title: Phenotypic and genotypic characterisation of biallelic mismatch repair deficiency (BMMR-D) syndrome.
abstract: Lynch syndrome, the most common inherited colorectal cancer syndrome in adults, is an autosomal dominant condition caused by heterozygous germ-line mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. Inheriting biallelic (homozygous) mutations in any of the MMR genes results in a different clinical syndrome termed biallelic mismatch repair deficiency (BMMR-D) that is characterised by gastrointestinal tumours, skin lesions, brain tumours and haematologic malignancies. This recently described and under-recognised syndrome can present with adenomatous polyps leading to early-onset small bowel and colorectal adenocarcinoma. An important clue in the family history that suggests underling BMMR-D is consanguinity. Interestingly, pedigrees of BMMR-D patients typically show a paucity of Lynch syndrome cancers and most parents are unaffected. Therefore, a family history of cancers is often non-contributory. Detection of BMMR-D can lead to more appropriate genetic counselling and the implementation of targeted surveillance protocols to achieve earlier tumour detection that will allow surgical resection. This review describes an approach for diagnosis and management of these patients and their families.
authors.affiliation: Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Disease, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada; Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. Electronic address: carol.durno@sickkids.ca.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Durno
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Sherman
authors.affiliation: Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Disease, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Melyssa
authors.initials: M
authors.lastname: Aronson
authors.affiliation: Division of Haematology/Oncology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Malkin
authors.affiliation: Division of Pathology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hawkins
authors.affiliation: Division of Haematology/Oncology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Doua
authors.initials: D
authors.lastname: Bakry
authors.affiliation: Division of Haematology/Oncology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Bouffet
authors.affiliation: Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Disease, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Aaron
authors.initials: A
authors.lastname: Pollett
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Brittany
authors.initials: B
authors.lastname: Campbell
authors.affiliation: Division of Haematology/Oncology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Uri
authors.initials: U
authors.lastname: Tabori
mesh_terms: D000328:Adult; D022981:Allelic Imbalance / Q000235:genetics; D001932:Brain Neoplasms / Q000145:classification / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D019080:Cafe-au-Lait Spots / Q000235:genetics / Q000473:pathology; D002648:Child; D015179:Colorectal Neoplasms / Q000145:classification / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D005192:Family Health; D005260:Female; D005838:Genotype; D019337:Hematologic Neoplasms / Q000235:genetics / Q000473:pathology; D006801:Humans; D007417:Intestinal Polyps / Q000235:genetics / Q000473:pathology; D008297:Male; D053842:Microsatellite Instability; D009386:Neoplastic Syndromes, Hereditary / Q000145:classification / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D010641:Phenotype
keywords: Café-au-lait macules; Colon cancer; Lynch syndrome; Polyposis; Surveillance; Turcot’s syndrome