Genetic Background and Genotype-Phenotype Correlations in Palmoplantar Epidermal Differentiation Disorders

Palmoplantar epidermal differentiation disorders (pEDDs) are a heterogeneous group of rare inherited skin diseases characterized by abnormal thickening of the epidermis on the palms and soles. In addition to cutaneous involvement, some pEDDs present with extracutaneous features such as cardiomyopathy. Although recent advances in gene technologies have improved the understanding of the molecular basis of pEDDs, the genetic diagnosis remains unresolved in a subset of patients, and genotype-phenotype relationships are not yet fully defined. The aim of this thesis was to elucidate the genetic background and genotype-phenotype correlations in pEDDs through detailed clinical and molecular characterization of patients with heterozygous pathogenic (P) or likely pathogenic (LP) variants or variants of uncertain significance (VUS) in desmoplakin (DSP) as well as those with SERPIN-associated disorders (SERPINA12- and SERPINB8-pEDDs). In the first two studies, cardiocutaneous phenotypes associated with heterozygous DSP variants were analyzed in 72 individuals carrying a total of 18 distinct DSP variants including 11 P or LP variants and seven VUS. Palmoplantar keratoderma was present in over 90% of the patients with heterozygous DSP variants. It was identified as a distinct form of focal keratoderma characterized by thickened skin around the heel rims, outer edges of the soles, and first toes. This childhood-onset DSP-pEDD, with a median onset age of 14 years old, was demonstrated to serve as a red flag for cardiomyopathy, which was typically diagnosed three decades later with a median age at cardiomyopathy diagnosis of 45 years old. Nearly half (45%) of the patients with heterozygous DSP variants fulfilled the diagnostic criteria for cardiomyopathy, 43% experienced arrhythmias including life-threatening ventricular arrhythmias, 24% had myocarditis-like inflammatory episodes, and 13% suffered cardiac arrest requiring resuscitation, which was sometimes the first clinical manifestation of cardiac disease. The subsequent studies focused on autosomal recessive SERPIN-associated pEDDs caused by loss-of-function (LoF) variants in SERPINA12 and SERPINB8. Three patients with biallelic SERPINA12 variants and four siblings with a homozygous SERPINB8 variant were identified that expanded the number of reported individuals to 11 and 10, respectively. LoF variants in both SERPINA12 and SERPINB8 were identified to cause early-onset pEDD. SERPINA12-pEDDs presented with diffuse palmoplantar keratoderma with transgradiens similar to the phenotype in the well-known SERPINB7-pEDD, while the SERPINB8-pEDD phenotype was characterized by palmoplantar peeling, which was often accompanied by diffuse or focal palmoplantar keratoderma. Palmoplantar hyperhidrosis and aquagenic whitening were common across all SERPIN-pEDDs, whereas thickened skin on the knuckles and malleoli, acral blistering, and cheilitis were unique to SERPINB8-pEDD. These SERPIN-associated disorders share a common pathophysiology involving protease overactivity and a disrupted proteolytic network, which underlies their overlapping clinical manifestations and represents a potential target for emerging therapies. Recognition of palmoplantar keratoderma as a potential early sign of DSP cardiomyopathy is crucial, as sudden cardiac death may occur as the initial cardiac event. The childhood-onset focal keratoderma on heel rims, outer edges of the soles, and first toes should alert clinicians to suspect the possibility of DSP-pEDD with underlying arrhythmogenic cardiomyopathy. The findings of this thesis emphasize the importance of early genetic testing in pEDD for accurate diagnosis, patient counselling, and implementation of appropriate surveillance and emerging pathogenesis-targeting therapies.

Grantor dc:publisher

Helsingin yliopisto

Year dc:date.issued

2026

Author dc:creator

• Brandt, Eveliina

• lääketiede

Statement dc:rights

• Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.
• This publication is copyrighted. You may download, display and print it for Your own personal use. Commercial use is prohibited.
• Publikationen är skyddad av upphovsrätten. Den får läsas och skrivas ut för personligt bruk. Användning i kommersiellt syfte är förbjuden.

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/10138/626861

OAI record oai:identifier

https://helda.helsinki.fi/server/oai/request?verb=GetRecord&metadataPrefix=dim&identifier=oai%3Ahelda.helsinki.fi%3A10138%2F626861