DSP-palmoplantar epidermal differentiation disorder: a distinct phenotype and red flag for cardiomyopathy.

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.