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DSP-palmoplantar epidermal differentiation disorder: a distinct phenotype and red flag for cardiomyopathy
Eveliina Brandt1, Krista Heliö2, Liisa Harjama1
1Department of Dermatology and Allergology, ERN-Skin Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Insights
Heterozygous desmoplakin (DSP) variants cause early-onset palmoplantar epidermal differentiation disorders (pEDD) that precede arrhythmogenic cardiomyopathy by decades. Genetic testing is crucial for patients with pEDD and cardiac evaluation for DSP variant carriers.
Area of Science:
- Cardiovascular Medicine
- Dermatology
- Genetics
Background:
- Pathogenic heterozygous desmoplakin (DSP) variants are linked to arrhythmogenic cardiomyopathy and sudden cardiac death.
- These DSP variants are also found in dermatologic patients with palmoplantar epidermal differentiation disorders (pEDD) and specific hair conditions.
- Variants of uncertain significance (VUS) in DSP complicate cardiac risk assessment in pEDD patients.
Purpose of the Study:
- To characterize the cardiocutaneous phenotypes associated with heterozygous DSP variants.
- To investigate the relationship between DSP variants, pEDD, and cardiomyopathy development.
- To clarify the clinical implications of DSP variants, including VUS, in affected individuals.
Main Methods:
- Enrolled 45 heterozygous DSP carriers and 10 non-carriers from 18 families.
- Conducted genetic evaluations including next-generation sequencing, whole exome, or Sanger sequencing.
- Performed comprehensive cardiac (ECG, echocardiography, MRI) and dermatologic (skin histology, hair microscopy) assessments.
Main Results:
- Identified 17 DSP variants (10 pathogenic/likely-pathogenic, 7 VUS), with 15 newly associated with pEDD.
- Observed characteristic focal hyperkeratosis in 86% of carriers, alongside other pEDD features and curly/wavy hair.
- Found cardiac abnormalities in 72% of carriers, with 60% meeting cardiomyopathy criteria and 44% experiencing arrhythmias; VUS showed similar phenotypes.
Conclusions:
- Heterozygous DSP variants cause childhood-onset focal pEDD that precedes midlife-onset arrhythmogenic cardiomyopathy.
- pEDD onset typically occurs decades before cardiac abnormalities become apparent.
- Genetic testing for DSP variants is essential in pEDD patients, and cardiac evaluation is vital for all DSP variant carriers.
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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