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

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 KRT9 or KRT1 genes. However, growing evidence suggests that defects in desmosomal genes, particularly desmoplakin (DSP), 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 DSP (c.6218_6219dup, p. Ala2074Ter), confirmed by Sanger sequencing. This is the first report of an atypical EPPK caused by a DSP 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 (CDH1, JUP, and CTNNA1) upon DSP knockdown, suggesting impaired desmosome-keratin anchoring as the pathogenic mechanism. This case reveals that DSP C-terminal domain variations can cause a new subtype of EPPK, providing new insights into PPK diagnosis and treatment.