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J Med Genet. 2014 Jun;51(6):355-65. doi: 10.1136/jmedgenet-2014-102284. Epub 2014 Apr 15.

Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD).

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Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
Department of Pediatric Hematology & Oncology, Hannover Medical School, Hannover, Germany.
Department of Gastroenterology & Hepatology, Leiden University Medical Centre, Leiden, The Netherlands.
Department of Medical Oncology, Gustave Roussy Cancer Institute, Villejuif, France.
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.
Pédiatrie Onco-Hématologie-Pédiatrie III-CHRU Hautepierre UdS-EA 3430, Strasbourg, France.
Department of Clinical Genetics, Copenhagen University Hospital Rigshospital, Copenhagen, Denmark.
Department of Oncology, Sharret Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
2nd Pediatric Department of Children University Hospital, Comenius University, Bratislava, Slovakia.
INSERM, UMR_S 938, CDR Saint-Antoine, Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, France.
Department of Children and Adolescents Oncology, Gustave Roussy Cancer Institute, Villejuif, France.
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.
Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
Department of Pediatric Hematology and Oncology, University Children's Hospital, Münster, Germany.


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.


CMMRD syndrome; biallelic mismatch repair gene mutations; cancer predisposition syndrome; childhood cancer; constitutional mismatch repair deficiency

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