Case Report: Dominant deafness-onychodystrophy syndrome and hypokalemic periodic paralysis in a single patient: a rare syndromic overlap

Dominant deafness-onychodystrophy syndrome (DDOD) and hypokalemic periodic paralysis (HypoPP) are distinct autosomal dominant disorders caused by mutations in <i>ATP6V1B2</i> and <i>CACNA1S</i>, respectively. We describe an eight-year-old female with congenital deafness, nail dysplasia, enamel hypoplasia, and recurrent episodes of hypokalemia-induced muscle weakness. Whole-exome sequencing (WES) revealed a <i>de novo ATP6V1B2</i> nonsense variant (c.1516C>T, p.Arg506Ter) and a maternally inherited <i>CACNA1S</i> missense variant (c.1583G>A, p.Arg528His). The proband's mother and maternal grandfather carried the same <i>CACNA1S</i> variant with milder periodic weakness, indicating intrafamilial variability and reduced penetrance. This dual diagnosis broadens the phenotypic spectrum of both DDOD and HypoPP and illustrates how comprehensive genomic testing can elucidate complex, blended phenotypes. Although no direct mechanistic link between <i>ATP6V1B2</i> and <i>CACNA1S</i> has been demonstrated, their coexistence highlights the importance of considering multilocus genetic etiologies in rare diseases and supports precision medicine approaches integrating genomic diagnostics and individualized management.