Epidermodysplasia verruciformis

Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports

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Epidermodysplasia verruciformis (EV) is a rare genetic disease characterized by an impaired immune response to human papillomavirus (HPV) and HPV-associated cutaneous oncogenesis. The exact prevalence of EV is unknown; however, about 500 cases have been described worldwide. Because of the rarity of EV, there are few controlled trials of therapeutic interventions. Thus, the treatments described herein are predominantly anecdotal. The therapies applied to EV are usually extensions of treatments for HPV infections and skin cancers in the general population, or treatments successfully used for other immunodeficiency diseases in which HPV infections are prominent.

The disease is manifested by development of widespread flat-wart and pityriasis versicolor-like lesions in early childhood, which persist throughout adulthood. Other lesions may be more verrucous or resemble seborrheic keratoses. In the fourth and fifth decades, 50%–70% of patients begin to develop multiple cutaneous malignancies, mainly squamous cell carcinomas (SCCs).

EV has been associated with increased susceptibility to specific HPV types, primarily involving β-human papillomaviruses (β-HPVs). Most β-HPVs are considered non-pathogenic in the general population and viewed as commensal viruses of the human skin. In EV, however, HPV-5 and HPV-8 genotypes account for up to 90% of EV-associated SCC. Malignant transformation has also been associated with HPV subtypes 17, 20, and 47. Other non-oncogenic HPV types commonly seen in EV include 4, 9, 12, 14, 15, 19, 21–25, 36–38, and 50. EV patients generally are concomitantly infected with more than one genotype. Notably, Merkel cell polyomavirus particles have been recently identified in EV lesions as well. Advancement in HPV typing systems has proven to be beneficial in discerning potentially oncogenic HPV types from non-pathologic types. Such HPV detection methods involving polymerase chain reaction protocols can further assist in confirming the diagnosis of EV when histology is unrevealing.

Inherited EV harbors autosomal recessive mutations of two genes located on chromosome 17: EVER1 / TCM6 and EVER2/TCM8 , both coding transmembrane proteins located in the endoplasmic reticulum and involved in zinc transportation. However, about 25% of EV cases are not associated with these genetic mutations. Various case reports presenting novel mutations such as MST-1 , RHOH , CORO1A , DOCK8 , DCLRE1C , RASGRP1 , ANKRD26 , IL2RG , and TPP2 have emerged. Loss of function gene mutation of CIB1 (calcium and integrin-binding protein 1), which is an integral part of the EVER1/EVER2 complex, has gained recent notoriety in its role in atypical EV cases. All associated mutations are thought to result in defective cell-mediated immune response to HPV, ultimately leading to formation of skin lesions.

A more novel entity is the occurrence of the EV phenotype in immunosuppressed individuals, which has been coined acquired epidermodysplasia verruciformis . This EV-like syndrome has been described in patients with HIV infection, organ transplantation, Hodgkin disease, common variable immunodeficiency, systemic lupus erythematosus, immunoglobulin M deficiency, adult T-cell leukemia, some cases of graft-versus-host reaction, and others. Although this condition affects a diverse range of immunocompromised patients, AEV is reported less frequently than congenital EV, which may be due to a yet unidentified, higher genetic predisposition to EV infections in affected individuals only. The high risk of malignant transformation in genetic EV seems to be reduced in the acquired variety.