Liddle Syndrome SCNN1B ENaC Gain-of-Function — ESENeph MCQ

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HardTubular DisordersLiddle Syndrome SCNN1B ENaC Gain-of-FunctionESENeph

A 38-year-old woman presents with hypokalaemia (K+ 2.8 mmol/L), metabolic alkalosis (bicarbonate 34 mmol/L), and hypertension (BP 162/98 mmHg). Plasma renin is suppressed, aldosterone is suppressed, and cortisol is normal. She is not taking liquorice or carbenoxolone. Genetic testing reveals a gain-of-function mutation in SCNN1B. What is the diagnosis?

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Correct answer: B — Liddle syndrome

Liddle syndrome is caused by gain-of-function mutations in the epithelial sodium channel (ENaC) subunits — SCNN1B (beta subunit), SCNN1G (gamma subunit), or rarely SCNN1A (alpha subunit). These mutations prevent ENaC degradation by disrupting its interaction with Nedd4-2 ubiquitin ligase, resulting in constitutively active sodium channels in the collecting duct. This causes excessive sodium reabsorption, volume expansion, hypertension, hypokalaemia, and metabolic alkalosis — mimicking hyperaldosteronism but with SUPPRESSED aldosterone and renin (because the sodium retention is aldosterone-independent). Treatment is amiloride or triamterene (direct ENaC blockers), NOT spironolactone (which blocks the MR receptor upstream of ENaC and is ineffective in Liddle syndrome).

Reference: Hansson et al 1995 – Liddle Syndrome Genetics; JRCPTB 2022 – Nephrology Curriculum