Professional Documents
Culture Documents
Pediatric Endocrine Protocols-1
Pediatric Endocrine Protocols-1
GROW Society
d i s a s t r o u s c o n s e q u e n c e s . would include health care professionals, school authorities, non
Excess growth in the form of
Growth & Obesity Workforce
governmental organizations and media. The concept would be
obesity on other hand leads to
piloted at Kanpur with subsequent nation wide implementation.
the development of lifestyle
1
diseases like diabetes and heart
disease.
2
Table of contents
1.5 Obesity 27
2.4 Hyperandrogenism 65
3
Section Page number
4
Pediatric Endocrinology Protocols
GROW Society
Growth & Obesity Workforce
Web- www.grow-india.org,
Email- grow_india@yahoo.com
GROW India
Growth & Obesity Workforce
Published by GROW Society Publications, Kanpur, 2014 (c) All rights reserved
Pediatric Endocrinology remains an exotic specialty dealing with rare and complicated disorders
requiring cumbersome work-up and exorbitant treatment for most pediatricians. On the contrary
Pediatric Endocrinology deals with a number of common disorders which can be worked up and
managed to a great extent with limited resources. Awareness of Pediatric Endocrinology is
mandatory for all Pediatricians for ensuring holistic evaluation of a child as growth and
development is what sets apart a child from an adult. Unfortunately lack of awareness and
training in the speciality results in missing and messing of a number of children with these
disorders. This is reflected by delayed presentation of children with growth and endocrine
disorders when not much can be done. GROW Society, growth and obesity workforce, was
formed as a non governmental workforce in Kanpur in 2013 with an aim of increasing
awareness about pediatric endocrine disorders amongst pediatricians, general physicians and lay
public. The organization has been working with schools, parents and pediatricians the three key
players involved in the management of children with pediatric endocrine disorders. Key efforts
have included development of school workshop modules for parents and teachers, formation of
patient support groups for growth hormone deficiency, celiac disease, hypothyroidism and type
1 DM and development of pediatric endocrine modules for pediatricians. The society has
developed six modules on growth, puberty, thyroid, glucose disorders, electrolyte and calcium
homeostasis that have been implemented across the country as three full day Practical Pediatric
Endocrine Course and 30 half day workshops.
The launch of GROW Society Pediatric Endocrinology Protocols forms the next logical step in
achieving the goal of the Society. The book covers almost the entire range of pediatric
endocrine disorders with special emphasis on common conditions presenting to the
pediatricians. The book is divided into six modules (corresponding to the GROW Society training
modules). They have been developed with an aim of providing practical approach for
assessment and management of the disorders. Clinical assessment has been given due
importance with an aim of minimizing investigations. The book is aimed at complimenting the
modules developed by the society and should be useful for postgraduate trainees and practicing
pediatricians.
Please let us know of your feedback that would be invaluable for us.
Anurag Bajpai, Pediatric Endocrinologist, Regency Hospital Kanpur
General Secretary, GROW Society,
Web- www.grow-india.org, www.dranuragbajpai.com
Email- dr_anuragbajpai@yahoo.com
Section 1- Growth
1.1 Growth Assessment
Interpretation
! Growth chart- Compared to population reference
! More than 97th percentile- Growth acceleration
! 3rd- 97th percentile- Normal
! Less than 3rd percentile- Growth retardation
! Adjustment for pubertal stage crucial
! Assessment
! Mark target height and range on growth chart
! Plot current height on growth chart
! Extrapolate current height percentile to final height
! Interpretation
• Height above target height range- Growth acceleration
Longitudinal assessment
Longitudinal measures of growth should ideally be done over a period of at
least six months (ideally one year) given the inherent errors in height
measurement and saltatory pattern of growth.
ADIPOSITY ASSESMENT
Obesity implies excessive body fat and not merely excess weight. As methods
of measuring body fat are cumbersome and expensive, clinical parameters are
used as markers of obesity.
Body mass index- Body mass index (BMI) is the most widely used parameter
to define obesity. It takes into account body weight as well as the height of the
individual. It is calculated by the formula
BMI = Weight kg/ height m2
Weight for height- This parameter compares the child’s weight to the
expected weight for his/her height. This is recommended for children below
two years of age. Values above 95% are indicative of obesity while those
below 80% indicate malnutrition.
FURTHER READING
1. Lifshitz F, Botero D. Worrisome growth. In: Pediatric Endocrinology, Eds:
Lifshitz F, Marcel Dekker, 2003, New York, 4th edition. Pp 1-47.
2. Khadilkar VV, Khadilkar AV, Choudhury P, Agarwal KN, Ugra D, Shah NK.
IAP growth monitoring guidelines for children from birth to 18 years. Indian
Pediatr 2007; 44: 187-97.
Growth charts represent the most important diagnostic tools for evaluating a
child with growth disorder. Careful plotting of growth charts often provides
reasonably good idea for the underlying diagnosis. There is thus a need for
routine monitoring of all children using growth charts.
What are growth charts? Growth charts are percentile curves prepared from
population based studies where anthropometric measures are collected from a
large number of children in a cross sectional manner.
Types of growth charts in use: Growth charts that are most commonly used
are height, weight, BMI and head circumference charts. Many other charts
such as sitting height, subischeal length, biacromial diameter, knee height,
skin fold thickness etc are available but are mainly used for research purpose.
Most growth charts have standard 7 percentile lines viz. 3rd ,10th, 25th, 50th,
75th ,90th and 97th.
Height Charts: Height charts are used from birth to 18 years of age in both
sexes. They are very useful to monitor the growth of the baby and child over a
period of time. These charts are also known as distance charts. Age is divided
into monthly intervals. Along with distance charts height velocity charts are
also used to monitor growth velocity. These charts are particularly useful to
pick-up growth failure early as growth velocity is a more sensitive indicator of
growth failure.
Weight Charts: These charts are used from birth to 18 years in both sexes. In
infancy they are more often used than in later childhood. Weight charts are
useful to diagnose both failure to thrive as well as obesity.
BMI Charts: BMI charts which are age and sex specific are useful in
diagnosing overweight and obesity at all ages.In addition to the usual standard
7 percentile lines BMI charts have two other lines viz. 85th and 95th to
diagnose overweight and obesity respectively.
Which growth charts to use? Given the plethora of growth charts available it
is often a dilemma to choose a growth chart. Some guidelines are as below.
Height chart- Below 5 years of age WHO charts are recommended. Beyond
that the options include CDC charts, KN Aggarwal charts recommended by
IAP and Khadilkar chart of affluent children. There are subtle differences in the
measures at different ages across the charts and are important in research
setting. From a clinical stand point use of any growth chart with correction for
parental height is adequate.
BMI- The options include CDC charts, IOTF charts and Khadilkar’s charts
based on affluent Indian children. The CDC charts tend to underestimate
obesity in Indian population data. The IOTF chart have been aimed to even
out regional differences in obesity and based on back tracking of adult obesity
cut-offs. These charts are more for research purposes. In practice most
children presenting for evaluation of obesity are much above 95th percentile for
age, the cut-off for obesity for most growth charts.
! Interpretation
! In children with growth failure
! Nutritional growth retardation (malnutrition, systemic illness and
malabsorption) has predominant effect on weight age which is
much lower than height age and chronological age.
! Endocrine causes (hypothyroidism, GHD) on the other hand result
in much greater compromise in height age than weight age.
• Wt age << Ht age < Bone age < Chronological age- Nutritional
• Ht age = Bone age << wt age < Chronological age- Endocrine
! Obesity
! Height age is greater than chronological age in exogenous obesity.
! Lower Ht indicates the possibility of pathological obesity.
• Chronological age < Ht age < weight age- Exogenous obesity
• Ht age < BA < chronological age < wt age- Pathological obesity
ILLUSTRATIVE CASES
INDICATIONS
! Assessment of growth failure
! Diagnostic role
! Severe delay- Endocrine etiology (Hypothyroidism, GHD)
! Mild delay- Constitutional delay of puberty, systemic diseases
! Normal- Turner syndrome, skeletal dysplasia
! Prognostic role- Prediction of adult height
! Confirmation of fetal hypothyroidism- Absent knee epiphysis
! Consideration of GnRH analog treatment in precocious puberty
! Bone age 2 years greater than chronological age
! Height SDS for bone age less than -2
! Assessment of obesity
! Delayed bone age suggests endocrine etiology
! Advances bone age is suggestive of constitutional obesity
SITE
! Infants- Knee AP
! Childhood and adolescence- Left hand AP (non dominant hand)
! For epiphyseal closure- Knee and shoulder AP
metaphysis till 6-10 years of age and become similar to metaphysis by around
12 years of age Capping of metaphysis indicates near fusion of epiphyses.
Physiological Pathological
Constitutional delay
Familial short stature
EVALUATION
! History
! Age of onset
! Prenatal- Genetic syndromes, intrauterine infections
! Infancy- Congenital growth hormone deficiency, hypothyroidism
! Early childhood- Malabsorption (celiac disease), RTA
! Late childhood- Acquired GHD, hypothyroidism, systemic diseases
! Perinatal history
! Birth weight, length, head circumference (IUGR)
! Mode of delivery (breech delivery associated with GHD)
! Jaundice (intrauterine infection, hypothyroidism, hypopituitarism)
! Hypoglycemia, micropenis (hypopituitarism)
! Lymphedema (turner syndrome)
! Feeding difficulty, hypotonia (Prader willi syndrome)
! Puberty
! Delayed- Hypothyroidism, hypopituitarism, CDPG, celiac disease
! Advanced- Hypothyroidism (girls), untreated precocious puberty
! Family history (familial short stature, GHD, GHIS, skeletal dysplasia)
! Onset and progression of puberty in parents (constitutional delay)
! History suggestive of urinary tract infection, tuberculosis, HIV infection
! Features of steatorrhea (cystic fibrosis, malabsorption)
! Features of liver disease, renal failure, cardiac disease, hypothyroidism
! History of exposure to steroids, radiotherapy, chemotherapy
! Developmental delay- PHP, hypothyroidism, genetic syndrome
! Examination
! Upper segment to lower segment ratio
! Increased- Achondroplasia, turner syndrome
! Decreased- Spondylo-ephiphyseal dysplasia
! Arm span- Decreased in achondroplasia and hypochondroplasia
! Metacarpal shortening- Turner syndrome, pseudohypoparathyroidism
! Pubertal status (delayed in CDGP, hypopituitarism, turner syndrome)
! Diagnostic clues, features of common disorders
Figure 1- Eight-year-old girl with disproportionate short stature. She had large
head, bowing of legs and short limbs. X ray of the lumbar spine showed
cuboid lumbar vertebrae confirming achondroplasia.
Figure 2 Six-year-old girl with severe growth retardation (height SDS −7) and
rickets. Investigations showed severe hyperchloremic acidosis and
nephrocalcinosis suggesting distal renal tubular acidosis
Figure 3 Six-year-old boy with severe growth retardation (height SDS- −3.4),
central obesity, micropenis and cryptorochidism. Peak GH after clonidine
stimulation test were 0.4 ng/ml confirming growth hormone deficiency.
APPROACH
MANAGEMENT
Nutritional therapy
! Correct iron deficiency (3 mg/kg/day iron for three months)
! Zinc supplementation (10 mg/day for 3-6 months)
Specific treatment
! Hypothyroidism- Thyroxin supplementation
! Celiac disease- Gluten free diet
! Constitutional delay of puberty and growth
! Androgens after bone age is greater than 12 year
! Testosterone 50 mg once a month intramuscularly for 6 months
! Experimental therapy
! Delay of epiphyseal fusion- GnRH agonist, aromatase inhibitors
! Limb lengthening (Ilizarov technique)- Skeletal dysplasia
! Turner Syndrome
! Indications
! Height less than fifth percentile
! No need of GH provocation test
! Dose- 50-100 µg/kg/day
! Concomitant treatment
! Oxandrolone (non aromatizable androgen)
! Pubertal induction after 13 years or five years after GH
FURTHER READING
1. Growth hormone research society. Consensus guidelines for the diagnosis
and treatment of growth hormone (GH) deficiency in childhood and
adolescence: summary statement of the GH Research Society. GH
Research Society. J Clin Endorinol Metab 2000; 85; 3990-3993.
2. Bajpai A, Menon PS. Growth hormone therapy. Indian J Pediatr 2005; 72;
139-144.
3. Rosenfeld GR, Cohen P. Disorders of growth hormone/insulin like growth
factor and action. In: Pediatric Endocrinology Eds: Sperling MA. WB
Saunders 2002, Philadelphia, 2nd Edn. Pp 211-288
1.5 Obesity
What is Obesity?
The term obesity implies excessive body fat and not merely excess body
weight. Thus body weight alone is not a reliable marker of obesity. The gold
standard for diagnosis of obesity is increased body fat measured by bio
impedance or dual energy enhanced X Ray absorbidometry (DEXA). In
practice surrogate markers of adiposity using a combination of height and
weight are used.
Body mass index: Body mass index (BMI) should be used for diagnosing
obesity after the age of two years. BMI takes into account the weight and
height of the individual.
BMI = Weight (kg) ÷ height (m)2
BMI correlates well with body fat and complications in children. The use of
BMI may however incorrectly diagnose obesity in muscular individuals while
underestimating adiposity in sedentary children with reduced muscle mass.
BMI cutoffs for diagnosing obesity have been developed using statistical
distribution (CDC charts) or extrapolating from adult cutoffs (International
obesity task force). Indians have greater risk of metabolic syndrome compared
to their western counterparts for the same BMI. BMI varies with age, ethnicity
and gender, age and gender specific local charts should thus be used to
interpret BMI. Body mass index between 85th-95th percentile for age indicate
overweight while that above 95th percentile suggest obesity. BMI greater than
99th percentile (120% of 95% percentile) implicate severe obesity. As the aim
of assessing BMI is to identify individuals at risk for metabolic complications
lower BMI cutoffs have been recommended for Indian adults (23 kg/m2 for
overweight and 28 kg/m2 for obesity). The applicability of lower cutoffs in
Indian children needs to be studied.
Weight for height: Weight for height should be used in children younger than
two years of age. Weight for height more than 120% suggests obesity.
receptor defects are the commonest monogenic form of obesity and are
associated with growth acceleration.
Drugs- Commonly used drugs associated with obesity include corticosteroids,
antipsychotics (olanzipine, resperidone), anti depressants (paroxitene) and
anti epileptics (valproate, lamotrigine).
Category Complications
Clinical evaluation- The clinical evaluation should include detailed history and
examination. Pathological obesity should be considered in children with early
onset of obesity, rapid weight gain, growth failure, dysmorphism,
developmental delay and pubertal delay. Pointers to specific disorders should
be evaluated (table 4, 5). Detailed dietary history including duration of breast
feeding, age at weaning, meal pattern, calorie intake, snacking, consumption
of junk food and features of feeding disorders should be evaluated. Duration of
activity and inactivity should be looked into. Family history of consanguinity,
type 2 DM, ischemic heart disease and dyslipidemia should be inquired. Drug
history should assess intake of steroids, valproate and antipsychotic drugs.
History of CNS infection, trauma, radiation, tumor or surgery indicates
hypothalamic obesity. Examination should include assessment of growth
parameters, pubertal status and clues to diagnosis. Pubertal assessment may
be challenging in obese children. Obese boys frequently present with
concerns of small penile size. This is usually due to penis buried in the
suprapubic pad. Stretched penile length should be measured after pressing
the suprapubic pad of fat to ascertain the actual size of penis.
Disorder Features
75 gm) blood sugar levels, lipid profile and liver function tests. Age appropriate
cutoffs should be used for these investigations (table 6). These tests should be
repeated every three years if normal. Fasting insulin has limited role and is not
routinely required. Mildly elevated liver transaminases are common in obese
children; persistent elevation beyond twice the upper limit indicates non
alcoholic steatohepatitis. Children with elevated transaminases should
undergo ultrasound abdomen and work-up for other causes of hepatic
dysfunction (hepatitis B and C, wilson disease and autoimmune hepatitis).
Sleep studies may be required in the presence of snoring, day time
somnolence or lethargy.
Blood sugar
Fasting < 100 mg/dL 100-125 mg/dL > 126 mg/dL
2 hours after < 140 mg/dL 140-199 mg/dL > 200 mg/dL
glucose
Total cholesterol < 170 mg/dL 170-199 mg/dL > 200 mg/dL
Specific management
Specific treatment should be initiated in children with hypothyroidism, growth
hormone deficiency and cushing syndrome. Children with mildly elevated TSH
level do not need treatment. Obese children with Prader Willi Syndrome and
growth failure may benefit from growth hormone therapy. Octretotide is
effective in hypothalamic obesity while the use of leptin is reserved for leptin
deficiency.
Treatment of complications
Complications should be treated early to avoid long term adverse effects.
Metformin is indicated in children with insulin resistance and type 2 DM, non
alcoholic fatty liver disease and polycystic ovarian disease. Statins are the
drug of choice for children with persistent dyslipidemia. Treatment of non
alchololic fatty liver disease includes the use of metformin, vitamin E and
pioglitazone. Girls with polycystic ovarian syndrome benefit from life style
modifications, metformin, oral contraceptives and antiandrogens.
Medroxyprogesterone acetate is beneficial in children with obesity
hypoventialtion syndrome while continuous positive airway pressure may be
used in obstructive sleep apnea.
Surgical management
Bariatric surgery should be considered only in severe obesity when other
measures have failed. The intervention should be done after achievement of
final height due to potential adverse growth effects. Bariatric surgery is a major
surgical undertaking and should be viewed as a potentially life saving
procedure and not just a cosmetic procedure. The patients need to adhere to
strict dietary restriction for life. Laparoscopic adjustable banding is the
recommended procedure in children. Malabsorptive procedures and gastric
sleeve should not be done in children.
Further reading
Section 2- Puberty
2.1 Pubertal assessment
AGE LIMITS
Gender Age of onset Criteria
Precocious Delayed
Girl
Breast development 8-13 years Before 8 years After 14 years
Pubarche 10-12 years Before 8 years After 14 years
Menarche 12-15 years Before 9 years After 16 years
Boys
Testicular enlargement 9-14 years Before 9 years After 14 years
* LWPES recommendations- Precocious puberty if thelarche occurs
before 7 years in white girls and 6.5 years in African American girls
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Growth spurt: Pubertal growth spurt in boys occurs later than that in
girls (Tanner stage III and IV) and is associated with higher peak
growth velocity (10–12 cm/year).
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Endocrine assessment
Gonadotropin secretion is characterized by pulsatile release of the
hormones making estimations of single sample unreliable. There levels
should therefore be measured in a pooled sample taken at 0, 15 and
30 minutes apart. LH is a better indicator of pubertal status compared
to FSH as it shows greater increase during puberty. Basal LH more
than 0.6 IU/L and LH to FSH ratio more than 1 is suggestive of
gonadotropin dependent precocious puberty. Recently basal LH levels
greater than 0.1 IU/L were shown to have sensitivity of 94% and
specificity of 88% for CPP. GnRH stimulation test is required if
baseline gonadotropin levels are inconclusive. Pubertal LH levels ( 5
U/L) and LH to FSH ratio more than 0.9 are diagnostic of central
precocious puberty. The difficulties in procuring GnRH has led to the
development of GnRH agonist test in the assessment of pubertal
disorders. Recently the test has been found to have good diagnostic
accuracy with the use of single sample after administration of GnRH
agonist Triptorelin (100 µg subcutaneously).
FURTHER READING
1. B a j p a i A , M e n o n P S N . P u b e r t y - P h y s i o l o g y a n d
Neuroendrocrinology. Pediatric Endocrine Disorders. Eds:
Desai M, Bhatia V, Menon PSN. Orient Longman, Second
Edition, 2007.
2. Grover S, Bajpai A. Puberty. WHO Encyclopaedia of public
health. Elseiver, In Press.
3. Menon PSN and Bajpai A. 2006. Pubertal disorders. In
Textbook of Adolescent Medicine 1st edition, Ed S Bhave,
84-94. New Delhi: Jaypee Brothers Medical Publishers Pvt Ltd.
4. Dattani MT and Hindmarsh PC. 2005. Normal and abnormal
puberty. In Clinical Pediatric Endocrinology 5th edition, Eds C
Brook, P Clayton and R Brown, 183-210. Oxford: Blackwell
Publishing.
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ETIOLOGY
Precocious puberty
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EVALUATION
History
• Onset
• Early childhood- Hypothalamic hamartoma, MAS
• Late childhood- Idiopathic central puberty
• Course
• Minimal progression- Slowly progressive variant
• Gradual progression- Idiopathic precocious puberty
• Rapid progression- Organic pathology
• Fluctuant- McCune Albright Syndrome
• Pattern
• Isolated breast development
• Isolated thelarche
• Evolving precocious puberty
• Isolated pubic hair development
• Premature adrenarche
• Non classical CAH
• Isolated vaginal bleeding
• Local cause- Infection, trauma, tumor
• Withdrawal bleed- Hypothyroidism, ovarian cyst
• Examination
• Growth parameters
• Features of hypothyroidism
• Café-au-lait spots, bony deformities, rickets (McCune Albright)
• Neurological examination including fundus examination
• Abdominal examination for ovarian or adrenal mass
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Investigations
Complete puberty
I GnRH dependent vs independent puberty
• Baseline gonadotropin
• LH more important than FSH
• Gonadotropin dependent LH > 0.6 mU/L (LH < 0.1 suggests
prepubertal levels)
• Stimulated gonadotropin levels- GnRH agonist test
• Inj Triprorelin 100 µg subcutaneously
• LH and FSH at 0,120 and 240 minutes
• GnRH dependent peak LH > 5 mU/L
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Approach
Initial assessment involves confirming the presence and extent of
pubertal development. Bone age is important in evaluation of girls with
early breast development. Retarded bone age in this setting is
suggestive of hypothyroidism while normal bone age indicates slowly
progressive variant of puberty. Basal and/or GnRH stimulated
gonadotropin levels should be performed in girls with advanced bone
age. Pubertal gonadotropin levels (elevated LH and LH to FSH ratio)
are diagnostic of central precocious puberty and should be followed by
neuroimaging (preferably MRI) Neuroimaging may be avoided girls
older than six years of age with slowly progressive puberty and no
neurological features. Normal basal and GnRH stimulated
gonadotropin levels are suggestive of gonadotropin independent
precocious puberty. These girls should undergo ovarian and adrenal
imaging to identify the source of estrogen production. Normal adrenal
and ovarian imaging in a girl with peripheral precocious puberty should
prompt evaluation for McCune Albright syndrome (skeletal survey,
bone scan and features of endocrinopathies). DHEAS levels should be
done in girls with isolated pubarche. Mildly elevated levels are
suggestive of premature adrenarche while very high levels should
prompt evaluation for congenital adrenal hyperplasia and adrenal
tumor (17 OHP and adrenal ultrasound). Endocrine etiology is unlikely
in girls with isolated vaginal bleeding. Endocrine work-up should be
done only after common causes like foreign body; trauma, infection
and sexual abuse have been excluded.
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Precocious puberty
Extent of pubertal
Low LH Elevated LH
GnRH stimulation test
Pre-pubertal Pubertal
MANAGEMENT
Gonadotropin Dependent
Indications
• Age of onset less than 6 years
• Age of onset between 6-8 years with rapid progression
• Bone age 2 years more than chronological age
• Height SDS for bone age less than −2
• Predicted Ht SDS > −2 SDS < target ht SDS
• Concern about early menarche
Options
Medroxyprogesterone acetate- Oral, im depot
o No effect on auxological outcome
o May be considered in intellectual disability
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GnRH analog
Preparation Dose Preparation Frequency
Triptorelin 50 µg/kg 3.75 mg Monthly
Leuprolein 50-300 µg/kg 3.75 mg Monthly
Leuprolide depot 150-450 µg/kg 11.25 mg Three monthly
Gosorelin - 10.8 mg Three monthly
Expected response
o Initial flare up for one to two months
o May cause withdrawal bleeding
o Decrease in growth velocity to normal levels
o Regression in pubertal changes and uterine size
o Stabilization of bone age
o No effect on pubarche
Discontinuation of treatment
o Chronological age of 10 years
o Bone age of 12 years
o Predicted height in the target height range
Gonadotropin independent
Hypothyroidism- Thyroid hormone replacement
Ovarian cyst
• No treatment from endocrine point of view
• Thyroid function tests
• McCune Albright syndrome with recurrent cysts
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36. Precocious
Precocious Puberty
puberty in boys
in boys
36.1 Criteria-
CRITERIA- Onset
Onset ofofpubertal
pubertal changes
changesbefore the age
before of 9age
the years
of 9.5 years
•Testicular volume more than
•Testicular volume more than 4 ml4 ml
••Pubic
Pubichair stage
hair II or II
stage more
or more
•Penile enlargement
•Penile enlargement
36.2 Etiology
ETIOLOGY
Precocious puberty
Gonadotropin dependent
Gonadotropin independent
Idiopathic
Organic
Brain tumor
Endogenous Exogenous Hypothalamic hamartomas
Testosterone cream Glioma
Congenital anomaly
Hydrocephalous
Testicular source Adrenal source Arachnoid cyst
CAH Cerebral dysgenesis
21 OH deficiency CNS insult
11 OH deficiency Infection
Head Trauma
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Confirmation of diagnosis
•Tanner staging
•Testicular volume (Orchidometer)
•Stretched penile length
•Bone age (Advanced bone age indicates precocious puberty)
EVALUATION
History
• Onset
• Infancy- Hypothalamic hamartomas, adrenal tumor
• Early childhood- Hypothalamic hamartoma, testotoxicosis
• Late childhood- CNS tumor, CAH, HCG tumor
• Progression
• Rapid- Organic CNS pathology, adrenal tumor
• Gradual- CAH, idiopathic precocious puberty
Examination
• Growth parameters
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• Testicular size
• Pubertal- Gonadotropin dependent puberty
• Pubertal but not commensurate with pubertal stage- HCG
secreting tumor, testotoxicosis
• Pre pubertal- Gonadotropin independent
• Unilateral enlargement- Testicular tumor, adrenal rests in long
standing CAH
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INVESTIGATIONS
! Gonadotropin dependent vs independent puberty
! Baseline gonadotropin levels - LH and FSH (pooled samples)
! Interpretation- Gonadotropin dependent if LH > 0.7 mU/L
! GnRH agonist test
! Indication- Low basal gonadotropin
! LH, FSH at 0, 120 and 240 minutes after 0.1 mg triptorelin
! GnRH dependent puberty if peak LH more than 5 mU/L
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APPROACH
Precocious puberty
Assess extent, testicular size
Baseline LH, FSH
Pre pubertal LH
GnRH stimulation test Pubertal LH
Pre-pubertal Pubertal
Adrenal imaging
Gonadotropin dependent
Normal Mass lesion
MRI head
ACTH test Adrenal tumor
Normal High
LH receptor study HCG tumor
CT head, chest and abdomen
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MANAGEMENT
• Gonadotropin dependent precocious puberty- GnRH analog
• Indication- All
• Duration- Age of 12 years, bone age of 14 years, predicted
height in the target height range
• Expected effect
• Regression in pubertal development
• Increase in predicted final height by 10-15 cm
• Testotoxicosis
• Antiandrogen- Flutamide
• Aromatase inhibitor- Anastrazole, letrozole
Further reading
1. Grover S, Bajpai A. Puberty. International Encyclopaedia of
public health. Elseiver, In Press.
2. Bajpai A, Menon PSN. Precocious puberty. Pediatric Endocrine
Disorders. Eds: Desai M, Bhatia V, Menon PSN. Orient
Longman, Second Edition, 2007.
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CRITERIA
No pubertal development by 15 years of age
Inability to complete development within five years of onset
ETIOLOGY
Delayed puberty
Physiological Pathological
Constitutional delay of puberty
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EVALUATION
History
• Pattern
• No initiation of pubertal development- Hypogonadotrophic
hypogonadism, steroidogenic defect, classical turner syndrome
• Failure to progress after normal initial development- Mosaic
turner syndrome, acquired ovarian, autoimmune ovarian failure
• Features of chronic systemic illness
• Family history of delayed puberty (constitutional delay)
• CNS insult (radiation, trauma, surgery, infections, asphyxia)
• Features of hypopituitarism, neurological involvement
• Features of hypothyroidism
• Abnormal smell sensation (Kallmann syndrome)
• Deafness (Turner, CHARGE syndrome, PHP)
• Developmental delay (Prader willi syndrome, CHARGE)
• Tetany (Hypoparathyrodism, pseudohypoparathyroidism)
• Alopecia, Vitiligo, candidiasis, adrenal insufficiency (APS)
Examination
• Short stature- Turner, Hypopituitarism, celiac disease
• Body mass index
• Low- Malnutrition or anorexia nervosa
• Obesity PHP, prader willi, leptin deficiency
• Features of Turner Syndrome
• Neurological examination including fundus examination
• Smell sensation
• Galactorrhea (hyperprolactinemia)
• Midline defects (hypopituitarism)
• Abdominal examination (adrenal mass)
• Dysmorphism suggestive of CHARGE, PW syndromes
• Pigmentation (steroidogenic defects)
• Vitiligo, alopecia (Autoimmune polyendocrinopathy)
• BP(hypertension in 17 beta hydroxylase deficiency)
Investigations
• Initial
• Bone age
• SGPT, creatinine, complete blood examination
• FSH- After bone age more than 12 years
• FSH > 2 mU/L- Hypogonadotropic
• FSH > 10 mU/L- Hypergonadotropic
• FSH 2-10 mU/L- Intermediate
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APPROACH
Delayed puberty
Exclude systemic illness, nutritional disorder
Gonadotropin levels
Low FSH
Prolactin levels High FSH
Exclude ovarian insult
Karyotype
High HH
Hyperprolactinemia Smell sensation Normal
Thyroid profile CNS imaging Ultrasound pelvis
CNS imaging Pituitary functions Autoimmune evaluation
Steroidogenic precursors
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MANAGEMENT
•Specific measures
! Malnutrition- Nutritional rehabilitation
! Hyperprolactinemia- Dopamine agonist
! Hypopituitarism- Hormone replacement
•Non Specific measure
Pubertal induction- Bone age more than 13 years
o Estrogen
! Synthetic- Ethinyl estradiol
! Conjugated estrogen- Premarin
! Start at 10-20% of adult dose
! Increase by 20% of adult dose every six months
! Achieve target adult dose in two years
o Progesterone- Withdrawal bleeding, Endo thickness > 5 mm
! Preparation- Medroxyprogesterone, norethisterone
! Dose- 10 mg OD for 10 days a month (day 11-21)
o Switch to oral contraceptives after adult dose achieved
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ETIOLOGY
Delayed puberty
Physiological Pathological
Constitutional delay of puberty
EVALUATION
History
• Extent
• No adrenarche- CDPG, steroidogenic defects
• Adrenarche present- Isolated HH
• Progression
• No initial development- Congenital cause, HH
• Initial development followed by arrest- Klinefelter
• Delayed puberty in family (constitutional delay in puberty)
• Mother- Age at menarche
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Examination
• Growth
• Short stature- Hypopituitarism, prader willi syndrome
• Tall stature- Klinefelter syndrome
• Testicular size
• Enlarged- Hypothyroidism, fragile X syndrome
• Atrophic- Radiation, Klinefelter, PW syndrome
Pointer Etiology
Growth failure, midline defects Hypopituitarism, celiac
Tall stature, eunuchoid habitus Klinefelter syndrome, isolated HH
Adrenal insufficiency Adrenal hypoplasia, StAR, 3β-HSD)
Abnormal smell sensation Kallmann syndrome
Obesity PW, LMMBB syndromes
Polydactyly LMBB, Smith-Lemli-Optiz
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Investigations
Initial Investigations
• Bone age
• Marked delay- Constitutional delay, hypopituitarism
• Normal, mild delay- Klinefelter, isolated HH
• Investigations
• DHEAS- Elevated levels suggestive of permanent HH
• Early morning testosterone- > 20 ng/dL impending puberty
• GnRH agonist test
• No response- Permanent HH
• Increase in Gn levels- Constitutional delay
• Hypergonadotropic hypogonadism
• Testicular insult- Infection, trauma, torsion, radiation
• Karyotype- No obvious testicular insult
• Gonadal biopsy- High FSH with normal karyotype
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APPROACH
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Delayed puberty
Screening investigations
Gonadotropin
Low
High
Clinical follow-up
Exclude testicular insult
GnRH/ HCG test
Karyotype
Normal
Response No response
Testosterone
CDPG Permanent HH
MRI head
Low High
HCG test DHT
Testicular biopsy
MANAGEMENT
Testosterone preparations
Preparation Route FrequencyDose
Initial Adult
Testosterone ester* Intramuscular 3-4 weekly 100 mg 300 mg
Testosterone pellets SC Implant 3 monthly 300 mg 900 mg
Testo undeconate Oral Daily 5 mg 10 mg
IM depot 3 monthly 500 mg 1000 mg
Non- Specific measures
• Constitutional delay of puberty and growth
• Indications- Bone age more than 13 years
• Injection testosterone ester 100 mg monthly for 3 doses
• Repeat course for three months if no improvement
• Testosterone one month after last dose of testosterone
• Less than 300 ng/ml-Permanent HH
• More than 300 ng/ml- CDGP, follow-up
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Hypogonadotropic hypogonadism
Testosterone ester 100 mg im monthly for 3 doses
Clinical response
Stop testosterone
Testosterone levels 1 month later
> 300 ng/dL (10 nmol/L) < 300 ng/dL (10 nmol/L)
Constitutional delay Likely permanent HH
No further treatment Continue testosterone
• Permanent HH
• Pubertal induction
• Inj testosterone ester 100 mg monthly for six doses
• Increase testosterone to 100 mg/week as
• Three weekly injection of 300 mg
• Testosterone pellets three to six monthly
• Testo undeconate depot- 1000 mg every 3 months
• Hypergonadotropic hypogonadism
• After a bone age of 13 years
• Initial dose- 100 mg testosterone ester monthly
• Adult dose- 100 mg weekly
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2.4 Hyperandrogenism
Hyperandrogenism
POINTERS TO DIAGNOSIS
•Dr Yuthika
Hirsuitism-
Bajpai, Sexual hairs in male distribution (face, chin, back,
chest,medial
Consultant Reproductive part of thigh,
Medicine, buttocks)
Regency Hospital Limited, Kanpur
•POINTERS
Acne-TOPre pubertal, requiring medical treatment
DIAGNOSIS
• Alopecia-
•Hirsuitism-Diffuse,
Growth of rapidly progressive
sexual hairs in male distribution (face, chin, back, chest, medial
part of thigh, buttocks)
• Menstrual irregularity-
•Acne- Pre pubertal, Amenorrhea,
requiring medical treatment polymenrorrhea
•Alopecia- Diffuse, rapidly progressive
•Menstrual irregularity- Amenorrhea, polymenrorrhea, menorrhagia
ETIOLOGY
Etiology
Hyperandrogenism
Exogenous Endogenous
Phenytoin
Diazoxide
Steroids
Cyclosporine
Ovarian Source
Adrenal source
Important
CAH- Congenitalcauses
adrenal in order of
hyperplasia, prevalence
PCOS- Polycystic Ovarian Syndrome, OHD- Hydroxylase
deficiency, HSD- Hydroxysteroid dehydrogenase deficiency
Table• 1 Differentiation
PCOS of hirsuitism and virilization
•
Feature
Hypothyroidism
Hirsuitism Virilization
• Hyperprolactenemia
Sites affected Skin, sebaceous gland Muscle, vocal chord, clitoris
• Drug Hair
Features
induced
growth, acne, menstrual Clitoromegaly, male habitus,
• Non classical
irregularity CAH muscularity, voice change
Etiology P C O S , n o n c l a s s i c a l C A H , Ovarian or adrenal tumor
functional hyperandrogenism
Course Slowly progressive Rapidly progressive
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EVALUATION
History
• Onset
• Prepubertal- CAH, adrenal tumor
• Pubertal- Polycystic ovarian syndrome
• Progression
• Gradual- Polycystic ovarian syndrome, CAH
• Rapid- Adrenal or ovarian androgen producing tumor
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Investigations
Confirmation of hyperandrogenism
• DHEAS (Dehydroandrostenidione sulfate)
• Adrenal androgen production (99% by adrenal)
• Prolonged half life and high secretion
• Normal levels- 100-200 ng/dL (2-5 nmol/L)
• High levels (>700 ng/dL) suggestive of adrenal etiology
• Testosterone
• Marker of adrenal or ovarian androgen production
• Normal levels- 0.3-3 nmol/L
• Post-pubertal girl with hyperandrogenism
• 80-150 ng/dL- PCOS, non-classic CAH
• > 150 ng/dL- Androgenic adrenal or ovarian tumor
Identification of source of androgen- DHEAS and testosterone
DHEAS Testosterone Interpretation
High Normal Mild adrenal cause
High High Significant adrenal cause
Normal High Ovarian cause
Normal Normal Measure free testosterone
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Identification of etiology
• Adrenal source (DHEAS > 700 ng/dL)
• Adrenal imaging- Tumor, adrenal hyperplasia
• Dexamethasone suppression test
• Indications- High DHEAS, normal imaging
• Protocol- Dexa 0.5 mg 6 hourly for 8 doses
• Normal response
• Cortisol less than 50 nmol/L (1.4 µg/dL)
• DHEAS less than 50 nmol/L (1.2 ng/dL)
• Testosterone less than 1 nmol/L (30 ng/dL)
• Ovarian source
• Imaging- Polycystic ovarian syndrome, ovarian tumor
• Work-up for PCOS- Glucose tolerance test
APPROACH
Features of hyperandrogenism like acne, hirsuitism and menstrual
irregularity are common in pubertal girls emphasizing the need for
careful patient selection. Hirsuitism should be differentiated from
hypertrichosis, generalized increase in body hair. Rapidly progressive
virilization (clitoromegaly, change in voice and increased muscularity)
is characteristic of androgen producing ovarian and adrenal tumor.
DHEAS and testosterone levels should be assessed in girls with
hyperandrogenism. Extremely high testosterone levels (more than 10
nmol/L, 300 ng/dL) should prompt evaluation for androgen producing
tumors. High testosterone with normal DHEAS levels indicates ovarian
hyperandrogenism and should be followed-up with ovarian imaging.
High DHEAS levels are pathognomic of adrenal pathology and should
prompt adrenal ultrasound and 17OHP to identify adrenal tumor and
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Hyperandrogenism
Confirm diagnosis, assess for virilization
Absent Present
DHEAS Adrenal and ovarian imaging
17OHP levels
Normal
Dexamethasone test
APPROACH TO MANAGEMENT
Mild hyperandrogenic symptoms and menstrual irregularity are
common in adolescent girls. Treatment should therefore be reserved
for girls with severe hirsuitism, acne or menstrual irregularity. Life style
measures and metformin should be initiated in girls with clinical
(obesity, acanthosis nigricans) or laboratory features of insulin
resistance (glucose intolerance or high fasting insulin levels). Lack of
response to these measures should prompt treatment according to
clinical features. Girl with predominant acne or hirsuitism with normal
menstrual cycles should be started on antiandrogens like cyperoterone
or spironolactone. Cosmetic measures should be advised during the
lag phase (6-12 months) of response to these drugs. Lack of response
to these agents or subsequent development of menstrual irregularity is
an indication for starting oral contraceptives. Antiandrogen containing
oral contraceptives (diane or yasmin) are preferred in these girls. Oral
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Present Absent
Life style measures, metformin
Improvement No improvement
Continue for 1 year
Mild hyperandrogenic symptoms and menstrual irregularity are common in adolescent girls.
Treatment should therefore be reserved for girls with severe hirsuitism, acne or menstrual
irregularity. Life style measures and metformin should be initiated in girls with clinical (obesity,
acanthosis nigricans) or laboratory features of insulin resistance (glucose intolerance or high
fasting insulin levels). Lack of response to these measures should prompt treatment according to
clinical features. Girl with predominant acne or hirsuitism with normal menstrual cycles should be
started on antiandrogens like cyperoterone or spironolactone. Cosmetic measures should be
advised during the lag phase (6-12 months) of response to these drugs. Lack of response to these
agents or subsequent development of menstrual irregularity is an indication for starting oral
contraceptives. Antiandrogen containing oral contraceptives (diane or yasmin) are preferred in
these girls. Oral contraceptives should be considered in girls presenting with menstrual irregularity.
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EPIDEMIOLOGY
Turner syndrome is the most common chromosomal abnormality
present in three percent of all fetuses. However 99% of 45 X fetuses
are aborted in the first and second trimester accounting for 10% of all
spontaneous abortions. This results in an overall prevalence of 1 in
2500 live girls.
CLINICAL FEATURES
The diagnosis of Indian girls with turner syndrome is delayed. Even in
developed countries a mean difference of five years from the onset of
growth failure to diagnosis has been observed. Early identification is
helpful in allowing early initiation of growth promoting therapy and
evaluation for potential life threatening diseases.
ANTENATAL
Ultrasound findings indicative of turner syndrome include increased
fetal nuchal translucency and cystic hygroma. These findings are non
specific and also observed in autosomal trisomy disorders.
INFANCY
The pointer of Turner syndrome in infancy include lymphedema ( 97%
of cases) and left sided cardiac defects (coarctation of aorta and
bicuspid aortic valve).
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ADULTHOOD
Women with turner syndrome may present later in life with secondary
ammenorhea or infertility.
DIAGNOSIS
Conventionally turner syndrome has been diagnosed in the presence
of complete deletion of X chromosome but mosaic and sub-
chromosomal deletions have been increasingly identified. The
karyotype analysis should study 30 metaphase plates to identify 10%
mosaicism with 95% confidence. In patients with characteristic features
but normal karyotype, analysis from additional sites like skin is
indicated.
CRITERIA
The diagnosis of turner syndrome requires complete or partial absence
of X chromosome and characteristic clinical features in a phenotypic
female. FSH may be normal before maturation of the hypothalamic-
pituitary axis and is an unreliable marker in young girls. Elevated FSH
levels should be followed up with karyotype to identify Y cell line.
Identification of 45X cell population in boys or girls with no turner
stigmata is not diagnostic of turner syndrome. Girls with ring
chromosome and Xq isochromosome are phenotypically
indistinguishable from those with classical turner syndrome and should
be included in the purview of the disorder. Xq24 deletion with
predominant ovarian involvement and normal growth and distal Xp
deletions (with the exception of Xp22.3) with short stature and minimal
ovarian involvement should not be diagnosed as turner syndrome.
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PRENATAL DIAGNOSIS
The increased use of prenatal karyotype has resulted in identification
of a number of fetuses with 45 X and 45 X mosaic karyotype. However
in many of these cases have normal female karyotype postnatally. This
is due to fallacy of antental karyotype in identifying mosaicism. This
should be considered while counseling families with antenatal
diagnosis of turner syndrome. The likelihood of turner syndrome with
suggestive antenatal karyotype depends on the pretest probability of
the disease. It is much higher when the karyotype is done as workup
for specific ultrasound findings than when done for advanced maternal
age. A postnatal karyotype is mandatory to confirm the antenatal
findings.
KARYOTYPE-PHENOTYPE CORRELATION
The manifestations of turner syndrome depend on the extent and
distribution of the defect. It is now understood that the classic turner
syndrome represents the most severe end of the spectrum. Most girls
with turner syndrome have mosaic form or sub-chromosomal deletions
with milder clinical spectrum. Girls with deletion of short arm of X
chromosome predominantly present with growth failure while those
with long arm involvement have ovarian failure as their presenting
feature. The presence of Y line is associated with risk of gonadal
tumors. Ring chromosome arrangement is predictor of mental
subnormality.
Anomaly Association
Xq Ovarian failure
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DETECTION OF Y LINE
Y chromosomal material is present in 5% girls with turner syndrome
while an additional 3% have marker chromosome (a fragment of either
X or Y chromosome). The presence of Y material is associated with
12% risk for development of gonadoblastoma, which carries a risk for
malignant transformation. This highlights the need for prophylactic
gonadectomy in girls with Y cell line. The need for universal screening
for girls with turner syndrome with FISH for Y material is questionable.
Currently FISH is recommended for girls with marker chromosome or
virlization. The identification of Y material without these features has
very low risk of development of gonadal tumors.
ASSOCIATIONS
Turner syndrome is associated with a constellation of abnormalities
affecting multiple body systems (Table 3). The impact of these
associations should be assessed in the holistic perspective of the
disease and not as extrapolation of isolated manifestations in normal
individuals. This is highlighted by the natural history of aortic root
dilatation and dissection in women with turner syndrome. Women with
turner syndrome are at much higher risk of aortic dissection at the
same aortic size corrected for body size compared to non turner
women. These differences highlight the need for turner specific
recommendations for assessment and management of associations.
GROWTH FAILURE
Short stature is universal in turner syndrome. Birth size is mildly
reduced along with reduced growth velocity during infancy. Many girls
however are above the fifth percentile for normal chart till five years of
age and height compromise usually manifests after this age. This
combined with delayed and blunted pubertal growth spurt results in
final height 20 cm below target height. The inevitability of growth failure
in turner syndrome has resulted in modification of guidelines for growth
promoting therapy in these girls. Traditionally GH has been initiated
after growth failure has set in. Unfortunately significant height deficit
has occurred by this stage. Given the inevitability of growth
compromise in turner syndrome, starting GH early when the height is
in the normal range would improve the likelihood of normal adult
height. The etiology of growth failure in turner syndrome is multi
factorial. The main cause is haploinsufficiency of SHOX (short stature
homeobox gene in X), a gene located on distal part of short arm of X
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Cardiovascular Coarctation of aorta, bicuspid aortic Four limb blood pressure, ECG,
OVARIAN DYSFUNCTION
The onset of ovarian failure in turner syndrome begins in utero with
accelerated degeneration of ovarian follicles. Estradiol levels are lower
than non turner girls even in the prepubertal age group. The decline in
estradiol levels triggers increase in LH and FSH during infancy and
early childhood. The levels decrease around five years of age and
increase again with the maturation of hypothalamic-pituitary axis. FSH
levels are therefore unreliable marker of turner syndrome between
5-12 years of age. The spectrum of ovarian dysfunction in turner
syndrome ranges from delayed puberty, primary amenorhea,
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CARDIOVASCULAR ASSOCIATION
Cardiovascular abnormalities occur in around 50% of girls with turner
syndrome and is a major cause of increased morbidity and mortality.
The common abnormalities include coarctation of aorta (11%), bicuspid
aortic valve (16%) and partial anomalous pulmonary venous return.
This mandates the need for baseline echocardiography. Webbing of
neck is a strong predictor of cardiovascular abnormality. Girls with
turner syndrome are at increased risk of hypertension that should be
periodically monitored and managed. The major concern in turner
syndrome is life threatening aortic dissection that has been reported in
around 1% of cases. This represents 100 fold increased risk compared
to general population. Risk factors for aortic dissection include bicuspid
aortic valve, hypertension, elongated transverse aortic arch and aortic
dilatation. Aortic arch size is an important predictor of aortic dissection.
Women with turner syndrome are at increased risk of dissection for the
same aortic dimension corrected to body surface area compared to
general population. Therefore lower cutoffs for aortic size index ( 2 cm/
m2 body surface area) are recommended for close follow-up. These
individuals should be put on beta blockers to lower the risk of
dissection. Increased aortic dimension is a contraindication for
pregnancy and competitive sports. Other cardiac abnormalities include
prolongation of QRS complex, hypertension and dyslipidemia.
UROLOGOCIAL ABNORMALITIES
Urological anomalies occur in 30-40% girls with turner syndrome. They
include collecting system malformation, horse shoe kidney and
positional abnormalities. All girls with turner syndrome should undergo
renal ultrasound at diagnosis. The risk of development of renal
complications is minimal if initial ultrasound is normal.
OPHTHALMOLOGICAL
The ocular manifestations of turner syndrome include strabismus,
ptosis, epicanthic folds and refractory errors. They predispose them at
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HEARING LOSS
Turner syndrome is associated with both conductive and sensorineural
hearing loss. This emphasizes the need for detailed otoscopic
examination and hearing assessment. Conductive hearing loss is
related to recurrent otitis media caused by abnormal ear anatomy. It is
important to identify and treat otitis media early to prevent long term
complications. Sensorineural hearing loss is particularly common
during adolescence.
DENTAL
Common dental problems in turner syndrome include dental
malocclusion and dental enamel hypoplasia. They are at increased risk
of root resorption. These abnormalities emphasizes the need for
regular dentist evaluation.
SKELETAL
Skeletal abnormalities associated with turner syndrome include short
neck, cubitus valgus, shield chest, congenital dislocation of hip,
brachymetacarpia and madelung abnormality. Scoliosis and kyphosis
is common in turner syndrome and may worsen with growth hormone
treatment. Bone mineral density corrected for body size assessed by
dual energy X Ray absorbometery is normal in adequately
estrogenized girls with turner syndrome. The cortical bone density in
girls with turner syndrome is however reduced. There is limited if any
benefit of adding bisphosphonate treatment in these girls as the drug
has limited effect on cortical bone density.
DERMATOLOGICAL
Pigmented nevi are common in girls with turner syndrome. The risk of
malignant transformation is similar to general population and not
increased with growth hormone treatment.
AUTOIMMUNE ASSOCIATIONS
Turner syndrome predisposes individuals to increased risk of
autoimmune disorders like type 1 diabetes mellitus, hypothyroidism
(24%), hyperthyroidism (2%) and celiac disease (5%). Thyroid disease
should be assessed at diagnosis and then annually due to high risk of
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MANAGEMENT
Advances in management have ensured near normal outcome in girls
with turner syndrome. This requires a holistic approach using a multi-
displinary team well versed with the nuances in the management of the
disease. Timely assessment to identify associations and management
is required for the same.
GROWTH
Strategies to increase adult height in turner syndrome aim at
increasing the growth rate (growth hormone and oxandrolone) or
duration (delayed initiation of estradiol).
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Growth benefit
GH increases height in turner syndrome, the extent of response is
however variable. Earlier studies suggested minimal response to 17
cm gain when compared to historical controls. There are only two
randomized controlled trials on the effect of GH in turner syndrome. In
the Canadian study GH treatment of 154 girls for 5.5 years from the
age of 7-13 years increased final height by 7.2 cm. In another trial a
gain of 0.78 SDS (5 cm) with GH treatment for 7.2 years (0.3 mg/kg/
week in three divided doses) was observed in 80 girls with turner
syndrome. Reduced response in this study may be related to the use
of lower dose and only thrice weekly GH. In the only Indian study,
Khadilkar et al, studied the effect of GH (0.3 mg/kg/week) for one year
in 16 girls. They observed an increase in growth velocity from 3.2 cm/
year to 6.7 cm/year with an increment of 2.4 cm in predicted adult
height. The overall evidence indicates an increase of 1.5 cm per
treatment year.
Duration
GH should be continued till final height is achieved as indicated by
growth velocity less than 2 cm per year and bone age of 14 years.
Treatment should be continued till at least two years to achieve
reasonable response.
Adverse effects
GH is safe as determined by follow up of a large number of girls with
turner syndrome. In particular no effect on aortal diameter and cardiac
size, a key area of concern, has been noted. GH treatment has been
associated with increased scoliosis, otitis media, benign intracranial
hypertension and glucose intolerance. There is no evidence of
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Androgen
Given the extent of growth compromise despite GH alternative growth
promoting strategies have been explored. This is particularly true when
diagnosis is delayed. Oxandronolone, a non aromatizable androgen,
was associated with mild increment in growth at a dose of 60
microgram/kg/day in initial studies at the risk of virlization and clitoral
enlargement. Subsequent studies have shown that lower dose (30
microgram/kg/day) results in equivalent growth benefits with lower
rates of virlization. In a randomized controlled trial oxandrolone at a
dose of 50 microgram/kg/day along with GH at the age of nine years
resulted in increase in final height by 4.6 cm. This was similar to
delaying pubertal induction to 14 years of age (3.8 cm). This indicates
that the use of oxandrolone in girls with delayed diagnosis may obviate
the need for delaying pubertal induction.
Timing
Earlier estradiol replacement was delayed till the age of 14 years (or at
least 4 years after starting GH) to increase final height. This increase in
adult height was offset by psycho-social problems of delayed pubertal
maturation. Early diagnosis and initiation of growth hormone therapy
now allows timely pubertal induction.
Preparation
Estradiol valerate and micronized progesterone are emerging as
physiological alternatives to conjugated equine estradiol (CEE) and
synthetic estrogen (ethinyl estradiol) and progesterone (medroxy
progesterone acetate).
Route
Transdermal route is superior to oral estrogen replacement as oral
estrogen suppresses hepatic IGF1 production. Moreover girls with
turner syndrome are at a higher risk for thrombotic effects of estradiol.
Transdermal estradiol has the advantage of lower thrombotic risk.
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Protocol
Estrogen should be started at 5-10% of adult dose (0.25 mg of
estradiol valerate, 5 microgram of ethinyl estradiol or 0.12 of CEE) at
the age of 12 years. The dose should be increased in quantums of
10-20% every six months to adult dose (2 mg of estradiol valerate,
0.625 mg of CEE and 30 microgram of ethinyl estradiol) over two
years. Progesterone (200 microgram daily of micronized progesterone
or 10 mg of medroxy progesterone acetate) is added after two years of
replacement or when withdrawal bleed occurs. This should be followed
by cyclical estrogen-progesterone replacement. Full adult dose of
estrogen should be used till the age of 30 years to mimic physiological
estradiol peak. Between 30 to 50 years the dose may be lowered to
the minimum dose required to prevent osteoporosis. After the age of
fifty years the need for estradiol replacement should be determined
based on recommendations for post menopausal women. Periodic
monitoring of endometrial thickness and breast examination is
required.
Table 4- Hormone replacement guideline in turner syndrome
12-13 years Start estrogen at 10-20% of adult dose (0.25 mg estradiol valerate,
14-15 years Gradually increase estrogen by 10-20% of adult dose every six
15-30 years Full adult dose with estradiol valerate and micronized progesterone
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CARDIOVASCULAR SYSTEM
Echocardiography, chest X Ray and ECG should be performed at of
diagnosis. Periodic assessment of blood pressure, blood sugar and
lipids is essential. Echocardiography should be repeated every five
years. Cardiac MRI provides a holistic picture about aortic root size
and should be done at the age when it is feasible to ascertain aortic
root size. MRI should be repeated periodically to monitor aortic size.
Individuals with increased root size index (more than 2 cm/m2) should
be started on beta blockers and advised to avoid pregnancy and
competitive sports.
HEARING
Hearing assessment and detailed otological examination should be
done at diagnosis. Hearing aid should be applied early to avoid long
term impact. Timely detection and treatment of otitis media is of
paramount importance.
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Criteria- Discordance
42.1 Criteria- Discordancebetween genetic,
between genetic, gonadal
gonadal and sex
and phenotypic phenotypic sex
42.2 Pointers
Pointers to diagnosis
to diagnosis
•Genital ambiguity
•Genital ambiguity
•Penoscrotal hypospadia
•Penoscrotal hypospadia
•Bilateral inguinal masses in girls
Bilateral
••Bilateral inguinal in
cryptorchidism masses
boys in girls, cryptorchidism in boys
Primary
••Primary amenorrhea
amenorrhea in normal
in girls with girls with normal
pubertal pubertal development
development
Etiology
42.3 Etiology
Gonadal dysgenesis
Undervirilization Virilization
Ovo-testicular DSD
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Urogenital ridge
Bipotential gonad
SRY, SOX 9
DAX 1
Testis
Ovary
Estrogen Testosterone
Mullerian development Anti mullerian hormone
Wolfian regression Mullerian regression
5 α reductase
Wolfian development Dihydrotesotsoterone External
genital development
Figure Figure
1 Sexual
41.1 Sexualdevelopment
development and itsbegins with development
disorders. Sexual the developmentbegins with of
bipotential gonad from
the development the urogenital
of bipotential gonad from the ridge under
urogenital ridgethe
underinfluence
the influence of
of WT1
(wilms tumor
WT1 (wilms1) and tumorSF1 genes.
1) and SF1 genes.TheseThese genes
genes play play an important
an important role in therole in
the development of other organs (WT1 for kidney and
development of other organs (WT1 for kidney and SF1 for adrenals). SRY SF1 for
gene (sex
regulatory region on Y chromosome)
adrenals). SRY gene (sex regulatory region on Y chromosome)is central to the process of gonadal is
differentiation. In boys, SRY gene induces testis determining genes like SOX9 while
central inhibiting
to the anti process of gonadal differentiation. In boys,
testis gene DAX1 resulting in testicular development. Sertoli cells of
SRY gene
inducesthetestis determining
testis secrete genes
anti mullerian hormonelikefromSOX9
6 weeks while inhibiting
of gestation while leydiganti
cell testis
gene DAX1 resulting
testosterone productioninstarts
testicular
from sevendevelopment.
weeks of gestation. Sertoli cellsareof the
These agents
testis secrete
responsibleantifor mullerian
regression of hormone
mullerian duct fromand 6development
weeks ofof gestation
wolfian duct while
leydig cell testosterone production starts from seven tissue
respectively. Testosterone is converted by the 5 alpha reductase II in genital weeks
to of
the potent hormone dihydrotestosterone, that is responsible for virilization of external
gestation. These agents are responsible for regression of mullerian
genitalia resulting in labioscrotal fusion and development of penile urethra. Absence
duct and development
of SRY of wolfian
gene in girls results in activationduct respectively.
of anti testis gene DAX1 Testosterone
and ovarian is
converted by theEstrogen
development. 5 alpha reductase
produced II involved
by ovaries are in genital tissue oftomullerian
in maintenance the potent
hormone ductdihydrotestosterone,
while lack of testosterone resultsthat is responsible
in the regression for Disorders
of wolffian ducts. virilization
of of
externalsexual
genitalia
developmentresulting in labioscrotal
can therefore fusion
result from disorders and development
of gonadal development or of
function. Disordered
penile urethra. Absence gonadal
of SRYdevelopment
geneisin observed
girls with
resultsdefectsininactivation
genes involvedof anti
in the development of the bipotential gonad (WT1 and SF1), testis (SRY and SOX9
testis gene DAX1 and ovarian development. Estrogen produced by
gene deletion in males and SRY insertion in females) and ovary (DAX1 over
ovaries expression
are involvedin males).in maintenance
Disorders of mullerian
of gonadal functions duct testosterone
include impaired while lack of
testosterone results in the regression of wolffian ducts. Disorders of
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Table 1 Karyotype
Table 42.2 based
Karyotype based classification
classification of DSD
of disorders of sexual differentiation
Karyotype Normal genital appearance* Genital ambiguity
46 XX SRY insertion Congenital adrenal hyperplasia
Severe 21OHD Aromatase deficiency
Maternal virilization
Maternal drug intake
46 XY SRY deletion Testicular dysgenesis
SF1 defect Steroidogenic defects
Gonadal dysgenesis Partial AIS
Severe StAR defect 5ARII deficiency
Complete AIS
46 XY/XO Gonadal dysgenesis
Ovo-testicular DSD
* Discordant to genotypic sex
Table 42.3 Classification of DSD ESPE-LWPES consensus statement 2005
Category Previous name Disorders
Ovo testicular DSD True Hermaphroditism
46 XY DSD Male pseudohermaphroditism Testicular dysgenesis
Steroidogenic defects
AIS, 5 AR II deficiency
46 XX DSD Female pseudohermaphroditism CAH, XX gonadal dysgenesis
Aromatase deficiency
AIS- Androgen insensitivity syndrome, CAH- Congenital adrenal hyperplasia
Table 42.4 Gene defects associated with gonadal dysgenesis
Gene Function Gender affected Features
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Gonadal dysgenesis Partial AIS
Severe StAR defect 5ARII deficiency
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Complete AIS
46 XY/XO Gonadal dysgenesis
Ovo-testicular DSD
* Discordant to genotypic sex
Table 2 Classification
Table 42.3 Classification of of
DSDDSD ESPE-LWPES
ESPE-LWPES consensus statement 2005
WT1 Gonadal, renal development Boys Renal dysplasia
Category Previous name Disorders
Ovo testicular DSD True Hermaphroditism Denys Drash, Frasier
46 XY DSD Male pseudohermaphroditism syndromedysgenesis
Testicular
SF1 Gonadal, adrenal development Boys Adrenal failure
Steroidogenic defects
SOX9 G o n a d a l , s k e l e t a l Boys Skeletal dysplasia
AIS, 5 AR II deficiency
development Female pseudohermaphroditism CAH, XX gonadal dysgenesis
46 XX DSD
DAX1 Anti testis factor Boys Complete sex reversal
SRY Testis determining factor Both Aromatase
Complete deficiency
sex reversal
AIS- Androgen insensitivity syndrome, CAH- Congenital adrenal hyperplasia
WT1- Wilms Tumor 1 gene, SF1- Steroidogenic factor 1, SOX9- Sexual development
Table 42.4 Gene defects
on X chromosome associated
9, DAX1- withRegulatory
, SRY- Sex gonadal dysgenesis
region on Y Chromosome
Gene 3Function
Table Gender affected Features
Table 42.5Steroidogenic defects
Steroidogenic defects associated
associated with DSDwith DSD
Enzyme Features Diagnostic test
Associated with under virilization
7 D H C SLO syndrome High 7 Dehydrocholesterol
dehydrogenase
StAR Adrenal insufficiency Low DHEA, pregnenolone, 17OHP
Complete sex reversal
17 hydroxylase Hypertension Low 1 7 O H P, high
deoxicorticosterone
17 βHSD III Complete sex reversal Low testosterone, high
androstenidione
5 α reductase Virilization at puberty High testosterone to DHT ratio
Associated with virilization
21 hydroxylase Adrenal insufficiency High 17OHP
11 β hydroxylase Hypertension High Deoxycortisol
Associated with both virilization and under virilization
3 βHSD Adrenal insufficiency High 17 OH pregnenolone, DHEA
SLO- Smith-Lemeli-Optiz syndrome, 17OHP- 17 hydroxy progesterone, DHEA-
Dehydroandrostinidione, DHT- Dihydrotestosterone
42.4 Evaluation
42.41 HISTORY
•Presentation
! Genital ambiguity
" Congenital adrenal hyperplasia
" Gonadal dysgenesis
" Partial AIS
" Steroidogenic defects
! Boy with cryptorchidism- Congenital adrenal hyperplasia
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Evaluation
HISTORY
Genital ambiguity- Congenital adrenal hyperplasia, gonadal
dysgenesis, partial AIS
Boy with cryptorchidism- Congenital adrenal hyperplasia
Girl with inguinal masses- complete AIS, 17 βHSD defect
Primary amenorrhea with normal pubertal development- Complete AIS
Perinatal history- Maternal virilization (virilization disorders, aromatase
deficiency), intake of steroids, progesterone
Family history- Genital ambiguity, consanguinity, sibling death
(congenital adrenal hyperplasia), infertility (complete androgen
insensitivity syndrome), delayed puberty (steroidogenic defects)
EXAMINATION
Genital examination
Exclude normal variants
Labial edema
Prominent but not enlarged clitoris
Apparent small penis embedded in suprapubic fat
Appearance of clitoromegaly in preterm girls
Labial adhesion without clitoromegaly
Appearance
Prader staging (Stage I-V)
Stage I- Clitoromegaly, no labioscrotal fusion
Stage II-III- Increasing clitoromegaly and early labial fusion
Stage IV- Increased labial fusion, single urogenital opening
Stage V- Male appearance with small penis
Labioscrotal fold
Anogenital index (> 0.5 suggests labio scrotal fusion)
Anogenital index = Anus to posterior forchutte/ Anus to clitoris
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Urogenital!opening-
Labioscrotal fold
Number, site of urethral opening
" Anogenital index (> 0.5 suggests labio scrotal fusion)
Anogenital index = Anus to posterior forchutte/ Anus to clitoris
Pigmentation (congenital adrenal hyperplasia, SF1 defect)
" Rugosity, pigmentation (suggestive of virlization)
Hypertension (11 beta hydroxylase, 17 alpha hydroxylase defect)
! Urogenital opening- Number, site of urethral opening
Hemihypertrophy (WT1 gene defect)
•Pigmentation (congenital adrenal hyperplasia, SF1 defect)
Skeletal dysplasia (SOX 9 defect)
•Hypertension (11 beta hydroxylase, 17 alpha hydroxylase defect)
Polydactyly, microcephaly, mid facial narrowing (SLO syndrome)
•Hemihypertrophy (WT1 gene defect)
•Skeletal dysplasia (SOX 9 defect)
Pointers to diagnosis in DSD
•Polydactyly, microcephaly, mid facial narrowing (SLO syndrome)
Pointer Likely diagnosis
Table 42.6 Pointers to diagnosis in DSD
Pigmentation Congenial adrenal hyperplasia, SF1 defect
Pointer Likely diagnosis
Genital asymmetry Mixed gonadal dysgenesis, ovo testicular
Pigmentation Congenial adrenal hyperplasia, SF1 defect
Skeletal dysplasia
Genital asymmetry Mixed SOX
gonadal9 dysgenesis,
defect ovo testicular DSD
Polydactyly, microcephaly
Skeletal dysplasia SOX 9Smith-Lemeli-Optiz
defect syndrome
Polydactyly, microcephaly Smith-Lemeli-Optiz
Hypertension syndrome defect
11 or17 hydroxylase
Hypertension 11 or17 hydroxylase defect
Hemihypertrophy WT1 mutation
Hemihypertrophy WT1 mutation
Renal failure
Renal failure Denys Denys Drash syndrome
Drash syndrome
Features of syndromic
Table 42.7 Features causes
of syndromic ofofDSD
causes DSD
Syndrome Underlying defect Features
Smith-Lemeli-Optiz 7 DHC dehydrogenase Undervirilization, sex reversal, adrenal
failure, microcephaly, polydactyly
Denys Drash WT1 mutation Undervirilization, nephrotic syndrome,
hemihypertrophy, abdominal tumors
Frasier WT1 mutation Undervirilization, renal dysplasia
Sweyer SRY Sex reversal, skeletal abnormalities
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INVESTIGATIONS
Initial investigations
Karyotype
FISH study for Y chromosome (For rapid diagnosis)
Ultrasound for mullerian structures
Electrolytes in neonates
Disease to identify CAH
classification
Disease classification
Karyotype Palpable gonads Mullerian structure Group
46 XX Absent Present Virilized female
46 XY Present/ absent Absent Undervirlized male
46 XX, XY Present Present Gonadal dysgenesis
Further!evaluation
Further evaluation
" Virilized female
Virilized female
Initial work-up♦ Initial work-up
! 17 Hydroxyprogesterone- Interpretation
" 17 Hydroxyprogesterone
• > 100 nmol/L,! 3000
Role-ng/dl- 21OHD
Diagnosis of congenital adrenal hyperplasia
• 20-100 nmol/L- 11 βOHD,
! Interpretation 3 βHSD deficiency
• < 20 nmol/L- CAH unlikely
• > 100 nmol/L, 3000 ng/dl- 21OHD
• 20-100 nmol/L- 11 βOHD, 3 βHSD deficiency
! Retrograde genitogram
• < 20 nmol/L- CAH unlikely
Role- Characterization of urogenital fusion
" Retrograde genitogramopening
Indications- Single urogenital
Procedure-! X Role-
ray Characterization
after injecting dyeof urogenital
through fusion
UG opening
! Indications- Single urogenital opening
! Further evaluation
! Procedure- X ray after injecting dye through UG opening
! Mildly elevated
♦ Further 17OHP levels (2-100 nmol/L)- 17
evaluation
hydroxypregnenolone
" Mildly elevated 17OHP (high levels
in 3(2-100
βHSD deficiency),
nmol/L)
Deoxycortisol (high in 11 βOHD), urinary steroid
! 17 hydroxypregnenolone (high in 3 βHSD profile
deficiency)
! Normal 17OHP levels- Gonadal biopsy (46 XX gonadal
! Deoxycortisol (high in 11 βOHD)
dysgenesis), aromatase gene study (aromatase deficiency)
! Urinary steroid profile
" Normal 17OHP levels
Under virilized male
Initial work-up- Serum! Gonadal biopsy (46 XX gonadal dysgenesis)
testosterone
! < 50 ng/dL- Gonadal
! Aromatasedysgenesis,
gene studysteroidogenic defects
(aromatase deficiency)
! More than 300 ng/dL- Testosterone action defects
" Under virilized male
Further work-up♦ Initial work-up- Serum testosterone
" < 50 ng/dL- Gonadal dysgenesis, steroidogenic defects
" More than 300 ng/dL- Testosterone action defects
♦ Further work-up
" Low testosterone levels
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! Mullerian inhibitory substance (MIS)
• Principle- Marker of sertoli cell functions
• Indications- Low testosterone levels
•
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Approach
Initial assessment should be directed towards excluding physiological
variants like prominent (but not enlarged) clitoris, small penis
embedded in supra pubic fat and labial adhesion that may be
misdiagnosed as genital ambiguity. Special care should be taken in
preterm girls where prominent clitoris may give rise to false impression
of clitoromegaly. Initial work-up should include detailed physical
examination, serum electrolytes, karyotype and pelvic ultrasound.
Careful examination and pelvic ultrasound is sufficient to categorize
the individual into broad diagnostic groups. Demonstration of mullerian
structures in a child with no palpable gonads suggests virilization
disorder and should be followed with 17OHP levels. High 17OHP
levels (more than 100 nmol/L, 3000 ng/dL) are characteristic of classic
21 hydroxylase deficiency; milder elevation (20-100 nmol/L, 600-3000
ng/dL) should prompt evaluation for 3 βHSD and 11 β hydroxylse
deficiency. Gonadal biopsy should be done if 17OHP levels are normal
to identify gonadal dysgenesis. Maternal virilization during pregnancy
in this setting is indicative of maternal hyperandrogenism or the rare
disorder of aromatase deficiency. Absence of mullerian structures
suggests normal fetal anti mullerian hormone production and a
diagnosis of undervirilised male. Most of these individuals have
palpable gonads; disorders of defective virilization should however be
considered even if gonads are not palpable. Testosterone levels help in
differentiating disorders of testosterone production (low levels;
steroidogenic defects or testicualr dysgenesis) and action (high or
normal levels; 5 α reductase defect or androgen insensitivity
syndrome). HCG stimulation test and gonadal biopsy should be
considered if testosterone levels are low. High testosterone levels
should prompt estimation of HCG stimulated DHT to differentiate 5α
reductase deficiency (low levels) from androgen insensitivity syndrome
(high levels). Presence of gonads and mullerian is suggestive of
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Present Absent
42.5 Management
Management
•Components
•Components
! Management of life threatening conditions
!! Management
Initiation of Specificof life threatening conditions
treatment
!! Initiation
Parental of Specific treatment
education
!! Parental
Decision abouteducation
gender of rearing
!! Decision
Surgical about
procedures gendertoof
according rearing
gender of rearing
! Surgical procedures according to gender of rearing
•Management team
•Management team
! Endocrinologist
!! Endocrinologist
Pediatric surgeon
!! Pediatric
Social worker surgeon
!! Social worker
Geneticist
! Geneticist
StepI-I-Exclude
Step Exclude life threatening
life threatening conditioncondition
!! Serum electrolytes
Serum electrolytes
!! Blood
Blood glucose
glucose
!! Initiate
Initiate hydrocortisone
hydrocortisone and fludrocortisone
and fludrocortisone if CAH diagnosed if CAH
diagnosed
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Epidemiology
•Prevalence- Preterm boys- 30%, term boys- 4%, one year of
age- 1%, adulthood- 0.8%
•Involvement- Unilateral (70%), bilateral (30%)
•Position- Inguinal (60%), pre scrotal (20%), abdominal (10%),
ectopic (10%)
44.3 Etiology
Etiology
Undescended testis
Unilateral Bilateral
Usually no underlying cause Idiopathic
Hypogonadism
Gonadotropin deficiency
Non-palpable Steroidogenic defects
Partial Androgen insensitivity
5 alpha reductase deficiency
Gonad present Gonad absent Growth hormone deficiency
Idiopathic Anorchia
Testicular dysgenesis Virilization disorder
Syndromes
Downs
Prader willi
Delange
Noonan
LMBB
Evaluation
Important causes (Bilateral undescended testis)
CLINICAL
• Idiopathic
Step I- Confirmation of diagnosis
• Hypogonadism
•Palpation for gonads
• Gonadal dysgenesis
•From anterior superior iliac spine to base of scrotum
44.4 Evaluation
•Examination in crossed legged and squatting position
44.41 CLINICAL
•Examination after warm compresses
Step I- Confirmation of diagnosis
• Palpation for gonads
Step II- Differentiation
• From anterior superior iliacfrom
spine toectopic and retractile testis
base of scrotum
• Examination in crossed legged and squatting position
• Examination after warm compresses
Step II- Differentiation from ectopic and retractile testis
• Scrotal sac (well formed in retractile testis)
• Cremasteric reflex (exaggerated in retractile testis)
• Hernia (indicative of undescended testis)
Step III- Evaluation for underlying cause
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• Genital ambiguity- Disorders of sexual development (please refer
42.2)
Testicular dysgenesis
Steroidogenic defects
Partial AIS
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INVESTIGATIONS
Localization studies
Indications
Non palpable unilateral undescended testis
Non palpable bilateral undescended testis with
Positive HCG response to testosterone
Detectable AMH levels
Approach
Most boys with undescended testis do not have an underlying disorder.
Extensive work-up should therefore be reserved for rare boys with
special features. Investigations are required in special situations like
neonatal period (to exclude potentially life-threatening virlizing CAH),
genital ambiguity (evaluation for disorders of sexual development) and
the presence of features of hypopituitarism (pituitary function tests).
Initial evaluation should be directed towards confirming the diagnosis
of undescended testis. Careful examination in squatting position after
application of warm compresses is required to confirm the diagnosis of
undescended testis. Well development scrotal sac on the side of
absent testis is against the diagnosis of undescended testis and
suggestive of ectopic or retractile testis. No treatment is requirement in
these boys. Poorly developed scrotal sac with palpable testis is
suggestive of true undescended testis and indication for treatment.
These boys should be given a trial of HCG (250-500 IU biweekly for
five weeks). Orchidopexy should be performed if there is no response
to HCG. This should be done before the age of one year to avoid
adverse effects on testicular dysfunction. Important considerations in
boys with bilateral non-palpable testis include intra abdominal testis or
anorchia. These conditions can be differentiated by HCG stimulation
test and inhibin levels with positive response to HCG and detectable
inhibin levels indicating the presence of abdominal testis. Laparoscopy
should be done in these boys as imaging modalities have limited role
in localizing abdominal testis. No increase in testosterone to HCG and
undetectable inhibin B or antimullerian hormone levels are indicative of
anorchia. No localization studies are required in these boys.
44.4 Approach
Undescended testis
Palpable gonads
Present No
Scrotal development HCG response/ MIS
Response No response
Follow-up Orchidopexy
Most boys with undescended testis do not have an underlying disorder. Extensive
Management
work-up should therefore be reserved for rare boys with special features.
•Adverse
Investigations effectsinofspecial
are required undescended
situations liketestis
neonatal period (to exclude
•Testicular
potentially dysfunction
life-threatening virlizing –CAH),
Unlikely if before
genital one(evaluation
ambiguity year for
disorders of sexual development)
•Malignancy and the presence of features
risk- Development of seminoma. Risk 10-20 of hypopituitarism
(pituitary function
times tests).
that Initial
thanevaluation
normally should be directed
located towardsIt confirming
testis. is relatedthe to
diagnosis of undescended testis. Careful examination in squatting position after
underlying testicular abnormality. Not related to site as
application of warm compresses is required to confirm the diagnosis of undescended
testis. Wellincreased
developmentrisk forsac
scrotal contralateral
on the side ofdescended
absent testis is testis
againstand
the no
diagnosis of reduction
undescendedin risk
testisafter orchidopexy
and suggestive of ectopic or retractile testis. No
•Testicular
treatment is requirementinjury-
in theseInguinal, ectopic
boys. Poorly testis
developed scrotal sac with palpable
testis •isTorsion
suggestive of true undescended testis and indication for treatment. These boys
should•Timing-
be given a Ideally
trial of HCG (250-500
before oneIU biweekly
year of age for five weeks). Orchidopexy
should•Treatment-
be performed if there
Injection HCG- 250-500 should
is no response to HCG. This be done before
IU biweekly forthefive
age of one year to avoid adverse effects on testicular dysfunction. Important
weeks. Response is good for inguinal testis but very poor
considerations in boys with bilateral non-palpable testis include intra abdominal testis
or anorchia. with abdominal
These conditions testis
can be differentiated by HCG stimulation test and
•Surgery
! Indications
! Palpable testis- No response to HCG
! Non palpable testis
♦ Positive HCG stimulation test
♦ Detectable inhibin levels
! Procedures
! Orchidopexy
! Cord lengthening and fixation
! Orchidectomy for dysgenetic testis
2.8 Gynecomastia
40 Gynecomastia
PCriteria
40.1 Criteria
Breast tissue enlargement more than tanner stage II. Breast tissue
• Breast tissue enlargement more than tanner stage II
should • beBreast
differentiated from fat from
tissue should be differentiated in fatobese
in obeseboys.
boys. Resistance while
approximating thumb
• Resistance while and index finger
approximating thumb andin the
indexchest towards
finger in the chestnipple and
tenderness suggests
towards true
nipple and gynecomastia.
tenderness suggests true gynecomastia.
40.2 Etiology
Etiology
Gynecomastia
Physiological Pathological
Puberty
Obesity
Approach • If indicated
Extensive evaluation is not required in most boys with gynecomastia
Gonadotropin
as most havephysiological form
Indications- Pubertal of disease. First step should be
delay
Interpretation
directed towards differentiating gynecomastia from fatty infiltration.
♦ Low- Hypogonadotropic hypogonadism
Work-up for pubertal boys should be restricted to exclude liver disease
♦ High- Hypergonadotropic hypogonadism
and history of exposure
Estrogen to drugs implicated in the pathogenesis of the
condition. They should
Indicationsbe followed up six monthly for two years.
Severe and progressive
♦ Rapid gynecomastia
progression in boys with delayed puberty is
indication for evaluation
♦ Severein the form of testosterone and gonadotropin
gynecomastia
levels. Low testosterone
♦ Normal levels are levels
gonadotropin suggestive of hypogonadism that
Workup for hyperestrogenic
should be evaluated as described in 39.4. states Estrogen levels should be
♦ Testicular ultrasound (estrogenic testicular cord tumor)
measured in boys with normal testosterone levels. High estrogen
♦ Adrenal ultrasound (estrogenic adrenal tumor)
levels should be ♦follow-ed up with evaluation for estrogen producing
Aromatase excess syndrome
testicular or adrenal
Human chorionic(adrenal
tumors and testicular ultrasound). Normal
gonadotropin
adrenal and testicular ultrasound in a boy with persistent elevation of
Indications
estrogen indicates ♦ Rapidrare aromatase excess syndrome. Normal
progression
testosterone and ♦estrogen levels in testosterone
Normal gonadotropin, a boy with severelevels
and estradiol gynecomastia
should prompt HCG Work-up for high
levels. BoysHCG levels
with high HCG levels should undergo
localization studies♦ Testicular
for HCG examination
secreting tumors (testicular ultrasound
♦ CT scan of chest, abdomen and brain
and chest, abdomen and head CT scan).
40.4 Approach
Gynecomastia
Assess severity and pubertal status
Exclude liver disease, drugs
Normal High
Exclude HCG tumor Hyper-estrogenic state
Testicular ultrasound
Adrenal imaging
Management
Self resolving in majority of cases by two years
Weight loss in obese children
Indications- Progressive disease, no improvement within 2 years
Treatment options
Aromatase inhibitors- Letrozole (2.5 mg/day) anastrazole (1 mg/day)
Tamoxifen 20 mg daily
Testosterone- May worsen disease as is converted to estrogen
Dihydrotestosterone- Limited studies Dose
Surgical- Laparoscopic breast tissue resection
Hyponatremia
ETIOLOGY
Resistance Deficiency
PHA Generalized
CAH- StAR, 21OHD, 3βHSD
Addison disease
SF1, DAX1 defect
POINTERS TO DIAGNOSIS
Related to rapidity of onset (rate of fall more important)
• Acute- Headache, vomiting, seizures, encephalopathy
• Chronic- Somnolence, lethargy, vominting
EVALUATION
History
• Onset
• Neonatal period- Renal failure, CAH, aldosterone resistance
• Infancy- Renal failure, adrenal failure
• Early childhood- Fluid overload, renal failure, SIADH
• Late childhood- Renal failure, addison disease, SIADH
• Presentation
• Acute- Adrenal insufficiency, renal failure, CSW
• Insidious- SIADH, fluid overload
• Fluid balance
• Positive- SIADH
• Negative- Salt wasting (adrenal, cerebral or renal)
Examination
• Fluid status
• Over hydration (edema)- Renal failure, liver disease, CCF
• Normal- SIADH, cortisol deficiency, hypothyroidism
• Dehydration- Diarrhea, salt wasting (renal, adrenal, cerebral)
• Neonatal period
• Genital ambiguity (congenital adrenal hyperplasia)
• Abdominal examination (renal mass)
• Features of cardiac failure, liver disease
INVESTIGATIONS
• Initial
• Exclude psuedohyponatremia- Blood glucose, lipid, albumin
• Serum potassium
• Hyperkalemia- Renal failure, inefficient aldosterone action
• Hypokalemia- Diuretic use, tubular necrosis
• Urine sodium
• < 20 mmol/L- Diarrhea, Cardiac failure, CLD
• > 20 nmol/L- ATN, Inefficient aldosterone action, CSW, SIADH
• High Potassium
Step I- Differentiate renal from adrenal cause
Feature Renal dysfunction Adrenal cause
Hydration status Edema, dehydrated* Dehydration
Blood pressure Normal or elevated Decreased
Pigmentation Absent Common
Hypoglycemia Absent May be present
Urinary sodium Variable More than 20 mmol/
L
Urea High High
Creatinine High Normal
Hematocrit Normal/ decreased Increased
Acidosis Moderate to severe Mild
APPROACH
Hyponatremia
Exclude hyperglycemia, hyperlipidemia
Hydration status
High Normal
High Low
Normal Low
Adrenal failure
Please refer
MANAGEMENT
Non specific
•Principles
! Rapid correction associated with risk of central pontine myelinolysis
! Not increase by more than 0.5 mmol/L/hour, 12 mmol/L/day
! Oral route if feasible
! Rapid correction only if neurological features present
! Target sodium for acute correction 120 mmol/L
•Management- According to sodium levels
! More than 120 mmol/L- Oral salt, maintenance as 0.9% saline
Specific
• Gastrointestinal loss- Oral correction preferred
• SIADH
o Treat underlying cause- Stop incriminated drugs, treat infection
o Fluid restriction- 1 L/m2/day
o Severe disease/ nor response
! Hypertonic saline (3% saline 10 ml/kg)
! Frusemide (2 mg/kg)- Induces free water loss
Hypernatremia
ETIOLOGY
EVALUATION
Clinical
• Onset
Age Etiology
Neonatal period Dehydration, DI, iatrogenic
Infancy Dehydration, central or nephrogenic DI
Childhood Incorrect ORS, central DI
• Presentation
• Acute- Diarrhea, salt load
• Insidious- Diabetes insipidus
• Fluid balance
• Positive- Overload
• Negative- Diabetes insipidus
• Hydration status
• Dehydration- Diarrhea, diabetes insipidus
• Normal or over hydrated- Salt load, hyperaldosteronism
Investigations
• Initial
• Urine osmolality/ specific gravity
• Less than 300 mOsm/kg- Diabetes insipidus
• More than 300 mOsm/kg- Diarrhea, salt load, osmotic diuresis,
hyperaldosteronism
• Urine sodium
• Less than 20 mmol/L- DI, diarrhea, insensible water loss
• More than 20 mmol/L- Salt load, hyperaldosteronism
• Further evaluation
• Low urine osmolality
• Diagnostic of diabetes insipidus
• Water deprivation not required
• Vasopressin response test (please refer 11.5)
• Injection vasopressin 0.1 unit/kg subcutaneous
• Urine osmolality after 4 hours
• Increase more than 50% of baseline- Central DI
• Increase less than 50% of baseline- Nephrogenic DI
• High urine osmolality- According to urinary sodium
• Less than" 20 mmol/L-
High Likely diarrhea,
urine osmolality- osmotic
According diuresis
to urinary sodium
• More than ♦ 20 Less
mmol/L- Rule out exogenous load
than 20 mmol/L- Likely diarrhea, osmotic diuresis
♦ More than 20 mmol/L- Rule out exogenous load
APPROACH
48.5 Approach
Hypernatremia
Exclude salt load, hyperthermia
Urine osmolality*
MANAGEMENT
• DI- Diabetes insipidus * Urine specific gravity 1010 equivalent to urine osmolality of
Principles
700
• mOsm/kg
Rate of correction depends on duration and severity
• Rapid fall in sodium should be avoided
• Decrease
Initial evaluationinissodium
directedshould be less
to exclude saltthan 12inappropriately
load, mmol/L/day prepared oral
• High risk
rehydration of seizures
solution duringwater
and insensible fall of serum
losses. sodium
Neonates levels
with hypernatremia should
be assessed for adequacy of breastfeeding by evaluating weight gain pattern,
frequency of urination and level of activity. Urine osmolality (or specific gravity)
helps in differentiating DI form other conditions. Urine osmolality less than 300
mOsm/kg (or specific gravity below 1005) in the presence of hypernatremia is
diagnostic of DI. Water deprivation test is not only not required but also potentially
hazardous in these conditions. Vasopressin response test (urine osmolality 1 and 4
hour after 0.1 unit/kg vasopressin) should be done to differentiate central (increase in
114 urine osmolality) from nephrogenic DIGrow
(no increase).
Society Urine sodium levels should be
measured if urine osmolality is high. Low urine sodium levels indicate diarrhea or
insensible water losses. High serum and urinary sodium is characteristic of sodium
load. Aldosterone excess (true of apparent) may present with mild hypernatremia;
Resource book Pediatric Endocrinology Protocols
• Management
• Oral correction preferred
• Correct dehydration and sodium over 48-72 hours
• Sodium content in fluid 70-80 mmol/L
• Hemodialysis if serum sodium more than 170 mmol/L
• SPECIFIC
• Gastrointestinal loss- Depending on severity
• Mild- Oral rehydration solution
• Severe- Intravenous correction
• Steps
• Calculated level of dehydration
• Add to maintenance requirements for 48 hours
• Calculate sodium requirement and deficit for 48 hours
• Calculate free water deficit
Free water deficit = 4 × weight × (Na – 150)
• Salt load- Rapid fall after cessation of load, frusemide if fall slow
• Breast mild related hypernatremia
• Usually related to poor feeding and dehydration
• Encourage breast feeding with monitoring
• Diabetes insipidus
• Central- DDAVP
• Nephrogenic- Thiazide-amiloride combination
Further reading
1. Bajpai A, Kabra M, Menon PS. 21-hydroxylase deficiency: clinical
features, laboratory profile and pointers to diagnosis in Indian children.
Indian Pediatr 2004; 41:1226-1232.
2. Sharma J, Bajpai A, Kabra M. Congenital adrenal hyperplasia
presenting as hematuria and acute renal failure. Indian J Pediatr 2001;
68:1161-1162.
Features
Serum sodium Features
3.2 Potassium
3-3.5 mmol/L
Disorders Asymptomatic
2.5-3 mmol/L Polyuria, muscle cramp, paralytic ileus
2-2.5 mmol/L
Hypokalemia ECG changes, neck flop, muscle weakness
Less than 2 mmol/L Respiratory paralysis, cardiac arrhythmia
CRITERIA- Serum potassium less than 3.0 mmol/L
Etiology
ETIOLOGY
Extra renal
Gastrointestinal Renal
CSF loss
Important causes
116 Grow Society
Resource book Pediatric Endocrinology Protocols
FEATURES
Serum potassium Features
3-3.5 mmol/L Asymptomatic
2.5-3 mmol/L Polyuria, muscle cramp, paralytic ileus
2-2.5 mmol/L ECG changes, neck flop, muscle weakness
Less than 2 mmol/L Respiratory paralysis, cardiac arrhythmia
Pointers to diagnosis
• Myopathy
• Acute flaccid paralysis
• Polyuria
• Muscle cramp
• ECG changes- Prolonged PR and QRS interval, flattened ST segment ,
U wave (positive wave after T wave)
• Pointers to endocrine etiology- Early onset, failure to thrive, severe
alkalosis, hypertension
EVALUATION
Clinical
• Onset
• Neonatal- Tubulopathy, aldosterone excess, low magnesium
• Infancy- Diarrhea, tubulopathy, barter syndrome, aldosterone excess
• Childhood- Diarrhea, malnutrition, diuretic use, RTA
• Presentation
• Acute- Diarrhea, diuretic use
• Insidious- Aldosterone excess, malnutrition, barter syndrome
• Blood pressure
• Hypertension- 11 βOHD, 17 αOHD, 11 βHSD defect, GRA
• Normal- Bartter syndrome, RTA, hypomagnesaemia
INVESTIGATIONS
• Initial
• Venous blood gas
Acidosis RTA, Diarrhea, acetazolamide use
Alkalosis Diuretic, aldosterone excess, bartter syndrome
• Serum sodium
• Hypernatremia- Aldosterone excess states
• Hyponatremia- Diuretic use, diarrhea
• Urinary potassium
• Less than 20 mmol/L- Extra renal loss
• More than 20 mmol/L- Renal loss, aldosterone excess
• Further evaluation
• Metabolic acidosis- Urine net charge
• Positive (impaired ammonium production)- RTA
• Negative (normal ammonium production)- Diarrhea
• RTA Classification
Feature Proximal RTA Distal RTA
Urine- blood CO2 > 10 mmol/L < 10 mmol/L
Urine pH Less than 7.5 More than 7.5
FEHCO3 More than 15% Less than 10%
Nephrocalcinosis Absent Common
Approach
APPROACH
Hypokalemia
Exclude malnutrition, diuretic, gastrointestinal loss
Venous blood gas
Metabolic alkalosis
Metabolic acidosis Magnesium
Urine net charge
Normal Elevated
Bartter, Gitelman syndrome Aldosterone
High Normal
Dexamethasone suppression Urinary steroids, DOC
Initial
DOC- evaluation is GRA-
Deoxycortisol, directed towards identifying
Glucocorticoid remediable gastrointestinal
aldosteronism, CAH- loss Congenital
and
diuretic use. Extensive work-up is required only
adrenal hyperplasia, βHSD- Beta hydroxysteroid dehydrogenase in the presence of severe
hypokalemia, failure to thrive, genital ambiguity, bony deformities or
hypertension.
Initial evaluationBlood gas istowards
is directed the most important
identifying investigation.
gastrointestinal lossHypokalemia is
(diarrhea, nasogastric
usually associated with alkalosis; metabolic acidosis should
aspiration, vomiting) and diuretic use (frusemide, acetazolamide, thiazide). Extensive raise the
possibility
work-up isofrequired
RTA orindiarrhea. Urine ofnetsevere
the presence charge helps in differentiating
hypokalemia, failure to thrive,RTAgenital
(positive) diarrhea (negative). Hypomagnesmia should be excluded
ambiguity, bony deformities or hypertension. Blood gas is the most important investigation. in the
setting of hypokalemic alkalosis. Hypertension and hypokalemic alkalosis
Hypokalemia is a potent stimulus of the renin-aldosterone axis resulting in alkalosis; is
suggestive of true or apparent aldosterone excess and should prompt
metabolic acidosis in a child with hypokalemia should raise the possibility of impaired acid
aldosterone levels.
excretion (distal RTA) or Low orloss
alkali normal aldosterone
(diarrhea and proximallevels
RTA). with
Urine hypokalemic
net charge helps in
alkalosis and hypertension indicates apparent mineralocorticoid
differentiating RTA (positive due to indicating impaired renal ammonium excess.
production)
Normal
diarrhea (negative due to normal urinary ammonium production). Hypomagnesmiatoshould
blood pressure in a child with hypokalemic alkalosis and failure
thrive is suggestive
be excluded in theofsetting
Bartterofand Gitelman syndromes.
hypokalemic alkalosis. Hypertension and hypokalemic
alkalosis is suggestive of true or apparent aldosterone excess and should prompt
aldosterone levels. Dexamethasone suppression test should be done if aldosterone levels
are high to differentiate GRA (suppression in aldosterone levels) from aldosterone
secreting tumor (no suppression). Low or normal aldosterone levels with hypokalemic
alkalosis and hypertension indicates apparent mineralocorticoid excess. Urinary steroid
GROW
profile Society !
and deoxycortisol levels are helpful in identifying 121 17 α
rare CAH variants (11β and
hydroxylase deficiency) and 11 βHSD deficiency. Liddle syndrome should be considered if
these investigations are normal. Therapeutic trial with hydrocortisone and spironolactone
GROW Society Pediatric Endocrinology Protcols
MANAGEMENT
Non specific
• Principles
• Oral correction preferred
• ECG monitoring essential during management
• Avoid rapid correction
• Maximum concentration of potassium chloride
• Peripheral line- 60 mmol/L
• Central line- 80 mmol/L
• Do not give potassium with dextrose (intracellular migration)
• Exclude hypomagnesaemia in refractory situations
• Protocol
• Potassium 2.5-3.0 mmol/L- Oral potassium chloride- 4-6 mmol/kg/
day, potchlor (1.3 mmol/L), KCl (2 mmol/ml)
• Potassium 2.0-2.5 mmol/L- Intravenous potassium 0.3 mmol/kg/hour
• Potassium less than 2.0 mmol/L- Admit in intensive care unit,
potassium infusion 0.3-1 mmol/kg/hour
Specific
Disorder Treatment
Diarrhea Oral or intravenous potassium
RTA Bicarbonate, oral potassium
Hypomagnesaemia IM MgSO4 50 mg/kg BD for 3 days
Oral milk of magnesia 100 mg/kg/d
Aldosterone secreting tumor Surgery
GRA Hydrocortisone 10 mg/m2/day
17 α, 11 β OHD deficiency Hydrocortisone 10 mg/m2/day
11 βHSD deficiency Spironolactone 1-2 mg/kg/day
Liddle syndrome Amiloride 1-2 mg/kg/day
Bartter syndrome Indomethacin (1-2 mg/kg/day)
Potassium (3-6 mmol/kg/day)
ETIOLOGY
Etiology
Hyperkalemia
Low renin
Primary
ACE inhibitors
Indomethacin
EVALUATION
Clinical
Onset
Neonatal Renal failure, hemolysis, iatrogenic, CAH, PHA
Infancy Renal failure, CAH, PHA, aldosterone deficiency
Childhood Renal failure, tissue lysis, adrenal failure
Investigations
Initial
• Venous blood gas
• Acidosis associated with hypekalemia
• Related to shift of intracellular potassium
• 0.6 mmol/L increase in potassium for every 0.1 decrease in pH
• Not related to respiratory or organic acidosis
• Acidosis disproportionate to potassium levels- Renal failure
• Urea, creatinine (Renal failure)
• Serum sodium (low in renal failure, inefficient aldosterone action)
Special situation
Neonate with hyponatremia- CAH versus ARF
Feature Renal failure CAH
Hydration Normal, overhydrated Dehydrated
Pigmentation Absent Common
Hypoglycemia Absent May be present
Urea High May be high
Creatinine High Normal
Hematocrit Normal or decreased Increased
Table Causes
Causes of hyponatremia
of hyponatremia andandhyperkalemia
hypokalemia
Disorder
Disorder Urea
Urea Creatinine ReninRenin Aldosterone
Creatinine Aldosterone
Renal failure High High Not needed Not needed
Renal failure High High Not needed Not needed
Adrenal insufficiency May be high Normal High Low
Adrenal insufficiency May be high Normal High Low
Cyp11AS deficiency May be high Normal High Low
Cyp11AS
PHA deficiency May
Maybe be
highhigh Normal High High High Low
Normal
PHA
Gordon syndrome May be high
Normal Normal High High High High
Normal
Gordon syndrome
Cyp11AS- NormalPHA- Pseudohypoaldosteronism
Aldosterone synthetase, Normal High High
Approach APPROACH
Hyperkalemia
Exclude renal failure, tissue lysis, drugs
Plasma renin activity
Low High
Hyporeninemic hypoaldosteronism Aldosterone levels
Renal imaging
High Low
Pseudohypoaldosteronism Cortisol levels
Normal Low
Cyp11AS deficiency Adrenal insufficiency
Please refer 24.5
MANAGEMENT
Non specific
• Indications
• Potassium more than 6.0 mmol/L without ECG changes
• Potassium more than 5.5 mmol/L with ECG changes
• Measures
• Stop K containing fluid, sparing diuretic, supplementation
• Calcium gluconate
• Sodium bicarbonate
• Mechanism- Intracellular shift of potassium
• Dose- 1-2 ml/kg of 10% solution over 10 minutes
• Salbutamol nebulization
• Mechanism- Intracellular migration
• Dose- 0.15 mg/kg every 20 minutes for 3 doses
Specific
Disorder Treatment
Renal failure Diuretic, low potassium diet
Congential adrenal hyperplasia Hydrocortisone, fludrocortisone
Aldosterone synthetase defect Fludrocortisone
Pseudohypoaldsoteronsim Salt supplementation
Gordon syndrome Frusemide
16. Neonatal
3.3 Metabolic Hypocalcemia
acidosis
16.1 Criteria
CRITERIA Age group Total mg/dL (mmol/L) Ionic mmol/L
• pH < 7.2
Preterm < 7 mg/dL (< 1.75 mmol/L) < 1.0 mmol/L
• Base excess > -5 mmol/L
Term < 8 mg/dL (< 2 mmol/L) < 1.1 mmol/L
• Bicarbonate < 20 mmol/L
16.2 Etiology
ETIOLOGY
Metabolic Acidosis
EVALUATION
Clinical
• History suggestive of renal failure, liver disease
• Toxin, drugs (acetazolamide, triametrene, spironolactone)
• Polyuria, polydipsia (DKA, RTA)
• Diarrhea, ureteosigmoidostomy
• Features of hypoglycemia (GSD I, Fatty acid oxidation defects)
• Bony deformities, myopathy (RTA)
• Sib deaths, developmental delay/regression, seizures (organic academia)
Investigations
• Initial
• Blood gas
• Serum electrolytes
• Urea, creatinine, SGPT
• Urinary ketones
• Blood Sugar, lactate
• Anion Gap
Anion gap = Na- (Cl+ HCO3)
• Normal- 10-12 mEq/L
• Increased- Increased organic anion,
• Decrease- Increased Ca/Mg/K, Li Intoxication, hyperviscocity
• Level II
• Urine Net Charge- Indicator of renal ammonia production
• Lactic Acidosis
• Blood sugar (Organic academia/ GSD)
• Urine Aminoacidogram (Organic academia)
• CSF Lactate (Mitochondrial disorder)
• LFT (Liver Failure)
Metabolic acidosis
Anion gap
Normal Elevated
Urine net charge Blood sugar
< 10 > 20
Distal RTA Proximal RTA
MANAGEMENT
• Indications
• Renal failure/ RTA- pH < 7.2, HCO3 < 15 mmol/L
• Metabolizable acid – pH < 7.1
• Requirement
• HCO3 (mEq)= 0.3x weight x SBE
• HCO3 (mEq)= 0.5x weight x (Target -HCO3 ) ( pH< 7.2)
• 7.5% NaHCO3= 0.9 mEq/ml
• Specific
• DKA: Avoid sodium bicrabonate
• CRF: HCO3 22-24 mmol/L Tab Sodamint- 4meq, Powder- 12 meq/1gm
• RTA
• Type I- HCO3- 0.5-2 mmol/kg/d (Polycitra- 2 meq/ml: Na K Citrate)
• Type II- PO4- 20-40 mg/kg/d in 4DD & HCO3 > 4 mmol/kg/d
• Type IV- Aldosterone- Flurinef 0.15 mg/m2 and loop diuretics
• Salisylate Poisoning
• Gastric lavage
• Sodium bicarbonate and acetazolamide
Further reading
1. Dubose TD. Acidosis and alkalosis. In: Fauci AS, Braunwald E,
Isselbacher KJ Wilson JD, Martin JB, Kasper DL et al. (eds) Harrison’s
Principles of Internal Medicine, 14th edn. New york, McGraw Hill, 1998. Pp
277-289.
2. Tote RD, Alpern RJ. Metabolic acidosis and alkalosis. In: Fluid and
electrolytes. Eds: Kokko JP, Tannen Rl. WB Saunders Philadelphia 3rd
Edn 1996. Pp201-266.
3. Haycock GB. Potassium and acid base. In: Pediatric Nephrology Eds:
Barratt TM, Avner ED, Harmon WE Lippincot Williams and Wilkins 4th Edn
1999. Pp155-191.
Neonatal hypocalcemia
Increased chelation
Decreased total calcium
Hyperphosphatemia
Cow milk, formula
Renal failure
Birth asphyxia
Alkalosis
Resistance to PTH
Hypoparathyroidism
Pseudohypoparathyroidism
Magnesium deficiency
Transient Permanent
Maternal hyperparathyroidism Isolated
Magnesium deficiency Activating Ca sensing receptor mutation
Infant of diabetic mother Parathyroid agenesis
PTH gene deletion
Syndromes
DiGeorge malformation complex
Kenny-caffey syndrome
Mitochondrial disorders- MELAS, KS syndrome
CRITERIA
Age group Total mg/dL (mmol/L) Ionic mmol/L
Preterm < 7 mg/dL (< 1.75 mmol/L) < 1.0 mmol/L
Term < 8 mg/dL (< 2 mmol/L) < 1.1 mmol/L
Classification Causes
Early (before three days of life) Prematurity
Birth asphyxia (33% of all neonates)
Infant of diabetic mother (15% of all)
Late (after three days of life) Formula feed
Maternal vitamin D deficiency
Hypomagensemia
Hypoparathyroidism
POINTERS TO DIAGNOSIS
Clinical
• Seizures, jitteriness, apnea
• Lethargy
• Cardiac failure
• Stridor
Investigation
• ECG- Prolonged corrected QoT interval (QoTc)
QoTc= QoT/ √RR (consider hypocalcemia if above 0.22)
QoT= Beginning of Q wave to beginning of T wave, RR- RR interval
• Features of rickets on X ray
EVALUATION
History
• Age at onset
• First week- Prematurity, birth asphyxia, infant of diabetic mother
• 1-3 weeks- HP, maternal hyperparathyroidism, hypomagnesemia
• 3-6 weeks- Phosphate load, vitamin D deficiency, renal failure
• Family history
• Hypocalcemia- VDDR, calcium sensing receptor defect, PHP
• Mother- Abdominal pain, renal colic (hyperparathyroidism), DM
• Exposure to cow milk or formula (hyperphosphatemia)
• Period of gestation (prematurity), birth asphyxia
• Exchange transfusion (chelation with citrate)
• Recurrent infections (Di George syndrome)
Examination
• Facies
• Low set ears, short philtrum, mandibular hypoplasia, small mouth,
hypertelorism (DiGeorge malforamtion complec)
• Frontal bossing, craniotabes, rachatic rosary (vit D deficiency, VDDR)
• Cardiac murmur (DiGeorge syndrome)
Investigations
• Initial
• Serum phosphate
• High- Renal failure, HP, pseudohypoparathyroidism, phosphate load
• Low- Vitamin D deficiency, VDDR, hypomagnesemia
• Creatinine
• Magnesium (low in hypoparathyroidism and hypomagnesemia)
• Alkaline phosphatase (high in vitamin D deficiency)
• X ray wrist- Rickets
• Urine calcium (high in activating calcium sensing receptor mutation)
• Investigations in mother- X ray pelvis (for osteomalcia), calcium (high
in hyperparathyroidism), alkaline phosphatase (high in vit D deficiency)
• Second Line
• Parathormone- Hyperphosphatemia, normal creatinine, no PO4 load
• Low, normal- Hypoparathyroidism
• High- Pseudohypoparathyroidism
MANAGEMENT
Acute
• Injection calcium gluconate (10%, 9 mg/ml)
• Indication- Total calcium < 6 mg/dL, ionic calcium < 2.9 mmol/L
• Precaution
• Avoid extravasation as may cause tissue necrosis
• Cardiac monitoring due to risk of cardiac arrest
• Avoid combination with phosphate or bicarbonate
• Follow-up
• Good response
• Calcium (75 mg/kg/day in four divided doses) for one day
• Reduce to 50 mg/kg/day on day 2 and 25 mg/kg/day on day 3
• Start oral calcium at a dose of 50 mg/kg/day on day 3
• Stop intravenous calcium on day 4
• No response
• Repeat calcium gluconate (1-2 ml/kg)
• Magnesium (50 mg/kg, IM or IV, 0.1 ml/kg of 50%)
Long term
• Vitamin D deficiency
• Calcitriol (20-40 ng/kg/day)/alpha D (40-60 ng/kg/day) for 3 days
• Cholecalciferol (300000 IU) over five days
• Calcium carbonate (50 mg/kg/day in three divided doses)
• Hypoparathyroidism
• Calcitriol (20-40 ng/kg/day)/ alpha D (40-60 ng/kg/day)
• Calcium carbonate (50 mg/kg/day eight hourly, avoid phosphate)
• Magnesium (50 mg/kg/day) if hypomagnesemia present
• Target calcium- 7.6-8.0 mg/dl (1.9-2.0 mmol/L)
• Hypomagnesemia
• Intramuscular magnesium sulphate- 0.1 ml/kg for three days
• Oral magnesium sulphate (50-100 mg/kg/day)
Duration of treatment
Disorder Duration
Maternal vitamin D deficiency, hyper PTH Three months
Nutritional phosphate load Three months
Vitamin D dependent rickets 1 and 2 Life long
Hypoparathyroidism, PHP Life long
Corrected calcium mg/dL = Total calcium mg/dL + 0.8 × (4- Alb g/dL)
POINTERS TO DIAGNOSIS
History
• Tetany
• Numbness and tingling around the mouth and in tips of fingers
• Stridor, cardiomyopathy
• Benign intracranial tension
• Muscle cramps
EVALUATION
History
• Onset
o Infancy- Vitamin D deficiency, renal failure, HP, PHP
o Childhood- Renal failure, vitamin D deficiency, hypoparathyroidism
o Adolescence- Vitamin D deficiency, renal failure, autoimmune HP
• Family history of PHP, rickets, hypoparathyroidism
• Acute onset anemia, hemoglobinuria (hemolysis), tumor lysis
• Exposure to phenytoin, phenobarbitone, cisplatinum, forscarnet
• Bony deformities (rickets, pseudohypoparathyroidism)
• Features of renal failure, liver disease
• Recurrent infections (DiGeorge syndrome, calcitriol resistance)
• Adrenal insufficiency, hypothyroidism, diabetes mellitus (APS 1)
• Recurrent diaorrhea, steatorhea (malabsorption)
Examination
• Pubertal development
Post Neonatal Hypocalcemia (delayed in PHP, hemochromatosis)
• Facies (abnormal in DiGeorge syndrome, PHP)
Criteria
• Hyperpigmentation (addisson disease, hemochromatosis)
• Total calcium less than 8.0 mg/dL (2 mmol/L) or
• Rickets (vitamin D related cause, reanl failure)
• Ionic calcium less than 1.1 mmol/L
Correction for albumin levels
•
Corrected calcium mg/dL = Total calcium mg/dL + 0.8 × (4- albumin g/dL)
ETIOLOGY
Etiology
Hypocalcaemia
Hyperphosphatemia
Tumor lysis
Hemolysis
Renal failure
Investigations
• Serum phosphate
• Low or normal- Vitamin D deficiency, VDDR, Hypomagnesemia
• High- Release of intracellular phosphate, renal failure,HP, PHP
APPROACH
Approach to diagnosis
Phosphate
Low High
1α hydroxylase deficiency Calcitriol resistance
Management
Intravenous
Initial calciumshould
investigations shouldinclude
be administered in all children
serum phosphate, with suspected
creatinine and albumin
symptomatic hypocalcemia
levels after exclusion of phosphate after obtaining blood
load. sample. Calcium
Hypophsophatemia gluconateexcludes
2
ml/kg of 10% solution (provides 9 mg Ca++ per ml) should be infused slowly over
inefficient PTH action and points to vitamin D related causes or
10 minutes under cardiac monitoring. Care should be taken to avoid
hypomagnesemia. 25OHD levels should be done if magnesium levels are
extravasation of calcium as this may cause dermal necrosis. Intravenous calcium
normal. Low 25OHD
should be reserved for indicates vitamin
asymptomatic D deficiency
individuals while
with calcium levelsnormal 25OHD in
lower than
this6.0setting suggests
mg/dl (Ionic VDDR,
calcium less which
than 0.8 canFollowing
mmol/L). be classified with 1,25
initial correction,
dihydroxyvitamin
calcium gluconate D should
(low bein continued
1 α hydroxylase
in a dose of deficiency
75-80 mg/kg/day high(2 in calcitriol
ml/kg
resistance). Hyperphosphatemia
every 6 hourly). This should ideally in be
a child withinhypocalcemia
dissolved maintenance fluids.suggests
Care renal
dysfunction or ineffecient
should however be taken PTH function.
to not Normalgluconate
mix calcium creatinine
withinphosphate
this setting
or points
bicarbonate to avoid crystallization in the IV tubing. Intravenous
to inefficient PTH action, which could be classified with PTH levels (low in HPcalcium should
and not bein
high mixed
PHP) with phosphate or bicarbonate as this may lead to crystallization in
the IV tubing. The dose of calcium gluconate is decreased to 75% on day 2 and
50% on day 3. Intravenous calcium should be replaced with oral calcium after
stabilization and initiation of specific therapy. Magnesium sulfate (0.1 ml/kg of
MANAGEMENT
Acute
Intravenous calcium should be administered in all children with suspected
symptomatic hypocalcemia after obtaining blood sample. Calcium gluconate 2
ml/kg of 10% solution (provides 9 mg Ca++ per ml) should be infused slowly
over 10 minutes under cardiac monitoring. Care should be taken to avoid
extravasation of calcium as this may cause dermal necrosis. Intravenous
calcium should be reserved for asymptomatic individuals with calcium levels
lower than 6.0 mg/dl (Ionic calcium less than 0.8 mmol/L). Following initial
correction, calcium gluconate should be continued in a dose of 75-80 mg/kg/
day (2 ml/kg every 6 hourly). The dose of calcium gluconate is decreased to
75% on day 2 and 50% on day 3. Intravenous calcium should be replaced with
oral calcium after stabilization and initiation of specific therapy. Magnesium
sulfate (0.1 ml/kg of 50% solution, 12 hourly for four doses IM) is indicated in
children with refractory hypocalcemia.
Long term
• Vitamin D deficiency
• Calcitriol (20-40 ng/kg/day)/alpha D (40-60 ng/kg/day) for 3 days
• Cholecalciferol (300000 IU) over five days
• Calcium carbonate (50 mg/kg/day in three divided doses)
• Hypoparathyroidism
• Calcitriol (20-40 ng/kg/day)/ alpha D (40-60 ng/kg/day)
• Calcium carbonate (50 mg/kg/day eight hourly, avoid phosphate)
• Magnesium (50 mg/kg/day) if hypomagnesemia present
• Target calcium- 7.6-8.0 mg/dl (1.9-2.0 mmol/L)
• Hypomagnesemia
• Intramuscular magnesium sulphate- 0.1 ml/kg for three days
• Oral magnesium sulphate (50-100 mg/kg/day)
Physiology
An understanding of vitamin D physiology is mandatory to plan preventive and
therapeutic strategies for vitamin D deficiency.
calcium. Thus serum calcitriol levels may be low, normal or high in children
with vitamin D deficiency making it a highly unreliable marker of vitamin D
status.
Vitamin D preparations
Vitamin D- Vitamin D has long half life (2-4 weeks) and is deposited in the
adipose tissue to replenish vitamin D store in the body. Ergocalciferol and
cholecalciferol have similar biological actions; cholecalciferol however is more
potent in increasing vitamin D stores in the body. Vitamin D is the preparation
of choice for prevention and treatment of vitamin D deficiency. Long half life of
vitamin D results in a lag of action making it inappropriate in the treatment of
acute severe hypocalcemia due to vitamin D deficiency. V Oral absorption of
vitamin D is excellent and provides a smooth increase in vitamin D levels.
Injectable preparations are associated with wide fluctuations of vitamin D. This
along with high risk for hypervitaminosis limits the use of injectable
cholecalciferol to children with malabsorption.
Activated vitamin D- Vitamin D analogs have short half life (24 hours for
calcitriol and 48 hours for 1 hydroxy vitamin D). The effects of 1 hydroxy
vitamin D and calcitriol are similar expect in children with liver disease where 1
hydroxy vitamin D is ineffective. High potency of these analogs increases the
risk of hypercalcemia mandating careful monitoring of calcium levels. These
agents do not replenish body store of vitamin D and have no role in long term
treatment of vitamin D deficiency. Their use should be restricted to children
with acute hypocalcemia due to vitamin D deficiency and conditions
associated with impaired 1 hydroxylase action (renal disease, liver disease,
hypophosphatemic rickets, vitamin D dependent rickets, hypoparathyroidism
and pseudohypoparathyroidism).
Vitamin D supplementation
Indications- The aim of vitamin D supplementation is to ensure normal
calcium and bone homeostasis. Prevention of infantile hypocalcemia, rickets
and reduced peak bone mass due to vitamin D deficiency are the major goals
for the supplementation. This requires adequate vitamin D intake across
infancy, childhood and adolescence.
Dose- Estimates for daily requirement of vitamin D are based on the amount
required to achieve normal 25OHD levels. Most studies indicate that the
minimum amount of vitamin D required to achieve 25OHD levels greater than
20 ng/ml are 400 IU (10 microgram) during infancy and 600 IU (15 microgram)
between 1-18 years of age. The requirement may be as high as 1000 IU daily
in some children (Table 3).
Dose- Administration of 1000 IU daily for six weeks usually increases vitamin
D levels by 1 ng/ml. Vitamin D should be given at a dose of 1000 units daily
for neonates, 1000-2000 units daily for children between 1-12 months and
2000 IU daily from 1-18 years of age for six weeks. Children with low calcium
stores (rickets, hypocalcemia, high PTH or high alkaline phosphatase levels)
should receive 30-75 mg/kg/day of elemental calcium vitamin D to avoid
hypocalcemia due to increased calcium requirement during rapid
mineralization. Calcium deficiency is an important contributory factor in the
pathogenesis of rickets and combined calcium and vitamin D supplementation
is more effective than only calcium or vitamin D supplementation.
Vitamin D toxicity
Vitamin D has a broad therapeutic window and toxicity is unlikely with oral
vitamin D. High doses of vitamin D (600000 IU or more) and parenteral vitamin
D are associated with supraphysiological levels of vitamin D. Vitamin D levels
excess of 100 ng/ml are toxic. Vitamin D toxicity causes hypercalcemia,
hypercalcicuria and renal calcification. Symptoms include polyuria, abdominal
pain, vomiting, headache and altered sensorium. Treatment is guided towards
correction of hypercalcemia (hydration, diuresis) and oral corticosteroids (1-2
mg/kg/day of prednisolone for 2-4 weeks). Children with decreased 24
hydroxylase action cannot metabolize vitamin D and are at risk of
hypercalcemia following vitamin D supplementation (idiopathic infantile
hypocalcemia).
ETIOLOGY
Refractory Rickets
EVALUATION
History
• Onset
o Infancy- Vitamin D deficiency, rickets of prematurity, VDDR
o Early childhood- Vitamin D deficiency, VDDR, RTA, celiac disease
o Late childhood- Vitamin D deficiency, HPR, renal failure
o Adolescence- Vitamin D deficiency, renal failure, malabsorption
• Family history of rickets or consanguinity (HPR, VDDR, fanconi syndrome)
• Features of renal failure, malabsorption, liver disease, antiepileptic drugs
EXAMINATION
• Growth retardation- Renal failure, RTA, malabsorption
• Pattern of limb involvement
o VDDR - Frontal bossing, rachatic rosary, wrist widening
o Hypophosphatemic rickets- Lower limb, genu valgum
o Vitamin D deficiency- Both upper and lower limb
INVESTIGATIONS
Initial
• Calcium
• Low- Vitamin D deficiency, vitamin D dependent rickets
• Normal- Vitamin D dependent rickets, HPR, RTA
• High- Hyperparathyroidism, jansens, hypophosphatasia
• Phosphate
• Low- Hypophosphatemic rickets, RTA, VDDR
• Normal- VDDR, vitamin D deficiency, distal RTA
• High- Renal failure, pseudohypoparathyroidism
• Alkaline phosphatase
• High- Vitamin D deficiency, VDDR, HPR, renal failure
• Normal- Renal failure, skeletal dysplasia, renal tubular acidosis
• Low- Hypophosphatasia
Confirmatory
• Blood gas- Rickets with normal or low phosphate levels
• Severe metabolic acidosis suggestive of RTA
• Mild metabolic acidosis in secondary hyperparathyroidism
• Classification of RTA
• Urine pH- During acidosis
• Urine pH less than 5.5- Proximal RTA
• Urine pH greater than 5.5- Distal RTA
Figure 1 Ten-year-old girl with severe bony deformities, multiple fractures and
growth retardation. Investigations showed metabolic aciodsis (bicrabonate 12
mmol/L, BE −18 mmol/L) with normal anion gap (12 mmol/L).
Nephrocalcinosis, high urine pH during metabolic aciodosis (7.8) and low urine
to blood CO2 difference after alkalinization (6 mm Hg) confirmed the diagnosis
of distal RTA.
Approach to diagnosis
Phosphate
Low High
1α hydroxylase deficiency Calcitriol resistance
Management
Intravenous calcium should be administered in all children with suspected
symptomatic hypocalcemia after obtaining blood sample. Calcium gluconate 2
ml/kg of 10% solution (provides 9 mg Ca++ per ml) should be infused slowly over
10 minutes under cardiac monitoring. Care should be taken to avoid
extravasation of calcium as this may cause dermal necrosis. Intravenous calcium
should be reserved for asymptomatic individuals with calcium levels lower than
6.0 mg/dl (Ionic calcium less than 0.8 mmol/L). Following initial correction,
calcium gluconate should be continued in a dose of 75-80 mg/kg/day (2 ml/kg
every 6 hourly). This should ideally be dissolved in maintenance fluids. Care
should however be taken to not mix calcium gluconate with phosphate or
bicarbonate to avoid crystallization in the IV tubing. Intravenous calcium should
not be mixed with phosphate or bicarbonate as this may lead to crystallization in
the IV tubing. The dose of calcium gluconate is decreased to 75% on day 2 and
50% on day 3. Intravenous calcium should be replaced with oral calcium after
stabilization
Figure and initiationboy
2 Five-year-old of specific therapy.deformity.
with knee Magnesium Hypophosphatemia
sulfate (0.1 ml/kg of with
normal bicarbonate, calcium and PTH hormone suggested the diagnosis of
hypophosphatemic rickets.
MANAGEMENT
• Renal failure
• Calcitriol (20-40 ng/kg/day) or 1α hydroxy D (30-60 ng/kg/day)
• Calcium carbonate (50-75 mg/kg/day)
• Sodium bicarbonate (1-2 mmol/kg)
• Hypophosphatemic rickets
• Calcitriol (30-60 ng/kg/day) or 1α hydroxy D (40-80 ng/kg/day)
• Phosphate (40-60 mg/kg/day) in four to six doses, Joulie’s solution
(acidic, 30 mg/ml), neutral phosphate
• 1α Hydroxylase deficiency
• Calcitriol (20-40 ng/kg/day) or 1α hydroxy D (30-60 ng/kg/day)
• Calcium carbonate (50-75 mg/kg/day)
• Calcitriol resistance
• High dose calcitriol (200-400 ng/kg/day)
• Calcium carbonate (3.5-9.0 g/m2/day)
• Intravenous calcium infusion (0.8-1.4 g/m2/day in refractory cases)
• Distal RTA
• Bicarbonate- 1-2 mmol/kg/day (may require higher doses at onset)
• Potassium- 2-4 mmol/kg/day
• Thiazide diuretics (1-2 mg/kg/day) if persistent hypercalciuria
• Proximal RTA
• Bicarbonate- 4-6 mmol/kg/day
• Phosphate- 40-50 mg/kg/day in four to five divided doses
• Potassium- 2-4 mmol/kg/day
Further reading
DIAGNOSTIC CRITERIA
• Fating blood glucose ≥ 126 mg/dL (7 mmol/L)
• Post glucose blood glucose at 2 hr ≥200 mg/dL (11.1 mmol/L)
• In presence of classic symptoms random blood glucose ≥ 200 mg/dl
• HbA1C ≥ 6.5
! Preparation
✴Adequate carbohydrate intake for three days (150 g/m2/day)
✴Overnight fast
✴Anhydrous glucose (1.75 g/kg, maximum 75 g) as chilled liquid
✴Blood glucose at 0 and 120 minutes
Interpretation
Category Glucose tolerance test*
Fasting 2 hour
Normal < 100 mg/dL** < 140 mg/dL
IGT 100-125 mg/dl 140-199
Diabetes mellitus ≥ 126 mg/dL ≥200 mg/dL
Practice points
• Venous plasma glucose is recommended for diagnosis
• Whole blood glucose is 10% lower than plasma blood glucose
• Laboratory sample essential for diagnosing diabetes mellitus
• HbA1c- NGSP level 1 certified and standardized to DCCT assay
ETIOLOGY
Diabetes mellitus
EVALUATION
Clinical
• Onset
• Early infancy- KATP channel, transient neonatal DM
• Late infancy to childhood- Type 1 DM
• Adolescence- Type 1 DM, type 2 DM, MODY
• Presentation
• Acute with diabetic ketoacidosis- Type 1 (60-80%), T2DM (30%)
• Insidious- MODY, type 2 DM
Investigations
• Indications for disease classification
• Onset after puberty (likely to be type 2 DM or MODY)
• No ketoacidosis at diagnosis (likely to be type 2 DM or MODY)
• Obesity, acanthosis nigricans (likely to be type 2 DM)
• Abdominal pain, steatorhea (exocrine pancreatic disorder)
• Investigation
• Ultrasound abdomen (pancreatic calcification)
• C peptide- Marker of beta cell function
• Less than 0.6 pmol/L- Type 1 DM (rarely low in type 2 DM)
• More than 0.6 pmol/L- Type 2 DM, MODY and occasionally in type
1 DM with residual beta cell function. Repeated over 6-12 months.
• Fasting insulin
• Indications
• Onset during adolescence, obesity with acanthosis nigricans
• No DKA at diagnosis
• Asymptomatic individuals for screening of insulin resistance
Pubertal status
Pubertal
Pre-pubertal Obesity
Absent Present
DKA at diagnosis C peptide
Yes No
GAD, insulin antibody
CRITERIA
• Hyperglycemia- Blood glucose greater than 200 mg/dL
• Metabolic acidosis
• pH less than 7.3
• Serum bicarbonate less than 15 mmol/L
• Base excess more than −5 mmol/L
Pointers to diagnosis
• Acute diabetic presentation- Polyuria, polydipsia, weight loss
• Encephalopathy
• Acute abdomen
• Unexplained dehydration
• Acidotic breathing
Differential diagnosis
• Clinical
• Encephalopathy- CNS infection, malaria, poisoning
• Acute abdomen- Pancreatitis, appendicitis
• Dehydration- Gastroenteritis
• Tachypnea- Pneumonia
• Laboratory
• Hyperglycemia with acidosis without ketosis
• Renal failure
• Septicemia
EVALUATION
Initial- Airway, breathing, circulation, hydration, perfusion, BP
• Clinical
• Precipitating factor
• First presentation- Infection
• Known case- Missed insulin, infection, insulin pump malfunction
• Serum potassium
• Status
• Intracellular- Deficit (3-6 mmol/kg)
• Extracellular- Elevated (acidosis, insulin deficiency)
• Implication- Treatment associated withhypokalemia
• Reversal of metabolic acidosis
• Correction of insulin deficiency
• Plasma osmolality
• Status- Elevated (300-350 mOsm/kg)
• Estimation- Effective plasma osmolality
• Anion gap
• Status- Elevated (marker of plasma ketoacids)
• Anion gap = Na- Cl- HCO3
• Blood lactate
• Status- Normal (0.4-1.8 mmol/L)
• Implication- Lactic acidosis in DKA suggestive of cerebral edema,
infection, hemodynamic compromise
• Infection screening
• Status- Infection an important precipitating factor for DKA
• Investigations
• Complete blood examination
• Transient leucocytosis common in DKA
• Persistent leuckocytosis suggestive of infection
• Urine examination, Blood and urine culture
• Chest X ray if persistent tachypnea and chest signs
MANAGEMENT
• Fluid therapy
• Initial bolus normal saline 10 ml/kg
• Combination of deficit and maintenance
• Volume must not exceed 3-3.5 L/m2/day (risk for cerebral edema)
• Evenly distributed over 48 hours
• Insulin
• Timing- Should be started after rehydration as
• Blood glucose falls rapidly even without insulin
• Route
• Continuous intravenous infusion- Preferred route
• Avoid insulin bolus - No benefit, increased risk of cerebral edema
• Preparation
• Dissolve 50 units of regular insulin in 50 ml NS
• Avoid over dilute insulin (decreased potency)
• Flush tubing with insulin (insulin binds to plastic tube)
• Ensure separate intravenous line for insulin
• Change infusion set every 24 hours
• Use burette set if infusion set not available
• Electrolyte management
• Sodium
• Significant sodium deficit in DKA (4-6 mmol/kg)
• Attenuated rise in serum sodium a risk factor for cerebral edema
• Fluid choice in the initial 4-6 hours should be 0.9% isotonic saline.
• At no point of time should fluid of < 0.45 % NS should be used
• Potassium
• Significant potassium deficit in DKA (3-6 mmol/kg)
• Extracellular levels high due to acidosis and insulin deficiency
• Risk of life threatening hypokalemia during treatment
• Correction of insulin deficiency
• Phosphate
• Significant depletion (0.5-1 mmol/kg)
• Replacement not presently recommended routinely.
• MONITORING
• Clinical- Hourly
• Neurological status- Level of consciousness, pupil
• Hemodynamic status- Heart rate, blood pressure, respiratory rate
• Fluid input and output
• Laboratory
• Capillary blood glucose- Hourly
• Venous blood gas
• Electrolytes- Sodium, potassium, anion gap
• Plasma osmolality, blood ketone
• Expected response
• Blood glucose
• Hydration phase- Rapid decrease during initial treatment due to
• Rehydration and expansion of extracellular volume
• Decrease in counter regulatory hormones
• Increased glomerular filtration rate and urinary excretion
• Metabolic acidosis
• Recovery over 6-12 hours
• Persistent acidosis- Infection, lactic acidosis, cerebral edema
• Actions- Exclude infections, consider antibiotics
• Plasma osmolality
• Desired response- Gradual decrease
• Fall more than 2 mOsm/kg/hour risk factor for cerebral edema
• Serum sodium
• Desired- Increase by 3 mmol/L per 100 mg/dL fall in blood glucose
• Less increase is a risk factor for cerebral edema
• Ketones
• Rapid decrease in blood ketones
• Urine ketones may persist for up to 48 hour
Blood glucose
Persistent Resolved
Add dextrose in fluid SC insulin, stop infusion
Management plan
Initial management is directed towards assessing adequacy of airway,
breathing and circulation and correction of dehydration (normal saline 10 ml/kg
over one hour). Further fluid boluses should be given judiciously as level of
dehydration is usually overestimated in DKA. Following initial hydration, fluid
should be administered at a rate to replace maintenance and deficit
requirement over 48 hours (72 hours if plasma osmolality above 350 mOsm/
kg). Half-normal saline is recommended for treatment of DKA; normal saline
may be considered in the presence of hyponatremia (corrected serum sodium
less than 132 mmol/L) or high plasma osmolality (more than 350 mOsm/kg).
Potassium (40 mmol/L) should be added in the hydration fluid unless serum
potassium is above 6 mmol/L or ECG changes of hyperkalemia or anuria are
present. Insulin infusion should be started at a rate of 0.1 IU/kg/hour and
titrated to achieve desirable fall in blood glucose (50-100 mg/dL/hour). Insulin
should be continued till resolution of metabolic acidosis. 5% Dextrose should
be added once blood glucose is below 270 mg/dL (15 mmol/L) and increased
to 10% when blood sugar is below 200 mg/dL (11.1 mmol/L). Subcutaneous
insulin (0.25 IU/kg) should be given after correction of dehydration and
normalization of blood gas and sensorium. Insulin infusion should be
discontinued thirty minutes after the insulin injection. Mixed split insulin should
be started from the next meal with regular glucose monitoring.
Protocol
• Allow oral feed
• Insulin- 0.25 IU/kg regular subcutaneously after feed
• Discontinue insulin and fluid infusion 30 minutes after insulin
• Monitor blood glucose after one hour and two hourly for six hours
• Shift to ambulatory insulin therapy subsequently
COMPLICATIONS
Acute Chronic
Cerebral edema Growth hormone deficiency
Infection- Bacterial, fungal Mental retardation
Hypoglycemia Diabetes insipidus
Hypokalemia
Acute respiratory distress syndrome
Cerebral edema
• Incidence- 0.5-1.0% (radiological features present in most cases)
• Risk factors
• Patient related- Age less than 5 years, severe disease
• Treatment related
• Insulin- Insulin bolus, Multiple intravenous injections
• Fluid- Excessive volume (more than 4 L/m2/day), Hypo-osmolar fluid
(sodium concentration less than 60 mmol/L)
• Alkali treatment
• Early markers
• Fall in blood glucose more than 100 mg/dL/hour in continuation phase
• Fall in plasma osmolality by more than 2 mOsm/kg/hour
• Rise in serum Na less than 2.5 per 100 mg/dL fall in blood glucose
• Indicators to diagnosis
• Persistent metabolic acidosis
• Persistent hemodynamic instability
• Worsening in clinical condition after initial improvement
• Clinical features
• Early- Headache, vomiting, drowsiness, hypertension, bradycardia
• Late- Unconsciousness, focal deficits, papiledema, fixed dilated pupil
• Treatment
• Mannitol- 0.25-1 g/kg intravenous push or
• Hypertonic saline- 10 ml/kg of 3% saline over 10 minutes
• Fluid restriction- Reduce fluid rate to 50%
• Head end elevation
• Hyperventilation- Impending respiratory failure
• Prevention
• Avoid insulin bolus
• Fluid treatment
• Use fluid boluses judiciously
• Fluid replacement less than 4 L/m2/day
• Gradual correction in children with high plasma osmolality
• Avoid sodium bicarbonate unless pH less than 6.9
• Use normal saline in children with high plasma osmolality
STABILIZATION
• Exclude diabetic ketoacidosis (blood gas and ketones)
• Site of care
• In patient preferred
• Ambulatory care in children older than 2 year, without DKA
• Initial management
• Insulin
• Dose-Guided by pubertal status
• Pre-pubertal- 0.6 unit/kg/day
• Pubertal- 0.8 unit/kg/day
• Post-pubertal- 1.0 unit/kg/day
INSULIN PREPARATIONS
Rapid acting analogs (Lispro, Aspart, Glulisine)
• Do not form hexamers after subcutaneous administration
• Rapid onset of action (5-10 minutes after injection)
• Advantage- Can be given with meal, better post-meal control
• Disadvantage- High cost, inadequate lunch time on two injection regimen
• Indications
• As bolus insulin in basal bolus regimen
• As post meal insulin in toddlers with unpredictable eating habits
• Continuous subcutaneous insulin infusion (insulin pump)
• Nigh time short acting insulin in children on mixed split regimen
• Sick day management
• Disadvantage
• Gap of 30 minutes required between insulin and meal
• Post meal hyperglycemia
• Nocturnal hypoglycemia with mixed split regimen
• Indications
• Treatment of diabetic ketoacidosis
• As short acting insulin in mixed split regimen
• Sick day management
• As bolus insulin in basal bolus regimen if analogs not available
Detemir
• Low intra individual variability in insulin absorption
• Advantage- Predictable insulin levels, may be mixed with other insulins
• Disadvantages- High cost, not peak less like glargine
• Indications- Basal insulin in basal bolus
INSULIN REGIMENS
• Mixed split regimen (two or three injection per day)
• Combination of short and intermediate acting insulin
• Regimens
• Conventional regimen
• Injections- Twice a day (before breakfast and dinner)
Long acting
• Dose distribution
• Basal insulin (bedtime)- 40-50% of daily dose
• Bolus insulin (pre-meal)- 50-60% of daily dose
Breakfast Lunch Dinner Bed time
• Advantages- Flexibility for meal timing, better control
Long acting
EDUCATION
Category Should know Can know Optional
Disease Life-long disease Role of insulin Glucose
Normal outcome Type 1 vs 2 DM homeostasis
possible Pathophysiology Disease
Complications classification
Autoimmunity
Associations
Treatment Insulin only treatment Insulin preparations Insulin regimens
Daily injections Time course Insulin pumps
No alternative medicine Injection devices Newer insulin
Hope for the future
Skills Insulin storage Glycemic targets Physical activity
Drawing up, mixing Insulin changes Ketone monitoring
Insulin injection Time sheet Glucagon injection
Nutrition Healthy eating RDA for age Carbohydrate
Avoid simple sugars Food exchanges counting
Mid meal snacks High fiber intake Insulin to carb ratio
Glycemic index
Follow-up Honey-moon phase Role of HbA1c DKA prevention
Hypoglycemia Complication CBGM
Sick day guidelines Physical activity
NUTRITIONAL RECOMMENDATIONS
MONITORING
• Self monitoring
• Recommended- Before each meal and at bedtime
• On different times of the day
• Post meal values if hemoglobin A1c high
• Suggested interventions according to pre-meal BG
Follow-up- Three-monthly
History
• Blood glucose, hypoglycemia, injection site
• Dietary history, physical activity
• Pointers to poor control- Failure to thrive, pubertal delay, polyuria
Examination
• Growth and pubertal status, blood pressure
• Injection sites- Lipohypertrophy, lipodystrophy
• Foot examination- Deformities, callus, infection, toe nail
• Oral examination- Caries, periodontitis
• Joint mobility
SPECIAL CIRCUMSTANCES
Children younger than five years
Consideration Management implications
Higher risk of hypoglycemia Higher glycemic targets
Unpredictable eating habits Consider rapid acting insulin after meals
Minor dose adjustments Dilute insulin with diluent (U 10)
Less subcutaneous fat Narrow gauge, short needle (8 mm)
Persistent hypoglycemia
• Immediately after diagnosis- Decrease insulin dose
• After long standing disease- Exclude
• Adrenal insufficiency
• Hypothyroidism
• Celiac disease
• Nephropathy with decreased insulin excretion
Procedures
• Major procedure
• Exclude diabetic ketoacidosis (surgery after correction of DKA)
• Insulin infusion
• Initially at 0.02 unit/kg/hour
• Modify by 10% to achieve BG of 90-180 mg/dL (5-10 mmol/L)
• Continue insulin infusion till on intravenous fluids
• Switch to subcutaneous insulin after discontinuation of intravenous
fluids and normal oral acceptance
• Minor procedure
• Admit overnight, post as first case in the morning
• Blood glucose at 6 AM
• Less than 72 mg/dL- Intravenous dextrose drip
• 72-180 mg/dL- Oral sugar containing drink 10 ml/kg
• More than 10 mmol/L- No intervention
• Give 10% of total daily dose of insulin prior to procedure
• Monitor blood glucose frequently
• Switch to subcutaneous insulin once accepting orally
Blood < 1 mmol/L Blood 1-1.5 mmol/L Blood > 1.5 mmol/L
Urine- Negative Urine- Trace or small Urine- Moderate or large
Extra insulin 5% of TDD Extra insulin- 10% of TDD Extra insulin- 20% of TDD
Blood glucose after 2 hr Blood glucose after 1 hour Hourly glucose, ketone
Consider hospitalization
TDD- Total daily dose
Pointers to diagnosis
Autonomic Neuroglucopenic
Sweating Headache
Palpitations Confusion
Hunger In-cordination
Tremor Drowsiness
Seizures
• Severe hypoglycemia
• Home- Glucagon 15 µg/kg to a maximum dose of 1 mg
• Hospital- Intravenous dextrose- 200 mg/kg (2 ml/kg of 10% dextrose)
COMPLICATION SCREENING
Complication Indication Procedure Management
Retinopathy Dilated fundus Better control
Prepubertal Duration more than 5 year* LASER
Pubertal Duration more than 2 year*
Nephropathy Urine albumin Better control
Prepubertal Duration more than 5 year* ACE inhibitor
Pubertal Duration more than 2 year* Control BP
Thyroid At diagnosis then 2 yearly TSH Thyroxin
Hyperlipidemia At diagnosis then Lipid profile Statin
Pre pubertal Five yearly
Pubertal Two yearly
In the history of diabetes, invention of insulin by Banting and Best in 1920 was
considered as one of the greatest medical breakthroughs of the 20th century.
Before that, only starvation and death was the future for patients with type 1
diabetes. We have already come a long way in the management of type 1
diabetes and we still have a long way to go. The future of T1DM as well as
that of children with the condition appears bright thanks to the tremendous
advances in science and medicine. There are ever expanding hopes for
disease prevention, near physiological insulin replacement, minimally invasive
insulin delivery systems and potential cure. However despite this leap in the
science of diabetes, the art of managing children and adolescents with
diabetes remains a day to day challenge. Central to this is the need to tailor
the management according to the changing requirements of different phases
of life. The Diabetes Control and Complications Trial (DCCT) showed that in
type 1 diabetes mellitus, compared with conventional daily or twice-daily
insulin therapy, intensive insulin therapy (at least three daily insulin injections
or pump treatment) resulted in a significant decrease in micro vascular
complications, and any improvement in HbA1c resulted in a decreased risk of
complications. Intensive insulin therapy is best delivered with multiple daily
injections [MDI] or basal bolus therapy.
INVASIVE CBGM
NON-INVASIVE CBGM
Electrochemical enzyme sensor- This device is worn like a wristwatch
(GlucoWatch Biographer). Glucose is extracted non-invasively via reverse
iontophoresis for collection in gel disc biosensor.
ADVANTAGES
CBGM are superior to intermittent glucose monitoring in the identification of
post-meal hyperglycemia and asymptomatic hypoglycemia. Intermittent blood
glucose monitoring provides spot values whereas CBGM provides a graphic
reading over a 72 hour period. They are useful adjuncts to pump therapy.
Recent studies have shown improved glycemic control and higher patient
satisfaction with CBGM use in children on insulin pumps.
DISADVANTAGES
These systems are relatively imprecise and need to be validated with 3 – 4
capillary blood glucose measurements per day. They have to be continuously
worn which some of them might find it uncomfortable. Otherwise, their only
disadvantage is their high cost.
PRINCIPLE
Insulin pumps are electronic devices that inject insulin using a subcutaneously
inserted catheter. The pump delivers insulin at a preset rate (basal rate) and
gives insulin boluses along with meals (meal bolus) and in the presence of
hyperglycemia (correction bolus). Rapid acting insulin analogs are used in
CSII due to their rapid onset and short duration of action.
PATIENT SELECTION
Insulin pumps are indicated in children with inadequate glycemic control
despite multiple daily injections. They are particularly helpful under following
circumstances:
1. Infants and toddlers with erratic eating habits
2. Recurrent unpredictable hypoglycemia
3. Active life style with inconsistent meal times and
4. Excessive glycemic excursions
Initiation of insulin pump therapy requires intense education of the child and
family spread over multiple sessions. Close review of blood glucose logs by
health professionals during the first couple of weeks is highly recommended.
Patient education
A comprehensive review of patient and family’s knowledge about diabetes
should be undertaken. Following issues specific for insulin pumps need to be
stressed.
• Different modes, setting of basal rates, retrieval of data
• Technique of catheter insertion
• Carbohydrate counting
• Calculation factors
• Management during sick day and exercise
• Management of hyperglycemia.
The total daily dose of insulin should be reduced by 20% while starting on
insulin pump because the requirement is low. The calculation of basal dose,
insulin to carbohydrate ratio and correction factor is based on the total daily
dose as highlighted below.
Basal dose – Total daily basal dose should be 40-50% of the total daily dose
(TDD). This should initially be evenly distributed throughout the day. This is
then modified according to premeal blood glucose levels in quantum of 10%.
Subsequently different basal rates may be required for different periods of the
day.
Lower basal rates are usually required in the late evening/midnight (between 8
PM and 2 AM) and during the day (between 10 AM and 4 PM). Higher basal
rates are often needed in the early evening (from 4 PM to 8 PM) and morning
hours (from 2 AM to 10 AM). Many prepubertal children need a higher basal
rate late in the evening (9 PM to 12 midnight).
FOLLOW-UP
DOSE MODIFICATIONS
Glucose monitoring should be done at least four times a day (pre-meals and
bed time). More frequent monitoring may be required in children with poor
control. The basal rate is adjusted according to pre meal blood glucose levels.
Post meal blood glucose provides information about the appropriateness of
meal bolus. Insulin to carbohydrate ratio should be reduced in children with
persistent post-meal hyperglycemia.
HYPERGLYCEMIA MANAGEMENT
Individuals with persistent hyperglycemia 1 hour after the bolus should receive
short or rapid acting insulin using a pen or syringe (0.25 unit/kg). The dose of
rapid acting analog should be repeated every 4 hours (6 hours for short acting
insulin) till the pump failure has been corrected. The pump should be carefully
examined for battery status, the amount of insulin in the reservoir and site and
patency of the catheter. Catheter should be removed and new tubing should
be inserted if these measures are unsuccessful.
ADVANTAGES
Insulin pumps are associated with better glycemic control, lower insulin dose
resulting in reduced hypoglycemia and weight gain and greater flexibility in life
style. A meta-analysis of 12 randomized controlled trials, mainly in adults but
with some adolescents, reported that pump patients had lower mean HbA1c
by 0.51% and lower insulin requirements by 14% compared to patients on
optimized insulin injections. Overall, hypoglycemia is much less frequent with
pumps than in intensive injection regimens. Observational studies have
reported significant improvements in HbA1c, reduction in hypoglycemia and
higher patient satisfaction. The capability of insulin pump to react to real time
changes in blood glucose (closed loop system) is expected to provide
significant advancement in the insulin treatment.
DISADVANTAGES
ILLUSTRATIVE CALCULATIONS
Insulin plan for a child on split-mix regimen on 50 units insulin per day
· Initial calculations
! Total daily dose on subcutaneous insulin = 50 units
! Total daily dose on insulin pump (reduce dose by 20%)= 50 –
10 = 40 units
! Total daily basal dose (50% of daily dose) = 20 units
! Initial hourly basal insulin rate = 20 ÷ 24 = 0.8 unit/hour
! Insulin to carbohydrate ratio = 500 ÷ 40 = 12.5 g/unit
! Correction factor = 1800 ÷ 40 = 45 mg/dL/unit
· Meal bolus
! Parameters
! Pre-meal blood glucose = 270 mg/dL
! Anticipated carbohydrate intake = 75 g
! Calculation
Insulin required to correct BG = (270 – 180) ÷ 36 = 2.5 units
Insulin required for carbohydrate intake = 75 ÷ 12.5 = 6 units
Bolus = Correction factor + Correction = 6 + 2.5 = 8.5 units
· Correction bolus
! Parameters
Blood glucose two hour post-meal = 305 mg/dL
Pre-meal insulin 5 units
! Calculation
Residual insulin – 30% used per hour (2 units left at two hours)
Correction dose = (305 – 180) ÷ 42 = 3 units
Correction required = (3 – 2) = 1 unit
FUTURE OF T1DM
Living with T1DM is not the same as a decade ago and would not be the same
a decade later. The changes in the management of the condition are
happening at a brisk pace and it is important for physicians caring for T1DM to
keep abreast with them. Some of these advances are highlighted below.
Hope for prevention- The efforts for prevention of T1DM have completed a
full circle. Large studies have failed to show benefit of oral and subcutaneous
insulin, nicotinamide and immunosuppressive agents in preventing the
development of T1DM. The outcome of ongoing research using inhaled
insulin, vitamin D analogs, delayed cow milk exposure and newer
immunosuppressant is also far from encouraging.
trials of oral insulin IN-105 are ongoing and if successful would be a welcome
development for children with T1DM. Ultra long acting insulin analogs injected
once a week are in the pipeline and would further reduce the burden of T1DM.
Finally the development of sensor augmented pump therapy is expected to
achieve the long sought goal of developing artificial pancreas.
Hope for cure- Given the need for lifelong treatment in T1DM, it is only
expected that most patients seek permanent cure from the malady.
Unfortunately no such cure is available at the moment. The efforts at
developing cure for T1DM are directed towards reversing the autoimmune
process or restoration of β cell mass. Immunosuppressive agents (steroids,
cyclosporine A, azathioprine, anti-thymocyte globulin and anti-CD3 antibody)
have resulted in only partial and transient response. Moreover these strategies
are limited by significant adverse effects. Recently autologous stem cell
transplant after high dose immunosuppression has been utilized to reset the
immune process with some success in young adults with T1DM. These
strategies are limited by the fact that over 95% of β cell mass is destroyed by
the time of diagnosis of the disease.
The other, more appealing approach for cure for T1DM involves restoration of
β cell mass using pancreatic, islet cell or stem cell transplantation. Pancreatic
transplant is a major endeavor requiring long term immunosuppression and
clearly out of question for adolescents with T1DM. Studies have failed to show
long term remission with islet cell transplantation T1DM. There is currently no
evidence of efficacy of stem cell therapy in the cure of T1DM. Thus while
parents should be counseled about the feasibility of cure of T1DM in the fore
seeable future, they should be cautioned about the tall claims of cure of the
disease by mushrooming stem cell centers.
5.5 Hypoglycemia
Neonatal hypoglycemia
SGA- Small for gestational age, GSD- Glycogen storage disease, UAC- Umbilical
artery catheter, BW- Beckwith Weidemann syndrome, GDH- Glutamate
dehydrogenase, GCK- Glucokinase
POINTERS TO DIAGNOSIS
Clinical
! Lethargy
! Hypotonia
! Seizures
! Jitteriness
! Hypothermia
! Cardiac failure, respiratory distress
! Recurrent apnea
Screening indications
• Small for gestational age (weight < 10th percentile for age)
• Large for gestational age (weight > 90th percentile for age)
• Prematurity (period of gestation less than 34 weeks)
• Infant of diabetic mother
• Birth asphyxia
• Rh incompatibility
• Cardiac disease
• Micropenis
EVALUATION
History
• Birth weight
• Low- Small for gestational age
• LGA - Infant of diabetic mother, BW syndrome, hyperinsulinism
• Onset
• Immediate postnatal period- Hyperinsulinism, hypopituitarism
• After initiation of feeds- Galactosemia, organic acidemia
• Around three weeks of life- Congenital adrenal hyperplasia
• Glucose requirement
• Supra physiological (>12 mg/kg/minute)- Hyperinsulinism
• Physiological (6-12 mg/kg/minute)- Substrate defect
• Perinatal history
• Pregnancy induced hypertension, diabetes mellitus
• Treatment with beta agonist, thiazide, Rh incompatibility
• Birth asphyxia, features of septicemia
Examination
Pointer Diagnosis
Micropenis Hypopituitarism, DAX1 mutation
Hyperpigmentation CAH, DAX1 mutation
Genital ambiguity Congenital adrenal hyperplasia
Midline defect, blindness Hypopituitarism
Hepatomegaly Hyperinsulinism, BW syndrome, GSD
Cataract, jaundice Galactosemia
Investigation
Indications
• Supra-physiological glucose requirement (GIR >12 mg/kg/minute)
• Persistent hypoglycemia (seventh postnatal day)
• No underlying cause
• Blood gas
• Acidosis- Organic acidemia, adrenal insufficiency
• Normal- Hyperinsulinism
Confirmatory investigations
• Serum insulin
• Indication- Hypoketotic hypoglycemia, negative urine RS
• Considerations
• Should be obtained in the presence of hypoglycemia
• Sample should be refrigerated immediately
• Insulin should be undetectable during hypoglycemia
• Hyperinsulinism- insulin detectable during hypoglycemia
• GALT assay
• Indication- Hypoketotic with positive urine RS
• Interpretation- Low levels in galactosemia
• Hyperinsulinism
• Criteria- When blood glucose < 2.8 mmol/L, 50 mg/dL
• Detectable insulin (more than 2 µU/ml)
• Blood β hydroxybutyrate less than 2 mmol/L
• Increase in blood glucose be more than 30 mg/dL (1.7 mmol/L) 30
minutes after glucagon injection (30 µg/kg)
• Evaluation
• Onset
• Early- Infant of diabetic mother, KATP defect
• Late- GDH, GCK mutation
• Severity
• Mild- GDH, GCK mutation and focal form
• Severe- KATP channel defect and diffuse form
• Macrosomia
• Present- IDM, BWS, KATP defect, diffuse form
• Absent- Prolonged form, GDH or GCK mutation
APPROACH
Hypoglycemia work-up should be restricted to neonates with severe (glucose
requirement greater than 12 mg/kg/minute), persistent (beyond one week) or
unusual (in the absence of identifiable cause or risk factors) hypoglycemia.
Critical samples should be obtained during the episode of hypoglycemia. The
processing of these samples is guided by blood lactate, urine ketones and
reducing substances. Assessment of ketone production is the first step of
evaluation of neonatal hypoglycemia. All neonates with hypoglycemia are
expected to produce ketone bodies unless ketogenesis is defective (fatty acid
oxidation defect) or suppressed (hyperinsulinism or galactosemia). Urine
reducing substances should be measured in neonates with hypoketotic
hypoglycemia to identify galactosemia. Hypoketotic hypoglycemia without
urinary reducing substances is a pointer to hyperinsulinism and should be
confirmed by serum insulin levels. Normal insulin levels in this setting indicate
the diagnosis of fatty acid oxidation defect. Neonates with ketotic
hypoglycemia should be evaluated for endocrine deficiencies (growth
hormone and cortisol) and organic acidemia. GSD is a rare cause of ketotic
hypoglycemia in the neonatal period and should be considered after exclusion
of other causes. Initial evaluation of a neonate with hyperinsulinism should be
directed towards identifying transient (infant of diabetic mother, maternal beta
agonist treatment, high umbilical artery catheterization) and prolonged causes
Negative
Positive
Reducing substances
Serum lactate
• Stabilization
• Dextrose- Glucose infusion rate (GIR)- 6 mg/kg/minute
• Monitoring
• Blood glucose 30 minutes after infusion and hourly
• Target blood glucose- Above 60 mg/dL (3.3 mmol/L)
Symptomatic Asymptomatic
Specific
Hyperinsulinism
• Medical treatment
• Diazoxide- Potassium channel opener
• Initial dose- 15 mg/kg/day in three divided doses then 5-20 mg/kg/
day in three divided doses
• Combination with hydrochlorothiazide (4-8 mg/kg/day) due to
synergistic effect on potassium channel and reduced fluid retention
• Adverse effects- Fluid overload, cardiac failure, hypertrichosis
• Efficacy- Dependent on clinical form; overall 20-50%
• KATP channel defect- Very poor (less than 10%)
• Diffuse form- Less than 40%
• Focal form, GDH, GCK defect- More than 70%
• Prolonged hyperinsulinism- 80-100%
• Surgical treatment
• Indications- Focal lesion, KATP channel mutation, lack of response to
diazoxide
• Procedure
• Focal form- Focal resection
• Diffuse form
• Initial procedure- Subtotal pancreatectomy (95%)
• Recurrence- Total pancreatectomy (99%)
• Response
• Focal resection- Good response
• Diffuse form- Recurrence in 30-50% cases
• Prolonged hyperinsulinism
• Diazoxide (5-15 mg/kg/day) till six months
• Discontinue diazoxide with monitoring of blood glucose
• No hypoglycemia- Monitor blood glucose off diazoxide
• Hypoglycemia- Continue diazoxide
POINTERS TO DIAGNOSIS
• Seizures
• Encephalopathy
• Episodic ataxia
ETIOLOGY
Important causes
Age group Etiology in order of prevalence
Late infancy Hyperinsulinism, GSD, hypopituitarism
Early childhood Adrenal insufficiency, FAO defect, GSD
Late childhood Adrenal insufficiency, FAO defect, insulinoma
Adolescence Insulinoma, adrenal insufficiency
33.2 Etiology
Glycogenolytic defect
Glucose 6 Phosphatase
Debranching enzyme
Insulin independent Hyperinsulinism
Phosphorylase
Fatty acid oxidation Endogenous
defect Genetic- GCK, GDH
Gluconeogenic defect
Reye syndrome Sporadic- Focal form
PEPCK, FDPase
IGF 2 excess Insulinoma
Galactosemia
Hepatoblastoma Dumping syndrome
Fructose intolerance
Wilms tumor Exogenous
IGF 2- Insulin like growth factor II, GCK- Glucokinase, GDH- Glutamate
EVALUATION
dehydrogenase, PEPCK- Pyruvate pyrophosphate carboxykinase, FDPase- Fructose 1,
History
• 6Gap
Diphosphatase
between meal and hypoglycemia
• Less than 2 hours- Galactosemia, HFI, dumping syndrome
• 2-4 hours- Hyperinsulinism
• 4-6 hours- GSD I
• 6-10 hours- GSD, gluconeogenic defect
• Prolonged fasting- FAO defect, accelerated starvation
• Course
• Acute transient- Reye, toxin, insulin, oral hypoglycemic agents
• Acute, persistent- Hyperinsulinism
• Chronic- GSD, gluconeogenic defect, fructose intolerance
• Recurrent- Accelerated starvation, FAO defect
• Glucose requirement
• Supra physiological (> 12 mg/kg/min)- Hyperinsulinism
• Physiological (6-12 mg/kg/minute)- Substrate defect
Examination
• Hepatomegaly- GSD, FI, FAO defect, gluconeogenic defect
• Cataract- Galactosemia, fructose intolerance
• Hypotonia- GSD, FAO defects
• Pigmentation- Adrenal insufficiency
• Abdominal lump- Hepatoblastoma, wilms tumor
• Renomegaly- GSD I
• Eruptive xanthoma- GSD I, gluconeogenic defect
• Jaundice- Liver disease, fatty acid oxidation defect
Investigations
• Critical samples
• In the presence of hypoglycemia- Prior to dextrose bolus
• In the absence of hypoglycemia
• Diagnostic fast- Start overnight duration dependent on age
• Less than 6 months- 12 hours
• 6-12 months- 18 hours
• More than 1 years- 24 hours
• Glucose monitoring- Initially two hourly than hourly
• Critical samples when blood glucose < 2.8 mmol/L
• Screening investigations
• Ketone- Blood β hydroxybutyrate or urine ketosticks
• Ketotic (Urine negative or one + blood > 0.6 mmol/L)
• Accelerated starvation (diagnosis of exclusion)
• Adrenal insufficiency
• Glycogen storage disease
• Gluconeogenic defects
• Confirmatory investigations
• Serum insulin
• Indication- Negative urinary ketones and RS
• Any detectable insulin is significant
• GALT assay
• Indication- Hypoketotic hypoglycemia with urine reducing substance
• Low levels diagnostic of galactosemia
• Hyperinsulinism
• Serum ammonia (elevated in activating GDH mutation)
• Imaging- High resolution ultrasound, MRI, F18 DOPA PET
APPROACH
Collection of critical blood and urine samples before correction of
hypoglycemia is vital. The processing of the samples is decided according to
the results of blood lactate and urinary ketone and reducing substances.
Ketosis is a physiological response to hypoglycemia; hypoketotic
hypoglycemia suggests disorders associated with impaired ketogenesis (fatty
acid oxidation defects, hyperinsulinism, galactosemia and fructose
intolerance). Urine reducing substances should be measured in these children
to identify galactosemia and fructose intolerance. Insulin levels should be
measured in children with hypoketotic hypoglycemia with no urinary reducing
substances. Normal insulin level in this setting is suggestive of fatty acid
oxidation defects which should be confirmed by estimation of urinary organic
acids. Lactic acidosis in children with ketotic hypoglycemia suggests GSD I or
gluconeogenic defects. Diagnostic considerations in children with ketotic
hypoglycemia without lactic acidosis include milder GSD variants (GSD III and
VI), endocrine deficiencies (hypopituitarism and adrenal insufficiency) and
accelerated starvation. Accelerated starvation is a diagnosis of exclusion and
should be considered only after work-up for other causes are non-contributory.
Glucagon response
Present- GNG defect
Absent- GSD I
High
Present Absent Normal
Hyperinsulinism
GSD III, VI GH, Cortisol FAO defect
Low Normal
Endocrine deficiency Accelerated starvation
MANAGEMENT
• Hyperinsulinism
• Medical treatment
• Diazoxide- 10 mg/kg/day with hydrochlorothiazide (7-10 mg/kg/day)
• Glucagon- 1-10 µg/kg/hour as subcutaneous infusion
• Octreotide- 5-10 µg/kg 4-6 hourly
• Nifedipine- 0.7-2.5 mg/kg/day in two divided doses
• Surgical treatment- Focal resection in insulinoma
Further reading
1. In: Pediatric Endocrinology Eds: Sperling MA. WB Saunders 2002,
Philadelphia, 2nd Edn Pp 97-110.
2. Wolsdorf JI, Weinstein DA. Hypoglycemia in children. In: Pediatric
Endocrinology, Eds: Lifshitz F, Marcel Dekker, 2003, New York, 4th edition
Thyroid gland is derived from a median analge derived from pharyngeal floor
and paired lateral analges developed from fourth pharyngobronchial pouch.
Following fusion of the median and lateral analges the thyroid gland migrates
caudally to attain its position behind the thyroid cartilage in the neck.
Remnants of thyroid tissue in this tract of descent may persist as thyroglossal
cyst. Incomplete migration of thyroid gland results in ectopic thyroid, a
common cause of congenital hypothyroidism.
Hypothyroidism
Etiology
Congenital hypothyroidism may be due to disorders of thyroid development
(dysgenesis), defective thyroid hormone synthesis (dyshormonogenesis),
hypothalamic-pituitary defect (central hypothyroidism) and trans placental
passage of TSH receptor blocking antibody (TBA) (Figure 2).
Clinical Features
Features of congenital hypothyroidism are non specific resulting in delayed
diagnosis in the absence of neonatal screening. This mandates the need for
screening for the disorder. Pointers to the diagnosis of congenital
hypothyroidism include increased sleepiness, prolonged jaundice,
hypothermia, poor feeding, post-term gestation (period of gestation more than
42 weeks), constipation and cold intolerance. Examination usually reveals
wide anterior and posterior fontanel (greater than 1 cm), coarse skin and
Neonatal screening
Neonatal screening for hypothyroidism has been one of the most gratifying
preventive interventions in pediatrics and has resulted in prevention of mental
retardation in a large number of children world wide.
Evaluation
Comprehensive evaluation is mandatory for appropriate management; the
treatment should not be delayed if these facilities are not available.
Treatment
Immediate treatment of congenital hypothyroidism is mandatory to avoid
intellectual deterioration. Close monitoring of thyroid functions and
development is essential.
range (13-20 pg/ml) and TSH in the normal range (below 5 mU/L; ideally
between 0.5-2.0 mU/L). TSH levels may be persistently high for up to two
years of age in some infants due to reset of the hypothalamic-pituitary axis.
Special Conditions
Central hypothyroidism: Treatment of central hypothyroidism should be
initiated only after excluding and treating ACTH deficiency. This is important as
thyroid replacement may precipitate covert cortisol deficiency due to increased
metabolism resulting in disastrous consequences.
Further Reading
Acquired hypothyroidism
Central Primary
CNS insult
Infection
Radiotherapy
Neurosurgery
Trauma
Brain tumor
Craniopharyngioma
Germinoma
Glioma
Arachnoid cyst
Important
Important causes presenting
causes presenting after after infancy
infancy (inoforder
(in order of importance)
importance)
• Autoimmune (chronic lymphocytic thyroiditis CLT, hashimotos’s disease)
Autoimmune
• • Iodine (chronic lymphocytic thyroiditis CLT, hashimotos’s disease)
deficiency
• • Missed congenital hypothyroidism
Iodine deficiency
• Missed congenital hypothyroidism
• Mild dyshormonogenesis
• Thyroid hemi agenesis
• Ectopic thyroid
214 Grow Society
• Goiterogen exposure
Resource book Pediatric Endocrinology Protocols
POINTERS TO DIAGNOSIS
History
• Growth retardation
• Cold intolerance
• Chronic constipation
• Precocious puberty with growth retardation in girls
• Chronic urticaria
• Proximal myopathy
• Unexplained cardiac tamponade
• Delayed dentition
Examination
• Coarse skin
• Bradycardia with narrow pulse pressure
• Pseudohypertrophy of calf muscles
• Hypothermia unrelated to systemic illness
• Macro-orchidism
• Galactorrhea
• Papiledema
Investigations
• Hyperprolactinemia
• Hypercholesterolemia
• Low voltage ECG complexes
• Enlarged pituitary on neuro-imaging
Indications for screening for acquired hypothyroidism
• Autoimmunity- Type 1 DM, adrenal insufficiency, hypoparathyroidism
• Dysmorphic syndrome- Down, turner syndrome, klinefelter syndrome
• Growth hormone treatment
• Anterior pituitary defect
Confirmation of diagnosis
Free T4 TSH Interpretation
Normal Normal Normal
Normal High Compensated hypothyroidism
Low High Primary hypothyroidism
Low Low, normal Central hypothyroidism
EVALUATION
History
• Onset
• Early childhood- Dyshormonogenesis, ectopic thyroid, CLT
• Late childhood- CLT, dyshormonogenesis
• Adolescence- Chronic lymphocytic thyroiditis, iodine deficiency
Examination
• Goiter
• Absent- Thyroid dysgenesis, central hypothyroidism
• Present
• Soft- Iodine deficiency, dyshormonogenesis
• Firm, bossolated- Chronic lymphocytic thyroiditis
Investigations
• Antithyroid antibodies- Thyroid peroxidase antibody (TPO)
• Central hypothyroidism- MRI head, cortisol
MANAGEMENT
• Principles
• Exclude adrenal insufficiency in children CLT and central
hypothyroidism
• Initiate at low doses (50% of target) in long standing hypothyroidism
• TSH is the most sensitive indicator of thyroid status
• Indication of treatment
• Overt hypothyroidism- All cases
• Compensated hypothyroidism- Positive TPO antibody, goiter,
increase in TSH during follow-up
• Administration
• Oral, once daily, empty stomach (food interferes with absorption)
• Avoid co administration with- Iron, calcium, phosphate
• Monitoring
• Clinical- Growth, pubertal status, goiter size
• TSH - Target level- 0.4- 4 mU/L
• Six weeks after initiation of treatment
• Eight weeks after dose modification
• Symptoms of hypo or hyperthyroidism
• Six monthly for two years, annually thereafter
• Duration of treatment
• Dyshormonogenesis, dysgenesis- Life long
• Chronic lymphocytic thyroiditis
• Non-goitorus- Life long
• Goitorus- Stop after resolution of goiter, TSH after six weeks
• High- Life long treatment
• Normal- Follow-up with TSH three monthly for one year
Further reading
1. Dallas JS, Foley TP Jr. Hypothyroidism. In: Pediatric Endocrinology, Eds:
Lifshitz F, Marcel Dekker, 2003, New York, 4th edition Pp 371-392.
2. Fisher DA. Disorders of the thyroid in the newborn. In: Pediatric
Endocrinology Eds: Sperling MA. WB Saunders 2002, Philadelphia, 2nd
Edn. Pp 161- 286
6.3 Hyperthyroidism
ETIOLOGY
Congenital
Acquired hyperthyroidism
POINTERS TO DIAGNOSIS
History
• Palpitations, increased appetite and weight loss, tremor, heat intolerance
• Irritability unrelated to metabolic and neurological cause
• Behavioral abnormality- Anxiety, insomnia, emotional lability
• Advanced linear growth
• Unexplained diarrhea
• Periodic paralysis and rarely unexplained fever
Examination
• Tachycardia, wide pulse pressure and high output cardiac failure
• Tremors
• Exophthalmos
• Proximal myopathy
• Rarely hepato-splenomegaly and jaundice without intrauterine infections
EVALUATION
• Clinical
• Hyperthyroidism in mother (neonatal graves disease)
• Family history (activating mutations of thyroid receptor)
• Onset
• First two days- Neonatal graves, TSH receptor activating mutations
• Around 10 days- Neonatal graves, antithyroid treatment to mother
• After 15 days- Simultaneous passage of TRA and TBA antibodie
• Chilhood- Graves disease, activating mutations of TSH receptor
• Adolescence- Graves disease, hashitoxicosis, functional adenoma
• Course
• Self limiting- Subacute thyroiditis, chronic lymphocytic thyroiditis
• Non-remitting- Graves disease, activating TSH receptor mutation
• Thyroid enlargement
• Tender- subacute thyroiditis
• Nodular enlargement- Toxic nodule
• Diffuse with pebbly consistency- Chronic lymphocytic thyroiditis
• Diffuse- Graves disease, pituitary resistance to T3, TSHR mutation
High Low
Thyrotroph adenoma Thyroid scan
Pituitary resistance to T3
MANAGEMENT
• Non-specific
• Propanolol- 1-2 mg/kg/day in three divided doses
• Prednisolone- 1-2 mg/kg/day in two divided doses
• Iodine preparations- Severe thyrotoxicosis, sodium ipodate 100 mg/d
Table Agents effective in hyperthyroidism
Agent Mechanism of action Dose
Propanolol Suppression of sympathetic features 1-2 mg/kg/day
Propyl thiouracil Decreased T4 to T3 conversion* 5-10 mg/kg/day
Prednisolone Decreased T4 to T3 conversion* 1-2 mg/kg/day
Sodium iopadate Decreased T4 to T3 conversion* 100 mg/day
* Inhibitor of type 1 mono deiodinase
Specific
Neonatal graves disease
• Antenatal
• Monitor thyroid function and TRAbs in mother
• Titrate anti thyroid doses to achieve high normal free T3
• Fetal monitoring
• Tachycardia- Increased antithyroid drugs in mother
• Cardiac failure- Digitalis to mother
• Postnatal
• Risk 1-3% of mothers with graves disease
• Onset
• Usually by two days
• Delayed with anti thyroid drugs and TSH receptor blocking antibody
• Duration- 3-12 weeks (half life of TRA is 2 weeks)
Acquired
• Thyroid storm
• General measures
• Ensure normal airway, breathing and circulation
• Correct hyperthermia, precipitating factors
• Monitor for cardiac arrhythmias, digitalis for cardiac failure
• Specific treatment
• Carbimazole- 0.5-1 mg/kg/day in three divided doses
• Propanolol- 1-2 mg/kg/day in three divided dose
• Prednisolone- 1-2 mg/kg in two divided doses
• Sodium iopadate- 100 mg/day
• Graves disease
• Medical Management
• Carbimazole
• Lag- 4-8 wks depending on amount of preformed thyroid hormone
• Dose- 0.5-1 mg/kg/d initially till euthyroid followed by maintainance
• Surgery
• Indications
• Non remitting hyperthyroidism
• Contraindications to antithyroid medication and radioactive I
• Large goiter
• Suspicious malignancy
• Procedure- Near total thyroidectomy
• Complications- Hypoparathyroidism, recurrent laryngeal nerve
palsy, thyroid hematoma, hypothyroidism
• Response
• Initial flare in symptoms (1-2 weeks)
• Fibrosis and reversal of hyperthyroidism (4-12 weeks)
Other conditions
• Chronic lymphocytic thyroiditis
• No effect of antithyroid drugs as thyroid hormone synthesis is normal
• Propanolol (1-2 mg/kg/day) for symptomatic relief
• Self-limiting ; monitor for subsequent hypothyroidism
Further reading
1. Brown RS, Huang S. The thyroid and its disorders. In: Clinical Pediatric
Endocrinology, Eds Brook CGD, Clayton PE, Brown RS, Blackwell
publishing, 2005, London, 5th Edition. Pp 218-253.Fisher DA. Disorders of
the thyroid in the newborn and infant. In: Pediatric En
2. docrinology Eds: Sperling MA. WB Saunders 2002, Philadelphia, 2nd Edn.
Pp 161-186. Vilet GV. Thyroid disorders in infancy. In: Pediatric
Endocrinology, Eds: Lifshitz F, Marcel Dekker, 2003, New York, 4th edition.
Pp 347-358.
Goiter
GRADING
Thyroid Swelling
Grade Feature Professor Anju Seth,
I Thyroid
Department swelling
of Pediatrics, palpable
Kalawati Saranbut not visible
Children’s Hospital, LHMC, New Delhi
II Thyroid swelling visible with neck in extended position only
Goiter
III Thyroid swelling visible with neck in flexed position
IV Criteria- Large
Visible or palpable thyroid tissue
thyroid swelling
WHO grading
ETIOLOGY
Goiter
14.2 Etiology
EVALUATION
History
• Onset
• Neonatal period- Dyshormonogenesis, maternal anti thyroid drug
• Early childhood- Iodine deficiency, dyshormonogenesis
• Late childhood- Iodine deficiency, CLT, colloid goiter
• Adolescence- CLT, iodine deficiency, colloid goiter, graves disease
Examination
• Consistency
• Firm- Chronic lymphocytic thyroiditis
• Soft- Dyshormonogenesis, I deficiency, colloid goiter, graves disease
• Surface
• Bossolated- Chronic lymphocytic thyroiditis
• Smooth- Dyshormonogenesis, I deficiency, colloid goiter, graves
• Size
• Large- Iodine deficiency, antithyroid treatment
• Small- CLT, dyshormonogenesis
Investigations
• Free T4
• High- Graves, TSH receptor mutation, thyrotroph adenoma
• Normal- Colloid goiter, CLT, I deficiency, dyshormonogenesis
• Low- CLT, iodine deficiency, dyshormonogenesis
• TSH
• Low- Graves disease, activating TSH receptor activating mutation
• Normal- Colloid goiter, chronic lymphocytic thyroiditis
• High- CLT, dyshormonogenesis, goiterogen exposure, I deficiency
Normal
Low High
TPO
TPO
Increased Decreased
Graves disease Hashitoxicosis
TSH receptor defect
Benign Malignant
Primary
Papilary cacinoma
Follicular carcinoma
Medullary carcinoma
Anaplastic carcinoma
Infiltrative disorders Tumor Secondary
Chronic lymphocytic thyroidits Colloid cyst Lymphoma
Histiocytoisis Thyroid duct cyst
Adenoma
• Rapid- Malignancy
• Sudden increase in size- Hemorrhage in a nodule
Examination
• Consistency
• Solid- Malignancy, chronic lymphocytic thyroiditis
• Cystic- Colloid cyst, thyroid duct cyst
• Tenderness (acute thyroditis)
• Bruit (hemnagioma)
• MEN 2- Hypertension, marfanoid habitus, swelling in the lips
• Pointer to malignancy- Solid mass, fixity, enlarged lymphnodes
Investigations
• Thyroid function tests- Free T4, TSH
• Hyperthyroidism- Functional thyroid adnoma
• Hypothyroidism- Chronic lymphocytic thyroiditis
• Normal- Cyst, teratoma, chronic lymphocytic thyroiditis, malignancy
MANAGEMENT
• Benign
• Functional adenoma- Surgery
• Cyst- Aspiration
• Chronic lymphocytic thyroiditis- Follow-up for hypothyroidism
• Malignancy
• Papilary-follicular carcinoma- Near total thyroidectomy
• Radio active I ablation
• Suppression
15.23 g Association of TSH- Thyroxine 100 µg/m2/day
and complications
• Malignancy- Chest X ray
• Medullary
• Screeningcarcinoma
for MEN 2
• Surgery-
• UrinaryToal thyroidectomy
catecholamines (phaeochromocytoma)
• Prophylactic
• Serum calcium,thyroidectomy- MEN 2 mutation before five years
phosphate (hyperparathyroidism)
• RET mutation
15.3 Approach to diagnosis APPROACH
Present Absent
Surgical biopsy TSH
Further reading
1) Assess risk factors for malignancy
1. Zimmerman D. Thyroid tumors in children. In: Pediatric Endocrinology,
a) Do surgical biospy if one or more risk factors (radiation exposure, family
Eds: Lifshitz F, Marcel Dekker, 2003, New York, 4th edition Pp 407-420.
2. Fisher DA.lymphnodes,
history, Disorders solidoflesion,
thefixation
thyroid in the structure)
to underlying newborn. In: Pediatric
are present
Endocrinology Eds: Sperling MA. WB Saunders 2002, Philadelphia,
b) Thyroid functions should be assessed in children without risk factors 2nd
Edn. Pp 161- 286
i) Low TSH suggests functional adenoma, confirm with thyroid scan
ii) Fine needle aspiration (FNA) if TSH is high or normal
(1) Ultrasound guided FNA if initial FNA is inconclusive
(2) Surgical biopsy is indicated if
GROW Society ! 229
(a) Initial FNA is suggestive of malignancy
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Growth & Obesity Workforce
Physician Awareness
growth is not restricted to linear
Teacher Sensitization
growth alone but encompasses
holistic development of an
individual including intellectual
and pubertal development and
bone growth. Improving growth is
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