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 café-au-lait macules and developed metastatic duodenal
adenocarcinoma that arose in a tubulovillous
adenoma. His 9-year-old sister with café-au-lait macules and axillary freckling presented with malignant colon
polyps. A 6-year-old sister with café-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.