title: Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.
abstract: BACKGROUND
  Constitutional mismatch repair deficiency (CMMRD) syndrome is a childhood cancer predisposition syndrome involving biallelic germline mutations of MMR genes, poorly recognised by clinicians so far.
  
  
  METHODS
  Retrospective review of all 31 patients with CMMRD diagnosed in French genetics laboratories in order to describe the characteristics, treatment and outcome of the malignancies and biological diagnostic data.
  
  
  RESULTS
  67 tumours were diagnosed in 31 patients, 25 (37%) Lynch syndrome-associated malignancies, 22 (33%) brain tumours, 17 (25%) haematological malignancies and 3 (5%) sarcomas. The median age of onset of the first tumour was 6.9 years (1.2-33.5). Overall, 22 patients died, 9 (41%) due to the primary tumour. Median survival after the diagnosis of the primary tumour was 27 months (0.26-213.2). Failure rate seemed to be higher than expected especially for T-cell non-Hodgkin's lymphoma (progression/relapse in 6/12 patients). A familial history of Lynch syndrome was identified in 6/23 families, and consanguinity in 9/23 families. PMS2 mutations (n=18) were more frequent than other mutations (MSH6 (n=6), MLH1 (n=4) and MSH2 (n=3)).
  
  
  CONCLUSIONS
  In conclusion, this unselected series of patients confirms the extreme severity of this syndrome with a high mortality rate mostly related to multiple childhood cancers, and highlights the need for its early detection in order to adapt treatment and surveillance.
authors: Department of Children and Adolescents Oncology, Gustave Roussy Cancer Campus, Villejuif, France.
authors: N
authors: N
authors: Lavoine
authors: Laboratory of Oncogenetics and Angiogenetics, Genetics Department, Pitié-Salpêtrière University Hospital, APHP, Paris, France INSERM, UMR_S 938, CDR Saint-Antoine, Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, France.
authors: C
authors: C
authors: Colas
authors: INSERM, UMR_S 938, CDR Saint-Antoine, Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, France.
authors: M
authors: M
authors: Muleris
authors: INSERM, UMR_S 938, CDR Saint-Antoine, Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, France.
authors: S
authors: S
authors: Bodo
authors: INSERM, UMR_S 938, CDR Saint-Antoine, Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, France.
authors: A
authors: A
authors: Duval
authors: Department of Pediatric Oncology, Strasbourg University Hospital, Strasbourg, France.
authors: N
authors: N
authors: Entz-Werle
authors: Laboratory of Oncogenetics and Angiogenetics, Genetics Department, Pitié-Salpêtrière University Hospital, APHP, Paris, France.
authors: F
authors: F
authors: Coulet
authors: Department of Biology and Medical Pathology, Unit of Genetics, Gustave Roussy Cancer Campus, Villejuif, France.
authors: O
authors: O
authors: Cabaret
authors: Department of Neuropathology, Sainte-Anne Hospital, APHP, Paris, France.
authors: F
authors: F
authors: Andreiuolo
authors: Department of Pathology, Gustave Roussy Cancer Institute, Villejuif, France.
authors: C
authors: C
authors: Charpy
authors: Department of Dermatology, Gustave Roussy Cancer Institute, Villejuif, France.
authors: G
authors: G
authors: Sebille
authors: Plateforme mixte de génétique constitutionnelle des cancers fréquents HCL-CLB, Centre Léon Bérard, Lyon, France.
authors: Q
authors: Q
authors: Wang
authors: Unit of Molecular Oncology and Genetics, Institute of Biochemistry and Molecular Biology, Lille University Hospital, Lille, France.
authors: S
authors: S
authors: Lejeune
authors: Unit of Molecular Oncology and Genetics, Institute of Biochemistry and Molecular Biology, Lille University Hospital, Lille, France Inserm UMR837, Lille, France North of France University, Lille, France.
authors: M P
authors: MP
authors: Buisine
authors: Department of Genetics, Grenoble University Hospital, Grenoble, France.
authors: D
authors: D
authors: Leroux
authors: Département of Pediatrics, Dijon University Hospital, Dijon, France.
authors: G
authors: G
authors: Couillault
authors: Paediatric Onco-Haematology Unit, APHP, Armand Trousseau Hospital, UPMC Univ Paris 06, France.
authors: G
authors: G
authors: Leverger
authors: Department of Oncogenetics, Centre Paul Strauss, Strasbourg, France.
authors: J P
authors: JP
authors: Fricker
authors: Department of Digestive Oncology, Claudius Régaud Institute and Toulouse University Hospital, Toulouse, France.
authors: R
authors: R
authors: Guimbaud
authors: Unit of Medical Genetics, Amiens University Hospital, Amiens, France.
authors: M
authors: M
authors: Mathieu-Dramard
authors: Unit of Medical Genetics, Amiens University Hospital, Amiens, France.
authors: G
authors: G
authors: Jedraszak
authors: Department of Oncogenetics, Saint-Louis University Hospital, APHP, Paris, France.
authors: O
authors: O
authors: Cohen-Hagenauer
authors: Department of Children and Adolescents Oncology, Gustave Roussy Cancer Campus, Villejuif, France.
authors: L
authors: L
authors: Guerrini-Rousseau
authors: Department of Pediatric Oncology, Curie Institute, Paris, France.
authors: F
authors: F
authors: Bourdeaut
authors: Department of Children and Adolescents Oncology, Gustave Roussy Cancer Campus, Villejuif, France CNRS UMR 8203 "Vectorology & Anticancer Treatments," Gustave Roussy & Paris-Sud University, Villejuif, France.
authors: J
authors: J
authors: Grill
authors: Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France.
authors: O
authors: O
authors: Caron
authors: Laboratory of Genetics, Rouen University Hospital, Rouen, France.
authors: S
authors: S
authors: Baert-Dusermont
authors: Laboratory of Genetics, Rouen University Hospital, Rouen, France.
authors: J
authors: J
authors: Tinat
authors: Laboratory of Genetics, Rouen University Hospital, Rouen, France.
authors: G
authors: G
authors: Bougeard
authors: Laboratory of Genetics, Rouen University Hospital, Rouen, France.
authors: T
authors: T
authors: Frébourg
authors: Department of Children and Adolescents Oncology, Gustave Roussy Cancer Campus, Villejuif, France.
authors: L
authors: L
authors: Brugières
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000235:genetics; D000293:Adolescent; D000328:Adult; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy; D002648:Child; D002675:Child, Preschool; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy; D009687:Nuclear Proteins / Q000235:genetics; D016896:Treatment Outcome; 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; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes
keywords: CMMRD; MMR; childhood cancer; genetic predisposition; multiple cancer