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Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium ‘Care for CMMRD’ (C4CMMRD)
  1. Katharina Wimmer1,
  2. Christian P Kratz2,
  3. Hans F A Vasen3,
  4. Olivier Caron4,
  5. Chrystelle Colas5,6,7,
  6. Natacha Entz-Werle8,
  7. Anne-Marie Gerdes9,
  8. Yael Goldberg10,
  9. Denisa Ilencikova11,
  10. Martine Muleris6,7,
  11. Alex Duval6,7,
  12. Noémie Lavoine12,
  13. Clara Ruiz-Ponte13,
  14. Irene Slavc14,
  15. Brigit Burkhardt15,
  16. Laurence Brugieres12,
  17. on behalf of the EU-Consortium Care for CMMRD (C4CMMRD)
  1. 1Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria
  2. 2Department of Pediatric Hematology & Oncology, Hannover Medical School, Hannover, Germany
  3. 3Department of Gastroenterology & Hepatology, Leiden University Medical Centre, Leiden, The Netherlands
  4. 4Department of Medical Oncology, Gustave Roussy Cancer Institute, Villejuif, France
  5. 5Department of Genetics, Pitié Salpêtrière Hospital, AP-HP, Paris, France
  6. 6INSERM, UMR_S 938, CDR Saint-Antoine, Paris, France
  7. 7Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, France
  8. 8Pédiatrie Onco-Hématologie—Pédiatrie III—CHRU Hautepierre UdS—EA 3430, Strasbourg, France
  9. 9Department of Clinical Genetics, Copenhagen University Hospital Rigshospital, Copenhagen, Denmark
  10. 10Department of Oncology, Sharret Institute, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
  11. 112nd Pediatric Department of Children University Hospital, Comenius University, Bratislava, Slovakia
  12. 12Department of Children and Adolescents Oncology, Gustave Roussy Cancer Institute, Villejuif, France
  13. 13Fundación 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
  14. 14Department of Pediatrics, Medical University of Vienna, Vienna, Austria
  15. 15Department of Pediatric Hematology and Oncology, University Children's Hospital, Münster, Germany
  1. Correspondence to Dr Katharina Wimmer, Medical University of Innsbruck, Division of Human Genetics, Peter-Mayr-Strasse 1, Innsbruck 6020, Austria; katharina.wimmer{at}


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.

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

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