Media type: E-Article Title: Compound heterozygosity for two MSH6 mutations in a patient with early onset colorectal cancer, vitiligo and systemic lupus erythematosus Contributor: Rahner, Nils; Höefler, Gerald; Högenauer, Christoph; Lackner, Caroline; Steinke, Verena; Sengteller, Marlies; Friedl, Waltraut; Aretz, Stefan; Propping, Peter; Mangold, Elisabeth; Walldorf, Constanze Published: Wiley, 2008 Published in: American Journal of Medical Genetics Part A, 146A (2008) 10, Seite 1314-1319 Language: English DOI: 10.1002/ajmg.a.32210 ISSN: 1552-4825; 1552-4833 Origination: Footnote: Description: AbstractLynch syndrome (hereditary non‐polyposis colorectal cancer, HNPCC) is an autosomal dominant condition caused by heterozygous germline mutations in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. Rare cases have been reported of an inherited bi‐allelic deficiency of MMR genes, associated with multiple café‐au‐lait spots, early onset CNS tumors, hematological malignancies, and early onset gastrointestinal neoplasia. We report on a patient with vitiligo in segments of the integument who developed systemic lupus erythematosus (SLE) at the age of 16, and four synchronous colorectal cancers at age 17 years. Examination of the colorectal cancer tissue showed high microsatellite instability (MSI‐H) and an exclusive loss of expression of the MSH6 protein. Immunohistochemical analysis of normal colon tissue also showed loss of MSH6, pointing to a bi‐allelic MSH6 mutation. Sequencing of the MSH6 gene showed the two germline mutations; c.1806_1809delAAAG;p.Glu604LeufsX5 and c.3226C > T;p.Arg1076Cys. We confirmed that the two mutations are on two different alleles by allele‐specific PCR. To our knowledge, neither parent is clinically affected. They did not wish to be tested for the mutations identified in their daughter. These data suggest that bi‐allelic mutations of one of the MMR genes should be considered in patients who develop early‐onset multiple HNPCC‐associated tumors and autoimmune disorders, even in absence of either hematological malignancies or brain tumors. © 2008 Wiley‐Liss, Inc.