IN THIS cohort study, genetic testing in 142 patients with palmoplantar keratoderma from 76 families identified 27 disease-causing variants across 13 genes, highlighting the role of genetics in diagnosis and subtype differentiation. Palmoplantar keratoderma is a complex dermatological condition characterised by thickened skin on the palms and soles. The condition exhibits significant clinical and genetic heterogeneity, which makes accurate diagnosis and subtype classification challenging. This study aimed to explore the clinical and genetic spectrum of palmoplantar keratoderma in a large cohort of Danish patients, to enhance understanding and inform clinical practice.
From September 1, 2016, to December 31, 2022, a cohort of 142 participants (90 females, median age 52 years) from 76 families was recruited across dermatology clinics in Denmark. Participants included both newly diagnosed patients and those under follow-up care for the disease. Clinical subtypes of palmoplantar keratoderma were classified as punctate (55%), diffuse (34%), focal (7%), and striate (4%). Genetic testing was conducted using whole-exome or genome sequencing, and Sanger sequencing for specific variants. A genetic diagnosis was found in 63 of the 76 families (83%), identifying 27 distinct disease-causing variants in 13 genes. The AAGAB gene variant was strongly associated with punctate palmoplantar keratoderma, showing a clear genotype-phenotype correlation. However, other subtypes exhibited more complex genotype-phenotype relationships. For example, patients with DSP gene variants were identified, with the added concern of a potential risk for cardiomyopathy, emphasising the importance of genetic testing in identifying associated risks.
This research provides valuable insights into the clinical and genetic heterogeneity of palmoplantar keratoderma. The findings demonstrate the utility of genetic testing in diagnosing the condition and distinguishing between different subtypes, which is critical for appropriate patient management. The discovery of variants in multiple genes underscores the need for tailored clinical care, particularly for those with more complex genotype-phenotype patterns. Given the association of some variants with additional health risks, such as cardiomyopathy in DSP-related cases, genetic testing should be integrated into clinical practice to ensure accurate diagnosis and comprehensive patient care. Future research should build on this cohort to further investigate genotype-phenotype correlations and explore the long-term outcomes for patients with palmoplantar keratoderma.
Abigail Craig, EMJ
Reference
Gram BJ et al. Clinical and genetic findings in patients with palmoplantar keratoderma. Jama Dermatol. 2024. DOI:10.1001/jamadermatol.2024.4824.
