Alternative titles; symbols
SNOMEDCT: 403825008; ORPHA: 79493, 867;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16q12.1 | Trichoepithelioma, multiple familial, 1 | 601606 | Autosomal dominant | 3 | CYLD | 605018 |
A number sign (#) is used with this entry because multiple familial trichoepithelioma-1 (MFT1) is caused by heterozygous mutation in the CYLD gene (605018) on chromosome 16q12.
Allelic disorders with overlapping features include familial cylindromatosis (CYLD; 132700) and Brooke-Spiegler syndrome (BRSS; 605041).
Genetic Heterogeneity of Multiple Familial Trichoepithelioma
See also MFT2 (612099), which has been mapped to 9p21.
Multiple familial trichoepithelioma (MFT), also called epithelioma adenoides cysticum (EAC), is an autosomal dominant dermatosis characterized by the presence of many skin tumors predominantly on the face. Since histologic examination shows dermal aggregates of basaloid cells with connection to or differentiation toward hair follicles, this disorder has been thought to represent a benign hamartoma of the pilosebaceous apparatus. Trichoepitheliomas can degenerate into basal cell carcinoma (Johnson and Bennett, 1993).
Because BRSS, familial cylindromatosis, and MFT1 are allelic, and because different manifestations of each have been described within a single family, many consider these disorders to represent a phenotypic spectrum of a single disease entity (Lee et al., 2005; Bowen et al., 2005; Young et al., 2006; Saggar et al., 2008).
Blake and Toro (2009) provided a detailed review of the spectrum of disorders associated with CYLD mutations.
Brooke (1892) and Fordyce (1892) described a familial syndrome characterized by tumors of skin appendages, 'epithelioma adenoides cysticum,' also known as trichoepitheliomas (Lee et al., 2005).
Fliegelman and Kruse (1948) described 'multiple benign cystic epithelioma' in 10 patients spanning 3 generations of a family. The authors indicated that despite some clinical similarities, the disorder could be distinguished from syringocystadenoma, adenoma sebaceum, and cylindroma.
Gaul (1953) reported a family with multiple cystic epitheliomas. A particularly severely affected woman was apparently homozygous for the disorder. Both her parents were affected, and 8 children by 2 husbands of hers were affected.
Ziprkowski and Schewach-Millet (1966) reported the dermatologic features in a mother and 2 children with multiple trichoepithelioma. The skin tumors showed differentiation in the direction of hair structures. One affected person developed basosquamous cell carcinoma. The authors noted that familial trichoepithelioma may be the same entity as familial cylindroma.
Welch et al. (1968) presented family data supporting the view that 'Ancell-Spiegler' cylindromas and 'Brooke-Fordyce' trichoepitheliomas are manifestations of a single entity.
Correa-Cerro et al. (1997) described hereditary multiple trichoepithelioma in a mother and daughter. Manifestations began in both at age 7 years, the daughter being more severely affected than the mother. The mother was the product of the second pregnancy of a sibship of 11. At 7 years of age the daughter had small skin lesions like comedones located on the surface of the nose and on the lower palpebral fissure. The mother had lesions involving the entire face by age 11 years. Small tumors of 2 to 10 mm in diameter most striking on the dorsal region of the nose were distributed over the entire face and ears. Correa-Cerro et al. (1997) commented on the excess of affected women.
Liang et al. (2005) reported 2 large unrelated Chinese families with autosomal dominant multiple familial trichoepithelioma. Age at onset ranged from birth to 30 years. Physical examination showed numerous dome-shaped, firm, skin-colored papules and nodules involving the nasal root, medial part of the eyebrows, and nasolabial folds. Skin biopsies showed trichoepitheliomas; cylindromatosis was not identified in either family. Liang et al. (2005) hypothesized that the germline mutation may be tissue-specific or influence the tissue type in which the second hit occurs, leading to tumor development.
Gerretsen et al. (1995) argued that the familial cylindromatosis and multiple familial trichoepithelioma may be caused by dysfunction of the same gene, because both tumors can occur in the same patient or in different patients within a single family. A gene for familial cylindromatosis was assigned to 16q12-q13 by Biggs et al. (1995).
The transmission pattern of MFT1 in the family reported by Hu et al. (2003) was consistent with autosomal dominant inheritance.
In affected members of a Turkish family with multiple familial trichoepithelioma, Hu et al. (2003) identified a heterozygous mutation in the CYLD gene (605018.0007). Hu et al. (2003) noted that the phenotype of most of the affected individuals in this family resembled MFT1, but 1 patient had cylindromas, suggesting BRSS. The findings suggested that BRSS and MFT1 represent phenotypic variability of a single entity.
In affected members of 2 unrelated Chinese families with multiple trichoepitheliomas but no cylindromas, Liang et al. (2005) identified 2 different mutations in the CYLD gene (605018.0005 and 605018.0006, respectively).
Young et al. (2006) identified a heterozygous mutation in the CYLD gene (605018.0008) in a 73-year-old man with cylindromatosis and turban tumor syndrome and in his 2 children with multiple familial trichoepitheliomas without cylindromas. The findings suggested that the 2 disorders represent phenotypic variation of a single genetic defect.
Saggar et al. (2008) performed genetic analysis of 25 probands with familial skin appendage tumor syndromes. In total, 18 mutations in CYLD, including 6 novel mutations, were identified in 25 probands (72%). The mutation frequencies among distinct phenotypes were 85% for BRSS, 100% for FC, and 44% for MFT1. The majority of the mutations resulted in truncated proteins. There were no apparent genotype-phenotype correlations. Saggar et al. (2008) concluded that mutations in the CYLD gene underlie all 3 disorders, but that the reasons for phenotypic variability remain to be explored.
Anderson, D. E., Howell, J. B. Epithelioma adenoides cysticum: genetic update. Brit. J. Derm. 95: 225-232, 1976. [PubMed: 974013] [Full Text: https://doi.org/10.1111/j.1365-2133.1976.tb07008.x]
Biggs, P. J., Wooster, R., Ford, D., Chapman, P., Mangion, J., Quirk, Y., Easton, D. F., Burn, J., Stratton, M. R. Familial cylindromatosis (turban tumour syndrome) gene localised to chromosome 16q12-q13: evidence for its role as a tumour suppressor gene. Nature Genet. 11: 441-443, 1995. [PubMed: 7493027] [Full Text: https://doi.org/10.1038/ng1295-441]
Blake, P. W., Toro, J. R. Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling. Hum. Mutat. 30: 1025-1036, 2009. [PubMed: 19462465] [Full Text: https://doi.org/10.1002/humu.21024]
Bowen, S., Gill, M., Lee, D. A., Fisher, G., Geronemus, R. G., Vazquez, M. E., Celebi, J. T., Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma. lack of genotype-phenotype correlation. J. Invest. Derm. 124: 919-920, 2005. [PubMed: 15854031] [Full Text: https://doi.org/10.1111/j.0022-202X.2005.23688.x]
Brooke, H. G. Epithelioma adenoides cysticum. Brit. J. Derm. 4: 269-287, 1892.
Correa-Cerro, L. S., Garcia-Cruz, D., Sarralde, A., Morales-Peralta, E., Gonzalez-Mendoza, A., Sanchez-Corona, J. Hereditary multiple benign cystic epithelioma (multiple trichoepithelioma) with onset at early age. Genet. Counsel. 8: 83-86, 1997. [PubMed: 9219004]
Fliegelman, M. T., Kruse, W. T. Hereditary multiple benign cystic epithelioma. J. Invest. Derm. 11: 189-196, 1948. [PubMed: 18888079]
Fordyce, J. A. Multiple benign cystic epithelioma of the skin. J. Cutan. Dis. 10: 459-473, 1892.
Gartler, S. M., Ziprkowski, L., Krakowski, A., Ezra, R., Szeinberg, A., Adam, A. Glucose-6-phosphate dehydrogenase mosaicism as a tracer in the study of hereditary multiple trichoepithelioma. Am. J. Hum. Genet. 18: 282-287, 1966. [PubMed: 17948511]
Gaul, L. E. Heredity of multiple benign cystic epithelioma: the Indiana family. Arch. Derm. Syph. 68: 517-524, 1953. [PubMed: 13091408] [Full Text: https://doi.org/10.1001/archderm.1953.01540110039005]
Gerretsen, A. L., Beemer, F. A., Deenstra, W., Hennekam, F. A. M., van Vloten, W. A. Familial cutaneous cylindromas: investigations in five generations of a family. J. Am. Acad. Derm. 33: 199-206, 1995. [PubMed: 7622645] [Full Text: https://doi.org/10.1016/0190-9622(95)90234-1]
Hu, G., Onder, M., Gill, M., Aksakal, B., Oztas, M., Gurer, M. A., Celebi, J. T. A novel missense mutation in CYLD in a family with Brooke-Spiegler syndrome. J. Invest. Derm. 121: 732-734, 2003. [PubMed: 14632188] [Full Text: https://doi.org/10.1046/j.1523-1747.2003.12514.x]
Johnson, S. C., Bennett, R. G. Occurrence of basal cell carcinoma among multiple trichoepitheliomas. J. Am. Acad. Derm. 28: 322-326, 1993. [PubMed: 8436650] [Full Text: https://doi.org/10.1016/0190-9622(93)70046-v]
Lee, D. A., Grossman, M. E., Schneiderman, P., Celebi, J. T. Genetics of skin appendage neoplasms and related syndromes. J. Med. Genet. 42: 811-819, 2005. [PubMed: 16272260] [Full Text: https://doi.org/10.1136/jmg.2004.025577]
Liang, Y. H., Gao, M., Sun, L. D., Liu, L. J., Cui, Y., Yang, S., Fan, X., Wang, J., Xiao, F. L., Zhang, X. J. Two novel CYLD gene mutations in Chinese families with trichoepithelioma and a literature review of 16 families with trichoepithelioma reported in China. Brit. J. Derm. 153: 1213-1215, 2005. [PubMed: 16307661] [Full Text: https://doi.org/10.1111/j.1365-2133.2005.06960.x]
Saggar, S., Chernoff, K. A., Lodha, S., Horev, L., Kohl, S., Honjo, R. S., Brandt, H. R. C., Hartmann, K., Celebi, J. T. CYLD mutations in familial skin appendage tumours. (Letter) J. Med. Genet. 45: 298-302, 2008. [PubMed: 18234730] [Full Text: https://doi.org/10.1136/jmg.2007.056127]
Welch, J. P., Wells, R. S., Kerr, C. B. Ancell-Spiegler cylindromas (turban tumours) and Brooke-Fordyce trichoepitheliomas: evidence for a single genetic entity. J. Med. Genet. 5: 29-35, 1968. [PubMed: 5653864] [Full Text: https://doi.org/10.1136/jmg.5.1.29]
Young, A. L., Kellermayer, R., Szigeti, R., Teszas, A., Azmi, S., Celebi, J. T. CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes. Clin. Genet. 70: 246-249, 2006. [PubMed: 16922728] [Full Text: https://doi.org/10.1111/j.1399-0004.2006.00667.x]
Ziprkowski, L., Schewach-Millet, M. Multiple trichoepithelioma in a mother and two children. Dermatologica 132: 248-256, 1966. [PubMed: 5958278] [Full Text: https://doi.org/10.1159/000254425]