Brooke-Spiegler syndrome represents an autosomal dominant disease characterized 
by the occurrence of multiple cylindromas, trichoepitheliomas and (sporadically) 
spiroadenomas. Patients with Brooke-Spiegler syndrome are also at risk of 
developing tumors of the major and minor salivary glands. Patients with 
Brooke-Spiegler syndrome have various mutations in the CYLD gene, a 
tumor-suppressor gene located on chromosome 16q. To date, 68 unique CYLD 
mutations have been identified. We describe two families with Brooke-Spiegler 
syndrome, one with familial cylindromatosis and one with multiple familial 
trichoepithelioma, which showed wide inter-family phenotypic variability. 
Analysis of germline mutations of the CYLD and PTCH genes was performed using 
peripheral blood. In addition, formalin-fixed paraffin-embedded tumor samples 
were analyzed for PTCH somatic mutations and cylindroma cell cultures were 
obtained directly from patients for further growth and analysis. Clinically, the 
major features of Brooke-Spiegler syndrome include the presence of heterogeneous 
skin tumors and wide inter- and intra-familial phenotypic variability. 
Histopathologically, both cylindromas and trichoepitheliomas were found in 
affected individuals. Mutations or loss of heterozygosity was not found in CYLD 
and PTCH genes. In CYLD and PTCH mutation-negative patients, other genes may be 
affected and further studies are needed to clarify whether these patients may be 
affected by de novo germline mutations.