Compound heterozygosity for two MSH6 mutations in a patient with early onset of HNPCC-associated cancers, but without hematological malignancy and brain tumor.

Heterozygous germline mutations in the human mismatch repair (MMR) genes MLH1, PMS2, MSH2 and MSH6 predispose to the hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Biallelic mutations in these genes have been reported for a limited number of cases resulting in hematological malignancies, brain tumors and gastrointestinal tumors early in childhood. These tumor phenotypes are frequently associated with café-au-lait spots (CALS), one of the clinical hallmarks of neurofibromatosis type 1 (NF1). We report the first case of compound heterozygosity for two MSH6 mutations resulting in a nonconservative amino-acid change of a conserved residue and in a premature stop codon in a patient who developed rectal and endometrial cancer at ages 19 and 24 years, respectively, and presented few CALS in a single body segment. Immunohistochemistry and Western blotting revealed only residual expression of the MSH6 protein in the normal cells. The disease history resembles the HNPCC phenotype rather than a phenotype associated with biallelic MMR gene mutations. Therefore, we assume that one or both mutations abolish protein function only partially, further supported by the parents, which are both carriers of one of the mutations each, and not affected by the disease at ages 57 and 58 years. Our data suggest considering biallelic mutations in MMR genes for patients who develop HNPCC-associated tumors at an unusually young age of onset, even without hematological or brain malignancies.