A 16-year-old girl has recurrent episodes of hypokalaemic metabolic alkalosis with serum magnesium 1.2 mg/dL, urinary calcium-to-creatinine ratio low, and normal-low blood pressure. Her elder brother has similar episodes. Which gene mutation is the most likely cause?

• A SLC12A1 encoding the furosemide-sensitive NKCC2 cotransporter
• B SLC12A3 encoding the thiazide-sensitive NaCl cotransporter ✓
• C SCNN1G encoding the epithelial sodium channel gamma subunit
• D KCNJ1 encoding the ROMK potassium channel

Explanation

Gitelman syndrome is caused by loss-of-function mutations in SLC12B3, the thiazide-sensitive NCC cotransporter in the distal convoluted tubule. Its signature combination is hypokalaemic alkalosis with hypomagnesaemia and hypocalciuria, mimicking chronic thiazide use, and onset is usually adolescence or adulthood. NKCC2 and ROMK mutations cause Bartter syndrome, which presents earlier with hypercalciuria and often nephrocalcinosis. SCNN1 mutations cause Liddle syndrome, which features hypertension and suppressed renin.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

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Written and medically reviewed by the StethoPrep medical team.