Clin Exp Dermatol. 2025 Oct 18:llaf443. doi: 10.1093/ced/llaf443. Online ahead of print.
ABSTRACT
BACKGROUND: Pathogenic heterozygous desmoplakin (DSP) variants cause arrhythmogenic cardiomyopathy, predisposing to sudden cardiac death, and occasionally found in dermatologic patients with palmoplantar epidermal differentiation disorders (pEDDs) and curly/woolly hair. DSP variants of uncertain significance (VUS) in pEDD patients complicate cardiac risk assessment.
OBJECTIVE: To characterize cardiocutaneous phenotypes associated with heterozygous DSP variants.
METHODS: We enrolled 45 heterozygous DSP carriers (aged 2-80 years; 18 probands followed for cardiomyopathy [n=16] or pEDD [n=2] and 27 family members) and 10 non-carriers from 18 families at Helsinki University Hospital, Finland. Genetic, cardiac and dermatologic evaluations included next-generation sequencing panels, whole exome or Sanger sequencing, laboratory tests, electrocardiography, echocardiography, cardiac magnetic resonance imaging, skin histology, immunohistochemistry, and hair microscopy.
RESULTS: Seventeen DSP variants (10 pathogenic/likely-pathogenic, seven VUS) were identified. Fifteen were newly associated with pEDD, including six also new for cardiomyopathy.Characteristic focal hyperkeratosis around heel rims and soles’ outer edges (DSP-pEDD) was observed in 86% of carriers, accompanied by palmar hyperkeratosis (36%), pEDD-related pain (59%), aquagenic whitening (58%), and curly/wavy hair (57%). Cardiac abnormalities occurred in 72%, with 60% meeting cardiomyopathy criteria, 44% exhibiting arrhythmias, and 16% requiring resuscitation. VUS-associated phenotypes were similar to pathogenic/likely-pathogenic variants.Onset of pEDD (median 13 years) preceded cardiomyopathy by three decades. Cardiac abnormalities affected 10% of adults with pEDD by age 30, 52% by age 50, and 83% by age 70.
CONCLUSIONS: Heterozygous DSP variants cause childhood-onset focal pEDD preceding midlife-onset arrhythmogenic cardiomyopathy. Genetic testing is essential in pEDD and cardiac evaluation in patients with DSP variants.
PMID:41108751 | DOI:10.1093/ced/llaf443
