Erythrokeratodermia-Cardiomyopathy Syndrome: Expanding the DSP Mutational Spectrum Beyond Proline Substitutions.

Abstract

Erythrokeratodermia cardiomyopathy (EKC) syndrome is a rare autosomal dominant disorder characterized by generalized erythrokeratoderma and progressive dilated cardiomyopathy, caused by pathogenic variants in the SR6 domain of desmoplakin (DSP). We report two cases of EKC with novel de novo missense DSP variants at phenylalanine position 590 (F590S and F590V), expanding the mutational spectrum beyond proline substitutions. Immunostaining demonstrated disrupted desmosomal protein localization. One patient showed significant clinical improvement with ustekinumab therapy. These findings underscore the need for early cardiac monitoring and support IL-12/23p40 inhibition as a potential therapeutic strategy in EKC.