Background. Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare childhood cancer predisposition syndrome resulting from biallelic germline mutations of mismatch repair (MMR) genes. CMMRD syndrome is characterised by early onset malignancies in children. Case. Here we present affected children of consanguinous parents diagnosed with CMMRD syndrome due to germline bi-allelic MSH 6 gene mutations with café au lait spots and multiple family cancers from Turkey and reported cases with CMMRD syndrome associated MSH 6 mutation in English literature. Hence, we reviewed English literature from 1990 to 2020 using Pub-Med database. Keywords used to search included constitutional mismatch repair deficiency syndrome, childhood cancer and MSH 6 gene mutation. Conclusions. We emphasize that the inclusion of CMMRD syndrome in the differential diagnosis of a patient who presents with cafe´ au lait spots and/or hypopigmented skin lesions and cancer especially when consanguinity and/or a history of cancer coexist in children.
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1. Lavoine N, Colas C, Muleris M, et al. Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort. J Med Genet 2015; 52: 770-778.
2. Wimmer K, Rosenbaum T, Messiaen L. Connections between constitutional mismatch repair deficiency syndrome and neurofibromatosis type 1. Clin Genet 2017; 91: 507-519.
3. Westdorp H, Kolders S, Hoogerbrugge N, de Vries IJM, Jongmans MCJ, Schreibelt G. Immunotherapy holds the key to cancer treatment and prevention in constitutional mismatch repair deficiency (CMMRD) syndrome. Cancer Lett 2017; 403: 159-164.
4. Wimmer K, Etzler J. Constitutional mismatch repairdeficiency syndrome: have we so far seen only the tip of an iceberg? Hum Genet 2008; 124: 105-122.
5. Alexander TB, McGee RB, Kaye EC, et al. Metachronous T-lymphoblastic lymphoma and Burkitt lymphoma in a child with constitutional mismatch repair deficiency syndrome. Pediatr Blood Cancer 2016; 63: 1454-1456
6. Bouffet E, Larouche V, Campbell BB, et al. Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J Clin Oncol 2016; 34: 2206-2211.
7. Ramchander NC, Ryan NA, Crosbie EJ, Evans DG. Homozygous germ-line mutation of the PMS2 mismatch repair gene: a unique case report of constitutional mismatch repair deficiency (CMMRD). BMC Med Genet 2017; 18: 40.
8. Ramachandra C, Challa VR, Shetty R. Constitutional mismatch repair deficiency syndrome: do we know it? Indian J Hum Genet 2014; 20: 192-194.
9. 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: 355-365.
10. Durno CA, Sherman PM, Aronson M, et al; International BMMRD Consortium. Phenotypic and genotypic characterisation of biallelic mismatch repair deficiency (BMMR-D) syndrome. Eur J Cancer 2015; 51: 977-983.
11. 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: 283-293.
12. 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: 987-996.
13. Kebudi R, Amayiri N, Abedalthagafi M, et al; International RRD Consortium on Low-Resource Settings Panel. Challenges and specific strategies for constitutional mismatch repair deficiency syndrome in low-resource settings. Pediatr Blood Cancer 2020; 67: e28309.
14. Menko FH, Kaspers GL, Meijer GA, Claes K, van Hagen JM, Gille JJ. A homozygous MSH6 mutation in a child with cafe-au-lait spots, oligodendroglioma and rectal cancer. Fam Cancer 2004; 3: 123-127.
15. Hegde MR, Chong B, Blazo ME, et al. A homozygous mutation in MSH6 causes Turcot syndrome. Clin Cancer Res 2005; 11: 4689-4693.
16. Østergaard JR, Sunde L, Okkels H. Neurofibromatosis von Recklinghausen type I phenotype and early onset of cancers in siblings compound heterozygous for mutations in MSH6. Am J Med Genet A 2005: 139A: 96-105.
17. 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: 130-134.
18. Poley JW, Wagner A, Hoogmans MM, et al; Rotterdam Initiative on Gastrointestinal Hereditary Tumors. Biallelic germline mutations of mismatchrepair genes: a possible cause for multiple pediatric malignancies. Cancer 2007; 109: 2349-2356.
19. Auclair J, Leroux D, Desseigne F, et al. Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation. Hum Mutat 2007; 28: 1084-1090.
20. Etzler J, Peyrl A, Zatkova A, et al. RNA-based mutation analysis identifies an unusual MSH6 splicing defect and circumvents PMS2 pseudogene interference. Hum Mutat 2008; 29: 299-305.
21. Rahner N, Höefler G, Högenauer C, et al. Compound heterozygosity for two MSH6 mutations in a patient with early onset colorectal cancer, vitiligo and systemic lupus erythematosus. Am J Med Genet A 2008; 146A: 1314-1319.
22. Peters A, Born H, Ettinger R, Levonian P, Jedele KB. Compound heterozygosity for MSH6 mutations in a pediatric lymphoma patient. J Pediatr Hematol Oncol 2009; 31: 113-115.
23. 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: 841-844.
24. Ilencikova D. Constitutional mismatch repairdeficiency syndrome (CMMR- D)- a case report of a family with biallelic MSH6 mutation. Klin Onkol 2012; 25(Suppl): S34-S38.
25. Hoell JI, Gombert M, Ginzel S, et al. Constitutional mismatch repair-deficiency and whole-exome sequencing as the means of the rapid detection of the causative MSH6 defect. Klin Padiatr 2014; 226: 357-361.
26. Bougeard G, Olivier-Faivre L, Baert-Desurmont S, et al. Diversity of the clinical presentation of the MMR gene biallelic mutations. Fam Cancer 2014; 13: 131- 135.
27. Elhasid, R, Dvir R, Keidar R, et al; BMMRD Consortium. Management of acute myeloblastic leukemia in a child with biallelic mismatch repair deficiency. J Pediatr Hematol Oncol 2015; 37: e490-e493.
28. AlHarbi M, Ali Mobark N, AlMubarak L, et al. Durable response to nivolumab in a pediatric patient with refractory glioblastoma and constitutional biallelic mismatch repair deficiency. Oncologist 2018; 23: 1401-1406.
29. Citak EC, Sagcan F, Gundugan BD, et al. Metachronous Wilms tumor, glioblastoma, and T-cell leukemia in an child with constitutional mismatch repair deficiency syndrome due to novel mutation in MSH6 (c.2590G>T). J Pediatr Hematol Oncol 2021; 43: e198-e202.
30. Athanasiadis DI, Athanasiadou KI, Voulgaridou A, et al. Coexistence of constitutional mismatch repair deficiency syndrome and Lynch syndrome in a family of seven: MSH6 mutation and childhood colorectal cancer – a case series. Acta Gastroenterol Belg 2020; 83: 479-481.
31. Guerrini-Rousseau L, Varlet P, Colas C, et al. Constitutional mismatch repair deficiencyassociated brain tumors: report from the European C4CMMRD consortium. Neurooncol Adv 2019; 1: vdz033.
32. Lenders EKSM, Westdrop H, Brüggeman RJ, et al. Cancer prevention by aspirin in children with Constitutional Mismatch Repair Deficiency (CMMRD). Eur J Hum Genet 2018; 26: 1417-1423.
33. Unal E, Ozyoruk D, Tacyildiz N, et al. ANTI-PD-1 treatment in a family with constitutional mismatch repair deficiency syndrome with multiple cancers from Turkey. Is cancer immunoprevention with checkpoint inhibitors HAS a role in Cases with homozygous mutationis? Blood 2019; 134(Suppl 1): 5632.