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SNOMEDCT: 239107007, 25201003; ORPHA: 79414; DO: 0111162;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p13.2 | Epidermal nevus, somatic | 162900 | 3 | NRAS | 164790 | |
| 3q26.32 | Nevus, epidermal, somatic | 162900 | 3 | PIK3CA | 171834 | |
| 4p16.3 | Nevus, epidermal, somatic | 162900 | 3 | FGFR3 | 134934 | |
| 11p15.5 | Nevus sebaceous or woolly hair nevus, somatic | 162900 | 3 | HRAS | 190020 |
A number sign (#) is used with this entry because of evidence that epidermal nevus can result from somatic mosaicism for mutations in the FGFR3 gene (134934), the PIK3CA gene (171834), and the RAS genes, including KRAS (190070), HRAS (190020), and NRAS (164790).
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).
Woolly hair nevus is a rare condition characterized by the development of woolly hair in a restricted area on the scalp, either present at birth or becoming evident later in life when scalp hair begins to grow. Woolly hair nevus can be an isolated finding or can occur in association with additional ectodermal defects; epidermal nevi have been reported in association with woolly hair nevi (summary by Ramot and Zlotogorski, 2015).
Nevus sebaceous, a benign congenital skin lesion that preferentially affects the scalp and face, 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).
Also see giant pigmented hairy nevus (137550) and malignant melanoma (155600).
Levinsohn et al. (2014) studied 2 unrelated girls with woolly hair nevus. The first patient was a 10-year-old girl who from infancy had regions of slightly curly hair lying alongside areas of straight hair. She exhibited hyperpigmented patches on her neck, trunk, and arms, with more keratotic lesions on her distal extremities and acanthosis nigricans in both axillae. She also had linear palmoplantar keratoderma (PPK) and hyperkeratosis over most metacarpophalangeal and some proximal interphalangeal joints. The second patient was a 6-year-old girl in whom the hair anomaly, which consisted of a mixture of poker-straight and thin curly hair, had developed at 1 year of age. In infancy, she developed linear dyspigmentation on her right arm and trunk, which gradually became more raised and scaly on the distal extremities. Neither girl had developmental delay or cardiac abnormalities.
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.
By paired whole-exome sequencing of DNA from affected tissue and blood from 2 unrelated girls with woolly hair nevus, Levinsohn et al. (2014) identified heterozygosity for a somatic mutation in the HRAS gene (G12S; 190020.0003) in both individuals. Analysis of hair bulbs from straight and curly patient hair confirmed that the G12S mutation was present in curly hair only. There was no evidence for loss of heterozygosity or a secondary somatic mutation, suggesting that HRAS mutation alone is sufficient to cause woolly hair nevus. Levinsohn et al. (2014) also screened 116 archival scalp nevus sebaceous lesions for mutations in the HRAS and KRAS genes and detected 88 HRAS and 9 KRAS mutations. Consistent with previous reports (Levinsohn et al., 2013; Sun et al., 2013), the HRAS G13R mutation was present in 85 specimens, but the G12S mutation was not found. Levinsohn et al. (2014) suggested that more strongly activating RAS mutations cause the alopecia and sebaceous hyperplasia of nevus sebaceous, whereas the more mildly activating G12S mutation causes the woolly hair nevus phenotype.
Bourdeaut, F., Herault, A., Gentien, D., Pierron, G., Ballet, S., Reynaud, S., Paris, R., Schleiermacher, G., Baumann, C., Philippe-Chomette, P., Gauthier-Villars, M., Peuchmaur, M., Radvanyi, F., Delattre, O. Mosaicism for oncogenic G12D KRAS mutation associated with epidermal nevus, polycystic kidneys and rhabdomyosarcoma. J. Med. Genet. 47: 859-862, 2010. [PubMed: 20805368] [Full Text: https://doi.org/10.1136/jmg.2009.075374]
Groesser, L., Herschberger, E., Ruetten, A., Ruivenkamp, C., Lopriore, E., Zutt, M., Langmann, T., Singer, S., Klingseisen, L., Schneider-Brachert, W., Toll, A., Real, F. X., Landthaler, M., Hafner, C. Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nature Genet. 44: 783-787, 2012. [PubMed: 22683711] [Full Text: https://doi.org/10.1038/ng.2316]
Hafner, C., Lopez-Knowles, E., Luis, N. M., Toll, A., Baselga, E., Fernandez-Casado, A., Hernandez, S., Ribe, A., Mentzel, T., Stoehr, R., Hofstaedter, F., Landthaler, M., Vogt, T., Pujol, R. M., Hartmann, A., Real, F. X. Oncogenic PIK3CA mutations occur in epidermal nevi and seborrheic keratoses with a characteristic mutation pattern. Proc. Nat. Acad. Sci. 104: 13450-13454, 2007. [PubMed: 17673550] [Full Text: https://doi.org/10.1073/pnas.0705218104]
Hafner, C., Toll, A., Gantner, S., Mauerer, A., Lurkin, I., Acquadro, F., Fernandez-Casado, A., Zwarthoff, E. C., Dietmaier, W., Baselga, E., Parera, E., Vicente, A., Casanova, A., Cigudosa, J., Mentzel, T., Pujol, R. M., Landthaler, M., Real, F. X. Keratinocytic epidermal nevi are associated with mosaic RAS mutations. J. Med. Genet. 49: 249-253, 2012. [PubMed: 22499344] [Full Text: https://doi.org/10.1136/jmedgenet-2011-100637]
Hafner, C., Toll, A., Real, F. X. HRAS mutation mosaicism causing urothelial cancer and epidermal nevus. (Letter) New Eng. J. Med. 365: 1940-1942, 2011. [PubMed: 22087699] [Full Text: https://doi.org/10.1056/NEJMc1109381]
Hafner, C., van Oers, J. M. M., Vogt, T., Landthaler, M., Stoehr, R., Blaszyk, H., Hofstaedter, F., Zwarthoff, E. C., Hartmann, A. Mosaicism of activating FGFR3 mutations in human skin causes epidermal nevi. J. Clin. Invest. 116: 2201-2207, 2006. [PubMed: 16841094] [Full Text: https://doi.org/10.1172/JCI28163]
Levinsohn, J. L., Teng, J., Craiglow, B. G., Loring, E. C., Burrow, T. A., Mane, S. S., Overton, J. D., Lifton, R. P., McNiff, J. M., Lucky, A. W., Choate, K. A. Somatic HRAS p.G12S mutation causes woolly hair and epidermal nevi. (Letter) J. Invest. Derm. 134: 1149-1152, 2014. [PubMed: 24129065] [Full Text: https://doi.org/10.1038/jid.2013.430]
Levinsohn, J. L., Tian, L. C., Boyden, L. M., McNiff, J. M., Narayan, D., Loring, E. S., Yun, D., Sugarman, J. L., Overton, J. D., Mane, S. M., Lifton, R. P., Paller, A. S., Wagner, A. M., Antaya, R. J., Choate, K. A. Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceus. (Letter) J. Invest. Derm. 133: 827-830, 2013. [PubMed: 23096712] [Full Text: https://doi.org/10.1038/jid.2012.379]
Meirowski, E. Moles and malformations of the skin and their relationship to inheritance and phylogenesis (new and old investigations). Brit. J. Derm. 54: 99-121, 1942.
Paller, A. S., Syder, A. J., Chan, Y.-M., Yu, Q.-C., Hutton, E., Tadini, G., Fuchs, E. Genetic and clinical mosaicism in a type of epidermal nevus. New Eng. J. Med. 331: 1408-1415, 1994. [PubMed: 7526210] [Full Text: https://doi.org/10.1056/NEJM199411243312103]
Ramot, Y., Zlotogorski, A. The twisting tale of woolly hair: a trait with many causes. J. Med. Genet. 52: 217-223, 2015. [PubMed: 25561463] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102630]
Sun, B. K., Saggini, A., Sarin, K. Y., Kim, J., Benjamin, L., LeBoit, P. E., Khavari, P. A. Mosaic activating RAS mutations in nevus sebaceus and nevus sebaceus syndrome. (Letter) J. Invest. Derm. 133: 824-827, 2013. [PubMed: 23096709] [Full Text: https://doi.org/10.1038/jid.2012.377]