Brooke-Spiegler syndrome (BSS) is an inherited autosomal dominant disease characterized by the development of multiple adnexal cutaneous neoplasms most commonly spiradenoma, cylindroma, spiradenocylindroma, and trichoepithelioma. Multiple familial trichoepithelioma (MFT) is a phenotypic variant of the disease characterized by the development of numerous trichoepitheliomas (cribriform trichoblastoma) only. Malignant tumors arise in association with preexisting benign cutaneous neoplasms in about 5-10% of the patients . Apart from the skin, major and minor salivary glands have been rarely involved in BSS patients. Extremely rare is the occurrence of breast tumors (cylindroma). The gene implicated in the pathogenesis of the disease is the CYLD gene, a tumor suppressor gene located on chromosome 16q12-q13. Germline CYLD mutations are detected in about 80-85% of patients with the classical BSS phenotype and in about 40-50% of the individuals with the MFT phenotype using a PCR based approach with analysis of exonic sequences and exon-intron junctions of the CYLD gene. There appears to be no genotype-phenotype correlations with respect to the severity of the disease, the possibility of malignant transformation, and development of extracutaneous lesions.

Department of Pathology Faculty of Medicine in Pilsen Charles University Prague Prague Czech Republic

Sikl's Department of Pathology Charles University Medical Faculty Hospital Alej Svobody 80 304 60 Pilsen Czech Republic

Zobrazit více v PubMed

Clarke J, Ioffreda M, Helm KF. Multiple familial trichoepitheliomas: a folliculosebaceous-apocrine genodermatosis. Am J Dermatopathol. 2002;24:402–405. doi: 10.1097/00000372-200210000-00005. PubMed DOI

Bignell GR, Warren W, Seal S, et al. Identification of the familial cylindromatosis tumour-suppressor gene. Nat Genet. 2000;25:160–165. doi: 10.1038/76006. PubMed DOI

Kazakov DV, Soukup R, Mukensnabl P, et al. Brooke-Spiegler syndrome: report of a case with combined lesions containing cylindromatous, spiradenomatous, trichoblastomatous, and sebaceous differentiation. Am J Dermatopathol. 2005;27:27–33. doi: 10.1097/01.dad.0000138049.86662.3e. PubMed DOI

Puig L, Nadal C, Fernandez-Figueras MT, et al. Brooke-Spiegler syndrome variant: segregation of tumor types with mixed differentiation in two generations. Am J Dermatopathol. 1998;20:56–60. doi: 10.1097/00000372-199802000-00011. PubMed DOI

Antonescu CR, Terzakis JA. Multiple malignant cylindromas of skin in association with basal cell adenocarcinoma with adenoid cystic features of minor salivary gland. J Cutan Pathol. 1997;24:449–453. doi: 10.1111/j.1600-0560.1997.tb00822.x. PubMed DOI

Kazakov DV, Zelger B, Rutten A, et al. Morphologic diversity of malignant neoplasms arising in preexisting spiradenoma, cylindroma, and spiradenocylindroma based on the study of 24 cases, sporadic or occurring in the setting of Brooke-Spiegler syndrome. Am J Surg Pathol. 2009;33:705–719. doi: 10.1097/PAS.0b013e3181966762. PubMed DOI

Tantcheva-Poór I, Vanecek T, Lurati MC, et al. Report of three novel germline CYLD mutations in unrelated patients with Brooke-Spiegler syndrome, including classic phenotype, multiple familial trichoepitheliomas and malignant transformation. Dermatology. 2016;232(1):30–37. doi: 10.1159/000437303. PubMed DOI

Bowen S, Gill M, Lee DA, et al. Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma: lack of genotype-phenotype correlation. J Invest Dermatol. 2005;124:919–920. doi: 10.1111/j.0022-202X.2005.23688.x. PubMed DOI

Young AL, Kellermayer R, Szigeti R, et al. CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes. Clin Genet. 2006;70:246–249. doi: 10.1111/j.1399-0004.2006.00667.x. PubMed DOI

Saggar S, Chernoff KA, Lodha S, et al. CYLD mutations in familial skin appendage tumours. J Med Genet. 2008;45:298–302. doi: 10.1136/jmg.2007.056127. PubMed DOI

Pingitore R, Campani D. Salivary gland involvement in a case of dermal eccrine cylindroma of the scalp (turban tumor). Report of a case with lung metastases. Tumori. 1984;70:385–388. PubMed

Rockerbie N, Solomon AR, Woo TY, et al. Malignant dermal cylindroma in a patient with multiple dermal cylindromas, trichoepitheliomas, and bilateral dermal analogue tumors of the parotid gland. Am J Dermatopathol. 1989;11:353–359. doi: 10.1097/00000372-198908000-00009. PubMed DOI

Scott AR, Faquin WC, Deschler DG. Parotid mass in a woman with multiple cutaneous cylindromas. Head Neck. 2010;32:684–687. doi: 10.1002/hed.21341. PubMed DOI

Nonaka D, Rosai J, Spagnolo D, et al. Cylindroma of the breast of skin adnexal type: a study of 4 cases. Am J Surg Pathol. 2004;28:1070–1075. doi: 10.1097/01.pas.0000126774.27698.27. PubMed DOI

Zarbo RJ, Ricci A, Jr, Kowalczyk PD, et al. Intranasal dermal analogue tumor (membranous basal cell adenoma). Ultrastructure and immunohistochemistry. Arch Otolaryngol. 1985;111:333–337. doi: 10.1001/archotol.1985.00800070085014. PubMed DOI

Kazakov DV, Michal M, Kacerovska D, et al. Cutaneous adnexal tumors. Philadelphia: LWW; 2012. p. 814.

Linos K, Schwartz J, Kazakov DV, et al. Recurrent CYLD nonsense mutation associated with a severe, disfiguring phenotype in an African American family with multiple familial trichoepithelioma. Am J Dermatopathol. 2011;33:640–642. doi: 10.1097/DAD.0b013e318209070a. PubMed DOI

Hester CC, Moscato EE, Kazakov DV, et al. A new cylindromatosis (CYLD) gene mutation in a case of Brooke-Spiegler syndrome masquerading as basal cell carcinoma of the eyelids. Ophthalmic Plast Reconstr Surg. 2013;29:e10–e11. doi: 10.1097/IOP.0b013e3182565c41. PubMed DOI

Kazakov DV, Vanecek T, Nemcova J, et al. Spectrum of tumors with follicular differentiation in a patient with the clinical phenotype of multiple familial trichoepitheliomas: a clinicopathological and molecular biological study, including analysis of the CYLD and PTCH genes. Am J Dermatopathol. 2009;31:819–827. doi: 10.1097/DAD.0b013e3181a70eef. PubMed DOI

Pincus LB, McCalmont TH, Neuhaus IM, et al. Basal cell carcinomas arising within multiple trichoepitheliomas. J Cutan Pathol. 2008;35(Suppl 1):59–64. doi: 10.1111/j.1600-0560.2008.01002.x. PubMed DOI

Headington JT, Batsakis JG, Beals TF, et al. Membranous basal cell adenoma of parotid gland, dermal cylindromas, and trichoepitheliomas. Comparative histochemistry and ultrastructure. Cancer. 1977;39:2460–2469. doi: 10.1002/1097-0142(197706)39:6<2460::AID-CNCR2820390624>3.0.CO;2-6. PubMed DOI

Reingold IM, Keasbey LE, Graham JH. Multicentric dermal-type cylindromas of the parotid glands in a patient with florid turban tumor. Cancer. 1977;40:1702–1710. doi: 10.1002/1097-0142(197710)40:4<1702::AID-CNCR2820400446>3.0.CO;2-A. PubMed DOI

Ellis GL, Wiscovitch JG. Basal cell adenocarcinomas of the major salivary glands. Oral Surg Oral Med Oral Pathol. 1990;69:461–469. doi: 10.1016/0030-4220(90)90380-B. PubMed DOI

Hyman BA, Scheithauer BW, Weiland LH, et al. Membranous basal cell adenoma of the parotid gland. Malignant transformation in a patient with multiple dermal cylindromas. Arch Pathol Lab Med. 1988;112:209–211. PubMed

Kazakov DV, Schaller J, Vanecek T, et al. Brooke-Spiegler syndrome: report of a case with a novel mutation in the CYLD gene and different types of somatic mutations in benign and malignant tumors. J Cutan Pathol. 2010;37:886–890. doi: 10.1111/j.1600-0560.2010.01511.x. PubMed DOI

Sima R, Vanecek T, Kacerovska D, et al. 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;19:83–91. doi: 10.1097/PDM.0b013e3181ba2d96. PubMed DOI

Grossmann P, Vanecek T, Steiner P, et al. Novel and recurrent germline and somatic mutations in a cohort of 67 patients from 48 families with Brooke-Spiegler syndrome including the phenotypic variant of multiple familial trichoepitheliomas and correlation with the histopathologic findings in 379 biopsy specimens. Am J Dermatopathol. 2013;35:34–44. doi: 10.1097/DAD.0b013e31824e7658. PubMed DOI

Kazakov DV, Thoma-Uszynski S, Vanecek T, et al. A case of Brooke-Spiegler syndrome with a novel germline deep intronic mutation in the CYLD gene leading to intronic exonization, diverse somatic mutations, and unusual histology. Am J Dermatopathol. 2009;31:664–673. doi: 10.1097/DAD.0b013e3181a05dad. PubMed DOI

van den Ouweland AM, Elfferich P, Lamping R, et al. Identification of a large rearrangement in CYLD as a cause of familial cylindromatosis. Fam Cancer. 2011;10:127–132. doi: 10.1007/s10689-010-9393-y. PubMed DOI PMC

Vanecek T, Halbhuber Z, Kacerovska D, et al. Large germline deletions of the CYLD gene in patients with Brooke-Spiegler syndrome and multiple familial trichoepithelioma. Am J Dermatopathol. 2014;36:868–874. doi: 10.1097/DAD.0000000000000068. PubMed DOI