Brooke–Spiegler syndrome tumor spectrum beyond the skin: a patient carrying germline R936X CYLD mutation and a somatic CYLD mutation in Brenner tumor

Abstract

ABSTRACT:  Brooke–Spiegler syndrome is a hereditary disorder characterized by a predisposition to the development of skin appendage neoplasms and the major and minor salivary glands neoplasms. The role of the CYLD mutation in visceral neoplasms is still unclear, except for the parathyroid tumor. We report the case of a 46-year-old patient with multiple cylindromas and trichoepitheliomas, a Brenner tumor of the ovary and a negative family history for Brooke–Spiegler phenotype. Genetic analysis revealed R936X germline mutation in the proband, but not in the patient’s relatives. The same somatic mutation was found in the Brenner tumor, together with a novel missense CYLD mutation (D889N), which has never been reported in the literature. A founder effect for R936X has been hypothesized due to its high prevalence; surprisingly, in our case, this mutation seems to be recognized as a de novo mutation. Future studies involving a greater number of cases, through the clinical analysis of the familial tumor spectrum and the associated molecular pathways, are necessary to understand possible genotype/phenotype correlations and the underlying molecular mechanisms.