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.