Brooke-Spiegler syndrome is an autosomal dominant disorder classically characterized by the appearance of multiple skin appendage tumors such as cylindroma, trichoepithelioma, and spiradenoma. These tumors are typically located in the head and neck region, appear in early adulthood, ... Brooke-Spiegler syndrome is an autosomal dominant disorder classically characterized by the appearance of multiple skin appendage tumors such as cylindroma, trichoepithelioma, and spiradenoma. These tumors are typically located in the head and neck region, appear in early adulthood, and gradually increase in size and number throughout life (Scheinfeld et al., 2003). 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 (Gerretsen et al., 1995; Lee et al., 2005; Bowen et al., 2005; Young et al., 2006; Saggar et al., 2008). Blake and Toro (2009) provided a review of Brooke-Spiegler syndrome and pathogenic mutations in the CYLD gene.
Schuermann and Weber (1937) presented a pedigree with cylindromas and trichoepitheliomas affecting 9 persons in 4 generations. Six of the 9 were female. Although no male-to-male transmission was noted, 2 daughters of an affected male were affected. ... Schuermann and Weber (1937) presented a pedigree with cylindromas and trichoepitheliomas affecting 9 persons in 4 generations. Six of the 9 were female. Although no male-to-male transmission was noted, 2 daughters of an affected male were affected. Autio-Harmainen et al. (1988) described a Finnish kindred in which many members had dominantly inherited trichoepithelioma and cylindromas. At least 4 generations and 7 sibships were affected, particularly with facial trichoepithelioma, and at least 4 members of the family were reported to have scalp cylindromas. One patient had eccrine spiradenoma, including painful spiradenomas on the upper chest, implying Brooke-Spiegler syndrome. In addition, an affected mother and daughter developed a malignant lymphoepithelial lesion of the parotid gland. Autio-Harmainen et al. (1988) noted that salivary gland lymphoepithelial lesions had been reported predominantly in the Mongoloid race, with a preponderance of Canadian and Greenland Eskimos and Chinese. Familial occurrence has been noted among the Eskimos (Merrick et al., 1986). Schramm et al. (1996) reported a 49-year-old woman and her 20-year-old daughter with multiple papular and nodular lesions on the face and scalp, showing the typical clinical and histopathologic features of trichoepithelioma. In addition, the mother developed multiple, blue-colored and painful lesions on her breast and back, showing the histopathologic characteristics of eccrine spiradenomas. The trichoepitheliomas and spiradenomas were found in close proximity in a tissue specimen. Weyers et al. (1993) reported a patient with Brooke-Spiegler syndrome in whom spiradenomas were found in the immediate vicinity of trichoepitheliomas and in continuity with follicles. Because of the embryonic relationship between follicles and apocrine glands, these features suggested that spiradenomas are apocrine neoplasms. Weyers et al. (1993) noted that basal cell carcinoma and cylindromas have also been observed in BRSS. Schirren et al. (1995) identified both cylindroma and trichoepithelioma in a single nevoid plaque from a patient with Brooke-Spiegler syndrome. Mixed differentiation in tumor specimens from 2 individuals from the same family had also been found (Puig et al., 1998). These findings suggested a defect in the stem cells of the folliculosebaceous-apocrine unit (FSAU), where mutations in genes regulating proliferation and differentiation of the putative stem cells would give rise to different combinations of adnexal skin tumors as well as to other neoplasms (Fenske et al., 2000). Scheinfeld et al. (2003) reported a family with BRSS. The proband was a 67-year-old man who presented with multiple disfiguring facial papules and scalp nodules. The lesions began in his late teenage years. Physical examination showed numerous flesh-colored, pink, and bluish 0.5- to 2.0-cm papules and nodules on the face, ears, and scalp. Histologic examination of at least 21 lesions showed predominantly cylindromas and spiradenomas, but also included epidermoid inclusion cysts, and basal cell carcinoma. Palmar pits were also observed. The patient's sister and father had a similar phenotype. Bowen et al. (2005) reported 3 unrelated women with BRSS confirmed by genetic analysis (see, e.g., 605018.0008). One patient had cylindroma and trichoepithelioma, another had cylindroma, trichoepithelioma, and spiradenoma, and the third had cylindroma, spiradenoma, and bilateral basal cell adenocarcinomas of the parotid gland. Nasti et al. (2009) reported an Italian mother and son with variable manifestations of Brooke-Spiegler syndrome. The 79-year-old mother began developing skin lesions at age 16. She had severe scalp involvement. Most were cylindromas, some with combined features of cylindroma and spiradenoma, and many smaller nodules were trichoepitheliomas. She also had a cutaneous carcinosarcoma on the trunk. Her 54-year-old son had 7 cylindromas and 6 basal cell carcinomas. Both patients carried a heterozygous truncating mutation in the CYLD gene (605018.0010).
In affected members of a German family with cylindromas, including 1 patient who also had trichoepitheliomas, suggesting BRSS, Gutierrez et al. (2002) identified a heterozygous truncating mutation in the CYLD gene (605018.0003). The results indicated that a single ... In affected members of a German family with cylindromas, including 1 patient who also had trichoepitheliomas, suggesting BRSS, Gutierrez et al. (2002) identified a heterozygous truncating mutation in the CYLD gene (605018.0003). The results indicated that a single CYLD mutation can result in phenotypically different tumor types, indicating that cylindromas and trichoepitheliomas are allelic disorders. In a man with Brooke-Spiegler syndrome, Scheinfeld et al. (2003) identified a heterozygous mutation in the CYLD gene (605018.0004). Hu et al. (2003) identified a heterozygous mutation in the CYLD1 gene (605018.0007) in a patient with cylindromas on the scalp. However, his affected family members, who carried the same mutation, all had multiple trichoepitheliomas without cylindromas. Since both features were present in this family, the diagnosis was consistent with Brooke-Spiegler syndrome. The findings suggested that MFT1 and BRSS may be variable manifestations of a single disease entity. Saggar et al. (2008) performed genetic analysis of 25 probands with familial skin appendage tumors. 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.