Demystifying the Mystery of Genes: A Case Report on Constitutional Mismatch Repair Deficiency

Abstract

Constitutional mismatch repair deficiency (CMMRD) is a rare childhood cancer predisposition syndrome that results from biallelic germline mutations in one of the four MMR genes, MLH1, MSH2, MSH6, or PMS2. This syndrome is characterized by a broad spectrum of early-onset malignancies, including hematologic malignancies, colorectal malignancies, brain tumors, and other malignancies. It is common to have more than one malignancy in an individual diagnosed with CMMRD. In addition to malignancies, primary immunodeficiency in the form of low or absent immunoglobulin levels can also be seen in CMMRD. Congenital abnormalities such as agenesis of the corpus callosum (ACC), cavernous hemangioma, and other non-neoplastic diseases can also be linked to it. In this case report, we discussed the case of a girl born out of consanguineous marriage initially identified as having T-cell acute lymphoblastic lymphoma and later found to have selective immunoglobulin A (IgA) deficiency. Her younger sibling with a pontine cavernous hemangioma was also diagnosed with lymphoma. The girl exhibited brain lesions on magnetic resonance imaging (MRI), which were initially diagnosed as posterior reversible encephalopathy syndrome (PRES) related changes; however, one of the lesions persisted and remained stable over a period of 2 years and more in favor of diffuse glioma. The younger sibling also showed a solitary lesion in the brain. Based on the clinical and radiological findings, a diagnosis of CMMRD was suspected. Next-generation sequence (NGS) analysis of her blood sample was done. The results showed a homozygous mutation in the MSH6 gene was diagnostic of CMMRD.

Keywords

CMMRD - IgA - MMR - MSH6

Publication History

Article published online:
21 April 2024

• References

• 1 Jiricny J. The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol 2006; 7 (05) 335-346
• 2 Péron S, Metin A, Gardès P. et al. Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination. J Exp Med 2008; 205 (11) 2465-2472
• 3 Martin A, Scharff MD. AID and mismatch repair in antibody diversification. Nat Rev Immunol 2002; 2 (08) 605-614
• 4 Wimmer K, Kratz CP, Vasen HF. et al; EU-Consortium Care for CMMRD (C4CMMRD). Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium “care for CMMRD” (C4CMMRD). J Med Genet 2014; 51 (06) 355-365
• 5 Scott RH, Mansour S, Pritchard-Jones K, Kumar D, MacSweeney F, Rahman N. Medulloblastoma, acute myelocytic leukemia and colonic carcinomas in a child with biallelic MSH6 mutations. Nat Clin Pract Oncol 2007; 4 (02) 130-134
• 6 Whiteside D, McLeod R, Graham G. et al. A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple café-au-lait spots. Cancer Res 2002; 62 (02) 359-362
• 7 Scott RH, Homfray T, Huxter NL. et al. Familial T-cell non-Hodgkin lymphoma caused by biallelic MSH2 mutations. J Med Genet 2007; 44 (07) e83
• 8 Gardès P, Forveille M, Alyanakian MA. et al. Human MSH6 deficiency is associated with impaired antibody maturation. J Immunol 2012; 188 (04) 2023-2029
• 9 Péron S, Metin A, Gardès P. et al. Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination. J Exp Med 2008; 205 (11) 2465-2472
• 10 Kerpel A, Yalon M, Soudack M. et al. Neuroimaging findings in children with constitutional mismatch repair deficiency syndrome. Am J Neuroradiol 2020; 41 (05) 904-910
• 11 Johannesma PC, van der Klift HM, van Grieken NC. et al. Childhood brain tumours due to germline bi-allelic mismatch repair gene mutations. Clin Genet 2011; 80 (03) 243-255
• 12 Shiran SI, Ben-Sira L, Elhasid R. et al. Multiple brain developmental venous anomalies as a marker for constitutional mismatch repair deficiency syndrome. Am J Neuroradiol 2018; 39 (10) 1943-1946
• 13 Jones BV, Linscott L, Koberlein G, Hummel TR, Leach JL. Increased prevalence of developmental venous anomalies in children with intracranial neoplasms. Am J Neuroradiol 2015; 36 (09) 1782-1785
• 14 Michaeli O, Tabori U. Pediatric high grade gliomas in the context of cancer predisposition syndromes. J Korean Neurosurg Soc 2018; 61 (03) 319-332
• 15 Hasan AMS, Hasan AK, Megally HI. et al. The combined role of MR spectroscopy and perfusion imaging in preoperative differentiation between high- and low-grade gliomas. Egypt J Radiol Nucl Med 2019; 50: 72
• 16 Vasen HF, Ghorbanoghli Z, Bourdeaut F. et al; EU-Consortium Care for CMMR-D (C4CMMR-D). Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium “Care for CMMR-D” (C4CMMR-D). J Med Genet 2014; 51 (05) 283-293