Clinical and Molecular Perspectives on Epidermodysplasia Verruciformis

Epidermodysplasia verruciformis (EV) is a rare dermatologic disorder marked by an increased susceptibility to β-human papillomavirus infections and a heightened risk of cutaneous squamous cell carcinoma. While classically associated with autosomal recessive pathogenic variants in TMC6, TMC8, and CIB1, recent reports have expanded the disease spectrum to include acquired forms occurring in immunocompromised individuals, including those with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), organ transplants, and autoimmune disease. Both inherited and acquired EV share similar clinical and histopathologic features: flat-topped or hypopigmented papules in sun-exposed areas and characteristic "blue cells" on biopsy. Advances in molecular diagnostics, such as RNA chromogenic in situ hybridization, allow for spatial detection of transcriptionally active human papillomavirus (HPV) within skin lesions. Although treatment remains largely symptomatic, topical and systemic retinoids, immunomodulatory agents, and HPV vaccines have shown variable success. Experimental strategies such as zinc supplementation and CRISPR/Cas9 gene-editing are under investigation and offer future therapeutic potential. This review highlights the evolving understanding of both genetic and acquired forms of EV and incorporates a comprehensive review of 47 inherited EV and 67 acquired EV publications. Cases were analyzed for demographic patterns, genotype-phenotype associations, and diagnostic trends with selected statistical testing to assess significant relationships. In classic and nonclassic EV cases, patients in the classic EV group were diagnosed at a significantly older age than those in the nonclassic group. In acquired EV (AEV), HIV-associated presentations occurred at significantly younger ages, and autoimmune-related AEV occurred primarily in female patients. There was a strong association between underlying disease and sex distribution. HIV-associated AEV predominantly affects males.