A 48-year-old with hypertension and hypokalemia is found to have an adrenal adenoma on CT. Adrenal vein sampling confirms primary aldosteronism lateralizing to the left adrenal. Aldosterone-producing adenoma (Conn's tumor) most frequently harbors a somatic mutation in which gene?

• A KCNJ5 (potassium channel Kir3.4) ✓
• B CYP11B2 (aldosterone synthase) promoter amplification
• C CTNNB1 (beta-catenin)
• D PRKACA (protein kinase A catalytic subunit)

Explanation

KCNJ5 mutations are the most common somatic mutations in aldosterone-producing adenomas (APAs), found in approximately 40–45% of cases. KCNJ5 encodes the potassium channel Kir3.4, which selects for K+ over Na+. Gain-of-function mutations (T158A, G151R, L168R) alter ion selectivity, allowing Na+ influx, membrane depolarization, calcium channel activation, and calcium influx — constitutively activating CYP11B2 (aldosterone synthase) without ACTH or angiotensin stimulation. KCNJ5 mutations are more common in women and cortisol-negative APAs. Other mutations include CACNA1D (L-type calcium channel, ~10%), ATP1A1 and ATP2B3 (Na+/K+ ATPase, ~6%), and CTNNB1 (rare, associated with bilateral adrenal hyperplasia).

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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