Epidermodysplasia verruciformis

INTRODUCTION — Epidermodysplasia verruciformis (EV; MIM #226400, #618231, #618267, #305350) is a rare autosomal recessive skin disease characterized by an abnormally high susceptibility to infection with certain types of human papillomavirus (HPV) called EV-HPV, mostly belonging to the beta-HPV genus, that preferentially affect the skin [1-7]. Patients have disseminated polymorphic lesions, including flat-topped, wart-like papules and pityriasis versicolor-like macules, predominantly on skin areas exposed to sunlight (picture 1A-B). In addition, patients with EV have an increased risk of developing nonmelanoma skin cancers, mainly cutaneous squamous cell carcinomas (SCCs), at an early age [8-11].

This topic will discuss the pathogenesis, clinical manifestations, diagnosis, and treatment of EV and distinguish genetic EV from acquired EV, which occurs in the setting of immunodeficiency. WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome (MIM #193670) is a rare genetic immunodeficiency disorder that also may present with increased susceptibility to HPV infection and cancer risk. Therefore, WHIM syndrome is also discussed briefly here. The epidemiology, virology, and natural history of HPV infection are discussed separately.

●(See "Human papillomavirus infections: Epidemiology and disease associations".)

●(See "Virology of human papillomavirus infections and the link to cancer".)

EPIDEMIOLOGY — The prevalence of EV is not known. A total of 501 patients have been described worldwide; most cases are sporadic, but there are several reports of familial cases [12].

PATHOGENESIS — The pathogenesis of EV is incompletely understood. It is thought to result from a combination of genetic factors leading to a selective immunodeficiency, infection from EV-human papillomaviruses (HPVs), and exposure to ultraviolet (UV) radiation [13,14].

Genetics — EV is inherited in an autosomal recessive fashion in most of the described families. Autosomal dominant and X-linked inheritance (EDVX) have also been reported [15,16]. Biallelic pathogenic variants in either TMC6 or TMC8 (also named EVER1 and EVER2) on chromosome 17q25.3 cause EV1 and EV2, respectively, and have been found in 36 patients from 22 families [12,13,17-28]. All described variants are loss-of-function variants (nonsense, splice site, frameshift variant, exon deletion, or insertion of amino acids) and result in a lack of functional protein production [29]. Variants in a third gene, CIB1 located on chromosome 15q26.1, were identified as causative for EV3. Homozygous CIB1 null variants were identified in 24 patients from six families [29].

Some patients with EV-like phenotypes do not have variants in TMC6, TMC8, or CIB1. Variants in other genes involved in primary T cell and/or natural killer (NK) cell immunodeficiencies, including RHOH (EV4), LCK, IL7 (EV5), MST1, CORO1A, RASGRP1, CARMIL2, DCLRE1C, DOCK8, and TTC7A, are reported in a limited number of patients with susceptibility to HPV types typically detected in patients with EV, indicating nonallelic heterogeneity of the disease [28,30]. (See "Severe combined immunodeficiency (SCID): Specific defects" and "NK cell deficiency syndromes: Clinical manifestations and diagnosis" and 'Immune system abnormalities' below.)

Role of TMC6 and TMC8 — TMC6 and TMC8 belong to a larger gene group named transmembrane channel-like gene family, which consists of a group of highly conserved transmembrane proteins [31]. Yeast two-hybrid screens and co-immunoprecipitation data suggest that both TMC genes form a complex with the zinc transporter ZnT-1 [24]. This complex is located within the membrane of the endoplasmic reticulum [32] and influences the zinc homeostasis in cells by decreasing Zn²⁺ release from the endoplasmic reticulum [24,33].

TMC6 and TMC8 proteins are involved in EV-HPV persistence and oncogenicity. It is hypothesized that the Zn²⁺ level controlled by the TMC/ZnT-1 complex leads to a reduced activity of transcription factors, which are essential for the replication of EV-HPV. Due to TMC/ZnT-1 complex disruption, transcription factors increase and enable EV-HPV replication, leading to the EV phenotype [32]. However, an effect on free zinc levels has not been detected in patients with TMC6 or TMC8 deficiency [29]. (See 'Human papillomavirus infection' below.)

One study showed that TMC8 supports tumor necrosis factor (TNF)-alpha-dependent apoptosis but prevents TNF-alpha-dependent NF-kB activation by interaction with TNF receptor-associated death domain protein (TRADD) [34]. Epidermis samples of patients with EV revealed an overexpression of transforming growth factor-beta-1 and TNF-alpha compared with samples of non-EV patients [35].

Role of CIB1 — CIB1 encodes the calcium- and integrin-binding protein 1, which is strongly expressed in human epidermis and hair follicles [29]. Even though it is reported to modulate cell migration and influence focal adhesion formation, influences on migration could not be observed in CIB1-deficient keratinocytes from patients with EV.

In TMC6- and TMC8-deficient cells derived from patients with EV, CIB1 is not expressed. In healthy cells it forms a complex with both TMCs [29]. Similarly to TMC6 and TMC8, which in previous studies have been shown to interact with HPV16 E5 [24], CIB1 interacts with beta-HPV5 E1 and HPV16 E2. These connections suggest the involvement of the TMC6-TMC8-CIB1 complex in the defense against mucosal and cutaneous HPVs.

Immune system abnormalities — Although the number of CD4⁺ and CD8⁺ T cells in patients with EV appears to be normal, a significant increase in memory CD4⁺ and effector memory CD8⁺ T cells as well as an increase in skin-homing CD4⁺ T cell subsets has been reported [36]. Both TMC6 and TMC8 are expressed in the skin and abundantly in T cells. Lymphoblastoid cells or primary T cells from patients with EV have increased levels of Zn²⁺ [37].

An EV-like phenotype has been described in patients with primary T cell and/or NK cell immunodeficiencies due to pathogenic variants of RHOH (EV4), LCK, IL7 (EV5), MST1, CORO1A, RASGRP1, CARMIL2, DCLRE1C, DOCK8, and TTC7A [38]. These patients also have increased susceptibility to bacterial and viral infections, including non-EV-HPV types [30].

A late-onset form of EV, named "acquired epidermodysplasia verruciformis," is reported in patients with acquired cell-mediated immunodeficiency (HIV-positive patients and immunosuppressive treatment in organ transplant recipients) [39-41]. (See 'Acquired epidermodysplasia verruciformis' below.)

Human papillomavirus infection — Infection from EV-HPV typically occurs during infancy [42]. Patients with EV are susceptible to skin infections by particular types of HPV predominantly belonging to the genus beta (EV-HPV), which are considered to be nonpathogenic to the general population (table 1) [14,43]. In contrast to other HPVs, EV-HPVs do not integrate into the human genome and do not have the HPV gene E5, encoding a protein that interacts, among others, with the zinc transporter ZnT-1. It is hypothesized that due to the missing E5 the general population is enabled to suppress the invasion of EV-HPV. Patients with EV are not able to eliminate EV-HPV-harboring keratinocytes due to impaired Zn²⁺ homeostasis [24,32]. (See 'Role of TMC6 and TMC8' above.)

Skin cancer — Over 60 percent of patients with EV develop cutaneous squamous cell carcinoma (SCC), including SCC in situ (Bowen's disease), at an early age. Basal cell carcinomas and keratoacanthomas have also been reported [44].

Cutaneous SCCs arise almost exclusively in sun-exposed skin areas, and approximately 90 percent harbor EV-HPV type 5 or type 8, both expressing the oncoproteins E6 and E7 [45]. However, the E6 and E7 proteins of most EV-HPVs have less transforming potential than E6 and E7 proteins of high-risk genital alpha-type HPVs (HPV16 and HPV18) [46]. (See "Virology of human papillomavirus infections and the link to cancer".)

These observations suggest that multiple factors are involved in the pathogenesis of cutaneous SCC in patients with EV, including direct damage of keratinocyte deoxyribonucleic acid (DNA) from UV radiation, inhibition of ultraviolet B (UVB)-induced keratinocyte apoptosis by HPV, activation of HPV promotors by UVB [47], and UV-induced local immunosuppression [45].

PATHOLOGY

Histopathology — The histopathology of EV-lesions, also called EV-plane warts, demonstrates basket-weave hyperkeratosis, mild acanthosis, and vacuolated cells in the upper epidermis (picture 2). The nuclei can be pyknotic and may be surrounded by clear halos. The cytoplasm of affected cells stains pale blue and contains numerous round basophilic keratohyalin granules.

Human papillomavirus detection — EV-human papillomavirus (HPV) types can be detected in all patients with EV in lesional skin and in plucked eyebrow hairs by polymerase chain reaction and direct sequencing. (See "Human papillomavirus infections: Epidemiology and disease associations", section on 'Detection of HPV'.)

Multiple HPV types, including some alpha-types with uncertain correlation with EV, are usually present in the same patient (table 1) [48-50]. Approximately 90 percent of cutaneous squamous cell carcinomas (SCCs) occurring in patients with EV harbor HPV types 5 or 8.

Immunohistochemistry — An analysis of specific epidermal markers (KRT1, 10, 14, 16, 4, involucrin, filaggrin, and E-cadherin) in EV lesions demonstrated diminished expression of K1 and K10, which were replaced by K14, reflecting immaturity and lack of differentiation in the abnormal epidermis [51]. In addition, K16 and K4, normally not found in the differentiated epidermis, as well as involucrin were overexpressed in the spinous layer, suggesting disturbed proliferation and differentiation of the epidermal cells. Such alterations could be induced by the E7 gene of some HPV types [52].

CLINICAL MANIFESTATIONS — Persons with EV usually develop multiple polymorphic skin lesions during early infancy or childhood. In many patients, the clinical appearance of the lesions does not immediately suggest verruca. Lesions may present as flat-topped, papular lesions similar to verrucae planae on the extremities (picture 1A) or as red, red-brownish, or hypopigmented plaques or pityriasis versicolor-like lesions mostly distributed on the trunk, neck, and face (picture 1B-C). Some patients may present verruca-like papillomatous lesions or seborrheic keratosis-like lesions [53,54].

Data on the clinical course of EV lesions are lacking. In the author's experience, the clinical phenotype of a specific skin area may change and spontaneous regression or progression may occur.

Patients with EV are not reported to have an increased susceptibility to infection from human papillomavirus (HPV) types causing cutaneous warts; anogenital warts; or cervical, anal, or penile cancer. In this regard, EV can be distinguished from other T cell, natural killer (NK) cell, and combined immunodeficiencies, such as that found in GATA2 deficiency, that are associated with recurrent mucocutaneous warts and HPV-related cancers [55]. (See "Cutaneous warts (common, plantar, and flat warts)" and "Condylomata acuminata (anogenital warts) in adults: Epidemiology, pathogenesis, clinical features, and diagnosis" and "Virology of human papillomavirus infections and the link to cancer".)

Skin cancer — Approximately two-thirds of patients with EV develop actinic keratoses and cutaneous squamous cell carcinoma (SCC), including Bowen-type carcinoma in situ, at an early age, usually in the second or third decade of life [56,57]. There is no known relationship between EV phenotypes and risk of skin cancer. (See "Cutaneous squamous cell carcinoma: Epidemiology and risk factors", section on 'Human papillomavirus infection'.)

DIAGNOSIS — The diagnosis of EV is suspected in a patient with a history of multiple diffuse, flat, wart-like skin lesions beginning in infancy or early childhood. The definitive diagnosis requires a skin biopsy and is based upon the histologic finding of hyperkeratosis, mild acanthosis, and vacuolated cells in the upper epidermis and demonstration of human papillomavirus (HPV) in the skin lesion. HPV DNA testing is performed in specialized laboratories. (See 'Histopathology' above and "Human papillomavirus infections: Epidemiology and disease associations", section on 'Detection of HPV'.)

Genetic testing — Clinical mutational analysis is available for mutations in TMC6 and TMC8 genes and may be useful for patients suspected to have an inherited form of EV. Mutations can be identified in approximately 75 percent of patients with EV.

PRENATAL DIAGNOSIS — In families with a known diagnosis of EV and molecularly confirmed mutations, DNA testing can be performed on chorionic villus-derived cells or amniocytes from the pregnant mother. Early referral for genetics consultation prior to pregnancy and planning of pregnancies are recommended for carrier parents of an affected child if they are interested in prenatal diagnosis.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of EV includes generalized verrucosis in the setting of primary immunodeficiencies, the acquired form of EV associated with secondary immunodeficiencies, and other skin conditions that can mimic EV clinically:

●Generalized verrucosis associated with primary immunodeficiencies – Disseminated and/or recalcitrant mucocutaneous warts and human papillomavirus (HPV)-related cancers may occur in persons with T cell and/or natural killer (NK) cell primary immunodeficiencies, including severe and milder forms of combined immunodeficiency and NK cell deficiency syndromes [38]. In contrast to patients with EV, patients with impaired cell-mediated immunity have increased susceptibility to infections with non-EV-HPV types and other common viruses, as well as with opportunistic, infectious agents. (See "Severe combined immunodeficiency (SCID): An overview" and "Combined immunodeficiencies: An overview" and "NK cell deficiency syndromes: Clinical manifestations and diagnosis" and 'Immune system abnormalities' above.)

WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is a rare, congenital disorder characterized by neutropenia associated with hypogammaglobulinemia and increased susceptibility to warts and bacterial infections. (See 'WHIM syndrome' below.)

●Acquired epidermodysplasia verruciformis associated with secondary immunodeficiencies – An EV-like phenotype has been described in patients with defective cell-mediated immunity, predominantly in solid organ transplant recipients and patients with HIV infection. Patients with acquired EV have an increased risk of developing infections with non-EV-HPV and related cancers. (See 'Acquired epidermodysplasia verruciformis' below.)

●Disseminated, flat warts – Flat warts (verrucae planae) are minimally elevated, flat-topped, skin-colored papules caused by HPV types 3, 10, and 28, commonly occurring on the face, neck, and legs (picture 3A-B). They are histologically indistinguishable from EV lesions. In contrast to EV, flat warts may disappear spontaneously in months to years. (See "Cutaneous warts (common, plantar, and flat warts)".)

●Clinical mimickers of epidermodysplasia verruciformis:

•Confluent and reticulated papillomatosis of Gougerot and Carteaud – Confluent and reticulated papillomatosis of Gougerot and Carteaud is an uncommon cutaneous disorder of unknown etiology usually occurring in young adults [58]. It presents with hyperpigmented, scaly patches with a reticulated appearance on the chest and upper back (picture 4A-D). Histology shows hyperkeratosis, acanthosis, and papillomatosis; HPV is absent. (See "Acquired hyperpigmentation disorders", section on 'Confluent and reticulated papillomatosis'.)

•Pityriasis versicolor – Pityriasis versicolor is a common superficial fungal infection presenting with hypopigmented, hyperpigmented, or erythematous macules on the trunk and proximal upper extremities (picture 5 and picture 6). A potassium hydroxide (KOH) preparation showing both hyphae and yeast cells confirms the diagnosis. (See "Tinea versicolor (pityriasis versicolor)".)

•Disseminated superficial porokeratosis – Disseminated superficial porokeratosis (DSAP) is a disorder of keratinization characterized by small erythematous, skin-colored, or hyperpigmented macules with a fine peripheral keratotic ridge (picture 7A-C). Histology shows the pathognomonic cornoid lamella, a thin column of tightly packed parakeratotic cells. (See "Porokeratosis".)

•Darier disease – Darier disease is an uncommon genodermatosis characterized by a persistent eruption of greasy, hyperkeratotic papules in seborrheic areas, such as forehead, scalp, chest, and back (picture 8A-E). Some patients may have warty, flat-topped papules on the dorsa of the hands and feet that are clinically indistinguishable from similar lesions occurring in EV. The histologic finding of acantholysis and dyskeratosis can clarify the diagnosis. (See "Darier disease".)

TREATMENT — There are no curative therapies for EV. Systemic retinoids, including acitretin and isotretinoin, have been used in a few patients with transient benefit [59-62]. Treatment of EV lesions with topical imiquimod has been reported in a few patients with inconsistent results [22,63-66]. There are isolated reports of successful use of photodynamic therapy [67] and topical fluorouracil [60]. Recurrence is usual when treatment is discontinued. High-dose oral cimetidine has been used in a few patients with inconsistent results [68,69].

Patients should be educated to adopt strict sun protection measures to prevent the development of actinic keratoses and nonmelanoma skin cancer. (See "Selection of sunscreen and sun-protective measures".)

Squamous cell carcinoma management — Cryotherapy is an appropriate first-line treatment for of actinic keratoses, Bowen's disease (cutaneous squamous cell carcinoma [SCC] in situ), and low-risk invasive cutaneous SCCs in patients with EV. Surgical excision is appropriate for both low-risk SCC and for SCC at increased risk of recurrence. (See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)".)

Treatment of SCC with radiotherapy in EV patients has been associated with aggressive tumor recurrence and should be avoided [70,71].

FOLLOW-UP — Patients with EV should undergo lifelong regular skin examination for early diagnosis and treatment of precancerous skin lesions and skin cancer. Patients without malignant tumors should be seen annually by a dermatologist. More frequent skin examinations at three- to six-month intervals may be necessary for patients treated for invasive squamous cell carcinoma (SCC). Approximately 70 to 80 percent of recurrences or metastases of cutaneous SCC occur within two years after therapy, and approximately 95 percent occur within five years. (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma".)

WHIM SYNDROME — WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome (MIM #193670) is a rare primary immunodeficiency disorder caused, in most cases, by gain-of-function pathogenic variants in the CXC chemokine receptor 4 gene (CXCR4; MIM #162643) [72,73]. Although WHIM syndrome is an autosomal dominant disorder, approximately 50 percent of cases result from a de novo mutation in children of unaffected parents. CXCR4 is expressed by most leukocyte subtypes [74]. Mutations in the CXCR4 gene cause an enhanced leukocyte response to the CXCR4 ligand, CXCL12, and thereby disrupt B cell and T cell development and traffic signaling. One consequence, called myelokathexis (characteristic neutropenia due to increased apoptosis and retention of atypical, hypersegmented, mature neutrophils in the bone marrow) is the hallmark feature of WHIM syndrome. (See "Approach to the patient with neutrophilia", section on 'Causes of neutrophilia' and "Congenital neutropenia", section on 'GATA2 deficiency/MonoMAC syndrome'.)

Pathogenic variants in the CXCR4 gene are not present in all patients with WHIM syndrome. In such patients, enhanced leukocyte responsiveness to CXCL12 may be due to defects that affect CXCR4 internalization and desensitization, such as the G protein-coupled receptor kinase 3 (GRK3) and arrestin beta 2 (ARRB2) [72,75,76]. However, other than CXCR4 variants, no other pathogenic variants have been identified so far in patients with WHIM syndrome. Some, but not all, newborns with WHIM syndrome are detected using expanded newborn screening for primary immunodeficiency disorders. One report describes low T cell receptor excision circle (TREC) levels in at least some newborns with WHIM syndrome [77].

Due to immunodeficiency, affected persons have increased susceptibility to human papillomavirus (HPV), chronic verrucosis, and recurrent respiratory tract infections [78-80]. Less commonly, lymphomas and HPV-associated malignancies, such as cervical cancer, have been reported [81]. However, the phenotype is variable, and not all patients have hypogammaglobulinemia or increased susceptibility to HPV infections, for example [82]. In a 2020 case series, only 5 of 24 patients had warts that were considered severe [81]. Congenital heart disease, including tetralogy of Fallot, and renal anomalies affect some patients [77,83]. Typically, patients present with recurrent, sinopulmonary, bacterial infections and recalcitrant, cutaneous warts. Affected children are at risk for hearing loss due to recurrent otitis media [81], and viral bronchiolitis is common in the neonatal period [77].

Leukopenia is a feature, primarily due to neutropenia, although moderate lymphopenia is also seen [82]. Peripheral blood neutrophil counts are typically low (<500 cells/microL) [78,84]. However, severely reduced counts may be absent at the time of medical attention since neutrophil count rises with infection. Bone marrow biopsy is required for diagnosis and reveals myelokathexis (mature neutrophils and accumulation of senescent neutrophils). Levels of immunoglobulin G (IgG) and/or immunoglobulin A (IgA) may be below normal. Antibody responses to vaccines are usually normal, but immunity may decrease rapidly, with absent protective titers one year after vaccination [82]. Peripheral blood lymphocytes generally function normally, but in vitro proliferative responses to mitogens and antigens may be impaired, and cutaneous anergy with delayed hypersensitivity skin testing may also be seen.

Immune globulin replacement therapy is effective for reducing bacterial infections in patients with WHIM syndrome [78]. Therapy with granulocyte colony-stimulating factor (G-CSF) results in increases in peripheral blood neutrophils but not other cell lines [78,81]. Some patients have been successfully treated with hematopoietic cell transplantation [85,86]. A small case series suggests treatment with plerixafor, a CXCR4 antagonist and stem cell mobilizing agent, is effective in increasing circulating leukocytes, decreasing infection frequency, and reducing the size and number of some warts in patients also treated with imiquimod [87-90]. Some patients also had improvement in anemia, thrombocytopenia, myelofibrosis, immunoglobulin levels off of replacement therapy, and HPV-associated tumors [90]. Similarly, mavorixafor, a selective CXCR4 antagonist, was shown to decrease the yearly infection rate (from 4.63 events, 95% CI 3.3-6.3 in the 12 months prior to the trial to 2.27 events, 95% CI 1.4-3.5 on therapy) and reduce the number of cutaneous warts by an average of 75 percent in a phase 2, open-label study in eight adults with WHIM syndrome [91]. Increased mobilization of neutrophils and lymphocytes was observed. No treatment-related serious adverse events were reported. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management" and "Immune globulin therapy in inborn errors of immunity".)

There is at least one report of spontaneous resolution of WHIM syndrome. In one female with WHIM syndrome, almost all of the clinical manifestations of the disease spontaneously resolved in her fourth decade of life [92]. Her cure is thought to demonstrate chromothripsis, a genetic process that is gaining importance in cancer biology. Chromothripsis refers to an event that causes multiple double-strand DNA breaks and chromosome arrangements in somatic cells [93]. This patient was shown to have deletion of the mutated CXCR4 allele on one copy of chromosome 2 via chromothripsis in a myeloid hemopoietic stem cell. That precursor cell was then able to reconstitute the granulocyte and monocyte compartments but not lymphocytes. Prior to this spontaneous "auto-reconstitution" via chromothripsis, the subject had already passed on the disorder in typical autosomal dominant fashion to two of her three children.

ACQUIRED EPIDERMODYSPLASIA VERRUCIFORMIS — A late-onset, EV-like condition has been reported in patients with impaired cell-mediated immunity and termed "acquired epidermodysplasia verruciformis" [39]. Most patients with acquired EV are solid organ transplant recipients or patients with HIV infection [39,94-98].

Acquired EV has also been reported in some patients with severe combined immunodeficiency (SCID) following hemopoietic stem-cell transplantation, probably due to residual immune deficiency [99,100]. Contributing factors may include deficiency of interleukin 2 receptor gamma, abnormal downstream signaling in keratinocytes, and/or a failure to meaningfully reconstitute natural killer (NK) cell development [101,102].

There are single-case reports of EV occurring in patients with lepromatous leprosy [103], Hodgkin lymphoma [104], and systemic lupus erythematosus [105].

Patients with acquired EV lack homozygous or compound heterozygous pathogenic variants in the TMC6 or TMC8 genes. Single-nucleotide polymorphism (SNP) variations in TMC have been reported in HIV-infected patients but not in transplant patients, suggesting a possible modulator function of SNPs in the development of acquired EV [95,96,106].

The clinical and histopathologic manifestations of EV are similar in inherited and acquired EV. Patients with acquired EV may present with diffuse xerosis as well as individual or coalescent flat-topped or hyperkeratotic papules.

Histologic examination of acquired EV lesions reveals the typical blue cells with pallor and a mild acanthosis similar to lesions of inherited EV. The demonstration of beta-human papillomavirus (HPV) types 5 and 8 (or others) in skin lesions confirms the diagnosis of acquired EV.

For patients with acquired EV, treatments are directed at reducing the immunosuppression or treating the underlying primary disease. In patients with HIV-associated acquired EV, improvement in cell counts after institution of antiretroviral therapy is inconsistently associated with clearance of EV-like lesions [107-110]. Management and monitoring of the skin lesions is similar to inherited EV.

SUMMARY AND RECOMMENDATIONS

●Definition and pathogenesis – Epidermodysplasia verruciformis (EV) is a rare autosomal recessive skin disease characterized by an abnormally high susceptibility to infection with certain types of human papillomavirus (HPV) called EV-HPV and increased risk of nonmelanoma skin cancer. In some families, EV is associated with biallelic pathogenic variants in either TMC6 or TMC8 (also named EVER1 and EVER2) on chromosome 17q25.3. (See 'Introduction' above and 'Pathogenesis' above.)

●Clinical manifestations – During early infancy or childhood, individuals with EV usually develop flat-topped, papular lesions similar to verrucae planae on the extremities (picture 1A) or red-brownish plaques or pityriasis versicolor-like lesions on the trunk, neck, and face (picture 1B). (See 'Clinical manifestations' above.)

●Risk of skin cancer – Approximately two-thirds of patients with EV develop actinic keratoses and cutaneous squamous cell carcinoma (SCC), including Bowen-type carcinoma in situ, at an early age, usually in the second or third decade of life. (See 'Skin cancer' above.)

●Diagnosis – The diagnosis of EV requires a skin biopsy and is based upon the histologic features and demonstration of HPV in a skin lesion. (See 'Diagnosis' above and "Human papillomavirus infections: Epidemiology and disease associations", section on 'Detection of HPV'.)

●WHIM syndrome – WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome typically includes increased susceptibility to HPV and chronic verrucosis as well as recurrent, sinopulmonary, bacterial infections. Potential treatment options include immune globulin replacement therapy, granulocyte colony-stimulating factor (G-CSF), and hematopoietic cell transplantation. Reports describe that patients with WHIM syndrome due to pathogenic variants in the CXC chemokine receptor 4 gene (CXCR4) may respond to CXCR4 antagonist treatment. (See 'WHIM syndrome' above.)

●Acquired epidermodysplasia verruciformis – A late-onset form of EV termed "acquired epidermodysplasia verruciformis" has been reported in patients with impaired cell-mediated immunity, such as solid organ transplant recipients or patients with HIV infection. (See 'Acquired epidermodysplasia verruciformis' above.)

●Treatment – There are no curative therapies for EV. Systemic retinoids have been used with transient benefit in a few patients. Patients should be educated to adopt strict sun protection measures to prevent the development of nonmelanoma skin cancer. (See 'Treatment' above.)

●Surveillance for skin cancer – Patients with EV should undergo lifelong regular skin examination for early diagnosis and treatment of precancerous skin lesions and skin cancer. (See 'Follow-up' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Peter Itin, MD, and Bettina Burger, DSc, who contributed to earlier versions of this topic review.