Liddle Syndrome: Clinical Phenotype and Therapeutic Response in a Novel Heterozygous SCNN1G Variant

Introduction: Liddle syndrome is a rare autosomal dominant disorder characterized by early-onset hypertension and hypokalemia due to constitutive activation of the epithelial sodium channel (ENaC). While typically associated with mutations in SCNN1B or SCNN1A genes, variants in SCNN1G are less frequently reported and may present diagnostic challenges. Case Description: A 70-year-old female presented to our outpatient clinic with difficult-to-control hypertension since age 40 and chronic hypokalemia. Family history revealed similar history on her diseased mother and grandmother. Despite multiple antihypertensive medications (including spironolactone), over the years her blood pressure had remained elevated (range: 145/80-155/85 mmHg). Laboratory studies showed suppressed plasma renin activity (0.8) and aldosterone (10), with potassium levels of 3.2 on 80 mEq KCl daily supplementation. Kidney function was stable and patient had a normal UA. Genetic testing identified a heterozygous SCNN1G variant (c.436G>A, p.Val146Ile), classified as a variant of uncertain significance. Treatment was modified to include amiloride (ENaC blocker), with discontinuation of potassium supplements. This targeted approach improved blood pressure control and stabilized potassium levels. The patient was referred for genetic counseling for family planning afterward. Discussion: This case highlights several important teaching points: (1) Liddle syndrome should be considered in patients with treatment-resistant hypertension and hypokalemia across all age groups; (2) SCNN1G variants, though less common, can present with classical Liddle syndrome features; (3) Clinical response to ENaC blockers may provide diagnostic confirmation when genetic findings are inconclusive; (4) Family screening is essential due to the autosomal dominant inheritance pattern; (5) Ongoing identification and functional characterization of novel ENaC variants is crucial, as expanding the spectrum of pathogenic variants improves diagnostic accuracy and enables earlier, targeted interventions for patients with atypical presentations or variants of uncertain significance.