Novel frameshift variant in the β subunit of epithelial sodium channels uncovers Liddle syndrome in a young patient with metabolic syndrome: a case report with review of literature

Abstract

Liddle syndrome is a rare monogenic form of hypertension that can be misdiagnosed as essential hypertension or, in the context of obesity, be mistaken for metabolic syndrome. This case report describes a 19-year-old Chinese male with obesity, hypertension, insulin resistance, impaired glucose tolerance, dyslipidemia, and hyperuricemia—a classic presentation of metabolic syndrome. However, the early onset of severe hypertension and a strong family history prompted further investigation. Laboratory evaluation revealed mild hypokalemia, suppressed plasma renin activity and normal aldosterone levels, raising suspicion for Liddle syndrome. Whole exome sequencing was performed to explore monogenic causes of hypertension, which identified a novel heterozygous frameshift variant in the SCNN1B gene (NM_000336.3:c.1711_1713delinsAA). This variant leads to the loss of the PY motif—a functionally critical and indispensable structural element of the epithelial sodium channel (ENaC) β-subunit—and was classified as likely pathogenic in accordance with the ACMG/AMP guidelines. The patient was initiated on targeted therapy with amiloride, which rapidly normalized his blood pressure and hypokalemia, thereby confirming the diagnosis. This case highlights the diagnostic challenge of distinguishing monogenic hypertension from metabolic syndrome in young, obese individuals. It emphasizes the necessity of systematically investigating for secondary causes in this population. Key steps include obtaining a family history, screening for hypokalemia, evaluating renin and aldosterone levels, and assessing the response to standard therapy. Identifying a rare disorder like Liddle syndrome allows for a paradigm shift in management from empiric to targeted treatment, which is essential for preventing the debilitating long-term sequelae of chronic hypertension.