Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Tesch, V.
Immunological aspects of Constitutional Mismatch Repair- Deficiency Syndrome (CMMRD) in Pediatric Hematology-Oncology
Humanmedizin; [ Diplomarbeit ] Graz Medical University; 2017. pp. 120
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Schwinger Wolfgang
- Seidel Markus
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- Abstract:
- Background: Biallelic mutations in Mismatch repair (MMR) genes result in a condition referred to as Constitutional Mismatch Repair- Deficiency Syndrome (CMMRD), a rare but devastating cancer predisposition syndrome with a high chance of developing childhood malignancies, reported in a total of only 198 patients to date. The MMR system is, apart from its main function of maintaining genomic stability, involved in Class switch recombination (CSR) and somatic hypermutation (SHM). Both processes are needed for B cell maturation and diversity of our immunoglobuline repertoire. It is therefore expected and has already been shown that CMMRD may lead to defective CSR and SHM, which in turn might result in clinically relevant immunodeficiencies. This project addressed both the in vivo cellular/ humoral and the to date unexplored clinical immunophenotype of CMMRD patients across Europe and the Middle East to increase our understanding of the role of MMR in immunoglobuline maturation. A thourough clinical description of patients suffering from this rare condition, was furthermore approached. Patients and Methods: A retrospective and descriptive evaluation of a patient series including 11 CMMRD patients from 8 different centers across Europe and the middle East was conducted. Participating centers provided us with filled out clinical questionnaires and laboratory parameters of the cellular and humoral immune system. Collected data were anonymized, analyzed and interpreted regarding immunodeficiency. The thourough descriptive analysis of clinical and immunological aspects was conducted using Microsoft Excel Version 2016 and Graph Pad Prism. Results & Conclusion: 20 malignancies were diagnosed in 10 out of 11 patients (90,91%), 7 hematological malignancies (35%), 6 malignant brain tumours (30%), 5 Lynch-syndrome associated malignancies (25%), 1 Wilms tumour (5%) and 1 malignant Phylloides tumour (5%). Most patients (n=6) included carried a biallelic PMS2 mutation (54,55%), three patients carried a bialleic MSH6 mutation (27,27%) and another two patients were found to carry a biallleic MSH2 mutation (18,18%). Family history concerning cancer was negative in nine patients and parental consanguinity was identified in seven patients. Nonmalignant features such as Café au lait maculae were exhibited by all patients. Clinical findings of this case series therefore strengthen previous descriptions of clinical presentation. Analysis of immunological aspects revealed no uniform cellular/humoral immunophenotype in this patient population. Partial in vivo CSR impairment is however implied by the results of our study including reduced circulating memory cells that have undergone class switch in 5 out of 10 patients (50%) and Immunoglobuline deficiencies in all but two patients (80%). The expected high levels of IgM were only detected in 2 patients (20%). Clinical correlates regarding immunodeficiencies, that were systematically analyzed in CMMRD patients for the first time in this study, were uniformly found not to be remarkable. Further prospective studies with larger patient numbers will be needed to add evidence to the knowledge, both clinical as well as immunological, of this rare syndrome, that is to date markedly based on observations.