Gastrointestinal cancers and neurofibromatosis type 1 features in children with a germline homozygous MLH1 mutation

Heterozygous germline DNA mismatch repair gene mutations are typically associated with hereditary nonpolyposis colorectal cancer. The molecular hallmark of this syndrome is high-frequency microsatellite instability in the tumors. Rare childhood cases with homozygous or compound heterozygous DNA mismatch repair gene mutations have a described predisposition to leukemia, lymphoma, and brain tumors but not to gastrointestinal cancer. We have now characterized a family in which 2 children with a homozygous germline DNA mismatch repair gene mutation developed early-onset gastrointestinal cancers. The 11-year-old proband had cafe-au-lait macules and developed metastatic duodenal adenocarcinoma that arose in a tubulovillous adenoma. His 9-year-old sister with cafe-au-lait macules and axillary freckling presented with malignant colon polyps. A 6-year-old sister with cafe-au-lait macules, hairy nevi, and a plexiform neurofibroma of the tongue has no malignancies to date. The family history did not fulfill the Amsterdam criteria for hereditary nonpolyposis colorectal cancer, but 2 relatives in their 60s had gastric cancer and colorectal cancer, whereas the parents, who are first cousins, remain cancer free. The proband's metastatic duodenal cancer and his sister's malignant colon polyps had high-frequency microsatellite instability but had detectable MLH1, MSH2, and MSH6 proteins by immunohistochemistry. Because some germline DNA mismatch repair gene deficiencies are associated with apparently intact immunohistochemical DNA mismatch repair gene expression in tumors, we proceeded to DNA sequencing, which showed that all 3 children had a germline homozygous MLH1 missense mutation (exon 18, codon 687, CGG-->TGG), whereas both parents were heterozygous for this mutation.