Neurofibromatosis and early onset of cancers in hMLH1-deficient children

Hereditary nonpolyposis colon cancer is a common hereditary disorder caused by the germ-line mutations of DNA mismatch repair (MMR) genes, especially hMLH1 and hMSH2. We report here the first identification of human compounds with a homozygous inactivation of a MMR gene. In a typical hereditary nonp olyposis colon cancer family, MMR-deficient children conceived from matings between heterozygotes for a hMLH1 deleterious mutation exhibited clinical features of de novo neurofibromatosis type 1 and early onset of extracoloni c cancers. This observation demonstrates that MMR deficiency is compatible with human development hut may lead to mutations during embryogenesis. On t he basis of clinical symptoms observed in MMR-deficient children, we specul ate that the neurofibromatosis type I gene is a preferential target for suc h alterations.