Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testing a child without malignancy

Abstract

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.

Mutational spectrum by phenotype: panel‐based NGS testing of patients with clinical suspicion of RASopathy and children with multiple café‐au‐lait macules

“…Our results support previous recommendations for testing children with multiple CALMs (with or without other symptoms) in a stepwise manner. 9,30,47 In cases with CALMs and pediatric cancers or familial history of cancer, the genetic testing recommendations include the analysis of cancer predisposition genes. 48 In these situations, the use of a panel such as the I2HCP could be convenient due to the possibility to analyze all recommended genes at once.…”

“…[6][7][8] However, multiple CALMs could also be indicative of other monogenic diseases, such as some RASopathies or other syndromes like PTEN hamartoma tumor or Cowden syndrome, Carney Syndrome or constitutive mismatch repair deficiency (CMMRD). 4, 5,9,10 The RASopathies constitute a clinically defined group of genetic conditions caused by germline mutations in genes that encode for components of the RAS/mitogen-activated protein kinase (MAPK) pathway. In addition to NF1, RASopathies include: Noonan syndrome (NS), NS with multiple lentigines (NSML), Costello syndrome (CS), Legius syndrome (LS), cardio-facio-cutaneous (CFC) syndrome and capillary malformationarteriovenous malformation (CM-AVM).…”

“…RASopathy genes, and finally, after a careful evaluation and following Suerink et al's recommendations, 9 other genes related with a multiple CALM-phenotype. 4,9…”

A sensitive and scalable microsatellite instability assay to diagnose constitutional mismatch repair deficiency by sequencing of peripheral blood leukocytes

“…Furthermore, and in contrast to assays of MMR function of patient cell extracts (Bodo et al, ; Shuen et al, ), our MSI assay could be used for high‐throughput screening of large patient cohorts or retrospective analysis of archived samples. The “missing” CMMRD cases may be identified by screening unselected pediatric cancer patients (Gröbner et al, ), and children suspected of NF1 or Legius syndrome who lack the causative NF1 or SPRED1 variants (Suerink et al, ). The assay also offers a means to investigate Lynch syndrome where CMMRD is a plausible explanation for an exceptional phenotype, given that it can distinguish between patients with mono‐ versus biallelic MMR variants.…”

“…However, the phenotypic spectrum is broad and it is likely that the clinical manifestation of CMMRD is not fully characterized (Durno et al, ). Furthermore, the phenotypic overlap with NF1 and Legius syndrome has led to the acknowledgment of CMMRD as a legitimate, but presumably rare, differential diagnosis in children without malignancy who are suspected of these syndromes but lack the causative NF1 or SPRED1 variants (Suerink et al, ). Family history can also be misleading as pathogenic variants in PMS2 , the gene implicated in more than 50% of CMMRD cases (Wimmer et al, ), have a much lower penetrance than other MMR variants in Lynch syndrome (Møller et al, ; Ten Broeke et al, ).…”