Global Molecular Epidemiology and Genotype-Phenotype Correlations in Keratinocytic Epidermal Nevus: A Systematic Review.

Keratinocytic epidermal nevi (KEN) represent a heterogeneous group of mosaic skin disorders driven by diverse causative genes. This systematic review aimed to delineate the global molecular epidemiology of KEN, establish genotype-phenotype correlations, and define a stratified framework for molecular diagnosis and targeted therapy. We searched PubMed, Embase, Scopus, and Web of Science from inception to May 31, 2026. Data from 141 patients across 77 reports were extracted, and associations were analyzed by histopathological subtype, lesion distribution, and systemic involvement. Generalized KEN was more common than localized forms (55.3% vs. 36.2%). Pathogenic mutations were detected in 79.4% of cases, most frequently in HRAS, KRT10, FGFR3, KRAS, and FGFR2. Non-epidermolytic KEN (n = 94) predominantly harbored RAS/MAPK and receptor tyrosine kinase pathway mutations, whereas epidermolytic KEN (n = 18) was associated with KRT1/2/10 mutations, and inflammatory linear verrucous epidermal nevus (n = 24) displayed heterogeneous alterations. Mutation detection in lesional skin was significantly higher than in peripheral blood (78.3% vs. 27.8%), with generalized forms showing higher peripheral blood positivity than localized forms (41.0% versus 14.0%). HRAS c.34G>A and FGFR3 c.742C>T were predominantly observed in generalized KEN, whereas HRAS c.37G>C, FGFR2 c.755C>G, and EGFR exon 20 insertions were mainly detected in localized disease. Extracutaneous manifestations (27.7% of cases, primarily with KRAS, FGFR3, and HRAS) and parent-to-offspring transmission (15 pedigrees, predominantly involving KRT1/10) more often occurred in generalized KEN. Nine patients received genotype-directed targeted therapies with satisfactory responses. These findings delineate a comprehensive genotype-phenotype landscape of KEN and propose a lesional tissue-based tiered molecular diagnostic strategy incorporating high-depth sequencing for mechanism-driven targeted therapy and genetic counseling. Integrating clinical, histopathological, and molecular data within this framework offers a practical foundation for diagnostic stratification and precision medicine in KEN.