Epidermal nevi are congenital lesions that affect about 1 in 1,000 people. They appear at or shortly after birth as localized epidermal thickening with hyperpigmentation that frequently follow the lines of Blaschko, suggesting that they result from postzygotic ... Epidermal nevi are congenital lesions that affect about 1 in 1,000 people. They appear at or shortly after birth as localized epidermal thickening with hyperpigmentation that frequently follow the lines of Blaschko, suggesting that they result from postzygotic somatic mutation in the skin (Paller et al., 1994). A rare subgroup of epidermal nevi is clinically indistinguishable from other epidermal nevi, but displays histopathologic features typical of epidermolytic hyperkeratosis (see EHK, 113800), and patients with this type of epidermal nevi sometimes have offspring with generalized EHK (Paller et al., 1994). See giant pigmented hairy nevus (137550) and malignant melanoma (155600). Nevus sebaceous is a benign congenital skin lesion that preferentially affects the scalp and face. It occurs in about 1 in 1,000 live births and is characterized by hairless, yellow-orange plaques of various size and shape. Histology shows that nevus sebaceous is a hamartoma consisting of epidermal, sebaceous, and apocrine elements. About 24% of nevi develop secondary tumors, some of which may be malignant (summary by Groesser et al., 2012).
Hafner et al. (2006) analyzed 39 common epidermal nevi from 33 patients using a multiplex PCR assay covering 11 FGFR3 (134934) point mutations and by direct sequencing of exon 19 ... - Mutations in the FGFR3 Gene Hafner et al. (2006) analyzed 39 common epidermal nevi from 33 patients using a multiplex PCR assay covering 11 FGFR3 (134934) point mutations and by direct sequencing of exon 19 of the FGFR3 gene. Somatic mutations were identified in 11 patients: 10 of them, including 8 with systematized epidermal nevus, had the R248C mutation (134934.0005); 1 patient had a double mutation in exon 10 of the FGFR3 gene (134934.0001 and 134934.0033). In 4 patients tested, FGFR3 mutations were not found in adjacent, histologically normal skin. Hafner et al. (2006) concluded that a large proportion of epidermal nevi are caused by mosaicism of activating FGFR3 mutations in the human epidermis secondary to a postzygotic mutation in early embryonic development, and that the R248C mutation appears to be a hotspot for FGFR3 mutations in epidermal nevi. Hafner et al. (2012) identified activating somatic mutations in the FGFR3 gene in 16 (22%) of 72 keratinocytic epidermal nevi. - Mutations in the PIK3CA Gene Hafner et al. (2007) identified a heterozygous somatic mutation in the PIK3CA gene (E545G; 171834.0004) in 9 (27%) of 33 epidermal nevi. Two of these tumors had a concomitant R248C mutation in the FGFR3 gene. The authors emphasized that these are benign lesions and noted that the same PIK3CA mutation had been observed in colorectal cancer. Hafner et al. (2012) identified activating somatic mutations in the PIK3CA gene in 6 (8%) of 72 keratinocytic epidermal nevi. - Mutations in RAS Genes Bourdeaut et al. (2010) found somatic mosaicism for a mutation in the KRAS gene (G12D; 190070.0005) in a female infant with an epidermal nevus who also developed a uterovaginal rhabdomyosarcoma (268210) at age 6 months. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. The phenotype was consistent with broad activation of the KRAS pathway. Hafner et al. (2011) reported a 49-year-old man with widespread congenital epidermal nevus and recurrent urothelial cancer who was mosaic for an HRAS G12S mutation (190020.0003). Groesser et al. (2012) analyzed tumor tissue from 65 individuals with nevus sebaceous for the presence of RAS hotspot mutations. Somatic KRAS mutations (190070.0005, 190070.0006) were present in 3 lesions (5%). Two of these tumors also carried somatic HRAS mutations. Isolated somatic HRAS mutations were present in 62 lesions (95%), with a G13R substitution (190020.0017) accounting for 91%. Five sebaceous nevi carried 2 RAS mutations. Nonlesional tissue from 18 patients showed a wildtype HRAS sequence. Eight individuals developed secondary tumors within the nevus sebaceous, including 2 syringocystadenoma papilliferum, 3 trichoblastomas, and 3 trichilemmomas, and all secondary tumors carried the same mutation as the nevi. Functional analysis of mutant cells carrying the G13R mutation showed constitutive activation of the MAPK (see 176948) and PI3K (see 171834)/AKT (164730) signaling pathways. No mutations were found in the FGFR3 or PIK3CA genes in any of the nevus sebaceous lesions. Hafner et al. (2012) found somatic activating RAS mutations in 28 (39%) of 72 keratinocytic epidermal nevi, all from unrelated patients. HRAS was the most commonly affected oncogene, with the HRAS G13R substitution (190020.0017) occurring in 21 lesions. One nevus had a somatic mutation in the KRAS gene (G12D; 190070.0005), and 3 had somatic mutations in the NRAS gene (Q61R, 164790.0002; P34L, 164790.0006; and G12D, 164790.0007). These findings identified keratinocytic epidermal nevi as a mosaic RASopathy.