput-
ers is likewise linked to the development of obe-
sity. Some electronic games require physical
activity but have not been shown to be beneficial
in the treatment of obesity in all studies.
Electronic screens also affect sleep. It is well
established that obesity can be linked to obstruc-
tive sleep apnea (OSA) which will decrease
effective sleep (see below). But limitation or vari-
ation in sleep time can also change carbohydrate
metabolism, increasing insulin resistance.
Children living in disordered households and
noisy neighborhoods as well as those with elec-
tronic screens in their rooms may be the ones
with an increased tendency toward obesity due to
this factor. Reading on e-readers or surfing the
Web before bed disturbs sleep due to the tone of
the light, while reading paper books does not
have the same effect before going to sleep.
The microwave oven in the home has allowed
more children to be responsible for much of
their diet, and the foods that are characteristi-
338
cally microwaved tend to be highly caloric,
often highly salted processed foods. “Latchkey”
children are those coming home from school to
an empty house while their parents are working
one or more jobs. At home may be a ready sup-
ply of highly caloric foods and the television set
which when combined increase likelihood of
obesity.
The environment of the child extends further
than the home in which they live. Many disadvan-
taged youth live in communities in which it is
either truly dangerous to play outside or where
parents perceive there is a danger which leads the
parents to keep the child inside rather than allow-
ing outdoor play. Zip codes with the lowest
income frequently lack playground, parks, and
access to indoor gymnasiums as well. Schools are
often built on the cheapest real estate which often
are located miles from where children live, neces-
sitating a car or bus ride rather than a walk to
school, cutting down energy expenditure on
school days. There is also a tendency to build
schools without gymnasiums, replacing them
with multipurpose rooms which by definition are
used for various activities, some of which likely
cut down physical activity. Likewise in some
states, gym teachers must have special licenses,
eliminating volunteer teachers of other subjects
from leading activities that would increase the
child’s activity. Low-income neighborhoods fre-
quently lack grocery stores, and even if there are
small stores, they are often convenience stores
without fresh fruits and vegetables (food deserts).
Suburban neighborhoods may lack sidewalks to
allow safely walking to stores and schools even
when the distance makes it feasible. The obesity
epidemic in a very substantial manner is rooted in
socioeconomic problems and poor city planning
of the built environment.
There is increasing evidence that endocrine
disrupters exert significant effects on the develop-
ing fetus and child. Cell culture and animal exper-
iments implicate certain substances, but causal
effects in human beings cannot be proven yet.
There are correlations between urine excretion or
plasma levels of certain endocrine disruptors such
as bisphenol A (BPA) and the development of
obesity, but correlation is not yet causal.
13 Obesity
Endocrine Causes
Many parents blame imbalance of “hormones”
or common conditions like hypothyroidism for
obesity in their children and wish for an easy
therapy for these conditions. In truth, while in
exceptionally rare circumstances hypothyroid-
ism can cause weight gain which is treatable
with thyroid hormone, this is not the cause of the
obesity epidemic and not the treatment for the
vast majority of children. There are endocrine
conditions which can lead to an obese appear-
ance, and they cluster around problems of
growth in most cases. Pseudohypoparathyroidism
with Albright’s hereditary osteodystrophy and
Cushing syndrome combine short stature with a
chubby or overweight appearance. Most children
with standard (sometimes called “exogenous”)
obesity are taller than average, eliminating
almost all endocrine causes. Obese individuals
with taller stature have low response of GH
secretion after stimulation but nonetheless have
advancement of bone age and normal IGF-1 val-
ues, while bona fide growth hormone deficiency
presents with short stature, delayed bone age,
and a secondarily increased BMI due to the lack
of normal lipolytic effect of GH. Hyperinsulinism
could lead to tall stature but will be accompanied
by such severe hypoglycemia that it is not likely
to be missed. In Chaps. 5 and 9, Prader–Willi and
Bardet–Biedl syndromes are described which
combine short stature and obesity as well. It is
notable that ghrelin levels are higher in Prader–­
Willi syndrome than in children with similar val-
ues of BMI who do not have the syndrome.
Suffice it to say that obesity can precipitate endo-
crine disorders, but endocrine disorders did not
cause the obesity epidemic, and endocrine treat-
ments will not solve this problem.
Sophisticated parents will always request that
testing be performed for hypothyroidism, and a
provider may consider carrying out such tests,
but they are going to be extremely low yield.
Children’s serum TSH values tend to be higher
than adults, and children with obesity also tend to
have higher TSH values, but these do not indicate
hypothyroidism in the vast majority of individu-
als (see Chap. 6).
Comorbidities of Childhood and Adolescent Obesity
Hypothalamic obesity is seen in some individu-
als with damage to the ventral medial nucleus of
the central nervous system. It is most well known
following surgery for craniopharyngioma. The sit-
uation in which even with food restriction weight
may increase as the brain is incapable of respond-
ing to leptin signals and treatment of the patient’s
condition with virtual starvation is counterproduc-
tive. Treatment with somatostatin agonists to sup-
press insulin secretion has been helpful in some
patients in clinical studies but is not FDA approved.
Iatrogenic Causes
Antipsychotic Medication
It is well known that high doses of glucocorti-
coids can cause Cushing syndrome. Perhaps less
well known but clearly established is weight gain
with atypical (second generation) antipsychotic
and other types of psychiatric medication; 80 %
of children and teenagers taking atypical antipsy-
chotic medications gain weight often to a signifi-
cant degree leading to obesity. Examples of
medication ­fostering weight gain are clozapine,
olanzapine, quetiapine, divalproex, paroxetine,
doxepin, imipramine, nortriptyline, and mono-
amine oxidase inhibitors (MAOIs) such as Nardil
(phenelzine), Parnate (tranylcypromine), and
Marplan (isocarboxazid) which cause an
increased risk for type 2 diabetes in treated chil-
dren as well as a higher risk if the child is a girl
and if the treatment is given in the teenage years.
The psychiatric literature recommends withhold-
ing such treatment if alternative methods of ther-
apy are available and that if such treatment is
used, dietary recommendations be given with the
medication and screening for comorbidities of
obesity including type 2 diabetes be carried out.
Insulin
Insulin treatment of diabetes can cause weight
gain; some teenage girls with diabetes skip insulin
doses to counteract this tendency, sometimes with
tragic consequences. A healthy balanced diet with
reasonable carbohydrate intake requiring reason-
able insulin dosing is the best approach to avoid
this situation. There is considerable controversy
over the effect of elevated endogenous insulin on
339
the development of obesity, but there is no ques-
tion that obesity is an insulin resistance condition.
Antibiotics
Recent evidence reports an association of expo-
sure to broad-spectrum antibiotics in the first 2
years of life with an increase in BMI, especially in
boys. Narrow-­spectrum antibiotics did not seem to
exert the same effect. In many cases, the antibiot-
ics are used for viral infections where they were
not indicated, making such a relationship all the
more unfortunate. The etiology of this relationship
is not clear but may relate to a change in the gut
microbiome and overuse of antibiotics in children.
More research is needed to confirm this finding.
Central nervous system surgery
or injury
The hypothalamus controls appetite. Injury to the
hypothalamus by a tumor, treatment for a tumor or
by other trauma can cause insatiable appetite
known as hypothalamic obesity. Increased insulin
secretion is proposed as one cause for this situa-
tion and suppression of insulin with, eg., octreo-
tide has been used as a treatment modality.
 omorbidities of Childhood
C
and Adolescent Obesity
An excess of visceral fat that surrounds the
abdominal organs and ectopic fat in muscle, liver,
and other organs, rather than the more visible
subcutaneous adipose tissue, is related to many
of the metabolic derangements of obesity such as
insulin resistance and hyperlipidemia. Waist cir-
cumference reflects the amount of visceral fat
and is measured regularly in adults, and this will
likely become common practice in children as
well in the future as standards become more
available although accurate repeatable measure-
ments are difficult to achieve (standards are
found in Table 13.2). Increasing waist circumfer-
ence is related to insulin resistance, blood pres-
sure, lipid levels, and metabolic syndrome.
About 30 % of adult obesity has its origin in
childhood obesity. With the more severe and the
younger onset of obesity in a child and the
340
p­ resence of obesity in one or more of parents, the
likelihood of the child with obesity becoming an
obese adult increases. Tracking of obesity from
childhood into adulthood becomes more certain
as the child becomes older and comes closer to the
adult age group. Further, an adult who was obese
as a child has substantially more severe comor-
bidities of the obesity during the adult years. BP is
higher, and lipid profiles are more adverse in
adults who were overweight or obese as children.
For example, the Indian Health Service data
shows that the highest BMI values in childhood
lead to greater risk of early death in the adult.
Psychological Conditions
While there have been significant numbers of
studies on the psychological effects of obesity in
childhood, there are concerns that the samples
might not be representative of the population that
does not seek help or did not come to the clinic.
Nonetheless, obesity has been shown to decrease
quality of life and have a relationship to the
development of depression. Anorexia nervosa is
well known to be a weight-losing condition, but a
majority affected in some studies previously suf-
fered from obesity. Likewise in the natural h­ istory
of the condition, in an obese person who later
develops anorexia nervosa, symptoms of the con-
dition preceded the loss of weight, and the clini-
cian must have a high index of suspicion for
disordered eating behavior. It goes without say-
ing that the clinician treating a child with over-
weight or obesity must have extreme caution and
not adversely affect their psychological state:
sensitive and careful approaches to the child with
obesity have not been linked to the development
of anorexia nervosa or other eating disorders.
Individuals with preexisting psychological
conditions may be predisposed to developing
­ in adolescence. A recent consensus conference
obesity which might be particularly difficult to
treat. There are screening instruments for depres-
sion available. The Pediatric Symptom Checklist
is in the public domain (http://www.massgeneral.
org/psychiatry/services/psc_home.aspx) while
others are availavle for purchase. Children with
developmental delay are frequently seen with
obesity or overweight.
13 Obesity
Weightism is prevalent in society, and chil-
dren may be the brunt of it as young children are
already the target of teasing and ridicule when
overweight. Young children may even express
aspects of weightism as children younger than 10
years demonstrate preference for playmates with
a thinner body habitus. The economic well-being,
likelihood of advanced education, and likelihood
of marriage are decreased with obesity in some
studies.
Type 2 Diabetes
Type 2 diabetes mellitus was rarely seen in child-
hood and is rising in childhood but cannot be
considered as epidemic as it affects 1.7 per 1,000
children lessons. American Indians have a 2–40
times increase in prevalence with other ethnic
groups also having higher percentages compared
to Caucasians. Diagnosis of type 2 diabetes mel-
litus rests on particular blood sugar values (see
Chap. 11) and not on increased fasting insulin
concentrations (see Chap. 13).
 he Metabolic Syndrome and Insulin
T
Resistance
The obesity epidemic has caused pediatricians to
shift focus to diagnosis and treatment of many
conditions previously found only in adults. The
metabolic syndrome was previously found in
middle-aged adults, often in males, but now is
found in teenagers and even prepubertal children
with increasing frequency. The diagnosis of the
metabolic syndrome in adults does not directly
transfer to the metabolic syndrome in children
and adolescents and numerous publications have
different definitions of the metabolic syndrome
suggested coordinating approaches to the meta-
bolic syndrome in adolescence so that studies can
be compared in the future and that studies should
use the same definition. The International
Diabetes Federation suggested a new definition
of the metabolic syndrome at 10 years of age; for
over 16 years of age, an adult definition can be
used. For children between 10 and <16 years of
Comorbidities of Childhood and Adolescent Obesity 341

Table 13.1  Estimated value of waist circumference for percentile regression in nationally representative samples of
American children according to sex
Percentile for boys Percentile for girls
10th 25th 50th 75th 90th 10th 25th 50th 75th 90th
Intercept 39.7 41.3 43.0 43.6 44.0 40.7 41.7 43.2 44.7 46.1
Slope  1.7  1.9  2.0  2.6 3.4  1.6  1.7  2.0  2.4 3.1
Age (years)
2 43.2 45.0 47.1 48.8 50.8 43.8 45.0 47.1 49.5 52.2
3 44.9 46.9 49.1 51.3 54.2 45.4 46.7 49.1 51.9 55.3
4 46.6 48.7 51.1 53.9 57.6 46.9 48.4 51.1 54.3 58.3
5 48.4 50.6 53.2 56.4 61.0 48.5 50.1 53.0 56.7 61.4
6 50.1 52.4 55.2 59.0 64.4 50.1 51.8 55.0 59.1 64.4
7 51.8 54.3 57.2 61.5 67.8 51.6 53.5 56.9 61.5 67.5
8 53.5 56.1 59.3 64.1 71.2 53.2 55.2 58.9 63.9 70.5
9 55.3 58.0 61.3 66.6 74.6 54.8 56.9 60.8 66.3 73.6
10 57.0 59.8 63.3 69.2 78.0 56.3 58.6 62.8 68.7 76.6
11 58.7 61.7 65.4 71.7 81.4 57.9 60.3 64.8 71.1 79.7
12 60.5 63.5 67.4 74.3 84.8 59.5 62.0 66.7 73.5 82.7
13 62.2 65.4 69.5 76.8 88.2 61.0 63.7 68.7 75.9 85.8
14 63.9 67.2 71.5 79.4 91.6 62.6 65.4 70.6 78.3 88.8
15 65.6 69.1 73.5 81.9 95.0 64.2 67.1 72.6 80.7 91.9
16 67.4 70.9 75.6 84.5 98.4 65.7 68.8 74.6 83.1 94.9
17 69.1 72.8 77.6 87.0 101.8 67.3 70.5 76.5 85.5 98.0
18 70.8 74.6 79.6 89.6 105.2 68.9 72.2 78.5 87.9 101.0
Data from Fernández JR, Redden DT, Pietrobelli A, Allison DB. Waist circumference percentiles in nationally
representative samples of African-American, European-American, and Mexican-American children and adoles-
cents. J Pediatr. 2004 Oct;145(4):439–44, with permission

age, the metabolic syndrome is diagnosed by a
waist ­circumference ≥90th percentile or adult
cutoff if lower, triglycerides ≥150 mg/dL, high-
density lipoproteins (HDL) <40 mg/dL, elevated
blood pressure over the 95th percentile for gen-
der age and height (use standards presented in
Table 13.3 or systolic ≥130/diastolic ≥85 mmHg),
and fasting blood sugar ≥100 mg/dL or known
type 2 diabetes.
Waist circumference percentile is part of the
diagnosis, but charts for waist circumference are
not readily available; they are provided in this
publication as Table 13.1. Thus, a clinician might
use a high BMI for a child or teenager, over the
95th percentile, hypertension, elevated triglycerides
with low HDL cholesterol, and prediabetes or true
type 2 diabetes for a diagnosis of metabolic syn-
drome. No definition for the metabolic syndrome is
provided for children under 6 years of age, but the
astute clinician will note who seems to be heading
in the direction of the metabolic syndrome and
institute anticipatory guidance for the parents.
The basis of the metabolic syndrome is insulin
resistance usually caused by obesity and predom-
inantly visceral adiposity. Thus increased BMI
and increased waist circumference are suggested
as basis for the diagnosis. Fasting lipid studies
demonstrate low HDL cholesterol and elevated
triglycerides. Glucose intolerance and type 2 dia-
betes are frequently manifestations of the meta-
bolic syndrome. While the basis of the metabolic
syndrome appears to involve insulin resistance,
single measurements of basal insulin in a child
are of little utility in the diagnosis of the meta-
bolic syndrome. The gold standard evaluation for
the metabolic syndrome is the euglycemic clamp
which is beyond the scope of any clinical office
encounter. Insulin sensitivity decreases normally
during puberty, and the metabolic syndrome
often becomes manifest during this age range.
Elevated basal insulin levels are frequently found
in obesity because obesity is an insulin-resistant
state. However, elevated ­ insulin levels do not
indicate that the child has or will get type 2 dia-
342
betes, just that there is insulin resistance, which is
expected in obesity. Thus the measurement of
insulin is not usually used in the definition of the
metabolic syndrome.
Insulin resistance in obesity and metabolic
syndrome appears to be selective as some organs
are more resistant to insulin than others. The
liver is resistant to the effects of insulin on
­carbohydrate metabolism such as the inhibition
of gluconeogenesis which leads to glucose intol-
erance. Further, the characteristic insulin effect
of inhibition of lipolysis fails, leading to elevated
circulating triglycerides. The metabolic
­syndrome is characterized by ectopic fat deposi-
tion, and fat may be found in the liver, pancreas,
omentum, myocytes, and visceral organs, and
ectopic fat deposition is related to dyslipidemia.
The ratio of visceral to subcutaneous fat is
directly related to insulin resistance.
Insulin resistance normally increases at
puberty, and this is likely the reason that T2DM
appears usually after puberty. Further, Caucasians
are normally more insulin sensitive than African
Americans, Hispanic Americans, Asians, and
American Indians, and this is why the latter
groups have the highest prevalence of T2DM.
Increased cortisol can foster visceral
adiposity, and obese individuals have decreased
11-β-hydroxysteroid dehydrogenase-1 (11b2HSD1)
which converts the active moiety cortisol to the
inactive-form cortisone. Thus the increased
­cortisol effect may promote the metabolic syn-
drome. While stress in adults which leads to
increased cortisol secretion is a factor to also pro-
mote the metabolic syndrome, this association is
not established in children.
The metabolic syndrome is accompanied by
high levels of insulin. Even though the body is
resistant to insulin in terms of carbohydrate
metabolism which leads to glucose intolerance,
elevated insulin can produce many other comor-
bidities. For example, elevated insulin levels can
interact with IGF-1 receptors to stimulate growth
of cells, increasing the risk of various types of
cancers later in life.
The metabolic syndrome is a condition of
increased inflammation as is obesity itself. Thus
inflammatory cytokines are elevated, but in the
clinic, the most easily measurable indication of
13 Obesity
the inflammatory state will be in elevation of
C-reactive protein (CRP) measured in sensitive
assays; IL6 rises as well in obesity in the meta-
bolic syndrome. Cytokine levels are not part of
the definition of the metabolic syndrome, and
analyses are not carried out in most clinical situ-
ations, but it is important to consider inflamma-
tion as a component of the metabolic syndrome
in childhood to explain why it can be so damag-
ing to cardiovascular health later in life. Further,
obesity is a state of elevated reactive oxygen
species which may arise in part from the effects
of the inflammatory cytokines. Reactive oxygen
species cause damage to DNA and cellular func-
tion. The sum of these activities is long-lasting
changes in health.
Polycystic Ovarian Syndrome
Polycystic ovarian syndrome or PCOS is the
most common reproductive problem of women
and often starts in the adolescent years. It is char-
acterized by irregular or absent menses and
increased prevalence of acne and hirsutism and
can often be found in a familial pattern. Patients
are not always obese, but when they are, the syn-
drome is worse. PCOS presents aspects of the
metabolic syndrome in women. A more complete
discussion is found in Chap. 9.
 yperlipidemia and Risk
H
for Cardiovascular Disease
Dyslipidemia is manifested as elevated low-­
density lipoprotein (LDL) cholesterol, non-HDL
cholesterol, and triglycerides but decreased HDL
cholesterol when measured after a 14-h fast
(except for water). Dyslipidemia is a risk factor
for cardiovascular disease, and the prevalence of
dyslipidemia is rising with the obesity epidemic.
There has been previous evidence of the presence
of atherosclerosis in young adults dating from
the Korean War and more recently in children
and teenagers from the Bogalusa heart study.
Atherosclerosis is now clearly established in
childhood and adolescence even though throm-
bosis does not usually occur until adulthood.
Comorbidities of Childhood and Adolescent Obesity
A brief summary of lipid metabolism involves
the following. Lipids are energy-rich com-
pounds; triglycerides provide energy storage in
adipocytes and muscle cells, while cholesterol
serves many roles in cell membranes, steroids,
bile acids, and signaling molecules. Because lip-
ids are insoluble since they are hydrophobic,
they are transported in the blood with hydro-
philic lipoproteins, apoproteins, or apolipopro-
teins. The surface proteins of the spherical
lipoproteins serve as ligands and cofactors for
the lipid-­processing enzymes. The size of the
lipoproteins and their density, the ratio of lipid to
protein, are the identifying characteristics that
define them. LDL cholesterol when elevated is a
risk factor for heart disease. The small dense
LDL contain the most cholesterol esters and are
especially atherogenic; these molecules are
associated with hypertriglyceridemia and insulin
resistance. Further, if HDL cholesterol levels are
decreased, the risk for atherosclerotic heart dis-
ease rises.
Ingested dietary fat, mainly triglycerides but
also cholesterol esters and phospholipids, free
fatty acids (FFAs), among other lipids, is
digested to fatty acids, monoglycerides, and
unesterified cholesterol in the gut. These are
made soluble by bile acid micelles and are
absorbed through passive and active processes
through the intestinal cellular wall. Once into the
enterocytes of the GI tract, production of lipo-
proteins within the intestinal cells proceeds by
attachment of apolipoprotein B-48 to a central
core of nonpolar cholesterol esters and triglycer-
ide and an outer region of free cholesterol and
phospholipids (polar lipids) which constitutes a
chylomicron. Thus the production of chylomi-
crons allows transport of the ingested triglycer-
ides and cholesterol into lymphatic ducts where
they are secreted and transferred to the venous
system. With the addition of other apolipopro-
teins to the chylomicrons, including apoC-II,
C-III, and apoE (apoprotein E which were trans-
ported by HDL), hydrolyzation of the triglycer-
ides within the apoC-II, C-III, and apoE proceeds
by lipoprotein lipase to produce fatty acids and
glycerol. In this process, lipoprotein lipase is
activated by apoC-II but inhibited by apoC-
III. The remaining smaller chylomicrons are
343
taken up by LDL receptors on the liver mediated
by apoprotein E (apo E). Very-low-density lipo-
protein (VLDL) is produced in the liver by com-
bining cholesterol and triglyceride produced
endogenously, rather than ingested, with apoB-­
100(apoB), and the VLDL is secreted into the
lymph and also transferred into the bloodstream
where much is converted to LDL. VLDL
increases with intrahepatic FFA as occurs with
high-fat diets, obesity, and diabetes. The VLDL
surface contains Apo C-II which activates lipo-
protein lipase on endothelial cells to break down
triglycerides into FFA and glycerol. VLDL
metabolism produces intermediate-density lipo-
proteins (IDL) which are cholesterol-rich VLDL
and chylomicron remnants which can be metab-
olized by hepatic lipase to produce LDL. IDL
contains Apo B.
LDL cholesterol is the product of VLDL and
IDL metabolism and contains the most cholesterol
of these molecules; LDL is associated with Apo B.
Lipoprotein(a) (LP(a)) consists of an LDL mol-
ecule and apoprotein A. This cholesterol-contain-
ing molecule is related to atherosclerosis, coronary
artery disease, and stroke, and LP(a) and LDL are
the most atherogenic lipoprotein molecules.
LDL is taken up by LDL receptors on the
liver, and other tissues, mediated by Apo B and
hepatic LDL receptors. There is a limit as to how
much LDL can be taken up, and the excess will
be oxidized which can lead to damage of epithe-
lial cells and contribute to atherosclerosis. High
LDL levels decrease LDL uptake, and lower LDL
levels increase the uptake of LDL.
HDL brings lipids from the periphery to the
liver, and this process can remove lipids from
atherosclerotic sites; HDL is antiatherogenic.
Apolipoprotein A is the main protein component
of HDL cholesterol.
Endogenous cholesterol is synthesized by the
mevalonate pathway; the rate-limiting step is
HMG-CoA reductase (3-hydroxy-3-methyl-
glutaryl-­CoA reductase) which is located in the
endoplasmic reticulum. HMG-CoA reductase is
inhibited by the class of drugs known as HMG-­
CoA reductase inhibitors or statins which are
­frequently used for the treatment of hypercholes-
terolemia (statins are teratogenic). LDL attaching
to the LDL receptor in the liver leads to meta-
344
bolic change, releasing cholesterol which inhibits
HMG-CoA reductase. HMG-CoA reductase
inhibitors induce an increase in LDL receptors
which lowers plasma cholesterol, serving to
decrease the risk of atherosclerosis. Cholesterol
esters are produced from free cholesterol by the
action of lecithin–cholesterol acyl transferase.
An increased ratio of apolipoprotein B (ApoB)
to apolipoprotein A-I (ApoA1) is directly related
to LDL levels as ApoB is associated with LDL
and ApoA with HDL.
While obesity tracks strongly in individual
between child and adulthood, meaning that child
with obesity has a higher likelihood of becoming a
obese adult, lipid abnormalities in childhood have
a less robust tracking pattern, but it is still disad-
vantageous to have dyslipidemia in childhood.
The office visit as discussed in Chap. 2 is a
time to investigate a family history of cardiovas-
cular events such as myocardial infarction or
strokes. It is not adequate to simply ask if there is
anyone in the family with high blood pressure or
dyslipidemia but instead to ask if anyone is tak-
ing medications for high blood pressure or dys-
lipidemia because often, once successfully
treated, the family thinks that a condition no lon-
ger exists. Likewise, determination of early car-
diovascular events or deaths even if unexplained
(early deaths are variously defined, but a useful
definition is under the age of 55 in males or 65 in
females or younger) indicates a strong history of
cardiovascular risk. It is important to realize that
the parents of our patients tend to be relatively
young and are still able to develop diabetes and
cardiovascular complications, so the family his-
tory must be updated for each visit for each child.
Risk factors should be evaluated in the indi-
vidual. Being born small for gestational age,
being an infant of diabetic mother, or having
macrosomic birth weight all lead to increased
risk of insulin resistance and obesity later in life.
Moderate-level risk factors are considered to be
hypertension not requiring drug therapy, BMI
equal to or >95th percentile and <97th percentile,
and HDL cholesterol <40 mg/dL. High-level risk
factors are considered to be hypertension requir-
ing drug therapy (BP > 99th percentile + 5 mmHg),
current cigarette smoker, and BMI at the >97th
13 Obesity
percentile. Other conditions add further risk, but
for the purposes of this discussion, the presence
of diabetes of either type is the most important
risk factor (see Chap. 11).
Universal lipid screening is recommended
between 9 and 11 and again between 17 and 21
years unless there is a family history of dyslipid-
emia at which time screening should be performed
at 2–8 years of age. Lipid screening is recom-
mended for BMI over the 95th %. Children with a
serious concern based upon family history should
have fasting lipid screening done twice at least 2
weeks apart but within 3 months with the average
determining the future management approach.
Lipid panels are best determined in the fasting
state, and results are of concern if LDL choles-
terol >130 mg/dL, non-HDL cholesterol >145 mg/
dL, HDL cholesterol <40 mg/dL, and triglycer-
ides >100 mg/dL if <10 years or >130 mg/dL if
>10 years. If there is concern that the patient will
not come back to get a fasting lipid level, perform
a non-fasting lipid panel. For a non-fasting lipid
level, the non-HDL cholesterol is calculated by
the formula non-HDL cholesterol = total choles-
terol minus the HDL cholesterol. Non-HDL cho-
lesterol is abnormal if the non-HDL > 145 mg/dL
and the HDL < 40 mg/dL.
As always, lifestyle change is the first
approach to complications of obesity such as
dyslipidemia. A heart-healthy diet and increased
activity with a decrease in sedentary time are
always the basis of treatment. The amount and
types of fat in the diet are important in construct-
ing a healthy lifestyle. Unsaturated fats are a
beneficial type of dietary fat and are usually
found in plants and include vegetable oils, nuts,
and seeds; unsaturated fats can be monounsatu-
rated or polyunsaturated, and omega-3 fatty
acids are a type of unsaturated fat. While there is
some controversy as to the link between satu-
rated fats and heart disease, saturated fats are
characteristically thought to be adverse to health
and should be replaced in the diet with unsatu-
rated fats but not replaced with foods containing
refined carbohydrates. There is no controversy
that transfatty acids or transfats are adverse to
health; these hydrogenated vegetable oils which
become more solid with lower temperature are
Comorbidities of Childhood and Adolescent Obesity
linked to increasing LDL and decreasing HDL,
an inflammatory state, and insulin resistance.
Until recently, most fast foods were laden with
transfatty acids, and stick margarine is another
product of transfatty acids. Transfatty acids
should be eliminated from the diet as much as
possible. Transfatty acids are decreasing in the
USA but may increase in the developing world.
The effect of dietary cholesterol intake on the
lipid profile is not as strong as previously
thought, but moderating cholesterol intake is still
a recommended approach to diet. For our pur-
poses, the recommended diet contains the follow-
ing: total fat 25–30 % of calories, saturated fat at
<10 % of calories, and cholesterol intake <300 mg/
day. If the person’s LDL was further elevated, the
diet is modified to contain saturated fat as 7 % of
calories and dietary cholesterol no more than
200 mg/day. Plant sterols up to 20 g per day appear
to be safe and effective in further lowering LDL
cholesterol levels. If there is only an elevated tri-
glyceride level, weight loss and a limited carbohy-
drate diet have been shown to be effective.
Medications are limited to children over 10
years of age who have met certain criteria. If the
total cholesterol is greater than 190 mg/dL and a
child with no other risk factors fails to respond
after 6 months of lifestyle modification or if the
LDL cholesterol is between 160 and 190 with a
positive family history of risk factor in the
­individual, medications may be considered. If the
child has diabetes mellitus and the LDL concen-
tration is greater than 130 mg/dl (or even 100 mg/
dl according to some), medication might be con-
sidered if lifestyle modification failed.
The medications most often used in childhood
dyslipidemia are HMG-CoA reductase inhibitors
which are commonly known as “statins.” Although
they are used in childhood with a generally safe
profile, there are few long-term data and especially
no data on outcomes many decades after childhood.
Knowing this, they still are instituted in appropriate
children. They are teratogenic so that any female of
reproductive age treated with this medication must
be on contraceptive agents or must be abstinent.
Other side effects are elevation of hepatic enzyme
concentrations and elevated creatine kinase with
myopathy which may progress to rhabdomyolysis.
345
Some parents find that there are cures on the
Internet for dyslipidemia such as red rice yeast
which contains agents similar to statins, but it must
be emphasized to these parents that herbal
­treatments are not regulated by the government and
the side effects of this herbal cure are exactly the
same as from the bona fide statin medications.
To emphasize again, statins are teratogenic, and
reproductive-aged females must be abstinent or on
birth control while taking statin medication.
Niacin has been used in the past but recent
studies demonstrate an increase in one unex-
pected death per 200 niacin users in adult studies
which effectively dissuade use of niacin in chil-
dren for dyslipidemia. There is little information
on the use of fibrates and cholesterol-binding
agents in children, and they should only be used
with a lipid specialist consultation.
While lipid abnormalities develop with obe-
sity, it is important to eliminate genetic causes of
dyslipidemia or secondary dyslipidemia.
 enetic Causes of Dyslipidemia:
G
Primary Hyperlipidemia
Familial hypercholesterolemia (#143890
I C D   +   H Y P E R C H O L E S T E RO L E M I A ,
FAMILIAL) is an autosomal dominant condition
due to an abnormality of the LDL receptor and is
the most common single-gene disorder leading
to hypercholesterolemia. The prevalence of
heterozygosity is 1,500 and homozygosity is
­
1,000,000. Plasma cholesterol levels may rise to
300–500 mg/dl in heterozygotes and as high as
1,000 in homozygotes. Physical findings include
corneal arcus of the eye, xanthelasma of the skin,
tendinous xanthomas, and planar xanthomas in
homozygotes.
Premature coronary artery disease may present
in childhood in homozygotes or after age 30 years
in heterozygotes. Dietary management is charac-
teristically initiated in disorders of lipid metabo-
lism, and medication may be considered for this
condition. National guidelines suggest implement-
ing a Cardiovascular Health Integrated Lifestyle
Diet (CHILD-1) for the first 3–6 months, and if
results are not achieved, progression to the more
lipid-­restrictive CHILD-2 diet (see ref #38 for
these diet recommendations) is recommended.
346
The addition of plant stanols to the diet has been
demonstrated to lower cholesterol levels safely.
The goal of dietary management is to achieve an
LDL cholesterol level less than or equal to 130 mg/
dL. Over the age of 10 years, if LDL is not less
than 190 mg/dL or in the presence of a risk factor,
less than 160 mg/dL, pharmacologic therapy, usu-
ally with statins, can be initiated; sometimes this
therapy is used in younger children with consulta-
tion with a lipid specialist.
Familial combined hyperlipidemia (#144250
ICD+HYPERLIPIDEMIA, FAMILIAL COMBI-
NED; FCHL) is an autosomal dominant condi-
tion with a prevalence of 1–2 % that is due to
overproduction of hepatic VLDL or LDL. While
there is variation, the lipid profile characteristi-
cally reveals elevated cholesterol, triglyceride, or
apoB found in a familial pattern. Xanthomas are
rare in this condition. Treatment by statins of the
hypercholesterolemia is considered. Treatment
of severely elevated triglycerides with fibrate
derivatives or fibrates increases degradation of
triglycerides and decreases production of VLDL
by the liver as well as raising HDL levels. Statins
and fibrates are not to be used together because
they share a similar list of side effects including
elevated liver transaminase enzymes, myopathy,
and gastrointestinal symptoms.
Familial hypertriglyceridemia (#145750
I C D + H Y P E R T R I G LY C E R I D E M I A ,
FAMILIAL) is an autosomal dominant condition
with a prevalence of about 5–10 %. The cause of
this condition is not definitely established, but it
has been related to mutations in apolipoprotein
A5 gene (APOA5) and the lipase I gene (LIPI) on
OMIM. The hypertriglyceridemia is caused by
secretion of large VLDL particles laden with tri-
glycerides. Atheroeruptive xanthoma is a feature
of this condition. Triglyceride values are in the
range of 200–500 mg/dL, VLDL values are ele-
vated, and apoprotein C-II are low, while LDL
and HDL cholesterol values are low to normal.
The condition is associated with an elevated risk
for very premature atherosclerosis.
Dietary management of hypertriglyceridemia
is suggested. The child is to follow a dietary pat-
tern which involves decreasing sugar intake in
solid or liquid foods and weight management to
13 Obesity
achieve a BMI below the 85th percentile. Increased
activity is beneficial. A diet or additives containing
omega-3 fatty acids may decrease serum triglycer-
ide, but there has been recently suggestive links
between elevated levels of omega-3 fatty acids and
prostatic carcinoma although an explanation for
this connection is not available. While statins can
decrease serum triglycerides, fibrates are more
direct treatment for hypertriglyceridemia.
Lipoprotein lipase deficiency (alleles of
+609708 LIPOPROTEIN LIPASE; LPL), some-
times known as familial chylomicronemia syn-
drome, is a group of rare conditions with various
presentations and is generally due to a monoge-
netic mutation in the lipoprotein lipase gene or
one of its cofactors. Thus lipoprotein cannot be
metabolized, and chylomicrons and triglycerides
accumulate, leading to a milky appearance to the
plasma in homozygotes. Manifestations occur in
childhood, and along with very elevated triglyc-
eride levels, affected individuals also have
abdominal pain, recurrent acute pancreatitis,
eruptive cutaneous xanthomata, and hepato-
splenomegaly. Diagnosis is accomplished by
measurement of LPL enzyme activity after
administration of heparin. Treatment is by dietary
management to maintain triglyceride levels
below 2,000 mg/dL to avoid GI pain and below
1,000 mg/dL ideally. Fibrates may be used if
dietary management is not successful.
Secondary Hyperlipidemia
The prevalence of the hypertriglyceridemia is ris-
ing in America, and it is associated with obesity
and insulin resistance which likewise cause
decreased HDL cholesterol values. Addressing
the underlying obesity should improve the
hypertriglyceridemia.
Combined hyperlipidemia can be found in
uncontrolled type 1 or type 2 diabetes mellitus
and type 2 diabetes mellitus and is associated
with increased small dense LDL particles.
Nephrotic syndrome and chronic kidney disease
will lead to dyslipidemia as will cholestatic liver
disease. LDL values are elevated in untreated
hypothyroidism. Cigarette smoking and alcohol
use will likewise lead to dyslipidemia. Successful
treatment of the underlying disorder or a change
Comorbidities of Childhood and Adolescent Obesity 347

in habits should resolve the secondary presenta- The latest national health and nutrition examina-
tion of combined hyperlipidemia. tion survey of the USA determined that 20 % of
Secondary hyperlipidemia can also cause children between 9 and 11 years already required
pancreatitis. an adult cuff, and 30 % of those children will
require a cuff larger than the standard adult cuff.
The appropriate cuff has an inflatable bladder
Hypertension width that is at least 40 % of the arm circumference
at a point midway between the olecranon and the
The prevalence of hypertension is increasing acromion, and the bladder length should cover
in childhood along with the increase in the 80–100 % of the circumference of the arm. Blood
­prevalence of obesity. Hypertension is ­diagnosed pressure should be determined in the resting state
if the mean systolic or diastolic blood pressure rather than in the excitement of entering the doc-
is above the 95th percentile for gender, age, and tor’s office, and measurements in the lying, sitting,
height on three or more occasions. The limit of and standing positions might be required if postural
stage 1 hypertension is a blood pressure between hypotension is suspected; pulse in each position
the 95th and 99th percentile plus 5 mmHg, should likewise be determined. A decrease in blood
while stage 2 hypertension is a blood pressure pressure of 10 mmHg or an increase in pulse rate of
over 5 mmHg above the 99th percentile plus 20 is considered significant as an indicator of pos-
5 mm of mercury. A new classification of pre-­ tural hypotension.
hypertension in childhood has been added and The family history must explicitly determine
defined as a mean systolic or diastolic blood whether close relatives have hypertension
pressure at or above the 90th percentile but (some will say their relatives do not have hyper-
below the 95th percentile. Pre-hypertension is tension while they are successfully treated
also diagnosed with blood pressures greater with ­medication, so the question should also be
than 120/80 mm of mercury. “do you take medication for hypertension”).
Evaluation of blood pressure may present Medication history must be obtained since stimulant
problems in some clinicians’ offices. The auto- medications may raise blood pressure as may
matic blood pressure device in frequent use may pseudoephedrine for allergies. Likewise, it is
not be as accurate as a manual sphygmomanom- important to determine if the individual smokes
eter, and the standards are derived from the man- or uses illicit drugs. Natural licorice can raise
ual sphygmomanometer method. If there is ever a blood pressure but not the candy version usually
question, the manual device must be used. Some found in the USA.
children may have white coat hypertension in Because elevated blood pressure may be sec-
which the blood pressure is elevated in the pres- ondary to another condition and may cause end-­
ence of the physician or in the clinicians’ office, organ complications, a phased approach to
while others may have masked hypertension in evaluation is required. Besides the standard eval-
which the blood pressure is normal in the office uations recommended for obesity including
but high in the ambulatory setting. In such cases, comprehensive metabolic panel and microalbu-
ambulatory 24-h blood pressure readings may be min determination in the urine, in addition,
invoked for definitive diagnosis. Ambulatory plasma renin activity and aldosterone determina-
blood pressure monitoring is recommended in tions, urinalysis and culture, CBC, and renal
patients with diabetes, chronic kidney disease, ultrasound are recommended. Echocardiogram
episodic hypertension, or autonomic dysfunc- to determine left ventricular mass and function is
tion. Coarctation of aorta is ruled out by mea- carried out if hypertension is discovered. In
surements of arm and leg blood pressures. selected cases suggesting pheochromocytoma or
The size of the cuff is of extreme importance, Cushing syndrome, evaluation of catechol-
and some children with obesity may require amines and glucocorticoid production is war-
remarkably large cuffs for accurate determinations. ranted (see Chap. 10).
348 13 Obesity

If the hypertension appears related to obesity, recommending initial use of angiotensin-­

lifestyle modification is always recommended as
is true in uncomplicated obesity although in the
case of hypertension, a DASH (Dietary
Approaches to Stop Hypertension) diet is also
invoked. If the DASH diet is not successful, phar-
macologic treatment would be next with most
converting enzyme (ACE) inhibitor with calcium
channel blockers next in line followed by diuretics
and beta-blockers; some recommend the use of
more than one agent in a refractory case. ACE
inhibitors are teratogenic as are statins and con-
traception or abstinence is required of

Table 13.2  Blood pressure levels for the 90th and 95th percentiles of blood pressure for boys aged 1 to 17 years by
percentiles of height
Age Systolic BP (mmHg) by percentiles height-> Diastolic BP (mmHg) by percentiles height->
(Year) BP % ile 5th 10th 25th 50th 75th 90th 95th 5th 10th 25th 50th 75th 90th 95th
1 90th 94 95 97 99 100 102 103 49 50 51 52 53 53 54
95th 98 99 101 103 104 106 106 54 54 55 56 57 58 58
2 90th 97 99 100 102 104 105 106 54 55 56 57 58 58 59
95th 101 102 104 106 108 109 110 59 59 60 61 62 63 63
3 90th 100 101 103 105 107 108 109 59 59 60 61 62 63 63
95th 104 105 107 109 110 112 113 63 63 64 65 66 67 67
4 90th 102 103 105 107 109 110 111 62 63 64 65 66 66 67
95th 106 107 109 111 112 114 115 66 67 68 69 70 71 71
5 90th 104 105 106 108 110 111 112 65 66 67 68 69 69 70
95th 108 109 110 112 114 115 116 69 70 71 72 73 74 74
6 90th 105 106 108 110 111 113 113 68 68 69 70 71 72 72
95th 109 110 112 114 115 117 117 72 72 73 74 75 76 76
7 90th 106 107 109 111 113 114 115 70 70 71 72 73 74 74
95th 110 111 113 115 117 118 119 74 74 75 76 77 78 78
8 90th 107 109 110 112 114 115 116 71 72 72 73 74 75 76
95th 111 112 114 116 118 119 120 75 76 77 78 79 79 80
9 90th 109 110 112 114 115 117 118 72 73 74 75 76 76 77
95th 113 114 116 118 119 121 121 76 77 78 79 80 81 81
10 90th 111 112 114 115 117 119 119 73 73 74 75 76 77 78
95th 115 116 117 119 121 122 123 77 78 79 80 81 81 82
11 90th 113 114 115 117 119 120 121 74 74 75 76 77 78 78
95th 117 118 119 121 123 124 125 78 78 79 80 81 82 82
12 90th 115 116 118 120 121 123 123 74 75 75 76 77 78 79
95th 119 120 122 123 125 127 127 78 79 80 81 82 82 83
13 90th 117 118 120 122 124 125 126 75 75 76 77 78 79 79
95th 121 122 124 126 128 129 130 79 79 80 81 82 83 83
14 90th 120 121 123 125 126 128 128 75 76 77 78 79 79 80
95th 124 125 127 128 130 132 132 80 80 81 82 83 84 84
15 90th 122 124 125 127 129 130 131 76 77 78 79 80 80 81
95th 126 127 129 131 133 134 135 81 81 82 83 84 85 85
16 90th 125 126 128 130 131 133 134 78 78 79 80 81 82 82
95th 129 130 132 134 135 137 137 82 83 83 84 85 86 87
17 90th 127 128 130 132 134 135 136 80 80 81 82 83 84 84
95th 131 132 134 136 138 139 140 84 85 86 87 87 88 89
From the The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and
Adolescents U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
National Heart, Lung, and Blood Institute
NIH Publication No. 05-5267
Originally printed September 1996 (96-3790)
Revised May 2005
Comorbidities of Childhood and Adolescent Obesity 349

Table 13.3  Blood pressure levels for the 90th and 95th percentile of blood pressure for girls aged 1 to 17 years by
percentiles of height
Systolic BP (mmHg) by percentiles height-> Diastolic BP (mmHg) by percentiles height->
Age % ile 5th 10th 25th 50th 75th 90th 95th 5th 10th 25th 50th 75th 90th 95th
(Year) Ht
1 90th 97 97 98 100 101 102 103 52 53 53 54 55 55 56
95th 100 101 102 104 105 106 107 56 57 57 58 59 59 60
2 90th 98 99 100 101 103 104 105 57 58 58 59 60 61 61
95th 102 103 104 105 107 108 109 61 62 62 63 64 65 65
3 90th 100 100 102 103 104 106 106 61 62 62 63 64 64 65
95th 104 104 105 107 108 109 110 65 66 66 67 68 68 69
4 90th 101 102 103 104 106 107 108 64 64 65 66 67 67 68
95th 105 106 107 108 110 111 112 68 68 69 70 71 71 72
5 90th 103 103 105 106 107 109 109 66 67 67 68 69 69 70
95th 107 107 108 110 111 112 113 70 71 71 72 73 73 74
6 90th 104 105 106 108 109 110 111 68 68 69 70 70 71 72
95th 108 109 110 111 113 114 115 72 72 73 74 74 75 76
7 90th 106 107 108 109 111 112 113 69 70 70 71 72 72 73
95th 110 111 112 113 115 116 116 73 74 74 75 76 76 77
8 90th 108 109 110 111 113 114 114 71 71 71 72 73 74 74
95th 112 112 114 115 116 118 118 75 75 75 76 77 78 78
9 90th 110 110 112 113 114 116 116 72 72 72 73 74 75 75
95th 114 114 115 117 118 119 120 76 76 76 77 78 79 79
10 90th 112 112 114 115 116 118 118 73 73 73 74 75 76 76
95th 116 116 117 119 120 121 122 77 77 77 78 79 80 80
11 90th 114 114 116 117 118 119 120 74 74 74 75 76 77 77
95th 118 118 119 121 122 123 124 78 78 78 79 80 81 81
12 90th 116 116 117 119 120 121 122 75 75 75 76 77 78 78
95th 119 120 121 123 124 125 126 79 79 79 80 81 82 82
13 90th 117 118 119 121 122 123 124 76 76 76 77 78 79 79
95th 121 122 123 124 126 127 128 80 80 80 81 82 83 83
14 90th 119 120 121 122 124 125 125 77 77 77 78 79 80 80
95th 123 123 125 126 127 129 129 81 81 81 82 83 84 84
15 90th 120 121 122 123 125 126 127 78 78 78 79 80 81 81
95th 124 125 126 127 129 130 131 82 82 82 83 84 85 85
16 90th 121 122 123 124 126 127 128 78 78 79 80 81 81 82
95th 125 126 127 128 130 131 132 82 82 83 84 85 85 86
17 90th 122 122 123 125 126 127 128 78 79 79 80 81 81 82
95th 125 126 127 129 130 131 132 82 83 83 84 85 85 86
From the The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and
Adolescents U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
National Heart, Lung, and Blood Institute
NIH Publication No. 05-5267
Originally printed September 1996 (96-3790)
Revised May 2005

reproductive-­aged girls. Long-term studies are Liver Disease

lacking, but there is some evidence that damage
will not progress or in some cases reverse with
appropriate therapy.
Blood pressure standards are found in
Tables 13.2 and 13.3.
Nonalcoholic fatty liver disease is now the most
common cause of chronic hepatic disease in child-
hood and adolescence and may be seen as young
as 3 years of age. It starts with fatty infiltration of
350
the liver (steatosis) and progresses to steatohepati-
tis and can further progress to fibrosis and cirrho-
sis; cirrhosis may lead to the development of liver
cancer. NAFLD was found in about 10 % of chil-
dren in autopsy study of all deaths in San Diego
and in about 40 % of children with obesity in that
study. Children with severe obesity may have a
prevalence of NAFLD as high as 80 %. NAFLD is
now considered as the hepatic manifestation of
the metabolic syndrome. Remarkably although
obesity rates are relatively similar in African-
American and Hispanic-­American children, the
NAFLD rate is highest in Hispanic children and
lowest in African-­American children.
The diagnosis of NAFLD is problematic as
liver enzyme (ALT) determination has poor speci-
ficity and sensitivity; elevated values are > 25 IU/L
in boys and > 22 IU/L in girls (may be lab depen-
dent). Ultrasound studies can show fat in the liver
but not fibrosis, leaving liver biopsy as the only
“gold standard,” but few children will have this
procedure, so proxy measures are used. During
this epidemic of obesity, any child who has liver
disease from an etiology other than NAFLD can
also be obese. Thus, it is important for the practi-
tioner to consider and eliminate other liver dis-
eases such as hepatitis B and C, autoimmune
hepatitis, drug-induced liver injury, Wilson’s dis-
ease, alpha 1-antitrypsin deficiency, inborn errors
of fatty acid or carnitine metabolism, peroxisomal
disorders, lysosomal storage disorders, and cystic
fibrosis before diagnosing NAFLD.
There appears to be a multifactorial etiology
of NAFLD. Elevated triglycerides reach the liver
and deposit ectopic fat; inflammatory cytokines
affect the liver and rise in obesity, and even the
gut microbiome plays a role. A gene related to
NAFLD is patatin-like phospholipase domain-­
containing 3 (PNPLA3) gene variant I148M.
Treatment of NAFLD starts, as in the treatment
of obesity, with lifestyle modification. Although
some medications have shown promise but ulti-
mately failed to be more beneficial than lifestyle
modification (these include vitamin E, metformin,
and ursodeoxycholic acid), there are still some
promising approaches. Beneficial effects have been
found with the use of probiotics to change the gut
13 Obesity
microbiome and polyunsaturated fatty acids
although it is premature to recommend these for
therapy at present. There is some information to
demonstrate beneficial effects of bariatric surgical
treatment of extreme obesity on NAFLD.
Obstructive Sleep Apnea
The Institute of Medicine calls sleep disorders
“an underrecognized public health problem.”
Obesity affects sleep, and abnormal sleep affects
metabolism.
OSA is characterized by chronic partial upper
airway obstruction with intermittent complete
airway obstruction that affects sleep and ulti-
mately has major effects on health. Most but not
all individuals with OSA snore. Diagnostic tech-
niques include parent reports, parental question-
naires on sleep habits, audio or video recording
of child sleeping, and, considered the gold stan-
dard, polysomnography. With polysomnography,
the number of apnea hypoxemia events per hour
expressed as the AHI is used for diagnosis. An
AHI higher than 5 is diagnostic of mild sleep
apnea, greater than 15 for moderate sleep apnea,
and greater than 30 for severe sleep apnea.
Obesity is a risk factor for OSA with increas-
ing risk with increasing BMI. OSA leads to CO2
retention, hypoxia, and right ventricular hyper-
trophy and failure and pulmonary hypertension.
This also is potentially associated with prolonga-
tion of the QTc interval and ventricular arrhyth-
mias. The obesity hypoventilation syndrome or
Pickwickian syndrome, characterized by
hypoventilation, somnolence, CO2 retention,
hypoxia, polycythemia, right ventricular hyper-
trophy and failure, pulmonary embolism, and
even sudden death, is an extreme example of this
process noted more frequently in older literature.
Pulmonary hypertension may result from OSA.
Disordered sleep is a risk factor for glucose
intolerance and weight gain in children and
adults. Limited sleep increases appetite and
caloric intake. Sleep quality should be investi-
gated by history and sleep hygiene advice pro-
vided if necessary.
Comorbidities of Childhood and Adolescent Obesity
Dermal Findings
Acanthosis nigricans manifest as dark pigmenta-
tion on the back of the neck or other flexural
surfaces, with thickening and even papilloma
­ deficiency, and pseudohypoparathyroidism, and
­formation in more severe cases. This is a physical
indication of insulin resistance. Intertrigo and
furunculosis may independently develop in skin
folds and increase pigmentation as well.
There is a correlation between obesity and
type 2 diabetes mellitus and the development of
psoriasis.
Orthopedic Conditions
Obesity in childhood and adolescence leads to a
host of orthopedic conditions mostly related to
weight-bearing extremities.
Slipped capital femoral epiphysis (SCFE)
occurs when the proximal femoral metaphysis sep-
arates from the epiphysis of the femoral head. This
condition most often occurs in obese individuals
and also is found in hypothyroidism or in the rapid
growth of growth hormone treatment. Usually hip,
leg, or foot pain develop and the child is noted to be
waddling during ambulation. The incidence of
slipped capital femoral epiphysis is increasing
along with the incidence of obesity in childhood.
Surgery is required for treatment of SCFE.
Blount disease develops from abnormal growth
of the medial part of the proximal tibial physis and
results from increased weight on the proximal
tibia. This leads to abnormal gait, discrepancy in
limb length, and a tendency toward the develop-
ment of arthritis. There are two forms, infantile
and adolescent Blount disease. Characteristically,
surgery is the mode for treatment, but the infantile
form might be amenable to nonsurgical treatment.
Low back pain is also more common in ado-
lescents with obesity.
I ncreased Growth and Advanced
Skeletal Development
Advancement of bone age and tall stature are
common in most otherwise normal but children
with obesity; bone age advancement is described
351
in MC4R mutation. A short child with obesity has
a greater likelihood of having a definable endo-
crine disorder such as hypothyroidism, Cushing
syndrome, hypopituitarism or growth hormone
these will generally have a delayed bone age.
Earlier Puberty
There is a trend to earlier puberty recently, and in
girls, this is often linked to increasing BMI.
Menarche and the other aspects of pubertal devel-
opment are found earlier than their peers. Early
menarche raises the risk of breast cancer later in life
so that earlier puberty is a cause for concern. This
problem is discussed in more detail in Chap. 9.
Enuresis
Enuresis is found more frequently in children
with obesity. It can occur without sleep apnea
although studies vary in this relationship.
Cholelithiasis
Cholesterol cholelithiasis is associated with pedi-
atric obesity, and while rare, the prevalence is ris-
ing. Cholelithiasis is also found with rapid weight
loss, and prophylactic treatment with oral
­ursodeoxycholic acid may be considered after
bariatric surgery. There is the added risk of the
development of pancreatitis.
Asthma
Asthmatic children may have limited physical
activity that fosters the development of obesity.
On the other hand, obesity in children causes pre-
existing asthma to worsen.
Pseudotumor Cerebri
Pseudotumor cerebri is more common in obesity
and presents with headaches. Clinical diagnosis
352
requires ophthalmoscopy to detect papilledema,
an otherwise normal neurologic exam, and MRI
to detect evidence of normal central nervous sys-
tem parenchyma, absence of hydrocephalus or
masses, normal spinal fluid composition, and
elevated cerebrospinal fluid pressure. Some
patients will have pseudotumor cerebri syn-
drome without papilledema which presents a
diagnostic challenge although the other criteria
noted above must be satisfied in this situation as
well. Weight loss will likely be curative, but
shunting may be necessary in some cases.
Psoriasis
Psoriasis is an inflammatory disease which has
been linked to obesity in adults and in children,
but no cause-and-effect relationship is yet
established.
 aboratory Evaluation of Childhood
L patients do not connect the intake of french fries
Obesity
The degree of investigation is dependent on
the BMI and the presence of risk factors.
Recommendations are based upon expert opinion
tempered by the prevalence of comorbidities of
obesity.
If the BMI for age is in the 85th to 94th
­percentile with no risk factors, a fasting lipid pro-
file is obtained.
If risk factors are present, and this is the case
in most situations, a comprehensive chemistry
panel with fasting glucose and an alanine amino-
transferase (ALT) measurement is obtained.
HgbA1c is measured. Although obesity is an insu-
lin resistance syndrome, a fasting insulin level
does not indicate the likelihood of type II diabe-
tes or any other complications and is generally
not recommended. Insulin levels are used for
clinical studies but not in individual patients.
If BMI is equal to or greater than the 95th per-
centile, all of the listed tests are recommended
irrespective of complications.
If appropriate historical features suggest par-
ticular problems, additional tests are required.
13 Obesity
For symptoms suggestive of obstructive sleep
apnea, a sleep study will be performed. For suspi-
cion of hypertension, ambulatory BP monitoring
is invoked. For orthopedic symptoms, extremity
exam and radiographs are obtained.
Thyroid-function tests (free T4 and TSH) are
of low yield as hypothyroidism should not cause
a significant level of obesity, but parents often
insist on thyroid testing, having obtained infor-
mation from the Internet suggesting that it is a
cause of obesity.
Genetic testing for one of the single gene muta-
tions listed above is reserved for those children
with the onset of obesity before 5 years of age,
have hyperphagia, demonstrate physical findings
of genetic syndromes or who have extreme obesity
in their family. Developmental delay is found in
some of the genetic obesity conditions but not all.
Treatment
It is indeed hard to believe, but some families and
and high-calorie drinks with the development of
obesity. Education rarely is sufficient to change
behavior, but it has to be the starting point of an
encounter. Of course a history of increased caloric
intake and/or decreased activity will be found in
many subjects with obesity; some may already be
quite active in sports or other activities and may
appear to follow a reasonable diet. In these cases,
often portion sizes or second helpings are respon-
sible for the excess caloric intake. These children
may still require changes in behavior to decrease
caloric intake and increase in energy expenditure
in a program of lifestyle modification. There is
only one approved drug for the treatment of child-
hood and adolescent obesity, and surgical approach
to obesity is quite a significant step, so lifestyle
modification must remain the basis of treatment.
The goal of lifestyle modification is not to
make a stick-thin child but a healthier child.
There is metabolic benefit from small changes in
BMI whatever treatment program brings about.
Thus a decrease in 0.5 BMI units or in 8 %
decrease in BMI, depending upon the study, has
been shown to improve metabolic balance and
insulin resistance in children.
Laboratory Evaluation of Childhood Obesity
It must be remembered that many families
have many psychosocial issues in their life over
and above the obesity of the child. The families
may come from lower socioeconomic status or
live in dangerous neighborhoods. All of these
issues impair their ability to follow the sugges-
tions we may offer in a clinic visit. Understanding
this situation may improve communication with
the families.
Lifestyle Modification
In clinical encounters, no provider should use the
terms obesity or overweight but rather should
discuss with the family healthy habits including
dietary intake and activity levels. The aim in life-
style modification is to decrease caloric intake
and to increase activity. There are sometimes
obvious changes which can be discussed with the
family. For instance, one goal can be the elimina-
tion of sugar-sweetened beverages such as colas
by replacing it with water. Intake of juice should
adhere to the recommendations of the Academy
of Pediatrics which suggest that 1- to 6-year-old
children should have only 120–150 mL of juice
per day and 7–18-year-olds limited to 240–
360 mL per day. Water is the best oral intake for
a child with obesity, but if flavor is craved, flavors
can be added with products such as Crystal Light
which contains no calories and has various fruit
flavors. Substituting diet drinks for high-calorie
high-­fructose corn syrup-laden sugar-sweetened
beverages is not an answer as there is evidence
that drinking diet drinks not only does not help to
stop weight gain but actually can also lead to
weight gain. A source of calcium must remain
even if the percent of fat in milk is decreased.
Schools should be encourage to offer water rather
than juice or sugar sweetened beverages in the
cafeteria or vending machines.
Approaches used in the adult can be beneficial
in children. Emphasizing eating breakfast rather
than skipping it is an important goal. When adults
actually write down what they are eating, it
focuses their attention on the content of the food,
and teenagers may benefit from this as well.
Decreased episodes of eating at restaurants or
fast-food outlets will decrease exposure to large
353
portion sizes and processed foods often with salt
and high-fructose corn syrup added. An impor-
tant goal is not to make the child feel that he or
she is always hungry which will sabotage any
attempts at moderate diet. Unfortunately as an
obese individual loses weight, it becomes harder
to lose more weight, and a plateau is reached. The
reduction of calories for weight maintenance or
weight loss in the obese person is greater than the
reduction of calories for weight maintenance or
weight loss in a nonobese patient, making caloric
deficits all the harder to achieve.
The primary dietary treatment for any child
requiring weight control is decreased caloric
intake (about 500-calorie/day decrease in older
children) but not so much as to stunt statural
growth. The provider will encounter numerous
different cultures which have their own forms of
high caloric intake. Every family must be treated
with respect for their cultural backgrounds, but
usually some traditional food can be invoked to
exclude others. For the Hispanic families, one
can discuss decreasing cooking food with lard or
frying food and replacing these methods with
cooking with vegetable oil and steaming. Some
traditional food such as cactus carry low caloric
content, while others such as rice and beans may
contain more. An Asian diet often can include
many vegetables cooked in vegetable oil to the
exclusion of fried foods or large servings of meat.
These adjustments must be suggested in a
respectful manner. Suggestions in English and
Spanish and handouts for Anglo and Hispanic
families are found at http://win.niddk.nih.gov/
index.htm and additional resources including
some for Asian families at HDL http://www.eat-
r i g h t . o rg / H e a l t h P r o f e s s i o n a l s / c o n t e n t .
aspx?id=250. Changes are encouraged by using
motivational interviewing discussed below in this
chapter. Change takes time, and it is essential to
negotiate a reachable goal during clinical encoun-
ters. Eliminating or cutting down on sugar-sweet-
ened beverages might be a goal for one visit and
eating one more serving of vegetable per day for
another. Figure 13.3 provides a starting point for
increasing the use of the MyPlate model in
English and Spanish as other reasonable goals.
The family must be involved in the approach to
younger children.
354
Increased energy expenditure aims to decrease
sedentary activity rather than forcing vigorous
exercise, which will rarely be maintained.
Increased activity benefits the least mobile
­children, the most in terms of their metabolism.
Even five episodes of 20 min of exercise per
week can improve insulin sensitivity and decrease
liver enzyme abnormalities over a period of
months. This may occur even without significant
weight loss since muscle weighs more than fat
tissue, and as muscle tissues build up, weight
may remain stable. The use of video games that
encourage physical activity may be invoked, and
family walks can be promoted. While many
schools are far from the student’s house, walking
to school with family members or using a “walk-
ing school bus” in which neighbors band together
to walk children to the school increases activity
levels and is a very beneficial manner. Gym
classes are not required in many schools at the
present time, so extracurricular physical activity
such as sports teams is important. Determination
of the child’s living environment is of great
importance. Is a child left at home as a “latchkey
child” having free access to chips and television
while parents work? Is it possible to have the
child go to an afterschool activity or Boys and
Girls Club in the neighborhood? Is it possible to
have some kind of exercise device in the house or
apartment if the outside environment is unsafe?
Standard approaches to the recommendation
of lifestyle changes to families are often ineffec-
tive unfortunately. Motivational interviewing is
suggested as a more effective manner of motivat-
ing families to make changes. In most common
medical communications, the provider directs
patient and family activities while motivational
interviewing aims to guide families into changes
using appropriate communication techniques and
their outlooks. The stages of change model is not
accepted by all authorities but may nonetheless
be useful in clinical interactions when evaluating
and motivating families. In this concept, there are
five stages: One is pre-contemplation when a
child’s weight is not even raised in the families’
consciousness; the second is contemplation which
they are at least thinking about the fact that the
child may be ­overweight or that his or her habits
might be unhealthy; the next step is preparation in
13 Obesity
which the family at least plans to make changes in
unhealthy behaviors; this is followed by action in
which the changes are actually made in unhealthy
behaviors; the last stage is maintenance of the
changes that have been made. Characteristically
an individual and family will move up and down
these five steps, so the provider might be able to
support progress toward maintenance more effec-
tively by continued motivational interviewing.
A practitioner might reinforce positive behav-
ior by lauding the family for any positive activity
such as exercise or eating vegetables. The pro-
vider might then ask what is more negative such
as excessive caloric drinks or sedentary time
which might be received more positively since it
follows a positive statement. The provider might
then ask what negative behavior the family might
want to talk about. Taking the lead from the fam-
ily in this way allows better communication. The
provider might talk about the positives and nega-
tives of the unhealthy behavior such as high-­
calorie sugar-sweetened beverages. After asking
for permission, the provider might then provide
information about the unhealthy behavior in
order to enhance the message. The provider
might then ask on a 1–10 score how important
this change in behavior is to the family and how
confident they are in making the changes. If they
choose a low number, the provider might ask
why the number is low in trying to guide the
family into a more positive outlook. Alternately,
the provider might ask why the number is high
such as 9 or 10, and the provider might comple-
ment the family on how important this decided
change is to them. The meeting then ends with a
summary to go over everything that was dis-
cussed in order to reinforce the messages
developed.
A group program of education and family sup-
port is superior to individual sessions for children.
Family therapy is used with success in some cen-
ters. Group programs may follow the Traffic
Light, Shapedown, or our UCDMC Fit-­Kid mod-
els. In the youngest children, the parents solely
determine the diet for the child and must play an
important role in the counseling, whereas the
message might be more focused on the subjects
during the adolescent years. Community involve-
ment in the approach to the obesity epidemic is
Laboratory Evaluation of Childhood Obesity
important in a global approach to the problem.
Unfortunately, only a few programs show long-
term success, as constant reinforcement of healthy
habits is necessary and not often available; obe-
sity should be considered as a chronic disease that
requires continuous management.
An essential point for anyone caring for chil-
dren with obesity is a sense of empathy and a
supportive manner that does not further decrease
the child’s self-esteem; if providers cannot mus-
ter such feelings, they should not be involved
with affected children or families.
The goals of weight management are based on
age, BMI, and complications (Fig. 13.2). If the
child can grow into the weight, stopping further
weight gain is the goal, but if any weight-based
complications are noted, weight loss is needed.
Thus in the child younger than 2 years, if the BMI
is less than 95 %, dietary counseling is recom-
mended, but if the BMI is greater than 95 %, spe-
cialty consultation is suggested. In a child or early
adolescent with a BMI of 85–94 % and no com-
plications, or in a child younger than 7 years who
has a BMI greater than 95 % but no complica-
tions, weight maintenance is recommended, as
the child will grow into the weight if no more is
gained. However, if the BMI is greater than 95 %
at older than 7 years or if complications are found,
weight loss rather than weight maintenance is
required. Specialty consultation becomes prob-
lematic in many locations as this type of a pro-
gram is usually available at academic medical
centers or large hospital systems rather than small
towns. With the growth of telemedicine, consulta-
tion can be offered from a distance to many rural
communities. Alternatively, expert education for
local practitioners through telemedicine by dis-
tant consultants might increase the abilities of the
community to deal with the obesity problems.
A protein-sparing modified fast (PSMF) has
been used in children with severe, often life-­
threatening, consequences of obesity (e.g., sleep
apnea) in which rapid weight loss is indicated, if
no other method appears applicable, but must be
administered only with an experienced practitio-
ner because of inherent dangers. There is very lit-
tle recent literature on this method. The PSMF is a
medically supervised (an experienced clinician
must direct the therapy) program of 600–800 kcal/
355
day intake, including 1.5–2.5 g high-quality pro-
tein per kilogram ideal body weight per day (sup-
plied from lean meats, poultry, and fish) but only
20–40 g/day of carbohydrate; daily vitamin and
mineral supplementation and encouragement to
consume more than 1,500 mL free water are addi-
tional important features. A PSMF is carried out
usually for no more than 12 weeks, with daily
monitoring for urinary ketones to demonstrate
adherence to the low-­caloric plan. The risks of
PSMF ­regimens include cholelithiasis; hyperuri-
cemia; decreases in serum proteins, including
transferrin, retinol-binding protein, and comple-
ment 1C; orthostatic hypotension; halitosis; and
diarrhea. Although long-­term weight control may
not result, lessening of the initial medical compli-
cations may be achieved. This technique has been
suggested as an initial step before bariatric surgery
is performed. It must be performed by an experi-
enced team.
Medication
Orlistat is the only medication approved for obe-
sity in childhood. Orlistat is an intestinal lipase
inhibitor that decreases fat intake and increases
the elimination of dietary fat. Side effects include
diarrhea and flatus if significant fat remains in the
diet, so this becomes a form of aversion therapy
if diet is not first modified. The unpleasant side
effects may make teenagers cease to take this
medication.
Metformin, a biguanide that decreases hepatic
release of glucose and decreases insulin resis-
tance, is approved for diabetes in children as
young as 10 years of age but not for weight
­control. Nonetheless, several studies have shown
a modest decrease in BMI (about 1.5 kg/m2) with
the use of this medication so that in selective
cases of extreme obesity, it may have benefited
even though it is used off label. While metformin
can cause abdominal distress, usually temporary,
it is generally considered safe. Rare individuals
will have elevations of creatinine kinase and
muscle pain or rhabdomyolysis. If so, metformin
must be immediately stopped. In adults, there is a
tendency toward lactic acidosis. Vitamin B12
deficiency is a risk with metformin treatment so
356
daily vitamin intake is advised with metformin
treatment. Exenatide is an injectable glucagon-
like peptide-­1 (GLP-1) agonist approved for the
treatment of type II diabetes in adults. It pro-
motes a feeling of fullness and decreases appe-
tite, leading to a degree of weight loss. A few
clinical studies in children suggested that a
decrease in BMI of 4 % is possible. Exenatide is
not approved by the FDA for use below 16 years
of age. Extended-­release exenatide is associated
with medullary thyroid carcinoma in rodents.
Surgery
The results of surgical treatment for obesity in
adolescents are limited compared to data from
adults, but short- and intermediate-term outcomes
are accumulating. Consensus guidelines suggest
that an adolescent with a BMI greater than 40 with
the presence of a severe comorbidity or those with
a BMI greater than 50 with a less severe comorbid-
ity may be candidate for bariatric surgery assum-
ing that an appropriate program is available.
Anyone considering bariatric surgical treatment
for adolescent obesity should ensure that the child
is enrolled in a long-term outcomes study so that
the much needed data on the best approach to
complications and the advantages of surgical treat-
ment can be determined. Surgery requires a team
to screen appropriate patients and support the pro-
cess long into the postoperative period and is best
carried out in the environment of a clinical study
rather than in a local hospital and only at an ado-
lescent bariatric surgery center of excellence.
The longest-term experience in surgical
approaches to adolescent obesity involves the
Roux-en-Y gastric bypass (RYGB) whereby a
small pouch is created, separating it from the rest
of the stomach and allowing food to exit the stom-
ach directly into the middle section of the small
intestine. This leads to restriction in the amount of
food that will be eaten and changes the endocrine
milieu by decreasing ghrelin secretion from the
stomach since less of the stomach is exposed to
ingested food. Patients may lose 10 BMI points or
approximately 35 % of their weight in the first 6
months. There is limited long-term data, but it is
13 Obesity
suggestive of the adult literature in which weight
loss continues for years after the procedure.
Adjustable gastric banding is approved for patients
over 18 years of age but not for those that are
younger. Adjustable gastric banding decreases the
diameter of the stomach at the caudal region,
restricting the amount of food ingested. An inflat-
able band is placed around the antrum of the stom-
ach; the band can be inflated through a port
subcutaneously. There is more limited information
on this procedure in teenagers and due to compli-
cations is rarely used anymore. A more recently
developed procedure, vertical sleeve gastrectomy
which involves stapling or surgically removing
most of the stomach, leaving a tube connecting the
esophagus with the duodenum, holds promise, but
there is less data in adolescents with this proce-
dure. Further data is required on the effects of sur-
gery in teenagers, and ongoing national studies
will direct the clinician in the future.
There are guidelines for the choice of appropri-
ate patients to undergo surgery. If a girl is 13 years
old or a boy is 15 years of age, bariatric surgery
can be considered according to recent guidelines if
the adolescent has failed 6 months of organized
attempts at weight management (determined by
their primary care provider), has attained or nearly
attained physiologic maturity, is severely obese
(BMI > 40) with serious obesity-related comor-
bidities or has a BMI of >50 with less severe
comorbidities, demonstrates commitment to com-
prehensive medical and psychologic evaluations
both before and after surgery, agrees to avoid preg-
nancy for at least 1 year postoperatively and will
not or is not breast feeding, is capable of and will-
ing to adhere to nutritional guidelines postopera-
tively, provides informed assent to surgical
treatment, demonstrates decisional capacity, and
has a supportive family environment. Severe com-
plications are type 2 diabetes mellitus, OSA, and
pseudotumor cerebri. Less severe complications
are hypertension, dyslipidemias, nonalcoholic ste-
atohepatitis, venous stasis disease, significant
impairment in activities of daily living,
­intertriginous soft tissue infections, stress urinary
incontinence, gastroesophageal reflux disease,
weight-related arthropathies that impair physical
activity, and obesity-related psychosocial distress.
Laboratory Evaluation of Childhood Obesity
Prevention
With one-third of the childhood and teenage pop-
ulations overweight or obese, it is clear that pre-
vention must take a preeminent role in addressing
this epidemic. The encouraging news is that the
prevalence of obesity in children and adolescents
is not increasing in most US groups demonstrat-
ing the likelihood that some of the public health
measures that have been instituted are having an
effect. Prevention includes anticipatory guidance
that providers may give to families and patients.
The important issues of city planning and archi-
tectural design may not seem to be within the
purview of a pediatric practitioner, but these
areas require advocacy to develop safe play areas
and structures and accessible buildings that have
stairs easily available rather than the omnipresent
elevators. Other countries limit advertising to
children. This is an important area as children are
exposed to foods totaling as much as 20,000 calo-
ries per hour while watching television on
Saturday a.m. The USA does not limit advertis-
ing to children, and this is another appropriate
target for advocacy.
Encourage Parental Modeling
The major role model of small children is of
course parents. Parents having excessive por-
tions, taking multiple servings, or “grazing”
throughout the day interspersing such activity
with sugar-sweetened beverages and a sedentary
lifestyle may have an effect in children as young
as toddler years in developing bad habits. Some
parents have adverse habits that they refuse to
change while professing to want the children to
develop healthier habits. The parent must model
appropriate behaviors in diet and activity, and
clearly the family must be the model for the child
and must participate in the treatment along with
the child. Sometimes only one child in the family
is overweight or obese, while the others are thin.
Parents may say that they cannot treat the whole
family the same way just because of one child.
Indeed they can because the needs of the child
with obesity are a healthy dietary intake and
357
healthy activity level, and everyone including the
parents and the siblings can benefit from this life-
style modification.
 xpose Children to Healthy Food
E
in a Young Age
Children are born with a taste for sweet and
salt and an aversion to bitter and sour and
­demonstrate a tendency to avoid new foods (neo-
phobia); the desire for fat or oil, spice (other than
salt), and fat may be learned at an early age. Thus
a child will initially spit out green vegetables; if
the parent gives up such trials of healthful food,
resorting to sugary or salty, initially more palat-
able substitutes, the child may lose the chance to
acquire long-term healthful dietary habits. But
just as a lenient approach to diet may be harmful,
overly restricting food choices to the point at
which the child cannot learn to regulate their
intake, conversely, also may foster the develop-
ment of obesity.
Encourage Breast-Feeding
For many reasons, breast-­ feeding should be
encouraged in all children. However, breast-
feeding has not been conclusively demonstrated
to decrease the risk for obesity. Modern research
into the gut microbiome demonstrates that the
gastrointestinal flora of children delivered by
C-section differs from those delivered vaginally,
differs from children raised on formula rather
than breast milk, and as stated above, differs
from those who are obese with those who are
lean. Breast-feeding therefore is an important
aspect of developing a normal microbiome
which is more likely to lead to a healthier weight.
Further research progresses in evaluating probi-
otic treatment of infants who were raised on for-
mula to restore the gut flora to the normal
condition of a breast-fed baby.
Bottle-fed babies may have increased weight
as they may grow up less likely to regulate the
intake by their own choice. Formula or breast
milk may belong in a bottle, but juice and soft
358 13 Obesity

drinks do not: It is remarkable to note that there in a sedentary manner, but the best situation
are baby bottles for sale that have soft drink would be to have the child in a guided after-
insignias on them, and some parents believe that school program which encourages good nutri-
they should be filled with soft drinks even during tion, increased activity, and studying.
the first year. Bottles should be used only up to
about 1 year, if used at all. Bedtime bottle-­feeding  ecrease “Screen” Watching
D
is particularly discouraged, as this often leads to Television viewing is the most proven modifi-
formation of dental caries as well as increased able factor linked to the development of obe-
caloric intake. sity. The average US child watches more than
28 h of television or watching other electronic
screens per week. Television viewing decreases
Decrease or Eliminate the Intake beneficial physical activity and socialization.
of Sugar Sweetened Beverages Exposure to television advertising that features
and Limit the Intake of Juice highly caloric foods may affect the diet. Some
success has occurred with a curriculum aimed
An increase in each soda consumed per day in to decrease television viewing. The Academy
early teenage years leads to doubling the likeli- of Pediatrics recommends limiting screen time
hood of developing obesity. Indeed in a rough to no more than 2 h per day. Since homework
sense, a daily serving of 12 ounces of sugar-­ now requires screen use a goal is to balance
sweetened carbonated beverage can lead to a 20 lb necessary screen exposure with activity.
weight gain after 1 year, all things being equal
(this is only illustrative as the actual weight equiv-
alence will vary). Juice may seem more healthful Modify the Diet
than sugared drinks, but 8 oz of juice contains 100
calories, just as 8 oz of soda! The best exposure to A small indiscretion in caloric intake adds up.
fruit is in the actual fruit rather than juice from the Consistent changes in diet toward decreased cal-
fruit. It is difficult to consume enough fruit to ories and increased fruit and vegetables will lead
cause weight gain, but when the fruit is rendered to a beneficial effect. A child cannot exercise off
into juice, it is very easy to drink excessive calo- a highly caloric children’s fast-food meal (con-
ries. Parents should limit juice and encourage tains 750–1,400 calories or more) in the gym or
water intake. Milk is an important source of vita- on the exercise bicycle. Approach to diet is noted
min D and calcium, but low-fat or skim milk is above, but there is no substitute for a dietician
best in the approach to overweight or obesity. being involved in counseling. Refer to Figs. 13.3
and 13.4 for examples of the use of the USDA
MyPlate model.
Increase Public Safety

If a child is not allowed to leave the house for
fear of injury, the child will eliminate vigorous
activity and may stay in front of the television
set all day with servings of chips or sugar-sweet-
ened beverages easily available. “Latchkey” kids
are an unfortunate phenomenon in this economic
environment where both parents have to work,
sometimes at multiple jobs, when childcare or
after-school programs are not available. It may
be possible for a child restricted to the house to
use a video game that requires activity rather
than simply watching television or while sitting
Decrease Sedentary Time
Decreasing the time spent sitting or being driven
around by replacement of this time with activities
such as walking or playing is beneficial. No child
will suddenly change from sedentary habits to
vigorous activity, so aim for sustainable small
changes. Many children simply watch others par-
ticipate in gym class, so substitution with fun
activities rather than competitive activities may
increase participation by all and lead to habits
that might be retained. Since schools are at a
Laboratory Evaluation of Childhood Obesity 359

Fig. 13.4 (a and b) An example of goal setting in English and in Spanish for the introduction of the MyPlate model
into daily life. This tool may be used in motivational interviewing. Courtesy of Marilyn Townsend UC Davis with
permission
360
d­ istance from the location where children live
and children may be too young and the environ-
ment may be too dangerous for them to walk
alone to school, parents have organized “walking
school buses” where parents walk along with the
children, keeping them safe while monitoring the
progress in bringing them to school. Thus the
children have walked moderate distance and
increased energy expenditure and saved the envi-
ronment from car or bus emissions.
Conclusion: The best we can say about the obe-
sity epidemic is that it seems to have leveled off.
We cannot be proud that one-third of the adults in
the USA are obese and that 33 % of ­children are
obese or overweight. If the factors that changed in
the environment in which we raise children con-
tributed to the epidemic of obesity, changing such
environmental factors should decrease the preva-
lence of obesity. The steps outlined in this chapter
are in some cases supported by compelling evi-
dence, while others are suggestive of the common
sense approach to the problem. This is going to be
a long-term project for our country and the world.
It is likely to take decades and maybe generations
due to the epigenetic phenomena that affects sub-
sequent generations.
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 Pediatric Endocrine Emergencies
Much of this information is derived from the
previous chapters but is summarized in this for-
mat. It is much preferable to read the indicated
chapter, which covers the issues in detail.
Acute Adrenal Insufficiency
Patients might present with acute adrenal insuf-
ficiency if they have undiagnosed adrenal failure
or if they have been treated with high-dose gluco-
corticoids over 10 days or more and have recently
been abruptly taken off this medication. Adrenal
insufficiency may present with signs of glucocor-
ticoid deficiency such as hypotension and hypo-
glycemia or with combined glucocorticoid and
mineralocorticoid deficiency which will add
hyponatremia and hyperkalemia to the situation
and more likely lead to shock.
1. Signs and symptoms
(a) Adrenal insufficiency should be suspected
in children or adolescents who:
• Have a history of central nervous sys-
tem (CNS) surgery, trauma, tumors, or
congenital defects of the CNS, as noted
in Chap. 3.
• Have a history of ambiguous genitalia.
– In this case, investigate possible viril-
izing or salt-losing congenital adrenal
hyperplasia, as described in Chap. 8.
© Springer International Publishing Switzerland 2016
D.M. Styne, Pediatric Endocrinology, DOI 10.1007/978-3-319-18371-8_14
14
– You may assume that salt-losing adre-
nal insufficiency is present if sodium
decreases and potassium increases in a
child with ambiguous genitalia and
treat appropriately while diagnostic
measures are pending. If the child is a
phenotypically normal male, the pro-
vider will have no physical clues to the
diagnosis in a newborn, but if a viril-
ized female infant or child presents
with hyponatremia and hyperkalemia
after the neonatal period the provider
should consider adrenal insufficiency.
• Have a history of microphallus in boys
(suggest hypothalamic deficiency of
gonadotropins and possibly ACTH).
• Have evidence of hyperpigmentation
on skin, flexural surfaces, or mucous
membranes which would indicate ele-
vated ACTH secretion.
• Have a history of cessation or rapid
tapering of previous glucocorticoid
maintenance or high dose therapy
because of preexisting conditions of
the pituitary gland or adrenal gland.
• Have a history of cessation or rapid
tapering of previous glucocorticoid
maintenance or high dose therapy
because of numerous conditions treated
with glucocorticoid therapy including
neoplasia, autoimmune disease, allergies,
363
364
pulmonary disease, and renal disease
among others.
• Have midline defects of the head which
might be an indicator of hypo-pituitarism.
(b) The patient might exhibit symptoms of
acute adrenal insufficiency which could
be severe enough to lead to death and if
mineralocorticoid deficiency also occurs,
severe electrolyte abnormalities will be
noted. Symptoms of chronic glucocorti-
coid deficiency include hypoglycemia
and hypotension and shock, whereas min-
eralocorticoid deficiency is heralded by
hyponatremia with hyperkalemia, low-
voltage electrocardiogram (EKG) with
small heart on radiograph, tachycardia,
and acidosis and acidemia.
Signs that may indicate acute or chronic
adrenal insufficiency include:
• Weakness; fatigue OR malaise; leth-
argy increasing to anorexia, nausea,
vomiting; fever; a history of weight
loss or failure to gain weight, history of
hypoglycemia, and abdominal pain.
• Dehydration with tachypnea, postural
hypotension, decreased skin turgor, or
shock.
• Petechiae and purpura may occur
if meningococcemia or Waterson–
Friderichsen occurs.
• Proximal and symmetrical weakness
of the muscles due to steroid-induced
due to prior glucocorticoid therapy.
• Hypoglycemic seizures are possible.
• Physical features of Cushing disease as
described in Chap. 10 which would
suggest long-term glucocorticoid
exposure which might have recently
been interrupted.
• Postural hypotension or an increase in
pulse rate on standing may be seen; a
decrease of blood pressure of 10 mmHg
or an increase in pulse rate of 20 is
considered significant.
• Hypotensive or hypoglycemic shock.
• Coma or death is possible.
(c) Laboratory evaluation reveals:
• Low-serum cortisol (cortisol should
increase in a stressful situation): This value
will not return in an emergency situation
14 Pediatric Endocrine Emergencies
but should be obtained for future reference
if adrenal insufficiency is suspected.
• Adrenocorticotropic hormone (ACTH)
may be high or low depending on etiol-
ogy from adrenal disease or hypotha-
lamic-pituitary disease. Likewise this
will not return until well after the
emergency situation but may be help-
ful in making the diagnosis.
• Serum Na is low and K is high if min-
eralocorticoids are affected, as well as
glucocorticoids.
• Serum/blood glucose is low.
NOTE: Acute adrenal insufficiency
may present with hypoglycemia which,
unless the child is known to have adre-
nal insufficiency or glucocorticoid
dependence, should lead the provider
to obtain a critical blood sample which
will allow the diagnosis of the etiology
of hypoglycemia. The critical blood
sample is discussed in Chap. 12.
• Low-voltage electrocardiogram (EKG)
with tachycardia and small heart on
radiograph.
• EKG changes due to hyperkalemia
(peaked T waves).
• Hypochloremic acidosis.
• Eosinophilia due to decreased cortisol
is possible.
2. Glucocorticoid replacement is accomplished by:
(a) Immediate administration of hydrocortisone
in a dose of 1–2 mg/kg or 60 mg/m2 or 50 mg
for children under 4 years of age and 100 mg
for those over 4 years of age by subcutaneous,
intramuscular, or intravenous route. No sig-
nificant side effects are likely from giving too
much glucocorticoid replacement acutely, so
err on the higher dose if necessary. Cortisone
acetate is not an emergency medication as it
takes too long to exert its effect as is converted
to the active principle, hydrocortisone.
(b) Stress doses are three times maintenance
dosage (i.e., 50 mg/m2 of cortisol or
7.5 mg/m2 of 6-αmethylprednisolone
(Solumedrol)); this is considered if the
patient is affected by infection, surgery, or
severe illness and is continued until the
situation improves or until the patient is
stable.
Diabetic Ketoacidosis
(c) The maintenance phase is accomplished
by the administration of standard replace-
ment doses of glucocorticoid (6–15 mg/
m2/day orally, divided into four or three
doses/day). This can be given by mouth if
the patient is able to tolerate oral
administration or by i.v. or subcutaneously
(the oral dose is double the parenteral
dose) until maintenance therapy is started.
3. Hypoglycemia is treated as described later.
4. Hyponatremia with hyperkalemia is treated as
described later.
5. Volume expansion is accomplished by 20 mL/
kg of 5 % dextrose and normal saline as a
bolus in the first hour and maintenance or
replacement fluids thereafter in accordance
with standard fluid management.
6. It is imperative that if hypothyroidism and glu-
cocorticoid deficiency coexist that glucocorti-
coid be administered before or with thyroid
hormone, or any minimal glucocorticoid that
may be present endogenously which may be
exerting some effect will be more rapidly metab-
olized, leading to acute glucocorticoid-deficient
crisis. Thyroid metabolism changes slowly, so
there is no effect of thyroxine given in the emer-
gency room, but the effects will occur in several
days later which might be the time frame in
which such adrenal insufficiency will manifest.
7. Pay careful attention to the type of glucocorti-
coid being used for emergency treatment.
Hydrocortisone sodium succinate known as
Solu-Cortef or methylprednisolone sodium
succinate known as Solu-Medrol are fast-
acting preparations. However, the administra-
tion of cortisone acetate or prednisone will
require conversion to the active moiety and
should not be used in emergency situations.
Diabetic Ketoacidosis
1. The diagnosis of diabetic ketoacidosis requires
a blood sugar over 200 mg/dL, there is ketone-
mia determined by a serum beta-OH butyrate
greater than 4 mEq/L or ketones strongly posi-
tive by ketostix measurement at a greater than
1:2 dilution of serum, ketonuria with urinary
365
ketones present venous pH less than or equal to
7.30 and bicarbonate equal to 15 mEq/L or less.
2. Measurement of sodium, potassium, blood
urea nitrogen (BUN), creatinine, phosphorus,
magnesium, and white blood cell (WBC) count
[usually elevated in diabetic ketoacidosis
(DKA) even without infection] is performed.
3. Vital signs and neurological checks must be
checked frequently hourly.
4. Fluid and electrolyte replacement
(a) Although excessive and rapid fluid admin-
istration might cause serious complica-
tions, dehydration leading to thrombosis
is an alternative risk, so each patient must
be individualized for appropriate fluid and
electrolyte therapy.
(b) Fluid administration must be done with
care, but if indicated by signs of fluid defi-
cit, an i.v. bolus of 10 mL/kg of “isotonic”
fluid (0.9 % saline or lactated Ringer’s)
over a 30- to 60-min period is used and
repeated if necessary.
(c) Maintenance fluids are added to the defi-
cit replacement.
(d) Potassium will be deficient in DKA, so
after establishing urine output, add potas-
sium to the infusion at 30–40 mEq/
mL. Monitor electrocardiogram (EKG)
for abnormalities of potassium, as peaked
T waves occur in hyperkalemia and low
T waves and the development of U waves
occur in hypokalemia. Adequate urine
output must be established before admin-
istering potassium.
(e) Low phosphorus is a potentially danger-
ous complication of DKA, so KPO4 is
used as at least a portion of the replace-
ment of K if Calcium is normal.
(f) Evaluate clinical deficit, which will usu-
ally be between 5 and 12 % or even 15 %;
average is 7 % dehydration; the following
can be altered for more significant
dehydration.
• Deficit: Assume 7 % dehydrated;
weight (kg) × 70 = (a) _____mL.
• Remaining deficit; subtract all boluses
given: (a) − bolus IVF = (b) _____mL.
• Replace remaining deficit over 48 h:
(b)/48 h = (c) _____mL/h.
366
• Maintenance IVF: (d)_____mL/h.
• Total IVF (maintenance + remaining
deficit): (c) + (d) = _______mL/h.
(g) If serum glucose > 250 mg/dL
• Normal saline with 20 mEq KCl and
20 mEq KPO4 at total IVF rate.
(h) If serum glucose < 250 mg/dL
• D10 1/2 normal saline with 20 mEq
KCl and 20 mEq KPO4 at 1/2 total IVF
rate plus 1/2 normal saline with 20 mEq
KCl and 20 mEq KPO4 at 1/2 total IVF
rate to make D5 1/2 NS with 20 mEq
KCl and 20 mEq KPO4 at total IVF
rate. (Note; there is controversy over
whether normal saline should be used
in almost all situations including this.
You must use clinical judgement in the
condition of the patient to decide on
this issue)
(i) The remaining fluid deficit is adminis-
tered over the next 36–48 h.
(j) Bicarbonate therapy is associated with a
higher risk for cerebral edema and so should
not be used unless symptomatic hyperkale-
mia is found or the acidosis is severe enough
to cause hemodynamic instability not
responsive to other therapeutic measures. If
pH is < 7.0 and there is cardiovascular insta-
bility or symptomatic hyperkalemia, bicar-
bonate at a dose of 1 mEq/kg over 60 min
may be considered to extend; this is rarely
invoked because the use of bicarbonate is
associated with worsening intracellular aci-
dosis (cardiovascular and CNS) and hypoka-
lemia and the development of cerebral
edema; this decision must be individualized;
this chapter does not advocate routine bicar-
bonate administration.
5. Insulin management
(a) Intravenous regular human insulin at a
rate of 0.075–0.1 unit/kg/h is infused, and
blood sugar monitored hourly. If BS is
over 1,000 mg/dL with mild acidosis, a
rate of 0.05 unit/kg/h may be used.
(b) When blood sugar decreases to 250 mg/dL,
i.v. dextrose (10 %) is added to allow con-
tinued administration of insulin to bring
about resolution of the ketoacidosis safely;
discontinue insulin infusion only if BS can-
not be maintained over 150 mg/dL. Insulin
14 Pediatric Endocrine Emergencies
infusion may continue until the serum
bicarbonate is above 17–18 mEq/mL.
6. Monitoring
(a) Measure blood sugar by glucometer
or laboratory determinations every hour and
aim to decrease blood glucose by 10 mg/
dL/h. This rate may easily be exceeded, as
renal function, fluid, and insulin administra-
tion all exert effects on decreasing blood
sugar, so careful observation is mandatory.
Check extreme values with a laboratory
determination of glucose.
(b) Measure serum electrolytes, PO4, and Mg
every 6 h.
(c) Measure arterial or venous blood gasses
every 3 h.
(d) Perform at least hourly neurological exams.
Watch for deteriorating mental condition,
headaches, vomiting, or unusual behavior, as
these might indicate the development of cere-
bral edema. Physical signs might include
changing neurologic examination and papill-
edema. If necessary, confirm the develop-
ment of cerebral edema with head magnetic
resonance imaging (MRI), but adequate
medical support must accompany the patient
in case herniation becomes imminent.
Treatment of cerebral edema is difficult, and
generally the methods are unproven, but
mannitol (0.25– 1 mg/kg, i.v., given over 20
minutes every 2–4 hours or a total of 10–20 g/
m2) may be beneficial as long as dehydration
is not allowed to develop after the use of such
a hyperosmolar agent.
Hypocalcemia
1. The neonate
(A) Definition of hypocalcemia
• Although there is controversy over the
cutoffs, in term infants, serum Ca < 8.5 mg/
dL and ionized Ca < 4.5 mg/dL might pre-
cipitate symptoms but the diagnosis of
hypocalcemia is usually serum total Ca
less than 7.0 mg/dL or ionized.
• Ca2+ less than 3.5 mg/dL.
• In premature infants, serum Ca < 7.5 mg/
dL and ionized Ca < 4.4 mg/dL (or
Hypocalcemia
1.1 mmol/L) for birth weight > 1,500 g
and < 7 mg/dL and ionized Ca < 3.6 mg/
dL (0.9 mmol/L) for birth
weight < 1,500 g.
(B) Signs in the neonate may be only poor
feeding, emesis, crying and apnea or
more specific signs including tachycar-
dia, irritability, jitteriness, tetany, laryn-
gospasm, and frank seizures.
(C) Specific conditions leading to neonatal
hypocalcemia are the following:
• Early hypocalcemia of infancy tran-
siently during the first 3 days after birth
is most common in infants who are pre-
mature, have intrauterine growth retar-
dation (IUGR) or small for gestational
age (SGA), have sepsis, have asphyxi-
ation, or are infants of diabetic mothers
(the worse the control of blood sugar,
the lower the Ca in the baby). This may
also occur in infants fed with cow’s
milk-based formula.
• Late neonatal hypocalcemia lasts lon-
ger than 3 days or occurs after 3 days
and may be due to hypoparathyroidism,
dietary or renal disease associated with
hyperphosphatemia, increase in dietary
phytates due to soy formula or the early
introduction of cereal, hypomagnese-
mia, or pseudohypoparathyroidism.
• Suspect hypocalcemia in neonates
with undiagnosed seizures, a family
history of hypocalcemia or various
autoimmune diseases, tendency to
infections, and a defect of the great
arteries (e.g., truncus arteriosus).
• Look for EKG abnormalities of hypo-
calcemia as described below.
(D) Mild cases might be treated by a change in
formula to a low-phosphorus formula (such
as pm 60/40) or one with at least a 4:1 cal-
cium-to-phosphorus ratio in addition to
oral calcium glubionate (30–50 mg/kg/day
in four divided doses) or calcium gluconate
(500 mg/kg/day in 4–6 feedings per day).
(E) With severe symptoms including seizures
and laryngospasm, intravenous (i.v.) 10 %
calcium gluconate (equivalent of 9.3 mg/mL
of elemental calcium) in a dose of 100 mg/
kg or 1 mL/kg infused over 15 –20 min with
367
a total dose no more than 3 grams per dose of
calcium gluconate is used. Alternatively,
10 % calcium chloride in a dose of 20 mg/kg
or 0.2 mL/kg might be substituted with the
same regimen. EKG monitoring for arrhyth-
mias or bradycardia is mandatory at any
time i.v. calcium is administered. If an
umbilical venous catheter is used and the tip
is inadvertently inserted in the liver, hepatic
necrosis may result from IV calcium admin-
istration. A repeated dose may be adminis-
tered after 10–15 min if there has been no
response of the symptoms and every 6 h but
only if clinically indicated for continued
hypocalcemia. Maintenance intravenous
calcium is 10–50 mg of elemental calcium/
kg/24 h given as 10 % i.v. calcium gluconate
at a dose of 100–500 mg/kg.
(F) Severe hypomagnesemia as etiology for
hypoparathyroidism is treated with IM
injection or a 1–2-h intravenous infusion
of 50 % magnesium sulfate at a dose of
0.1–0.2 mL/kg, again with careful EKG
monitoring. The goal is to achieve a mag-
nesium level of 1.5 mg/dL.
2. The older child
(A) Symptoms of hypocalcemia include the
following:
• Neuromuscular signs including mus-
cle cramping, carpopedal spasms, tet-
any, weakness, and paresthesias.
• Cardiovascular signs including
Lengthening of the QTc interval may be
seen on the electrocardiogram (EKG) or
ventricular dysrhythmias, hypotension,
and syncope.
• The respiratory system might be affected
by laryngospasm or stridor, broncho-
spasm, respiratory distress, or apnea.
• Gastrointestinal symptoms include dys-
phasia, vomiting, and abdominal disten-
tion, and, in infants, feeding and crying.
(B) The classic signs of hypocalcemia are the
following:
• The Chvostek sign, in which tapping
the facial nerve below the zygomatic
arch causes a twitch at the angle of the
mouth due to contraction of the peri-
oral muscles, a demonstration of mus-
cular irritability.
368
• The Trousseau sign, in which a blood
pressure cuff is inflated at least
15 mmHg above the systolic blood pres-
sure for 2–5 min; a positive response is
indicated by carpopedal spasms in the
arm to which the cuff was applied.
• The peroneal sign, in which a tap on
the peroneal nerve near the lateral tib-
ial prominence causes plantar flexion
(although tapping any nerve may lead
to contraction of the associated mus-
cle, other contractions may be more
difficult to demonstrate).
(C) EKG changes of hypocalcemia include
the following:
• Prominent U wave
• Narrowing of the QRS complex
• Reduced PR interval
• T wave flattening and inversion
• Prolongation of the QTc interval
• Prolonged ST and ST depression
(D) Etiologies of hypocalcemia:
• Endocrine diseases as discussed in
Chap. 7.
• Other medical conditions and treatment
include the use of phosphate-contai-
ning enemas and calcium chelation
occurring with blood transfusions.
3. While symptoms might occur if total Ca is
less than 8.5 mg/dL, hypocalcemia is defined
as serum total Ca less than 7.0 mg/dL or ion-
ized Ca2+ less than 3.5 mg/dL.
4. For severe symptomatic hypocalcemia, oral
elemental calcium of 45–64 mg/kg/day given
in 4 equal doses or 10 % calcium gluconate is
given as a dose of 100 to 200 mg/kg/dose or
1–2 ml/kg/dose over 5–20 min up to a total of
10 mL, given with EKG monitoring (brady-
cardia and asystole are possible complica-
tions, and infusion should stop if pulse
decreases to less than 60 beats/min or given
extremely carefully if pulse decreases to less
than 100 beats/min). During the administra-
tion of i.v. calcium, it is important to avoid
extravasation, which may cause severe slough-
ing of the skin, possibly requiring plastic sur-
gery. The infusion may be repeated if it is
necessary for the relief of symptoms but is
followed by a maintenance dose of oral ele-
14 Pediatric Endocrine Emergencies
mental calcium of 400–1200 mg/day or by
10 % i.v. calcium gluconate at a dose of 100–
500 mg/kg over a 24-h period for neonates
and 100–200 mg/kg for infants or older
subjects.
5. Prolonged therapy in hypoparathyroid states
includes 1,25(OH)2 vitamin D (this form,
known as rocaltrol, eliminates the need for
1-hydroxylation of vitamin D that is impaired
in hypoparathyroidism), given at a dose of
20–40 ng/kg/day (0.25–0.75 μg, calculated as
twice daily) with, if necessary, oral calcium
supplementation adequate to maintain serum-
ionized calcium.
6. In the hyperphosphatemic state due to hypo-
parathyroidism, phosphorus is restricted in the
diet until serum phosphorus decreases to near-
normal levels, which should occur when
serum-ionized calcium approaches normal.
7. Serum-ionized calcium should be measured
regularly until stability is achieved to assure
that serum calcium remains in the normal range.
8. If magnesium is low and is a possible etiology
for hypoparathyroidism, magnesium sulfate
(50 % solution) may be given as 0.1–0.2 mL/
kg i.m. every 12–24 h, as needed. The goal is
to achieve a magnesium level of 1.5 mg/dL.
Hypercalcemia
1. Hypercalcemia is defined as serum calcium
value above the age-related normal for the
laboratory for age, but symptoms are usually
noted above 10.8–11.3 mg/dL.
Symptoms of hypercalcemia are the
following:
(a) Weakness and listlessness.
(b) Irritability.
(c) Abdominal discomfort and symptoms
including nausea and vomiting, abdomi-
nal pain, and constipation.
(d) CNS symptoms including depressed con-
sciousness and confusion.
(e) Polyuria and polydipsia.
• In the neonate may manifest gastroesoph-
ageal reflux, lethargy, decreased weight
gain, and lack of growth in length.
Hypercalcemia
• In the older child:
– Neurological symptoms including
lethargy, weakness, inability to con-
centrate, and depression.
– Abdominal discomfort and symp-
toms including nausea and vomit-
ing, abdominal pain, constipation,
and weight loss.
• Hypercalcemia leads to polyuria due to
an inability to concentrate the urine;
dehydration and azotemia may result.
2. Signs of hypercalcemia are the following:
(a) Band keratopathy of the medial and lat-
eral margins of the cornea (nonpurulent
conjunctivitis).
(b) EKG changes of hypercalcemia include
the following:
• With mild hypercalcemia, broad-based
tall peaking T waves
• With severe hypercalcemia
– Extremely wide QRS
– Low R wave
– Disappearance of P waves
– Tall peaking T waves
• Shortening of the QTc interval
• Shortening of the ST interval
(c) Hypertension.
(d) Hypercalciuria and nephrolithiasis.
(e) Pancreatitis.
(f) Peptic ulcer disease.
(g) If serum calcium increases to more than
16 mg/dL, stupor and coma may develop.
3. Suspect hypercalcemia in a:
(a) Child with history of hypoparathyroidism
treated with a long acting vitamin D prepa-
ration, perhaps with calcium replacement.
(b) Child with family history of multiple
endocrine neoplasia type 2 (MEN 2).
(c) Child with mucosal neuromas characteristic
of multiple endocrine neoplasia type 3
(MEN 3).
(d) Immobilized child.
(e) Child with various malignancies including
leukemia.
(f) Child with megavitamin therapy particu-
larly with vitamin D or A.
(g) Child with physical features of Williams
syndrome.
(h) Neonate with subcutaneous fat necrosis.
369
(i) Child with treatment with thiazide
diuretics.
4. Laboratory values include the following:
(a) Serum Ca more than 10.8–11.3 mg/dL.
(b) If parathyroid hormone (PTH) is present
in excess, serum PO4 is low.
5. Treatment is as follows:
(a) Nonsymptomatic hypercalcemia requires
simple measures including increasing
hydration with, e.g., sodium chloride
infusion at twice maintenance if the
patient can tolerate increased hydration,
decreasing oral calcium intake, and lim-
iting vitamin D intake including
multivitamins.
(b) For severe hypercalcemia furosemide,
1 mg/kg, may be given by i.v. slowly if
calcium is not decreasing, to increase
urinary calcium excretion. Because the
patient may initially have some degree of
dehydration, the sodium chloride infusion
must be used in concert with the diuretic.
Thiazide diuretics should not be used in
hypercalcemia if it is able to enhance
calcium retention.
(c) Sodium sulfate and sodium phosphate
may be administered and other phos-
phates to bind calcium in the intestine, but
oral phosphates may result in diarrhea.
(d) Oral glucocorticoids (prednisone at
1–2 mg/kg/day) decrease calcium absorp-
tion from the intestines and may be used
in severe cases of hypervitaminosis D but
are not effective in cases of hyperparathy-
roidism.
(e) If serum calcium is greater than 14 mg/dL,
calcitonin (2–4 units/kg/injection s.c., every
6–12 h as needed) or bisphosphonates
(e.g., pamidronate, 0.5–1.0 mg/kg/dose i.v.
over 4–5 h, repeated once as necessary up
to 2 mg/kg/dose) may be effective, but nei-
ther are FDA approved for children.
6. If renal failure coexists, renal dialysis might
be necessary to decrease serum calcium.
7. If malignancy-derived PTH-related protein
(PTHRP) is the etiology, Plicamycin (for-
merly known as mithramycin) at 25 μg/kg/day
may be used but may not be available; liver
toxicity is a side effect.
370
Hyperthyroidism in the Neonate
1. Hyperthyroidism is rare as a primary diagnosis
in the newborn but is seen in infants whose
mothers have hyperthyroidism (which might
yet not be diagnosed in the mother). If the
mother has previously diagnosed hyperthyroid-
ism and was taking oral meds, e.g., imidazole or
propylthiouracil to treat the hyperthyroidism,
the medication will pass through the placenta to
the fetus and the newborn may have a positive
hypothyroid screen initially only to develop
symptoms of hyperthyroidism several days
after birth when the antithyroid medication is
metabolized and eliminated. Sometimes the
appearance of hyperthyroidism in this situation
occurs weeks after birth.
If the mother is receiving excessive doses of
antithyroid medication, the fetus may develop a
goiter so severe that respiratory compromise
occurs immediately after birth: newborns have
died in this situation.
2. Signs of hyperthyroidism in the newborn
include the following:
(a) Neurologic symptoms including shakiness.
(b) Cardiovascular signs including tachycar-
dia or even congestive heart failure due to
supraventricular tachycardia. (Some
babies have been admitted to the neonatal
intensive care unit with supraventricular
tachycardia and may receive suboptimal
treatment if hyperthyroidism is not ini-
tially suspected.)
(c) Hepatosplenomegaly may occur with the
development of congestive heart failure.
3. Laboratory findings include:
(a) Elevated serum-free T4 or total T4 accord-
ing to age-appropriate standards for
newborns according to the laboratory per-
forming the analysis.
(b) TSH is usually suppressed as the thyroid
gland is stimulated by immunoglobulins
in this condition. As stated above, TSH
might be elevated in the first days after
birth in infancy if the mother was taking
thyroid-suppressive medication.
14 Pediatric Endocrine Emergencies
4. Emergency treatment includes the following:
(a) Propranolol (1–2 mg/kg/day divided into
three or four oral doses) may be used to
counter the sympathetic effects of hyper-
thyroidism (see later).
(b) Corticosteroids given as an intravenous
injection of 5 mg/kg of hydrocortisone
(the maximal dose of 100 mg ) inhibit the
conversion of thyroxine to T3 and
decrease secretion of thyroxine and the
thyroid gland.
(c) Lugol’s solution of supersaturated potas-
sium iodine may be used to suppress thy-
roid hormone secretion (one drop every
8 h is usually adequate).
(d) Some have suggested the use of digitalis
or sedatives might be indicated in severely
affected neonates.
(e) A severely affected neonate with hyper-
thyroidism may have symptoms for up to
6 weeks or more and for that reason
methimazole is started (0.25–1 mg/kg/
day divided into three doses). However,
the child must be watched closely for res-
olution of hyperthyroidism that usually
occurs before 12 weeks or sooner.
Continued treatment with methimazole
when thyroid function escapes from stim-
ulation by the maternal immunoglobulins
would lead to iatrogenic hypothyroidism
and subsequent developmental delay.
Thyroid Storm in Children
and Adolescents
1. This is a rare complication to be suspected in
children with:
(a) A history of hyperthyroidism with
intercurrent
• Infection
• Surgery including thyroid surgery
• Radioactive iodine therapy
• Diabetic ketoacidosis
• Pregnancy
(b) Alternatively it can occur as the first
manifestation of an undiagnosed case of
hyperthyroidism.
Hypoglycemia
2. Thyroid storm is indicated by an acute onset
of hyperthermia and tachycardia in a patient
with underlying hyperthyroidism. It may
occur during surgical or radioiodine therapy
for hyperthyroidism.
3. Symptoms include
(a) High fever
(b) Sweating
(c) Tachycardia
(d) Reduced mental status, ranging from con-
fusion to coma
4. Immediate therapy is indicated.
(a) Propranolol is used in a starting dose of
1–3 mg/kg/day, divided into an oral dose
every 6 h to control adrenergic symptoms
of thyroid storm. Propranolol may be given
i.v. at a dose of 0.01 starting dose mg/kg,
up to a total of 5 mg over 10–15 min, but
an intraatrial pacing catheter is a necessary
precaution: start with the lower range of
doses. Atenolol is suggested to be prefera-
ble to propranolol due to its more selective
cardiac effects but there is little experience
in children. It is reported to be used in 1–2
mg/kg per day as a single daily dose or
given every 12 hours; maximum is reported
to be 100 mg/dose.
(b) Dexamethasone in a dose of 1–2 mg (i.v.
dose is 0.2 mg/kg) and/or hydrocortisone
at 5 mg/kg every 6 h (the maximal dose of
100 mg ) can decrease conversion of T4 to
T3 and decreases secretion of thyroxine
from the thyroid gland.
(c) Intravenous NaI in a dose of 125–250 mg
up to 1–2 g/day may decrease the release
of thyroid hormone from the thyroid
gland; Lugol’s solution of concentrated
iodine in a dose of five drops once every
8 h by mouth should be given if the
patient is conscious.
(d) A cooling blanket or tepid bath can help
control the hyperpyrexia as can acetamin-
ophen (do not use aspirin in childhood).
(e) Methimazole will not take effect for sev-
eral days, but to plan for the likely
extended course of the disorder, a dose of
0.6–0.7 mg/kg/d up to 20–30 mg/day can
be given every 6 h by slurry, if necessary.
371
(f) Appropriate fluid management must be
instituted, and if tachycardia causes heart
failure, digitalis may be necessary.
Hypoglycemia
1. Diagnosis is made if:
(a) Plasma glucose is less than 60 mg/dL or,
because whole-blood glucose is 15 % lower
than serum or plasma glucose, blood glu-
cose is less than 50 mg/dL or capillary sugar
is less than 60 mg/dL (but not when the
blood has been sitting for hours at room
temperature allowing the red cells to metab-
olize the glucose bringing down the value).
(b) A critical sample must be obtained if BS is
<50 mg/dL or an important opportunity to
make a diagnosis of the etiology of hypo-
glycemia will be lost. Obtain, if safe,:
• Glucose
• Insulin
• Ketones
• Growth hormone
• Cortisol
• Lactate
• Pyruvate
And if possible:
• Free fatty acids
• C-peptide
• IGF-1
• IGF-11
• IGF BP1
• Ammonia
• Amino acids
• Free and bound carnitine
• Save as much serum/plasma as possi-
ble for future determinations
(c) Hypoglycemia is suspected in a child with a
host of resulting conditions including sepsis
or exposure to toxins. In terms of endocrine
disorders, the following is a basic list:
• Child with diabetes mellitus receiving
insulin treatment
• Child with disorder of carbohydrate
metabolism
• Child with congenital hypopituitarism
• Boy with microphallus
372
• Child with midline defect
• Child recently discontinued on sup-
pressive doses of glucocorticoids
• Child fasted for extended period
• Infant who was recently exposed to
fructose and sucrose and developed
symptoms thereafter
2. Presenting symptoms awakening concern for
hypoglycemia in the newborn are nonspecific
and range from:
(a) Grand mal or localized seizures to
(b) Irritability
(c) Hypotonia
(d) Lethargy
(e) Difficulty in feeding, to
(f) Other rather nonspecific findings, to
(g) No findings at all because of the immatu-
rity of the CNS
(h) Hypoglycemia may occur during sepsis
and some of the hypoglycemia symptoms
may be mistaken for sepsis
3. Presenting symptoms in the child are
(a) Adrenergic including
• Sweating
• Shaking
(b) Neuroglycopenic
• Confusion
• Stupor
• Coma
• Seizures
4. Physical exam aims to rule out
(a) Hyperpigmentation of primary adrenal
insufficiency.
(b) Microphallus in a boy.
(c) Midline defects, optic nerve hypoplasia,
and pendular nystagmus, all suggestive of
hypopituitarism.
(d) Hepatomegaly which might be found in
glycogen storage disease type 1, gluconeo-
genesis defects, hereditary fructose intoler-
ance, or fatty accident oxidation disorders.
5. The initial treatment of hypoglycemia must be
the administration of glucose sufficient to
bring the blood glucose to adequate levels to
return neurologic function to normal but not
excessive glucose which will cause severe
increased osmolality.
(a) In a child who is only moderately symptom-
atic, oral glucose is adequate; table sugar,
14 Pediatric Endocrine Emergencies
honey (only if the child is well older than 1
year and not at risk for infant botulism), or
glucose gel/jelly can be ingested or admin-
istered to the child’s buccal mucosa if the
child is too disoriented to swallow.
(b) For more severe hypoglycemia, i.v. glu-
cose is necessary.
• Dextrose in water is given in 25 % con-
centration or less as a bolus of 1–2 mL/
kg or 0.25–0.5 g of dextrose/kg body
weight: alternatively, 1–2 mL/kg/dose
of 10 % dextrose; 0.1–0.2 mg/kg/dose
may also be used for initial therapy. If
more dextrose in higher concentration
(dextrose vials are supplied as 50 %) is
administered, a risk exists of causing
hyperosmolality, and in infants and neo-
nates, D10W is preferable to any more
concentrated preparation.
• The dextrose percentage may be multi-
plied by the number of milliliters
administered per kilo and the result
should equal 50 or less for appropriate
therapy.
• Glucagon Emergency Kit for children
with diabetes or hyperinsulinism if i.v.
access proved difficult. Glucagon will
not work in most types of ketotic
hypoglycemia.
• Once the blood sugar increases, the
child should be observed for improved
clinical condition; if the sugar again
decreases, an infusion of dextrose,
5–10 %, should be started. Sodium
chloride must be in the maintenance
dextrose infusion to avoid hyponatre-
mia developing as the hypoglycemia is
repaired. The infusion rate will usually
be 6–8 mg/kg/min of glucose which is
approximately 1.5 times maintenance.
• If a glucose infusion rate of more than
12–15 mg/kg/min of glucose is
required or repeated larger glucose
boluses needed, the child has severe
hypoglycemia, most likely due to
hyperinsulinism. Abrupt discontinua-
tion of dextrose support may lead to
rebound hypoglycemia in a child who
does not have hyperinsulinism due to
Hyponatremia/Hyperkalemia Due to Adrenal Insufficiency
the normal increase in insulin secre-
tion caused by dextrose administra-
tion. This rebound condition should
not be confused with bona fide
hyperinsulinism.
• As transient hypoglycemia resolves,
weaning off i.v. dextrose is followed by
frequent oral administration of glucose-
containing substances as the child can
tolerate under careful observation.
• Prolonged treatment aims to achieve a
value of more than 60 mg/dL at all
times and normal values of 70–120 mg/
dL at least most of the time.
Hyponatremia/Hyperkalemia
Due to Adrenal Insufficiency
1. Laboratory values include
(a) Serum sodium less than 135 mg/dL.
(b) Serum potassium greater than the upper
limits of normal for age the laboratory
has used. For example:
• Above 7.2 mEq/L in premature infants
• Above 5.2 mEq/L in term newborns
• Above 5.8 mEq/L in older children
• Above 5.5 mEq/L in adults
2. This situation is suspected in
(a) Children with ambiguous genitalia who
might have virilizing congenital adrenal
hyperplasia.
(b) Children with a history of glucocorticoid
deficiency who may also have mineralo-
corticoid deficiency.
(c) Children in shock (who might have adre-
nal failure).
(d) Children with acquired hyperpigmentation
who might have elevated ACTH secretion.
(e) Children with an autoimmune disease
such as Hashimoto’s thyroiditis who pres-
ent with hyponatremia.
(f) Diabetes mellitus can present with hypo-
natremia due to elevated glucose or
osmotic diuresis in DKA but there should
be some historical or laboratory indica-
tions of the presence of diabetes.
3. Hypoglycemia may occur as well as hypona-
tremia because adrenal insufficiency may be
373
generalized: follow the guidelines for hypo-
glycemia listed earlier.
4. Hyponatremia is treated as follows:
(a) With the intravenous infusion of normal
saline in normal replacement volumes.
(b) If the patient is seizing from hyponatre-
mia, 3 % NaCl might be infused in doses
sufficient to increase the serum Na until
seizures stop; 3 mL/kg every 10–20 min is
a useful dose.
5. Hyperkalemia
(a) Replacement of i.v. fluid with sodium will
usually reduce potassium levels to a
degree or may normalize them.
(b) If the EKG demonstrates the following
abnormalities, calcium infusion may be
administered but is quite dangerous (as is
severe hyperkalemia):
• Peaked T waves
• Widening of the PR interval
• First-degree heart block
• Loss of the P wave
• Ventricular arrhythmia
(c) 10 % calcium gluconate at a dose of
0.5 mL/kg i.v., over 5–20 min, may be
administered to stabilize the membranes.
• If pulse decreases to less than 60 beats/
min, calcium infusion should cease.
• If the pulse decreases to less than
100 beats/min, calcium infusion can be
continued, but only with exceptional
care under continued EKG monitoring.
(d) Sodium bicarbonate, 7.5 %, given as
2–3 mL/kg over 30–60 min, will tend to
drive K into the cells as pH rises, reducing
serum K.
(e) 50 % Glucose plus 1 unit of insulin for
every 5–6 g of glucose given over 30 min
will tend to drive K into the cells, reduc-
ing serum K. However, because children
with adrenal insufficiency have a ten-
dency toward hypoglycemia, this therapy
carries danger and must be used with the
utmost caution.
(f) Sodium polystyrene sulfonate
(Kayexalate) resin in a dose of 1 g/kg
(possibly given in 10 % glucose at
1 g/4 mL) may be given every 4–6 h to
increase loss of potassium in the gastroin-
374
testinal (GI) tract. This is not an emergency
treatment.
(g) Oral Florinef is the best treatment for
hyponatremia and hyperkalemia of adre-
nal insufficiency but will take a matter of
hours to work. At present, no parenteral
treatment exists for mineralocorticoid
deficiency.
Hyponatremia Resulting
from Syndrome of Inappropriate
Secretion of Antidiuretic Hormone
1. Syndrome of inappropriate secretion of antid-
iuretic hormone (SIADH) should be suspected
in a child who:
(a) Has had CNS trauma or infection.
(b) Has increased intrathoracic pressure due
to, for example, pneumonia or is receiv-
ing positive-pressure ventilation.
(c) Has decreased serum sodium (sodium
less than 135 mg/dL), or decreased serum
osmolality in spite of:
• Urinary concentration out of propor-
tion for the serum osmolality.
• No hyperlipidemia, hyperproteinemia,
or hyperglycemia as a cause of low-
serum sodium.
• No concomitant hyperkalemia along
with hyponatremia.
2. During the episode of hyponatremia, i.v. infu-
sion of normal saline is used in a milliliter-
per-milliliter replacement given every 1–4 h
for all urinary losses; this will allow an effec-
tive increase in serum sodium without an
increase in fluid volume since insensible
losses will not be covered. Alternatively, with-
holding fluids under close observation until
the condition resolves may be tried in less
severe cases. This process must consider the
state of hydration so that the patient does not
become clinically dehydrated and/or go into
hypotensive shock while fluids are limited.
3. If the patient is seizing from hyponatremia,
3 % NaCl might be infused in doses sufficient
to increase the serum Na until seizures stop;
3 mL/kg given every 10–20 min until symptoms
of hyponatremia resolve is one recommended
14 Pediatric Endocrine Emergencies
therapy. Sodium loss in the urine will continue
until SIADH is resolved, so 3 % sodium chlo-
ride treatment used to resolve hyponatremic
seizures will be effective only temporarily
until the cause of SIADH is resolved.
4. Furosemide (1 mg/kg) might be used and the
volume excreted replaced with 3 % NaCl to
allow an effective increase of serum sodium to
control the seizure; frank dehydration is a pos-
sible outcome if fluid volume is not watched
carefully. This process is dangerous.
5. Dilantin, 5–10 mg/kg, has been used in patients
with seizures due to CNS etiologies of SIADH.
6. Demeclocycline is a tetracycline derivative that
reduces the ability of the nephron to respond to
vasopressin (AVP) and may be used for chronic
SIADH in a dose of 10 mg/kg; this molecule is
a modification of tetracycline, this might
adversely affect tooth development if used for
long periods in young children.
7. For chronic cases of SIADH, refer to Chap. 3.
Hypernatremia Due to Diabetes
Insipidus
1. Diabetes insipidus is suggested in a child
who has:
(a) Increased serum osmolality
(b) Increased serum sodium
(c) Low urine osmolality
(d) Voluminous urinary output in spite of
high-serum osmolality
2. This condition is suspected in a patient who
presents with:
(a) Signs of dehydration including sunken
eyes, dry mucous membranes, and sunken
fontanel in infants (because a tendency
exists toward hypernatremic dehydration,
the loss of skin turgor may not occur, and
the skin might feel “doughy” as a result).
(b) Has a history of CNS tumor, surgery or
accident, or bitemporal hemianopsia.
(c) Has a condition causing increased intra-
cranial pressure.
(d) Has midline defects of the head which
might be indicators of congenital hypo-
thalamic–pituitary disease.
Suggested Reading
3. This form of hypernatremia is due to loss of free
water rather than a condition of excess sodium.
4. The length of time since dehydration began
is important, as a chronic state will require
slower fluid-replacement program than in
acute cases.
5. If serum sodium is greater than 160 mEq/L, a
bolus of normal saline in a dose of 20 mL/kg
may be helpful; it is essential to bring the
serum sodium down slowly.
6. Volume deficit is calculated, and fluid replace-
ment is planned for the next 48 h.
7. The volume of urine output will change
remarkably from the large volumes before the
administration of DDAVP to lower volumes
afterward; using characteristic maintenance
formulas for IV fluids will lead to wide shifts
in serum osmolality and sodium concentra-
tions. Thus it is best to replace the urine vol-
ume lost over 1–4 h with an equivalent volume
of i.v. fluid over the next 1–4 h rather than
using simple maintenance formula to deter-
mine i.v. fluid administration. Once the vol-
ume of urine is controlled, routine maintenance
fluid calculations may again be appropriate.
8. DDAVP treatment is described as in Chap. 3,
but if the child cannot take oral or nasal
DDAVP, i.v. aqueous pitressin, at a dose of
2–3 mg/kg/min, or i.m. administration at
1–5 units per dose is an alternative.
9. At all times, evaluation of changes in serum
sodium and urine osmolality as well as con-
tinuous evaluation of the fluid balance with
respect to fluids administered and urinary
excretion are essential.
Hypertension
Due to Pheochromocytoma
1. These rare tumors are described in Chap. 10.
2. Symptoms may include headaches of a pound-
ing nature, palpitations with tachycardia and
sweating, and possibly flushing.
3. Signs include hypertension, usually of a
constant pattern, but episodic hypertension as
found in adults may occur in children.
4. Nervousness, tremor, fatigue, and thoracic
pain may be present.
375
5. Patients developing hypertension during the
induction of anesthesia, in patients suspected
of having MEN 2 or 3, and with malignant
hypertension unresponsive to usual methods
of therapy might be treated as follows:
(a) Alpha-adrenergic block should be admin-
istered before β-adrenergic blockade.
• Phenoxybenzamine is given orally (0.2
mg/kg/day increasing by 0.2 mg/kg/day
in 4 days and repeatedly until a maxi-
mum dose of 1.2mg/kg/day is reached
and high blood pressure is controlled;
doses start as once per day but split
daily doses given every 8–12 hours is
an alternatively) for long-term therapy.
• Phentolamine administered i.v. or i.m.
(high blood pressure is controlled) is
used for hypertensive crises that may
occur while the phenoxybenzamine
block is being established. Phentolamine
is not available in the US at the time of
this writing so an alternative Alpha
blocking agent must be used.
(b) β-Blockade by:
• Propranolol (5–10 mg given 3–4 times
per day orally for larger children) is
added when the heart rate increases as
the α-adrenergic blockade is being
established.
• Propranolol may cause paradoxic
hypertension if given before the
α-adrenergic block is established.
• If propranolol is ineffective in control-
ling blood pressure, α-methyltyrosine
(a tyrosine hydroxylase inhibitor) can
be started at 250–500 mg increased to
4 grams per day given in divided dos-
ing four times per day.
(c) Nitroprusside is used as a vasodilator
during surgical hypertension.
(d) Surgical preparation also includes admin-
istration of salt to repair the plasma
volume, which is invariably low.
Suggested Reading
Protocols are taken from the other chapters in the book,
with specific sources listed.
 Medications for Pediatric
Endocrinology
The following is a list of the some of the most
commonly used mediations for pediatric endo-
crinology. It is incumbent upon the prescriber to
check for allergies, contraindications, side
effects, and safety in pregnancy. Also note that
many of the medications are used in clinical
studies and presented in publications dealing
with children without FDA approval: they are
presented here for information, but the pre-
scriber must take the age of the patient into con-
sideration and understand that many medications
below are used “off-label” and precautions and
consent of parents are the responsibility of the
treating physician.
Some medications requiring more discussion
or used for specific testing are found in detail in
other chapters rather than listed here. Every effort
was made to check for accuracy of dosage listed
but recheking based upon the clinical situation
and age of the child is incumbent upon the reader
who may prescribe a medication.
Calcitonin, Human
While bisphosphonates are usually used in
osteogenesis imperfecta, calcitonin in a dose of 2
international units/kg three times a week with oral
calcium supplements (230–345 mg/day) for up to
48 months have been shown to be effective as well.
© Springer International Publishing Switzerland 2016
D.M. Styne, Pediatric Endocrinology, DOI 10.1007/978-3-319-18371-8_15
15
Calcitriol
(1,25-Dihydroxycholecalciferol)
Hypoparathyroidism:
0.04–0.08 μg/kg under 1 year of age, 0.25–0.50
between 1 and 5 years and 0.05 to 2 μg/day over 6
years of age.
Hypocalcemia:
0.25 μg/dose, p.o./day initially. Increase by
0.25 μg every 2–4 weeks while observing effects
on serum calcium.
Younger than 1 year, 0.04–0.08 μg/kg/dose/ day.
1–5 years, 0.25–0.75 μg/dose/day.
Older than 6 years, 0.5–2 μg/dose/day.
Calcium
Calcium Carbonate, Oral
40 % elemental calcium, so each mg contains
0.4 mg of elemental calcium.
200mg of elemental calcium is found in 500
mg tablet of Tums.
For calcium deficiency or for prophylaxis,
RDA values are:
0–6 months, 200 mg elemental calcium/day to
a maximum of 1,000 mg/day.
6–12 months, 260 mg elemental calcium per
day to a maximum of 1,500 mg/day.
377
378
1–3 years, 700 mg elemental calcium per day
to a maximum of 2,500 mg/day.
4–8 years, 1,000 mg elemental calcium per day
to a maximum of 2,500 mg/day.
9–13 years, 1,300 mg elemental calcium per y
to a maximum of 3,000 mg/day.
14–18 years, 1,300 mg elemental calcium per
day to a maximum of 3,000 mg/day.
These doses are usually divided into three
portions per day.
Calcium Citrate, Oral
21 % elemental calcium so that each mg of cal-
cium citrate contains 0.211 mg elemental cal-
cium. Dosing is as for calcium carbonate.
Calcium Glubionate, Oral
Elemental calcium (6 %), available as 115 mg
elemental calcium/5 mL in a 10% solution.
Neonate with hypocalcemia: 1,200 mg/kg/
day, divided into q.i.d. to t.i.d.
Maintenance: 600–2,000 mg/kg/day, up to
9 g/day, divided q.i.d.
Adults: 6–18 g/day, divided into q.i.d.
Calcium Gluconate IV
9 % elemental calcium so that each mg of cal-
cium gluconate contains 0.093 mg of elemental
calcium; injection is 10 % solution so that each
mL of a 10 % calcium gluconate solution con-
tains 9.3 mg (0.465 mEq) of elemental calcium.
All calcium infusion can cause severe scarring if
extravasation occurs.
Hypocalcemia
Neonates: By slow IV injection at 100 mg/kg/day
(1 ml/kg/day) infusion over 15–20 minutes with
constant EKG monitoring; dose can be repeated
in 10 minutes if necessary or can be divided into
4–6 doses over the day to no more than 1 gram
for each dose. Maximum rate of infusion is
15 Medications for Pediatric Endocrinology
1.5 mL/min or 200 mg/min. For severe
symptomatic hypocalcemia 100 to 200 mg/kg/
dose which can be repeated if needed in 6 hours.
Alternatively 200 to 800 mg/kg/day can be given
by continuous IV infusion.
Children: 200 up to 500 mg/kg/day which is
2–5 mL of a 10 % solution by slow IV injection
at about 1.5 mL/min infusion over 15–20 min-
utes; dose can be divided into 4–6 doses over the
day to no more than 2–3 gram for each dose.
Alternatively a continuous infusion of 200–
800 mg/min may be given.
Oral: 400–800 mg/kg/day, divided into q.i.d.
Child: Oral or IV is 200–500 mg/kg/day,
divided into q.i.d.
Adult: Oral or IV is 5–15 g/day, divided into
q.i.d.
Calcium Lactate, Oral
13 % elemental calcium.
Infants: 400–500 mg/kg/day, divided into q4
to 6 h.
Children: 500 mg/kg/day, divided into q4 to 6 h.
Adults: 1.5–3 g/given t.i.d.
DDAVP
1-Deamino-8-D-arginine vasopressin.
Dosages of spray dispenser is 0.1 mL (10 μg)
per spray or 10 μg per dose.
Concentration of the preparation using the
rhinal tube is 0.01 mg/0.1 mL the tube divided
into 0.2, 0.15, 0.1 and 0.05 mL for 20, 15, 10 and
5 μg doses.
Tablets are available in 0.1, 0.2 mg forms.
Injectable dose is 1/10 the intranasal dose.
For diabetes insipidus.
Children: 0.05 mg/dose orally given up to
0.8 mg given qd to b.i.d.; 10–30 μg/day given
intranasally divided into qd to b.i.d.
Ergocalciferol (Vitamin D2)
Usually given with calcium supplementation.
Monitoring of vitamin D levels is necessary.
Hydrochlorothiazide 379

Dietary Supplementation Estrogen

Newborn infant: 400 IU/day. See Chap. 9.

Premature infants: Doses equal to or greater
than 400 IU/day with monitoring.
Infants over 1 year and children: 600 IU/day. Fludrocortisone Acetate (Florinef)

0.05–0.1 up to 0.2 mg/day, with added salt to

Vitamin D Deficiency diet, depending on the degree of salt-losing ten-
dencies and response. Watch for hypertension as
There are various schema of therapy depending an indication of excessive dosage.
upon the degree of deficiency which differ but for
example: 1,000 IU daily for infants less than 1
month for 6 weeks. Glucagon HCl
1,000–2,000 IU daily for age 1–12 months for
6 weeks. Given IV, i.m., sc or p.o. for severe hypoglycemia
2,000 IU daily for >1-year-olds or 50,000 IU if oral administration of glucose is difficult or
per week for 6 weeks. dangerous due to decreased mentation.
Monitoring 25 OH vitamin D is necessary to Neonates and children less than 20 kg: Give
avoid overdosage. 0.5 mg/dose or 0.02–0.03 mg/kg dose.
Children more than 20 kg: 1 mg/dose, repeat
in 15–20 min if necessary.
Nutritional Rickets Give oral carbohydrates if they are awake if
possible instead.
1,000–2,000 IU/day orally. Mini glucagon dose may be used to raise
200,000 IU every 3 months is an alternative blood sugar in nonemergent situations if the
method. ketones are less than moderate or large:
If there is malabsorption or hepatobiliary dis- For a child 2 years old or under, give 20 μg
ease: 10,000–25,000 IU/day. and give 10 μg more for each year of age for chil-
If there is anticonvulsant-related rickets: dren over age 2 to a maximum of 150 μg.
1,000 IU/day.

Vitamin D-Resistant Rickets Glucocorticoid Preparations

25,000–100,000 IU/day and increase as necessary. See Table 15.1 and Chaps. 8 and 10.

Vitamin D-Dependent Rickets

Growth Hormone Secretagogue
3,000–50,000 IU/day and increase as necessary. Testing

L-Dopa: 125 mg for body weight up to 15 kg,

Hypoparathyroidism or
Pseudohypoparathyroidism
Initiate with doses up to 8,000 IU/day for 1–2 weeks.
Children: 2,000 IU/day maintenance.
250 mg for weight up to 35 kg, and 500 mg for
body weight over 35 kg.
Clonidine 0.1–0.15 mg/m2.
Intravenous arginine infusion of 0.5 g/kg body
weight up to 20 g over a 20-min period.
380 15 Medications for Pediatric Endocrinology

Table 15.1 Glucocorticoid preparations

Glucocorticoid effect
(based on anti- Mineralocorticoid effect
inflammatory effect [fludrocortisone Time of biologic
with cortisol = 1.0) (fluorine) = 1.0] action (h)
Cortisol (hydrocortisone) 1 0.005 8
Cortisone 0.8 0.005 8
Prednisone 4 0 18
Prednisolone 4–5 0 16–36
6α-Methylprednisolone 5–8 0 16–36 est
Dexamethasone 27–66 0 36–54
9α-Fluorocortisone 15 1 24–36

Insulin-induced hypoglycemia (0.075–0.1 units/ Table 15.2 Actions of commercially available insulin
kg body weight of insulin given IV) is an extremely preparations
dangerous test; read warnings in Chap. 5. Onset of Peak Duration
Glucagon 30 μg/kg up to 1 mg Preparation action activity of action (h)
Aspart 10– 40–50 min 3(to 5)
20 min
Lispro 15– 30–90 min 3(to 5)
30 min
Hydrochlorothiazide Apidra 20– 30–90 min 1–2.5
30 min
Central diabetes insipidus alternative therapy to Regular 30– 2–5 h 5–8
DDAVP. 60 min
Neonates: Younger than 6 months, 1–2 mg/ NPH 1–2 h 4–12 h 18–24
kg/day, divided b.i.d. or t.i.d., p.o. (maximum Glargine 1h None 24
dose, 37.5 mg/day). (Chlorothiazide may be used Detemir 1–2 h 6–8 h 24
instead at a dose of 5–10 mg/kg/day.) NPH neutral protamine Hagedorn

Insulin Preparations Older than 12 years: 2–3 μg/kg/dose/day

After cessation of growth dose: 1.7 μg/kg/
See Table 15.2 and Chap. 11. dose/day

Thyroxine (Levo)
Note if profoundly hypothyroid, slow increase to
recommended dose is suggested to avoid poten-
tial cardiac failure.
If adrenal insufficiency is suspected, glucocor-
ticoid replacement is recommended before thy-
roxine to avoid acute adrenal failure.
Children: p.o. dosing:
0–3 months: 10–15 μg/kg/dose/day
3–6 months: 6–10 μg/kg/dose/day
6–12 months: 6–8 μg/kg/dose/day
1–5 years: 5–6 μg/kg/dose/day
6–12 years: 4–5 μg/kg/dose/day
Magnesium Sulfate
1 g magnesium sulfate equals 98.6 mg, 8.12 mEq,
or 4.06 mmol elemental Mg.
Hypomagnesemia or Hypocalcemia
IV (slow given over 15–20 minutes)/i.m.:
25–50 mg/kg/dose, divided into t.i.d. to q.i.d.;
repeat as needed.
Maximum single dose: 2 g.
Oral: 100–200 mg/kg/dose, q.i.d., p.o.
Phosphate Supplements
Daily Maintenance
In TPN 0.25–1.25 g magnesium sulfate (25–
125 mg elemental magnesium) per day for
infants.
Mannitol (5, 10, 15, 20, 25 %)
Cerebral edema: 0.25–1 g/kg/dose, IV, over
20–30 min. May increase gradually to 1–2 g/kg/
dose if needed. (May give furosemide, 1 mg/kg
concurrently or 5 min before mannitol.)
Maximum dose: 12.5 g over 3–5 min.
However, dosage in children under 12 years is
not officially established.
Medroxyprogesterone Acetate
Amenorrhea: 5–10 mg, p.o., qd × 5–10 days.
Abnormal uterine bleeding: 5–10 mg, p.o.,
qd × 5–10 days, initiated on day 16 or 21 of the
menstrual cycle.
Metformin
Start with 500 mg p.o. with morning meal, after 1
week if tolerated increase to 500 mg b.i.d., with
morning and evening meals; may increase by
500 mg every week, administered in divided
doses up to a maximum of 2,500 mg/24 h
(2,000 mg/24 h in younger teenagers).
Start with one tablet to evaluate abdominal
distress and then increase as needed.
Extended release forms are available.
Daily multivitamins should accompany this
treatment to avoid vitamin B12 deficiency.
Mecasermin (rhIGF-1)
0.04–0.08 mg/kg/dose SC bid, may increase over
weeks by 0.04 mg/kg/dose to maximum of
0.12 mg/kg/dose given twice daily.
381
Hypoglycemia is a risk of therapy, and a snack
or meal must accompany the dose within 20 min
or the dose must be omitted. If hypoglycemia
persists, the dose must be decreased.
Methimazole
Hyperthyroidism
Children:
Initial: 0.4 mg/kg/24 h p.o., divided into q8h.
Maintenance: Half to two-thirds of initial
dose, p.o., q8h.
Maximum dose: 30 mg/24 h.
Adults:
Initial: 15–60 mg/24 h from mild to severe
hyperthyroidism, p.o., divided into t.i.d.
Maintenance: 5–15 mg/24 h, p.o., divided
into t.i.d.
The total daily dose may be effective if
divided into twice per day administration or
even one dose per day in some.
Nitroprusside
Children and adults: IV, continuous infusion.
Dose: Start at 0.3–0.5 μg/kg/min, titrate to
effect.
Usual dose: 3 μg/kg/min.
Maximum dose: 10 μg/kg/min.
Pamidronate
Hypercalcemia
Children:
Mild hypercalcemia: 0.5–1 mg/kg/dose, IV ×
over 24 h. Maximal dose is 90 mg.
Severe hypercalcemia: 1.5–2 mg/kg/dose, IV
× over 24 h. Maximal dose is 90 mg.
Adults:
Corrected serum Ca2+: 12–13.5 mg/dL: 60 mg,
IV, × 1 over 4 h OR 90 mg IV, × 1 over 24 h.
382
Corrected serum Ca2+: More than 13.5 mg/
dL: 90 mg, IV × 1 over 24 h.
(Dose may be repeated after 7 days.)
Osteogenesis Imperfecta
Children: Doses start low on day 1 and are higher
on the 2nd and 3rd day of the first 3 day cycle and
in subsequent cycles can start in the higher range.
0.25–1 mg/kg/dose, IV, may be repeated in 3–4
months for total yearly dose of 4 mg/kg/year for
3 years.
Maintenance is then 1 mg/kg/dose twice per
year for a yearly dose of 2 mg/kg/year until
growth is completed.
Monitor for hypocalcemia and hyposphatemia
before administration and thereafter. Flu like
symptoms may occur at first use.
Note: therapy is switching to Zoledronate for
Osteogenesis Imperfecta although this medica-
tion also is not approved for this condition.
Phosphate Supplements
Note: 1 mmol phosphate= 31 mg
Acute hypophosphatemia: 0.15–0.33 mmol/
kg/dose over 6 h until serum phosphorous is
greater than 2 mg/dL.
Maintenance/Replacement
IV 0.5–1.5 mmol/kg/24 h.
Oral 2–3 mmol/kg/24 h.
Recommended infusion rate: 0.1 mM/kg/h of
phosphate. When potassium salt is used, the rate
will be limited by the maximum potassium
infusion rate. Do not co-infuse with calcium-
containing products.
Potassium Iodide
Neonatal Graves disease: 1–2 drops of Lugol’s
sol p.o., q8h.
15 Medications for Pediatric Endocrinology
Thyrotoxicosis: Children: About 1–5 drops of
SSKI containing 1 g/mL every 6 h after starting
methimazole and only temporarily.
Potassium Supplements
Hypokalemia
Oral:
Children: 4–5 mEq/kg/24 h divided into b.i.d.
to q.i.d. Monitor serum potassium.
Intravenous: 0.5–1 mEq/kg/day with EKG
monitoring and physician in attendance if higher
rate used.
Monitor Serum K Closely and Watch
EKG at All Times
Children: 0.3 mEq/kg/h, given as an infusion of
less than 40 mEq/L at a rate of no more than
20 mEq/h for 1–2 h.
This may be used in critical situations such as
hypokalemia with arrhythmia.
Maximum peripheral IV concentration:
Usually 40 mEq/L. Extravasation can cause
severe scaring.
Propranolol
Neonates with thyroid storm:
Oral: 0.5–2 mg/kg/24 h divided into q6 to
8 h.
Children:
Oral: Start at 0.5–1 mg/kg/24 h divided into
q6 to 8 h; increase dosage q3 to 5 days prn.
Usual dosage range: 2–4 mg/kg/24 h divided
into q6 to 8 h. Maximum dose: 10–40 mg/24 h or
16 mg/kg/24 h.
Atenolol is suggested to be preferable to pro-
pranolol due to its more selective cardiac effects
but there is little experience in children. It is
reported to be used in 1–2 mg/kg per day as a
single daily dose or given every 12 hours; maxi-
mum is reported to be 100 mg/dose.
Suggested Reading 383

Hypertension The doses arise from the differing recommen-

dations from various manufacturers for the indi-
Children: cations noted.
p.o.: Initial: 0.5–1 mg/kg/24 h divided into q6
to 12 h. May increase dose by 1 mg/kg q3 to 7
days prn. Noonan’s Syndrome
Maximum dose: 6 mg/kg/24 h divided into q6
to 12 h. Up to 0.066 mg/kg/day SC.
Adults:
p.o.: 40 mg/dose p.o., b.i.d., or 60–80 mg/
dose (sustained-release capsule) p.o., qd. May Prader–Willi Syndrome
increase by 10–20 mg/dose, q3 to 5 days.
Maximum dose reported: 640 mg/24 h 0.24 mg/kg/week SC.
although lower doses must be tried first.

Propylthiouracil: Black box warning: Not to be SGA

used in children due to risk of liver damage.
Up to 0.48 mg/kg/week or 0.033 mg/kg/day.

Sodium Bicarbonate SHOX Deficiency

To Correct Metabolic Acidosis BUT NOT 0.33–0.35 mg/kg/week SC.
RECOMMENDED FOR USE IN DKA OTHER
THAN EXCEPTIONAL CIRCUMSTANCES
Calculate patient’s dose with the following Turner Syndrome
formulas:
Neonates, infants, and children: 0.375 mg/kg/week SC dose depending upon the
HCO3– (mEq) = 0.3 × weight (kg) × base deficit manufacturer’s recommendations.
(mEq/L)
Adults:
HCO3− (mEq) = 0.2 × weight (kg) × base deficit Spironolactone
(mEq/L)
HCO3− (mEq) = 0.5 × weight (kg) × [24 − serum Diuretic
HCO3− (mEq/L)]
For either: Neonates: 1–3 mg/kg/24 h divided into qd to
HCO3− (mEq) = 0.5 × weight (kg) × [24 − serum b.i.d., p.o.
HCO3− (mEq/L)] Children: 1–3.3 mg/kg/24 h divided into qd to
q.i.d., p.o.
Adults: 25–200 mg/24 h divided into qd to
Somatropin (Growth Hormone) q.i.d., p.o.
Maximum dose: 200 mg/24 h.
Given 6–7 days per week (longer term prepara-
tions are soon to be available).
Primary Aldosteronism

Growth Hormone Deficiency Children: 125–375 mg/m2/24 h divided into b.i.d.

to q.i.d., p.o.
0.16–0.34 mg/kg/week SC dose depending upon Adults: 100–400 mg qd and titrate down for
the manufacturer’s recommendations. maintenance dosage.
384 15 Medications for Pediatric Endocrinology

Hirsutism or Acne in Women Subcutaneous/Intramuscular

Adults: 50–200 mg/24 h qd or divided into b.i.d., p.o. Children: 2.5–10 U, b.i.d. to q.i.d. as needed to a
Results may not appear for 6–12 months. maximum of 60 U per day.
Adults: 5–10 U, b.i.d. to q.i.d.
Continuous infusion (adults and children):
Testosterone Start at 0.5 milliunit/kg/h (0.0005 U/kg/h).
Double dosage every 30 min prn up to maximum
See Chap. 9. dose of 10 mU/kg/h (0.01 U/kg/h).

Vasopressin Suggested Reading

Diabetes Insipidus Dosages as presented in:

Branden Engorn, Jamie Flerlage, editors. The Harriet

DDAVP is the preferred treatment of diabetes
Lane handbook: a manual for pediatric house officers,
insipidus but in case the oral or nasal route is not the Harriet Lane Service, Children’s Medical and
appropriate the following is used. Titrate dose to Surgical Center of the Johns Hopkins Hospital, 20th
antidiuretic effect and watch for hypertension or ed. Elsevier; 2015.
Dosages from Thomson Truven Health MICROMEDEX.
hyponatremia.
Dosages from various textbook chapters or articles noted
in the other chapters.
Dosages from manufacturers’ information.
 Laboratory Values for Pediatric
Endocrinology 16

This list includes some of the reference ranges laboratory values used most frequently in pediatric
endocrinology with sample preparation and sample sizes from Quest Diagnostics/Nichols Institute
and Esoterix/Labcorp. Other laboratories perform these tests and a few also have pediatric standards
(e.g., ARUP). However, we do not recommend using a laboratory that has not established pediatric
standards because the lower detectable limits, or the accurate area of the standard curves of the labora-
tory, might be well above pediatric values. Laboratories that are set up for pediatric endocrine samples
will accept smaller volumes than requested of adult patients. The minimum volumes listed here can
be used for smaller children but there may not be a duplicate test available to check results when such
small quantities are utilized; consult with the laboratory for details of the most recent collection size,
storage, and transport. You must check your results against the standards of the laboratory you choose,
as the laboratories recommend, as the reference ranges have changed during the development of this
text and will likely have been modified further since the time of publication of this book; the following
is only a guide.
Laboratories may combine tests into a panel for more efficient use of the sample, e.g., CAH
panel or hirsutism panel, so check with the laboratories for what panels are available. Panels are
offered from the major laboratories and provide the ability to collect small sample volumes for
multiple tests; if each individual test was ordered separately the volume might be prohibitive for
small children.

Adrenocorticotropic Hormone (ACTH) Quest

1.5 mL plasma in ethylenediaminetetraacetic acid (EDTA; lavender-top tube).

Minimum quantity: 0.5 mL.
Absolute minimum: 0.3 mL.
Transfer the plasma to a special transport tube, and ship frozen. Do not thaw.
Drawn at 7–10 a.m.

Adults 6–50 pg/mL

Dexamethasone suppressed 2–8 pg/mL
Children
3–17 years 9–57 pg/mL

© Springer International Publishing Switzerland 2016 385

D.M. Styne, Pediatric Endocrinology, DOI 10.1007/978-3-319-18371-8_16
386 16 Laboratory Values for Pediatric Endocrinology

Adrenal Antibody Screen with Reflex Titer QUEST

2 mL refrigerated serum.
0.5 mL serum
0.05 mL absolute minimum quantity
Adrenal antibody screen with reflex to titer
Red-top tube with no gel
0.5 mL minimum
0.05 mL absolute pediatric minimum
Negative
<1:10

Albumin (Microalbumin), 24-h Urine Quest

5 mL urine from 24-h urine collection; avoid glass container; 2 mL minimum in sterile screw-cap
container. Ship refrigerated.
Absolute minimum: 0.3 mL.
Record 24-h urine volume on test-request form and urine vial. Do not use preservatives. Ship
refrigerated.
Children and adults: ≤30 mg/24 h

Albumin Serum Quest

1 mL serum.
Minimum quantity: 0.5 mL.
Overnight fasting is preferred. Ship refrigerated.
3.6–5.1 g/dL.

Aldosterone, 24-h Urine Quest

5 mL urine from 24-h urine collection.

Minimum quantity: 0.8 mL.
Absolute minimum: 0.5 mL.
Collect urine with 10 g of boric acid to maintain pH <7.5. Record 24-h urine volume on test-request
form and urine vial. Refrigerate during collection and ship refrigerated.

Children
2–7 years <5.7 μg/24 h
8–11 years <10.2 μg/24 h
12–16 years <15.6 μg/24 h
Adults
2.3–21.0 μg/24 h

See creatinine standards as many urine test results are standardized to creatinine values.
Alkaline Phosphatase, Bone-Specific Labcorp 387

Aldosterone Serum, LC/MS/MS Quest

1 mL serum in no additive (red-top tube).

Minimum quantity: 0.25 mL.
Absolute minimum: 0.1 mL.
Draw “upright” samples ≥30 min after patient sits up. Ship refrigerated.

Children (random sodium diet)

Premature infants (31- to 35-week gestation) ≤144 ng/dL
Term infants, 3 days old ≤217 ng/dL
1–12 months 2–70 ng/dL
1–4 years 2–37 ng/dL
5–9 years <9 ng/dL
10–13 years <21 ng/dL
14–17 years <35 ng/dL
Tanner II–III
Males 1–13 ng/dL
Females 2–20 ng/dL
Tanner IV–V
Males 3–14 ng/dL
Females 4–32 ng/dL

Alkaline Phosphatase, Serum Quest

1 mL serum in no additive (red-top tube).

Minimum quantity: 0.5 mL.
Hemolyzed specimens are not acceptable. Ship frozen.

Male (U/L) Female (U/L)

<1 month 75–316 48–406
1–11 months 82–383 124–341
1–3 years 104–345 108–317
4–6 years 93–309 96–297
7–9 years 47–324 184–415
10–12 years 91–476 104–471
13–15 years 92–468 41–244
16–19 years 48–230 47–176

Alkaline Phosphatase, Bone-Specific Labcorp

2 mL frozen serum in no additive (red-top tube) allow serum to clot completely before centrifuging.
Minimum quantity: 1.0 mL.
Ship serum frozen in plastic screw top tube.
388 16 Laboratory Values for Pediatric Endocrinology

Age Male (μg/L) Female (μg/L)

0–5 months Not established Not established
6–11 months 48.2−170.2 50.4−154.0
1 year 41.9−229.6 44.2−178.3
2 years 41.7−139.4 34.9−195.4
3–4 years 37.2−127.7 37.4−96.8
5–6 years 42.0−104.2 31.4−100.8
7–8 years 59.0−101.3 44.0−135.8
9–10 years 50.4−133.0 47.9−150.8
11–12 years 53.3−156.8 24.2−133.3
13–14 years 77.5−169.8 19.8−92.7
15–16 years 26.8−173.4 11.2−30.2
17–18 years 15.4−69.8 8.8−29.0

Androstenedione LC/MS/MS Quest

1 mL room temperature serum in no additive (red-top tube).

Minimum quantity: 0.3 mL.
Absolute minimum: 0.15 mL
An early morning specimen is preferred. Ship refrigerated.

Children
Premature infants (31- to 35-week gestation) ≤480 ng/dL
Term infants, 3 days old ≤290 ng/dL
1–12 months 6–78 ng/dL
1–4 years 5–51 ng/dL
5–9 years 6–115 ng/dL
10–13 years 12–221 ng/mL
14–17 years 22–225 ng/mL
Tanner II–III
Males 17–82 ng/dL
Females 43–180 ng/dL
Tanner IV–V
Males 57–150 ng/dL
Females 73–220 ng/dL

Angiotensin II Quest

1 mL plasma in EDTA (lavender-top tube).

Minimum quantity: 0.3 mL.
Absolute minimum: 0.15 mL.
Freeze within 1 h of collection. Ship frozen.
Adults: <86 ng/L.
Children: No data available.
C Peptide, Serum Quest 389

Anti-Mullerian Hormone (AMH) Quest

1 mL frozen serum
Absolute minimum: 0.5 mL

Male
<1 year 37.20–345.67 ng/mL
1–6 years 59.54–320.65 ng/mL
7–11 years 40.99–203.67 ng/mL
12–17 years <128.29 ng/mL
≥18 years 1.15–15.23 ng/mL
Female
<14 years 0.49–3.15 ng/mL
14–19 years 1.28–16.37 ng/mL
20–29 years 0.76–11.34 ng/mL
30–39 years <9.24 ng/mL
40–49 years <4.50 ng/mL
≥50 years <0.45 ng/mL

Arginine Vasopressin Quest

4 mL plasma in EDTA (lavender-top tube).

Minimum quantity: 1.1 mL.
Absolute minimum: 0.55 mL
Draw blood in prechilled lavender-top tube. Transport in an ice bath to a refrigerated centrifuge.
Separate and freeze immediately. Do not thaw. Ship frozen.
Children and adults: 1.0–13.3 pg/mL (2.5 pg = 1 μU).

Congenital Adrenal Hyperplasia 21-Hydroxylase Deficiency Common

and Rare Mutations Quest

Collected lavender-top tube 3 mL minimum.

C Peptide, Serum Quest

2 mL frozen serum.
Minimum quantity: 0.5 mL.
Overnight fasting is required. Ship frozen.
Adults: 0.8–3.1 ng/mL. Values will vary based upon blood sugar.
390 16 Laboratory Values for Pediatric Endocrinology

Calcitonin Quest

1 mL frozen serum in no additive (red-top tube).

Minimum quantity: 0.5 mL.
Absolute minimum: 0.5 mL
Overnight fasting is preferred. Ship frozen.

<6 months <41 pg/mL

6 months to 3 years <14 pg/mL
3–17 years <6 g/mL

Calcium, 24-h Urine Quest

10 mL urine from a 24-h urine collection.

Minimum quantity: 2 mL.
Collect urine with 25 mL of 6 N HCl to maintain a pH <3. Record 24-h urine volume on test-request
form and urine vial. Ship refrigerated.

Adults
Males 50–300 ng/24 h
Females 50–250 ng/24 h
Children mg/mg creatinine
1–11 months 0.03–0.81
1 year 0.032–0.56
2 years 0.0–0.50
3–4 years 0.022–0.41
5–6 years 0.01–0.30
7–9 years 0.01–0.25
10–17 years 0.01–0.24

Calcium Ionized, Serum Quest

2 mL serum in no additive (red-top tube).

Minimum 0.6 mL
Absolute minimum: 0.3 mL.
Collect in gel-barrier tube, let clot, and spin immediately with cap on. Ship the unopened gel-barrier
tube refrigerated, so sample is not exposed to dry ice. Do not open. Ship refrigerated.

Children
8 months to 10 years 4.9–5.4 mg/dL
11–17 years 4.8–5.3 mg/dL
Adults
4.8–5.6 mg/dL
Catecholamines, Fractionated, 24-h Urine Quest 391

Calcium, Serum Quest

1 mL serum in no additive (red-top tube).

Minimum quantity: 0.5 mL.
Absolute minimum: 0.2 mL.
Overnight fasting is preferred. Ship refrigerated.

Children
<1 month 8.4–10.6 mg/dL
1–11 months 8.7–10.5
1–3 years 8.5–10.6
4–19 years 8.9–10.4 mg/dL

Carnitine, Serum Quest

3 mL serum in no additive (red-top tube).

Minimum quantity: 1 mL.
Serum or plasma should be removed from cells immediately after collection. Ship frozen.

Children (M)
Carnitine total Carnitine free Carnitine esters
1–17 years females 28–59 19–48 3–16
1–17 years males 32–62 25–54 4–12

Carotene Quest

1 mL serum in no additive (red-top tube).

Minimum quantity: 0.5 mL.
Separate from cells as soon as possible after clotting. Wrap tube in aluminum foil to protect from
light. Overnight fasting is preferred. Ship refrigerated.

Children
9 months to 6 years 5–80 μg/dL
7–17 years 9–190 μg/dL

Catecholamines, Fractionated, 24-h Urine Quest

Includes dopamine, epinephrine, and norepinephrine.

10 mL urine from a 24-h urine collection.
Minimum quantity: 5 mL.
Collect urine with 25 mL of 6 N HCl to maintain a pH <3. Urine without preservatives is accept-
able if pH is <6 and the sample is shipped frozen. Record 24-h urine volume on test-request
392 16 Laboratory Values for Pediatric Endocrinology

form and urine vial. It is preferable for the patient to be off medication for 3 days before collection.
Ship refrigerated.

Epinephrine
3–8 years 1–7 μg/24 h
9–12 years ≤8 μg/24 h
13–17 years ≤11 μg/24 h
Adults 2–24 μg/24 h
Norepinephrine
3–8 years 5–41 μg/24 h
9–12 years 5–50 μg/24 h
13–17 years 12–88 μg/24 h
Adults 15–100 μg/24 h
Dopamine
3–8 years 80–378 μg/24 h
9–12 years 51–474 μg/24 h
13–17 years 51–645 μg/24 h
Adults 52–480 μg/24 h
Total (N + E)
3–8 years 9–51 μg/24 h
9–12 years 9–71 μg/24 h
13–17 years 13–90 μg/24 h
Adults 26–121 μg/24 h

Catecholamines, Fractionated, Plasma Quest

Includes dopamine, epinephrine, and norepinephrine.

4 mL plasma in sodium heparin (green-top tube).
Minimum quantity: 2.5 mL.
Absolute minimum: 1 mL.
Vacutainer is to be chilled before venipuncture. Draw sample as follows: Insert catheter in patient’s
vein. Instruct patient to lie down for 30 min with catheter in place, and then draw supine specimen
in green-top tube. Chill specimen immediately in ice water. Next, instruct patient to sit up for
15 min with catheter still in place. Draw upright specimen in green-top tube. Chill specimen imme-
diately in ice water. Plasma should be separated in a refrigerated centrifuge within 30 min of col-
lection and then frozen immediately at −20 °C in plastic vials. Plasma must stay frozen. Thawed
samples are unacceptable. Overnight fasting is required. Ship frozen.

Adults

Supine Upright
Dopamine <10 pg/mL <20 pg/mL
Epinephrine <50 pg/mL <95 pg/mL
Norepinephrine 112–658 pg/mL 217–1,109 pg/mL
Total (N + E) 123–671 pg/mL 242–1,125 pg/mL
Catecholamines, Fractionated, Random Urine Quest 393

Children supine
Plasma catecholamine measurements are generally unreliable because of stress in infants and small
children. Urinary catecholamine assays are more reliable.

Age 3–15 years

Dopamine <60 pg/mL
Epinephrine ≤464 pg/mL
Norepinephrine ≤1,251 pg/mL

Catecholamines, Fractionated, Random Urine Quest

Includes epinephrine, norepinephrine, and dopamine.

10 mL urine in sterile screw-cap container.
Minimum quantity: 5 mL.
After urine collection, add 6 N HCl to maintain a pH <3. Urine without preservative is acceptable if
pH is <6 and the sample is shipped frozen. It is preferable for the patient to be off alcohol, coffee,
tea, tobacco and strenuous exercise as well as certain medications if possible for 3 days before
collection.

Epinephrine
Birth to 6 months 2–45 μg/g Cr
7–11 months 5–45 μg/g Cr
1–2 years 1–49 μg/g Cr
3–8 years 4–32 μg/g Cr
9–12 years 1–15 μg/g Cr
13–17 years 1–10 μg/g Cr
Adults 2–16 μg/g Cr
Norepinephrine
Birth to 6 months 12–286 μg/g Cr
7–11 months 19–250 μg/g Cr
1–2 years 25–210 μg/g Cr
3–8 years 20–108 μg/g Cr
9–12 years 20–73 μg/g Cr
13–17 years 15–58 μg/g Cr
Adults 7–65 μg/g Cr
Total N + NE
Birth to 6 months 24–322 μg/g Cr
7–11 months 10–295 μg/g Cr
1–2 years 30–263 μg/g Cr
3–8 years 30–130 μg/g Cr
9–12 years 25–90 μg/g Cr
13–17 years 20–70 μg/g Cr
Adults 9–74 μg/g Cr
(continued)
394 16 Laboratory Values for Pediatric Endocrinology

(continued)
Dopamine
Birth to 6 months 107–2,180 μg/g Cr
7–11 months 96–2,441 μg/g Cr
1–2 years 86–1,861 μg/g Cr
3–8 years 295–1,123 μg/g Cr
9–12 years 164–744 μg/g Cr
13–17 years 156–551 μg/g Cr
Adults 40–390 μg/g Cr

Corticosterone LC/MS/MS Quest

1 mL serum in no gel or additive (red-top tube); early morning specimen is best.

Minimum quantity: 0.25 mL.
Absolute minimum: 0.10.
Ship refrigerated.
Adults
8–10:00 a.m.: 59–1,293 ng/dL.
4–6:00 p.m.: ≤386 ng/dL.

1–12 months
Males 78–1,750 ng/dL
Females 89–1,200 ng/dL
1–4 years
Males 120–1,290 ng/dL
Females 160–2,040 ng/dL
5–9 years
Males <677 ng/dL
Females <677 ng/dL
10–13 years
Males <1,420
Females <1,420
14–17 years
Males <1,238
Females <1,238
Tanner II–III
Males 115–1,220 ng/dL
Females 110–600 ng/dL
Tanner IV–V
Males 165–840 ng/dL
Females 160–390 ng/dL
Cortisol-Free Serum Quest 395

Corticotropin-Releasing Hormone (Mainly Use for Ectopic Production

of CRH) Quest

3 mL plasma into a sodium heparin green top tube.

Minimum quantity: 1.1 mL.
Do not thaw. Ship frozen.

Men and women ≤42 pg/mL

Pregnancy
First trimester ≤40 pg/mL
Second trimester ≤153 pg/mL
Third trimester ≤847 pg/mL
Cord blood ≤338

Cortisol-Binding Globulin (Transcortin) Quest

1 mL serum in no additive (red-top tube).

Minimum quantity: 0.2 mL.
Ship refrigerated.

Preterm infants younger than 8 days 6–26 mg/L

Adults 19–45 mg/L

Cortisol Urinary Free 24-h Quest

10 mL urine from a 24-h urine collection.

Minimum quantity: 2.6 mL.
Collect urine with 10 g of boric acid or keep urine refrigerated during collection if preservative is not
used. Record 24-h urine volume on test-request form and urine vial.

Adults
Males and females 4–50 μg/24 h
Children
1–4 years 0.9–8.2 μg/24 h
5–9 years 1.0–30.0 μg/24 h
10–13 years 1.0–45 μg/24 h
14–17 years 3.0–55 μg/24 h

Cortisol-Free Serum Quest

2 mL serum in no additive (red-top tube).

Minimum quantity: 0.7 mL.
396 16 Laboratory Values for Pediatric Endocrinology

Absolute minimum: 0.4 mL.

Grossly hemolyzed specimens are unacceptable. Ship refrigerated.

Adults
8–10:00 a.m. 0.07–0.93 μg/dL
4–6:00 p.m. 0.04–0.45 μg/dL
10.00–11:00 p.m. 0.04–0.35 μg/dL

Cortisol, Salivary

0.5 mL refrigerated saliva

Minimum quantity: 0.2 mL
Absolute minimum: 0.1 mL
Collected in a salivette tube 10 min after rinsing mouth with water. No oral intake (or smoking) for
1 h before collection. Blood from brushing teeth can affect result.

Adults
8–10 a.m. 0.04–0.56
4–6 p.m. <0.15
10–11 p.m. <0.09

Cortisol Serum Total LC/MS/MS Esoterix

0.5 mL serum plasma: Serum: Tigertop (SST) tube or redtop tube or Plasma: Lavendertop (EDTA)
tube.
Minimum quantity: 0.1 mL.
Specify the time of day specimen was collected. Grossly hemolyzed specimens are unacceptable.
Ship refrigerated.

Age Range (μg/dL)

Premature (26–28 weeks) Day 4 1.0–11
Premature (31–35 weeks) Day 4 2.5–9.1
Full-term Day 3 1.7–14
Full-term Day 7 2.0–11
31 days to 11 months 2.8–23
12 months to 15 years (8:00 a.m.) 3.0–21
8:00 a.m. 4:00 p.m.
Adults 8.0–19 4.0–11

Response to ACTH stimulation

Cortisol baseline 5–21 μg/dL
Cortisol 30 min 14–36 μg/dL
Cortisol 60 min 14–41 μg/dL
Creatinine Clearance Quest 397

Creatinine 24-h Urine Quest

10 mL with urine in 24-h urine container collection.

Minimum quantity: 0.5 mL.
Record 24-h urine volume on test-request form and urine vial. Ship refrigerated. No preservative.

Adults
Males and females 0.63–2.5 g/24 h
Children
3–8 years 0.11–0.68 g/24 h
9–12 years 0.17–1.41 g/24 h
13–17 years 0.29–1.87 g/24 h
>17 years 0.63–2.50 g/24 h

Creatinine Random Urine Quest

10 mL urine in sterile screw-cap container.

Minimum quantity: 2 mL.
Ship refrigerated.

Adults
Males and females 0.27–3.00 g/L
Children
≤6 months 2–32 mg/dL
7–11 months 2–36 mg/dL
1–2 years 2–128 mg/dL
3–8 years 2–149 mg/dL
9–12 years 2–183 mg/dL
>12 years male 20–370 mg/dL
>12 years female 20–320 mg/dL

Creatinine Clearance Quest

Includes serum and urine creatinine.

10 mL urine from a 24-h urine collection and 1 mL serum in no additive (red-top tube).
Minimum quantity: 0.5 mL serum and urine.
Record patient height, weight, and total 24-h urine volume on test-request form and urine vial. Serum
must be collected within 24 h of urine collection. Ship refrigerated.

Adults
Males 85–125 mL/min/1.73 m2 surface area (SA)
Females 75–115 mL/min/1.73 m2 SA
398 16 Laboratory Values for Pediatric Endocrinology

Creatinine Serum Quest

2 mL serum in no additive (red-top tube).

Minimum quantity: 0.2 mL.
Hemolyzed specimens are not acceptable. Ship refrigerated.

Adults
Male Female
0.6–1.4 mg/dL 0.6–1.4 mg/dL
Children
Age Male (mg/dL) Female (mg/dL)
≤2 days 0.79–1.58 0.79–1.58
3–27 days 0.35–1.23 0.35–1.23
1 month to 9 years 0.20–0.73 0.20–0.73
10–12 years 0.30–0.78 0.30–0.78
13–15 years 0.40–1.05 0.40–1.00
16–17 years 0.60–1.20 0.50–1.00
18–19 years 0.60–1.26 0.50–1.00

DHEA Serum Quest Esoterix

0.5 mL serum in no additive SST or (red-top tube).

Minimum quantity: 0.3 mL.
Specify age and sex on test-request form. Overnight fasting is preferred. Ship refrigerated.

Children
Premature infants
26–31 weeks 82–1,484 ng/dL
32–35 weeks 56–1,853 ng/dL
Full-term infants
2–7 days 41–1,292 ng/dL
8 days to 5 months <948 ng/dL
6–12 months <136 ng/dL
Prepubertal children
1–5 years <68 ng/dL
6–7 years <111 ng/dL
8–10 years <186 ng/dL
Pubertal children and adults
11–12 years <202 ng/dL
13–14 years <319 ng/dL
15–16 years 39–481 ng/dL
17–19 years 40–491 ng/dL
Deoxycorticosterone (DOC), Serum Esoterix 399

DHEA Sulfate, Serum Esoterix

0.5 mL serum in no additive (red-top tube).

Minimum quantity: 0.1 mL.
Specify age and sex on test-request form. Ship refrigerated.

Range (μg/dL)
Premature infants
26–28 weeks, day 4 123–882
31–35 weeks, day 4 122–710
Full-term infants
3 days 88–356
1–11 months DHEA-S levels fall to <112 μg/dL during the first month and decrease further
to <49 μg/dL by 6 months of age
Prepubertal children
1–5 years <57
6–7 years <72
8–10 years <193

Puberty
Tanner stage Age (years) Range (μg/dL) Tanner stage Age (years) Range (μg/dL)
Male Female
1 <9.8 13–83 1 <9.2 19–144
2 9.8–14.5 42–109 2 9.2–13.7 34–129
3 10.7–15.4 48–200 3 10.0–14.4 32–226
4 11.8–16.2 102–385 4 10.7–15.6 58–260
5 12.8–17.3 120–370 5 11.8–18.6 44–248

Deoxycorticosterone (DOC), Serum Esoterix

Age Range (ng/dL)

Premature (26–28 weeks) Day 4 20–105
Premature (34–36 weeks) Day 4 28–78
Newborn Levels are markedly elevated at birth and decrease
rapidly during the first week to the range of 7–49
as found in older infants.
1–11 months 7–49
Prepubertal children 2–34
Pubertal children and adults 8:00 a.m. 2–19
400 16 Laboratory Values for Pediatric Endocrinology

11-Deoxycortisol (Compound S) Corticosterone, Serum Esoterix

Eso range (ng/dL)

Premature infants
26–28 weeks, day 4 110–1,376
31–35 weeks, day 4 48–579
Full-term infants
3 days 13–147
31 days to 11 months <10–156
Prepubertal children
8:00 a.m. 20–155
Pubertal children and adults
8:00 a.m. 12–158

Dihydrotestosterone Esoterix

0.3 mL serum in no additive (red-top tube).

Minimum quantity: 0.1 mL.
Specify age and sex on test-request form. Ship refrigerated.

Male range (ng/dL) Female range (ng/dL)

Premature infants 10–53 2–13
Full-term newborns 5–60 <2–15
2 weeks to 6 months DHT decreases rapidly in the first week, and Levels decrease during the first
then increases to 12–85 ng/dL between 30 and month to < 3 ng/dL and remain
60 days. Levels then decrease gradually to there until puberty.
prepubertal values by 7 months.
Prepubertal children 1–10 years: <3 1–9 years: <3

Puberty
Tanner stage Age (years) Range (ng/dL) Tanner stage Age (years) Range (ng/dL)
Male Female
1 <9.8 <3 1 <9.2 3
2 9.8–14.5 3–17 2 9.2–13.7 5–12
3 10.7–15.4 8–33 3 10.0–14.4 7–19
4 11.8–16.2 22–52 4 10.7–15.6 4–13
5 12.8–17.3 24–65 5 11.8–18.6 3–18

Range (ng/dL)
Adults
Male 30–85
Female 4–22
Estradiol, Serum Esoterix 401

Dihydrotestosterone, Free, Serum Quest

Includes total, free, and percentage free dihydrotestosterone (DHT).

5 mL serum in no additive (red-top tube).
Minimum quantity: 2.5 mL.
Ship refrigerated.
% Free
Postpubertal males: 0.62–1.10 %.
DHT, free
Postpubertal males: 1.00–6.20 pg/mL.
Postpubertal females: 0.30–1.90 pg/mL.

Estradiol, Serum Esoterix

3 mL serum in no additive (red-top tube).

Minimum quantity: 1.2 mL.
Separate serum within 1 h; transfer into a plastic transport tube.
Specify age and sex on test-request form. Ship refrigerated frozen.

Range (pg/mL)
Newborn Levels are markedly elevated at birth and fall rapidly during the first week to
prepubertal values of <15 pg/mL.
1–6 months
Male Levels increase to 10–32 pg/mL between 30 and 60 days, and then decline to
prepubertal levels of <15 pg/mL by 6 months.
1–11 months
Female Levels increase to 5.0–50 pg/mL between 30 and 60 days, and then decline to
prepubertal levels of <15 pg/mL during the first year.
Prepubertal children
Males (1–10 years) <15
Females (1–9 years) <15

Puberty
Tanner stage Age (years) Range (μg/dL) Tanner stage Age (years) Range (μg/dL)
Male Female
1 <9.8 5.0–11 1 <9.2 5.0–20
2 9.8–14.5 5.0–16 2 9.2–13.7 10–24
3 10.7–15.4 5.0–25 3 10.0–14.4 7.0–60
4 11.8–16.2 10–36 4 10.7–15.6 21–85
5 12.8–17.3 10–36 5 11.8–18.6 34–170

Adults Range (pg/mL)

Male 8–35
Female
Follicular 30–100
Luteal 70–300
Postmenopausal <15
402 16 Laboratory Values for Pediatric Endocrinology

Estrone, Serum Esoterix

3 mL serum in no additive (red-top tube).

Minimum quantity: 1.2 mL.

Puberty
Tanner stage Age (years) Range (μg/dL) Tanner stage Age (years) Range (μg/dL)
Male Female
1 <9.8 5.0–17 1 <9.2 4.0–29
2 9.8–14.5 10–25 2 9.2–13.7 10–33
3 10.7–15.4 15–25 3 10.0–14.4 15–43
4 11.8–16.2 15–45 4 10.7–15.6 16–77
5 12.8–17.3 20–45 5 11.8–18.6 29–105

Adults Range (pg/mL)

Male 10–50
Female
Follicular 30–100
Luteal 90–160
Postmenopausal <40

Follicle-Stimulating Hormone, Third Generation, Serum Esoterix

1 mL serum in no additive (red-top tube).

Minimum quantity: 0.2 mL, not for eso
Ship refrigerated.
Eso range (mIU/mL)

Infants
Male Female
4 weeks to 11 months 0.16–4.1 0.24–14.2
Levels are for infants from 4 weeks Levels are for infants from 4 weeks of
of age to 1 year. FSH in males declines age to 1 year. FSH declines more slowly
to prepubertal levels by the end of the than in males to reach prepubertal levels
first year. by the end of the second year.
Prepubertal children
Male Female
12 months to 8 years 0.26–3.0 1.0–4.2
Gastrin Serum Quest 403

Puberty
Tanner Age Range Mean Tanner Age Range Mean
stage (years) (pg/dL) (μg/dL) stage (years) (pg/dL) (μg/dL)
Male Female
1 <9.8 0.26–3.0 0.98 1 <9.2 1.0–4.2 2.1
2 9.8–14.5 1.8–3.2 2.5 2 9.2–13.7 1.0–10.8 4.0
3 10.7–15.4 1.2–5.8 2.9 3 10.0–14.4 1.5–12.8 5.1
4 11.8–16.2 2.0–9.2 4.4 4 10.7–15.6 1.5–11.7 6.4
5 12.8–17.3 2.6–11.0 6.1 5 11.8–18.6 1.0–9.2 4.9

Adults Range (pg/mL)

Males
20–50 years 2.0–9.2
Females
Follicular and luteal 1.8–11.2
Midcycle 6–35
Postmenopausal 30–120

Fructosamine, Serum Quest

1 mL serum in no additive (red-top tube).

Minimum quantity: 0.5 mL.
0.2 absolute minimum.
Ship refrigerated.

Adults
Males and females 190–270 μM

Gastrin Serum Quest

2 mL serum.
Minimum quantity: 0.5 mL.
Absolute minimum 0.175 mL
Overnight fasting is required. Ship frozen.

Adults
Males and females <100 pg/mL
Children
5–17 years 13–64 pg/mL
404 16 Laboratory Values for Pediatric Endocrinology

Glucagon Quest

3 mL plasma in EDTA (lavender-top tube).

Minimum quantity: 1.1 mL.
Absolute minimum 0.55 mL.
Do not thaw. Overnight fasting is required. Ship frozen.

Adults <134 pg/mL

Children
Cord blood <2:15
Day 1 <240
Day 2 <400
Day 3 <420
Day 4–14 <148

Glucose, Serum

1 mL serum in no additive (red-top tube), but grey top at local lab is best.
Minimum quantity: 0.2 mL.
Overnight fasting is preferred. Ship refrigerated.

Children and adults

Fasting 65–100 mg/dL
Impaired fasting glucose 101–125 mg/dL (ADA Guidelines)
Provisional diagnosis of diabetes ≥126 mg/dL fasting or >200 mg/dL casual, non-fasting
(ADA Guidelines)

Glutamic Acid Decarboxylase-65 Autoantibodies Quest

1 mL serum in no additive (red-top tube).

Minimum quantity: 0.2 mL.
Absolute minimum 0.04 mL.
Ship frozen.
Children and adults: Positive result, ≥1.0 U/mL.

Glycated Albumin Quest

3 mL plasma in EDTA (lavender-top tube).

Minimum quantity: 2 mL.
Absolute minimum 0.3 mL.
Spin and separate plasma immediately. Overnight fasting is required. Ship refrigerated.
Children and adults: 0.8–1.4 %.
Growth Hormone-Binding Protein (GHBP) Esoterix 405

1,5-Anhydroglucitol Esoterix

1 mL room-temperature serum in a red-top tube without gel or SST.

Minimum 0.75 mL.

Age Range (μg/mL)

<18 years Not established
Adult males 10.7–32.0
Adult females 6.8–29.3
Glycemic control goal for diabetic patients: >10

Growth Hormone, Serum Esoterix

1 mL serum in no additive (red-top tube).

Minimum quantity: 0.4 mL.
Ship refrigerated.

Newborn Eso range (ng/mL)

1 day 5–53
2–7 days 5–27
31 days to 11 months 2–10
Following an 8–12-h overnight fast:
Children <6
Adults <6

Adults: ≤10.0 ng/mL.

Children: ≤20 years ≤13 ng/mL.
Because of diurnal variability, random human growth hormone (hGH) values are not reliable for diag-
nosis of GH deficiency or acromegaly. Values are quite elevated for several days after birth. See
Chap. 5 for instructions on GH testing.

Growth Hormone Antibody Quest

0.5 mL serum in no additive (red-top tube).

Minimum quantity: 0.2 mL.
Absolute minimum 0.03 mL.
Ship refrigerated.
Children and adults: Negative.

Growth Hormone-Binding Protein (GHBP) Esoterix

1 mL serum in no additive (red-top tube).

Minimum quantity: 0.2 mL.
Ship frozen.
406 16 Laboratory Values for Pediatric Endocrinology

Range (pmol/L)
Children
<1 year <125–762
2–9 years 267–1,638
10–14 years 431–1,892
Adults
20–50 years 686–2,019
Laron dwarfism <300

Growth Hormone-Releasing Hormone Quest

4 mL plasma in parathyroid hormone-related protein and releasing factor tube.

Minimum quantity: 1.1 mL.
Use special collection tube labeled parathyroid hormone RP and releasing factor tube, available from
Quest Diagnostics Incorporated, Nichols Institute. Do not thaw. Ship frozen.

Adults
Males and females ≤49 pg/mL
Children
4–14 years ≤19 pg/mL

Hemoglobin A1C, Blood Quest

1 mL whole blood in EDTA (lavender-top tube).

Minimum quantity: 0.5 mL.
Absolute minimum 0.15 mL.
Transfer whole blood to plastic shipping vial to prevent breakage. Avoid freezing and thawing. Ship
refrigerated.

Children and adults although children have more

variable results
Nondiabetic <5.7 %
Increased diabetes risk 5.7–6.0 %
High diabetes risk 6.1–6.4 %
Diabetes ≥6.5
Reevaluate therapy >8 %

Homovanillic Acid, 24-h Urine Quest

10 mL urine from 24-h urine collection.

Minimum quantity: 5 mL.
Absolute minimum 1.1 mL.
18-Hydroxycorticosterone, Serum Esoterix 407

Collect urine with 25 mL of 6 N HCl to maintain a pH <3. Urine without preservative is acceptable
if pH is <6 and the sample is shipped frozen. Record 24-h urine volume on test-request form and urine
vial. It is preferable for the patient to be off medications for 3 days before collection. Ship
refrigerated.

Adults
Males and females 1.6–7.5 mg/24 h
Children
3–8 years 0.5–6.7 mg/24 h
9–12 years 1.1–6.8 mg/24 h
13–17 years 1.4–7.2 mg/24 h

17-Hydroxycorticosteroids, 24-h Urine Quest

20 mL urine from 24-h urine collection.

Minimum quantity: 5 mL.
Collect urine with 10 g of boric acid to maintain pH <7.5. Record 24-h urine volume on test-request
form and urine vial. Ship refrigerated.

Adults
Males 4–11 mg/24 h
Females 3–10 mg/24 h
Children
1–2 years 0.5–2.5 mg/24 h
3–4 years 1.0–4.0 mg/24 h
5–6 years 1.0–4.8 mg/24 h
7–8 years 1.0–5.6 mg/24 h
9–10 years 1.0–7.0 mg/24 h
11–12 years 1.5–8.0 mg/24 h
Males
13–16 years 2.0–6.0 mg/24 h
17–20 years 3.0–10.0 mg/24 h
Females
13–16 years 2.8–6.8 mg/24 h
17–20 years 2.0–7.0 mg/24 h

18-Hydroxycorticosterone, Serum Esoterix

3 mL serum in no additive (red-top).

Minimum quantity: 1.0 mL.
408 16 Laboratory Values for Pediatric Endocrinology

18-OH-Corticosterone
Range (ng/dL)
Premature infants
26–28 weeks, day 4 10–670
31–35 weeks, day 4 57–410
Full-term infants
3 days 31–546
31 days to 11 months 5–220
Children
12–23 months 18–155
24 months to 9 years 6–85
10 to 14 years 10–72
Adults 9–58

8:00 a.m. Supine: 4–21.

8:00 a.m. Upright: 5–46.

5-Hydroxyindoleacetic Acid (5-HIAA), 24-h Urine Quest

10 mL urine from 24-h urine collection.

Minimum quantity: 5 mL.
Collect urine with 25 mL of 6 N HCl to maintain a pH <3. Urine without preservative is acceptable if
pH is <6 and the sample is shipped frozen. Keep urine refrigerated during collection if preservative
is not used. Record 24-h volume on test-request form and urine vial.
2–10 years: ≤8.0 mg/24 h: or ≤12 mg per gram creatinine.
<10 years: ≤6.0 mg/24 h: or ≤10 mg per gram creatinine.

5-Hydroxyindoleacetic Acid (5-HIAA), Random Urine Quest

10 mL urine in sterile screw-cap container.

Minimum quantity: 5 mL.
After urine collection, add 0.5–1.0 g boric acid (or 6 N HCl) to maintain a pH <3. Urine without pre-
servative is acceptable if pH is <6 and the sample is shipped frozen. Keep urine refrigerated during
collection if preservative is not used. Record patient’s age on test-request form and urine vial. Ship
refrigerated.
2–10 years: ≤12 mg/g Cr.
>10 years: ≤10 mg/g Cr.

17-Hydroxypregnenolone, Serum Esoterix

1 mL serum in no additive (SST).

Minimum quantity: 0.1 mL.
17-Hydroxyprogesterone (17OHP), Serum Esoterix 409

Range (ng/dL)
Premature infants
26–28 weeks, day 4 375–3,559
31–35 weeks, day 4 64–2,380
Full-term infants
3 days 10–829
1–5 months 36–763
6–11 months 42–540
Prepubertal children
12–23 months 14–207
24 months to 5 years 10–103
6–9 years 10–186
Pubertal age groups 44–235
Adults 53–357

17-Hydroxyprogesterone (17OHP), Serum Esoterix

1 mL serum in no additive (red-top or SST).

Minimum quantity: 0.1 mL.
Ship in plastic transport tube; ship frozen.

Range (ng/dL)
Premature infants
26–28 weeks, day 4 124–841
31–35 weeks, day 4 26–568
Full-term infants
Day 3 <78
Male 1–11 months Levels increase after the first week to peak values ranging from
40 to 200 ng/dL between 30 and 60 days. Levels then decline to
a prepubertal value of <91 before 1 year.
Female 1–11 months 13–106
Prepubertal children
Males (1–10 years) <91
Females (1–9 years) <91

Puberty
Tanner Age Range Mean Tanner Age (years) Range Mean
stage (years) (μg/dL) (μg/dL) stage (μg/dL) (μg/dL)
Male Female
1 <9.8 <91 38 1 <9.2 <83 31
2 9.8–14.5 <116 51 2 9.2–13.7 11–98 49
3 10.7–15.4 10–138 57 3 10.0–14.4 11–155 70
4 11.8–16.2 29–180 80 4 10.7–15.6 18–230 91
5 12.8–17.3 24–175 97 5 11.8–18.6 20–265 108
410 16 Laboratory Values for Pediatric Endocrinology

Adults Range (pg/mL)

Male 27–199
Female
Follicular 15–70
Luteal 35–290

Insulin-Like Growth Factor 1 (IGF-1) (Previously Called Somatomedin C)

Esoterix

1 mL serum in no additive (red-top tube or SST).

Minimum quantity: 0.5 mL.
Ship refrigerated.

Age Term Preterm

Range (ng/mL) Mean (ng/mL) Range (ng/mL) Mean (ng/mL)
Birth 15–109 59 21–93 51
2 months 15–109 55 23–163 81
4 months 7–124 50 23–171 74
6 months 7–93 41 15–132 61
12 months 15–101 56 15–179 77
Male Female
Age Range (ng/mL) Mean (ng/mL) Range (ng/mL) Mean (ng/mL)
1–2 years 30–122 76 56–144 100

Female Tanner 1 Tanner 2 Tanner 3 Tanners 4 and 5

Age Range Mean Range Mean Range Mean Range Mean
(years) (ng/mL) (ng/mL) (ng/mL) (ng/mL) (ng/mL) (ng/mL) (ng/mL) (ng/mL)
3 26–162 77
4 32–179 88
5 39–198 100
6 47–217 113
7 55–238 127
8 64–259 142 89–369 181
9 74–282 158 96–399 196 192–568 350
10 85–306 175 104–431 212 192–568 350 279–664 446
11 97–332 194 112–466 229 192–568 350 268–646 433
12 110–358 213 121–504 247 192–568 350 248–612 406
13 131–545 267 192–568 350 229–579 380
14 136–566 278 192–568 350 211–547 356
15 192–568 350 194–516 332
16 177–487 309
17 162–458 287
18 147–430 266
Total N Tanner 1: 138 Tanner 2: 158 Tanner 3: 114 Tanners 4 and 5: 155
subjects
IGF-Binding Protein-2 (IGFBP-2) Quest 411

IGF-2 Esoterix

0.5 mL plasma in EDTA (SST).

Minimum quantity: 0.1 mL.
Overnight fasting is preferred. Ship frozen in plastic transfer tube.

Range (ng/mL) Mean

Prepubertal 334–642 488
Pubertal 245–737 491
Adults 288––736 512

IGF-Binding Protein-1 (IGFBP-1) Quest

1 mL serum in no additive (red-top tube).

Minimum quantity: 0.2 mL.
Absolute minimum 0.025 mL.
Overnight fasting is preferred. Ship frozen.

Adults
Males and females 5–34 ng/mL
Children
5–9 years 15–95 ng/mL
10–14 years 8–64 ng/mL
15–18 years 5–40 ng/mL

IGF-Binding Protein-2 (IGFBP-2) Quest

1 mL serum in no additive (red-top tube).

Minimum quantity: 0.2 mL.
Absolute minimum 0.25 mL.
Ship frozen.

Adults
18–49 years 38–267 ng/mL
>49 years 47–350 ng/mL
Children
5–9 years 49–208 ng/mL
10–13 years 41–167 ng/mL
14–17 years 37–135 ng/mL
412 16 Laboratory Values for Pediatric Endocrinology

IGF-Binding Protein-3 (IGFBP-3) Esoterix

1 mL serum in no additive (red-top tube or EDTA lavender top).

Minimum quantity: 0.1 mL.
Ship frozen.

Range (mg/L) Mean (mg/L)

Premature infants
<1 month 0.3–1.4 0.9
2–3 months 0.9–2.3 1.6
4–5 months 0.4–2.2 1.5
6–11 months 1.0–2.3 1.5
Full-term infants
<1 month 0.4–1.7 0.9
2–3 months 0.5–2.1 1.3
4–5 months 0.6–2.4 1.4
6–11 months 0.5–2.4 1.4
Children
12 months to 4 years 0.8–3.0 2.1
5–6 years 1.5–3.4 2.4
7–8 years 2.1–4.2 3
9–11 years 2.0–4.8 3.3
12–13 years 2.1–6.2 3.8
14–15 years 2.2–5.9 4.2
16–18 years 2.5–4.8 3.8

Inhibin B Quest

1 mL frozen serum and red-top tube with no gel.

0.5 mL absolute minimum.

Men 47–308 pg/mL

Women
Premenopausal <153 pg/mL
Postmenopausal <10 pg/mL

Children
Males Females
5–9.9 years 21–166 <18
10–13.9 years 41–328 <86
14–17.9 years 135–368 <123
Leptin, Serum Quest 413

Insulin Antibodies, Highly Sensitive Quest

For detection of insulin autoantibody in patients not receiving insulin therapy.

1 mL serum in no additive (red-top tube).
Minimum quantity: 0.3 mL.
Absolute minimum 0.06 mL.
Ship refrigerated.
Children and adults: ≤0.4 U/mL

Insulin, Free Quest

The free (bioactive) insulin test is recommended for patients who have detectable levels of insulin
autoantibodies.
0.5 mL serum in no additive (red-top tube).
Minimum quantity: 0.3 mL.
Overnight fasting is required. Ship refrigerated.
Children and adults: 1.5–14.9 U/mL.
Insulin levels may vary widely in specimens taken from non-fasting individuals.

Insulin, Serum Quest

0.4 mL serum in no additive (red-top tube only).

Minimum quantity: 0.2 mL.
Absolute minimum 0.1 mL.
Ship refrigerated. Overnight fasting is required. This assay is not recommended for patients with posi-
tive insulin autoantibody. Please use the free insulin assay in those cases. Insulin levels vary widely
in specimens taken non-fasting individuals.
Children: ≤13.7 μU/L.

Islet Cell Antibody Quest

2 mL serum in no additive (red-top tube).

Minimum quantity: 0.5 mL.
Absolute minimum 0.05 mL.
Ship refrigerated.
Children and adults: <1.25 JDF units.
Note: End-point titers are compared with a single international reference standard, and values are
reported in JDF (Juvenile Diabetes Foundation) units.

Leptin, Serum Quest

1 mL serum in red-top or SST tube.

Minimum quantity: 0.2 mL.
Ship refrigerated.
414 16 Laboratory Values for Pediatric Endocrinology

Children
5–9 years 0.6–16.8 ng/mL
10–13 years 1.4–16.5 ng/mL
14–18 years 0.6–24.9 ng/mL

Luteinizing Hormone (LH), Third-Generation Serum Esoterix

Values begin to increase about 2 weeks after birth to a range of 0.02–7.0 mIU/mL within the first 3
months, and then decline to prepubertal values, by the end of the first year.

Range (mIU/mL)
Infants 2 weeks 1 mL serum in no
to 11 months additive (red-top tube).
Minimum quantity:
0.2 mL.
Ship refrigerated.
Prepubertal children 0.02–0.3
12 months to 8 years
Puberty
Tanner stage Age (years) Range Tanner Age Range
(mIU/mL) stage (years) (mIU/mL)
Male Female
1 <9.8 0.02–0.3 1 <9.2 0.02–0.18
2 9.8–14.5 0.2–4.9 2 9.2–13.7 0.02–4.7
3 10.7–15.4 0.2–5.0 3 10.0–14.4 0.10–12.0
4–5 11.8–17.3 0.4–7.0 4–5 10.7–18.6 0.4–11.7
Adults Range (mIU/mL)
Male 1.5–9.0
Female
Follicular 2.0–9.0
Midcycle 18.0–49.0
Luteal 2.0–11.0
Postmenopausal 20.0–70.0

Metanephrine and VMA, Fractionated 24-h Urine Quest

5 mL urine from 24-h urine container.

Minimum quantity: 1.5 mL.
Absolute minimum 1.1 mL.
Collect urine with 25 mL of 6 N HCl to maintain a pH <3. Urine without preservative is acceptable if
pH is <6 and the sample is shipped frozen. Record 24-h urine volume on test-request form and
urine vial. Record patient’s age on test-request form and urine vial. It is preferable for the patient
to be off medications for 3 days before collection. Ship refrigerated.
Metanephrine, Fractionated Random Urine Quest 415

Age
Metanephrine (μg/24 h)
3 months to 4 years 25–117
5–9 years 11–139
10–13 years 51–275
14–17 years 40–189
Normetanephrine, 24 h (μg/24 h)
3 months to 4 years 54–249
5–9 years 31–398
10–13 years 67–503
14–17 years 69–531
Total Metanephrines (μg/24 h)
3 months to 4 years 79–345
5–9 years 49–408
10–13 years 110–714
14–17 years 107–741

Metanephrine, Fractionated Random Urine Quest

Includes metanephrine, normetanephrine, and total metanephrine.

10 mL urine in sterile screw-cap container.
Minimum quantity: 3 mL.
Collect urine with 15 g of boric acid or 15 mL of 6 N HCl to maintain a pH <3. Urine without preser-
vative is acceptable if pH is <6 and the sample is shipped frozen. Record patient’s age on test-
request form and urine vial. It is preferable for the patient to be off medications for 3 days before
collection. Ship refrigerated.

Metanephrine
5–9 years 106–527 μg/g Cr
10–13 years 34–357 μg/g Cr
14–17 years 24–302 μg/g Cr
13–17 years 34–126 μg/g Cr
Normetanephrine
5–9 years 149–781 μg/g Cr
10–13 years 38–523 μg/g Cr
14–17 years 14–302 μg/g Cr
Total metanephrine
5–9 years 255–1,167 μg/g Cr
10–13 years 86–845 μg/g Cr
14–17 years 39–578 μg/g Cr
416 16 Laboratory Values for Pediatric Endocrinology

Metanephrine, Fractionated Free Plasma Quest

Minimum quantity: 1.5 mL.

Metanephrine ≤57 g/mL.
Normetanephrine ≤148 pg/mL.
Metanephrines total ≤205 pg/mL.

Microalbumin

Urine
Range (mg/24 h) Range (mg/g creatinine)
24-h collection <30 <30
Microalbuminuria 30–299 30–299
Clinical albuminuria >300 >300

Osmolality, Random Urine Quest

1 mL urine in sterile screw-cap container.

Minimum quantity: 0.2 mL.
Do not use preservatives. Ship refrigerated.
Children and adults: 50–1,200 mOsm/kg.

Osmolality, Serum Quest

1 mL serum in no additive (red-top tube).

Minimum quantity: 0.2 mL.
Ship refrigerated.
Children and adults: 278–305 mOsm/kg.

Osteocalcin, Serum Quest

This test is performed by using a test kit that has not been approved or cleared by the Food and Drug
Administration (FDA). The performance characteristics of this test have been determined by Quest
Diagnostics, Nichols Institute.
1 mL serum in no additive (red-top tube).
Minimum quantity: 0.5 mL.
Avoid hemolysis. Avoid lipemia. Overnight fasting is preferred. Ship refrigerated.
Parathyroid Hormone (PTH), Intact, Serum Quest 417

Adults
Male Female
9.0–38 ng/mL 8–32 ng/mL
Children
Male Female
5–9 years 47–142 ng/mL 47–142 ng/mL
10–13 years 49–167 ng/mL 49–167 ng/mL
14–17 years 26–203 ng/mL 14–85 ng/mL
Tanner stages
I 20–89 ng/mL 20–89 ng/mL
II 26–91 ng/mL 44–144 ng/mL
III–IV 48–123 ng/mL 31–90 ng/mL

Pancreatic Polypeptide Quest

2 mL EDTA plasma.
0.6 mL minimum.
0.55 mL absolute minimum.
Cord blood.

Term infants <163

Preterm infants <180
Term infants to 6 days <276
1 month for 2 years <644
3–9 years <519
10–13 years <361
14–17 years <297

Parathyroid Hormone Antibody, Serum Quest

1 mL serum in no additive (red-top tube).

Minimum quantity: 0.2 mL.
Absolute minimum 0.125 mL.
Ship refrigerated.
Children and adults: Negative

Parathyroid Hormone (PTH), Intact, Serum Quest

Includes total calcium. The intact PTH is the recommended initial assay for the differential diagnosis
of calcium-related abnormalities.
2 mL serum in no additive (red-top tube).
Minimum quantity: 1 mL.
Absolute minimum 0.275 mL.
Spin and separate serum immediately. Ship refrigerated.
418 16 Laboratory Values for Pediatric Endocrinology

Adults
Males and females 10–65 pg/mL
Children
6–9 years 9–59 pg/mL
10–13 years 11–74 pg/mL
14–17 years 9–69 pg/mL

Parathyroid Hormone and Related Protein (PTH-RP) Quest

0.5 mL plasma in sodium heparin tube at room temperature PTH-RP and releasing factor tube.
Minimum quantity: 0.3 mL.
Absolute minimum 0.25 mL.
Do not thaw. Transfer the plasma to a plastic transport tube and ship frozen.
Males and females: 14–27 pg/mL.

Pregnenolone, Serum Esoterix

2.5 mL serum in no additive (red-top tube).

Minimum quantity: 1.1 mL.
Ship refrigerated.

Adults
Males 13–208 ng/dL
Females 7–188 ng/dL

Eso

Pregnenolone, HPLC-MS/MS
Range (ng/dL)
Premature infants
26–28 weeks, day 4 260–2,104
34–36 weeks, day 4 203–1,024
Infants
1–7 days 150–2,000
Levels decrease after birth, and are within the prepubertal range by 3 months.
Prepubertal children 20–140
Pubertal and adults <151

Progesterone, Serum Esoterix

1 mL serum in no additive (red-top tube).

Minimum quantity: 0.3 mL.
Specify age, sex, and menopausal status on test-request form. Ship refrigerated.
Eso
Proinsulin, Serum Quest 419

Progesterone, HPLC-MS/MS
Range (ng/dL)
Males
1–16 years <10–15
Adults <10–11
Females
1–10 years <10–26
11 years <10–255
12 years <10–856
13 years <10–693
14 years <10–1,204
15 years <10–1,076
16 years <10–1,294
Adult female cycle days
1–6 <10–17
7–12 <10–135
13–15 <10–1,563
16–28 <10–2,555
Postmenopausal <10
Note: Luteal progesterone peaked from 350 to 3,750 ng/dL on
days ranging from 17 to 23.

Progesterone, Free, HPLC-MS/MS

Range (% free) Range (ng/dL)

Males
Adults 1.9–4.2 <0.42
Females
Luteal 1.6–3.3 7.971.5
Follicular 1.5–3.4 <6.1
Postmenopausal 1.6–3.1 <7.1

Proinsulin, Serum Quest

1 mL frozen serum in no additive (red-top tube).

Minimum quantity: 1 mL
0.8 mL minimum.
Overnight fasting is required. Ship refrigerated.
Children and adults: ≤18.8 pmol/L.
420 16 Laboratory Values for Pediatric Endocrinology

Prolactin, Serum Quest

1 mL serum in no additive (red-top tube).

Minimum quantity: 0.5 mL.
Absolute minimum 0.25 mL.
Overnight fasting is preferred. Ship refrigerated.

Adults
Males Females
2.0–18 ng/mL 3–30 ng/mL
Children
Tanner stage Males Females
I ≤10 ng/mL 3.6–12.0 ng/mL
II–III ≤6.1 ng/mL 2.6–18.0 ng/mL
IV–V 2.8–11.0 ng/mL 3.2–20.0 ng/mL

Renin Activity (PRA), Plasma Esoterix

2 mL plasma in EDTA (lavender-top tube).

Minimum quantity: 0.4 mL.
Centrifuge and separate blood at room temperature. Avoid refrigerated temperatures. Patient should
refrain from taking medications, preferably 3 weeks before draw. Patient should be ambulatory for
30 min before draw. Patient should be on a moderate sodium diet during collection. Ship frozen.

Range (ng/mL/h)
Premature
1–7 days 11–167
Full term
1–7 days 2.00–35
Plasma renin activity in newborns is elevated and highly variable.
Children
31 days to 11 months 2.35–37
12 months to 2 years 1.71–11
3–4 years 1.00–6.50
5–9 years 0.50–5.85
10–14 years 0.50–3.30
Range (ng/mL/h)
Adults, normal sodium intake
Upright 0.70–3.30
Supine 0.20–1.60

Sex Hormone-Binding Globulin (SHBG) Esoterix

0.5 mL serum in no additive (red-top tube).

Minimum quantity: 0.2 mL.
0.3 mL absolute minimum.
T3 (Triiodothyronine), Free, Nondialysis Esoterix 421

Specify age and sex on test-request form. Ship refrigerated.

Eso

Range (nmol/L)
Infants
1–23 months 60.0–252.0
Prepubertal children 72.0–220.0
Pubertal children
Males 16.0–100.0
Females 36.0–125.0
Males
20–49 years 16.5–55.9
>49 years 19.3–76.4
Females
20–49 years 24.6–122.0
>49 years 17.3–125.0

Somatostatin Quest

1.8 mL plasma in EDTA (lavender-top tube).

Minimum quantity: 0.6 mL.
0.55 mL absolute minimum.
Draw a prechilled lavender-top tube. Separate and freeze plasma immediately. Do not thaw. Ship
frozen.
<30 pg/mL

T3 (Triiodothyronine), Free, Nondialysis Esoterix

1 mL serum in no additive (red-top tube).

Minimum quantity: 0.5 mL.
Absolute minimum 0.1 mL.
Ship at room temperature.

Range (pg/mL)
Infants
<4 days 2.0–7.9
4 days to 1 month 2.0–5.2
1–11 months 1.6–6.4
Children and adults
1–5 years 2.0–6.0
6–10 years 2.7–5.2
11–19 years 2.3–5.0
≥20 years 2.0–4.4
422 16 Laboratory Values for Pediatric Endocrinology

T3 (Triiodothyronine), Free, Dialysis Esoterix

T3, Free is determined by measuring T3, total, and the dialyzable fraction of labeled T3.
1 mL serum in no additive (red-top tube).
Serum or EDTA plasma ship frozen on dry ice.
Minimum quantity: 0.3 mL.

Age Range (pg/mL) Mean (pg/mL)

Premature (0–4 weeks) 1.35–6.25 3.13
Newborn (0–2 weeks) 0.99–8.03 4.21
Newborn (2 weeks to 12 months) 1.59–6.15 3.87
Prepubertal 1–10 years 2.21–4.99 3.60
Children >10 years and adults 1.81–4.06 2.77
Pregnant females Range (pg/mL) Mean (pg/mL)
First trimester 1.6–3.3 2.5
Second trimester To be determined
Third trimester 1.0–3.2 2.1

T3 (Triiodothyronine), Reverse Esoterix

1 mL serum in no additive (red-top tube).

Separate serum within 45 min of venipuncture; transfer into a plastic transport tube.
Minimum quantity: 0.3 mL.
Ship frozen on dry ice.

Range (ng/dL)
Premature infants
26–31 weeks 33–147
32–35 weeks 49–217
Full-term infants
2–7 days 33–206
8 days to 5 months 13–107
6–12 months 8.1–52.8
Children and adults
1–15 years 8.3–22.9
≥16 years 9.2–24.1

T3 (Triiodothyronine), Total, Radioimmunoassay Esoterix

1 mL serum in no additive (red-top tube).

Separate serum within 1 h; transfer into a plastic transport tube.
Minimum quantity: 0.2 mL.
Ship frozen on dry ice.
T4 (Thyroxine), Free, Nondialysis, Serum Esoterix 423

Range (ng/dL)
Premature infants
26–30 weeks, days 3–4 24–132
Full-term infants
1–3 days 89–405
1 week 91–300
1–11 months 85–250
Prepubertal children 119–218
Pubertal children
11–17 years 80–185
Adults 55–170

T4 (Thyroxine), Free, Direct Dialysis Serum Quest

Direct dialysis is the preferred method for determining Free T4. Free T4 is measured in undiluted
serum by radioimmunoassay of the dialyzable T4.
2 mL serum in no additive (red-top tube).
Minimum quantity: 0.5 mL.
Absolute minimum 0.15 mL.
Ship refrigerated in plastic screw top tube.

Adults
21–87 years 0.8–2.7 ng/dL
Children
Prematures, 25–20 weeks
Birth–7 days 0.5–3.3 ng/dL
Prematures, 31–36 weeks
Birth–7 days 1.3–4.7 ng/dL
>37 weeks 1.2–2.2 ng/dL
Cord blood
0–4 days 2.2–5.3 ng/dL
2 weeks to 2 years 0.8–2.0
3–20 years 1–2.4 ng/dL

T4 (Thyroxine), Free, Nondialysis, Serum Esoterix

0.8 mL serum in no additive (SST tube).

Minimum quantity: 0.3 mL.
Absolute minimum.
Ship frozen.
424 16 Laboratory Values for Pediatric Endocrinology

Range (ng/dL)
Infants
<4 days 0.66–2.71
4 days to 1 month 0.83–3.09
1–11 months 0.48–2.34
Children and adults
1–5 years 0.85–1.75
6–10 years 0.90–1.67
11–19 years 0.93–1.60
20 years 0.82–1.77

T4 (Thyroxine), Total, Serum Esoterix

1 mL serum in no additive (red-top tube).

Minimum 0.2 mL.
Ship refrigerated.

Range (μg/dL)
Premature infants
26–30 weeks, Day 3–4 2.6–14.0
Full-term infants
1–3 days 8.2–19.9
1 week 6.0–15.9
1–11 months 6.1–14.9
Prepubertal children
12 months to 2 years 6.8–13.5
3–10 years 5.5–12.8
Pubertal children
11–17 years 4.9–13.0
Adults 4.2–13.0

Testosterone, Total, Serum Esoterix

0.8 mL serum in no additive (red-top tube).

Minimum quantity: 0.4 mL.
Specify age and sex on test-request form. Ship refrigerated.

Male range Female

(ng/dL) range
(ng/dL)
Premature infants
26–28 weeks, day 4 59–125 5–16
31–35 weeks, day 4 37–198 5–22
Full-term infants 75–400 20–64
Newborns
(continued)
Testosterone Free, Serum or Plasma Esoterix 425

(continued)
Male 1–7 months Levels decrease
rapidly in the first
week to 20–50 ng/
dL, and then
increase to
60–400 ng/dL
(mean = 190)
between 20 and 60
days. Levels then
decline to
prepubertal range of
<2.5–0 by 7 months.
Female 1–7 months Levels decrease
during the first
month to <10 ng/dL
and remain there
until puberty.
Prepubertal children
Males (1–10 years) <2.5–10
Females (1–9 years) <2.5–10
Puberty
Tanner stage Age Range Mean Tanner Age Range Mean
(years) (ng/dL) (ng/dL) stage (years) (ng/dL) (ng/dL)
Male Female
1 <9.8 <2.5–10 4.9 1 <9.2 <2.5–10 4.9
2 9.8–14.5 18–150 42 2 9.2–13.7 7–28 18
3 10.7–15.4 100–320 190 3 10.0–14.4 15–35 25
4 11.8–16.2 200–620 372 4 10.7–15.6 13–32 22
5 12.8–17.3 350–970 546 5 11.8–18.6 20–38 28
Adults 20–50 years Range
(ng/dL)
Male 348–1,197
Female
Premenopausal 10–55
Postmenopausal 7–40

Testosterone Free, Serum or Plasma Esoterix

Includes total, free, and percentage free testosterone.

2 mL serum in no additive (SST tube).
Separate serum within 1 h; transfer into a plastic transport tube.
Minimum quantity: 1 mL.
426 16 Laboratory Values for Pediatric Endocrinology

Testosterone, free, by Blood assays

equilibrium dialysis
Male range (pg/mL) Female range (pg/mL)
Full-term infants
1–15 days 1.5–31 0.5–2.5
1–2 months 3.3–18 0.1–1.3
3–4 months 0.7–14 0.3–1.1
5–6 months 0.4–4.8 0.2–0.6
Prepubertal children
1–10 years 0.15–0.6 0.15–0.6
Puberty Comprehensive values for free testosterone by
dialysis for both males and females throughout
puberty are currently unavailable.
Adults 52–280 1.1–6.3
% Free testosterone
Male range (%) Female range (%)
Full-term infants
1–15 days 0.9–1.7 0.8–1.5
1–2 months 0.4–0.8 0.4–1.1
3–4 months 0.4–1.1 0.5–1.0
5–6 months 0.4–1.0 0.5–0.8
Prepubertal children
1–10 years 0.4–0.9 0.4–0.9
Puberty Comprehensive values for free testosterone by
dialysis for both males and females throughout
puberty are currently unavailable.
Adults 1.5–3.2 0.8–1.4

Testosterone Saliva Esoterix

Testosterone, Saliva, HPLC-MS/MS.

Adults Range (pg/mL)

Male 23–85
Female <9.8

Testosterone Bioavailable Esoterix

Prepubertal Range
children (ng/dL)
Males <0.2–1.3
(1–10 years)
Females <0.2–1.3
(1–9 years)
(continued)
Thyroid-Stimulating Hormone (TSH), Serum Quest 427

(continued)
Puberty
Tanner stage Age Range Mean Tanner Age Range Mean
(years) (ng/dL) (ng/dL) stage (years) (ng/dL) (ng/dL)
Male Female
1 <9.8 <0.2–3.4 1 < 9.2 < 0.2–3.4
2 9.8–14.5 2–58 12 2 9.2–13.7 0.8–4.7 3.6
3 10.7–15.4 12–70 30 3 10.0–14.4 1.1–9.6 4.7
4–5 11.8–17.3 84–350 210 4–5 10.7–18.6 2.3–13.9 6.1
Adults Range (ng/
dL)
Male: 20–39 128–430
years
40–49 years 95–350
50–69 years 95–285
70–79 years 60–240
Female 1.1–14.3

Thyroglobulin Antibody, Serum Quest

1 mL serum in no additive (red-top tube).

Minimum 0.5 mL.
Minimum quantity: 0.15 mL.
Ship refrigerated.
Children and adults: ≤20 IU/mL.

Thyroid Peroxidase Antibody (Anti-TPO), Serum Quest

1 mL serum in no additive (red-top or SST tube).

Minimum 0.5 mL.
Absolute minimum 0.25 mL.
Ship refrigerated.
Children and adults: <35 IU/mL.

Thyroid-Stimulating Hormone (TSH), Serum Quest

2 mL serum in no additive (red-top tube).

Minimum 0.5 mL.
Minimum quantity: 0.5 mL.
Ship refrigerated.

Adults
Males and females (nonpregnant) 0.4–4.5 mU/L
Children
Prematures, 28–36 weeks (first week of life) 0.20–27.90 mU/L
(continued)
428 16 Laboratory Values for Pediatric Endocrinology

(continued)
Cord blood, >37 weeks 1–39 mU/L
Birth to 4 days 3.2–35 mU/L
1–4 weeks 1.0–9.1 mU/L
1–11 months 0.8–8.2 mU/L
1–19 years 0.5–4.3 mU/L

Thyroid-Stimulating Immunoglobulin (TSI) Quest

1 mL serum in no additive (red-top or SST tube).

Minimum quantity: 0.2 mL.
Ship refrigerated.
Children and adults: <140 % of basal activity.

TSH Receptor Antibody (TRAb) Esoterix

1 ml serum in SST tube.

Minimum 0.3 mL.
Ship frozen on dry ice.

Titer at all ages Eso RANGE (U/L)

<1 U/L = Negative
1.1–1.5 U/L = Equivocal
>1.5 U/L = Positive

Thyroxine-Binding Protein/Globulin (TBG), Serum Quest

1 mL serum in no additive (red-top tube) or transport plasma in plastic tube.

Minimum quantity: 0.5 mL.
Ship refrigerated.

Adult male 12.7–25.1 μg/mL

Adult female 13.5–30.9 μg/mL
Pediatric
4–6 Years 14.8–32.9 μg/mL
7–8 Years 16.3–30.7 μg/mL
9–10 Years 15.8–27.4 μg/mL
11 Years 15.5–27.4 μg/mL
12 Years 14.8–26.2 μg/mL
13 Years 13.8–25.2 μg/mL
14 Years 12.2–25.2 μg/mL
15 Years 10.8–23.8 μg/mL
16 Years 10.0–23.8 μg/mL
17 Years 8.5–23.1 μg/mL
Vitamin D, 1,25-Dihydroxy, Serum Esoterix 429

Vanillylmandelic Acid (VMA), Random Urine Quest

10 mL urine from a 24 h collection in sterile screw-cap container.

Minimum quantity: 5 mL.
Absolute minimum 1.1 mL.
Collect urine with 6 N HCl to maintain a pH <6, and the sample is shipped frozen. It is preferable for
the patient to be off medication for 3 days before collection. Ship refrigerated.

Adults
Males and females 1.1–4.1 mg/g Cr
Children
Birth to 6 months 5.5–26 mg/g Cr
7–11 months 6.1–20 mg/g Cr
1–2 years 2.5–21 mg/g Cr
3–8 years 1.7–6.5 mg/g Cr.
9–12 years 1.5–5.1 mg/g Cr
13–17 years 1.5–3.6 mg/g Cr

Vanillylmandelic Acid (VMA), 24-h Urine Quest

10 mL urine from 24-h urine collection.

Minimum quantity: 5 mL.
Absolute minimum 1.1 mL.
Collect urine with 25 mL 6 N HCl to maintain a pH <3. Urine without preservative is acceptable if pH
is <6 and the sample is shipped frozen. Record 24-h urine volume on test-request form and urine
vial. It is preferable for the patient to be off medications for 3 days before collection. Ship
refrigerated.

Adults
Males and females ≤6.0 mg/24 h
Children
3–8 years ≤2.3 mg/24 h
9–12 years ≤3.4 mg/24 h
13–17 years ≤3.9 mg/24 h

Vitamin D, 1,25-Dihydroxy, Serum Esoterix

0.5 mL serum in no additive (red-top or SST tube).

Minimum quantity: 0.3 mL.
Absolute minimum 0.05 mL.
Overnight fasting preferable.
Ship refrigerated.
430 16 Laboratory Values for Pediatric Endocrinology

Vitamin D, 1,25(OH)2, Total

Age Range (pg/mL)
1–9 years 31–87
10–13 years 30–83
14–17 years 19–83
Adult 18–72

Vitamin D, 25-Hydroxy, Serum or Plasma Esoterix

0.5 mL serum in no additive (red-top or SST tube).

Minimum quantity: 0.3 mL.
Absolute minimum 0.05 mL.
Ship refrigerated.

Adults
Males and females 30–100 ng/mL
Deficiency <20
Insufficiency 21–29
Optimum >30
Toxicity >150
S.I. Unit Conversion Table from Esoterix/Labcorp 431

S.I. Unit Conversion Table from Esoterix/Labcorp

Hormone When you know Multiply by To find

ACTH (corticotropin) pmol/L 4.5 pg/mL
Antidiuretic hormone (ADH) pmol/L 1.084 pg/mL
Albumin g/L 0.1 g/dL
Aldosterone, serum nmol/L 36.04 ng/dL
Aldosterone, urine nmol/d 0.3604 μg/24 h
Aldosterone/creatinine nmol/mmol 3.1859 μg/g
Androstanediol nmol/L 29.2 ng/dL
Androstanediol glucuronide nmol/L 46.9 ng/dL
Androstenedione nmol/L 28.64 ng/dL
Androsterone, urine μmol/d 0.2905 mg/24 h
Androsterone/creatinine μmol/mmol 2.568 mg/g
Angiotensin I pmol/L 1.296 pg/mL
Angiotensin II pmol/L 1.046 pg/mL
Angiotensin III pmol/L 0.931 pg/mL
Angiotensin I-converting enzyme U/L 1 mU/mL
Atrial natriuretic peptide (ANP) pmol/L 3.08 pg/mL
C-Peptide nmol/L 3.021 ng/mL
C-Peptide, urine nmol/L 3.021 ng/mL
C-Peptide/creatinine nmol/mmol 26.7109 μg/g
Calcitonin pmol/L 3.418 pg/mL
Calcium mmol/L 4.008 mg/dL
Calcium, urine mmol/d 40.08 mg/24 h
Catecholamines, urine nmol/d 0.1762 μg/24 h

Hormone When you know Multiply by To find

Catecholamines/creatinine nmol/mmol 1.5572 μg/g
Corticosterone nmol/L 34.65 ng/dL
18-Hydroxycorticosterone nmol/L 36.25 ng/dL
Cortisol, serum nmol/L 0.0363 μg/dL
Cortisol, urine nmol/d 0.3625 μg/24 h
Cortisol/creatinine nmol/mmol 3.2045 μg/g
Cortisone nmol/L 0.0361 μg/dL
Creatinine, urine μmol/d 0.1131 mg/24 h
Cyclic Amp, urine μmol/L 1 nmol/mL
Cyclic Amp/creatinine nmol/mmol 0.0088 μmol/g
Dehydroepiandrosterone (DHEA) nmol/L 28.84 ng/dL
Dehydroepiandrosterone-sulfate nmol/L 0.0368 μg/dL
(DHEA-S)
Deoxycorticosterone (DOC) pmol/L 0.0331 ng/dL
18-Hydroxydeoxycorticosterone pmol/L 0.0347 ng/dL
(18-OH-DOC)
11-Desoxycortisol (compound S) nmol/L 34.65 ng/dL
(continued)
432 16 Laboratory Values for Pediatric Endocrinology

(continued)
Hormone When you know Multiply by To find
Dexamethasone nmol/L 39.25 ng/dL
Dihydrotestosterone (DHT) nmol/L 29.04 ng/dL
Dopamine, plasma pmol/L 0.153 pg/mL
Dopamine, urine nmol/d 0.153 μg/24 h
Dopamine/creatinine nmol/mmol 1.3528 μg/g
Endorphin, beta pmol/L 4 pg/mL

Hormone When you know Multiply by To find

Epinephrine, plasma pmol/L 0.1831 pg/mL
Epinephrine, urine nmol/d 0.1831 μg/24 h
Epinephrine/creatinine nmol/mmol 1.6186 μg/g
Estradiol pmol/L 0.272 pg/mL
Estriol pmol/L 0.0288 ng/dL
Estrogens, serum pmol/L 0.271 pg/mL
Estrone pmol/L 0.27 pg/mL
Estrone sulfate pmol/L 0.035 ng/dL
Folic acid pmol/L 0.0441 ng/dL
Follicle-stimulating hormone (FSH) IU/L 1 mIU/mL
Follicle-stimulating hormone, urine IU/d 1 IU/24 h
FSH/creatinine IU/mmol 8.842 IU/g
Gastrin ng/L 1 pg/mL
Glucagon ng/L 1 pg/mL
Growth hormone μg/L 1 ng/mL
Human chorionic gonadotropin (HCG) IU/L 1 mIU/mL
HCG, urine IU/d 1 IU/24 h
HCG/creatinine IU/mmol 8.842 IU/g
5-Hydroxyindoleacetic acid nmol/d 0.1912 μg/24 h
5-HIAA, urine 5-HIAA/creatinine nmol/mmol 1.6906 μg/g
Homovanillic acid (HVA), urine nmol/d 0.1822 μg/24 h
HVA/creatinine nmol/mmol 1.611 μg/g

Hormone When you know Multiply by To find

17-Hydroxycorticosteroids, urine nmol/d 0.3625 μg/24 h
17-Hydroxycorticosteroids/creatinine nmol/mmol 3.2045 μg/g
IGF-I (somatomedin C) nmol/L 7.6490 ng/mL
IGF-II nmol/L 7.5000 ng/mL
Inhibin U/L 0.0010 U/mL
Insulin pmol/L 0.1440 μU/mL
17-Ketosteroids, urine μmol/d 0.2884 mg/24 h
17-Ketosteroids/creatinine μmol/mmol 2.5495 mg/g
Luteinizing hormone (LH) IU/L 1.0000 mIU/mL
Luteinizing hormone, urine IU/d 1.0000 IU/24 h
S.I. Unit Conversion Table from Esoterix/Labcorp 433

Hormone When you know Multiply by To find

LH/creatinine IU/mmol 8.8420 IU/g
Metanephrine, urine nmol/d 0.1972 μg/24 h
Metanephrine/creatinine nmol/mmol 1.7432 μg/g
Metanephrines, total, urine nmol/d 0.1902 μg/24 h
Metanephrines, total/creatinine nmol/mmol 1.6814 μg/g
Methoxytyramine, urine nmol/d 0.1672 μg/24 h
Methoxytyramine/creatinine nmol/mmol 1.4786 μg/g
Norepinephrine, plasma pmol/L 0.1692 pg/mL
Norepinephrine, urine nmol/d 0.1692 μg/24 h
Norepinephrine/creatinine nmol/mmol 1.4957 μg/g
Normetanephrine, urine nmol/d 0.1832 μg/24 h
Normetanephrine/creatinine nmol/mmol 1.6195 μg/g
Osteocalcin nmol/L 6.5000 ng/mL

Hormone When you know Multiply by To find

Parathyroid hormone pmol/L 9.5 pg/mL
Prednisolone nmol/L 36.04 ng/dL
Prednisone nmol/L 35.84 ng/dL
Pregnanediol, urine μmol/d 0.3205 mg/24 h
Pregnanediol/creatinine ng/dL μmol 2.8332 mg/g/mmol
Pregnanetriol, urine μmol/d 0.3365 mg/24 h
Pregnanetriol/creatinine μmol/mmol 2.9747 mg/g
Pregnenolone nmol/L 31.65 ng/dL
17-Hydroxypregnenolone nmol/L 33.25 ng/dL
Progesterone nmol/L 31.45 ng/dL
17-Hydroxyprogesterone nmol/L 33.05 ng/dL
20-Hydroxyprogesterone nmol/L 31.65 ng/dL
Prolactin μg/L 1 ng/mL
Renin (plasma renin activity) ng/L/s 3.6 ng/mL/h
Reverse T-3 pmol/L 0.0651 ng/dL
Secretin pmol/L 3.055 pg/mL
Sex hormone-binding globulin (SHBG) nmol/L 0.0288 μg/dL
(Binding capacity)
Somatostatin-14 pmol/L 1.638 pg/mL
Somatostatin-28 pmol/L 3.276 pg/mL
Testosterone nmol/L 28.84 ng/dL
Free testosterone pmol/L 0.2884 pg/mL

Hormone When you know Multiply by To find

Testosterone, urine nmol/d 0.2884 μg/24 h
Testosterone/creatinine nmol/mmol 2.5495 μg/g
Thyroglobulin μg/L 1 ng/mL
(continued)
434 16 Laboratory Values for Pediatric Endocrinology

(continued)
Hormone When you know Multiply by To find
Thyroid-stimulating hormone (TSH) mU/L 1 U/mL
Thyroxine (T-4) nmol/L 0.0777 μg/dL
Thyroxine-binding globulin mg/L 0.1 mg/dL
Thyrotropin-releasing hormone pmol/L 0.362 pg/mL
(TRH or TRF)
Triiodothyronine (T-3) nmol/L 65.1 ng/dL
Vanillylmandelic acid (VMA), urine nmol/d 0.1982 μg/24 h
VMA/creatinine nmol/mmol 1.7525 μg/g
Vitamin B-12 pmol/L 0.1355 ng/dL
25-Hydroxy-vitamin D nmol/L 0.4006 ng/mL
1,25-Dihydroxy-vitamin D pmol/L 0.4166 pg/mL

Suggested Reading

Laboratory Values from

Endocrinology Expected values & S.I. Unit Conversion Tables. Esoterix/LabCorp, 2014.
Nakamoto J, Mason P. Quest Diagnostics. The quest diagnostics manual endocrinology. San Juan Capistrano, CA:
Quest Diagnostics; 2012.
 Index
A B
Abrams, S.A., 147
Acute adrenal insufficiency, 245, 246, 255, 363–365
Addison’s disease/primary adrenal failure, 4, 31, 109,
117, 134, 173, 210, 240–242, 245, 247–249, 257,
272, 291, 292
Adjusted midparental height, 65, 86
Adrenal androgens, 169, 170, 174, 175, 200, 214, 219,
221–223, 230, 234, 237, 239
Adrenal cortex, 233, 238, 240–257
Adrenal medulla, 233, 257–261, 268, 307, 309
Adrenal tumor, 223, 224, 247, 249, 251–252, 255
Adrenarche, 198, 200, 203, 221, 223, 224, 228,
237, 252
Adrenocorticotropic hormone (ACTH), 1–4, 7, 18, 20,
22, 25, 26, 30, 31, 75, 76, 80, 83, 101, 166, 167,
169, 171–174, 200, 207, 220, 223, 233–241,
243–257, 259, 268, 291, 308, 309, 314, 317, 318,
320, 324, 331, 363, 364, 373, 385, 386, 391, 413
Adrenoleukodystrophy, 242
Age at onset of puberty, 191, 214
Aldosterone, 30, 34, 41, 42, 137, 167, 177, 221, 234,
236, 238, 241, 244, 248, 250, 251, 256–257, 349,
383, 386, 399, 413
Alkaline phosphatase, 129–130, 133, 141, 143–147, 155,
202, 203, 386
Aloia, J.F., 147
Androgen insensitivity, 178–179, 185, 186, 211
Anorchia/testicular regression syndrome, 179, 180,
212–213
Antidiuretic hormone (ADH), 21, 29–31, 35, 41–45, 136,
148, 374, 413
Anti-Müllerian hormone (AMH), 162, 166, 168, 176,
178, 180, 183, 184, 194, 201, 212, 223, 230, 387
5α-reductase deficiency, 167
Arginine vasopressin (AVP), 20, 29, 30, 33–35, 39, 43,
45, 198, 378, 387
Arm span, 14, 15, 52, 84, 87, 211
Atrial natriuretic hormone (ANH), 387
Autocrine, 1, 2
Autoimmune polyendocrinopathy syndrome, 100, 133,
134, 240, 272
Autoimmune polyglandular endocrinopathy, 240–242
Autoimmune polyglandular syndrome, 240–242, 246, 291
© Springer International Publishing Switzerland 2016
D.M. Styne, Pediatric Endocrinology, DOI 10.1007/978-3-319-18371-8
Bariatric surgery, 21, 143, 351, 355, 356
Baroreceptors, 30, 31
Behrman, R.E., 85
Beta cells of the islets of Langerhans, 265, 270
Birth history, 11, 12
Bisphosphonates, 129, 146, 150, 155, 369
Body mass index (BMI), 13–15, 62, 84, 325–327, 403
in percentiles, 325–329, 346, 348, 352
Bone age, 20, 52, 58, 62–64, 67, 69–71, 77, 81, 82,
84–88, 106, 108, 109, 111, 116, 117, 169, 171,
172, 175, 182, 193, 198–200, 203, 207, 214–216,
222–224, 324, 331, 338, 351
Bone mineralization, 138, 145, 154
Brannon, P.M., 147
C
Calcitonin, 100, 119, 123, 124, 127–129, 139, 140, 145,
151, 152, 156, 369, 377, 387, 414
human, 377
Calcium, 4, 75, 78, 107, 115, 119, 123–157, 193, 205,
214, 259, 275, 279, 312, 332, 349, 353, 358,
367–369, 373, 377, 378, 382, 387–388, 405, 414
Calcium sensing receptor (CASR), 124, 128, 134, 135,
137, 149, 150 , 153
Catecholamines, fractionated
24-hr urine, 388–389
plasma, 389
Cell membrane GH receptor, 61
Cell-membrane protein receptors, 4, 243, 267, 269
Central diabetes insipidus (DI), 29, 32–41, 76, 206, 379
Central nervous system control of appetite, 329–332
Central nervous system tumors, 19–21, 78, 202,
204–206, 227
Central (complete or true) precocious puberty (CPP),
22, 24, 169, 190, 193, 194, 197, 206, 217–220,
222, 224
Cerebral edema (CE), 32, 276–277, 279, 366, 380
Cerebral salt wasting (CSW), 34, 42
Cholecalciferol, 127, 128, 138, 146, 150, 151
Circadian rhythm, 21, 80, 239
Clinton, S.K., 147
Comorbidities of obesity, 339–352, 356
435
436
Congenital adrenal hyperplasia (CAH), 64, 68, 166–171,
173–174, 176, 181–185, 198, 217, 219–221, 223,
230, 233, 235, 237–240, 247–249, 256, 314, 363,
373, 385, 387
Congenital adrenal hypoplasia (AHC), 192, 205, 242
Congenital hypothyroidism, 64, 83, 96, 98, 101–108, 111,
112, 131
Constitutional delay in growth, 63, 68–70, 84, 192,
203, 215
Constitutional delay in puberty (CDP), 194, 201–203, 213,
214, 218
Constitutive activation, 5, 116
Corticotropin (or ACTH), 1, 18, 19, 30, 234, 235
Corticotropin-releasing factor (CRF), 1, 3, 4, 18,
233–235, 241, 244, 245, 249–251, 254
Cortisol, 1–3, 7, 8, 19, 41, 75, 80, 83, 86, 166, 167, 170,
171, 174, 177, 182, 199, 221, 234–241, 244–257,
266, 270, 291, 306–310, 314, 318–321, 324, 344,
364, 371, 380, 390–391, 414
salivary, 391
Cortisol-binding globulin (CBG/transcortin), 237
Cortisol serum total LC/MS/MS, 391
Cortisol urinary free 24-hour, 390
C peptide, 204, 265, 274, 300, 301, 308, 317, 319, 321,
371, 387, 414
Craniopharyngioma, 20–21, 33, 35, 44, 45, 78, 85, 192,
205, 217, 339
Cushing disease, 4, 8, 192, 237, 239, 249–256, 267, 364
Cushing’s syndrome, 2, 7, 64, 83, 86, 221, 222, 229, 237,
247, 249, 251–257, 338, 339, 349, 351
Cytokine receptors, 4, 18
Cytoplasmic steroid receptors, 6
D Follicle-stimulating hormone (FSH), 4, 18, 25, 26, 76,
D-arginine-D-amino-vasopressin (DDAVP), 38–40, 375,
378, 379
Defects in gluconeogenesis, 314–316, 321–322,
324, 372
Dehydroepiandrosterone sulfate (DHEAS), 174, 177, 183,
191, 200, 203, 221, 223, 228, 233, 238, 239, 414
Delayed puberty, 14, 15, 21–25, 52, 62, 67, 69, 75, 77,
81, 82, 84, 192, 201–207, 213–219, 228,
249, 295
Developmental defects of the midline, 24
DHEA Serum, 392–393
DHEA Sulfate, serum, 393
Diabetic ketoacidosis (DKA), 40, 43, 116, 125, 266–267,
270, 272–281, 284, 287, 289–291, 295, 296, 300,
303, 365–366, 370, 373, 382
Dietary history, 280–281, 317, 323, 347, 348
Dihydrotestosterone (DHT), 163–167, 176–178, 183,
184, 198–200, 230, 394, 414
1,25-Dihydroxy vitamin D, 123, 125–128, 131, 132, 137,
139, 143–145, 144, 145, 147, 152, 155, 413
Disorders of sexual differentiation (DSD), 159–187, 201,
208–211
Diurnal rhythm, 7, 97, 197, 253
Durazo-Arvizu, R.A., 147
Dyslipidemia, 13, 228, 230, 294, 295, 344, 346–348, 356
Index
E
Ectopic hormone production, 390
Endemic cretinism, 102, 104, 110
Endocrine, 1–8, 11–15, 17–19, 21–25, 35, 47, 58–62, 65,
67, 74–86, 91, 109, 116, 118, 124, 127, 138, 140,
149, 150, 152, 153, 159, 165, 168, 170, 179, 180,
184, 187, 191–202, 205, 207, 210, 213, 214,
216–218, 220–228, 230, 233, 250–252, 258, 260,
267–269, 272, 275, 290, 309, 314, 332, 337–339,
351, 356, 363–376, 385
Endocrine causes of obesity, 338
Energy expenditure, 208, 291, 336, 338, 352–354
Energy intake, 208
Epigenetics, 72, 77, 330, 337, 360
Ergocalciferol, 127, 128, 141, 146, 150, 151, 378–379
Estradiol, 60, 61, 82, 88, 124, 176–178, 191, 194, 195,
198–201, 216, 220–222, 225, 227, 233, 394–395
Estradiol, serum, 220, 222, 395
Euthyroid sick syndrome, 111
External genitalia, 163, 165, 166, 168, 175, 179–181,
185, 209, 210, 221, 222
Extracellular domain, 4, 5
F
Familial hypocalciuric hypercalcemia (FHH),
124, 148–150, 153
Familial short stature, 82
Family history, 12, 13, 84, 109, 131, 153, 154, 203, 213,
216, 219, 220, 223, 230, 273, 293, 299, 346, 347,
349, 367, 369
Fetal adrenal gland, 233
Fine needle aspiration under ultrasound guidance, 118–119
Fisher, D.A., 133, 142, 148
184, 191–195, 197–201, 205, 206, 209, 211, 212,
214, 219, 220, 222, 224, 227, 230, 396, 414
third generation, serum, 396
Free FT4 (or FT4), 93, 97–98, 101, 103, 105, 109, 110,
113, 116
G
Gallagher, J.C., 147
Gallo, R.L., 147
Gardner, D.G., 86
Gastrointestinal (GI) hormones, 267–270
GeneTests, 8, 182–184
Genetic factors indiabetes, 271
Genotype, 159–161, 210
Germinoma, 21–22, 33, 39, 78, 85, 192, 206, 217,
219–221
GH-binding protein (GHBP), 4, 6, 62, 63, 76–77, 398
Glucagon, 4, 5, 58, 266–271, 281, 290–291, 307, 311,
314, 318, 322, 323, 330, 356, 372, 376, 397, 414
Glucagon Hcl, 379
Glucocorticoid withdrawal, 255
Glucorticoid preparations, 246, 379, 380
Glucose infusion rate, 305, 308, 311, 313, 372
Glucose regulatory factors, 306–307
Index
GLUT 4, 266, 270, 306
Glutamic acid decarboxylase 65 (GAD 65) antibodies,
264, 271, 272, 274
Glycogen storage disease, 308, 310, 318, 323, 372
Glycoprotein hormones, 18, 205
Glycosylated hemoglobin/hemoglobin A1c, 288
Goiter, 14, 15, 98–102, 104–106, 108–110, 112–114,
117, 370
Gonadal DSD, 179–180
Gonadal sex, 159, 161–162
Gonadarche, 194–200, 203, 214
Gonadotropin-releasing hormone (GnRH), 4, 18, 22, 82,
89, 169, 193–197, 199, 201, 204, 206, 212–213,
215, 217, 219, 220, 222, 225, 227, 228
Gonadotropin-releasing hormone analogues (GnRH-As),
224–225
G protein complex, 4, 5
Graves’ disease, 91, 92, 97–99, 105, 109, 112–114, 116,
117, 382
Greenspan, F.S., 86
Greulich, W.W., 58, 69
Growth charts, 13, 47, 48, 50–52, 55, 56, 65–67, 69, 70,
74, 75, 203, 328
Growth factors, 1, 62, 66, 67, 175, 204
Growth hormone (GH), 4–6, 17–27, 47, 56, 58–70,
72–89, 102, 124, 127, 140, 145, 172, 193, 203,
206–207, 209, 211, 215, 216, 230, 240, 243, 252,
259, 266–268, 270, 291, 307–310, 314, 317–320,
321, 322, 324, 330, 338–339, 351, 371, 379,
397–398, 414
deficiency, 17, 19, 20, 23–25, 27, 33, 56, 58–60,
62–65, 67, 68, 74–83, 86, 179, 206, 215, 216,
250, 256, 308, 314, 324, 338–339, 351, 382, 398
resistance, 59, 62, 68, 76–78, 80, 317
secretion tests, 18, 22, 58–64, 70, 74, 77–80, 83, 86,
88, 89, 259, 267, 268, 338
serum, 397–398
Growth hormone release inhibitory factor (or
somatostatin or SRIF or SS), 58
Growth hormone releasing factor (GHRH/GRF), 4, 17–19,
58, 59, 76, 80, 84, 136
Growth velocity, 52, 56, 70, 87, 193, 233
Gut microbiome, 336, 339, 350, 357
Gynecomastia, 177, 178, 211, 217, 221, 223, 252
H Hypothalamic inhibiting factors, 17
Hamartomas of the tuber cinereum, 217, 219, 224
Hashimoto’s thyroiditis, 71, 98–100, 109–110, 112–114,
209, 246, 272, 373
Health disparities, 325
Hemoglobin A1c (HgbA1c), blood, 230, 274, 286, 288,
292, 294, 296, 300, 352, 398
Home measurement by glucometer, 281–282
Homeodomain proteins, 17, 25
Honeymoon period, 273, 289, 292, 300, 303
Hormone-receptor complex, 6, 7
Hungry bone syndrome, 115, 125, 128, 149
25 Hydroxy vitamin D, 126, 128, 139, 141, 144–146,
149, 415
437
Hypercalcemia, 36, 124, 126–130, 135, 137, 138, 146,
148–156, 259, 368–369, 381
Hyperglycemia, 34, 43, 264–267, 272, 273, 279, 280,
283, 288–290, 294, 296–300, 302, 303, 309, 311,
312, 317, 374
Hypergonadotropic hypogonadism, 73, 134, 177, 192,
197, 203, 207–213
Hyperinsulinism, 63, 88, 259, 309–311, 313, 314,
316–317, 321–324, 331, 338, 372, 373
Hyperkalemia, 128, 138, 149, 167, 168, 171, 172, 184,
238, 245, 248, 277, 279, 363–366, 373–374
Hypernatremia due to diabetes insipidus, 39, 374–375
Hyperosmolality, 32, 323, 372
Hyperparathyroidism, 7, 130, 143–145, 148–153, 155,
259, 269, 369
Hyperphosphatemia, 84, 125, 127, 130, 131, 136–138,
143, 151, 367
Hypertension, 13, 34, 71, 96, 113, 117, 148, 149, 167,
174, 177, 209, 210, 216, 228, 230, 249, 256–260,
277, 292, 295, 296, 331, 343, 347–350, 352, 356,
369, 375, 376, 379, 382, 383
Hypertension due to pheochromocytoma, 375–376
Hyperthyroidism, 74, 85, 92, 93, 97–99, 101, 105, 106,
109, 110, 112–117, 120, 148, 150, 152, 221, 241,
269, 370, 371, 381
Hyperthyroidism in the neonate, 370
Hypocalcemia, 84, 115, 123–126, 128–143, 151, 155,
296, 366–368, 377, 378, 380, 381
Hypoglycemia, 6, 12, 26, 61, 101, 168, 207, 240, 265,
305, 338, 363, 379
Hypogonadotropic hypogonadism (HH), 19, 25, 27, 73,
78, 185, 192, 194–196, 203–207, 213, 214, 216,
218, 242, 331
Hyponatremia, 30, 34, 40–44, 75, 167, 172, 173, 184,
238, 245, 248, 323, 363–365, 372–374
Hyponatremia due to the syndrome of inappropriate
ADH secretion, 45
Hyponatremia/hyperkalemia due to adrenal insufficiency,
373–374
Hypoosmolality, 32
Hypoparathyroidism, 7, 109, 119, 131–137, 149, 240,
242, 367–369, 377, 379
Hypophosphatemic rickets, 75, 84, 125, 142,
145–146, 221
Hypophysiotropic hormones, 1
Hypophysiotropic portal system, 59, 193, 234
Hypothalamic pituitary axis, 4, 17–27, 91, 199, 218, 219,
226, 235, 249, 251
Hypothalamic releasing factors, 17
Hypothalamic thyrotropin-releasing hormone
(TRF), 91
Hypothalamus, 1, 2, 17, 19, 23, 24, 29, 30, 32, 44, 58,
59, 61, 91, 96, 101, 193, 195, 197, 198, 204, 219,
233–235, 237, 243, 330, 332
Hypothyroidism, 15, 20, 24, 31, 34, 52, 56, 62, 64, 67,
68, 74–76, 78, 80, 83, 85, 91, 92, 96–113, 115,
116, 119, 131, 134, 192, 205, 208, 217, 219,
223, 240–243, 247, 292, 338, 348, 351, 352,
365, 370
438
I Loss of function mutations of MKRN3, 219
IA-2 (islet cell associated phosphorylase) antibodies,
271, 272
Iatrogenic glucocorticoid deficiency, 247
Iatrogenic obesity, 339
Idiopathic hypopituitarism, 25–27, 206–207
Idiopathic short stature, 67, 69
IGF-BINDING PROTEIN-3 (IGFBP-3), 63, 401–402
Inhibin B, 180, 184, 201, 203, 212–214, 223, 402
Insulin, 5, 21, 40, 58, 109, 125, 193, 239, 263, 305, 330,
366, 379, 402
preparations, 282, 283, 380
pump, 275, 276, 281, 286–289, 291, 303
receptor, 5, 6, 63, 65, 266, 316
resistance, 82, 228, 249, 264, 268, 270, 286, 289,
296, 299, 316, 317, 330, 331, 337, 339–346, 348,
352, 355
Insulin-like growth factor 1 (IGF-1), 5, 6, 59, 62, 63, 77,
78, 88, 127, 259, 338, 400–401
Insulin like growth factor binding protein 3 (IGFBP3),
63, 77, 85
Insulin-like growth factor 1 receptors (IGF1R), 6
Insulin-receptor substrates (IRSs), 5
Internal sexual ducts, 162–164
Intracellular domain, 4
Intracrine, 1, 2, 230
Ionized calcium, 123, 131, 135, 149, 150, 155, 368
Islet cell antibodies, 264, 300, 402
J Microvascular and macrovascular complications of
Janus kinase-signal transducer and activator of
transcription (Jak-STAT) pathway, 62
Jones, G., 147
K Multidisciplinary team management, 186
Kallmann syndrome (KS), 192, 203–205
Ketotic hypoglycemia, 308, 315, 317–319, 321–323, 372
Kinases, 4, 5, 62, 65, 118, 205, 242, 252, 300, 318,
347, 355
Kisspeptin, 194, 197, 204, 218–219
Klinefelter’s syndrome, 15, 52, 86, 88, 110, 160, 179,
180, 192, 201, 203, 210–211, 213, 223
Kovacs, C.S., 147
L Negative feedback loop, 127
Laboratory values for pediatric endocrinology,
385–415
Langerhans cell histiocytosis, 23, 33, 68, 110
Lengthening of the QTc interval, 132, 134
Leptin, 4, 199, 268, 330–332, 339
Leptin, serum, 403
Leydig cells, 5, 162, 176, 179, 180, 183, 184, 194,
198, 199, 205, 210–212, 217, 220, 221, 223–227,
257, 317
Lifestyle modification, 230, 347, 349, 350, 352–355, 357
Lipid (prostaglandin) structures, 3, 331
Index
Luteinizing hormone (LH), 4, 18, 26, 76, 164, 179,
192–194, 205, 242, 403, 414, 415
M
Magnesium, 123, 125–126, 131–133, 136–137, 257, 275,
279, 314, 365, 367, 368, 380
Manson, J.E., 147
Maternal age of menarche, 12, 13, 84
Maturity-onset diabetes of the young (MODY), 264, 265,
273, 298, 301–302
Mayne, S.T., 147
McCune–Albright syndrome, 5, 88, 112, 116, 130, 146,
217, 221, 223, 225, 252
Measurement of growth, 47–58
MECASERMIM (rhIGF-1), 77
Medical history, 11–13, 84, 181, 299, 309, 319
Medication and complementary medical
history, 11
Medications for pediatric endocrinology, 377–383
Medullary carcinoma of the thyroid (MCT), 100, 118,
119, 128, 260
Membrane protein receptor, 124, 126, 221, 235, 243,
267, 269, 307
Metabolic syndrome, 228, 230, 299, 329, 337,
339–344, 350
Metformin, 230, 300, 350, 355, 356, 381
Microphallus, 75, 76, 105, 165, 179, 186, 194, 203, 207,
314, 319, 363, 371, 372
diabetes, 294
Mineralocorticoids, 124, 168, 172, 174, 176, 177, 199,
221, 233, 234, 238, 240, 242–247, 249, 252–253,
255–257, 363, 364, 373, 374, 380
Motivational interviewing, 353
Multiple-dose injection regimen, 283–286
Multiple-dose injections, 283–286, 289, 300
Multiple endocrine neoplasia, 22, 23, 88, 100, 118, 149,
152, 153, 252, 258–260, 267–269, 314, 369
N
Natruretic peptides, 30, 32, 33
Negative feedback, 3, 19, 59, 127, 178, 194–196, 199,
235, 240, 251
Neonatal diabetes mellitus (NDM), 265, 297–299
Neonatal hyperinsulinemic hypoglycemia, 268
Neonatal hypoglycemia, 26, 88, 101, 311, 314, 317
Neonatal screening, 83, 101, 103, 105, 106, 168, 170
Nephrogenic diabetes insipidus, 29, 32, 34–36, 39, 41
Neuroblastoma, 249, 258, 260–261, 268
Neurophysin, 19, 29, 39
Nodular adrenal hyperplasia, 251–252, 255, 267
Nonalcoholic liver disease (NAFLD), 350
Nonketotic hyperosmolar coma, 303
Normal bone growth, 138–140
Index
O Primary IGF deficiency, 68
Obesity, 12, 21, 58, 108, 136, 189, 243, 263, 316, 325
Obesogenic environment, 337–338
Online mendelian inheritance in man, 8, 156
Osmolality, 30, 32, 34, 36–39, 41–43, 80, 278, 323, 372,
375, 404
Osmolality, serum, 29–33, 36–38, 41, 43, 245, 278, 303,
374, 375, 405
Osmoreceptor, 30
Osteogenesis imperfecta, 68, 140, 155, 156, 377, 382
Osteoporosis, 88, 141, 153–156, 193, 207, 249
Overweight, 218, 264, 325, 329, 338, 340, 353, 354, 357,
358, 360
Ovotesticular DSD, 162, 163, 179–180
Ovulation and menarche, 201–202
P Radiation damage to the hypothalamus, 24, 332
Paracrine, 1, 2, 62, 65, 127, 162, 168
Paragangliomas, 258, 268
Parathyroid hormone (PTH), 2, 4, 7, 83, 123–128, 130–136,
138, 141–144, 147–151, 153, 155, 259, 369, 405
Parathyroid hormone-and related protein (PTH-RP),
405–406
Parathyroid hormone (PTH), intact, 126, 131, 405
Parathyroid hormone-related protein (PTHrP), 123, 126,
127, 148, 150, 369
Pediatric Sex steroid and gonadotropin and their assays,
200–201
Peptide hormones, 4, 5, 58, 128, 212, 235, 269, 330
Peripheral Precocious Puberty, 206, 218–221, 224, 226
Phenotypic sex, 159, 162–165
Pheochromocytoma, 119, 152, 249, 252, 258–261, 268,
269, 349, 375–376
Phosphate, 124–126, 129–131, 135, 138, 140, 143–146,
149, 151–153, 155, 157, 275, 279, 369, 381–382
Phosphorylation, 4, 5
Physical examination, 11, 13–15, 47, 84, 85, 89, 99, 101,
131, 148, 155, 156, 213, 292, 319
Pituitary adenomas, 3, 22–24, 250, 252, 259, 268
Pituitary gland, 1, 2, 17, 19, 20, 22, 25, 30, 59, 78, 86,
91, 105, 108, 116, 193–195, 205, 234, 240, 243,
250, 251, 255, 267, 268, 330, 363
Pituitary stalk section, 19, 29
Polycystic ovarian disease, 169, 192, 223
Polycystic ovarian syndrome (PCOS), 169, 174, 199,
201, 202, 223, 228–230, 299, 316, 344
Positive feedback, 2, 201–202
Posterior pituitary gland or neurohypophysis, 19, 25,
29–45
Premature Adrenarche, 200, 217, 221, 223, 228, 252
Premature Leydig and germinal cell maturation, 198,
220, 227
Premature Thelarche, 217, 222, 224
Prenatal history, 12
Prevention of obesity, 301
Primary endocrine disorders, 4, 207
Primary hyperaldosteronism, 256–257
Primary hypothyroidism, 64, 75, 91, 92, 97, 98, 105–110,
208, 217, 223
439
Proinsulin, 265, 270, 298, 331, 406–407
Prolactin, serum, 407
Pro-opiomelanocortin (POMC), 235, 243, 330–331
Propranolol, 80, 115, 116, 259, 311, 319, 370, 371,
375, 382
Protein binding, 93–94, 96, 123, 132, 201, 239
Pseudohypoparathyroidism (PHO), 2, 68, 79, 83–84,
131, 133, 135–136, 138, 143, 338, 351, 367, 379
Psychogenic polydipsia, 29, 32, 34, 36–39
Psychosocial dwarfism, 13, 65, 68, 78–81, 84
Pubertal growth spurt, 60, 63, 64, 193, 202–204
Pyle, L., 58, 69
R
Radiation damage to the gonads, 212
Radioactive iodine (131I; RAI) therapy, 99, 105, 112,
115–117, 120, 370
Radioiodine imaging of a thyroid gland, 97
Renal osteodystrophy, 74, 143
Renal water channel aquaporin, 35
Renin activity (PRA), plasma, 93, 96, 98, 105,
111, 409
Reverse T3 (RT3), 93, 96, 98, 105, 110, 111
Rickets, 15, 68, 75, 84, 129, 130, 141, 143–147,
154–156, 221, 379
Rocaltrol, 368
Rosen, C.J., 147
Ross, A.C., 147
S
Secondary adrenal insufficiency, 244, 245, 255, 331
Secondary endocrine disorders, 4, 207
Secondary hypothyroidism, 91, 98, 105
Secondary sexual development, 176, 191, 210, 214–216
Secular trend, 191
Seminiferous tubules, 194, 205, 210, 220, 224
Sense of thirst, 21, 30, 32, 33
7 Trans-membrane domain G protein coupled type 1
parathyroid hormone receptor (PTHR), 126
Seven transmembrane domains, 4, 5, 92, 126, 220
Sexual differentiation, 159–187, 194, 201, 208–211
Sexual precocity, 22, 86, 169, 217–218, 221–222, 227
Shapses, S.A., 147
Sick day management, 289–290
Signal transducer and activator of transcription (STAT),
4, 6, 62
Small for gestational age (SGA), 69–73, 77, 81, 130, 223,
296, 298, 309, 310, 317, 319, 337, 346, 367, 383
Social gender, 166
Somatropin (Growth hormome), 382
SRY gene, 160–162, 179, 180, 184, 211
Stadiometer, 14, 49
STAT. See Signal transducer and activator of
transcription (STAT)
Stature in percentiles or standard deviations, 51, 58,
65–67, 154, 155, 200, 212, 325
440
Steroid, 1–4, 6, 7, 24, 60, 63, 64, 66, 78, 94, 95, 127,
128, 152, 155, 162, 163, 165, 170, 172–178,
181–183, 194–203, 206, 208, 210, 214, 215,
217–221, 224, 226, 227, 233, 235, 236, 239–240,
247–248, 252, 257, 344, 364
Styne, D.M., 68, 86
Syndrome of inappropriate secretion of Antidiuretic
Hormone (SIADH), 31, 32, 34, 40–44, 374
T 180, 192, 194, 201, 203, 208, 209, 211, 213, 216,
Tall stature, 83, 86–89, 175, 222, 338, 351
Tanner staging or Sexual maturation ratings (SMR), 189,
223, 386, 393–396, 400, 403, 405, 407, 410, 411
Tertiary adrenal insufficiency, 238, 243, 245
Tertiary endocrine disorders, 4
Tertiary hypothyroidism, 91, 92, 98, 101, 105, 111
Testicular enzyme deficiencies, 176
Testosterone, 3, 11, 18, 64, 81, 82, 87, 140, 160,
162–165, 167, 172, 176–179, 183, 184, 186, 191,
193–196, 198–201, 205, 207, 210–217, 220, 223,
226, 227, 230, 238, 239, 252, 383, 410–411, 415
bioavailable, 411
total, 410
Tetany, 124, 130–132, 134, 137, 145, 156, 241, 257,
366, 367
T3 (triiodothyronine), free, 408
T4 (thyroxine), free, 409
The built environment, 31
The critical sample, 309, 316, 320–322, 371
The fasting state, 267, 295, 307, 322, 346
The fed states, 266, 305, 307, 313, 319, 322
Thyroglossal duct cyst, 96, 110
Thyroid antibodies, 106, 109, 111
Thyroid-binding globulin (TBG), 93, 96, 97, 101, 105,
111, 113, 412
Thyroid carcinoma, 98, 99, 110, 117–120, 150, 252,
269, 356
Thyroidectomy, 115, 118, 119, 260
Thyroid hormone receptors, 6, 94, 105
Thyroiditis, 71, 98–100, 109–110, 116, 120, 241, 293
Thyroid nodules, 117, 118
Thyroid peroxidase antibody (Anti-TPO), serum, 412
Thyroid stimulating hormone (TSH), 4, 18, 20, 25, 26,
58, 64, 76, 91, 92, 94, 96–113, 116, 118–120,
131, 136, 206–208, 219, 240–241, 243, 293, 338,
352, 370, 412, 415
Thyroid-stimulating hormone (TSH), serum, 412
Thyroid-stimulating immunoglobulin (TSI), 92, 113, 412
Thyroid storm, 115–117, 370–373, 382
Index
Thyroxine (Levo), 380
Thyroxine (or T4), 82, 92–97, 100, 101, 103,
105–107, 110–114, 116, 118, 119, 293, 352,
370, 371, 409
Triiodothyronine (or T3), 92–94, 117, 415
Triphasic Response after Surgery for
Craniopharyngioma, 40, 44, 45
T3 (triiodothyronine), total, 408
T4 (thyroxine), total, 409
Turner syndrome, 51, 68, 71–72, 81, 82, 110, 159, 162,
301, 383
Type 1 diabetes mellitus, 35, 74, 82, 85, 109, 134,
240, 241, 264, 269–273, 280–294, 297–298, 307,
316, 348
Type 2 diabetes mellitus, 82, 264, 299–303, 328, 340,
348, 356
U
Ultrasensitive TSH assays, 97, 98
Ultrasonographic scanning of the thyroid gland, 98, 99,
110, 117
Upper-to-lower segment ratio, 14, 15, 52, 58, 62, 64, 84,
87, 103, 109, 204, 211
V
Vasopressin, 4, 17–21, 25, 26, 29–45, 198, 199, 234, 238,
245, 374, 378, 383, 387
Vitamin D deficiency, 127, 128, 130, 133, 140–149,
378–379
Vitamin D-dependency rickets, 142, 144, 379
Vitamin D,25-hydroxy, serum/plasma esoterix, 413
Vitamin D-resistant rickets, 68, 123, 142, 144, 379
W
Weight in percentiles/standard deviations, 14, 278,
328, 356
Weight loss and chronic disease, 207–208
X
46 XX DSD, 166, 169, 171, 174, 175, 177, 182, 185, 210
46 XY DSD, 162, 166, 176–179, 185, 186, 211
Z
ZnT8 (zinc transporter molecules) antibodies, 273, 274