Adrenal disorders | Renal, endocrine and reproductive system | Pathology

i) Congenital adrenal hyperplasia or CAH: It refers to a group of disorders that arise from defective adrenal synthesis of steroid hormones. CAH is inherited as an AR disorder. More than 90% of all CAH cases is caused by the deficiency of the cytochrome P450 enzyme 21-hydroxylase, followed by 11 beta hydroxylase deficiency. Impaired cortisol synthesis leads to chronic elevations of ACTH which causes hyperplasia of the adrenal cortex.

Common features in CAH types

Disease	Features
21 hydroxylase deficiency	Virilization of female fetus, normal male genitalia; decreased cortisol, increased 17 OH progesterone, DHEA and androstenedione plus salt wasting features due to mineralocorticoid deficiency with high potassium, low sodium and hyperpigmentation seen in salt wasting type; virilizing type has all except salt wasting features; CYP21A gene defect
11 beta hydroxylase deficiency	Females virilized with ambiguous genitalia, males unchanged; low renin HT, elevated DOC, 11-deoxycortisol and androgens, low K, elevated Na; CYP11B1 gene defect
3 beta HSD (hydroxysteroid dehydrogenase deficiency)	Virilization of female fetus , salt wasting, elevated DHEA, pregnenolone and potassium, low androstenedione, testosterone and sodium. In postnatal form, genitalia are normal and salt wasting is absent with mild features of hyperandrogenism
17 alpha hydroxylase deficiency	Low renin hypertension, hypokalemia, metabolic alkalosis, variable sexual development, normal or decreased androgens, estrogens, elevated DOC* and corticosterone
17,20 lyase deficiency	Infantile female genitalia, decreased androgens and estrogens

*DOC deoxycortisone

Virilization of female genitalia presents as clitoral enlargement, ambiguous genitalia, fusion of labia etc. In CAH, internal genitalia develop normally. Patients also have premature pubarche, acne, infertility, rapid growth, precocious puberty, premature fusion of bony epiphyses and hirsutism, temporal balding, short stature as an adult. Some cases may present with primary amenorrhea. PCOS may be associated. Salt wasting type is caused by decreased aldosterone synthesis and presents with poor feeding, weight loss, failure to thrive, vomiting, dehydration, hypotension, hyponatremia, hyperkalemic metabolic acidosis and fatal adrenal shock. Male newborns are at increased risk as their external genitalia appears normal hence diagnosis may be missed.

1 = enzyme desmolase (converts cholesterol to pregnenolone), 2 = 17 alpha hydroxylase (17-OH), 3 = 3 beta hydroxysteroid dehydrogenase (3 ß HSD), 4 = 21 hydroxylase (21-OH), 5 = 11 beta hydroxylase (11-OH), B is corticosterone; S is deoxycortisol

Diagnosis is by clinical features confirmed by measuring hormone levels. X ray shows increased bone age. CAH screening in newborns is done by measuring levels of 17-hydroxyprogesterone in blood by heel prick. Gold standard for diagnosis of 21 hydroxylase deficiency is the corticotropin (ACTH) or cosyntropin stimulation test which measures 17 hydroxyprogesterone and androstenedione levels at baseline and 1 hour after intravenous cosyntropin. Levels of both hormones are high in 21 hydroxylase deficiency. Amniotic fluid levels of 17 OH progesterone are also elevated. Chorionic villus sampling at 9-11 weeks of pregnancy can be done for molecular genetic testing for CAH mutations. Dexamethasone administered prenatally helps to treat virilization of a female fetus in-utero. Fetal DNA can be extracted from maternal blood as early as 4 weeks of gestation and CAH identified by molecular genetic testing.

Postnatal therapy is with glucocorticoids like hydrocortisone, prednisone or dexamethasone , which indirectly also suppresses excess androgen secretion. Oral contraceptive pills can be used in adult females who develop PCOS. Patients with salt wasting forms need replacement with fludrocortisone and salt supplementation.