MSH6 mutation in Muir–Torre syndrome: could this be a rare finding?

Clinical criteria for diagnosis of Muir–Torre syndrome (MTS, MIM 158320) include synchronous or metachronous occurrence of at least one sebaceous gland neoplasia (adenoma, epithelioma or carcinoma) and at least one internal neoplasm in a patient. A subset of patients with MTS was found to be carriers of germline mutations in DNA mismatch repair (MMR) genes mainly in MSH2. This finding uncovered many clinically diagnosed MTS cases as phenotypic variants of the autosomal dominant cancer susceptibility syndrome known as Lynch syndrome or ‘hereditary nonpolyposis colorectal cancer’ (HNPCC). HNPCC is diagnosed clinically when the patient’s family meets the Amsterdam criteria (three family members affected with colorectal cancer or an HNPCC-associated tumour over at least two consecutive generations, one of them being a first-degree relative of the other two, and one of them diagnosed before the age of 50 years). HNPCC should also be suspected when the patient’s individual history or family history meet one of the less stringent Bethesda criteria, e.g. early-onset colorectal cancer (before age 50 years), synchronous or metachronous HNPCC-associated tumours, or a certain less stringent familial clustering of tumours irrespective of age at onset. Diagnosing Lynch syndrome through identification of the underlying MMR gene mutation (in MSH2, MLH1, MSH6 or PMS2) is of utmost importance not only for the patient but also for the patient’s family, as patients with Lynch syndrome and their families are known to profit from specific surveillance recommendations (for review see Lynch et al.). To date, patients with MTS with mutations in MSH2 and MLH1 have been reported in the literature, with the majority of mutations located in MSH2, a finding also recently presented in our large sample of patients with MTS. Here, we present the first MSH6 mutation in MTS. In addition, we present nine patients with mutations in either MSH2 or MLH1 and provide an update on proportions of MSH2, MLH1 and MSH6 mutations in our mutation-positive patients with MTS.