Brooke–Spiegler syndrome (BSS) is a rare, inherited, autosomal dominant disorder characterized by development of multiple adnexal cutaneous neoplasms including spiradenoma, cylindroma, spiradenocylindroma, and trichoepithelioma. The syndrome of multiple familial trichoepitheliomas (MFT) is considered a phenotypic variant of BSS in which patients present with trichoepitheliomas only. We studied germline and somatic mutations of the CYLD gene by direct sequencing in patients with BSS (n = 49) and MFT (n = 18) using peripheral blood and 90 samples of frozen or formalin-fixed paraffin-embedded tumor tissue selected from 379 available histology specimens. Germline CYLD mutations were found in 51 patients (76%) from 36 families (75%). Germline CYLD mutations were found in 43 of the 49 patients with BSS (88%) but in only 8 of 18 MFT cohort (44%). Twenty-one frameshift, 15 nonsense, 3 missense, and 4 splice site mutations were found in patients with BSS, whereas 1 frameshift, 5 nonsense, and 2 splice site mutations were identified in the MFT cohort. Five novel mutations were identified including 4 frameshift mutations (c.1027dupA/p.T343NfsX7, c.2155dupA/p.M719NfsX5, c.2288_2289delTT/p.F763X, and c.2641delG/p.D881TfsX32) and 1 nonsense mutation (c.2713C>T/p. Q905X). Of the 76 tumors from 32 patients with a germline CYLD mutation, 12 were spiradenomas, 15 spiradenocylindromas, 26 cylindromas, 15 trichoepitheliomas, and 7 were other tumor types. Somatic mutations were detected in 67 specimens of these 76 tumors (88%). Of the 67 somatic mutations, 21 (31%) represented a sequence alteration and 46 (69%) showed loss of heterozygosity. In the remaining 9 cases (12%), the somatic changes remained unknown. A germline CYLD mutation was not detected in 14 tumor samples from 8 patients. In these 14 tumors, somatic mutations were identified in 6 samples (43%), all consisting of sequence alterations (1 sample showed 2 different sequence alterations). In the remaining 8 samples (53%), neither germline nor somatic mutations were found in the lesional tissue. Our study increases the catalog of known CYLD mutations in patients with BSS/MFT to 86 and documents the variability of somatic mutations that may occur in them. We confirm the absence of firm genotype–phenotype correlations and the existence of a subset of patients with BSS/MFT who lack a demonstrable germline CYLD mutation. Further studies are needed to explain the reasons for this phenomenon.
*Bioptical Laboratory, Pilsen, Czech Republic
†Sikl's Department of Pathology, Charles University Medical Faculty Hospital, Pilsen, Czech Republic
‡PathWest Laboratory Medicine WA Nedlands, Australia
§School of PALM, University of Western Australia
¶Clinique Dermatologique, Hôpitaux Universitaires, Strasbourg, France
‖Department of Dermatology, Allergology and Venereology, Schleswig-Holstein University Hospital, Lübeck, Germany
**Department of Pathology, Academy of Medical Postgraduate Education of Belarus, Minsk, Republic of Belarus
††Division of Dermatopathology, Albany Medical College, Albany, NY
‡‡Department of Dermatology, Paracelsus Private Medical University Salzburg, Salzburg, Austria
§§Hollywood Specialist Centre, Nedlands, Australia
¶¶Royal Children's Hospital, Herston, Australia.
Reprints: Dmitry V. Kazakov, MD, PhD, Sikl's Department of Pathology, Charles University Medical Faculty Hospital, Alej Svobody 80, 304 60, Pilsen, Czech Republic (e-mail: email@example.com).
Supported in part by the Internal Grant Agency of the Ministry of Health of the Czech Republic (NS 9734).
P. Grossmann and T. Vanecek contributed equally to the study.
The authors declare that they have no conflicts of interests to disclose.