CONGENITAL ADRENAL

HYPERPLASIA
OKOLUGBO, JULIA CHIGOZIE
MBBS(BENIN)
DEPARTMENT OF PAEDIATRICS,
FEDERAL TEACHING HOSPITAL, IDO-EKITI
Congenital adrenal hyperplasia
• A family of inherited disorders in which defects occur in one of the enzymatic
steps required to synthesize cortisol from cholesterol in the adrenal gland.
• Autosomal recessive mode of inheritance.
• Disorders can lead to virilization in females or undervirilized males.
• With deficiency of an enzyme, there is reduction in end products, a build-up
of precursors above the enzyme deficiency and shunting to an alternate
pathway
• Cortisol deficiency increases secretion of corticotropin (ACTH), which in turn
leads to adrenocortical hyperplasia and overproduction of intermediate
metabolites.
CAH cont’d
• Three major pathways of mineralocorticoid, glucocorticoid and
androgen synthesis take place in the glomerulosa, fasciculata and
reticularis zones of the cortex of the adrenal gland respectively.
• Aldosterone is the main mineralocorticoid while cortisol is the main
glucocorticoid.
• Cortisol increases glucose production while aldosterone causes
reabsorption of sodium and secretion of potassium at the distal
convoluted tubules and collecting duct.
Steroid biosynthesis
21-hydroxylase deficiency
• Most common type, accounts for >90% of cases.
• Incidence is 1:15000 to 1:20,000 live birth.
• Gene is located on the short arm of chromosome 6 near the C4
locus in close association with HLA genes.
• Several mutations completely prevent synthesis of functional
protein while others yield enzymes with 1-50% of normal
activity.
• Disease severity correlates well with mutations carried by an
individual.
21-hydroxylase deficiency cont’d

• Impairment of the conversion of 17α-hydroxyprogesterone

(17OHP) to 11-deoxycortisol.
• There is also impairment of progesterone conversion to
aldosterone, causing abnormal salt loss.
• Precursors are shunted through the androgen pathway,
resulting in elevated levels of adrenal androgens that cause
ambiguous genitalia in the genetic female foetus.
21-hydroxylase deficiency cont’d
There are 2 types: classic and non-classic 21OHD:
Classic
• Simple virilising form
• Salt wasting form (70%)
Non- classic (late - onset)
• Diagnosis is made by the detection of extremely high
concentrations of 17-OHP after performing an ACTH stimulation
test and confirmed by molecular genetic analysis of the CYP21
gene(located on the short arm of chromosome 6).
21-hydroxylase deficiency cont’d
• Clinical signs and symptoms include apparent genital
ambiguity in the females with simple virilizing form but the
males appear normal.
• Postnatally, genitalia continue to virilize and
pseudoprecocious puberty can occur.
• Rapid somatic growth and accelerated skeletal maturity.
Affected patients are tall in childhood but premature closure
of the epiphysis causes growth to stop relatively early
21-hydroxylase deficiency cont’d
• The salt-wasting type is more common(75% of cases) and
distinct because of the deficiency of aldosterone leading to
hyponatraemia, hyperkalaemia, high plasma renin activity,
and fluid volume depletion.

• In partial enzyme deficiencies, the aldosterone

deficiency is not expressed, and patients remain
normonatremic and normokalemic.
Lab findings (21-OH DEF)
• Low Na, high k, metabolic acidosis, low glucose.
• High renin
• High 17- hydroxyprogesterone
• Low cortisol and aldosterone
• High androstenedione/testosterone
• High urinary 17-ketosteroids and pregnanetriol
• High ACTH
21-hydroxylase deficiency cont’d
• Hormonal replacement therapy with corticosteroids.
Hydrocortisone 15-20mg/m2/day in 2-3 divided doses.
• Adrenalectomy in some selected cases.
• With the salt-losers, mineralocorticoid replacement
with 0.05-0.2mg of fludrocortisone.
• Oral salt supplement.
• Corrective surgery for the genetic females.
21-hydroxylase deficiency cont’d
• Prevention of antenatal virilization in affected females is
possible with proper prenatal diagnosis and treatment
programmes.

• Appropriate prenatal treatment with dexamethasone

before 9 weeks gestation to the pregnant mother carrying
at-risk foetus .

• Mass neonatal screening using filter paper blood sample for

17-OH-Progesterone is used in the USA.
 11β- hydroxylase deficiency
• Represents 5-8% of all cases of CAH in the general population.
• Gene is located on the long arm of chromosome 8.
• Accumulation of 11-deoxysteroids precursors which are shunted
into the androgenic pathway.
• Due to accumulation of deoxycorticosterone which has strong
mineralocorticoid activity, it is characterized by salt retention,
hypertension & hypokalemic alkalosis.
• Affected females have ambiguous genitalia .
• Hypertension occurs in two-thirds of the patients due to
accumulation of deoxycorticosterone.
• The hallmark serum abnormality is suppressed renin.
11β-hydroxylase deficiency cont’d
• Diagnosis is made by extremely high levels of
deoxycorticosterone (DOC) after performing an ACTH
stimulation test and confirmed by molecular genetic
analysis of the CYP11B1 gene.
• Treatment is the same as in 21-OHD but for reduced
salt intake to control fluid intake and hypertension.
17- hydroxylase deficiency
• Genetic defect is on chromosome 10.
• The enzyme catalyses more than one reaction- the 17α-hydroxylation
and 17,20- lyase reaction.
• Affected individuals cannot produce cortisol but synthesize a lot of
corticosterone and deoxycorticosteroid which causes hypertension
and hypokalaemia.
• Deficiency of 17,20-lyase impairs the ability to synthesize androgens
and oestrogens and cause male pseudohermaphroditism at birth and
failure to virilize at puberty.
• Presents with similar features of those of 11-Hydroxylase
deficiency except that androgens are low, so no virilization in
girls & genitalia is ambiguous in boys.
17- hydroxylase deficiency cont’d
• Affected females have primary amenorrhoea and clinical
hypogonadism.
• Typical features include hypertension and hypokalaemia with
associated sexual infantilism in genetic females and
pseudohermaphroditism and sexual infantilism in genetic
males.
• Treatment include the use of glucocorticoids , adult females
are given oestrogens while testes are removed and
androgens given to males.
3β- hydroxysteroid dehydrogenase deficiency
• This is a very rare disorder that results in accumulation of DHEA, which
is converted to testosterone in peripheral tissues.
• It can cause virilization of female fetus and leads to ambiguous
genitalia in the newborn.
• This results in incomplete virilization of the external genitalia in males
presenting with ambiguous external genitalia characterised by
micropenis, hypospadias, bifid scrotum with or without salt loss.
• At puberty, gynaecomastia is common.
• Management is same as other forms of CAH.
• Males may need testosterone replacement at puberty if reared as males.
Lipoid Adrenal Hyperplasia
• Severe form of CAH

• Due to mutations in the gene for steroidogenic acute regulatory

protein(StAR), a mitochondrial protein that promotes the movement
of cholesterol from the outer to the inner mitochondrial membrane.

• There is inability to transfer cholesterol to the inner mitochondrial

membrane resulting in lipid droplet accumulation in the cytoplasm of
the adrenocorticoid cells which is cytotoxic.
Lipoid Adrenal Hyperplasia cont’d
• Affected patients exhibit glucocorticoid and mineralocorticoid
deficiencies and the males exhibit undervirilization.

• Males are phenotypic females because of Leydig cell destruction and

impaired testosterone production while the ovaries of the females are
spared because steroidogenesis is delayed until puberty.
 0ther investigations
• Karyotype: to establish chromosomal sex.
• Pelvic ultrasound: in the infant with ambiguous genitalia to
demonstrate the presence or absence of a uterus or
associated renal anomalies
• Urogenitogram is often helpful to define the anatomy of the
internal genitalia.
• CT scan of the adrenal gland to R/O bilateral adrenal
hemorrhage in the patient with signs of acute adrenal failure
• A bone age study is useful in the evaluation of the child who
develops precocious pubic hair, clitoromegaly, or accelerated
linear
Treatment

• Treatment is life-long
• Treatment goals are:
• To maintain growth velocity and skeletal maturation.
• To replace the body's requirement under normal conditions
and during stress.
• To normalize electrolytes and hormone levels using the
smallest dose of glucocorticoids that will suppress the ACTH
to normal.
Treatment cont’d

• Steroid replacement
• Supportive therapy when needed
• Treatment is life-long
• Surgery
• Genetic counseling
• Psychological support
Acute medical management

• Fluid therapy in babies with salt losing crisis 0.9% sodium

chloride 20 ml/kg as IV bolus, followed by a continuous IV
infusion of 0.9% or 0.45% saline.
• If the patient is hypoglycemic, 2-4 ml/kg of 10% dextrose will
correct the hypoglycemia.
• Patients with 11-b-hydroxylase and 17-alpha-hydroxylase
deficiency, may be hypokalemic and require potassium.
Long term treatment
• Glucocorticoid replacement
• Hydrocortisone 10-15 mg/m2/day divided in 3 oral doses.
• Dose should doubled during crisis and stressful conditions
• Mineralocorticoids Treatment
• Fludrocortisone acetate 0.05-0.2 mg once daily orally is indicated for
patients who have salt-wasting forms of CAH to replace the
aldosterone that is insufficiently produced by the adrenal cortex.
• It will restore the sodium- potassium balance.
AMBIGUOUS GENITALIA
(DISORDERS OF SEX
DEVELOPMENT)
OKOLUGBO, JULIA CHIGOZIE
27/11/2018
Introduction
• After every birth, the question most often asked is “is it a boy or a
girl?” .
• Ambiguity therefore needs to be addressed with urgency and
sensitivity.
• Care must be taken to avoid premature gender assignment.
• The degree of genital virilization is an important determinant of
gender assignment.
Embryology
DSD cont’d
There are 4 general classifications that cause disorders of sexual
differentiation:
• Masculinization of the 46XX female
• Incomplete masculinization of the 46XY male
• Gonadal differentiation and chromosomal disorders
• Syndromes associated with incomplete genital development.
46 XX virilized female
Congenital adrenal hyperplasia
• 21-hydroxylase deficiency
• 11- hydroxylase deficiency
• 3β- hydroxysteroid dehydrogenase deficiency
• Aromatase deficiency
Virilizing maternal conditions
• Congenital adrenal hyperplasia
• Adrenal/ovarian tumours
• Maternal ingestion of progestin , androgens
46XY undervirilized male
• Androgen insentivity- partial or complete
• 5α-reductase-2 deficiency
• Testosterone biosynthetic defects
17β hydroxysteroid dehydrogenase deficency
3β- hydroxysteroid dehydrogenase deficiency
17α-hydroxylase/17,20-lyase deficiency
Congenital lipoid adrenal hyperplasia
46XY undervirilized male cont’d
• Leydig cell hypoplasia
• Idiopathic , undetermined
• Drug ingestion – progestin, spironolactone, cimetidine , phenytoin
• Persistent mullerian duct syndrome
Gonadal differentiation and chromosomal disorders

46 XY gonadal dysgenesis
• Complete –Swyer syndrome
• Partial
• Mixed – 46X,46XY

True hermaphroditism
• 46 XX, 46 XY, 46 XX/ 46 XY
Syndromes associated with incomplete genital development.

• Gonadal dysgenesis
46 XY partial dysgenesis- Turner syndrome features
Camptomelic dysplasia
• Renal degenerative diseases and gonadal dysgenesis
Dennys-Drash syndrome
Frasier syndrome
WAGR syndrome
• Smith-Lemli-Opitz syndrome
Clinical assessment
• HISTORY
• A detailed family history is important –information about
• early neonatal death,
• consanguinity or
• urogenital abnormalities.
• Information about female infertility or amenorrhoea,
• presence of maternal virilization- severe acne, deepening voice,
hirsutism, clitorimegaly.
• Ingestion of recreational drugs, alcohol or medications.
Physical examination
• Determine the degree of virilization of the external genitalia and the
presence of palpable gonads.
• Clitoral enlargement
• Measurements of the phallic stretch length and middle shaft.
• Degree of fusion of the labioscrotal folds, presence of ruggae or
hyperpigmentation.
• Presence of gonads, bilateral or unilateral
• Severity of hypospadias, urethral or vaginal openings, blindfolding
vagina.
Radiologic investigations
• Pelvic USS- presence or absence of uterus, undescended testes,
gonadal size or irregularity, enlarged adrenal glands.
• Genitourethrogram- presence or absence of the vagina and the
relationship between the vagina and the urethra.
• MRI- assesses the internal genitalia , distinguishes between an
enlarged clitoris and a penis
Laboratory investigations
• Serum testosterone and dihydrotestosterone levels on day 1
• Chromosomal studies (karyotyping)
• Enzymatic studies if CAH is entertained
• Laparoscopy with gonadal biopsy
Management
• Assessed on a case-by-case basis
• Feminizing genitoplasty- most common
• Clitoral reduction
• Vaginoplasty
• Gonadectomy
• Psychotherapy
Ovotesticular DSD (A), CAH (B-E)
5a-Reductase deficiency
Partial androgen insensitivity
Partial androgen insensitivity syndrome at
adolescence (male sex of rearing)
Conclusion
• DSD is a challenging and complicated situation, but when understood
can often be dealt with effectively
• Many potential medical, social, and psychological ramifications
• Multidisciplinary approach involving urology, endocrinology, genetics
and social work is essential
EXERCISE
• A 15 yr old , previously healthy female, presents with acne, hirsutism and
irregular menses. Her pubertal history reveals breast development at 8 yrs of
age and pubic hair development at 6 yrs of age and she reported 1 episode of
vaginal spotting at 10 years of age. A family history indicates some female
relatives with symptoms of infertility, irregular menses, polycystic ovarian
syndrome or alopecia. She is significantly shorter than her target height. What
is the most likely diagnosis?
• Classic congenital adrenal hyperplasia
• Non-classic CAH
• Cushing syndrome
• Androgen insensitive syndrome
EXERCISE
• An XX genotypic infant is born with ambiguous genitalia. Lab exam
reveals hypoglycaemia, hyperkalaemia, salt wasting. 17-OH
progesterone is markedly increased. Which of the following is the
most likely diagnosis?
• 5-a Reductase deficiency
• 11-B-hydroxylase deficiency
• 17- a- hydroxylase deficiency
• 21 hydroxylase
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