Epidermodysplasia Verruciformis, Susceptibility To, 3

A number sign (#) is used with this entry because of evidence that susceptibility to epidermodysplasia verruciformis-3 (EV3) is conferred by homozygous mutation in the CIB1 gene (602293) on chromosome 15q26.

Description

Epidermodysplasia verruciformis-3 is characterized by onset in childhood or early adulthood of persistent disseminated flat warts and pityriasis versicolor-like lesions of the skin that are induced by cutaneous human papillomaviruses (HPVs) of the beta genus. Some patients develop nonmelanoma skin cancer, particularly on areas of the body exposed to the sun. Patients are otherwise healthy and normally resistant to other microorganisms, including other viruses and skintropic pathogens, and even all other cutaneous and mucosal HPVs (de Jong et al., 2018).

For a discussion of genetic heterogeneity of susceptibility to epidermodysplasia verruciformis, see EV1 (226400).

Clinical Features

Imahorn et al. (2017) reported a 49-year-old Swiss woman with epidermodysplasia verruciformis (EV), born of first-cousin parents, who developed reddish skin lesions in early childhood that were located on the backs of her hands and extensor sides of knees. The lesions extended to the retroauricular area, neck, chest, arms, and lower legs. Histologic analysis revealed the typical appearance of plane (flat) warts, with minimal hyperkeratosis and acanthosis, as well as some cells with perinuclear halos and bluish staining. The patient exhibited palmar pits, which the authors noted were a rare feature of EV; these lesions were dermatoscopically consistent with plane warts. She also developed multiple cutaneous squamous cell carcinomas (SCCs) and carcinomas in situ (Bowen type), primarily on her forehead and nose. Because the proband had never had plane warts on her nose, the authors suggested that a preexisting EV lesion is not a prerequisite for development of SCC.

De Jong et al. (2018) studied 24 patients from 6 families with 'typical' epidermodysplasia verruciformis but no mutations in known EV-associated genes. The patients included 2 Swiss sisters (P13 and P14) who were among the first EV patients to be documented (Lutz, 1946); the Swiss woman (P15) previously described by Imahorn et al. (2017); 11 affected individuals (P1 to P11) from 2 branches of an extended Colombian family, previously reported by Rueda and Rodriguez (1976) and Rueda (1993); a French man (P12; Kienzler et al., 1979); 4 Togolese sibs (P16 to P19; Saka et al., 2009); and 5 affected individuals (P20 to P24) from a previously undescribed Iranian family. The cohort was clinically homogeneous, with disseminated beta-HPV-positive flat warts and pityriasis versicolor-like skin lesions beginning in childhood or early adulthood. Beta-HPV5 and/or beta-HPV8 genotypes were identified in the lesions of the 12 patients who were tested. Cutaneous SCC developed in 14 of the 24 patients, mostly on sun-exposed areas. None of the patients displayed any other unusually severe infectious diseases despite exposure to a large number of different infectious agents in urban or rural areas of their diverse countries. Immunophenotyping of P3, P5, P15, and P16 revealed normal numbers and compartmentalization of circulating T cells, B cells, and NK cells, and T-cell and B-cell responses to CD3 stimulation and DNA and RNA viruses, respectively, were normal. More detailed analyses of skin-homing T-cell populations showed no frequency abnormalities in the 5 patients tested (P1-P4 and P15). Noting that none of the patients tested displayed any detectable lymphocyte abnormalities, the authors concluded that this represented a novel form of EV involving keratinocyte-intrinsic immunity.

Mapping

By genomewide linkage analysis in 6 families with EV, de Jong et al. (2018) obtained a peak lod score of 16.7 for a 2.4-Mb interval on chromosome 15. Haplotype analysis narrowed the interval of interest to a 1.74-Mb region between 89.8 and 91.5 Mb.

Molecular Genetics

By whole-exome and/or Sanger sequencing, de Jong et al. (2018) identified homozygosity for mutations in the CIB1 gene in all 24 patients from 6 families with EV mapping to chromosome 15 (602293.0001-602293.0005).