Genotype-Phenotype Correlations in KRT17-PEDD: The Critical Role of Codon 88.

KRT17-pEDD (formerly pachyonychia congenita Type 2) is a rare autosomal dominant palmoplantar epidermal differentiation disorder caused by pathogenic variants in the KRT17 gene. Most variants cluster within highly conserved helix boundary motifs essential for keratin filament assembly. This multicenter registry-based study evaluated genotype-phenotype correlations among three KRT17 codon 88 substitutions: p.(Met88Lys), p.(Met88Arg), and p.(Met88Thr). Sixteen affected individuals from eight unrelated families across eight countries were identified through the International Pachyonychia Congenita Research Registry. Clinical data were collected using standardized questionnaires and medical record review. A genotype-phenotype correlation was observed according to substitution properties. Charged substitutions (lysine and arginine) were associated with earlier onset and more severe disease, including marked hypertrophic nail dystrophy and painful plantar keratoderma frequently requiring treatment. Persistent hoarseness was noted in all three p.(Met88Arg) carriers, a preliminary finding that may suggest a broader phenotypic spectrum in KRT17-pEDD pending confirmation in larger cohorts, while natal teeth showed complete penetrance in the p.(Met88Lys) group. In contrast, p.(Met88Thr) was associated with a milder and more variable clinical course. Cutaneous adnexal manifestations were common across all groups. These findings identify codon 88 as a structurally sensitive functional hotspot in KRT17, where the physicochemical nature of the amino acid substitution may influence clinical severity. The results refine clinical interpretation of KRT17-pEDD and support improved counseling and future pathogenesis-based precision therapies.