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Congenital Adrenal Hyperplasia & Ambiguous Genitalia

Name: Congenital Adrenal Hyperplasia & Ambiguous Genitalia
Creator: Veli Bakalov, MD

From salt-wasting shock to the ambiguous-genitalia workup

Pediatrics·Neurology, Genetics & Metabolism·5 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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21-hydroxylase deficiency causes ~95% of CAH: ↓cortisol and aldosterone, ↑ACTH, and 17-OHP shunted to androgens.
Newborn screening measures 17-OHP; preterm, sick, and early (<24 h) samples give false positives.
Salt-wasting crisis at 1–3 weeks: vomiting, dehydration, shock, ↓Na, ↑K, ↓glucose — often a boy with normal genitalia.
Treat adrenal crisis with 20 mL/kg saline boluses, IV dextrose, and stress-dose IV hydrocortisone (~50–100 mg/m²).
Virilized 46,XX infant with nonpalpable gonads has normal ovaries and uterus: CAH until proven otherwise.
Simple virilizing and nonclassic CAH: early pubarche, advanced bone age, tall child but short adult; nonclassic mimics PCOS.
11β-hydroxylase deficiency = virilization + hypertension/hypokalemia; 17α-hydroxylase deficiency = hypertension + absent puberty or undervirilized 46,XY.
Lifelong hydrocortisone + fludrocortisone; double to triple doses for illness, IM hydrocortisone when vomiting.
Ambiguous genitalia: karyotype/SRY, electrolytes, glucose, 17-OHP, pelvic ultrasound; defer sex assignment and irreversible surgery.

21-Hydroxylase deficiency: mechanism and forms

Mechanism. Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive defects in cortisol synthesis. Deficiency of 21-hydroxylase (CYP21A2) causes about 95% of cases. Without cortisol there is no negative feedback, so ACTH rises and the adrenals become hyperplastic; 17-hydroxyprogesterone (17-OHP) accumulates behind the block and is shunted into androgen synthesis. Aldosterone deficiency causes salt wasting, cortisol deficiency causes hypoglycemia and poor stress tolerance, and androgen excess causes virilization. Excess ACTH can darken the scrotum or labia.

Classic salt-wasting form. The most severe form. Affected 46,XX fetuses are virilized: clitoromegaly, fused and rugated labioscrotal folds, and a single urogenital sinus. Their ovaries, uterus, and fallopian tubes are normal, because there are no testes to make anti-Müllerian hormone (AMH), and fertility is possible. Boys have normal genitalia, so without newborn screening their first sign is an adrenal crisis.

Simple virilizing and nonclassic forms. Enough aldosterone is made to prevent salt wasting. Androgen excess produces early pubic hair, acne, rapid growth, and advanced bone age; boys have penile growth with prepubertal testes, a sign of a gonadotropin-independent source. Early epiphyseal fusion turns a tall child into a short adult. Nonclassic CAH in adolescent girls mimics polycystic ovary syndrome, with hirsutism and oligomenorrhea. Screen with an early-morning 17-OHP (follicular phase in women) and confirm equivocal results with an ACTH stimulation test.

Ambiguous genitalia with no palpable gonads is CAH in a 46,XX infant until proven otherwise.

Newborn screening and the salt-wasting crisis

Screening. All US newborns are screened for 17-OHP. False positives are common in preterm, sick, or stressed infants and in samples collected before 24 hours. Positive screens are confirmed with serum 17-OHP (with ACTH stimulation if needed) and electrolytes; CYP21A2 genotyping supports the diagnosis.

Crisis. Salt wasting typically appears at 1–3 weeks of life with poor feeding, vomiting, weight loss, dehydration, and lethargy that progress to shock. Laboratory findings are hyponatremia, hyperkalemia, hypoglycemia, and metabolic acidosis, with high renin. Pyloric stenosis, a key mimic of a vomiting infant, instead causes hypokalemic, hypochloremic metabolic alkalosis.

Draw labs if no delay17-OHP, cortisol, renin, electrolytes, glucose
Restore volume20 mL/kg normal saline boluses, repeated as needed
Correct hypoglycemiaIV dextrose bolus, then dextrose-containing fluids
Stress-dose hydrocortisoneIV, about 50–100 mg/m² (for example 25 mg in an infant); at this dose it also provides mineralocorticoid effect
Monitor potassiumhyperkalemia usually corrects with fluids and steroids; treat dangerous levels directly

Other enzyme defects

The mnemonic "starts with 1 means hypertension, ends with 1 means virilization" sorts the main defects. In 11β-hydroxylase deficiency (about 5% of CAH), 11-deoxycorticosterone accumulates and acts as a mineralocorticoid, producing hypertension, hypokalemia, and low renin and aldosterone, while androgen excess virilizes 46,XX infants. In 17α-hydroxylase deficiency, cortisol and all sex steroids are absent while mineralocorticoid precursors accumulate: 46,XY infants look female but have no uterus (AMH is intact), and 46,XX girls have absent puberty and primary amenorrhea, both with hypertension and hypokalemia.

Enzyme defects in CAH

Enzyme	BP and potassium	46,XX	46,XY	Key lab
21-hydroxylase	Salt wasting: low BP, ↑K	Virilized	Normal genitalia	↑17-OHP
11β-hydroxylase	Hypertension, ↓K	Virilized	Normal; early pubarche	↑11-deoxycortisol, ↑11-deoxycorticosterone
17α-hydroxylase	Hypertension, ↓K	Absent puberty	Undervirilized, female-appearing	↓sex steroids, ↑mineralocorticoid precursors
3β-HSD	Salt wasting	Mild virilization	Undervirilized	↑DHEA

Long-term treatment

Replacement. Hydrocortisone (about 10–15 mg/m²/day in divided doses) replaces cortisol and suppresses ACTH-driven androgen excess; it is preferred in growing children because potent long-acting glucocorticoids such as prednisone and dexamethasone suppress growth. Salt-wasting forms also need fludrocortisone, plus sodium chloride supplements in infancy. Doses are adjusted by growth velocity, bone age, 17-OHP and androstenedione, and renin; overtreatment causes Cushingoid features and poor growth, undertreatment causes virilization and advanced bone age.

Stress dosing. Double to triple the oral hydrocortisone dose for fever or illness, give IM hydrocortisone when vomiting prevents oral dosing, and give an IV stress dose for surgery. Every family needs an emergency injection kit, a written sick-day plan, and medical identification.

Evaluating ambiguous genitalia

Red flags. Bilateral nonpalpable testes in an apparent boy, hypospadias with an undescended testis, clitoromegaly, or posterior labial fusion. Evaluation is urgent because salt-wasting CAH can be lethal:

Karyotype with rapid FISH or PCR for X, Y, and SRY
Serial electrolytes and glucose; 17-OHP after 24 hours
Pelvic ultrasound for a uterus and gonads
Testosterone, dihydrotestosterone (DHT), LH, FSH, and AMH

Principles. Defer sex assignment until the evaluation is complete, which usually takes days, and avoid irreversible genital surgery. A multidisciplinary team (endocrinology, urology, genetics, psychology) supports parents in shared decisions, using neutral language and allowing them to delay naming. Dysgenetic gonads containing Y material carry a high risk of gonadoblastoma and are usually removed.

Differential. In 46,XY infants, androgen insensitivity (X-linked androgen-receptor defect) produces female external genitalia with a blind vaginal pouch, no uterus, and high testosterone, LH, and estradiol; complete forms may present as an inguinal hernia containing a testis or as primary amenorrhea with breast development. 5α-reductase deficiency (autosomal recessive, low DHT) causes ambiguous genitalia at birth and virilization without breast development at puberty; Wolffian structures form normally, the prostate is small, and the testosterone-to-DHT ratio is high. In 46,XX infants with normal 17-OHP, consider maternal androgens (luteoma of pregnancy, Sertoli-Leydig tumor, exogenous androgens) or aromatase deficiency, both often accompanied by maternal virilization.