A frameshift variation in the DSP gene causes a novel subtype of atypical epidermolytic palmoplantar keratoderma: Case report

Palmoplantar keratoderma (PPK) represents a heterogeneous group of disorders characterized by hyperkeratosis of the palms and soles. Epidermolytic palmoplantar keratoderma (EPPK) is typically caused by variations in <i>KRT9</i> or <i>KRT1</i> genes. However, growing evidence suggests that defects in desmosomal genes, particularly desmoplakin (<i>DSP</i>), may underlie atypical variants. We report a 17-year-old girl with a 10-year history of yellowish, hyperkeratotic plaques with greasy scales on the dorsal hands, soles, and axillae. Histopathology revealed hyperkeratosis, parakeratosis, and acantholysis. Whole-exome sequencing (WES) identified a novel heterozygous frameshift variation in <i>DSP</i> (c.6218_6219dup, p. Ala2074Ter), confirmed by Sanger sequencing. This is the first report of an atypical EPPK caused by a <i>DSP</i> frameshift variation in the C-terminal domain, expanding the genotypic and phenotypic spectrum of PPK. The variant was absent from the gnomAD database. Functional studies demonstrated significant downregulation of adhesion molecules (<i>CDH1</i>, <i>JUP</i>, and <i>CTNNA1</i>) upon <i>DSP</i> knockdown, suggesting impaired desmosome-keratin anchoring as the pathogenic mechanism. This case reveals that <i>DSP</i> C-terminal domain variations can cause a new subtype of EPPK, providing new insights into PPK diagnosis and treatment.