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Brooke-Spiegler syndrome

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Description

Brooke-Spiegler syndrome is a condition involving multiple skin tumors that develop from structures associated with the skin (skin appendages), such as sweat glands and hair follicles. People with Brooke-Spiegler syndrome may develop several types of tumors, including growths called spiradenomas, trichoepitheliomas, and cylindromas. Spiradenomas develop in sweat glands. Trichoepitheliomas arise from hair follicles. The origin of cylindromas has been unclear; while previously thought to derive from sweat glands, they are now generally believed to begin in hair follicles. The tumors associated with Brooke-Spiegler syndrome are generally noncancerous (benign), but occasionally they may become cancerous (malignant). Affected individuals are also at increased risk of developing tumors in tissues other than skin appendages, particularly benign or malignant tumors of the salivary glands.

People with Brooke-Spiegler syndrome typically begin developing tumors in early adulthood. The tumors are most often found on the head and neck. They grow larger and increase in number over time. In severe cases, the tumors may get in the way of the eyes, ears, nose, or mouth and affect vision, hearing, or other functions. The tumors can be disfiguring and may contribute to depression or other psychological problems. For reasons that are unclear, females with Brooke-Spiegler syndrome are often more severely affected than males.

Frequency

Brooke-Spiegler syndrome is a rare disorder; its prevalence is unknown.

Causes

Brooke-Spiegler syndrome is caused by mutations in the CYLD gene. This gene provides instructions for making a protein that helps regulate nuclear factor-kappa-B. Nuclear factor-kappa-B is a group of related proteins that help protect cells from self-destruction (apoptosis) in response to certain signals. In regulating the action of nuclear factor-kappa-B, the CYLD protein allows cells to respond properly to signals to self-destruct when appropriate, such as when the cells become abnormal. By this mechanism, the CYLD protein acts as a tumor suppressor, which means that it helps prevent cells from growing and dividing too fast or in an uncontrolled way.

People with Brooke-Spiegler syndrome are born with a mutation in one of the two copies of the CYLD gene in each cell. This mutation prevents the cell from making functional CYLD protein from the altered copy of the gene. However, enough protein is usually produced from the other, normal copy of the gene to regulate cell growth effectively. For tumors to develop, a second mutation or deletion of genetic material involving the other copy of the CYLD gene must occur in certain cells during a person's lifetime.

When both copies of the CYLD gene are mutated in a particular cell, that cell cannot produce any functional CYLD protein. The loss of this protein allows the cell to grow and divide in an uncontrolled way to form a tumor. In people with Brooke-Spiegler syndrome, a second CYLD mutation typically occurs in multiple cells over an affected person's lifetime. The loss of CYLD protein in different types of cells in the skin leads to the growth of a variety of skin appendage tumors.

Some researchers consider Brooke-Spiegler syndrome and two related conditions called multiple familial trichoepithelioma and familial cylindromatosis, which are also caused by CYLD gene mutations, to be different forms of the same disorder. It is unclear why mutations in the CYLD gene cause different patterns of skin appendage tumors in each of these conditions, or why the tumors are generally confined to the skin in these disorders.

Inheritance

Susceptibility to Brooke-Spiegler syndrome has an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell increases the risk of developing this condition. However, a second, non-inherited mutation is required for development of skin appendage tumors in this disorder.

Other Names for This Condition

  • BRSS
  • BSS
  • Spiegler-Brooke syndrome

Additional Information & Resources

Genetic and Rare Diseases Information Center

Patient Support and Advocacy Resources

Catalog of Genes and Diseases from OMIM

Scientific Articles on PubMed

References

  • Almeida S, Maillard C, Itin P, Hohl D, Huber M. Five new CYLD mutations in skin appendage tumors and evidence that aspartic acid 681 in CYLD is essential for deubiquitinase activity. J Invest Dermatol. 2008 Mar;128(3):587-93. Epub 2007 Sep 13. Citation on PubMed
  • Blake PW, Toro JR. Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling. Hum Mutat. 2009 Jul;30(7):1025-36. doi: 10.1002/humu.21024. Review. Citation on PubMed or Free article on PubMed Central
  • Bowen S, Gill M, Lee DA, Fisher G, Geronemus RG, Vazquez ME, Celebi JT. Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma: lack of genotype-phenotype correlation. J Invest Dermatol. 2005 May;124(5):919-20. Citation on PubMed
  • Dubois A, Rajan N. CYLD Cutaneous Syndrome. 2020 Apr 16. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from http://www.ncbi.nlm.nih.gov/books/NBK555820/ Citation on PubMed
  • Lee DA, Grossman ME, Schneiderman P, Celebi JT. Genetics of skin appendage neoplasms and related syndromes. J Med Genet. 2005 Nov;42(11):811-9. Review. Citation on PubMed or Free article on PubMed Central
  • Saggar S, Chernoff KA, Lodha S, Horev L, Kohl S, Honjo RS, Brandt HR, Hartmann K, Celebi JT. CYLD mutations in familial skin appendage tumours. J Med Genet. 2008 May;45(5):298-302. doi: 10.1136/jmg.2007.056127. Epub 2008 Jan 30. Citation on PubMed
  • Sima R, Vanecek T, Kacerovska D, Trubac P, Cribier B, Rutten A, Vazmitel M, Spagnolo DV, Litvik R, Vantuchova Y, Weyers W, Pearce RL, Pearn J, Michal M, Kazakov DV. Brooke-Spiegler syndrome: report of 10 patients from 8 families with novel germline mutations: evidence of diverse somatic mutations in the same patient regardless of tumor type. Diagn Mol Pathol. 2010 Jun;19(2):83-91. doi: 10.1097/PDM.0b013e3181ba2d96. Citation on PubMed
  • Young AL, Kellermayer R, Szigeti R, Tészás A, Azmi S, Celebi JT. CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes. Clin Genet. 2006 Sep;70(3):246-9. Citation on PubMed
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