Monogenic etiologies of persistent human papillomavirus infections: A comprehensive systematic review

Abstract

Purpose: Persistent human papillomavirus infection (PHPVI) causes cutaneous, anogenital, and mucosal warts. Cutaneous warts include common warts, Treeman syndrome, and epidermodysplasia verruciformis, among others. Although more reports of monogenic predisposition to PHPVI have been published with the development of genomic technologies, genetic testing is rarely incorporated into clinical assessments. To encourage broader molecular testing, we compiled a list of the various monogenic etiologies of PHPVI.

Methods: We conducted a systematic literature review to determine the genetic, immunological, and clinical characteristics of patients with PHPVI.

Results: The inclusion criteria were met by 261 of 40,687 articles. In 842 patients, 83 PHPVI-associated genes were identified, including 42, 6, and 35 genes with strong, moderate, and weak evidence for causality, respectively. Autosomal recessive inheritance predominated (69%). PHPVI onset age was 10.8 ± 8.6 years, with an interquartile range of 5 to 14 years. GATA2,IL2RG,DOCK8, CXCR4, TMC6, TMC8, and CIB1 are the most frequently reported PHPVI-associated genes with strong causality. Most genes (74 out of 83) belong to a catalog of 485 inborn errors of immunity-related genes, and 40 genes (54%) are represented in the nonsyndromic and syndromic combined immunodeficiency categories.

Conclusion: PHPVI has at least 83 monogenic etiologies and a genetic diagnosis is essential for effective management.

Keywords: HPV; Inborn errors of immunity; Monogenic disorder; Persistent human papillomavirus infection; Recalcitrant wart.

Figure 1:. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 flow diagram of included and excluded articles for persistent human papillomavirus infections (PHPVI)

Figure 2:. Clinical characteristics, functional defect classification, and age-of-onset distributions in patients with persistent HPV infection (PHPVI)

(A) Various clinical manifestations of PHPVI, such as multiple common warts in a patient with a homozygous WAS pathogenic variant (left first panel), multiple flat warts in a typical epidermodysplasia verruciformis (EV) patient with a homozygous TMC8 pathogenic variant (second panel), multiple exophytic warts and cutaneous horns in a tree-man syndrome (TMS) patient with a homozygous CD28 pathogenic variant (third panel), and a cutaneous squamous cell carcinoma (cSCC) in a TMC8-related typical EV patient (right panel). (B) Distribution of age-of-onset for PHPVI in IEI patients with different mutated genes; each blue dot denotes a patient, and the vertical red lines indicate the means, with the horizontal line showing the standard deviation (upper panel). (C) Number of reported monogenic PHPVI cases and published articles stratified by mutated genes; only genes that have 15 or more cases are listed. Dark and light blue bars indicate the number of cases and articles, respectively. (D) Categorization of PHPVI-linked genes based on functional defects according to International Union of Immunological Societies (IUIS) classification; (E) Comparison of the number of genes in each IUIS category with the number of PHPVI-associated genes in that category; note the overrepresentation of PHPVI genes in isolated and syndromic combined immunodeficiency, which is shown with a green background, and the underrepresentation of PHPVI genes in categories related to phagocyte defects and autoinflammatory disorders, which is shown with a red background. We excluded ND category-related genes for this result; (F) A pie chart demonstrating different warts based on anatomical location; Out of 83 genes, 50 (60.2%) were exclusively linked to cutaneous warts, highlighted with red background. Additionally, anogenital and mucosal warts are individually and exclusively linked to two genes. Fifteen genes are associated with both cutaneous and anogenital warts. Three genes were associated with cutaneous and other mucosal warts. Lastly, eleven genes are associated with all three types of warts.

Figure 3.. Personalized management of persistent human papillomavirus infections (PHPVI) is proposed via a phenotype- and genotype-based diagnostic algorithm.

(A) PHPVI is characterized by the presence of over ten lesions in multiple localized body regions that have not responded to multiple treatment modalities for a duration of six months. (B) Clinical and immunological investigations, such as familial history, sampling, complete blood counts, flow cytometry, and quantitative immunoglobulin analyses (IgG, IgA, IgM, and IgE), are utilized to guide a phenotype-based diagnosis of PHPVI patients. (C) Besides Sanger sequencing, sequencing variants can be detected via next-generation sequencing (NGS) and subsequently prioritized and annotated via bioinformatics pipelines. The identified pathogenic variants are contextualized with pedigree structures, co-segregation within the family, and phenotypic correlations. (D) The finalized list of prioritized variants is sent to the referring physician so that personalized medical intervention can be administered. This figure was created by Biorender (app.biorender.com).