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

doi:10.1053/j.gastro.2003.11.008

Gastroenterology

Volume 126, Issue 2, February 2004, Pages 576-585

https://doi.org/10.1053/j.gastro.2003.11.008 Get rights and content

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.

Section snippets

Proband

The proband (Figure 1; subject IV-1), an 11-year-old boy, presented with an 8-month history of fatigue, abdominal pain, weight loss, and iron-deficiency anemia. Physical examination showed a cachectic-appearing prepubertal boy with occult blood positive stools but no perianal disease and no extraintestinal manifestations of inflammatory bowel disease. On his lower back, there were several café-au-lait macules, each measuring 5–10 mm. Eye examination showed no Lisch nodules, and dilated fundus

Immunohistochemistry

Formalin-fixed, paraffin-embedded tissues were sectioned at 4 μm, deparaffinized, and rehydrated with xylene and alcohol. The slides underwent microwave antigen retrieval (10 mmol/L citrate buffer, pH 6.0; 3 minutes at 115°C in microMED T/T Mega [Hacker Instruments & Industries, Inc., Fairfield, NJ]). Nonspecific binding was blocked by 20% Protein Blocker with Avidin (Signet Laboratories, Inc., Dedham, MA). The slides were washed with Tris-buffered saline. The sections were then incubated with

Tumor and germline molecular analysis

The development of gastrointestinal cancers in these young children prompted referral to the Familial Gastrointestinal Cancer Registry at Mount Sinai Hospital, Toronto, for genetic counseling and molecular testing. Research and service genetic testing studies were performed according to protocols approved by the Mount Sinai Hospital and the Ottawa Hospital Research Ethics Boards.

Subjects IV-1 and IV-2 had a normal karyotype and had normal chromosome fragility testing. Genetic testing for a

Discussion

Gastrointestinal cancer is very uncommon in childhood, and the development of duodenal cancer and colon cancer in 2 young siblings is so rare that a strong predisposing genetic factor should be considered in such families. This report describes an unusual genetic event in which heterozygous MMR gene mutation carrier parents produced 3 children with a homozygous mutant genotype for the MLH1 gene. Although a small number of subjects with homozygous MMR gene mutations have been published

Acknowledgements

The authors acknowledge the technical assistance of Hyeja Kim in APC gene analysis.

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^☆: Supported by grants from the National Cancer Institute of Canada (H.S.L.C.).

¹: S.G. and M.A. contributed equally to this article.

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Case reportGastrointestinal cancers and neurofibromatosis type 1 features in children with a germline homozygous MLH1 mutation☆

Abstract

Section snippets

Proband

Immunohistochemistry

Tumor and germline molecular analysis

Discussion

Acknowledgements

Cancer Genet Cytogenet

Gastroenterology

Gastroenterology

Am J Hum Genet

Am J Hum Genet

Am J Hum Genet

Genomics

Lab Invest

Am J Hum Genet

Cancer Genet Cytogenet

Molecular biology of colorectal cancer

Curr Probl Cancer

Clinical findings with implications for genetic testing in families with clustering of colorectal cancer

N Engl J Med

Evaluation of microsatellite instability and immunohistochemistry for the prediction of germ-line MSH2 and MLH1 mutations in hereditary nonpolyposis colon cancer families

Cancer Res

Extensive molecular screening for hereditary non-polyposis colorectal cancer

Br J Cancer

Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes

Cancer Res

Impact of microsatellite testing and mismatch repair protein expression on the clinical interpretation of genetic testing in hereditary non-polyposis colorectal cancer

J Cancer Res Clin Oncol

Neurofibromatosis and early onset of cancers in hMLH1-deficient children

Cancer Res

Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1

Cancer Res

Extensive somatic microsatellite mutations in normal human tissue

Cancer Res

A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple cafe-au-lait spots

Cancer Res

Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer

N Engl J Med

A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predispositiondevelopment of international criteria for the determination of microsatellite instability in colorectal cancer

Cancer Res

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