17-hydroxylase deficiency

**Genetics/Enzyme:** Autosomal recessive mutation in CYP17A1, which encodes a single enzyme with two activities: 17α-hydroxylase (converts pregnenolone→17-OH-pregnenolone and progesterone→17-OH-progesterone) and 17,20-lyase (converts 17-OH-pregnenolone→DHEA and 17-OH-progesterone→androstenedione). It is expressed in the adrenal cortex (zona fasciculata/reticularis) and gonads. (Note: Isolated 17,20-lyase deficiency also exists, causing sex steroid deficiency without mineralocorticoid excess.)

**Pathophysiology:** - ↓ Cortisol → ↑ ACTH (loss of negative feedback) → adrenal hyperplasia and shunting of precursors into the mineralocorticoid pathway (zona fasciculata is not blocked at this step upstream). - ↑ 11-deoxycorticosterone (DOC) and corticosterone (weak mineralocorticoid activity; corticosterone also provides some glucocorticoid activity, so patients typically do not develop adrenal crisis) → sodium and water retention, hypertension, hypokalemia, metabolic alkalosis. - Volume expansion and hypertension suppress renin → ↓ aldosterone (low renin, low aldosterone hypertension, unlike primary hyperaldosteronism where aldosterone is high). - ↓ Androgens and estrogens (loss of 17,20-lyase activity) → lack of sex steroid production.

**Clinical features:** - Hypertension, hypokalemia (weakness, cramps), metabolic alkalosis. - 46,XX: Normal female internal/external genitalia but primary amenorrhea, absent secondary sexual characteristics (no puberty), ovaries with impaired follicular maturation; ↑ FSH/LH (hypergonadotropic hypogonadism). - 46,XY: Undervirilization – female-appearing external genitalia (or ambiguous), blind-ending vagina, no uterus/fallopian tubes (Müllerian structures regress due to AMH from Sertoli cells), testes intra-abdominal or inguinal; no puberty. Often raised as females (male pseudohermaphroditism/ 46,XY DSD). - Absence of adrenal crisis/salt wasting, unlike 21-hydroxylase and 11β-hydroxylase deficiencies’ differing pictures (21-OH: salt wasting and virilization; 11β-OH: hypertension + virilization).

**Labs:** - ↑ Progesterone, pregnenolone, DOC, corticosterone, ACTH. - ↓ Cortisol, 17-OH-progesterone, DHEA, androstenedione, testosterone, estrogens, aldosterone, renin. - ↓ K⁺, ↑ or normal Na⁺; metabolic alkalosis. - ↑ FSH/LH.

**Board-relevant comparison of CAH:** - 21-hydroxylase (most common, >90%): ↑ 17-OH-progesterone, ↓ cortisol/aldosterone, ↑ androgens → hypotension, hyperkalemia, volume depletion, virilization/ambiguous genitalia in females. - 11β-hydroxylase: ↑ 11-deoxycorticosterone (hypertension), ↓ cortisol/aldosterone, ↑ androgens → virilization + hypertension, low renin. - 17α-hydroxylase: ↑ mineralocorticoids (hypertension, hypokalemia), ↓ cortisol, ↓ sex hormones → no virilization in females (sexual infantilism); XY individuals have female/ambiguous genitalia. Mnemonic: "17 = no sex hormones, HTN."

**Treatment:** - Glucocorticoid replacement (e.g., hydrocortisone/dexamethasone) to suppress ACTH, reducing mineralocorticoid excess and normalizing BP and K⁺. - Mineralocorticoid antagonists (spironolactone, eplerenone) if hypertension persists. - Sex steroid replacement at puberty (estrogen ± progestin in genetic females and in 46,XY individuals raised as females). - Gonadectomy in 46,XY patients raised female (risk of gonadal malignancy with intra-abdominal testes). - Gender identity counseling/psychosocial support.

**Exam pearls:** Hypertensive young female with hypokalemia and primary amenorrhea lacking secondary sexual characteristics + low renin/aldosterone = 17α-hydroxylase deficiency. Phenotypic female with a blind vaginal pouch and no uterus plus hypertension = 46,XY 17α-hydroxylase deficiency.