Two decades of presumed Liddle syndrome: biochemical reverse phenotyping reveals apparent mineralocorticoid excess despite a coexisting SCNN1B variant: a case report

Abstract Background Apparent mineralocorticoid excess (AME) is a rare autosomal recessive disorder caused by deficiency of 11β-hydroxysteroid dehydrogenase type 2, in which cortisol activates the mineralocorticoid receptor. AME is clinically and biochemically near-identical to Liddle syndrome, yet the two differ in mechanism and in optimal targeted therapy. The growing use of multigene panels increasingly yields variants of uncertain significance in genes with overlapping phenotypes, creating diagnostic ambiguity that genetic testing alone cannot resolve. We report how targeted biochemical phenotyping adjudicated a genuinely conflicting panel result. Case presentation A woman in her early thirties had been managed since childhood under a presumptive diagnosis of Liddle syndrome, with longstanding hypertension, recurrent symptomatic hypokalemia, metabolic alkalosis, and renal potassium wasting despite amiloride and potassium supplementation. Multigene panel testing identified a homozygous likely pathogenic HSD11B2 variant (p.Ala237Val) together with a heterozygous SCNN1B variant of uncertain significance (p.Met395Ile) — two findings pointing to the two overlapping disorders. Twenty-four-hour urinary steroid profiling demonstrated a urinary free cortisol-to-cortisone ratio of 20.2 (normal approximately 0.54), providing direct biochemical evidence of impaired 11β-HSD2 activity and establishing AME as the dominant mechanism. The SCNN1B variant lay outside the PY motif where pathogenic Liddle-associated mutations cluster, arguing against Liddle syndrome. Addition of spironolactone to existing therapy was followed by normalization of serum potassium over three months of follow-up, consistent with the biochemical diagnosis. Conclusions This case demonstrates that biochemical reverse phenotyping remains essential for interpreting multigene panels when variants are found in genes with overlapping phenotypes. Urinary steroid profiling distinguished a causative HSD11B2 variant from an incidental SCNN1B variant of uncertain significance, illustrating a diagnostic principle of broad relevance as genomic testing becomes routine in the evaluation of monogenic hypertension.