1. ¹Department of Surgical Research, Dresden University of Technology, Dresden, Germany
2. ²Department of Molecular Pathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
3. ³Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
4. ⁴Department of Clinical Genetics, Dresden University of Technology, Dresden, Germany
5. ⁵Department of Pathology, Dresden University of Technology, Dresden, Germany

Correspondence: Dr J Plaschke, Department of Surgical Research, Carl Gustav Carus Klinikum, Dresden University of Technology, Fetscherstrasse 74, D-01307 Dresden, Dresden, Germany. Tel: +49 351 458 3348; Fax: +49 351 458 5365; E-mail: plaschke@rcs.urz.tu-dresden.de

⁶These authors contributed equally to this work.

Received 15 August 2005; Revised 11 October 2005; Accepted 24 November 2005; Published online 18 January 2006.

Abstract

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.