Hematological malignancies in constitutional mismatch repair deficiency syndrome
Yu. A. Tikhonova,
V. V. Klyukhin,
D. A. Evstratov,
M. A. Klimentova,
L. A. Yasko,
N. V. Myakova,
M. A. Kurnikova https://doi.org/10.35754/0234-5730-2026-71-2-238-250
Abstract
Introduction. Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare childhood cancer predisposition syndrome.
Aim: to present a unique clinical case of a patient with relapsed T-lymphoblastic lymphoma who was diagnosed with a rare hereditary cancer predisposition syndrome (constitutional mismatch repair deficiency syndrome).
Main findings. The cause of CMMRD is considered to be the presence of biallelic germline homo- or compound-heterozygous variants in one of the four MMR genes ( MLH1, MSH2, MSH6 or PMS2 ); inactivation of these genes leads to an increased mutational burden and, consequently, to malignant transformation of cells. Loss of MMR system function underlies the development of a broad spectrum of malignancies in children and adolescents, with the first neoplasm often presenting as a hematological malignancy. The long-term prognosis for patients with CMMRD remains extremely poor due to the high risk of developing metachronous malignancies of other localizations, which necessitates systematic surveillance of this patient group.
About the Authors
Yu. A. Tikhonova
Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of Russian Federation
Russian Federation
Russian Federation
Yuliana A. Tikhonova, Resident Physician
117997, Moscow
V. V. Klyukhin
Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of Russian Federation
Russian Federation
Russian Federation
Vladislav V. Klyukhin, Hematologist, Consultative Department
117997, Moscow
D. A. Evstratov
Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of Russian Federation
Russian Federation
Russian Federation
Dmitrii A. Evstratov, Cand. Sci. (Med.), Pediatric Oncologist, Department of Oncohematology
117997, Moscow
M. A. Klimentova
Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of Russian Federation
Russian Federation
Russian Federation
Maria A. Klimentova, Hematologist, Department of Hematopoietic Stem Cell Transplantation No. 1
117997, Moscow
L. A. Yasko
Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of Russian Federation
Russian Federation
Russian Federation
Ludmila A. Yasko, Cand. Sci. (Biol.), Senior Researcher, Laboratories of Molecular Oncology and Molecular Biology
117997, Moscow
N. V. Myakova
Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of Russian Federation
Russian Federation
Russian Federation
Natalia V. Myakova, Dr. Sci. (Med.), Professor, Deputy Chief Physician for Medical Affairs
117997, Moscow
M. A. Kurnikova
Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of Russian Federation
Russian Federation
Russian Federation
Maria A. Kurnikova, Cand. Sci. (Med.), Medical Geneticist, Senior Researcher, Laboratory of Molecular Biology
117997, Moscow
References
1. Liu D., Keijzers G., Rasmussen L.J. DNA mismatch repair and its many roles in eukaryotic cells. Mutat Res Rev Mutat Res. 2017;773:174–87. DOI: 10.1016/j.mrrev.2017.07.001.
2. Dominguez-Valentin M., Sampson J.R., Seppala T.T., et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med. 2020;22(1):15–25. DOI: 10.1038/s41436-019-0596-9.
3. Wimmer K., Kratz C.P., Vasen H.F., et al. Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium ‘care for CMMRD’ (C4CMMRD). J Med Genet. 2014;51(6):355–65. DOI: 10.1136/jmedgenet-2014-102284.
4. Wimmer K., Kratz C.P. Constitutional mismatch repair-deficiency syndrome. Haematologica. 2010;95(5):699–701. DOI: 10.3324/haematol.2009.021626.
5. Ercan A.B., Aronson M., Fernandez N.R., et al. Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study. Lancet Oncol. 2024;25(5):668–82. DOI: 10.1016/S1470-2045(24)00026-3.
6. Colas C., Guerrini-Rousseau L., Suerink M., et al. ERN GENTURIS guidelines on constitutional mismatch repair deficiency diagnosis, genetic counselling, surveillance, quality of life, and clinical management. Eur J Human Genet. 2024;32(12):1526–41. DOI: 10.1038/s41431-024-01708-6.
7. Suerink M., Ripperger T., Messiaen L., et al. Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testing a child without malignancy. J Med Genet. 2019;56(2):53–62. DOI: 10.1136/jmedgenet-2018-105664.
8. Amayiri N., Tabori U., Campbell B., et al. High frequency of mismatch repair deficiency among pediatric high grade gliomas in Jordan. Int J Cancer. 2016;138(2):380–5. DOI: 10.1002/ijc.29724.
9. Baris H.N., Barnes-Kedar I., Toledano H., et al. Constitutional Mismatch Repair Deficiency in Israel: High Proportion of Founder Mutations in MMR Genes and Consanguinity. Pediatr Blood Cancer. 2016;63(3):418–27. DOI: 10.1002/pbc.25818.
10. Ponti G., Castellsague E., Ruini C., et al. Mismatch repair genes founder mutations and cancer susceptibility in Lynch syndrome. Clin Genet. 2015;87(6):507–16.
11. Martin-Giacalone B.A., Weinstein P.A., Plon S.E., Lupo P.J. Pediatric Rhabdomyosarcoma: Epidemiology and Genetic Susceptibility. J Clin Med. 2021;10(9):2028. DOI: 10.3390/jcm10092028.
12. Perez-Valencia J.A., Gallon R., Chen Y., et al. Constitutional mismatch repair deficiency is the diagnosis in 0.41 % of pathogenic NF1/SPRED1 variant negative children suspected of sporadic neurofibromatosis type 1. Genet Med. 2020;22(12):2081–8. DOI: 10.1038/s41436-020-0925-z.
13. Bodo S., Colas C., Buhard O., et al. Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents. Gastroenterology. 2015;149(4):1017–29.e3. DOI: 10.1053/j.gastro.2015.06.013.
14. Blount J., Prakash A. The changing landscape of Lynch syndrome due to PMS2 mutations. Clin Genet. 2018;94(1):61–9. DOI: 10.1111/cge.13205.
15. Durno C., Ercan A.B., Bianchi V., et al. Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance. J Clin Oncol. 2021;39(25):2779–90. DOI: 10.1200/JCO.20.02636.
16. Li C.Y., Liu A.P., Mo S., et al. Germline mismatch repair gene mutations in children with tumors: a case series from two centers. Translat Pediatr. 2024 Oct 1;13(10):1810–9. DOI: 10.21037/tp-24-343.
17. Hizuka K., Hagiwara S.I., Maeyama T., et al. Constitutional mismatch repair deficiency in childhood colorectal cancer harboring a de novo variant in the MSH6 gene: a case report. BMC Gastroenterol. 2021;21(1):60. DOI: 10.1186/s12876-021-01646-3.
18. Wimmer K., Rosenbaum T., Messiaen L. Connections between constitutional mismatch repair deficiency syndrome and neurofibromatosis type 1. Clin Genet. 2017;91(4):507–19. DOI: 10.1111/cge.12904.
19. Ripperger T., Schlegelberger B. Acute lymphoblastic leukemia and lymphoma in the context of constitutional mismatch repair deficiency syndrome. Eur J Med Genet. 2016;59(3):133–42. DOI: 10.1016/j.ejmg.2015.12.014.
20. Rigaud C., Forster V.J., Al-Tarrah H., et al. Comprehensive analysis of constitutional mismatch repair deficiency-associated non-Hodgkin lymphomas in a global cohort. Pediatr Blood Cancer. 2024;71(12):e31302. DOI: 10.1002/pbc.31302.
21. Lavoine N., Colas C., Muleris M., et al. Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort. J Med Genet. 2015;52(11):770–8. DOI: 10.1136/jmedgenet-2015-103299.
22. Sainulabdin G., Kanvinde P., Khurana R., et al. Biallelic Mismatch Repair Deficiency in Children and Adolescents: A Review of Published and Unpublished Data from India — Need for an Indian Consortium. Indian J Med Paediatr Oncol. 2025;46:288–96. DOI: 10.1055/s-0044-1790202.
23. Bakry D., Aronson M., Durno C., et al. Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: report from the constitutional mismatch repair deficiency consortium. Eur J Cancer. 2014;50(5):987–96. DOI: 10.1016/j.ejca.2013.12.005.
24. Mar K., Ameri K., Lam J.M. Constitutional Mismatch Repair Deficiency: Scoping Review of a Cancer-Predisposition Syndrome With Distinctive Cutaneous Findings. Pediatr Dermatol. 2025;42(3):437–46. DOI: 10.1111/pde.15878.
25. Alexander T.B., McGee R.B., Kaye E.C., et al. Metachronous T-Lymphoblastic Lymphoma and Burkitt Lymphoma in a Child With Constitutional Mismatch Repair Deficiency Syndrome. Pediatr Blood Cancer. 2016;63(8):1454–6. DOI: 10.1002/pbc.25989.
26. Bulsa J., Pastorczak A.K., Taha J., et al. Synchronous childhood T-lymphoblastic lymphoma and B-cell precursor acute lymphoblastic leukemia associated with constitutional MMR deficiency syndrome -a case report. Front Oncol. 2025;15:1580494. DOI: 10.3389/fonc.2025.1580494.
27. Campbell B.B., Light N., Fabrizio D., et al. Comprehensive Analysis of Hypermutation in Human Cancer. Cell. 2017;171(5):1042–56.e10. DOI: 10.1016/j.cell.2017.09.048.
28. Kroeze E., Weijers D.D., Kleisman M.M., et al. T-cell lymphoblastic lymphoma in constitutional mismatch repair deficiency (CMMRD): Exploring treatment opportunities. Hemasphere. 2024;8(5):e73. DOI: 10.1002/hem3.73.
29. Oshrine B., Grana N., Moore C., et al. B-cell acute lymphoblastic leukemia with high mutation burden presenting in a child with constitutional mismatch repair deficiency. Blood advances. 2019;3(12):1795–8. DOI: 10.1182/bloodadvances.2019000358.
30. Palova H., Das A., Pokorna P., et al. Precision immuno-oncology approach for four malignant tumors in siblings with constitutional mismatch repair deficiency syndrome. NP J Precis Oncol. 2024;8(1):110. DOI: 10.1038/s41698-024-00597-8.
31. Evensen N.A., Madhusoodhan P.P., Meyer J., et al. MSH6 haploinsufficiency at relapse contributes to the development of thiopurine resistance in pediatric Blymphoblastic leukemia. Haematologica. 2018;103(5):830–9. DOI: 10.3324/haematol.2017.176362.
32. Diouf B., Cheng Q., Krynetskaia N.F., et al. Somatic deletions of genes regulating MSH2 protein stability cause DNA mismatch repair deficiency and drug resistance in human leukemia cells. Nat Med. 2011;17(10):1298–303. DOI: 10.1038/nm.2430.
33. Das A., Sudhaman S., Morgenstern D., et al. Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency. Nat Med. 2022;28(1):125–35. DOI: 10.1038/s41591-021-01581-6.
34. Galati M.A., Hodel K.P., Gams M.S., et al. Cancers from Novel Pole-Mutant Mouse Models Provide Insights into Polymerase-Mediated Hypermutagenesis and Immune Checkpoint Blockade. Cancer Res. 2020;80(24):5606–18. DOI: 10.1158/0008-5472.CAN-20-0624.
35. Mandryk M., Owoc-Lempach J., Cecot J., et al. Clinical Insights and Potential Benefits of Stem Cell Transplantation for Constitutional Mismatch Repair Deficiency: A Case Report of Two Siblings. Cureus. 2024;16(8):e66441. DOI: 10.7759/cureus.66441.
36. Heath J.A., Campbell M., Tiedemann K., et al. Successful matched sibling cord blood transplant for ALL in a child with constitutional mismatch repair deficiency syndrome. Bone marrow Transplant. 2016;51(6):848–9.
37. Elhasid R., Dvir R., Rosenfeld Keidar H., et al. Management of Acute Myeloblastic Leukemia in a Child With Biallelic Mismatch Repair Deficiency. J Pediatr Hematol Oncol. 2015;37(8):e490–3. DOI: 10.1097/MPH.0000000000000415.
38. Ripperger T., Beger C., Rahner N., et al. Constitutional mismatch repair deficiency and childhood leukemia/lymphoma--report on a novel biallelic MSH6 mutation. Haematologica. 2010;95(5):841–4. DOI: 10.3324/haematol.2009.015503.
39. Burkhardt B., Reiter A., Landmann E., et al. Poor outcome for children and adolescents with progressive disease or relapse of lymphoblastic lymphoma: A report from the Berlin-Frankfurt-Muenster group. J Clin Oncol. 2009;27(20):3363–9. DOI: 10.1200/JCO.2008.19.3367.
40. Kroeze E., Weijers D.D., Hagleitner M.M., et al. High Prevalence of Constitutional Mismatch Repair Deficiency in a Pediatric T-cell Lymphoblastic Lymphoma Cohort. Hemasphere. 2021;6(1):e668. DOI: 10.1097/HS9.0000000000000668.
Review
For citations:
Tikhonova Yu.A., Klyukhin V.V., Evstratov D.A., Klimentova M.A., Yasko L.A., Myakova N.V., Kurnikova M.A. Hematological malignancies in constitutional mismatch repair deficiency syndrome. Russian journal of hematology and transfusiology. 2026;71(2):238-250. (In Russ.) https://doi.org/10.35754/0234-5730-2026-71-2-238-250
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