Clinical and Genetic Findings in Patients With Palmoplantar Keratoderma

Abstract

Importance: Palmoplantar keratoderma poses diagnostic challenges due to its clinical and genetic heterogeneity, and knowledge on the value of systematic genetic testing on clinically well-described patient cohorts is sparse.

Objective: To improve knowledge of the clinical and genetic spectrum of patients with palmoplantar keratoderma.

Design, setting, and participants: This cohort study prospectively recruited patients and affected family members with palmoplantar keratoderma between September 1, 2016, and December 31, 2022. Patients were recruited from private practitioners in dermatology and dermatology departments in Denmark. Study participants were patients 18 years or older either newly diagnosed with palmoplantar keratoderma or being followed up for the disease at referral centers.

Main outcomes and measures: Phenotypes and clinical subtypes were classified. Genetic testing was performed by whole-exome or genome sequencing using an in silico panel containing genes related to palmoplantar keratoderma, or by Sanger sequencing for specific variants. Descriptive analysis, such as proportions and frequency, were used to describe clinical characteristics, distribution of disease-causing variants, and genotype-phenotype associations.

Results: This study included 142 study participants from 76 families (90 [63%] female; median [range] age, 52 [18-92] years). Clinical subtypes included 42 punctate (55%), 26 diffuse (34%), 5 focal (7%), and 3 striate (4%). A genetic diagnosis was found in 63 of 76 families (83%), including 27 disease-causing variants within 13 different 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 participants with AAGAB variants presented with punctate palmoplantar keratoderma, showing a clear genotype-phenotype correlation. The other subtypes (diffuse, focal, and striate) proved more challenging to clinically subclassify, and disease-causing variants were identified in 12 genes, contributing to more complex genotype-phenotype patterns. Patients with palmoplantar keratoderma due to DSP variants were found, which is important to identify because of an associated risk of cardiomyopathy.

Conclusion and relevance: This study provides novel insights into the clinical and genetic spectrum of patients with palmoplantar keratoderma. It demonstrates the value of genetic testing for accurate diagnoses and to distinguish between different subtypes. The established and well-described cohort lays the foundation for future research in palmoplantar keratoderma.

Figure 1.. Clinical Images of Patients With Palmoplantar Keratoderma

Clinical images illustrating phenotypic features of the genotypes identified in the cohort: AAGAB (proband 70), KRT1 (proband 32), KRT 9 (proband 30), KRT16 (proband 13), DSP (proband 60), DSG1 (proband 41), AQP5 (relative 55), SERPINA12 (proband 64), LORICRIN (proband 4), DST (proband 59), ABCA12 (proband 19), COL7A1 (proband 63), and CARD14 (proband 31).

Figure 2.. Clinical Subtypes and Molecular Genetic Diagnosis in 76 Families With Palmoplantar Keratoderma

Distribution of clinical subtypes based on patterns of hyperkeratosis and overview of genes with disease-causing variants identified in each clinical subtypes.

Figure 3.. Genetic Subtypes and Phenotypic Features

A, Number of study participants per genotype. B, Age at onset of palmoplantar keratoderma for each participant. Enlarged dots represent more participants with the same age at onset. C, Progression in symptoms per genotype. D, Patient-reported treatment response to systemic retinoids per genotype. E, Associated symptoms per genotype. Total indicates the total number of participants with a genetically confirmed diagnosis. Numbers presented are based on informative cases (cases with missing data are omitted). For panels B and E, clinical data per genotype are reported for genes represented by at least 2 participants in the study cohort. Data and specific numbers and percentages are also available in eTable 2 in Supplement 1. NA indicates not applicable.