Novel TMC8 splice site mutation in epidermodysplasia verruciformis and review of HPV infections in patients with the disease

J Eur Acad Dermatol Venereol. 2017 Oct;31(10):1722-1726. doi: 10.1111/jdv.14431. Epub 2017 Aug 4.

Abstract

Background: 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.

Objective: 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.

Patients and methods: 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.

Results: 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.

Conclusion: 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.

Publication types

  • Case Reports
  • Review
  • Systematic Review

MeSH terms

  • Adolescent
  • Child
  • Epidermodysplasia Verruciformis / complications
  • Epidermodysplasia Verruciformis / genetics*
  • Female
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Mutation*
  • Papillomavirus Infections / complications*
  • RNA Splicing*

Substances

  • Membrane Proteins
  • TMC8 protein, human