adrenal hyperplasia

**Pathophysiology:** Steroidogenesis proceeds cholesterol → pregnenolone → (mineralocorticoid, glucocorticoid, and sex steroid pathways). An enzyme block causes cortisol deficiency → ↓ negative feedback on CRH/ACTH → ↑ ACTH → bilateral adrenal hyperplasia. Precursors proximal to the block accumulate and are shunted into pathways that remain open (usually androgens).

**Major enzyme deficiencies (all autosomal recessive):**

1. **21-hydroxylase deficiency (CYP21A2) – most common (~90-95%)** - ↓ cortisol, ↓ aldosterone, ↑ androgens, ↑ 17-hydroxyprogesterone (diagnostic; newborn screen). - ↓ Na⁺, ↑ K⁺, ↓ BP, ↓ volume (salt-wasting form), metabolic acidosis. - Females: virilization/ambiguous genitalia (46,XX with normal internal female structures). Males: normal genitalia at birth, early virilization/precocious pseudopuberty. - Classic severe: salt-wasting crisis at 1-2 weeks of life (vomiting, poor feeding, hypotension, shock). Simple virilizing: enough aldosterone. Non-classic (late-onset): mild, presents with hirsutism, acne, oligomenorrhea (mimics PCOS), and accelerated growth/early bone age. - Labs/imaging: ↑ renin. Tall as child, short as adult from early epiphyseal closure.

2. **11β-hydroxylase deficiency (CYP11B1)** - ↓ cortisol, ↓ aldosterone, ↑ androgens, ↑ 11-deoxycorticosterone (DOC, a weak mineralocorticoid) and 11-deoxycortisol. - Hypertension with hypokalemia, low renin, plus virilization.

3. **17α-hydroxylase deficiency (CYP17A1)** - ↓ cortisol, ↓ sex steroids, ↑ mineralocorticoids (DOC, corticosterone). - Hypertension, hypokalemia, low renin. 46,XY: ambiguous genitalia/undervirilized (female-appearing phenotype, testes, no uterus). 46,XX: lack of secondary sexual development (primary amenorrhea, no puberty). - Mnemonic: 17α absent → no sex hormones, no cortisol → "everything is low except mineralocorticoids" → hypertension.

4. **Rarer:** StAR (lipoid CAH) and 3β-HSD deficiency (↓ everything; ambiguous genitalia in both sexes, salt wasting).

**Memory tool:** Deficiency of 21 or 11 → virilization (↑ androgens); 17 → no sex steroids. Deficiency of 11 or 17 → hypertension (↑ DOC); 21 → hypotension.

**Diagnosis:** Newborn screening with ↑ 17-OH-progesterone; ACTH stimulation test if equivocal. Also ↑ androstenedione, ↑ renin (21-OH). Karyotype in ambiguous genitalia.

**Treatment:** Lifelong glucocorticoid replacement (hydrocortisone in children, to suppress ACTH) ± mineralocorticoid (fludrocortisone) for salt wasting. Stress-dose steroids during illness/surgery. Acute adrenal crisis: IV fluids (normal saline with dextrose), IV hydrocortisone. Surgical genital reconstruction considered for affected females. Prenatal dexamethasone has been used but remains controversial.

**Other adrenal hyperplasia (distinct from CAH):** - **Primary bilateral macronodular adrenal hyperplasia (PBMAH)** and primary pigmented nodular adrenal disease cause ACTH-independent Cushing syndrome. - **Bilateral idiopathic (micronodular) adrenal hyperplasia** is a common cause of primary hyperaldosteronism (Conn syndrome mimic), along with aldosterone-producing adenoma. Treat with spironolactone rather than surgery. - **Secondary hyperplasia** results from ↑ ACTH (Cushing disease, ectopic ACTH).

**Boards high-yield:** A newborn with ambiguous genitalia, hyponatremia, hyperkalemia, and hypotension → 21-hydroxylase deficiency → check 17-OH-progesterone. A hypertensive hypokalemic child with virilization → 11β-hydroxylase deficiency. A hypertensive, hypokalemic teen with no puberty → 17α-hydroxylase deficiency.