title: Gastrointestinal Findings in the Largest Series of Patients With Hereditary Biallelic Mismatch Repair Deficiency Syndrome: Report from the International Consortium.
abstract: OBJECTIVE
  Hereditary biallelic mismatch repair deficiency (BMMRD) is caused by biallelic mutations in the mismatch repair (MMR) genes and manifests features of neurofibromatosis type 1, gastrointestinal (GI) polyposis, and GI, brain, and hematological cancers. This is the first study to characterize the GI phenotype in BMMRD using both retrospective and prospective surveillance data.
  
  
  METHODS
  The International BMMRD Consortium was created to collect information on BMMRD families referred from around the world. All patients had germline biallelic MMR mutations or lack of MMR protein staining in normal and tumor tissue. GI screening data were obtained through medical records with annual updates.
  
  
  RESULTS
  Thirty-five individuals from seven countries were identified with BMMRD. GI data were available on 24 of 33 individuals (73%) of screening age, totaling 53 person-years. The youngest age of colonic adenomas was 7, and small bowel adenoma was 11. Eight patients had 19 colorectal adenocarcinomas (CRC; median age 16.7 years, range 8-25), and 11 of 18 (61%) CRC were distal to the splenic flexure. Eleven patients had 15 colorectal surgeries (median 14 years, range 9-25). Four patients had five small bowel adenocarcinomas (SBC; median 18 years, range 11-33). Two CRC and two SBC were detected during surveillance within 6-11 months and 9-16 months, respectively, of last consecutive endoscopy. No patient undergoing surveillance died of a GI malignancy. Familial clustering of GI cancer was observed.
  
  
  CONCLUSIONS
  The prevalence and penetrance of GI neoplasia in children with BMMRD is high, with rapid development of carcinoma. Colorectal and small bowel surveillance should commence at ages 3-5 and 8 years, respectively.
authors.affiliation: Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Melyssa
authors.initials: M
authors.lastname: Aronson
authors.affiliation: Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.affiliation: Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Zane
authors.initials: Z
authors.lastname: Cohen
authors.affiliation: Pediatric Gastro-Enterology Unit, Dana Dwek Children's Hospital, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel.
authors.forename: Shlomi
authors.initials: S
authors.lastname: Cohen
authors.affiliation: Department of Pediatric Hemato-Oncology, Dana Dwek Children's Hospital, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel.
authors.forename: Rina
authors.initials: R
authors.lastname: Dvir
authors.affiliation: Department of Pediatric Hemato-Oncology, Dana Dwek Children's Hospital, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Elhasid
authors.affiliation: The Genetics Institute, Rambam Health Care Campus, Haifa, Israel, and Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Hagit N
authors.initials: HN
authors.lastname: Baris
authors.affiliation: Department of Gastroenterology and Liver Disease, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel.
authors.forename: Revital
authors.initials: R
authors.lastname: Kariv
authors.affiliation: Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Harriet
authors.initials: H
authors.lastname: Druker
authors.affiliation: Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Helen
authors.initials: H
authors.lastname: Chan
authors.affiliation: Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Ling
authors.affiliation: St Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Kortan
authors.affiliation: Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Spring
authors.initials: S
authors.lastname: Holter
authors.affiliation: Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Kara
authors.initials: K
authors.lastname: Semotiuk
authors.affiliation: Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Malkin
authors.affiliation: Saint George Hospital University Medical Center, Beirut, Lebanon.
authors.forename: Roula
authors.initials: R
authors.lastname: Farah
authors.affiliation: Lebanese American University Medical Centre, Beirut, Lebanon.
authors.forename: Alain
authors.initials: A
authors.lastname: Sayad
authors.affiliation: Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Brandie
authors.initials: B
authors.lastname: Heald
authors.affiliation: Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Kalady
authors.affiliation: IWK Health Centre, Halifax, Nova Scotia, Canada.
authors.forename: Lynette S
authors.initials: LS
authors.lastname: Penney
authors.affiliation: IWK Health Centre, Halifax, Nova Scotia, Canada.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Rideout
authors.affiliation: IWK Health Centre, Halifax, Nova Scotia, Canada.
authors.forename: Mohsin
authors.initials: M
authors.lastname: Rashid
authors.affiliation: Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Hasadsri
authors.affiliation: Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Pavel
authors.initials: P
authors.lastname: Pichurin
authors.affiliation: Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Riegert-Johnson
authors.affiliation: Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Brittany
authors.initials: B
authors.lastname: Campbell
authors.affiliation: Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Doua
authors.initials: D
authors.lastname: Bakry
authors.affiliation: Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan.
authors.forename: Hala
authors.initials: H
authors.lastname: Al-Rimawi
authors.affiliation: Department of Pediatric Hematology/Oncology and Stem Cell Transplant, King Fahad Specialist Hospital, Dammam, Saudi Arabia.
authors.forename: Qasim Kholaif
authors.initials: QK
authors.lastname: Alharbi
authors.affiliation: King Fahad Medical City, Riyadh, Saudi Arabia.
authors.forename: Musa
authors.initials: M
authors.lastname: Alharbi
authors.affiliation: Children Cancer Hospital, Karachi, Pakistan.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Shamvil
authors.affiliation: Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Uri
authors.initials: U
authors.lastname: Tabori
authors.affiliation: Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.|Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Carol
authors.initials: C
authors.lastname: Durno
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics / Q000601:surgery*; D000236:Adenoma / Q000209:etiology / Q000235:genetics / Q000601:surgery*; D000251:Adenosine Triphosphatases / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000483:Alleles; D001932:Brain Neoplasms / Q000150:complications / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D002648:Child; D002675:Child, Preschool; D015179:Colorectal Neoplasms / Q000150:complications / Q000209:etiology / Q000235:genetics / Q000503:physiopathology / Q000601:surgery*; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D005910:Glioma / Q000209:etiology; D006801:Humans; D007414:Intestinal Neoplasms / Q000209:etiology / Q000235:genetics / Q000601:surgery; D007421:Intestine, Small / Q000601:surgery*; D007680:Kidney Neoplasms / Q000209:etiology; D007938:Leukemia / Q000209:etiology; D008223:Lymphoma / Q000209:etiology; D008297:Male; D008545:Melanoma / Q000209:etiology; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D009386:Neoplastic Syndromes, Hereditary / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D011446:Prospective Studies; D012189:Retrospective Studies; D009396:Wilms Tumor / Q000209:etiology; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D045643:DNA Repair Enzymes