Genetic causes in 83% of palmoplantar keratoderma cases were identified, revealing 27 pathogenic or likely pathogenic variants across 13 genes, including a founder mutation in AAGAB, according to a recent cohort study.

Researchers examined the clinical and genetic characteristics of palmoplantar keratoderma (PPK), a heterogeneous group of disorders affecting the palms and soles. Conducted in Denmark between 2016 and 2022, the study, published in JAMA Dermatology, included 142 participants from 76 families recruited from private practitioners in dermatology and dermatology departments. Whole-exome and genome sequencing, along with targeted Sanger sequencing, were used to detect disease-causing variants.

The participants were categorized into 4 clinical subtypes: punctate (55%), diffuse (34%), focal (7%), and striate (4%). A genetic diagnosis was achieved in 83% of families (63/76), highlighting the hereditary nature of PPK. Disease-causing variants were distributed across 13 genes: AAGAB (n=39), DSG1 (n=8), KRT1 (n=3), DSP (n=2), KRT9 (n=2), AQP5 (n=2), KRT16 (n=1), SERPINA12 (n=1), ABCA12 (n=1), COL7A1 (n=1), CARD14 (n=1), DST (n=1), and LORICRIN (n=1). All cases with AAGAB variants exhibited a clear genotype-phenotype correlation.

DSP variants were identified in 2 families and are associated with cardiomyopathy, necessitating targeted cardiac monitoring. Genetic testing was essential in identifying these cases, as no distinct clinical features distinguished them from other subtypes.

The median age of participants was 52 years (range, 18-92 years), with diffuse PPK cases showing the earliest median onset at 5.3 years (range, 0-44.0 years). Most participants (92%) had symptoms affecting both palms and soles, with 68% reporting pain or soreness and 37% experiencing excessive sweating. A founder variant, AAGAB c.370C>T, was identified in 35 of 42 punctate cases (83%), emphasizing its diagnostic relevance in the Danish cohort.

The study achieved a genetic diagnosis rate of 83% and identified 27 disease-causing variants, including several novel variants. The findings highlighted the importance of genetic testing for identifying patients who may need cardiac monitoring.

Full disclosures can be found in the published study.