Key result
Heterozygous DSP variants link to childhood focal hyperkeratosis in 86% of carriers preceding midlife arrhythmogenic cardiomyopathy.
Why the study?
Pathogenic heterozygous DSP variants cause arrhythmogenic cardiomyopathy and are occasionally found in patients with palmoplantar epidermal differentiation disorders (pEDDs), but variants of uncertain significance complicate cardiac risk assessment.
Observational (n=55)
No
Heterozygous DSP variants cause childhood-onset focal palmoplantar epidermal differentiation disorders that precede midlife-onset arrhythmogenic cardiomyopathy, highlighting the skin phenotype as a red flag requiring cardiac evaluation.
May flag DSP variant carriers via childhood skin findings for cardiac surveillance; hypothesis-generating, requiring prospective validation.
BACKGROUND: Pathogenic heterozygous desmoplakin (DSP) variants cause arrhythmogenic cardiomyopathy, predisposing to sudden cardiac death, and occasionally are found in dermatology patients with palmoplantar epidermal differentiation disorders (pEDDs) and curly/woolly hair. DSP variants of uncertain significance (VUS) in patients with pEDD complicate cardiac risk assessment. OBJECTIVES: 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 family members who were noncarriers from 18 families at Helsinki University Hospital, Finland. Genetic, cardiac and dermatological 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, 7 VUS) were identified. Fifteen were newly associated with pEDD, including six also new for cardiomyopathy. Characteristic focal hyperkeratosis around heel rims and outer edges of soles (DSP-pEDD) was observed in 86% (36/42) of carriers, accompanied by palmar hyperkeratosis (36%, 15/42), pEDD-related pain (59%, 16/27), aquagenic whitening (58%, 19/33) and curly/wavy hair (57%, 24/42). Cardiac abnormalities occurred in 72% (31/43), with 60% (26/43) meeting cardiomyopathy criteria, 44% (19/43) exhibiting arrhythmias, and 16% (7/43) requiring resuscitation. VUS-associated phenotypes were similar to pathogenic/likely pathogenic variants. Onset of pEDD (median 13 years, range 1.5-70 years) preceded cardiomyopathy by three decades. Cardiac abnormalities affected 10% (3/29) of adults with pEDD by age 30, 52% (15/29) by age 50 and 83% (24/29) by age 70 years. 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.
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Brandt et al. (2025) conducted an observational in Heterozygous desmoplakin (DSP) variants (n=55). Heterozygous DSP variants vs. Noncarriers was evaluated on Cardiocutaneous phenotypes (focal hyperkeratosis, cardiac abnormalities). Heterozygous DSP variants were associated with childhood-onset focal palmoplantar epidermal differentiation disorders in 86% of carriers, preceding midlife-onset arrhythmogenic cardiomyopathy.
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