Defective production of adrenal steroids (cortisol, aldosterone)

• Decreased cortisol → increased ACTH → adrenal gland enlargement
• 95% of CAH - defective conversion of 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol
• Most commonly mutation in CYP21A2 gene → defect in 21-hydroxylase (autosomal recessive)
• Tested for in routine neonatal screening
• 11β-hydroxylase deficiency - HTN, masculinization
• 17α-hydroxylase deficiency - HTN, hypokalemia, ambiguous male genitalia (no DHT), normal female genitalia but without secondary sex characteristics
• (First digit '1' = hypertension. Second digit '1' = virilization.)

Three main phenotypes

• Classic salt-wasting (75%)
• 46XX - ambiguous genitalia (clitoral enlargement, labial fusion, UG sinus) from androgen excess in utero
• 46-XY - usually normal but can have scrotal hyperpigmentation/phallic enlargement
• Failure to thrive, dehydration, hyperK, hypoNa (1-2 weeks of life)
• Due to lack of aldosterone
• Classic non-salt-wasting (simple virilizing)
• 46XX - ambiguous genitalia
• 46-XY - as above
• Early virilization (pubic hair, growth spurt) (2-4 years of age)
• Non-classic (late onset)
• Early pubarche/sexual precocity
• Hirsutism/menstrual irregularity in girls
• Can be asymptomatic
• Can have impaired growth due to early epiphyseal closing

• Confirm positive newborn screen with second blood test
• elevated ↑ 17-hydroxyprogesterone (17-OHP) generally > 3500 ng/dL
• check electrolytes
• Can also measure 11-deoxycortisol, 17-hydroxypregnenolone, cortisol, androstenedione, DHEA
• Classic 21-hydroxylase deficiency = mineralocorticoid deficiency; risk for hyperK and hypo Na, volume depletion
• Genetic testing only if biochemical testing is equivocal
• Screening scrotal US in adolescence
• CAH a/w testicular adrenal rest tumors in 80-90% of males
• Can lead to infertility (seminiferous tubule obstruction)
• Some regress during glucocorticoid therapy

• Infant with ambiguous genitalia and nonpalpable gonads - assume 46XX CAH
• Get 17-OHP blood sample first
• Then start glucocorticoid/mineralocorticoid therapy (stress dose hydrocortisone which has mineralocroticoid activity as well), NS bolus while awaiting results, to prevent adrenal crisis
• Long-term management (manage classic salt + non-salt wasting similarly)
• Glucocorticoid replacement (hydrocortisone TID, or prednisone if older)
• In all classic CAH
• If non-classic CAH, only need if symptomatic
• Mineralocorticoid replacement (fludrocortisone)
• In all classic CAH, even 'non-salt-wasting' as aldosterone secretion is still impaired
• Bilateral adrenalectomy only if failed medical therapy (intractable hyperandrogenism, iatrogenic Cushing syndrome)
• Adrenal crisis
• Lack of normal cortisol response to stress and normal RAAS (aldosterone) response to hypovolemia
• Can be triggered by routine illnesses
• Double/triple glucocorticoid dose
• Stress dose if severe illness/trauma
• eg surgery stress dosing: 50 mg hydrocortisone IV before procedure, then 25 mg q8h x 24 hours (double doses if major surgery)
• Risks
• Volume depletion, hyperK, hypoNa
• Hypoglycemia during adrenal crisis