Epidermodysplasia Verruciformis

Epidermodysplasia verruciformis (EV) is a rare, inherited disorder that predisposes patients to widespread human papillomavirus (HPV) infection and cutaneous squamous cell carcinomas. ^{[1, 2, 3, 4]} Although epidermodysplasia verruciformis is most commonly inherited in an autosomal recessive manner, ^[5] sporadic, sex-linked, and autosomal dominant inheritance have been described. In those cases of autosomal recessive inherence, there may be a history of consanguinity in the parents of the afflicted individual. In those cases of atypical inheritance, there may be an association with chronic lymphopenias. Regardless of the mode of inheritance, the phenotype of the disease is characterized by chronic infection with HPV. Widespread skin eruptions of flat-to-papillomatous, wartlike lesions and reddish-brown pigmented plaques on the trunk, the hands, the upper and lower extremities, and the face are typical.

Malignant skin tumors (carcinomas), especially squamous cell carcinoma (in situ or invasive), develop frequently in these patients (30–70%), most commonly in sun-exposed areas starting between the ages of 20 and 40 years, which reflects the high-risk nature of the HPV infection. Skin cancers initially appear on sun-exposed areas, such as the face, neck, chest, and arms, reflecting the role of ultraviolet light and HPV infection in the promotion of skin cancer development. Patients with epidermodysplasia verruciformis are usually infected with multiple types of HPV, including common types that affect individuals without epidermodysplasia verruciformis (eg, HPV types 3 and 10) and those unique to epidermodysplasia verruciformis, the so called epidermodysplasia verruciformis–associated HPVs (EV-HPVs).

More than 30 EV-HPVs, such as types 4, 5a, 5b, 8,9, 12, 14, 15, 17, 19-25, 36-38, 47, and 50, have been identified in epidermodysplasia verruciformis lesions. Some EV-HPVs are detected in up to 20% of the non–epidermodysplasia verruciformis population, but they are only pathogenic in epidermodysplasia verruciformis patients. HPV-5 and HPV-8 have been isolated in more than 90% of epidermodysplasia verruciformis–associated squamous cell carcinomas. In 2017, Merkel cell polyomaviruses also were isolated from lesions. ^[6]

The pathophysiology of epidermodysplasia verruciformis is linked to defective cell-mediated immunity, with elucidation of mutations in EVER1 (TMC6) and EVER2 (TMC8) genes (band 17q25). ^{[2, 7]} Their gene products are integral membrane proteins localized to the endoplasmic reticulum.

Although the role of EVER1 and EVER2 genes in the pathogenesis of epidermodysplasia verruciformis remains unclear, one hypothesis is that they are involved in the control of HPV infection within keratinocytes, or they play a role in the immune response to the infection itself. Intracellular zinc homeostasis regulated by a complex of EVER proteins and zinc transporter proteins may play a role in inhibiting EV-HPV expression. ^[8]  It has been reported that mutations of EVER genes impair the ZnT-1/EVER complex, leading to increased zinc levels in the cytoplasm and allowing replication of EV HPV and abnormal sensitivity to infections by EV HPV. ZnT-1/EVER has been found to bind the E5 protein, resulting in increased concentrations of free zinc in keratinocytes. In non–epidermodysplasia verruciformis patients, the absence of E5 protects against EV HPV infections. ^{[9, 10]}

However, an estimated 25% of patients with epidermodysplasia verruciformis lack mutations in EVER1 and EVER2, with the genetic defect in these patients not yet elucidated. ^[11] Sporadic reports have described patients with the epidermodysplasia verruciformis phenotype who exhibit mutations in other genes.

In 2012, two siblings who were homozygous for a mutation that created a stop codon in the Ras homolog gene family member H (RHOH) gene exhibited an epidermodysplasia verruciformis phenotype and their T cells exhibited impaired T-cell receptor (TCR) signaling. ^[12] A report also described a 19-year-old with an autosomal recessive MST1 (or STK4, serine/threonine kinase 4) deficiency who exhibited the epidermodysplasia verruciformis phenotype as well as a global immune deficiency with susceptibility to other bacterial and viral infections. ^[13] MST1 deficiency leads to naive T-cell lymphopenia and an impaired egress of mature T lymphocytes from the thymus to secondary lymphoid organs, associated with an impaired chemotactic response to several chemokines, including the CCR7 ligands CCL19 and CCL21. ^[13] Additionally, it is theorized that MST-1 deficiency causes susceptibility to EV-HPV infections through an antiproliferative mechanism by directly restricting viral replication in keratinocytes through the Hippo tumor suppressor pathway. ^[6]

Another report describes three siblings who lacked EVER1/EVER2 mutations and exhibited atypical epidermodysplasia verruciformis, but who exhibited a homozygous splicing deficiency in the gene encoding LCK (lymphocyte specific kinase), resulting in a deletion of three exons of this gene. ^[14] These three siblings exhibited T-cell defects and epidermodysplasia verruciformis phenotype, including skin cancers.

Inactivating mutations of CORO1A, DCLRE1C (encoding the Artemis protein), DOCK8, RASGRP1, TPP2, ANKRD26, IL2RG, and JAK3 have also been reported in patients with atypical epidermodysplasia verruciformis. ^{[15, 16, 17, 18]} In patients with severe combined immunodeficiency (SCID) caused by mutations of IL2RG or JAK3, these patients develop epidermodysplasia verruciformis only after successful bone marrow transplantation, suggesting that development of disease in these patients is associated with a keratinocyte defect. ^[15]

Mutations in an increasingly investigated gene, CIB1, which encodes CIB1, have been identified in patients with typical epidermodysplasia verruciformis. ^{[19, 20, 21, 22]} This gene encodes calcium and integrin-binding protein 1, which forms a complex with EVER1 and EVER2. ^[20] The complex operates as a restriction factor in the skin, limiting infections by β-HPVs. One 2018 study identified five homozygous loss-of-function alleles of CIB1, which greatly increases the number of epidermodysplasia verruciformis cases for which genetic and molecular explanations have been found. ^[22] It should be noted that CIB1 deficiency does not have any impact on zinc homeostasis and NF-κB activation, indicating that EVER proteins have other functions shared by CIB1 that are involved in the pathophysiology of epidermodysplasia verruciformis. ^[22] The precise mechanisms through which the CIB1/EVER1/EVER2 complex operates still remain unclear, but the literature has established that epidermodysplasia verruciformis is a result of genetic mutations encoding the proteins of the CIB1/EVER1/EVER2 complex, which acts as a restriction factor for HPVs in keratinocytes.

These reports indicate that there are multiple genetic defects that can be associated with an epidermodysplasia verruciformis phenotype, and that genes resulting in T-cell defects play a permissive role in allowing the epidermodysplasia verruciformis‒associated HPV to cause skin lesions.

Several epidermodysplasia verruciformis variants have been described, and the majority of these cases occur in association with immunosuppression, such as HIV infection, organ transplantation, or idiopathic lymphopenia. ^[23] Generalized verrucosis (GV) has been defined as a progressive, chronic cutaneous HPV infection, and not synonymous with epidermodysplasia verruciformis as it was in the past. ^[6] They are now regarded as separate entities and distinguished by differences in clinical manifestations, histopathology, and genotype of HPV. GV describes a systemic immune deficiency, but one that is not confined to HPV and includes many other infectious agents. The term acquired epidermodysplasia verruciformis (AEV), also referred to as secondary epidermodysplasia verruciformis or immunodeficient epidermodysplasia verruciformis, was introduced to describe epidermodysplasia verruciformis occurring in patients with impaired cell-mediated immunity. This can be caused by infection (eg, HIV infection), Hodgkin lymphoma, lepromatous leprosy, lipoid proteinosis, or medications. ^[6] In the case of AEV, the status of EVER1 or EVER2 has not been fully evaluated. These patients may harbor previously silent mutations, epigenetic changes, or splice variants of EVER1 or EVER2, but it is clear that in these cases, global immune suppression allows the phenotype to develop. One report described three patients of one family carrying a homozygous splice site mutation in the donor splice site of IVS9 of TMC8. ^[24] This mutation resulted in abnormal transcripts that could not retain the usual phenotype. There have also been reports of acquired epidermodysplasia verruciformis in patients on immunosuppressive regimens. Azathioprine has been related to cases of acquired epidermodysplasia verruciformis as have tumor necrosis factor-alpha inhibitors such as adalimumab. ^{[25, 26]} Clinically, AEV resembles inherited epidermodysplasia verruciformis. The disease displays no sex or age predisposition, and cases have been reported both in early childhood (age 4 years) as well as in elderly individuals. ^[6]

Zavattaro et al reported a rare case of an epidermodysplasia verruciformis patient who had clinical features of epidermodysplasia verruciformis but lacked the EVER1 or EVER2 mutation. ^[27] This patient was older at diagnosis and had no premalignant or malignant lesions upon examination. Defective Fas protein function (CD95, apoptosis receptor) was identified along with perforin gene variations, suggesting that this combination resulted in increased susceptibility to HPV infection owing to defective viral clearance.

In addition, a profound CD8⁺ T-cell lymphocytopenia was identified, a finding also described by Azzimonti et al in a patient who also had a clinical diagnosis of epidermodysplasia verruciformis but who lacked EVER1 or EVER2 mutations. ^[28]

The papillomavirus genus is a member of the Papovaviridae family. HPVs are small, nonenveloped viruses, measuring approximately 55 nm in diameter. Their icosahedral capsid is composed of 72 capsomers, with a 56,000-d major protein, which is the genus-specific antigenic determinant of the virus, and a 76,000-d minor protein. The HPV genome contains a double-stranded circular DNA of approximately 7900 base pairs, functionally divided into an early region (E) of 5-7 open reading frames E1-E7, a late region (L) of open reading frames L1 and L2, and a noncoding upstream regulatory region. The HPV types are primarily classified on the basis of their DNA homology.

Patients with epidermodysplasia verruciformis have a defective cell-mediated immune response to HPV infection. In classic, autosomal recessive epidermodysplasia verruciformis, the immune defect is very specific, as these patients do not exhibit global defects in cell-mediated immunity, and there is no evidence that there are any defects in controlling other types of viral infections or bacterial or fungal challenges. Many HPV types found in epidermodysplasia verruciformis lesions are nonpathogenic to the general population. The exact mechanism by which cancer occurs frequently in patients with epidermodysplasia verruciformis is unclear. The role of HPV in cancer development is supported by the identification of viral DNA within epidermodysplasia verruciformis–induced malignancies. Carcinogenic cofactors, such as ultraviolet B and x-ray irradiation, are probably involved in the progression from benign warts (verrucae) to cancer. Cells with early signs of malignant transformation have been found closely connected with virus-infected epidermal regions.

The exact mechanisms involved in the malignant transformation of keratinocytes in skin lesions of patients with epidermodysplasia verruciformis are still unclear. Studies have shown that interactions occur between oncogenic HPVs and antioncogene proteins, such as p53 and pRb, in cell cycle regulation, DNA repair, and the execution of programmed cell death (apoptosis).

The persistence of HPV infection in epidermodysplasia verruciformis is thought to be the result of an immunogenetic defect, which generates several cytokines capable of down-regulating cell-mediated immunity. Patients with epidermodysplasia verruciformis reportedly show an increased rate of low-production genotypes of interleukin 10 compared with control subjects. Patients with epidermodysplasia verruciformis and skin cancer are more likely to have low-production interleukin 10 genotypes than patients with benign forms of epidermodysplasia verruciformis. ^[29]

In epidermodysplasia verruciformis tumors, within the early region of the HPV genome, E6 and E7 code for major oncoproteins responsible for the oncogenic potential of HPV. These viral proteins are crucial for tumorigenesis. In cancerous lesions, the high-risk HPV types, such as HPV types 5, 8, and 47, selectively retain and express the E6 and E7 portions of the viral genome. Working together, these E6/E7 regions cause cell immortalization, or failure of programmed cell death, resulting in transformation of normal human keratinocytes into malignant cells. ^[30]

Genus β-HPVs have been implicated in UV light–induced nonmelanoma skin cancer in patients with inherited epidermodysplasia verruciformis, and data from 2017 point to an early role of genus-β HPV in skin carcinogenesis. ^{[31, 32]} It has been supported that β-HPV type 8 infection expands the stem cell compartment in patients by suppressing microRNA-203, an initial major step in skin carcinogenesis. The E6 protein targets the transcription factor CCAAT/enhancer-binding protein (C/EBP)α, which is a tumor suppressor of UV-induced carcinogenesis. Thus, HPV8 E6 prevents microRNA-203 expression, leading to prominent up-regulation of ∆Np63 (NH2-terminally deleted p63). ∆Np63 consequently promotes proliferation and blocks differentiation of keratinocytes.

Both E6 and E7 are multifunctional proteins that promote cell growth via multiple mechanisms. Each has the ability to neutralize an antioncogene product, specifically p53 and pRb, that is essential for intracellular defense mechanisms against the development of neoplasms. However, the exact mechanism of carcinogenesis of E6 and E7 oncoproteins and the effects of these oncoproteins on p53 and pRb still requires more research.

There is also reported evidence that HPV8 actively suppresses epithelial immunosurveillance by interfering with the recruitment of Langerhans cells, favoring viral persistence. Data from a 2018 study suggest that the HPV8 E2 protein contributes to the recruitment of myeloid cells into epidermodysplasia verruciformis skin lesions, which may progress to chronic inflammation and skin cancer. ^[33]

Failure of programmed cell death to eliminate cells with DNA damage may play an important role in malignant transformation of squamous epithelium. A decrease in UV-induced DNA repair synthesis, coupled with an oncogenic viral infection, further enhances the susceptibility toward somatic mutations and malignant transformation in patients with epidermodysplasia verruciformis. ^{[34, 35, 36, 37]}

Renal transplant recipients and immunosuppressed patients have an increased risk of developing lesions of epidermodysplasia verruciformis. ^[11] There is a positive correlation between the length of immunosuppression and the development of HPV lesions, with most patients developing lesions within 5 years following immunosuppression. ^[38]

Epidermodysplasia verruciformis–associated HPVs can be divided into 2 groups. One group has high oncogenic potential (HPV types 5, 8, 10, and 47). More than 90% of epidermodysplasia verruciformis–associated skin cancers contain these virus types. The other group has low oncogenic potential (HPV types 14, 20, 21, and 25). These types are usually detected in benign skin lesions.

Proposed mechanisms for the development of epidermodysplasia verruciformis include the following:

• An autosomal recessive mode of inheritance is supported by the finding that 10% of patients with epidermodysplasia verruciformis are offspring of consanguineous marriages. X-linked inheritance has rarely been reported. ^[1] A clear mode of inheritance is not evident in all cases.
• Pathogenic mutations in two adjacent genes, EVER1 and EVER2, have been identified. ^{[2, 7]}
• Mutations of the CIB1/EVER1/EVER2 complex may act as a restriction factor for HPVs in keratinocytes.
• Major histocompatibility complex (MHC) class II alleles (DR-DQ) have been found in a large series of patients with epidermodysplasia verruciformis from Europe, Africa, and America.
• Neither chromosomal abnormalities nor the relationship to any specific MHC class I antigens has been found in patients with epidermodysplasia verruciformis.
• The exact mechanisms involved in the keratinocytic transformation within epidermodysplasia verruciformis skin lesions are unclear. Transcripts of the early region of viral genomes (E6 and E7 gene proteins) have been detected in epidermodysplasia verruciformis tumors. However, in most carcinomas, viral sequences are not integrated into the host genome.
• Studies have shown that interactions occur between oncogenic HPVs and the antioncogene products, p53 and pRb, in cell cycle regulation, DNA repair, and the execution of programmed cell death (apoptosis). Failure of programmed cell death to eliminate cells with DNA damage may play an important role in the malignant transformation of squamous epithelium, with resultant proliferation, disruption of epithelial structural order, and development of cellular atypia. A decrease in UV-induced DNA repair synthesis, coupled with antioncogenic viral infection, further enhances the disposition for somatic mutations and malignant transformation in patients with epidermodysplasia verruciformis.
• A specific defect of cell-mediated immunity, manifested by the inhibition of natural cytotoxicity and the proliferation of T lymphocytes against HPV-infected squamous cells in epidermodysplasia verruciformis skin lesions, is a characteristic feature of epidermodysplasia verruciformis.
• Chronic sun-exposure coupled with immunologic defects in patients with epidermodysplasia verruciformis is likely to induce mutations of the tumor suppressor gene protein (p53), leading to the development of malignant skin cancer in adult patients.
• UV-B–induced local immunosuppression on the skin of patients with epidermodysplasia verruciformis is known to be related to overproduction of immunosuppressive cytokines, such as tumor necrosis factor-alpha (TNF-a), transforming growth factor-beta (TGF-b), interleukin 4, and interleukin 10, as well as excessive formation of cis- urocanic acid.
• Studies have implicated a defect within keratinocytes. The activity of Langerhans cell antigen presentation appears normal in epidermodysplasia verruciformis, thus suggesting other cells cause immunotolerance to epidermodysplasia verruciformis–associated HPVs.
• Lesions of epidermodysplasia verruciformis have been associated with common variable immunodeficiency and graft versus host disease. ^[27]

Frequency

United States

The exact frequency of epidermodysplasia verruciformis is unknown.

International

The largest series of epidermodysplasia verruciformis reported in the literature includes 195 cases, mainly from Eastern Europe, Poland, ^[39] and Latin America. A review of literature in 2017 found about 500 patients with this disease reported worldwide. ^[40]

Race

Epidermodysplasia verruciformis is universal and affects persons of all races.

Sex

No sexual preference is noted for epidermodysplasia verruciformis, although sex-linked ^[1] and autosomal dominant inheritance have been described.

Age

Patients with epidermodysplasia verruciformis typically present early in childhood with flat wartlike lesions of the dorsal hands, extremities, face, and neck. The disease manifests as a congenital form in infancy (approximately 7.5%), during childhood (61.5% in children aged 5-11 y), or at puberty (22.5%). Malignant tumors typically appear during the fourth and fifth decades of life. The reported frequency of malignant change ranges from 30-60%.

Epidermodysplasia verruciformis tumors evolve progressively, from childhood through adolescence, into adulthood. Fatality due to metastasizing invasive squamous cell carcinoma arising in conjunctiva has occasionally been reported. ^[41] Malignant skin tumors develop during the fourth and fifth decades of life in approximately one third of patients. Epidermodysplasia verruciformis tumors are numerous, and they initially progress as noninvasive in situ carcinomas. Approximately 30-60% of patients with lesions develop invasive cancers. These include seborrheic keratosis, actinic keratosis, and cutaneous malignancies such as Bowen disease and squamous cell carcinoma after sun exposure of more than 20-30 years. ^[42] Cancers such as Burkitt lymphoma and EBV lymphoma have also been reported in some patients. ^[40] Most cancers remain local, and metastasis is extremely uncommon. Epidermodysplasia verruciformis tumors are locally destructive without treatment. No disease-related fatality has been reported.

For excellent patient education resources, visit eMedicineHealth's Skin Conditions and Beauty Center and Cancer Center. Also, see eMedicineHealth's patient education articles Warts, Skin Cancer, and Skin Biopsy.