title: Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD).
abstract: Constitutional mismatch repair deficiency (CMMRD) syndrome is a distinct childhood cancer predisposition syndrome that results from biallelic germline mutations in one of the four MMR genes, MLH1, MSH2, MSH6 or PMS2. The tumour spectrum is very broad, including mainly haematological, brain and intestinal tract tumours. Patients show a variety of non-malignant features that are indicative of CMMRD. However, currently no criteria that should entail diagnostic evaluation of CMMRD exist. We present a three-point scoring system for the suspected diagnosis CMMRD in a paediatric/young adult cancer patient. Tumours highly specific for CMMRD syndrome are assigned three points, malignancies overrepresented in CMMRD two points and all other malignancies one point. According to their specificity for CMMRD and their frequency in the general population, additional features are weighted with 1-2 points. They include multiple hyperpigmented and hypopigmented skin areas, brain malformations, pilomatricomas, a second childhood malignancy, a Lynch syndrome (LS)-associated tumour in a relative and parental consanguinity. According to the scoring system, CMMRD should be suspected in any cancer patient who reaches a minimum of three points by adding the points of the malignancy and the additional features. The diagnostic steps to confirm or refute the suspected diagnosis are outlined. We expect that application of the suggested strategy for CMMRD diagnosis will increase the number of patients being identified at the time when they develop their first tumour. This will allow adjustment of the treatment modalities, offering surveillance strategies for second malignancies and appropriate counselling of the entire family.
authors.affiliation: Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Katharina
authors.initials: K
authors.lastname: Wimmer
authors.affiliation: Department of Pediatric Hematology & Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Kratz
authors.affiliation: Department of Gastroenterology & Hepatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Hans F A
authors.initials: HF
authors.lastname: Vasen
authors.affiliation: Department of Medical Oncology, Gustave Roussy Cancer Institute, Villejuif, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Caron
authors.affiliation: Department of Genetics, Pitié Salpêtrière Hospital, AP-HP, 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.forename: Chrystelle
authors.initials: C
authors.lastname: Colas
authors.affiliation: Pédiatrie Onco-Hématologie-Pédiatrie III-CHRU Hautepierre UdS-EA 3430, Strasbourg, France.
authors.forename: Natacha
authors.initials: N
authors.lastname: Entz-Werle
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital Rigshospital, Copenhagen, Denmark.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Gerdes
authors.affiliation: Department of Oncology, Sharret Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Goldberg
authors.affiliation: 2nd Pediatric Department of Children University Hospital, Comenius University, Bratislava, Slovakia.
authors.forename: Denisa
authors.initials: D
authors.lastname: Ilencikova
authors.affiliation: INSERM, UMR_S 938, CDR Saint-Antoine, Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Muleris
authors.affiliation: INSERM, UMR_S 938, CDR Saint-Antoine, Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, France.
authors.forename: Alex
authors.initials: A
authors.lastname: Duval
authors.affiliation: Department of Children and Adolescents Oncology, Gustave Roussy Cancer Institute, Villejuif, France.
authors.forename: Noémie
authors.initials: N
authors.lastname: Lavoine
authors.affiliation: Fundación Pública Galega de Medicina Xenómica (FPGMX) SERGAS, Grupo de Medicina Xenómica, IDIS, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERer), Santiago de Compostela, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Ruiz-Ponte
authors.affiliation: Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: Irene
authors.initials: I
authors.lastname: Slavc
authors.affiliation: Department of Pediatric Hematology and Oncology, University Children's Hospital, Münster, Germany.
authors.forename: Brigit
authors.initials: B
authors.lastname: Burkhardt
authors.affiliation: Department of Children and Adolescents Oncology, Gustave Roussy Cancer Institute, Villejuif, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Brugieres
mesh_terms: D001932:Brain Neoplasms; D015179:Colorectal Neoplasms; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis; D005060:Europe; D006801:Humans; D009386:Neoplastic Syndromes, Hereditary / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D010859:Pigmentation Disorders
keywords: CMMRD syndrome; biallelic mismatch repair gene mutations; cancer predisposition syndrome; childhood cancer; constitutional mismatch repair deficiency