Hereditary syndromes in pediatric hematooncology

Hematooncological diseases head the list in the structure of malignant neoplasms of childhood. Somatic mutations in tumor clone cells have been well studied, included in modern classifications, and are used to stratify patients into prognostic risk groups and select a therapy program. At the same time, more than 50 hereditary syndromes associated with the development of hemoblastoses have been described. Some of them (Down’s syndrome, Klinefelter’s syndrome, microdeletion syndromes et al.) are caused by chromosomal pathology, while others describe alterations of one or more genes with different types of inheritance and age of manifestation of hematooncological diseases. Genes of predisposition to hematooncological diseases are involved in the processes of DNA repair, regulation of the cell cycle, immune response and bone marrow function. This article presents current data on genetic syndromes associated with the development of hemoblastosis with a description of their own clinical observations.

1. Rio-Machin A, Vulliamy T, Hug N, et al. The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants. Nat Commun. 2020;11(1):1044. doi: https://doi.org/10.1038/s41467-020-14829-5

2. Douglas SPM, Lahtinen AK, Koski JR, et al. Enrichment of cancer-predisposing germline variants in adult and pediatric patients with acute lymphoblastic leukemia. Sci Rep. 2022;12(1):10670. doi: https://doi.org/10.1038/s41598-022-14364-x

3. Kaseb H, Rayi A, Hozayen S. Chromosome Instability Syndromes. 2022 Sep 19. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023.

4. Valiev TT, Kovrigina AM, Kluchagina YuI, Senderovich AI. Cytogenetic Research Experience in Pediatric Non-Hodgkin’s Lymphomas. Onkopediatria. 2016;3(2):125–132. doi: https://doi.org/10.15690/onco.v3i2.1547]

5. Sahoo SS, Kozyra EJ, Wlodarski MW. Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes. Best Pract Res Clin Haematol. 2020;33(3):101197. doi: https://doi.org/10.1016/j.beha.2020.101197

6. Swaminathan M, Bannon SA, Routbort M, et al. Hematologic malignancies and Li-Fraumeni syndrome. Cold Spring Harb Mol Case Stud. 2019;5(1):a003210. doi: https://doi.org/10.1101/mcs.a003210

7. Duployez N, Goursaud L, Fenwarth L, et al. Familial myeloid malignancies with germline TET2 mutation. Leukemia. 2020;34(5):1450–1453. doi: https://doi.org/10.1038/s41375-019-0675-6

8. Churchman ML, Qian M, Te Kronnie G, et al. Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia. Cancer Cell. 2018;33(5):937–948.e8. doi: https://doi.org/10.1016/j.ccell.2018.03.021

9. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2022 update on diagnosis, therapy, and monitoring. Am J Hematol. 2022;97(9):1236–1256. doi: https://doi.org/10.1002/ajh.26642

10. Kantarjian HM, Hughes TP, Larson RA, et al. Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis. Leukemia. 2021;35(2):440–453. doi: https://doi.org/10.1038/s41375-020-01111-2

11. Ostrye mieloidnye leikozy: Clinical guidelines. 2020. 95 p. (In Russ).] Доступно по: https://oncology-association.ru/wp-content/uploads/2020/09/ostrye_mieloidnye_lejkozy.pdf. Ссылка активна на 08.12.2023.

12. McDonald-McGinn DM, Reilly A, Wallgren-Pettersson C, et al. Malignancy in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Am J Med Genet A. 2006;140(8):906–909. doi: https://doi.org/10.1002/ajmg.a.31199

13. Shestakova VV. Clinical case of biphenotypic acute leukaemia a child with Williams syndrome. Russian Journal of Pediatric Hematology and Oncology. 2015;2(2):89–92. (In Russ). doi: https://doi.org/10.17650/2311-1267-2015-2-2-89-92]

14. J rviaho T, Zachariadis V, Tesi B, et al. Microdeletion of 7p12.1p13, including IKZF1, causes intellectual impairment, overgrowth, and susceptibility to leukaemia. Br J Haematol. 2019;185(2):354–357. doi: https://doi.org/10.1111/bjh.15494

15. Vaisvilas M, Dirse V, Aleksiuniene B, et al. Acute Pre-B Lymphoblastic Leukemia and Congenital Anomalies in a Child with a de Novo 22q11.1q11.22 Duplication. Balkan J Med Genet. 2018;21(1):87–91. doi: https://doi.org/10.2478/bjmg-2018-0002

16. Kosmidou A, Tragiannidis A, Gavriilaki E. Myeloid Leukemia of Down Syndrome. Cancers (Basel). 2023;15(13):3265. doi: https://doi.org/10.3390/cancers15133265

17. Brown AL, de Smith AJ, Gant VU, et al. Inherited genetic susceptibility to acute lymphoblastic leukemia in Down syndrome. Blood. 2019;134(15):1227–1237. doi: https://doi.org/10.1182/blood.2018890764

18. Bchir M, Ayed W, Neji HB, et al. Leukemia in Patients with Klinefelter Syndrome: A Report of Two Cases. Indian J Hematol Blood Transfus. 2016;32(Suppl 1):66–68. doi: https://doi.org/10.1007/s12288-015-0590-6

19. Ji J, Z ller B, Sundquist J, Sundquist K. Risk of solid tumors and hematological malignancy in persons with Turner and Klinefelter syndromes: A national cohort study. Int J Cancer. 2016;139(4):754–758. doi: https://doi.org/10.1002/ijc.30126

20. Siddiqui N, Ali Baig MF, Khan BA. A case report of acute myelogenous leukemia with Turner Syndrome. J Pak Med Assoc. 2017;67(9):1438–1440.

21. Seghezzi L, Maserati E, Minelli A, et al. Constitutional trisomy 8 as first mutation in multistep carcinogenesis: clinical, cytogenetic, and molecular data on three cases. Genes Chromosomes Cancer. 1996;17(2):94–101. doi: https://doi.org/10.1002/(SICI)1098-2264(199610)17:2<94::AID-GCC4>3.0.CO;2-W

22. Bencharef H, Lamchahab M, Dassouli D, et al. Xeroderma pigmentosum and acute myeloid leukemia: a case report. J Med Case Rep. 2021;15(1):437. doi: https://doi.org/10.1186/s13256-021-02969-1

23. Janjetovic S, Bacher U, Haalck T, et al. Acute megakaryoblastic leukemia in a patient with xeroderma pigmentosum: discussion of pathophysiological, prognostic, and toxicological aspects. Acta Haematol. 2013;129(2):121–125. doi: https://doi.org/10.1159/000342897

24. Zghal M, Fazaa B, Abdelhak S, Mokni M. Xeroderma pigmentosum. Ann Dermatol Venereol. 2018;145(11):706–722. doi: https://doi.org/10.1016/j.annder.2018.09.004

25. Trimbath JD, Petersen GM, Erdman SH, et al. Caf -aulait spots and early onset colorectal neoplasia: a variant of HNPCC? Fam Cancer. 2001;1(2):103–108. doi: https://doi.org/10.1023/A:1013881832014

26. Ricciardone MD, Ozcelik T, Cevher B, et al. Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. Cancer Res. 1999;59(2):290–293.

27. Baas A, Gabbett M, Rimac M, et al. Agenesis of the corpus callosum and gray matter heterotopia in three patients with constitutional mismatch repair deficiency syndrome. Eur J Hum Genet. 2013;21(1):55–61. doi: https://doi.org/10.1038/ejhg.2012.117

28. Whiteside D, McLeod R, Graham G, et al. A homozygous germline mutation in the human MSH2 gene predisposes to hematological malignancy and multiple cafe-au-lait spots. Cancer Res. 2002;62:359–362. doi: https://doi.org/10.1038/ejhg.2012.117

29. Bougeard G, Charbonnier F, Moerman A, et al. Early-onset brain tumor and lymphoma in MSH2-deficient children. Am J Hum Genet. 2003;72(1):213–216. doi: https://doi.org/10.1086/345297

30. Hegde MR, Chong B, Blazo ME, et al. A homozygous mutation in MSH6 causes Turcot syndrome. Clin Cancer Res. 2005;11(13):4689–4693. doi: https://doi.org/10.1158/1078-0432.CCR-04-2025

31. Poley JW, Wagner A, Hoogmans MM, et al. Biallelic germline mutations of mismatch-repair genes: a possible cause for multiple pediatric malignancies. Cancer. 2007;109(11):2349–2356. doi: https://doi.org/10.1002/cncr.22697

32. Tiao G, Improgo MR, Kasar S, et al. Rare germline variants in ATM are associated with chronic lymphocytic leukemia. Leukemia. 2017;31(10):2244–2247. doi: https://doi.org/10.1038/leu.2017.201

33. Stubbins RJ, Korotev S, Godley LA. Germline CHEK2 and ATM Variants in Myeloid and Other Hematopoietic Malignancies. Curr Hematol Malig Rep. 2022;17(4):94–104. doi: https://doi.org/10.1007/s11899-022-00663-7

34. Yuille MR, Condie A, Hudson CD, et al. ATM mutations are rare in familial chronic lymphocytic leukemia. Blood. 2002;100(2):603–609. doi: https://doi.org/10.1182/blood.v100.2.603

35. Palles C, West HD, Chew E, et al. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome. Am J Hum Genet. 2022;109(5):953–960. doi: https://doi.org/10.1016/j.ajhg.2022.03.018

36. Wagner JE, Tolar J, Levran O, et al. Germline mutations in BRCA2: shared genetic susceptibility to breast cancer, early onset leukemia and Fanconi anemia. Blood. 2004;103(8):3226–3229. doi: https://doi.org/10.1182/blood-2003-09-3138

37. Dhanraj S, Matveev A, Li H, et al. Biallelic mutations in DNAJC21 cause Shwachman-Diamond syndrome. Blood. 2017;129(11):1557–1562. doi: https://doi.org/10.1182/blood-2016-08-735431

38. Kawashima N, Oyarbide U, Cipolli M, et al. Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants. Haematologica. 2023;108(10):2594–2605. doi: https://doi.org/10.3324/haematol.2023.282949

39. Farooqui SM, Ward R, Aziz M. Shwachman-Diamond Syndrome. 2023 Jul 17. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023.

40. Carapito R, Konantz M, Paillard C, et al. Mutations in signal recognition particle SRP54 cause syndromic neutropenia with ShwachmanDiamond-like features. J Clin Invest. 2017;127(11):4090–4103. doi: https://doi.org/10.1172/JCI92876

41. Vlachos A, Rosenberg PS, Atsidaftos E, et al. Incidence of neoplasia in Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry. Blood. 2012;119(16):3815–3819. doi: https://doi.org/10.1182/blood-2011-08-375972

42. Ramos H, Aly MM, Balasubramanian SK. Late Presentation of Dyskeratosis Congenita: Germline Predisposition to Adult-Onset Secondary Acute Myeloid Leukemia. Hematol Rep. 2022;14(4):294–299. doi: https://doi.org/10.3390/hematolrep14040042

43. Hahn CN, Chong CE, Carmichael CL, et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet. 2011;43(10):1012–1017. doi: https://doi.org/10.1038/ng.913

44. Holme H, Hossain U, Kirwan M, et al. Marked genetic heterogeneity in familial myelodysplasia/acute myeloid leukaemia. Br J Haematol. 2012;158(2):242–248. doi: https://doi.org/10.1111/j.1365-2141.2012.09136.x

45. Pasquet M, Bellanne-Chantelot C, Tavitian S, et al. High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia. Blood. 2013;121(5):822–829. doi: https://doi.org/10.1182/blood-2012-08-447367

46. Gao J, Gentzler RD, Timms AE, et al. Heritable GATA2 mutations associated with familial AML-MDS: a case report and review of literature. J Hematol Oncol. 2014;7:36. doi: https://doi.org/10.1186/1756-8722-7-36

47. Rossini J, Mercorella B, Townshend S, et al. Familial platelet disorders with a predisposition to acute myelogenous leukaemia: a RUNX1 update. Hered Cancer Clin Pract. 2012;10(Suppl 2):A64. doi: https://doi.org/10.1186/1897-4287-10-S2-A64

48. Preudhomme C, Renneville A, Bourdon V, et al. High frequency of RUNX1 biallelic alteration in acute myeloid leukemia secondary to familial platelet disorder. Blood. 2009;113(22):5583–5587. doi: https://doi.org/10.1182/blood-2008-07-168260

49. Zhang MY, Churpek JE, Keel SB, et al. Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nat Genet. 2015;47(2):180–185. doi: https://doi.org/10.1038/ng.3177

50. Noetzli L, Lo RW, Lee-Sherick AB, et al. Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nat Genet. 2015;47(5):535–538. doi: https://doi.org/10.1038/ng.3253

51. Chen DH, Below JE, Shimamura A, et al. Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L. Am J Hum Genet. 2016;98(6):1146–1158. doi: https://doi.org/10.1016/j.ajhg.2016.04.009

52. Germeshausen M, Grudzien M, Zeidler C, et al. Novel HAX1 mutations in patients with severe congenital neutropenia reveal isoform-dependent genotype-phenotype associations. Blood. 2008;111(10):4954–4957. doi: https://doi.org/10.1182/blood-2007-11-120667

53. Lopes BA, Barbosa TC, Souza BKS, et al. IKZF1 Gene in Childhood B-cell Precursor Acute Lymphoblastic Leukemia: Interplay between Genetic Susceptibility and Somatic Abnormalities. Cancer Prev Res (Phila). 2017;10(12):738–744. doi: https://doi.org/10.1158/1940-6207.CAPR-17-0121

54. Ben-Omran TI, Cerosaletti K, Concannon P, et al. A patient with mutations in DNA ligase IV: clinical features and overlap with Nijmegen breakage syndrome. Am J Med Genet. 2005;137A(3):283–287. doi: https://doi.org/10.1002/ajmg.a.30869

55. Booth C, Gilmour KC, Veys P, et al. X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease. Blood. 2011;117(1):53–62. doi: https://doi.org/10.1182/blood-2010-06-284935

56. Ravell JC, Chauvin SD, He T, Lenardo M. An Update on XMEN Disease. J Clin Immunol. 2020;40(5):671–681. doi: https://doi.org/10.1007/s10875-020-00790-x

57. Ravell JC, Matsuda-Lennikov M, Chauvin SD, et al. Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease. J Clin Invest. 2020;130(1):507–522. doi: https://doi.org/10.1172/JCI131116

58. Malik MA, Masab M. Wiskott-Aldrich Syndrome. 2023 Jun 26. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023.

59. Yoshimi A, Kamachi Y, Imai K, et al. Wiskott-Aldrich syndrome presenting with a clinical picture mimicking juvenile myelomonocytic leukaemia. Pediatr Blood Cancer. 2012;60(5):836–841. doi: https://doi.org/10.1002/pbc.24359

60. Sun X, Luo C, Tang R, et al. Sinonasal diffuse large B-cell lymphoma in a patient with Wiskott-Aldrich syndrome: A case report and literature review. Front Immunol. 2023;13:1062261. doi: https://doi.org/10.3389/fimmu.2022.1062261

61. Du S, Scuderi R, Malicki DM, et al. Hodgkin’s and non-Hodgkin’s lymphomas occurring in two brothers with Wiskott-Aldrich syndrome and review of the literature. Pediatr Dev Pathol. 2011;14(1):64–70. doi: https://doi.org/10.2350/10-01-0787-CR.1

62. Senthil S, Thrasher AJ, Gilmour KC, et al. Wiskott Aldrich Syndrome-2 Caused by Novel Wiskott Aldrich Syndrome ProteinInteracting Protein (WIP) Deficiency Is Associated with Juvenile Myelomonocytic Leukaemia — a Case Report. J Clin Immunol. 2023;43(1):82–84. doi: https://doi.org/10.1007/s10875-022-01367-6

63. Taskinen M, Ranki A, Pukkala E, et al. Extended follow-up of the Finnish cartilage-hair hypoplasia cohort confirms high incidence of non-Hodgkin lymphoma and basal cell carcinoma. Am J Med Genet. 2008;146A(18):2370–2375. doi: https://doi.org/10.1002/ajmg.a.32478

64. Klemetti P, Valta H, Kostjukovits S, et al. Cartilage-hair hypoplasia with normal height in childhood — 4 patients with a unique genotype. Clin Genet. 2017;92(2):204-207. doi: https://doi.org/10.1111/cge.12969

65. Yang L, Liu H, Zhao J, et al. Mutations of perforin gene in Chinese patients with acute lymphoblastic leukemia. Leuk Res. 2011;35(2):196–199. doi: https://doi.org/10.1016/j.leukres.2010.06.016

66. Churpek JE, Smith-Simmer K. DDX41-Associated Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia. 2021 Oct 28. In: GeneReviews® [Internet]. Adam MP, Mirzaa GM, Pagon RA, et al., eds. Seattle (WA): University of Washington, Seattle; 1993–2023.

67. Clark RD, Hutter JJ Jr. Familial neurofibromatosis and juvenile chronic myelogenous leukemia. Hum Genet. 1982;60(3):230–232. doi: https://doi.org/10.1007/BF00303009

68. Coffin CM, Cassity J, Viskochil D, et al. Non-neurogenic sarcomas in four children and young adults with neurofibromatosis type 1. Am J Med Genet. 2004;127A(1):40–43. doi: https://doi.org/10.1002/ajmg.a.20651

69. Choong K, Freedman MH, Chitayat D, et al. Juvenile myelomonocytic leukemia and Noonan syndrome. J Pediatr Hematol Oncol. 1999;21(6):523–527.

70. Villani A, Greer MC, Kalish JM, et al. Recommendations for Cancer Surveillance in Individuals with RASopathies and other rare genetic conditions with increased cancer risk. Clin Cancer Res. 2017;23(12):e83–e90. doi: https://doi.org/10.1158/1078-0432.CCR-17-0631

71. Niemeyer CM, Kang MW, Shin DH, et al. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nature Genet. 2010;42(9):794–800. doi: https://doi.org/10.1038/ng.641

72. Hyde RK, Liu PP. Germline PAX5 mutations and B cell leukemia. Nat Genet. 2013;45(10):1104–1105. doi: https://doi.org/10.1038/ng.2778

73. Duployez N, Jamrog LA, Fregona V, et al. Germline PAX5 mutation predisposes to familial B-cell precursor acute lymphoblastic leukemia. Blood. 2021;137(10):1424–1428. doi: https://doi.org/10.1182/blood.2020005756

74. Zhao X, Qian M, Goodings C, et al. Molecular Mechanisms of ARID5B-Mediated Genetic Susceptibility to Acute Lymphoblastic Leukemia. J Natl Cancer Inst. 2022;114(9):1287–1295. doi: https://doi.org/10.1093/jnci/djac101

75. Varon R, Muuer A, Wagner K, et al. Nijmegen breakage syndrome (NBS) due to maternal isodisomy of chromosome 8. Am J Med Genet A. 2007;143(A):92–94. doi: https://doi.org/10.1002/ajmg.a.31540

76. Waltes R, Kalb R, Gatei M, et al. Human RAD50 deficiency in a Nijmegen breakage syndrome-like disorder. Am J Hum Genet. 2009;84(5):605–616. doi: https://doi.org/10.1016/j.ajhg.2009.04.010

77. Martin CA, Sarlos K, Logan CV, et al. Mutations in TOP3A cause a Bloom syndrome-like disorder. Am J Hum Genet. 2018;103(2):221–231. doi: https://doi.org/10.1016/j.ajhg.2018.07.001

78. Ansar S, Malcolmson J, Farncombe KM, et al. Clinical implementation of genetic testing in adults for hereditary hematologic malignancy syndromes. Genet Med. 2022;24(11):2367–2379. doi: https://doi.org/10.1016/j.gim.2022.08.010