Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.
Medical Genetics Department, Eskişehir Osmangazi University, Eskişehir, Turkey.
J Eur Acad Dermatol Venereol. 2017 Oct;31(10):1722-1726. doi: 10.1111/jdv.14431. Epub 2017 Aug 4.
Epidermodysplasia verruciformis (EV) is a genodermatosis leading to infections with cutaneous HPV, persistent plane warts and a high rate of non-melanoma skin cancer (NMSC). Biallelic loss-of-function mutations in TMC6 and TMC8 are known to be causative.
The aim of this study was to report EV-causing mutations in four patients with EV and to give an overview of all described patients with EV.
We investigated four patients with classical features of EV from two families. All patients were affected by plane warts with typical EV histology since early childhood, and β-HPVs were detected on their skin. One patient had recurring cutaneous squamous cell carcinomas (cSCC) and carcinomas in situ (Bowen type). We sequenced both TMC6/8 for disease-causing mutations and quantified levels of gene expression. We also performed a systematic literature review to discuss these patients in the context of previously reported cases, mutations already identified, as well as HPV types.
Three patients of one family carried a homozygous splice site mutation in TMC8 resulting in aberrantly spliced transcripts that were not degraded. By contrast, no TMC6/8 mutation was detected in the patient from the other family. A systematic literature review revealed 501 described patients with EV. Around 40% of patients with EV analysed for genetic alterations carried no mutation in TMC6/8. While β-HPVs were identified in the majority of cases, α-HPVs were detected in several individuals.
The relatively high proportion of EV patients without mutation in TMC6/8 indicates the existence of EV-causing mutations in additional, presently unknown gene(s). However, a homozygous TMC8 splice site mutation in our patients resulted in aberrant transcripts which cannot retain the healthy phenotype. The literature review revealed that HPV-5 is the most commonly identified HPV in patients with EV, but HPV-3, HPV-14 and HPV-20 were unexpectedly identified more frequently than HPV-8.
疣状表皮发育不良（EV）是一种遗传性皮肤病，可导致皮肤 HPV 感染、持续性扁平疣和非黑色素瘤皮肤癌（NMSC）发生率高。现已证实 TMC6 和 TMC8 的双等位基因功能丧失突变是致病原因。
本研究旨在报道 4 例 EV 患者的致病突变，并对所有已报道的 EV 患者进行综述。
我们对来自两个家族的 4 例具有 EV 典型特征的患者进行了研究。所有患者自幼年起均患有典型 EV 组织学特征的扁平疣，且其皮肤中检测到 β-HPV。1 例患者曾反复发作皮肤鳞状细胞癌（cSCC）和原位癌（鲍文样）。我们对 TMC6/8 进行了致病突变测序，并对基因表达水平进行了定量分析。我们还进行了系统的文献回顾，以便在先前报道的病例、已鉴定的突变以及 HPV 类型的背景下讨论这些患者。
一个家族的 3 例患者携带 TMC8 的纯合剪接位点突变，导致异常剪接的转录本不能被降解。相比之下，另一个家族的患者未检测到 TMC6/8 突变。系统的文献回顾显示，共有 501 例 EV 患者被描述。约 40%的 EV 患者经基因改变分析未发现 TMC6/8 突变。尽管大多数病例中鉴定出 β-HPV，但在一些个体中也检测到 α-HPV。
TMC6/8 无突变的 EV 患者比例相对较高，表明存在其他未知基因引起 EV 的突变。然而，我们的患者中 TMC8 的纯合剪接位点突变导致异常转录本，使其无法保持健康表型。文献回顾显示，HPV-5 是 EV 患者中最常见的 HPV，但出人意料的是，HPV-3、HPV-14 和 HPV-20 的检出频率高于 HPV-8。
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