Palmoplantar Keratoderma: A Mechanism-Based Disease Classification.

BACKGROUND: Palmoplantar keratoderma (PPK) represents a diagnostically challenging group of genodermatoses due to its extensive genetic heterogeneity. Although multiple causative genes have been identified, the clinical utility of these discoveries remains limited, because few studies directly compare how distinct molecular mechanisms translate into divergent clinical phenotypes. METHODS: We describe and analyze three paradigmatic PPK cases with genetically confirmed diagnoses involving SERPINB7-related Nagashima-type PPK, TRPV3-related Olmsted spectrum disorder, and KRT1-associated PPK. Clinical features, disease severity, and genetic mutations were systematically compared. These observations generated a novel classification framework and were then integrated with a comprehensive review of contemporary literature to contextualize and support the comparative findings. RESULTS: Three patients with palmoplantar keratoderma (PPK) harboring distinct pathogenic variants were analyzed and comparatively evaluated. Despite overlapping clinical features, these cases corresponded to three distinct pathogenic mechanisms: defective barrier homeostasis, overactive signaling, and structural collapse. A mechanism-based classification framework was established accordingly. Through comprehensive literature review, 56 PPK-associated genes were identified, the majority of which could be systematically assigned to the three mechanistic categories based on their primary molecular functions. CONCLUSION: This study highlights that clinically overlapping PPK phenotypes arise from distinct molecular mechanisms. Our mechanism-based classification provides a framework linking genotype to pathogenesis, which may improve diagnostic precision, support the development of mechanism-targeted therapeutic strategies, and thereby advancing personalized management in hereditary PPK.