Epidermodysplasia verruciformis (EV)(OMIM 226400) is a rare autosomal recessive genodermatosis characterized by susceptibility to cutaneous infections with β-human papillomaviruses (HPVs), with particular propensity to developing cutaneous malignancies (Lutzner et al., 1984). Characteristically, the early manifestations consist of thin tinea versicolor-like plaques and flat warts during childhood. Not infrequently, pigmented, papillomatous, and verrucous lesions may be found on the forehead or trunk. In their 30s and 40s, patients develop nonmelanoma skin cancers, mostly squamous cell carcinomas. Carcinogenesis is apparently caused by EV-HPV infection, particularly members of the β subfamily, and the majority of patients harbor EV-HPV types 5 and 8, but types 20 and 14 have also been detected, and a broader range of HPV types appears to be present in atypical EV (Imahorn et al., 2017, Lutzner et al., 1984, Orth, 2008). EV can be considered to be “typical,” as originally described by Lewandowsky and Lutz in 1922 (cited in Imahorn et al., 2017), when the infections are strictly limited to EV-HPV–associated skin lesions, suggesting an aberration in cutaneous-intrinsic immunity, whereas in “atypical” forms the cutaneous HPV lesions are associated with other infections of the skin and other tissues because of altered T-cell immunity. Over 500 cases of typical EV have been reported since the first clinical description of the disease. In contrast, fewer than 20 cases of atypical EV have been reported in association with sequence variants in eight distinct genes (de Jong et al., 2018a). Thus, a unifying classification of EV at the early stages of the disease would appear appropriate, before distinguishing features of atypical EV become evident.

Initially, the genetic basis of EV was shown to consist of mutations in two closely linked genes, EVER1 and EVER2, also known as TMC6 and TMC8, encoding endoplasmic reticulum transmembrane proteins (Ramoz et al., 2002). Consequently, typical EV has been defined as a defect in innate immunity affecting keratinocytes, linked to EVER1 and EVER2 deficiency (Notarangelo et al., 2004). Loss-of-function mutations in these two genes result, by an unknown mechanism, in the proliferation of infected keratinocytes and in replication of EV-HPVs in the terminally differentiating host cells. It was suggested that mutations in EVER1/2 account for roughly 60% of individuals affected worldwide by typical EV (Imahorn et al., 2017, Orth, 2008). In addition to EVER1/2, we have recently identified mutations in another gene, CIB1, in several consanguineous families (de Jong et al., 2018b). This gene encodes calcium and integrin-binding protein 1, which forms complexes with EVER1 and EVER2. Patients harboring mutations in EVER1, EVER2, and CIB1 all have clinical features of typical EV.