CONGENITAL ADRENAL HYPERPLASIA

Congenital adrenal hyperplasia (CAH) is a group of inherited autosomal recessive disorders, characterized by deficiency of any one of the five enzymes involved in cortisol production from cholesterol, (Fig.

21-hydroxylase deficiency blocks the formation of mineralocorticoids and glucocorticoids and leads to excess production of androgenic steroids (DHEA, DHEAS and androstenedione) and testosterone. Several mutations involving gene CYP21 on chromosome 6p21.3 are responsible for CAH.

Clinical features depend on severity of enzyme defi­ciency, ranging from salt-losing variety with complete absence of enzyme) to the non-salt losers with partial enzyme deficiency.

Clinically, these cases are classified as—(a) salt­wasting type presenting in infancy, (b) simple virilizing type presenting in infancy or childhood, and (c) non­classic CAH, presenting in adolescents or adults.

Salt-wasting CAH is associated with complete enzyme deficiency and presents in infancy with:

• Virilization in females at birth, with variable severity ranging from mild clitoral hypertrophy to labial fusion and even complete masculinisation (Fig. 22.5). Virilizing effect in males is not that obvious and present later with hyperpigmentation of the body, nipples, umbilicus and genitals.

• Signs of salt-losing are present since neonatal period in 75% cases and include-failure to thrive, polyuria, recurrent vomiting and sepsis-like features with negative sepsis screen. Adrenal crisis with hypotension and shock is common in severe cases. Symptoms may not manifest till serum sodium falls lt;125 mEq/L.

• Hypertension is characteristically absent in this enzymatic variety of CAH.

Simple virilizing form with partial enzyme deficiency presents only with virilization in girls and precocious puberty in boys, with no signs of salt-losing.

Non-classical forms, also due to partial enzyme deficiency, present with very mild features of hyper- androgenism, e.g. hirsutism, acne and menstrual irregularities.

Diagnosis must be suspected in any infant with virili­zation or ambiguous genitals with/without features of salt-loosing. History of consanguinity, similar illness in siblings or unexplained deaths in previous newborns with vomiting are important diagnostic clues. Laboratory diagnosis depends on:

• Elevated Serum 17-hydroxy progesterone (17-OHP) levels gt; 200 ng/dl. These levels depend on the severity of enzyme deficiency, being as high as gt;10000 ng/dl in salt-wasting CAH.

• ACTH challenge test, showing 2-3 fold rise in 17-OHP levels without rise in cortisol levels, after 60 minutes of ACTH administration (IM 0.25 mg).

Serum cortisol levels are normal or reduced, with elevated ACTH, androstenedione and testosterone levels. USG reveals female structures in 46 XX individuals with virilisation.

Biochemical indicators of salt-loosing include hypo­natremia, hyperkalemia, increased urinary sodium, increased plasma renin activity and low aldosterone levels.

D/D includes other causes of virilization, e.g. adreno­cortical tumors, as well as rare enzymatic defects in CAH, discussed later.

Management of CAH includes:

• Life-long glucocorticoid therapy to replace the deficient cortisol and suppress overproduction of ACTH. Oral hydrocortisone (15-20 mg#8725;m²#8725;day q8hr) is preferred. Higher doses (double or triple the maintenance dose) are necessary during stress, e.g. infection and surgery.

• Salt-wasting type also requires mineralocorticoid therapy with fluorohydrocortisone (PO 0.05-0.3 mg#8725; day q12hr) and oral sodium supplements in infancy.

• Assigning the sex of rearing is important at birth to avoid later complications. Females should be reared as females irrespective of the degree of virilization, as they have normal internal genitalia, normal onset of puberty and normal fertility.

Males do not suffer from wrong gender assignment but have problems of precocious pseudopuberty as well as accelerated physical and skeletal maturation. Prenatal diagnosis is possible by chorionic villus sampling or amniocentesis to detect CYP21 mutations. High-risk mothers should be initiated on Dexamethasone (PO 20 #956;g#8725;kg#8725;day q8-12hr) from 6-8 weeks of gestation to prevent fetal virilisation and continued throughout pregnancy after confirmation of prenatal diagnosis.

Neonatal screening by estimation of 17-OHP on a dried blood sample (DBS) is possible and carried out at many centers.

Rare but important enzymatic variants of CAH include:

• 11-#946;-hydroxylase deficiency (5-8%) characterized by presence of hypertension and persistent hypokalemia, along with virilization. Salt wasting is uncommon.

• 3-#946;-hydroxysteroid dehydrogenase deficiency, characterized by mild virilization, clitoromegaly and menstrual irregularities in girls or ambiguous genitalia in boys.

22.5.3