Epidermodysplasia Verruciformis, Susceptibility To, 1

A number sign (#) is used with this entry because of evidence that susceptibility to epidermodysplasia verruciformis-1 (EV1) is conferred by homozygous or compound heterozygous mutation in the TMC6 gene (605828) on chromosome 17q25.

Description

Epidermodysplasia verruciformis (EV) is a rare genodermatosis associated with a high risk of skin cancer. EV results from an abnormal susceptibility to specific related human papillomavirus (HPV) genotypes and to the oncogenic potential of some of them, mainly HPV5. Infection with EV-associated HPV leads to the early development of disseminated flat wart-like and pityriasis versicolor-like lesions. Patients are unable to reject their lesions, and cutaneous Bowen carcinomas in situ and invasive squamous cell carcinomas develop in about half of them, mainly on sun-exposed areas (summary by Ramoz et al., 2000).

Genetic Heterogeneity of Susceptibility to Epidermodysplasia Verruciformis

Susceptibility to EV2 (618231) is conferred by mutation in the TMC8 gene (605829) on chromosome 17q25; EV3 (618267) by mutation in the CIB1 gene (602293) on chromosome 15q26; EV4 (618307) by mutation in the RHOH gene (602037) on chromosome 4p13; and EV5 (618309) by mutation in the IL7 gene (146660) on chromosome 8q12.

Clinical Features

The lesions in epidermodysplasia verruciformis often resemble verrucae planae (Sullivan and Ellis, 1939). The mucous membranes, hair, and nails are not affected. Malignant degeneration, usually of the superficial basal cell type, is frequent. Characteristic changes in the epidermal cells with peculiar vacuolization are observed. Ellis (1953) stated that this disorder occurs most frequently in Orientals.

Ramoz et al. (2002) described 5 families with epidermodysplasia verruciformis. Patients had early onset of the disease, a disseminated infection by EV-specific HPV genotypes, including at least one of the potentially oncogenic genotypes (HPV types 5, 8, 14, 17, or 20), and lesions of the skin showing the cytopathic effect pathognomonic of EV. Significant variations were observed, however, in the HPV genotypes detected, the extension of the lesions and the development of skin carcinomas. HPV5, the genotype most frequently associated with EV cancers, was detected only in families A1, A2, and C1, whereas the less oncogenic HPV20, an HPV5-related genotype, was found in all 5 families.

Tate et al. (2004) reported a 65-year-old Japanese woman with EV. The patient had suffered from warts beginning when she was a teenager. Excision of Bowen disease from the skin of the hand was carried out 3 times at the ages of 51, 52, and 64 years, and gastrectomy was performed for gastric cancer when she was 53 years of age. Multiple skin cancers of the face showed squamous cell carcinoma and Bowen disease. The parents were unaffected and were not related. Three of 6 sibs were also affected.

Inheritance

Sullivan and Ellis (1939) found that of the 16 previously reported families, 4 had consanguineous parents. Familial aggregation was described by Midana (1949) and by Jablonska et al. (1966). Hermann (1955) found parental consanguinity. Lutzner (1977) considered this an autosomal recessive disorder. The family reported by Jablonska et al. (1979) suggested autosomal dominant inheritance. The fact that spouses and some family members stayed free of the disease speaks against intrafamilial infection as the cause. Feuerman et al. (1979) reported the cases of 2 Arab brothers. The parents and 7 sibs were unaffected.

Mapping

In Algerian and Colombian consanguineous families segregating EV, Ramoz et al. (2000) mapped the disorder to a 1-cM interval on chromosome 17q25.

Pathogenesis

The view that epidermodysplasia verruciformis is an extensive form of viral verrucae planae is supported by successful autoinoculation and heteroinoculation experiments. Lutz (1957) was one of the first to describe the condition; he accepted that it is not an entity but suggested that genetic predisposition may account for the extensiveness of the eruption of warts. By electron microscopy, Baker (1968) and others demonstrated particles suggesting papovavirus. The common wart virus can be demonstrated in the warts by both electron and fluorescent microscopy (Yabe and Sadakane, 1975). Warts appear to progress to squamous cell carcinoma in about 10% of cases (Lutzner, 1977). As in Shope papilloma, virus is no longer demonstrable in the cancers. Jablonska et al. (1979) observed papillomaviruses (HPVs), either HPV3 or HPV4 and sometimes both, in cases and found that the clinical picture differed depending on which virus was involved. Malignancies developed only in family members infected with HPV4. Orth et al. (1979) pointed to papillomavirus type 5 as the determinant of malignant evolution of the warts. Individuals with epidermodysplasia verruciformis are not prone to bacterial, fungal, or viral infections, and are not abnormally susceptible to genital papillomaviral infections.

Molecular Genetics

In affected members of consanguineous Colombian and Algerian families with EV mapped to chromosome 17q25, Ramoz et al. (2002) identified 2 homozygous nonsense mutations in the EVER1 gene (TMC6; 605828.0001-605828.0002) in EV1 and 2 homozygous mutations in the EVER2 gene (TMC8; 605829.0001-605829.0002) in EV2 (618231).

In a Japanese woman with EV1, Tate et al. (2004) found compound heterozygosity for mutations in the TMC6 gene (605828.0003-605828.0004). The parents were unaffected and were not related.