Multiple familial trichoepitheliomas (MFT) constitute an autosomally inherited syndrome possibly related to Brooke-Spiegler syndrome (BSS). Although some early studies suggested a role for the PTCH gene on chromosome 9q22.3 in the etiopathogenesis of MFT, recent studies of occasional patients with the MFT clinical phenotype identified mutations in the CYLD gene on chromosome 16q12-q13, a gene responsible for BSS. A systematic investigation of PTCH and CYLD mutations in patients with MFT has never been performed. Our main objective was to collect a reasonably large series of patients with MFT to (1) study the clinicopathological spectrum of the disease, (2) determine whether the PTCH gene is implicated in the pathogenesis of MFT, and if so (3) determine the relative frequency of CYLD and PTCH mutations, (4) establish if there may be any possible genotype-phenotype correlations, and (5) study the spectrum of somatic mutations. Clinical analysis including family histories, histopathological investigations, and molecular genetic studies were performed. There were 9 female and 7 male patients ranging in age from 11 to 63 years. They presented with multiple, small, discrete and sometimes confluent, skin-colored to pink, asymptomatic nodules preferentially located on the face, being especially prominent and confluent in the nasolabial folds and inner aspects of the eyebrows. A total of 66 conventional trichoepitheliomas (TEs) were studied microscopically. Aside from typical features of TE, some also exhibited variant morphological patterns including areas reminiscent of other benign adnexal neoplasms and melanocytic hyperplasia. In none of the 9 patients tested was a germline mutation of the PTCH gene identified. Germline CYLD mutations were detected in 6 of 13 patients tested (identical in 2 unrelated patients) including 2 novel mutations, whereas the remaining 7 individuals showed wild-type alleles. Two patients with germline wild-type CYLD showed, however, a somatic mutation in the gene (1 duplication, 1 substitution mutation). Neither CYLD nor PTCH germline mutations were found in the 5 patients in whom both genes were analyzed. MFT seems to be a phenotypic variant of BSS. The PTCH gene is rarely, if ever, involved in the pathogenesis of MFT. Absence of a germline mutation of the CYLD gene in cases harboring a somatic mutation may be explained by large deletions in the gene or by mutation in intronic sequences or in the promoter region. Considering our 5 patients with no mutation in either gene, the final possibility is that another, as yet undescribed gene (neither CYLD nor PTCH) is implicated in the pathogenesis of some patients with MFT.
From the *Sikl's Department of Pathology, Charles University Medical Faculty Hospital, Pilsen, Czech Republic; †Bioptical Laboratory, Pilsen, Czech Republic; ‡Clinical Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria; §Division of Dermatopathology, Albany Medical College, Albany, NY; ¶Division of Tissue Pathology, PathWest Laboratory Medicine WA, Nedlands, WA, Australia; ∥Department of Dermatohistology, Catholic Clinics Duisburg, Gerrmany; **Department of Pathology, Academy of Medical Postgraduate Education of Belarus, Minsk, Republic of Belarus; ††Department of Pathology, La Paz, Bolivia; ‡‡Department of Dermatology, Paracelsus Private Medical University Salzburg, Salzburg, Austria; §§Department of Dermatology, Medical Military Academy, Saint-Petersburg, Russia; ¶¶Department of Pathology, Hospital Universitari Germans Trias i Pujol, Autonomous University of Barcelona, Barcelona, Spain; ∥∥Kempf und Pfaltz, Histologische Diagnostik, Zürich, Switzerland; ***Department of Ophthalmology, Albany Medical College, Albany, NY; and †††Dermatopathologische Gemeinschaftspraxis, Friedrichshafen, Germany.
Supported in part by the Internal Grant Agency of the Ministry of Health of the Czech Republic (NS 9734).
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: firstname.lastname@example.org).