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

2018 ◽  
Vol 56 (2) ◽  
pp. 53-62 ◽  
Author(s):  
Manon Suerink ◽  
Tim Ripperger ◽  
Ludwine Messiaen ◽  
Fred H Menko ◽  
Franck Bourdeaut ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Mismatch Repair ◽  
Neurofibromatosis Type 1 ◽  
Healthy Child ◽  
Neurofibromatosis Type ◽  
Mismatch Repair Deficiency ◽  
Repair Deficiency ◽  
Legius Syndrome ◽  
Constitutional Mismatch Repair Deficiency

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.

Paediatric systemic lupus erythematosus as a manifestation of constitutional mismatch repair deficiency

2019 ◽  
Vol 57 (7) ◽  
pp. 505-508 ◽  
Author(s):  
Helen Toledano ◽  
Naama Orenstein ◽  
Efrat Sofrin ◽  
Noa Ruhrman-Shahar ◽  
Gil Amarilyo ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Mismatch Repair ◽  
Lupus Erythematosus ◽  
Neurofibromatosis Type ◽  
Diagnostic Feature ◽  
Mismatch Repair Deficiency ◽  
Systemic Lupus ◽  
Repair Deficiency ◽  
Biallelic Mutations ◽  
Constitutional Mismatch Repair Deficiency

Biallelic mutations in any of the four mismatch repair genes MSH2, MSH6, MLH1 and PMS2 result in one of the most aggressive childhood cancer predisposition syndromes, termed constitutional mismatch repair deficiency (CMMRD) syndrome. In addition to a very high tumour risk, the CMMRD phenotype is often characterised by the presence of signs reminiscent of neurofibromatosis type 1. Although paediatric systemic lupus erythematosus (pSLE) has been reported so far in three patients with CMMRD, it has not been considered a diagnostic feature of the syndrome. We report here two additional female patients with pSLE and CMMRD due to biallelic pathogenic variants in MSH6. Hence, there are a total of five out of approximately 200 (2.5%) currently reported patients with CMMRD that also have pSLE, suggesting pSLE should raise the suspicion of a diagnosis of CMMRD, especially if supported by additional indicative features

scholarly journals Glioblastoma and Colorectal Adenocarcinoma in an Adolescent Girl with Constitutional Mismatch Repair Deficiency syndrome mimicking Neurofibromatosis Type-I

2020 ◽  
pp. 34-38
Author(s):  
Firdevs AYDIN ◽  
Derya ALTAY ◽  
Orhan GÖRÜKMEZ ◽  
Aslıhan Hafo KİRAZ ◽  
Filiz KARAMAN ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Neurofibromatosis Type ◽  
Index Patient ◽  
Deficiency Syndrome ◽  
Type I ◽  
Neurofibromatosis Type I ◽  
Colonic Adenocarcinoma ◽  
Mismatch Repair Deficiency ◽  
Repair Deficiency ◽  
Constitutional Mismatch Repair Deficiency

Children with constitutional mismatch repair deficiency syndrome (CMMRDS) are prone to different types of cancers. A 16-year-old girl who was misdiagnosed with neurofibromatosis Type-I (NF-I) for 1 years had experienced glioblastoma and colonic adenocarcinoma. After operation, chemotherapy and radiotherapy were started for adenocarcinoma. Genetic analysis from the patient, effected brother, and mother showed heterozygote (c.479 + 36A> G) mutation in the intron 4 region of NF-1 gene. Initially, it was thought that this genetic variant was causative. Furthermore, next generation sequencing showed that the index patient and his brother have homozygote (c.1444 C>T) mutations in the MSH6 gene which are associated with CMMRDS both died because of colonic adenocarcinoma, and T cell non-Hodgkin lymphoma, respectively. Patients with CMMRDS may resemble NF-I. The physicians must not be confused with the previous diagnosis. Increased awareness of CMMRDS, and prompt evaluation for an underlying genetic background is advised if there are unexpected cancer in patients with NF-I.

Constitutional mismatch repair deficiency in a healthy child: On the spot diagnosis?

2017 ◽  
Vol 93 (1) ◽  
pp. 134-137 ◽  
Author(s):  
M. Suerink ◽  
T.P. Potjer ◽  
A.B. Versluijs ◽  
S.W. ten Broeke ◽  
C.M. Tops ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Healthy Child ◽  
Mismatch Repair Deficiency ◽  
Repair Deficiency ◽  
Constitutional Mismatch Repair Deficiency

Functional Repair Assay for the Diagnosis of Constitutional Mismatch Repair Deficiency From Non-Neoplastic Tissue

2019 ◽  
Vol 37 (6) ◽  
pp. 461-470 ◽  
Author(s):  
Andrew Y. Shuen ◽  
Stella Lanni ◽  
Gagan B. Panigrahi ◽  
Melissa Edwards ◽  
Lisa Yu ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Cell Lines ◽  
Neurofibromatosis Type ◽  
Lymphoblastoid Cell Lines ◽  
Mismatch Repair Deficiency ◽  
Cancer Syndrome ◽  
Li Fraumeni Syndrome ◽  
Repair Deficiency

Purpose Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD. Patients and Methods In vitro MMR activity was quantified using a 3′-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus–transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome. Results All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days. Conclusion On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.

scholarly journals RARE-55. CHALLENGES AND SPECIFIC STRATEGIES FOR CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY SYNDROME IN LOW RESOURCE SETTINGS. ON BEHALF OF THE INTERNATIONAL RRD CONSORTIUM IN LOW RESOURCE SETTINGS PANEL

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii454-iii454
Author(s):  
Rejin Kebudi ◽  
Nisreen Amayiri N ◽  
Malak Abedalthagafi ◽  
Asim Noor Rana ◽  
Slman Kirmani ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Malignant Gliomas ◽  
Mismatch Repair Deficiency ◽  
Term Survival ◽  
Low Resource Settings ◽  
Low Resource ◽  
Repair Deficiency ◽  
Constitutional Mismatch Repair Deficiency

Abstract Germline biallelic mutations in one of the mismatch repair genes (MSH2/MSH6/MLH1/PMS2 results in constitutional mismatch repair deficiency (CMMRD), a condition associated with multiple tumors arising from multiple organs during childhood, and these individuals rarely reach adulthood. The paucity of information with respect to these conditions leads to mismanagement and may be a factor in the high mortality of patients with CMMRD. Two international consortia, the European CARE4CMMRD, and the international replication repair deficiency (RRD) consortium, are addressing the many challenges associated with this condition. To address specific issues surrounding the management of CMMRD in low and middle income countries (LMIC), a multidisciplinary taskforce of 11 specialists from nine countries was formed. Preliminary conclusions are: 1) Immunohistochemistry for CMMRD should be considered for all patients with suggestive clinical features. In countries where CMMRD is common, malignant gliomas, colon cancers and T cell lymphomas should be stained routinely as the prevalence of CMMRD in these tumors can exceed 40%. 2) Temozolomide should not be used in the management of malignant glioma. By contrast, preclinical studies have suggested increased sensitivity to nitrosoureas. For the management of CMMRD related lymphoma and leukemia, mercaptopurines should not be avoided or discontinued as a part of the standard of care before more data are collected. 3) Management with checkpoint inhibitors should be limited to centers with intensive care units and expertise in complex supportive care to manage side effects of immune therapy. 4) Surveillance protocols have demonstrated long term survival benefits and should be implemented in LMIC.

scholarly journals The Challenge of Diagnosing Constitutional Mismatch Repair Deficiency Syndrome in Brain Malignancies from Young Individuals

2021 ◽  
Vol 22 (9) ◽  
pp. 4629
Author(s):  
Cristina Carrato ◽  
Carolina Sanz ◽  
Ana María Muñoz-Mármol ◽  
Ignacio Blanco ◽  
Marta Pineda ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Mismatch Repair ◽  
Rare Event ◽  
Deficiency Syndrome ◽  
Mismatch Repair Deficiency ◽  
Malignant Brain Tumors ◽  
Repair Deficiency ◽  
Clinical Awareness ◽  
High Degree ◽  
Constitutional Mismatch Repair Deficiency

Biallelic germline mismatch repair (MMR) gene (MLH1, MSH2, MSH6, and PMS2) mutations are an extremely rare event that causes constitutional mismatch repair deficiency (CMMRD) syndrome. CMMRD is underdiagnosed and often debuts with pediatric malignant brain tumors. A high degree of clinical awareness of the CMMRD phenotype is needed to identify new cases. Immunohistochemical (IHC) assessment of MMR protein expression and analysis of microsatellite instability (MSI) are the first tools with which to initiate the study of this syndrome in solid malignancies. MMR IHC shows a hallmark pattern with absence of staining in both neoplastic and non-neoplastic cells for the biallelic mutated gene. However, MSI often fails in brain malignancies. The aim of this report is to draw attention to the peculiar IHC profile that characterizes CMMRD syndrome and to review the difficulties in reaching an accurate diagnosis by describing the case of two siblings with biallelic MSH6 germline mutations and brain tumors. Given the difficulties involved in early diagnosis of CMMRD we propose the use of the IHC of MMR proteins in all malignant brain tumors diagnosed in individuals younger than 25 years-old to facilitate the diagnosis of CMMRD and to select those neoplasms that will benefit from immunotherapy treatment.

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