Genotype–phenotype correlations and cancer risk in monogenic epidermodysplasia verruciformis

Epidermodysplasia verruciformis (EV) is an ultrarare genodermatosis characterized by lifelong disseminated and persistent flat-like warts due to susceptibility to weakly virulent β-Human papilloma viruses (bHPVs), which exclusively have tropism towards keratinized keratinocytes. In sun-exposed locations, EV lesions frequently develop into skin carcinomas.1 EV can be categorized into typical (isolated) and atypical (syndromic). Isolated EV manifests solely as HPV susceptibility, whereas syndromic EV includes additional infectious or tumoural phenotypes.2 To investigate genetic, immunologic and clinical findings for reported monogenic EV, we conducted a PRISMA-compliant systematic review across Scopus, MEDLINE, Web of Science and Google Scholar on 8 July 2024. The protocol was registered on INPLASY (ID: 2023100006, https://inplasy.com/inplasy-2023-10-0006/). Only pathogenic and likely pathogenic sequence variants classified according to ACMG criteria were included.3, 4 From the 1173 screened articles, 59 matched the inclusion criteria, with 183 identified EV patients. Among 169 patients with reported sex, 91 (54%) were male and 78 (46%) female. The mean and median age of onset for EV-related symptoms were 6.80 ± 4.85 years (IQR = 4–8 years, R = 6 months–23 years) and 6 years, respectively (Figure 1a). Percentages of age-of-onset distributions for patients under 7 years, 7–12 years and over 12 years were 55%, 35% and 10%, respectively. The most reported EV patients were from Iran. We identified 21 genes from 183 cases, 3 of which met the criteria for isolated EV, including TMC6, TMC8 and CIB1, which were identified in 141 patients (77%), and 18 (23%) of which met the criteria for syndromic EV, including STK4, DOCK8, ITK, LCK, JAK3, CORO1A, RHOH, CHUK, CARD11, DCLRE1C, FLT3LG, IKBKG, IL2RG, NF1, RASGRP1, SMARCAL1, TPP2 and ZAP70, with TMC6, CIB1, TMC8, STK4 and DOCK8 being the most commonly reported genes overall (Figure 1b).5-10 Any adaptive T-cell immunity defects were not reported in association with isolated EV. Based on number of identified genes, most EV-associated genes belong to nonsyndromic and syndromic combined immunodeficiency groups (Figure 1c,d). The most common mode of inheritance was autosomal recessive (AR) β-(17 genes, 81%), followed by autosomal dominant (AD) (two genes, including CARD11 and NF1, or 9.5%) and X-linked recessive (XLR) (two genes, or 9.5%, including IL2RG, IKBKG). Except for NF1 and FLT3LG, 19 of the 21 EV-related genes are classified into four groups by IUIS. Detected HPVs include 33 distinct HPVs belonging to α-, γ- and β-HPV genera, with HPV-5, HPV-8, and HPV-20 being the most common types of HPV identified (Figure 2a). Syndromic EV patients exhibited broader microbial susceptibility, often with concurrent or sequential infections. Cancer was reported in 102 of 183 patients (56%) (Figure 2b). Skin cancers were more prevalent in isolated EV (61%) versus syndromic EV (10%) (odds ratio [OR] = 13.57 [95% CI: 5.1–36.2]). Conversely, non-skin cancers were more prevalent in syndromic EV (26%) versus isolated EV (3%) (OR = 16.28 [95% CI: 5.1–52]; Figure 2d). Our team performed basic calculations, which did not account for age factors, skin type or total UV exposure, as the studies lacked complete information on these variables. In a typical EV, CIB1 patients show the highest skin-cancer prevalence (65%, 29/45), followed by TMC6 (56%, 29/52) and TMC8 (51%, 23/45). Among typical EV genes, the three most frequent mutations associated with skin cancers are CIB1 c.465 + 1dup (82%, 9/11), TMC6 c.892-2A>T (57%, 8/14) and CIB1 c.52-2A>G (55%, 11/20). The age of onset for cancer is significantly earlier than that of the general population. For skin cancers (n = 58), the mean age of onset was 28.9 ± 14.4 years (median: 26, Range = 7–68 years) versus a population mean of 57 years (difference: 28.1 years; Z = −14.67). For non-skin cancers (n = 13), the mean age was 26.5 ± 19.5 years (median: 22, range = 4–538 years) versus a general mean of 60 years (difference: 23.5 years; Z = −6.19; Figure 2c). In summary, our data establish genotype–phenotype correlations in single-gene EV patients. The distinction between isolated and syndromic EV has prognostic, therapeutic and diagnostic implications for patient management. Early cancer screening is essential, given the younger age at which cancer develops in the EV population. The LEO Foundation (grant LF-OC-22-000965) and the US NIH (grant R01AI143810) supported the authors' studies. Johann E. Gudjonsson has served as an advisor for Almirall, Eli Lilly, Sanofi, Novartis, BMS, Janssen, Boehringer Ingelheim, and has received research grants from Almirall, Prometheus Biosciences, Janssen, Eli Lilly, Boehringer Ingelheim and Galderma. Hakon Hakonarson, together with the Children's Hospital of Philadelphia, is an equity holder in Nobias Therapeutics, which is developing MEK inhibitor therapy for complex lymphatic anomalies. Jean-Laurent Casanova serves on the scientific advisory boards of ADMA Biologics Inc., Kymera Therapeutics and Elixiron Immunotherapeutics. Sajjad Biglari, Leila Youssefian, Atefeh Sohanforooshan Moghaddam, Roya Sherkat, Fatemeh Vahidnezhad, Amir Hossein Saeidian, Mahdi Akbarzadeh, Vivien Béziat, Emmanuelle Jouanguy and Hassan Vahidnezhad have no conflicts of interest to declare. This study was approved by the Ethics Committee of Isfahan University of Medical Sciences (IR.MUI.MED.REC.1401.255). This study is part of S.B.'s PhD thesis and was conducted in accordance with institutional ethical standards and the Declaration of Helsinki. The data that support the findings of this study are available from the corresponding author upon reasonable request.