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

Eva Cabrera-Borrego,Eduardo Fernández-Segura,Trinidad Montero-Vilchez,Jesús Tercedor-Sánchez,Francisco Javier Cañizares-García,Juan Jiménez-Jáimez,Rosa Macías-Ruiz,María Molina-Jiménez,Manuel Sánchez-Díaz,Angel Fernandez-Flores,Salvador Arias-Santiago,Luis Tercedor-Sánchez,Francisco José Bermúdez-Jiménez

doi:10.3390/jcm10194608

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.

Highlights

Eight patients met definitive criteria for the diagnosis of arrhythmogenic cardiomyopathy (AC) according to the 2010 TFC: two with exclusive left ventricular involvement, two with right ventricular involvement and four with biventricular involvement
Most of these cases showed segregation of the DSP mutation with a phenotype consisting of left ventricular fibrofatty replacement, low QRS complex voltages and an increased arrhythmic risk (Figure A1 of Appendix B)
One case showed a borderline AC status according to the TFC

Summary

Introduction

The first genetic variants associated with this condition were described in genes encoding desmosomes, critical structures involved in adherence regulation and mechanical integrity of tissues, especially in the myocardium and the skin. Familial characterization of this disease as a genetically conditioned disorder of desmosomes was first made by studying patients with Naxos disease, an autosomal recessive cardiocutaneous syndrome caused by mutations in plakoglobin and featured by the presence of AC, palmoplantar hyperkeratosis and „woolly” hair [2]. The published series have shown that heterozygous carriers can develop as severe heart disease as homozygotes, in heterozygosis the penetrance of the disease is incomplete The causes of this incomplete penetrance are not yet fully understood. The age at onset of AC is variable with an estimated mean age of 31 years, being rare after the age of 60 years [4]

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