Heterozygous Arrhythmogenic Cardiomyopathy-desmoplakin Mutation Carriers Exhibit a Subclinical Cutaneous Phenotype with Cell Membrane Disruption and Lack of Intercellular Adhesion

Abstract

Genetic variants that result in truncation in desmoplakin (DSP) are a known cause of arrhythmogenic cardiomyopathy (AC). In homozygous carriers, the combined involvement of skin and heart muscle is well defined, however, this is not the case in heterozygous carriers. The aim of this work is to describe cutaneous findings and analyze the molecular and ultrastructural cutaneous changes in this group of patients. Four women and eight men with a mean age of 48 ± 14 years were included. Eight met definitive criteria for AC, one was borderline and three were silent carriers. No relevant macroscopic changes in skin and hair were detected. However, significantly lower skin temperature (29.56 vs. 30.97 °C, p = 0.036) and higher transepidermal water loss (TEWL) (37.62 vs. 23.95 g m 2 h 1, p = 0.028) were observed compared to sex- and age-matched controls. Histopathology of the skin biopsy showed widening of intercellular spaces and acantholysis of keratinocytes in the spinous layer. Immunohistochemistry showed a strongly reduced expression of DSP in all samples. Trichogram showed regular nodules (thickening) compatible with pseudomonilethrix. Therefore, regardless of cardiac involvement, heterozygous patients with truncation-type variants in DSP have lower skin temperature and higher TEWL, constant microscopic skin involvement with specific patterns and pseudomonilethrix in the trichogram.