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Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testing a child without malignancy
  1. Manon Suerink1,
  2. Tim Ripperger2,
  3. Ludwine Messiaen3,
  4. Fred H Menko4,
  5. Franck Bourdeaut5,
  6. Chrystelle Colas6,7,
  7. Marjolijn Jongmans8,9,
  8. Yael Goldberg10,
  9. Maartje Nielsen1,
  10. Martine Muleris7,
  11. Mariëtte van Kouwen11,
  12. Irene Slavc12,
  13. Christian Kratz13,
  14. Hans F Vasen14,
  15. Laurence Brugiѐres15,
  16. Eric Legius16,
  17. Katharina Wimmer17
  1. 1 Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
  2. 2 Department of Human Genetics, Hannover Medical School, Hannover, Germany
  3. 3 Department of Genetics, University of Alabama, Birmingham, Alabama, USA
  4. 4 Family Cancer Clinic, Antoni van Leeuwenhoek Hospital and The Netherlands Cancer Institute, Amsterdam, The Netherlands
  5. 5 Département d’Oncologie Pédiatrique et d’Adolescents Jeunes Adultes, Institut Curie, Paris, France
  6. 6 Department of Genetics, Institut Curie, Paris Sciences Lettres Research University, Paris, France
  7. 7 Centre de Recherche Saint-Antoine, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Paris, France
  8. 8 Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
  9. 9 Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
  10. 10 Recanati Genetics Institute, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel
  11. 11 Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
  12. 12 Department of Pediatrics, Medical University Vienna, Vienna, Austria
  13. 13 Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
  14. 14 Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
  15. 15 Children and Adolescent Oncology Department, Gustave Roussy Cancer Institute, Villejuif, France
  16. 16 Department of Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium
  17. 17 Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria
  1. Correspondence to Dr Katharina Wimmer, Division of Human Genetics, Medical University Innsbruck, Innsbruck 6020, Austria; katharina.wimmer{at}


Constitutional mismatch repair deficiency (CMMRD) is a rare childhood cancer predisposition syndrome caused by biallelic germline mutations in one of four mismatch-repair genes. Besides very high tumour risks, CMMRD phenotypes are often characterised by the presence of signs reminiscent of neurofibromatosis type 1 (NF1). Because NF1 signs may be present prior to tumour onset, CMMRD is a legitimate differential diagnosis in an otherwise healthy child suspected to have NF1/Legius syndrome without a detectable underlying NF1/SPRED1 germline mutation. However, no guidelines indicate when to counsel and test for CMMRD in this setting. Assuming that CMMRD is rare in these patients and that expected benefits of identifying CMMRD prior to tumour onset should outweigh potential harms associated with CMMRD counselling and testing in this setting, we aimed at elaborating a strategy to preselect, among children suspected to have NF1/Legius syndrome without a causative NF1/SPRED1 mutation and no overt malignancy, those children who have a higher probability of having CMMRD. At an interdisciplinary workshop, we discussed estimations of the frequency of CMMRD as a differential diagnosis of NF1 and potential benefits and harms of CMMRD counselling and testing in a healthy child with no malignancy. Preselection criteria and strategies for counselling and testing were developed and reviewed in two rounds of critical revisions. Existing diagnostic CMMRD criteria were adapted to serve as a guideline as to when to consider CMMRD as differential diagnosis of NF1/Legius syndrome. In addition, counselling and testing strategies are suggested to minimise potential harms.

  • genetic screening/counselling
  • clinical genetics
  • paediatric oncology

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  • Contributors The question of when to counsel and test children without malignancy for CMMRD was addressed by four presentations (KW, MS, TR, LM) at a workshop of the C4CMMRD consortium in Brussels on 26 September 2017. Guidelines to answer this question were discussed during the workshop by MS, TR, LM, FHM, CC, MJ, YG, MN, MM, MvK, IS, CK, HFV, LB, EL and KW. Thereafter, MS and KW summarised the presentations and discussion points in a manuscript draft including unpublished data coming from the C4CMMRD patient database provided by LB and from the NF1 mutation database of the Medical Genomics Laboratory of the University of Alabama at Birmingham provided by LM. The manuscript was commented and discussed in two rounds of revisions by TR, LM, FHM, FB, CC, MJ, YG, MN, MM, MvK, IS, CK, HFV, LB and EL until consent on the guidelines and the manuscript was reached. Being a member of GENTURIS, EL represented in this process also the interests of this European Reference Network.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.