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 (AR) inheritance predominated (69%). PHPVI onset age was 10.8±8.6 years, with an interquartile range of 5–14 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 (IEI)-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.

Introduction

It has long been understood that an individual's genetic makeup strongly influences their susceptibility to infectious diseases. The underlying genetic cause of infectious diseases may involve rare monogenic sequence variants (mutations) and more common variants in genes governing immunity, including leukocytes (1). In the latest International Union of Immunological Societies (IUIS) classification, there are as many as 485 inborn errors of immunity (IEI). While some of these monogenic IEI make people more vulnerable to several infections at once or over time, others make the host more vulnerable to a small, selected group of microbes (2).

There are more than 200 types of human papillomavirus (HPV) grouped into five genera (α-, β-, γ-, μ-, and ν-HPV). All these HPV types have a strict tropism for keratinocytes, the main cell type in stratified squamous epithelia. While α-HPVs display cutaneous or mucous membrane tropism, non-α-HPVs (including β-, γ-, μ-, and ν-HPVs) have an exclusive cutaneous tropism. HPV infections are associated with a spectrum of conditions ranging from subclinical infections and transient warts, which resolve spontaneously in immunocompetent individuals, to persistent HPV infections (PHPVI), the most frequent of which recalcitrant warts (RW). Over the course of a lifetime, HPV DNA can be detected in 45% of infants, and this prevalence increases over the lifespan to 80% in healthy individuals. Transient warts affect up to 35% of children and more than 20% of adults. PHPVI was estimated to affect 3–5% of individuals in any population. (3). Even though transient warts typically disappear on their own within a few months or years at the most (4), there are some cases in which PHPVI continues to persist or appear despite repeated treatments using multiple approaches. PHPVI is defined as having more than ten lesions across more than one localized body region and being unresponsive to multiple treatment methods over six months (5).

PHPVI causes cutaneous, anogenital, and/or mucosal warts. Cutaneous warts include common warts (CW), epidermodysplasia verruciformis (EV), and Treeman syndrome (TMS), among others. (6-10) (Figure 2A). Cutaneous warts are caused by all α-, β-, γ-, μ-, and ν-HPV. Disseminated flat lesions underlying EV are caused by β-HPVs and TMS by α-HPV-2, respectively. Anogenital and mucosal warts are exclusively caused by α-HPV infections. Therefore, α-HPVs display cutaneous or mucosal tropism, and they are associated with cutaneous CW (HPV-2, -3, -7, -10, -27, -28, and -57), benign mucosal diseases (e.g., HPV-6 and -11), or genital and oropharyngeal carcinomas (e.g., HPV-16 and -18). In fact, the genus Alpha mainly contains mucosal HPV types and a few cutaneous types (11). γ-, μ-, and ν-HPVs cause benign CW. Cutaneous common or plantar warts have been associated with 14 α-HPV types, 17 γ-HPV, two μ-HPV, and one ν-HPV (13, 14).

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.

β-HPVs cause asymptomatic infections in the general population but are responsible for skin lesions other than CW in rare cases of epidermodysplasia verruciformis (EV). EV lesions often evolve into non-melanoma skin carcinomas (NMSC) in sun-exposed areas later in life. EV can be categorized into isolated (or typical), syndromic (or atypical), and acquired types (15).

This report aims to catalog the known monogenic etiologies of cutaneous, mucosal, and anogenital PHPVI. In addition, we have attempted to classify PHPVI based on phenotypes and have unified disease pathologies based on a deficient immune pathway. We further classify each monogenic disorder according to its evidence level to serve as a reference for geneticists conducting exome sequencing (ES) or building gene panels for PHPVI. Since ES is phenotype-driven, its utility increases proportionately with the number of genes previously linked to an RW diagnosis.

Materials and Methods

This study used the checklist and flowchart provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (16) approach.

Eligibility criteria

Articles were included when the diagnosis of PHPVI was linked to a single-gene etiology. These articles included letters to the editor, case series, case reports, cross-sectional studies, clinical trials, and case-control studies. Articles were excluded from our study if they didn't mention any specific causal gene; articles with non-monogenic causality for HPV infection, including multigene deletions, duplications, and aneuploidies; articles with acquired HPV subjects; articles that didn't provide enough information about the patient's phenotype or clinical information. By reviewing authors, nationality, hospital, and patient attributes, we tried to prevent duplication of patient registration.

Search strategy

On September 17, 2022, a comprehensive systematic search of the following electronic bibliographic databases was carried out: MEDLINE, Scopus, Web of Science (science and social science citation index), and Google Scholar. The language was limited to English. The systematic search was performed again before the final analysis, and new studies were included (June 2, 2023). Search criteria included using keywords related to HPV infection and causal genes (see Supplementary for a search strategy in detail). We did not restrict our search based on the date of publication. All retrieved publications were imported into the Endnote and Excel programs for screening, and these programs removed duplicate citations. Titles and abstracts were evaluated based on our inclusion criteria. To avoid the exclusion of potentially relevant papers, abstracts with indeterminate methods or phenotypes were included in the full-text evaluation. To ensure no publication was overlooked, we also examined the "References" section of the pertinent research papers to find further monogenic cases of HPV cited in these publications.

Selection process

Three researchers (SB, ASM, and HV) independently evaluated the first 100 included papers and discussed their disagreements until they agreed. Two researchers (SB and ASM) separately assessed the titles and abstracts of all the retrieved papers. Disputes were resolved by discussing those articles in cases of disagreement with the included papers. If necessary, the other researcher (HV) was consulted before making the final choice. The full texts of the articles were then reviewed for inclusion by two researchers independently. Again, if there was disagreement, inclusion or exclusion was decided upon through discussion and consultation with the senior researchers (HV, JLC, VB, JG, HH, and EJ).

Data collection process

Two investigators carried out the data extraction and aggregation. The following data were retrieved from the included papers: (i) phenotypes of PHPVI and other co-morbidities; (ii) causal gene; (iii) inheritance; (iv) number of patients; (v) immunological features; (vi) age-of-onset; (vii) types of HPV tropism and infected bodily anatomical regions; and (viii) HPV genotype. The genetic relationship with PHPVI was considered acceptable if a variant met the American College of Medical Genetics and Genomics (ACMG) variant classification criteria for pathogenic or likely pathogenic (17). We divided the level of evidence of a gene's association with PHPVI into three groups. Group 1, genes strongly associated with PHPVI (Table 1), comprises genes discovered in many (three or more) reported cases of PHPVI. Group 2 genes with moderate evidence for a causal relationship with PHPVI (Table 1) consist of genes identified in two reported cases of PHPVI. Group 3, genes with weak evidence for a relationship with PHPVI (Table 1), consists of genes discovered in just one HPV case. Genes with solid functional evidence, including SPINK5, have been shifted from groups 2 and 3 to 1. Also, we searched for the types of HPV tropism in the patients, and we divided those affected areas into cutaneous, anogenital, and mucosal. We qualitatively estimated the penetrance of the PHPVI for each monogenic IEI and subcategorized those genes into three groups: Group 3, which was associated with the PHPVI in all or most cases, was considered “high-penetrance” (>50%). Those genes with occasional and rare associations with the PHPVI were considered moderate- (Group 2, 20–50%) or low-penetrance (Group 1, <20%), respectively (see Supplementary Materials and Methods). The authorized symbol and term for genes and proteins, respectively, were utilized based on the Human Genome Organization (HUGO) Gene Nomenclature Committee. Phenotypes were named using OMIM phenotype names (18), the IUIS Committee (2), or the MalaCards phenotype name (19). In the case of having more than one name for a disease, the name that was most closely associated with PHPVI was selected. If there is no entry for a condition in OMIM, the phenotype named was extracted from the original reporting article. Based on the IUIS classification, we determined the category of each gene to determine the immune pathways involved in each single-gene defect.

Table 1:

A list of genes related to monogenic etiologies of persistent human papillomavirus infections

Genes	Disease	Inheritance	Penetrance	Cutaneous Wart	Anogenital Wart	Mucosal Wart	IEI Groupa	Associated features	Immunology	Ref. HPV
Strong Association with HPV infectious
ADA	Adenosine deaminase (ADA) deficiency	AR	1	+		+	1	Skeletal and Kidneys defects, potential pulmonary alveolar proteinosis, and cognitive impairment	Extremely low T and B cells count, with similarly reduced or declining levels of Ig and NK cells	(58-62)
ADA2 (CECR1)	ADA2 deficiency	AR	2	+	+		7	Vascular defects, such as Polyarteritis nodosa, and ischemic stroke recurrence and fever; neurologic and skin defects	Variable leukopenia or lymphopenia, hypogammaglobulinemia (in some patients)	(279-284)
ARPC1B	Arp2/3-mediated filament branching defect	AR	1	+			2	FTT, colitis, mild thrombocytopenia, anemia, recurrent infections (bacterial and viral); allergies, recurrent fever	Leukocytosis, B-cell lymphocytosis, T-cell lymphopenia (most notably CD8+ T cells), impaired neutrophil chemotaxis and T-cell function, elevated serum IgE and IgA, autoantibodies (ANA, ANCA)	(140, 141)
ATM	Ataxia-telangiectasia	AR	1	+			2	Short stature; conjunctival telangiectasia; neurologic defects such as cerebellar ataxia; bronchiectasis; neoplasia; elevated alpha fetoprotein and radiosensitivity	Lymphocytopenia, faulty B cell differentiation, decreased T cell counts, declining CD4+ T cells, higher numbers of T cells with gamma/delta antigen receptor, frequently higher IgM monomers, decreased numbers of cells containing IgM receptors, reduced IgA, IgE, and IgG subtypes,	(135-137)
ATP2C1	Hailey-Hailey disease, Benign Chronic Pemphigus (BCPM)	AD	1		+		ND	Erythema, skin blisters and erosions, suprabasal acantholysis	The dermis has been infiltrated by eosinophils and lymphocytes	(290-292)
CARD11	Immunodeficiency 11b with Atopic Dermatitis (IMD11B)	AD	2	+	+		2	Severe atopic dermatitis, molluscum infection, abscesses, pneumonia, asthma, food allergies	Failure to activate and proliferate T cells, elevated serum IgE, reduced B cells, and low IgM	(142, 143)
CARMIL2 (RLTPR)	RLTPR deficiency	AR	2	+	+	+	4	Increased susceptibility to infections, viral, bacterial, fungal; smooth muscle tumors, EBV-related; multiple skin defects such as ichthyosis, abscesses, and mucocutaneous candidiasis	Reduced memory B cells, raised naive CD4+ T cells, normal/elevated T-cell counts, reduced Treg cells, subsets of T helper, and T memory cells, hypogammaglobulinemia, insufficient antibody response	(198-204)
CD3D	CD3D deficiency	AR	1	+			1	FTT, otitis media, thrush, respiratory infections, diarrhea, gastroenteritis	Lymphopenia, lack of peripheral CD3+ T cells, decreased T-cell proliferative responses in vitro	(62, 63)
CD28	CD28 deficiency	AR	3	+			2	Susceptibility to RW only	Normal T cells, B cells and Ig	(12)
CD40LG	Immunodeficiency with Hyper-Igm, Type 1 (HIGM1), CD40 ligand (CD154) deficiency	XLR	1	+	+		1	Severe and opportunistic infections, thrombocytopenia, tonsillar hypertrophy, idiopathic neutropenia, gingivitis, chronic hepatitis, anemia, peripheral neuroectodermal tumors	Reduced T cell activation, very low serum IgA, IgG, and IgE levels, normal or elevated IgM; dysgammaglobulinemia	(92-95)
CF	Cystic fibrosis	AR	1		+		5	FTT, bronchopulmonary infection, elevated sweat sodium/chloride, pancreatic insufficiency	Defective chemotaxis function, defective monocyte cells	(276)
CIB1	CIB1 deficiency	AR	3	+			6	Group B1 HPV infections and skin cancer	Defective Keratinocytes	(20, 27, 49, 50)
CORO1A	Coronin-1A deficiency	AR	2	+			1	Recurrent respiratory infections, EBV-induced B cell lymphoma, detectable thymus	Decreased longevity of mature T lymphocytes, reduced quantities of naive CD4+ and CD8+ T cells, Ig levels below or equal to normal	(64, 65)
CXCR4	WHIM (Warts, Hypogammaglobulinemia, infections, Myelokathexis) syndrome	AD	3	+	+	+	6	Recurrent infections, neutropenia, vulval condylomata acuminata, myelokathexis, HPV-related carcinoma, lymphoma	Low B cells count, pancytopenia (T cells, monocytes, neutrophils, DCs, NK cells), hypogammaglobulinemia	(169-189)
DCLRE1C (Artemis)	DCLRE1C (Artemis) deficiency, Severe Combined Immunodeficiency with Sensitivity to Ionizing Radiation (SCIDA), Athabaskan-type SCID	AR	1	+	+		1	Recurrent upper respiratory tract infections, radiation sensitivity	Low B cells count, hypogammaglobulinemia, normal NK cell count, but elevated graft rejection risk, probably owing to activated NK cells	(66-68)
DOCK8	DOCK8 deficiency, HIES2	AR	3	+	+	+	1	Recurrent infections (bacterial, viral, fungal); eosinophilia, atopic dermatitis, increased susceptibility to carcinomas	Decreased naïve CD8 T cells, elevated exhausted CD8+ TEM cells, elevated γδ T cells, impaired T cell immunity, low Treg with poor function, decreased NKT, MAIT cells, elevated total B cells, decreased memory B cells, normal/high IgA and IgG, low IgM, extremely high IgE, low NK cells, insufficient antibody responses	(49, 112-127)
FANCA	Fanconi Anemia Type A	AR	1	+	+	+	8	Growth, bone, skin, heart, GI, urogenital, CNS anomalies; anemia, leukemia, elevated chromosomal breakage	T cell, B cell, and NK cell count low to normal	(224, 226-229)
FANCC	Fanconi Anemia Type C	AR	1	+	+	+	8	Growth, bone, skin, heart, GI, urogenital, CNS anomalies; anemia, leukemia, elevated chromosomal breakage	T cell, B cell, and NK cell count low to normal	(224, 226-229)
FANCD2	Fanconi Anemia Type D2	AR	1	+	+	+	8	Growth, bone, skin, heart, GI, urogenital, CNS anomalies; anemia, leukemia, elevated chromosomal breakage	T cell, B cell, and NK cell count low to normal	(224-229)
FANCF	Fanconi Anemia Type F	AR	1	+	+	+	8	Growth, bone, skin, heart, GI, urogenital, CNS anomalies; anemia, leukemia, elevated chromosomal breakage	T cell, B cell, and NK cell count low to normal	(224, 226-229)
FANCI	Fanconi Anemia Type I	AR	1	+	+	+	8	Growth, bone, skin, heart, GI, urogenital, CNS anomalies; anemia, leukemia, elevated chromosomal breakage	T cell, B cell, and NK cell count low to normal	(224, 226-229)
GATA2	Emberger syndrome, Lymphedema, Primary, with Myelodysplasia (LMPM), GATA2 deficiency, MonoMAC	AD	3	+	+	+	5	Pulmonary alveolar proteinosis (in some patients), Pulmonary alveolar proteinosis (in some patients), histoplasmosis, alveolar proteinosis, MDS/AML/CMML, lymphedema	Monocytopenia, dendritic cell cytopenia, B-cell lymphopenia, neutropenia, decreased NK cells, particularly NK cell precursors; decreased NK cells, particularly NK cell precursors	(49, 134, 230-275)
HRAS	Costello syndrome	AD	1	+			ND	Macrocephaly, Coarse facies, Hypertrophic cardiomyopathy, Respiratory failure, Dark skin pigmentation, Mental retardation, Vestibular schwannoma		(293)
ICOS	ICOS Deficiency	AR	1	+	+		1	Recurrent infections, autoimmunity, gastroenteritis, granulomas	Hypogammaglobulinemia, defective antibody production, variable degree of T cell dysfunction	(103, 104)
IKBKG (NEMO)	Ectodermal Dysplasia and Immunodeficiency 1 (EDAID1), IKBKG deficiency	XLR	1	+			2	Recurrent infections (bacteria, viruses, fungi), colitis, osteopetrosis; various hair, skin, and tooth defects such as ectodermal dysplasia, anhidrosis	Dysgammaglobulinemia, increased IgM (in some patients), hypogammaglobulinemia, aberrant IgG and IgA, poor class-switching in B cells, T-cell receptor (TCR) activation impaired, impaired NK cytotoxic function	(155-158)
IL2RG	Severe Combined Immunodeficiency, X-Linked (SCIDX1), γc deficiency	XLR	3	+	+	+	1	Hepatomegaly, thymic hypoplasia, infection by bacteria, fungi, and viruses frequently	Reduced proportion of CD4+ helper T cells, lack of T lymphocytes, normal to high B cells, lymphoid depletion, very low specific antibody production, reduced quantities of natural killer cells and cytotoxicity	49, 62, 69, 76-89)
IL7	IL7 deficiency	AR	3	+			ND	Seborrheic keratosis-like lesions, higher risk of squamous cell carcinomas (SCC) in sun-exposed areas, probably higher risk of opportunistic infections	T-cell lymphopenia, decreased serum levels of IL7	(294, 295)
IL7R	IL7Rα deficiency	AR	1	+			1	FTT, candida albicans infection, recurrent pneumonia, rash, dermatitis	T-cell lymphopenia, decreased TRECs, normal or elevated functional NK cells count, serum Ig may be absent, normal, or elevated; peripheral blood B cells could be normal or elevated.	(62, 69, 70)
ITK	Lymphoproliferative syndrome 1 (LPFS1) - ITK Deficiency	AR	1	+	+		1	Increased EBV virus load, anemia, High EBV viral load, lymphoma Hodgkin disease risk is elevated	Hypogammaglobulinemia, polymorphic B cell lymphoproliferation, reduced CD4+ T cells, NKT cells	(96-98)
JAK3	SCID T-negative/B-positive type, JAK3 deficiency	AR	3	+			1	Bacterial, viral, fungal skin infection, BCG nodules	Markedly reduced CD3+ proportion, intrinsic B cell defect, elevated proportion of CD19+ B cells, markedly decreased numbers of NK cells, low Ig	(62, 69, 82, 84, 89-91)
LIG4	LIG4 syndrome, DNA ligase IV deficiency	AR	1	+	+		1	Photosensitivity, Telangiectasia, Psoriasis, Microcephaly, Developmental delay	Extremely low both T and B cells count, reduced Ig, normal NK cells	(71-74)
MAGT1	X-linked magnesium EBV and neoplasia (XMEN),	XLR	2	+	+		4	Respiratory infections; splenomegaly, Autoimmune cytopenias, elevated susceptibility to EBV-related B-cell lymphoproliferative diseases	Reduced memory B cells and CD4+ T cells count, inverted CD4+/CD8+, poor CD3 proliferation, decreased MAIT cells, variably reduced Ig	(205, 206)
NFKB1	NFKB1 deficiency	AD	1	+			3	Recurrent infections (bacterial, viral, and fungal), hepatitis, GI infections, recurrent skin infections, increased risk for solid malignant tumors and lymphoma	Enhanced CD4− or CD8− T cells, reduced class-switch B cells count, reduced NK cells, hypogammaglobulinemia	(172, 216)
NLRP1	Palmoplantar Carcinoma, Multiple Self-Healing (MSPC)	AD	1	+		+	7	Palmoplantar carcinoma, corneal scarring, recurrent respiratory papillomatosis, SCC	Defective Keratinocytes and increased IL1β	(285-287)
PIK3CD	Activated p110δ syndrome (APDS)	AD	2	+			3	Recurrent ear and respiratory infections; autoimmune complications (IBD), lymphadenopathy	Hypogammaglobulinemia, increased serum IgM, and reduced CD4+ T cells count	(211-215)
PTEN	Cowden syndrome 1, PTEN Deficiency	AD	1	+		+	3	Facial dysmorphic features, recurrent infections, DD, various carcinomas, autoimmunity	Normal or decreased Ig	(219-221)
SASH3	SASH3 deficiency	XLR	3	+			1	Recurrent infections, refractory autoimmune cyto-/neutropenia, autoimmune hemolytic anemia	Lymphopenia, low B cell class-switched cells, low CD4+ T cells, neutropenia, NK cell deficiency, defective TCR, hypogammaglobulinemia	(105, 106)
SPINK5	Netherton Syndrome (NETH), Bamboo Hair Syndrome	AR	1	+	+		2	FTT, congenital lamellar ichthyosis, angioedema, developmental delay (DD), bamboo hair, asthma, recurrent infections, hay fever	Reduced switched/non switched B cells, decreased NK cell cytotoxicity, elevated IgA and IgE, reduced IgG levels, antibody variably reduced	(147, 148)
STK4 (MST1)	T-Cell Immunodeficiency, Recurrent Infections, and Autoimmunity with or Without Cardiac Malformations (TIIAC), STK4 deficiency	AR	2	+	+		1	Intermittent neutropenia, bacterial, recurrent infections, bacterial, viral, and fungal, lymphoproliferation, autoimmune hemolytic anemia, lymphoma, congenital cardiac defects	Decreased naïve T cells, enhanced TEM/TEMRA cells, poor T cell proliferation, lymphopenia of the CD4, reduced memory B cells, elevated IgA, IgE, IgG, low IgM	(49, 128-134)
TMC6 (EVER1)	EVER1 deficiency,	AR	3	+			6	Basal cell carcinoma, widespread pityriasis versicolor-like lesions, SCC in situ (Bowen disease)	Defective keratinocytes, naïve T cells are low, normal T-cell number	(23-36)
TMC8 (EVER2)	EVER2 deficiency	AR	3	+			6	Basal cell carcinoma, trunk pityriasis versicolor-like lesions, large granular or spinous keratinocytes, SCC in situ (Bowen disease)	Defective keratinocytes, naïve T cells are low, normal T-cell number	(26, 27, 30, 31, 37-48)
WAS	Wiskott-Aldrich Syndrome (WAS)	XLR	1	+	+		2	Thrombocytopenia, myeloid maturation arrest, anemia, variable lymphoid anomalies	Lymphopenia, elevated IgE and IgA levels, reduced IgM levels, progressive decrease in number of T cells	(49, 138, 139)
Emerging Evidence for Association with HPV infectious
CD4	CD4 Deficiency	AR	3	+			ND	Respiratory infections, recurrent (in some patients)	Absence of CD4+ T cells, increased CD4−/CD8− T cells ratio, impaired B cell development, impaired NK cell function	(296, 297)
NF1	Neurofibromatosis, Type I (NF1)	AD	1	+			ND	Macrocephaly, lisch nodules, Neurofibromas, plexiform neurofibroma, Cafe-au-lait spots, learning disabilities (30%), tumors at multiple sites including CNS	Ig and complement component serum levels were normal, normal lymphocyte subset percentages and numbers.	(298, 299)
NFKBIA	Ectodermal Dysplasia and Immunodeficiency 2 (EDAID2)	AD	1	+			2	Facial dysmorphic features, recurrent infections; skin, hair, and tooth defects such as ectodermal dysplasia, anhidrosis	Reduced isotype switched and memory B cells, impaired TCR and BCR activation, reduced IgA and IgG; increased IgM	(151, 152)
RFXANK	Bare Lymphocyte Syndrome, Type Ii (BLS2), MHC class II deficiency, complementation group B	AR	1			+	1	FTT, respiratory and GI infections; autoimmune cytopenia; liver, biliary tract, and GI disorder	Low CD4+ and high CD8+ counts, agammaglobulinemia/ panhypogammaglobulinemia, decreased lymphocyte MHC II expression	(102)
TPP2	Tripeptidyl-Peptidase II Deficiency	AR	1	+			4	Facial dysmorphic features, Variable lymphoproliferation, hearing loss, DD, severe autoimmune cytopenias, Vascular disorder	B and T-cell lymphopenia, hypergammaglobulinemia, elevated IgE, reduced IgM, decreased NK cells	(208, 209)
ZAP70	ZAP-70 deficiency	AR	1	+	+	+	1	FTT, possibility of immune dysregulation, various lung diseases	Numerous CD4+ T cells having poor function, lack of CD8+ T lymphocytes, decreased B cell function	(100, 101)
Limited Evidence for Association with HPV infectious
ANKRD26	Thrombocytopenia 2	AD	1	+			ND	Mild to moderate bruisability, thrombocytopenia, rash	-	(300)
CARD9	CARD9 deficiency	AR	1	+			6	Chronic candidiasis infection, dermatophytosis, other severe candida infections	Dermatophytic lymphadenitis, deficiency of mononuclear phagocytes	(190)
CASP10	Autoimmune lymphoproliferative syndrome, type II, ALPS-Caspase10	AD	1	+			4	Adenopathies, splenomegaly, autoimmunity	Defective lymphocyte apoptosis, elevated B cell and peripheral CD3+ T cell counts, higher IgG, IgA, and IgM levels	(210)
CD27	Lymphoproliferative Syndrome 2 (LPFS2), CD27 deficiency	AR	1	+			4	Fever, hemophagocytic lymphohistiocytosis, aplastic anemia, increased susceptibility to EBV infection	Lymphadenopathy, decreased T cell-dependent antibody production, hypogammaglobulinemia, defective CD8+ T cell function, lack of CD27 expression on lymphocytes, decreased NK levels, hemophagocytosis, systemic inflammatory response	(168)
CHUK	IKKα deficiency	AR	3	+			1	FTT, recurrent infections (bacterial, viral, and fungal), skeletal anomalies, lack secondary lymphoid tissues	Normal T cells, Reduced B cells, low Ig	(107)
DNMT3B	Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome 1 (ICF1)	AR	1	+			2	Facial dysmorphic features, FTT, DD, macroglossia; pneumonia, cytopenias; malignancies, centromeric instability of chromosomes 1, 9 and 16	Reduced T cells and NK cells count, decreased IgA, elevated IgM, reduced or normal B cells	(168)
FAT4	Hennekam Lymphangiectasia-Lymphedema Syndrome 2	AR	1	+			2	Facial dysmorphic features, lymphangiectasia	Low or variable B cells and T cells, and reduced Ig	(161)
FCGR3A (CD16)	CD16 Deficiency	AR	1	+			6	Recurrent infections, especially EBV, Varicella zoster virus (VZV)	Decreased or normal numbers of NK cells, defective NK function in spontaneous cellular cytotoxicity	(191)
HYOU1	HYOU1 deficiency	AR	1	+	+		5	Recurrent skin infections, hypoglycemia, inflammatory complications	Absent response to polysaccharide antigens, normal CD4+ and CD8+ T cells	(277)
ICOSLG	ICOSL deficiency	AR	3	+	+		1	Recurrent infections (bacterial and viral), neutropenia	Reduced B cells, T cells, and Ig	(99)
IFNGR2	IFN-γ receptor 2 deficiency	AR	1	+			6	Mycobacteria and Salmonella susceptibility	Poor or absent response to gamma-interferon	(196)
IKZF3 (AIOLOS)	AIOLOS deficiency	AD	2	+			2	Respiratory and sinopulmonary recurrent infections, susceptibility to EBV, B cell lymphoma	Low B cell numbers, defective B-cell development, hypogammaglobulinemia, pancytopenia, skewed T-cell subsets	(162)
IRF8	IRF8 deficiency	AR	1	+			6	Susceptibility to mycobacteria (after BCG immunization), EBV, and other infectious agents	Decreased circulating monocytes and dendritic cells, decreased NK cells, reduced NK cell function	(195)
ITGB2 (CD18)	Leukocyte adhesion deficiency type 1 (LAD1)	AR	1	+	+		5	Prolonged separation of the umbilical cord, peritonitis, gingivitis, leukocytosis	Deficient adhesion-related abilities, including chemotaxis, and antibody-dependent cellular cytotoxicity and adhesion to endothelial cells; defective T/NK cytotoxicity	(278)
IVNS1ABP	Immunodeficiency 70 (IMD70)	AD	3	+			ND	Cutaneous boils, retinal vasculitis (1 patient), Sinusitis, pneumonia, inflammatory colitis, celiac disease, achalasia, recurrent infections	CD4+ T-cell and CD19+ B cells lymphopenia, hypogammaglobulinemia	(301)
LCK	LCK deficiency	AR	1	+	+		1	FTT, recurrent infections, immune dysregulation, autoimmunity	Low CD4+ and Treg, limited repertoire of T cells, poor TCR signaling, elevated IgM	(334)
LRBA	LRBA deficiency	AR	1	+			4	FTT, recurrent infections, IBD, autoimmunity	Neutropenia, decreased IgG, IgA, and IgM; decreased NK cells, T cells may be increased or decreased	(168)
MALT1	MALT1 deficiency	AR	1	+			1	Poor growth, Bacterial, fungal and viral infections	Normal numbers of lymphocytes, impaired B-cell differentiation, poor antibody response, decreased T-cell proliferative response to mitogens	(108)
MR1	MR1 deficiency	AR	3	+			ND	Primary immunodeficiency, campylobacter gastroenteritis, pneumonia, varicella-zoster virus infection	Lack of MAIT cells, expansion of Vγ9/Vδ2+ T cells, reduction in memory B cells, normal or lower (for NK cells)	(302)
MYD88	MYD88 Deficiency	AR	1	+			6	Bacterial infections (pyogenes)	Impaired cytokine production in response to LPS, certain TLRs, and IL1B, neutropenia	(192)
MYH7	Laing distal myopathy	AD	1	+			ND	Facial muscle weakness, weakness and atrophy of ankle and toe extensor muscles	NA	(303)
PGM3	PGM3 deficiency	AR	1	+			2	Facial dysmorphic features, hearing loss, severe atopy, recurrent infections; DD, asthma, skeletal dysplasia, autoimmunity	Reduced CD4+ and CD8+ T cells, reduced CD27+ B cells, elevated serum IgA, IgG, IgE	(149)
PIK3R1	Activated p110δ syndrome 2 (APDS2)	AD	1	+			3	Hodgkin lymphoma, severe bacterial infections, B-cell lymphoma	Reduced memory B cells, reduced naive CD4+ and CD8+ T cells, reduced IgA and IgG levels, elevated IgM levels	(222)
POLD1	Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL), Polymerase δ deficiency	AR	1	+			1	Recurrent respiratory tract, bronchiectasis, and skin infections, short stature, intellectual disability	B, CD4+ T, and NK cell lymphopenia, low IgG, low B cells but normal maturation	(109)
PTPRC (CD45)	CD45 deficiency	AR	1	+			1	FTT, rash, dermatitis, fever, recurrent infections	Reduced or absent T cells, normal or elevated B cells count, normal or mildly reduced NK cells, hypogammaglobulinemia	(62)
RAC2	Defective Neutrophil Chemotaxis and Hypogammaglobulinemia, RAC2 deficiency	AR	1	+			3	FTT, recurrent infections, urticaria, erythematous plaques, hypothyroidism, growth hormone deficiency	Reduced IgA, IgM, IgG, decreased B-cells, decreased Ab responses after vaccination	(168)
RAG1	Severe combined immunodeficiency, B cell-negative, RAG deficiency	AR	1	+			1	FTT secondary to recurrent infections, failure to reject allogenic cells, otitis, arthritis	Lack of T and B lymphocytes in peripheral blood, panhypogammaglobulinemia	(75)
RHOH	RHOH deficiency	AR	3	+			1	Lung granulomas, molluscum contagiosum, lymphoma	Reduced naive T cells count, impaired TCR signaling, poor CD3 proliferation, limited repertoire	(110)
RASGRP1	RASGRP1 deficiency	AR	2	+			4	Pneumonia, EBV-related lymphoma, herpesvirus infections	Decreased naive T cells, decreased CD4+ T cells counts, increased delta/gamma CD8+ T cells, reduced B cell counts, impaired cytotoxicity of NK cells, hypergammaglobulinemia, hypogammaglobulinemia	(207)
RBCK1 (HOIL1)	Polyglucosan Body Myopathy 1 with or Without Immunodeficiency (PGBM1), HOIL1 deficiency	AR	1	+			2	Bacterial infections; autoinflammation; amylopectinosis	Hyper IgA, reduced memory B cells, poor antibody reactions to polysaccharides	(160)
SMARCAL1	Schimke Immunoosseous Dysplasia (SIOD)	AR	1	+			2	Hyperpigmented macules, coarse hair, skeletal deformities, intrauterine growth retardation; recurrent infections (bacterial, viral, fungal), nephrotic syndrome	Reduced CD4+ and CD3+/CD4+ lymphocytes, T cell deficiency, Ig levels abnormalities	(159)
STAT1	Immunodeficiency 31c (IMD31C), STAT1 deficiency	AD	1			+	6	Recurrent infections (bacterial, viral, fungal), autoimmune disorders (anemia, thyroiditis, cytopenias, diabetes), CMC	Immune dysregulation, progressive Lymphopenia, progressive reduced memory B cells, progressive reduced Igs	(193)
STAT3	Hyper-IgE Recurrent Infection Syndrome 1, Autosomal Dominant (HIES1), Job's Syndrome	AD	1	+			2	Coarse facies, bacterial infections, pulmonary Aspergillus, skeletal deformities, Pneumocystis jirovecii; severe eczema	Reduced NKT cells and memory B cells, Tregs may be elevated, impaired responses to STAT3-activating cytokines, elevated BAFF expression, very elevated IgE, reduced specific antibody production	(150)
TNFSF12 (TWEAK)	TWEAK deficiency	AD	1	+			3	Pneumonia, bacterial infections, thrombocytopenia, Neutropenia	Reduced IgA and M, absence of pneumococcal antibody	(223)
TRAC	TCRα deficiency	AR	2	+			1	FTT, recurrent infections (bacterial, viral, fungal), immune dysregulation and autoimmune disorders	Decreased number of TCR α/β T cells, decreased CD4+ and CD8+ T cells, increased serum IgE, IgA, increased TCR δ/γ T cells	(111)

SCID, severe combined immunodeficiency; EBV, Epstein-Barr virus; MHC, major histocompatibility complex; HPV, human papillomavirus; Treg, T regulatory cell; XL, X-linked inheritance; AR autosomal recessive inheritance, AD autosomal dominant inheritance; FTT, failure to thrive; BCG, Bacillus Calmette-Guerin; IBD inflammatory bowel disease; LAD, leukocyte adhesion deficiency; NK, natural killer; CNS, central nervous system; CMC, chronic mucocutaneous candidiasis; GI, gastrointestinal; Ig, immunoglobulin

^aGroup 1: Combined immunodeficiencies; Group 2: Combined immunodeficiencies with syndromic features; Group 3: Predominantly antibody deficiencies; Group 4: diseases of immune dysregulation; Group 5: congenital defects of phagocytes; Group 6: defects in intrinsic and innate immunity; Group 7: autoinflammatory diseases; Group 8: bone marrow failure; ND: (not determined)

Results

Collection of data

The four databases were searched during the initial search on September 17, 2022, yielding 44,746 articles. After the elimination of duplicates, a total of 40,687 articles remained for title and abstract review. After the screening, out of 40,687, a total of 39,979 irrelevant articles were eliminated based on their titles, leaving 708 records. After scrutinizing abstracts, 386 publications remained to evaluate the full text further. In addition, 175 articles were identified through manual searches of references (from websites and citation searches), and from these 175 articles, 141 records met inclusion criteria, resulting in 527 papers for full-text assessment. After full-text scrutinization, 261 publications were finally included for data extraction (see Figure 1 and Supplementary for the list of references in the included publications). A total of 83 genes from 842 patients were studied in this study, with 42 meeting the criteria for group 1 (strong evidence), 6 meeting the criteria for group 2 (moderate evidence), and 35 meeting the criteria for group 3 (weak evidence) (Figure 1).

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).

Epidemiological description of the PHPVI cases reported with IEI

As previously mentioned, PHPVI causes cutaneous, anogenital, and/or mucosal warts. There are various manifestations within cutaneous warts, including, but not limited to, CW, EV, TMS, and cutaneous squamous cell carcinomas (cSCC), among other presentations (Figure 2A). The mean age of onset for PHPVI in the group of 196 patients with a known age of onset was 10.8 years (SD = 8.6), with a median age of onset of 8 years (Figure 2B, lower panel). The interquartile range of age-of-onset was 5 to 14 years. The age range at which PHPVI first appeared in these patients was four months to 44 years, as reported with CXCR4 and SASH3, respectively (Figure 2B, lower panel). There are 12 PHPVI-related genes, with at least 15 or more reported cases. GATA2, with 217 reported cases in 47 papers, is ranked first, significantly surpassing the interleukin 2 receptor gamma chain gene (IL2RG), which is ranked second by a considerable margin. Other genes include DOCK8, CXCR4, TMC6, TMC8, CIB1, CARMAIL2, ADA2, STK4, ATM, and JAK3, which follow IL2RG, which has 76 reported cases in 17 papers (Figure 2C).

IEI related to PHPVI

The Expert Committee of the IUIS periodically classifies and updates the IEI. In their last consensus, they included 485 IEI in their classification. IEI are categorized into ten groups based on their molecular and cellular pathobiology. Out of 83 PHPVI-related genes, 74 genes are present in the IUIS classification distributing in eight groups. We added another group under the title “ND”, which encompasses nine genes, unrelated to IEI or waiting to be included in the IUIS list on the next consensus (Table 1).

The majority of our list of 83 genes belongs to the “Immunodeficiencies affecting cellular and humoral immunity” group (25 genes, 30%), followed by the “Combined immunodeficiencies with associated or syndromic features" group (15 genes, 18%), “Defects in intrinsic and innate immunity” group (10 genes, 12%), “Not determined (ND)” group (nine genes, 11%), “Diseases of immune dysregulation” group (seven genes, 9%), “Predominantly antibody deficiencies” group (six genes, 7%), “Bone marrow failure” group (five genes, 6%), “Congenital defects of phagocyte number or function” group (four genes, 5%), and “Autoinflammatory disorders” group (two genes, about 2%). There is no reported PHPVI-associated gene belonging to the “complement deficiencies” or “phenocopies of IEI” groups (Figure 2D). Among the nine genes belonging to the ND group, IL7 and CD4 will probably be classified as combined immunodeficiencies.

The 485 types of IEI in the IUIS panel are currently divided into ten groups (2). The most affected pathway in IEI patients is "Defects in intrinsic and innate immunity," which has 74 genes (15% of all reported genes). A similar percentage (ten genes, or 14%) was observed in our gene list (out of 74 genes in eight groups, except the ND group). This is followed by "Combined immunodeficiencies with associated or syndromic features," which has 69 genes (14% of all reported genes), and "Immunodeficiencies that affect cellular and humoral immunity," which has 66 genes (14% of all reported genes). With 28% of IEI-related genes, these two latter groups have a spectrum of combined immunodeficiencies as a common phenotype. However, in the HPV-related gene list, 54% of genes (40 out of 74) belong to these two latter groups. This overrepresentation of HPV-related genes in these two groups provides clues regarding the pathogenesis of wart formation (Figure 2E).

The most prevalent mode of inheritance in our 83-gene list was AR (57 genes, 69%), followed by autosomal dominant (AD) (20 genes, 24%), and X-linked recessive (XLR) (six genes, 7%) (see Supplementary Table). The penetrance of the PHPVI in IEI patients with pathogenic variants in 83 genes was high-penetrant in 17 genes (21%), moderate-penetrant in 10 genes (12%), and low-penetrant in 56 genes (67%). It is worth noting that for several genes, including CD28, RHOH, MR1, IVNS1ABP, ICOSLG, and CHUK, there have been few known patients, and the observed penetrance may change in the future when additional patients are discovered.

PHPVI was the only phenotype observed in patients with biallelic pathogenic variants in TMC6, TMC8, CIB1, and CD28. The TMC6, TMC8, and CIB1 genes each encode a component of a heterotrimeric complex found on the endoplasmic reticulum of skin keratinocytes. This complex has been shown to function as a restriction factor in PHPVI, justifying the lack of extracutaneous and non-HPV infections in the affected patients (20). All three reported CD28 patients had a degree of functional T-cells due to reverent mosaicism, which probably enables the host to effectively combat all types of infections except HPV2 or HPV4 (12).

Genotype-phenotype correlations in PHPVI patients

Out of 83 genes, 50 were exclusively linked to cutaneous warts. PHPVI in patients with pathogenic variants in ATP2C1 and CFTR present as anogenital warts. Besides, patients with RFXANK and STAT1 pathogenic variants manifest other mucosal warts (oral, oropharyngeal, respiratory papillomatosis, and warts around the vocal cords). Fifteen genes are associated with both cutaneous and anogenital warts. Three genes, including ADA, NLRP1, and PTEN, were associated with cutaneous and other mucosal warts. Lastly, eleven genes are associated with all three types of warts. Putting it another way, out of 83 genes, 79 were linked to cutaneous warts, 28 to anogenital lesions, and 16 to other mucosal warts (Figure 2F).

Cutaneous warts can be further categorized based on morphology, virology, histology, and anatomic location. CW (verruca vulgaris), palmar and plantar warts (verrucae palmares et plantares), mosaic warts, flat warts (verrucae planae), butcher’s warts, and EV are various presentations of cutaneous warts. In extremely rare cases, α-HPV-2-related CW can also transform into TMS (12).

Additionally, cutaneous warts can be categorized based on HPV type into EV and non-EV types. The non-EV type of cutaneous warts is caused by α-, γ-, μ-, and ν-HPV. EV is caused by specific types of β-HPV infections (5, 6). Characteristically, the early cutaneous manifestations in EV patients consist of thin tinea versicolor-like plaques and flat-like warts during childhood. Not infrequently, pigmented, papillomatous, and verrucous lesions may be found on the forehead or trunk. After several decades, patients might develop NMSCs, mostly squamous cell carcinoma (SCC). Carcinogenesis is caused by EV-HPV infection, and the majority of patients harbor EV-HPV types 5 and 8 (9, 10, 15).

EV can be further categorized into isolated (or typical), syndromic (or atypical), and acquired types. The “typical” form of EV, not vulnerable to other infections, is caused by fully penetrant bi-allelic pathogenic variants in CIB1, TMC6, or TMC8, which impair keratinocyte-intrinsic (peripheral) immunity to β-HPV infection. Pathogenic variants in genes that leukocytes, such as myeloid compartments or T lymphocytes, predisposing patients to β-HPVs and other infections, are associated with “syndromic” EV (20). Acquired EV is most commonly found in patients with secondary immunodeficiency or immunosuppression (21, 22).

So far, 21 genes in 156 EV patients have been identified, including three genes in 127 typical EV patients and 18 genes in 29 atypical EV patients. Typical EV patients include 49, 39, and 39 patients with TMC6, TMC8, and CIB1 pathogenic variants, respectively. Additionally, as many as 27, 25, and 14 HPV types have been identified in patients with the TMC6, TMC8, and CIB1 pathogenic variants, respectively (20, 23-50). The 18 genes in atypical patients include ARPC1B, CHUK, CORO1A, DCLRE1C, DOCK8, IKBKG, IL2RG, ITK, JAK3, LCK, NF1, PTEN, RASGRP1, RHOH, SMARCAL1, STK4, TPP2, and ZAP70, with DOCK8, PTEN, and STK4 being the most frequently mutated gene.

While TMS is extensively dubbed in mass media under the name “EV,” it is essential to note that they are not the same condition, as TMS is the consequence of α-HPV infection and not β-HPV. In TMS patients, the phenotype includes a disfiguring skin condition marked by atypical susceptibility to α-HPV-2, resulting in the development of persistent, wart-like growths that can resemble gnarled bark (51) (Figure 2A). Thus far, only eight unrelated cases of TMS have been reported (12, 52-54). The rarity and non-contagious nature of TMS, as well as the unusual susceptibility of TMS patients to α-HPV-2, despite normally being resistant to other infections (12), raise intriguing questions about the disease's etiology (55). We recently published a family with cutaneous warts and giant horns with AR CD28 deficiency (Fig. 2A). In affected members of this family with severe verrucosis who were otherwise healthy, α-HPV-2 and γ-HPV-4 were detected (12) (Fig. 2H). CD28 has a major costimulatory role in TCR signaling (56). Interestingly, we found evidence of somatic mosaicism in CD4+ memory T cells of patients (12)

Most HPV-related genes belong to inborn errors of immunity.

As previously stated, 74 genes from the 83 PHPVI-related genes were also found in the panel of 485 IEI-related conditions compiled by IUIS. There are already eight categories for these 74 genes, but we have added a ninth, "ND,", to accommodate the nine genes that aren't related to IEI or will not be added to the IUIS list until the next consensus is reached. Most genes (54%, 40 out of 74) are represented in the nonsyndromic and syndromic combined immunodeficiency categories.

Group 1: Persistent HPV infections in severe combined immunodeficiency

Ten genes previously linked with severe combined immunodeficiency (SCID) have been reported in association with PHPVI, including ADA, CD3D, CORO1A, DCLRE1C, IL2RG, IL7R, JAK3, LIG4, PTPRC, and RAG1, with 76 and 16 reported IL2RG and JAK3 patients as the most common causes of PHPVI in this category, respectively (57-75). Phenotypically, the SCID spectrum ranges from infancy-lethal SCID to less severe phenotypes such as Omenn syndrome (OS), "leaky" SCID, or less profound combined immunodeficiency (CID) phenotypes due to pathogenic variants in genes involved in T and B cell immunity or hypomorphic variants in several SCID-related genes. Hematopoietic stem cell transplantation (HSCT) is the most common treatment for children with infancy-lethal SCID, with a 90% increased survival rate. In treated patients, PHPVI manifests as post-HSCT. Thus, PHPVI can be a presentation of both untreated SCID and post-HSCT SCID patients.

Both X-linked IL2RG and JAK3 deficiencies cause T-B+SCID. The IL2RG deficiency is the most common type of SCID, and the patients develop primary cutaneous PHPVI with high penetrance as both primary (49, 76-81) and post-HSCT (62, 82-89), with HPV-2 being the most common HPV type (49, 81, 86, 87). Unlike IL2RG, only two JAK3 patients developed post-HSCT cutaneous PHPVI (62, 69, 82, 84, 89-91).

HPV infections in less profound combined immunodeficiency

Less severe forms of CID include CD40LG, DOCK8, ICOS, ITK, STK4, RFXANK, SASH3, ZAP70, CHUK, ICOSLG, LCK, MALT1, POLD1, RHOH, and TRAC. These 15 genes in the CID category have been linked to PHPVI, with 60 and 21 reported DOCK8 and STK4 patients as the most common causes of PHPVI in this category, respectively (92-111).

Pathogenic variants in the dedicator of cytokinesis 8 (DOCK8) cause an AR CID with hyper-IgE. DOCK8 patients manifest with cutaneous PHPVI, combined with either anogenital or oral warts (the latter is known as Heck disease). Based on different reports, 20–62% of DOCK8 patients showed PHPVI (49, 112-127). A few studies genotyped the HPVs and found persistent infections with α-HPV (HPV-2, -3) and β-HPV (HPV-5) (49, 119, 121). All reported STK4-deficient patients developed cutaneous wart, except a family with anogenital and cutaneous warts (49, 128-134).

Group 2: HPV infections in patients with “combined immunodeficiencies with associated or syndromic features”

“Combined immunodeficiencies with associated or syndromic features” is the second common category of IEI that is associated with PHPVI (18%). “immunodeficiency with congenital thrombocytopenia,” “DNA repair defects,” “immunoosseous dysplasias,” “Hyper IgE syndromes (HIES),” “anhidrotic ectodermodysplasia with immunodeficiency (EDA-ID),” and “other defects” are part of this category, and “other defects” are part of this category (2).

So far, 69 genes associated with this category have been identified in IEI defects, of which 15 have been reported with PHPVI, including ARPC1B, ATM, CARD11, CD28, IKBKG, SPINK5, WAS, NFKBIA, DNMT3B, FAT4, IKZF3, PGM3, RBCK1, SMARCAL1, and STAT3, with 20 ataxia-telangiectasia (A-T) patients with ATM pathogenic variants as the most common cause of cutaneous warts in this category (12, 49, 135-162). Two genes (ATM and DNMT3B) have been linked to DNA repair defects associated with PHPVI. ATM is necessary for the double-strand DNA break repair system, which is essential for the T-cell receptor (TCR) and B-cell receptor (BCR) V(D)J recombination (163-167). A patient has been identified with Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome 1 (ICF1) and cutaneous warts due to a pathogenic variant in DNMT3B (168).

Group 3: Defects in intrinsic and innate immunity

“Defects in intrinsic and innate immunity,” the third common category of IEI defects, are associated with PHPVI (12%). “Mendelian Susceptibility to Mycobacterial Disease (MSMD),” “EV,” “Predisposition to Severe Viral Infection,” “Predisposition to Invasive Fungal Diseases,” “Predisposition to Mucocutaneous Candidiasis,” and “TLR Signaling Pathway Deficiency with Bacterial Susceptibility” are parts of this category (2).

So far, 74 genes associated with this category have been identified in IEI defects, of which ten have been reported in association with cutaneous, anogenital, and oral warts and vulval and cervical dysplasia, including CXCR4, TMC6, TMC8, CIB1, CARD9, FCGR3A, MYD88, STAT1, IRF8, and IFNGR2, with 59 WHIM (warts, hypogammaglobulinemia, recurrent bacterial infections, and myelokathexis) syndrome patients with gain-of-function (GOF) variants in the CXCR4 gene as the most common cause of cutaneous warts in this category (169-189), followed by cutaneous warts in a total of 127 patients with typical EV-related genes including TMC6, TMC8, and CIB1 (20, 23-50, 190-196).

Group 4: Diseases of immune dysregulation

“Diseases of immune dysregulation” is the fourth common category of IEI defects with 52 associated genes (9%), and seven genes from this category (CARMIL2, MAGT1, CD27, RASGRP1, TPP2, CASP10, and LRBA) have been reported in association with PHPVI, with cutaneous, anogenital, and oral warts in 28 reported patients with CARMIL2 (RLTPR) deficiency as the most common causes of PHPVI in this category (168, 197-210). "Susceptibility to EBV and lymphoproliferative conditions," "Autoimmunity with or without Lymphoproliferation," "Autoimmune Lymphoproliferative Syndrome (ALPS, Canale-Smith syndrome)," and "Regulatory T Cell Defects" are subcategories of this group (2).

Group 5: Predominantly antibody deficiencies

“Predominantly antibody deficiencies” arethe fifth common category of IEI defects associated with PHPVI. So far, 45 genes (out of 485 genes, or 9%) have been associated with this category, of which six genes (PIK3CD, NFKB1, PTEN, PIK3R1, RAC2, and TNFSF12) have been reported to be associated with PHPVI (2), with ten patients with cutaneous warts and PIK3CD pathogenic variants and eight patients with cutaneous and oral warts and PTEN pathogenic variants as the most common causes of PHPVI in this category (168, 172, 211-223).

Group 6: Bone marrow failure

“Bone marrow failure," the sixth common category of IEI defects (6%), has been linked so far with 44 genes (2). Five Fanconi anemia genes (FANCA, FANCC, FAND2, FANCF, and FANCI) have been reported in association with cutaneous, anogenital, and oral PHPVI (224-229).

Group 7: Congenital defects of phagocyte number or function

"Congenital defects of phagocyte number or function" is the seventh most common category of IEI defects associated with PHPVI (5%). To date, 42 genes have been associated with this category, and four genes (GATA2, CF, HYOU1, and ITGB2) have been reported to be associated with PHPVI, (2) with monoallelic GATA2 variants in 217 patients, with cutaneous, oral, and anogenital warts being the most common cause of PHPVI (49, 134, 230-274). The wart phenotype is highly penetrant in GATA2 patients, and it is presented in up to 70% of patients. Warts are, for the most part, HPV-2 positive, and they are typically refractory to treatments and are often the first manifestation of the disease (233, 268, 275-278).

Group 8: Autoinflammatory disorders

Among IEI defects, 56 genes have been classified under the umbrella of autoinflammatory disorders, of which only two genes (ADA2 and NLRP1) have been linked with PHPVI. All 22 reported ADA2 patients manifested cutaneous warts (279-284), and only one had both anogenital and cutaneous warts (281). Five patients with multiple self-healing palmoplantar carcinomas (MSPC) due to pathogenic variants in NLRP1 manifested cutaneous and laryngeal PHPVI (285-287).

“Not Determined Yet” group

The last miscellaneous group of genes that are not a part of the IUIS category but have been reported in association with PHPVI includes nine genes (11%). These genes include ATP2C1, IL7, HRAS, CD4, NF1, ANKRD26, IVNS1ABP, MR1, and MYH7 (288-303).

Discussion

PHPVI present as cutaneous, anogenital, and mucosal warts. CW, EV, and TMS are manifestations of cutaneous warts with an increased risk of invasive or malignant NMSC in some cases, especially in patients with EV (Figure 2A). Even though single-gene pathogenic variants in 83 genes have been found, neither genetic testing is part of clinical workups nor are PHPVI patients usually referred for genetic counseling. In this report, we performed a systematic literature review reporting the association of PHPVI with a well-defined genetic diagnosis. To facilitate more extensive molecular testing of PHPVI, we compiled a list of the 83 monogenic disorders associated with PHPVI. 79 out of 83 genes were associated with cutaneous warts, 28 with anogenital lesions, and 16 with mucosal warts. Eleven genes have been connected to all three types of warts (Figure 2F).

Interestingly, 74 out of 83 genes belong to a catalog of IEI-related genes (Fig. 2B). The knowledge we gained from this study is crucial for patient counseling, pathogenesis guidance, the creation of global follow-up protocols and guidelines, and potential future therapies. This review also presents valuable and novel information about HPV types (Table 1), IUIS-based classification-related genes (Figures 2D and 2E), and the number of patients for each gene (Figure 2C). Our extensive literature search led us to the conclusion that pathogenic variants in GATA2 are the most common cause of PHPVI (217 patients), followed by IL2RG (76 patients), CXCR4 (59 patients), and DOCK8 (60 patients) (Figure 2C). The susceptibility to PHPVI in monogenic patients may show incomplete clinical penetrance and variable expression (1, 304, 305).

In our list of 83 genes, we found that AR accounted for 57 (69%). Effective strategies for reducing the risk of consanguineous marriages for AR disorders include carrier detection for families with known AR disorders in the extended family, establishing genetic counseling programs in regions with the tendency to customary consanguinity, and offering diagnostic exome-based preconception carrier testing in consanguineous couples with a positive or negative familial history of AR disorders (306, 307). It is widely recognized that consanguineous kinship patterns are an essential part of the social structures in many Middle Eastern countries (308). These cultural norms should be considered when designing effective strategies for genetic counseling.

In the presence of suspected PHPVI, a combination of clinical evaluation, laboratory investigation, and genetic testing is required for achieving a final diagnosis (Figure 3). Laboratory evaluations of PHPVI patients with or without apparent IEI entail immunological investigations, such as complete blood counts, flow cytometry, and qualitative and quantitative immunoglobulin analyses (IgG, IgA, IgM, and IgE), which are utilized to guide a phenotype-based diagnosis of PHPVI patients (309-311) (Figure 3A and 3B). It is important to highlight that flow cytometric immunophenotyping results falling within the expected range do not rule out the possibility of a Mendelian disease for the reasons outlined below. First, some PHPVI-associated genes do not belong to the list of IEI genes. Second, the immunophenotypic results for certain IEI-associated genes, including TMC6, TMC8, and CIB1, are consistently normal. Third, the revertant mosaicism event observed in genes associated with IEI has the potential to restore the disease phenotype to its normal state by compensating for the impact of pathogenic germline variants. This could result in a single infection with a normal immunophenotyping outcome, similar to PHPVI, as opposed to multiple infections (12).

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).

The next step is to determine a genetic diagnosis (Figure 3C). Establishing a genetic diagnosis for PHPVI patients has several diagnostic and prognostic implications. Firstly, genetic diagnosis may improve the preliminary diagnosis and consequent clinical management, as a recent study in the context of IEI patients suggested an alteration of the preliminary diagnosis in 55% of cases after genetic testing, resulting in a change in clinical management in 25% (312). Secondly, several monogenic disorders that present as RW have specific treatments, such as HSCT, depending on the type of mutated gene. For example, patients with DOCK8 deficiency respond favorably to HSCT, whereas others, such as STAT3-deficient patients, do not (313, 314). Thirdly, to implement allele-specific precision medicine, it is necessary to be aware of the mutant genes and identify the specific pathogenic variants (315-317). The fourth benefit of a molecular diagnosis is the ability to more accurately predict the course of the pregnancy and the child’s future health and development. Fifthly, knowing a molecular diagnosis offers psychological benefits to a parent, who can be assured that a negative outcome results from a random genetic event. Sixthly, knowing the molecular etiology permits a more accurate prediction of the recurrence risk for future pregnancies and, in many instances, permits earlier fetal genetic screening or preimplantation genetic diagnosis in future pregnancies. Lastly, it also allows for identifying heterozygotes within extended families at risk for IEI recurrence with PHPVI (Figure 3D).

In addition to genetic testing, viral genotyping is also important in the management of premalignant and malignant lesions in RW patients in multiple scenarios. First, a specific group of cutaneous HPVs, known as β-HPVs, cause flat warts in patients with EV. These lesions gradually transform into NMSC, especially invasive and metastatic cSCC (Figure 2A). The need for annual monitoring of EV warts is vital. Second, in TMS patients, all cutaneous lesions are positive for HPV-2, and they have the potential to transform into lesions with genetic and viral profiles reminiscent of high-grade cervical cancers. These cutaneous horns overexpress oncogenic E6 and E7 (12). Finally, infections with certain α-HPV types, known as high-risk HPVs (HR-HPV), are strongly associated with the development of a considerable proportion of cervical, anogenital, and head and neck squamous cell carcinoma (HNSCC) (318-321). Therefore, viral profiling is very important in the management of malignancy in patients with monogenic susceptibility to PHPVI. There are more than 200 commercially available molecular HPV assays on the global market, including DNA- and RNA-based amplification tests, signal amplification tests, and direct, in situ hybridization-based detection tests (322). Additionally, HPV serology testing, such as Virscan, detects antibodies related to active and past viral infections (323). Besides, GS (genome sequencing) and RNA-Seq can also unbiasedly detect all HPV types from lesion biopsies and have the advantage of simultaneously detecting host monogenic sequence variants, underlying susceptibility to IEI in these patients. Thus, with an eye to their limited access in many places in the world, they can be considered a genetic testing platform (324, 325). RNA-Seq is not only able to detect pathogenic sequence variants; it can also perform pathogenicity confirmation and RNA expression profiling. While GS can detect the presence of HPV types in skin biopsy samples, only RNA-Seq can detect the presence of active HPVs (27, 49).

Current genetic testing for PHPVI prioritizes the NGS panel of IEI-associated genes, or ES to identify the underlying monogenic cause (312, 326-330). Although standard genetic testing for IEI detects germline variations, it is now understood that IEI can also result from de novo variants in somatic and/or germ cells. Somatic mosaicism, or post-zygotic genetic alterations in DNA sequence, is now recognized as a cause for IEI (121, 331-333). Due to limitations in current genetic testing strategies, detecting mosaic variants in a routine clinical context is challenging. The treatment of an IEI may also be impacted by the mosaicism diagnosis, as in the case of DOCK8 deficiency (121). Therefore, incorporation of new strategies for sequencing into current diagnostic algorithms is essential, especially for individuals without a germline disease-causing variant but with a high clinical suspicion of an underlying IEI.

Abbreviations:

ACMG

American College of Medical Genetics and Genomics

ADA

adenosine deaminase

AD

autosomal dominant

APC

antigen-presenting cells

AR

autosomal recessive

A-T

ataxia-telangiectasia

BCG

Bacillus Calmette-Guerin

BCR

B-cell receptor

CBT

cord blood transplantation

CID

combined immunodeficiency

cSCC

cutaneous squamous cell carcinoma

DD

developmental delay

DOCK8

dedicator of cytokinesis 8

EBV

Epstein-Barr Virus

EDA-ID

anhidrotic ectodermodysplasia with immunodeficiency

EDAID2

ectodermal dysplasia and immunodeficiency 2

EV

epidermodysplasia verruciformis

FTT

failure to thrive

GI

gastrointestinal

GOF

Gain-of-function

HIES

hyper-IgE syndromes

HNSCC

head and neck squamous cell carcinoma

HUGO

Human Genome Organization

HPV

human papillomavirus

HR-HPV

high-risk HPVs

HSCT

hematopoietic stem cell transplantation

ICF1

immunodeficiency, centromeric instability, facial anomalies syndrome 1

IEI

inborn errors of immunity

Ig

immunoglobulin

IL2RG

interleukin 2 receptor gamma chain gene

IUIS

International Union of Immunological Societies

LIG4

DNA Ligase IV

MSMD

Mendelian susceptibility to mycobacterial disease

MSPC

Multiple Self-Healing Palmoplantar Carcinoma

ND

not determined

NMSC

non-melanoma skin carcinoma

NS

Netherton syndrome

OS

Omenn syndrome

PHPVI

persistent human papillomavirus infection

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

RW

recalcitrant warts

SCC

squamous cell carcinoma

SCID

severe combined immunodeficiency

SD

standard deviation

TCR

T-cell receptor

TMS

Treeman syndrome

WAS

Wiskott-Aldrich syndrome

ES

exome sequencing

GS

genome sequencing

WHIM

warts, hypogammaglobulinemia, recurrent bacterial infections, and myelokathexis

XLR

X-linked recessive

XMEN

X-linked magnesium EBV and neoplasia

Data Availability

The data sets generated and/or analyzed during this study are available from the corresponding author on request.