title: Gastrointestinal cancers and neurofibromatosis type 1 features in children with a germline homozygous MLH1 mutation.
abstract: 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.
authors.affiliation: Familial Gastrointestinal Cancer Registry and Centre for Cancer Genetics and Department of Surgery, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, ON, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.forename: Melyssa
authors.initials: M
authors.lastname: Aronson
authors.forename: Katayoon
authors.initials: K
authors.lastname: Shayan
authors.forename: Elyanne M
authors.initials: EM
authors.lastname: Ratcliffe
authors.forename: Justin T
authors.initials: JT
authors.lastname: Gerstle
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Parkin
authors.forename: Heidi
authors.initials: H
authors.lastname: Rothenmund
authors.forename: Marina
authors.initials: M
authors.lastname: Croitoru
authors.forename: Ewa
authors.initials: E
authors.lastname: Baumann
authors.forename: Peter R
authors.initials: PR
authors.lastname: Durie
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
authors.forename: Aaron
authors.initials: A
authors.lastname: Pollett
authors.forename: Robert H
authors.initials: RH
authors.lastname: Riddell
authors.forename: Bo Y
authors.initials: BY
authors.lastname: Ngan
authors.forename: Ernest
authors.initials: E
authors.lastname: Cutz
authors.forename: Alain E
authors.initials: AE
authors.lastname: Lagarde
authors.forename: Helen S L
authors.initials: HS
authors.lastname: Chan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D002648:Child; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D018095:Germ-Line Mutation / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D000070957:MutL Protein Homolog 1; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics*; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins; D010375:Pedigree
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1