Tumor Mapping in 2 Large Multigenerational Families With CYLD Mutations

Abstract

Objective To comprehensively ascertain the extent and severity of clinical features in multiple affected individuals from two large families with proven heterozygous mutations in the CYLD locus and to correlate these findings with the three appendageal tumor predisposition syndromes, familial cylindromatosis (FC), Brooke-Spiegler syndrome (BSS), and multiple familial trichoepitheliomas (MFT) known to be associated with such germline mutations. Design Inter- and intra-familial observational study. Setting Tertiary genetic and dermatology referral centre. Participants 32 individuals were recruited from two large multigenerational families with CYLD mutations. Clinical details, history and tumor maps were obtained from all participants whilst 18 were further corroborated with detailed clinical examination. Main outcome measures Severity of tumor density, distribution and histology, associated medical conditions, patient symptoms and impact of disease on quality of life. Results We demonstrate a wide variation in clinical presentation seen in individuals from the same family. In addition, we provide clinical evidence that correlates with hormonally stimulated hair follicles being particularly vulnerable to loss of heterozygosity and tumor induction. Conclusion In view of our findings, we propose that the burden of disease at sites other than the head and neck is underreported in the literature, but impacts greatly on quality of life. The differentiation between the clinical diagnoses has little prognostic or clinical utility in genetic counselling even within individuals from the same family. Thus, we suggest an encompassing diagnosis of “CYLD cutaneous syndrome”. Finally, our results relating to the clinical distribution of tumors suggest hormonal factors may play an important role in tumor induction in these patients.

Functional Inactivation of CYLD Promotes the Metastatic Potential of Tumor Epidermal Cells

“…We observed that keratin K5 and K10 expression was also downregulated in most of the tumor islets of the three types of familial cylindromatosis tumors (Figure 5m-r). These results show that, as occurs in CYLD C/S tumor cells, where the lack of the deubiquitination function of CYLD was accompanied by diminished expression of Maspin, in tumor cells of cylindromatosis patients carrying a functionally similar inactivating mutation in the CYLD gene (Rajan et al, 2009), a decreased expression of Maspin was also observed.…”

Report of Three Novel Germline <b><i>CYLD</i></b> Mutations in Unrelated Patients with Brooke-Spiegler Syndrome, Including Classic Phenotype, Multiple Familial Trichoepitheliomas and Malignant Transformation

“…Mutations in introns leading to intronic exonization and large deletions have been reported in some of those ‘negative' cases [30,34]. So far, no genotype-phenotype correlation has been found [11,17,35]. Bigger cohorts with accurate correlation of molecular, clinical and histomorphologic data may eventually help in developing prognostic criteria.…”

Brooke-Spiegler Syndrome Associated with Ulcerative Rectosigmoiditis

“…To confirm the diagnosis of BSS, mutation analysis of the CYLD gene was performed by sequence analysis of all coding exons [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], exon/intron boundaries and Q-PCR analysis (laboratory of the Department of Clinical Genetics of Erasmus MC, Rotterdam, The Netherlands). A splice-site mutation, 2350+5G>A in the exon 17 of the CYLD gene was found.…”

“…The most common tumour types include trichoepitheliomas, cylindromas and spiradenomas originating from the basal cell layer of the epidermis and fi-om hair follicles in the areas of the head and neck (3,4). In some patients BSS may cause turban tumour (5).…”