Review
Re-evaluation of epidermodysplasia verruciformis: Reconciling more than 90 years of debate

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Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by abnormal susceptibility to cutaneous human beta-papillomavirus infections causing persistent flat warts or pityriasis versicolor–like lesions. This generalized verrucous skin disorder resembles generalized verrucosis, but these 2 conditions are distinguished by differences in clinical manifestation and the human papillomavirus types involved. A breakthrough in our understanding of EV was the discovery that homozygous inactivating mutations in TMC6 (EVER1) and TMC8 (EVER2) determine susceptibility to this disorder; however, they have not solved all EV cases fully. These deficiencies account for 75% of affected individuals, leaving a substantial number of patients without an underlying genetic cause. Recently, it has been revealed that mutations in additional genes (RHOH, MST-1, CORO1A, and IL-7) result in extensive human beta-papillomavirus replication and therefore manifest with an EV-like phenotype. The term “acquired EV” is used to describe an EV-like phenotype that develops in immunocompromised hosts, and the introduction of this entity further aggravates the confusion. Reevaluation of these entities is warranted. Here, we review the available data on this issue, provide up to date information on the major characteristics that differentiate between these seemingly clinically similar disorders, and highlight the different mechanisms involved in each disorder.

Section snippets

Back to the beginning

Heritage was known to be important in EV almost since the first time this identity was described by Lewandowsky and Lutz in 192230; many cases of EV are familial and 10% of patients originate from consanguineous families.31 This observation enabled Cockayne et al in 1933 to hypothesise that EV could be inherited as an autosomal recessive trait. This hypothesis was confirmed almost 90 years later, with the discovery of the first 2 genetic etiologies of EV, inactivating nonsense homozygous

New discoveries

All of these newly discovered mutations do not proclaim EV stricto sensu. The proteins encoded by RHOH, MST-1, and CORO1A are found on hematopoietic cells only and are absent from keratinocytes. RHOH encodes an atypical, hematopoietic cell–specific Rho GTPase,47 which lacks GTPase activity and remains locked in guanosine triphosphate–bound conformation. Therefore, it is unable to function as an intracellular switch and conduct signals from T and B cell membrane receptors.48, 49 CORO1A encodes

Exogenous immunodeficiency

The term AEV—also referred to as secondary EV, immunodeficient EV, and EV-like—was recently introduced57 to describe EV occurring in patients with defective cell-mediated immunity. This can be caused by infection (eg, HIV infection with severe immunosuppression with CD4+ counts <200 cells/μL),58, 59, 60 non–Hodgkin lymphoma,61 lepromatous leprosy,62 lipoid proteinosis,63 or medications (eg, bendamustine64 and cyclosporine for atopic dermatitis65). Sometimes, medications and immune dysregulation

Generalized verrucosis—A different entity

Generalized verrucosis (GV) has recently been defined as a progressive, chronic cutaneous HPV infection. On harsher scrutiny, 2 GV types might be distinguished; the first features a distribution pattern in which >20 lesions are located in >1 arbitrary region of the body, and the second features an acral distribution pattern that affects the majority of digits and additionally impairs the individual's ability to function independently.43, 81 It manifests clinically as verrucous papules and

Conclusions and clinical perspectives

We believe that dermatologists, geneticists, immunologists, and all the other specialists that are involved in research concerning EV and AEV can agree that well-established distinctive measures to differentiate between GV, EV, and AEV are lacking. Before the discovery of new mutations, the situation was much clearer, and the separation of exogenous (occurring in immunocompromised hosts) and endogenous (caused by homozygous frameshift, nonsense, or splice-site TMC6 and TMC8 mutations) EV was

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  • Cited by (0)

    Supported in part by the Israel Cancer Association (20150020) and the Hadassah–Hebrew University Joint Research Fund (6070803).

    Conflicts of interest: None declared.

    Reprints not available from the authors.

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