RT Journal Article
SR Electronic
T1 Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testing a child without malignancy
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 53
OP 62
DO 10.1136/jmedgenet-2018-105664
VO 56
IS 2
A1 Suerink, Manon
A1 Ripperger, Tim
A1 Messiaen, Ludwine
A1 Menko, Fred H
A1 Bourdeaut, Franck
A1 Colas, Chrystelle
A1 Jongmans, Marjolijn
A1 Goldberg, Yael
A1 Nielsen, Maartje
A1 Muleris, Martine
A1 van Kouwen, Mariëtte
A1 Slavc, Irene
A1 Kratz, Christian
A1 Vasen, Hans F
A1 Brugiѐres, Laurence
A1 Legius, Eric
A1 Wimmer, Katharina
YR 2019
UL http://jmg.bmj.com/content/56/2/53.abstract
AB 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.