Skip to main content

Advertisement

SpringerLink
Log in

The International Consensus Classification (ICC) of hematologic neoplasms with germline predisposition, pediatric myelodysplastic syndrome, and juvenile myelomonocytic leukemia

  • Review
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Updating the classification of hematologic neoplasia with germline predisposition, pediatric myelodysplastic syndrome (MDS), and juvenile myelomonocytic leukemia (JMML) is critical for diagnosis, therapy, research, and clinical trials. Advances in next-generation sequencing technology have led to the identification of an expanding group of genes that predispose to the development of hematolymphoid neoplasia when mutated in germline configuration and inherited. This review encompasses recent advances in the classification of myeloid and lymphoblastic neoplasia with germline predisposition summarizing important genetic and phenotypic information, relevant laboratory testing, and pathologic bone marrow features. Genes are organized into three major categories including (1) those that are not associated with constitutional disorder and include CEBPA, DDX41, and TP53; (2) those associated with thrombocytopenia or platelet dysfunction including RUNX1, ANKRD26, and ETV6; and (3) those associated with constitutional disorders affecting multiple organ systems including GATA2, SAMD9, and SAMD9L, inherited genetic mutations associated with classic bone marrow failure syndromes and JMML, and Down syndrome. A provisional category of germline predisposition genes is created to recognize genes with growing evidence that may be formally included in future revised classifications as substantial supporting data emerges. We also detail advances in the classification of pediatric myelodysplastic syndrome (MDS), expanding the definition of refractory cytopenia of childhood (RCC) to include early manifestation of MDS in patients with germline predisposition. Finally, updates in the classification of juvenile myelomonocytic leukemia are presented which genetically define JMML as a myeloproliferative/myelodysplastic disease harboring canonical RAS pathway mutations. Diseases with features overlapping with JMML that do not carry RAS pathway mutations are classified as JMML-like. The review is based on the International Consensus Classification (ICC) of Myeloid and Lymphoid Neoplasms as reported by Arber et al. (Blood 140(11):1200–1228, 2022).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Arber DA, Orazi A, Hasserjian RP et al (2022) International Consensus Classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data. Blood 140(11):1200–1228

    Article  CAS  Google Scholar 

  2. Kobayashi S, Kobayashi A, Osawa Y et al (2017) Donor cell leukemia arising from preleukemic clones with a novel germline DDX41 mutation after allogenic hematopoietic stem cell transplantation. Leukemia 31(4):1020–1022

    Article  CAS  Google Scholar 

  3. Galera P, Hsu AP, Wang W et al (2018) Donor-derived MDS/AML in families with germline GATA2 mutation. Blood 132(18):1994–1998

    Article  CAS  Google Scholar 

  4. Xiao H, Shi J, Luo Y et al (2011) First report of multiple CEBPA mutations contributing to donor origin of leukemia relapse after allogeneic hematopoietic stem cell transplantation. Blood 117(19):5257–5260

    Article  CAS  Google Scholar 

  5. Owen CJ, Toze CL, Koochin A et al (2008) Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy. Blood 112(12):4639–4645

    Article  CAS  Google Scholar 

  6. Keeshan K, Santilli G, Corradini F, Perrotti D, Calabretta B (2003) Transcription activation function of C/EBPalpha is required for induction of granulocytic differentiation. Blood 102(4):1267–1275

    Article  CAS  Google Scholar 

  7. Pabst T, Mueller BU (2009) Complexity of CEBPA dysregulation in human acute myeloid leukemia. Clin Cancer Res 15(17):5303–5307

    Article  CAS  Google Scholar 

  8. Tawana K, Wang J, Renneville A et al (2015) Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood 126(10):1214–1223

    Article  CAS  Google Scholar 

  9. Pathak A, Seipel K, Pemov A et al (2016) Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family. Haematologica 101(7):846–852

    Article  CAS  Google Scholar 

  10. Pabst T, Eyholzer M, Haefliger S, Schardt J, Mueller BU (2008) Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia. J Clin Oncol 26(31):5088–5093

    Article  CAS  Google Scholar 

  11. Linder P (2006) Dead-box proteins: a family affair—active and passive players in RNP-remodeling. Nucleic Acids Res 34(15):4168–4180

    Article  CAS  Google Scholar 

  12. Polprasert C, Schulze I, Sekeres MA et al (2015) Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell 27(5):658–670

    Article  CAS  Google Scholar 

  13. Lewinsohn M, Brown AL, Weinel LM et al (2016) Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies. Blood 127(8):1017–1023

    Article  CAS  Google Scholar 

  14. Guha T, Malkin D (2017) Inherited TP53 mutations and the Li-Fraumeni syndrome. Cold Spring Harb Perspect Med 7(4).

  15. Holmfeldt L, Wei L, Diaz-Flores E et al (2013) The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet 45(3):242–252

    Article  CAS  Google Scholar 

  16. Bougeard G, Renaux-Petel M, Flaman JM et al (2015) Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol 33(21):2345–2352

    Article  CAS  Google Scholar 

  17. Li FP, Fraumeni JF Jr, Mulvihill JJ et al (1988) A cancer family syndrome in twenty-four kindreds. Cancer Res 48(18):5358–5362

    CAS  Google Scholar 

  18. Law JC, Strong LC, Chidambaram A, Ferrell RE (1991) A germ line mutation in exon 5 of the p53 gene in an extended cancer family. Cancer Res 51(23 Pt 1):6385–6387

    CAS  Google Scholar 

  19. Birch JM, Alston RD, McNally RJ et al (2001) Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene 20(34):4621–4628

    Article  CAS  Google Scholar 

  20. Talwalkar SS, Yin CC, Naeem RC, Hicks MJ, Strong LC, Abruzzo LV (2010) Myelodysplastic syndromes arising in patients with germline TP53 mutation and Li-Fraumeni syndrome. Arch Pathol Lab Med 134(7):1010–1015

    Article  Google Scholar 

  21. Godley LA, Larson RA (2008) Therapy-related myeloid leukemia. Semin Oncol 35(4):418–429

    Article  CAS  Google Scholar 

  22. Kanagal-Shamanna R, Loghavi S, DiNardo CD et al (2017) Bone marrow pathologic abnormalities in familial platelet disorder with propensity for myeloid malignancy and germline RUNX1 mutation. Haematologica 102(10):1661–1670

    Article  CAS  Google Scholar 

  23. Bluteau D, Balduini A, Balayn N et al (2014) Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation. J Clin Invest 124(2):580–591

    Article  CAS  Google Scholar 

  24. Zaninetti C, Santini V, Tiniakou M, Barozzi S, Savoia A, Pecci A (2017) Inherited thrombocytopenia caused by ANKRD26 mutations misdiagnosed and treated as myelodysplastic syndrome: report on two cases J. Thromb Haemost 15(12):2388–2392

    Article  CAS  Google Scholar 

  25. Poggi M, Canault M, Favier M et al (2017) Germline variants in ETV6 underlie reduced platelet formation, platelet dysfunction and increased levels of circulating CD34+ progenitors. Haematologica 102(2):282–294

    Article  CAS  Google Scholar 

  26. Bluteau D, Glembotsky AC, Raimbault A et al (2012) Dysmegakaryopoiesis of FPD/AML pedigrees with constitutional RUNX1 mutations is linked to myosin II deregulated expression. Blood 120(13):2708–2718

    Article  CAS  Google Scholar 

  27. Song WJ, Sullivan MG, Legare RD et al (1999) Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet 23(2):166–175

    Article  CAS  Google Scholar 

  28. Schlegelberger B, Heller PG (2017) RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM). Semin Hematol 54(2):75–80

    Article  Google Scholar 

  29. Pippucci T, Savoia A, Perrotta S et al (2011) Mutations in the 5′ UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2. Am J Hum Genet 88(1):115–120

    Article  CAS  Google Scholar 

  30. Noris P, Perrotta S, Seri M et al (2011) Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families. Blood 117(24):6673–6680

    Article  CAS  Google Scholar 

  31. Noris P, Favier R, Alessi MC et al (2013) ANKRD26-related thrombocytopenia and myeloid malignancies. Blood 122(11):1987–1989

    Article  CAS  Google Scholar 

  32. Zhang MY, Churpek JE, Keel SB et al (2015) Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nat Genet 47(2):180–185

    Article  CAS  Google Scholar 

  33. Noetzli L, Lo RW, Lee-Sherick AB et al (2015) Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nat Genet 47(5):535–538

    Article  CAS  Google Scholar 

  34. Hsu AP, Sampaio EP, Khan J et al (2011) Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood 118(10):2653–2655

    Article  CAS  Google Scholar 

  35. Dickinson RE, Griffin H, Bigley V et al (2011) Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte B and NK lymphoid deficiency. Blood 118(10):2656–2658

    Article  CAS  Google Scholar 

  36. Hahn CN, Chong CE, Carmichael CL et al (2011) Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet 43(10):1012–1017

    Article  CAS  Google Scholar 

  37. Ostergaard P, Simpson MA, Connell FC et al (2011) Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat Genet 43(10):929–931

    Article  CAS  Google Scholar 

  38. Spinner MA, Sanchez LA, Hsu AP et al (2014) GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood 123(6):809–821

    Article  CAS  Google Scholar 

  39. Wlodarski MW, Collin M, Horwitz MS (2017) GATA2 deficiency and related myeloid neoplasms. Semin Hematol 54(2):81–86

    Article  Google Scholar 

  40. Wlodarski MW, Hirabayashi S, Pastor V et al (2016) Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood 127(11):1387–1397; quiz 1518.

  41. Pasquet M, Bellanne-Chantelot C, Tavitian S et al (2013) High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia. Blood 121(5):822–829

    Article  CAS  Google Scholar 

  42. Bluteau O, Sebert M, Leblanc T et al (2018) A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. Blood 131(7):717–732

    Article  CAS  Google Scholar 

  43. Dickinson RE, Milne P, Jardine L et al (2014) The evolution of cellular deficiency in GATA2 mutation. Blood 123(6):863–874

    Article  CAS  Google Scholar 

  44. Koegel AK, Hofmann I, Moffitt K, Degar B, Duncan C, Tubman VN (2016) Acute lymphoblastic leukemia in a patient with MonoMAC syndrome/GATA2 haploinsufficiency. Pediatr Blood Cancer 63(10):1844–1847

    Article  CAS  Google Scholar 

  45. Esparza O, Xavier AC, Atkinson TP, Hill BC, Whelan K (2019) A unique phenotype of T-cell acute lymphoblastic leukemia in a patient with GATA2 haploinsufficiency. Pediatr Blood Cancer 66(6):e27649

    Article  CAS  Google Scholar 

  46. Calvo KR, Vinh DC, Maric I et al (2011) Myelodysplasia in autosomal dominant and sporadic monocytopenia immunodeficiency syndrome: diagnostic features and clinical implications. Haematologica 96(8):1221–1225

    Article  Google Scholar 

  47. Ganapathi KA, Townsley DM, Hsu AP et al (2015) GATA2 deficiency-associated bone marrow disorder differs from idiopathic aplastic anemia. Blood 125(1):56–70

    Article  CAS  Google Scholar 

  48. Narumi S, Amano N, Ishii T et al (2016) SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat Genet 48(7):792–797

    Article  CAS  Google Scholar 

  49. Chen DH, Below JE, Shimamura A et al (2016) Ataxia-pancytopenia syndrome is caused by missense mutations in SAMD9L. Am J Hum Genet 98(6):1146–1158

    Article  CAS  Google Scholar 

  50. Sahoo SS, Pastor VB, Goodings C et al (2021) Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes. Nat Med 27(10):1806–1817

    Article  CAS  Google Scholar 

  51. Schwartz JR, Ma J, Lamprecht T et al (2017) The genomic landscape of pediatric myelodysplastic syndromes. Nat Commun 8(1):1557

    Article  Google Scholar 

  52. de Jesus AA, Hou Y, Brooks S et al (2020) Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases. J Clin Invest 130(4):1669–1682

    Article  Google Scholar 

  53. Cheah JJC, Brown AL, Schreiber AW et al (2019) A novel germline SAMD9L mutation in a family with ataxia-pancytopenia syndrome and pediatric acute lymphoblastic leukemia. Haematologica 104(7):e318–e321

    Article  Google Scholar 

  54. Sahoo SS, Kozyra EJ, Wlodarski MW (2020) Germline predisposition in myeloid neoplasms: unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes. Best Pract Res Clin Haematol 33(3):101197

    Article  Google Scholar 

  55. Wong JC, Bryant V, Lamprecht T et al (2018) Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes. JCI Insight 3(14).

  56. Alter BP, Giri N (2016) Thinking of VACTERL-H? Rule out Fanconi anemia according to PHENOS. Am J Med Genet A 170(6):1520–1524

    Article  Google Scholar 

  57. Rosenberg PS, Huang Y, Alter BP (2004) Individualized risks of first adverse events in patients with Fanconi anemia. Blood 104(2):350–355

    Article  CAS  Google Scholar 

  58. Alter BP, Giri N, Savage SA et al (2010) Malignancies and survival patterns in the National Cancer Institute inherited bone marrow failure syndromes cohort study. Br J Haematol 150(2):179–188

    Google Scholar 

  59. Alter BP (2014) Fanconi anemia and the development of leukemia. Best Pract Res Clin Haematol 27(3–4):214–221

    Article  CAS  Google Scholar 

  60. Skokowa J, Dale DC, Touw IP, Zeidler C, Welte K (2017) Severe congenital neutropenias. Nat Rev Dis Primers 3:17032

    Article  Google Scholar 

  61. Rosenberg PS, Alter BP, Bolyard AA et al (2006) The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy. Blood 107(12):4628–4635

    Article  CAS  Google Scholar 

  62. Rosenberg PS, Zeidler C, Bolyard AA et al (2010) Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy. Br J Haematol 150(2):196–199

    CAS  Google Scholar 

  63. Touw IP (2015) Game of clones: the genomic evolution of severe congenital neutropenia. Hematol Am Soc Hematol Educ Program 2015:1–7

    Article  Google Scholar 

  64. Boocock GR, Morrison JA, Popovic M et al (2003) Mutations in SBDS are associated with Shwachman-Diamond syndrome. Nat Genet 33(1):97–101

    Article  CAS  Google Scholar 

  65. Furutani E, Liu S, Galvin A et al (2022) Hematologic complications with age in Shwachman-Diamond syndrome. Blood Adv 6(1):297–306

    Article  Google Scholar 

  66. Myers KC, Bolyard AA, Otto B et al (2014) Variable clinical presentation of Shwachman-Diamond syndrome: update from the North American Shwachman-Diamond Syndrome Registry. J Pediatr 164(4):866–870

    Article  Google Scholar 

  67. Myers KC, Furutani E, Weller E et al (2020) Clinical features and outcomes of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia: a multicentre, retrospective, cohort study. Lancet Haematol 7(3):e238–e246

    Article  Google Scholar 

  68. Maserati E, Minelli A, Pressato B et al (2006) Shwachman syndrome as mutator phenotype responsible for myeloid dysplasia/neoplasia through karyotype instability and chromosomes 7 and 20 anomalies. Genes Chromosomes Cancer 45(4):375–382

    Article  CAS  Google Scholar 

  69. Hashmi SK, Allen C, Klaassen R et al (2011) Comparative analysis of Shwachman-Diamond syndrome to other inherited bone marrow failure syndromes and genotype-phenotype correlation. Clin Genet 79(5):448–458

    Article  CAS  Google Scholar 

  70. Donadieu J, Fenneteau O, Beaupain B et al (2012) Classification of and risk factors for hematologic complications in a French national cohort of 102 patients with Shwachman-Diamond syndrome. Haematologica 97(9):1312–1319

    Article  CAS  Google Scholar 

  71. Kennedy AL, Myers KC, Bowman J et al (2021) Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome. Nat Commun 12(1):1334

    Article  CAS  Google Scholar 

  72. Dokal I, Vulliamy T, Mason P, Bessler M (2015) Clinical utility gene card for: dyskeratosis congenita - update 2015. Eur J Hum Genet 23(4).

  73. Ballew BJ, Savage SA (2013) Updates on the biology and management of dyskeratosis congenita and related telomere biology disorders. Expert Rev Hematol 6(3):327–337

    Article  CAS  Google Scholar 

  74. Bertuch AA (2016) The molecular genetics of the telomere biology disorders. RNA Biol 13(8):696–706

    Article  Google Scholar 

  75. Niewisch MR, Savage SA (2019) An update on the biology and management of dyskeratosis congenita and related telomere biology disorders. Expert Rev Hematol 12(12):1037–1052

    Article  CAS  Google Scholar 

  76. Alter BP, Giri N, Savage SA, Rosenberg PS (2018) Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up. Haematologica 103(1):30–39

    Article  CAS  Google Scholar 

  77. Calado RT, Young NS (2009) Telomere diseases. N Engl J Med 361(24):2353–2365

    Article  CAS  Google Scholar 

  78. Vlachos A, Ball S, Dahl N et al (2008) Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference. Br J Haematol 142(6):859–876

    Article  CAS  Google Scholar 

  79. Lipton JM, Molmenti CLS, Hussain M et al (2021) Colorectal cancer screening and surveillance strategy for patients with Diamond Blackfan anemia: preliminary recommendations from the Diamond Blackfan Anemia Registry. Pediatr Blood Cancer 68(8):e28984

    Article  Google Scholar 

  80. Vlachos A, Rosenberg PS, Atsidaftos E, Alter BP, Lipton JM (2012) Incidence of neoplasia in Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry. Blood 119(16):3815–3819

    Article  CAS  Google Scholar 

  81. Vlachos A, Muir E (2010) How I treat Diamond-Blackfan anemia. Blood 116(19):3715–3723

    Article  CAS  Google Scholar 

  82. Hitzler JK, Zipursky A (2005) Origins of leukaemia in children with Down syndrome. Nat Rev Cancer 5(1):11–20

    Article  CAS  Google Scholar 

  83. Izraeli S (2016) The acute lymphoblastic leukemia of Down syndrome—genetics and pathogenesis. Eur J Med Genet 59(3):158–161

    Article  Google Scholar 

  84. Shah S, Schrader KA, Waanders E et al (2013) A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia. Nat Genet 45(10):1226–1231

    Article  CAS  Google Scholar 

  85. Churchman ML, Qian M, Te Kronnie G et al (2018) Germline Genetic IKZF1 variation and predisposition to childhood acute lymphoblastic leukemia. Cancer Cell 33(5):937–948 e938.

  86. Schutte P, Moricke A, Zimmermann M et al (2016) Preexisting conditions in pediatric ALL patients: spectrum, frequency and clinical impact. Eur J Med Genet 59(3):143–151

    Article  CAS  Google Scholar 

  87. Winter G, Kirschner-Schwabe R, Groeneveld-Krentz S et al (2021) Clinical and genetic characteristics of children with acute lymphoblastic leukemia and Li-Fraumeni syndrome. Leukemia 35(5):1475–1479

    Article  Google Scholar 

  88. Auer F, Ruschendorf F, Gombert M et al (2014) Inherited susceptibility to pre B-ALL caused by germline transmission of PAX5 c.547G>A. Leukemia 28(5):1136–1138

    Article  CAS  Google Scholar 

  89. Kuehn HS, Boisson B, Cunningham-Rundles C et al (2016) Loss of B cells in patients with heterozygous mutations in IKAROS. N Engl J Med 374(11):1032–1043

    Article  CAS  Google Scholar 

  90. Sarasin A, Quentin S, Droin N et al (2019) Familial predisposition to TP53/complex karyotype MDS and leukemia in DNA repair-deficient xeroderma pigmentosum. Blood 133(25):2718–2724

    Article  CAS  Google Scholar 

  91. Oetjen KA, Levoska MA, Tamura D et al (2020) Predisposition to hematologic malignancies in patients with xeroderma pigmentosum. Haematologica 105(4):e144–e146

    Article  Google Scholar 

  92. Zhang MY, Keel SB, Walsh T et al (2015) Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity. Haematologica 100(1):42–48

    Article  CAS  Google Scholar 

  93. Pastor V, Hirabayashi S, Karow A et al (2017) Mutational landscape in children with myelodysplastic syndromes is distinct from adults: specific somatic drivers and novel germline variants. Leukemia 31(3):759–762

    Article  CAS  Google Scholar 

  94. Baumann I, Fuhrer M, Behrendt S et al (2012) Morphological differentiation of severe aplastic anaemia from hypocellular refractory cytopenia of childhood: reproducibility of histopathological diagnostic criteria. Histopathology 61(1):10–17

    Article  Google Scholar 

  95. Locatelli F, Strahm B (2018) How I treat myelodysplastic syndromes of childhood. Blood 131(13):1406–1414

    Article  CAS  Google Scholar 

  96. Kardos G, Baumann I, Passmore SJ et al (2003) Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7. Blood 102(6):1997–2003

    Article  CAS  Google Scholar 

  97. Hasegawa D, Chen X, Hirabayashi S et al (2014) Clinical characteristics and treatment outcome in 65 cases with refractory cytopenia of childhood defined according to the WHO 2008 classification. Br J Haematol 166(5):758–766

    Article  CAS  Google Scholar 

  98. Yoshimi A, van den Heuvel-Eibrink MM, Baumann I et al (2014) Comparison of horse and rabbit antithymocyte globulin in immunosuppressive therapy for refractory cytopenia of childhood. Haematologica 99(4):656–663

    Article  CAS  Google Scholar 

  99. Hasegawa D (2016) The current perspective of low-grade myelodysplastic syndrome in children. Int J Hematol 103(4):360–364

    Article  Google Scholar 

  100. Moriwaki K, Manabe A, Taketani T, Kikuchi A, Nakahata T, Hayashi Y (2014) Cytogenetics and clinical features of pediatric myelodysplastic syndrome in Japan. Int J Hematol 100(5):478–484

    Article  Google Scholar 

  101. Wlodarski MW, Sahoo SS, Niemeyer CM (2018) Monosomy 7 in pediatric myelodysplastic syndromes. Hematol Oncol Clin North Am 32(4):729–743

    Article  Google Scholar 

  102. Niemeyer CM, Arico M, Basso G et al (1997) Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS). Blood 89(10):3534–3543.

  103. Luna-Fineman S, Shannon KM, Atwater SK et al (1999) Myelodysplastic and myeloproliferative disorders of childhood: a study of 167 patients. Blood 93(2):459–466

    Article  CAS  Google Scholar 

  104. Niemeyer CM, Kang MW, Shin DH et al (2010) Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet 42(9):794–800

    Article  CAS  Google Scholar 

  105. Martinelli S, Stellacci E, Pannone L et al (2015) Molecular diversity and associated phenotypic spectrum of germline CBL mutations. Hum Mutat 36(8):787–796

    Article  CAS  Google Scholar 

  106. Passmore SJ, Hann IM, Stiller CA et al (1995) Pediatric myelodysplasia: a study of 68 children and a new prognostic scoring system. Blood 85(7):1742–1750

    Article  CAS  Google Scholar 

  107. Niemeyer CM, Flotho C (2019) Juvenile myelomonocytic leukemia: who’s the driver at the wheel? Blood 133(10):1060–1070

    Article  CAS  Google Scholar 

  108. Wintering A, Dvorak CC, Stieglitz E, Loh ML (2021) Juvenile myelomonocytic leukemia in the molecular era: a clinician’s guide to diagnosis, risk stratification, and treatment. Blood Adv 5(22):4783–4793

    Article  CAS  Google Scholar 

  109. Perez B, Mechinaud F, Galambrun C et al (2010) Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia. J Med Genet 47(10):686–691

    Article  CAS  Google Scholar 

  110. Hecht A, Meyer JA, Behnert A et al (2022) Molecular and phenotypic diversity of CBL-mutated juvenile myelomonocytic leukemia. Haematologica 107(1):178–186

    Article  CAS  Google Scholar 

  111. Yoshida N, Yagasaki H, Xu Y et al (2009) Correlation of clinical features with the mutational status of GM-CSF signaling pathway-related genes in juvenile myelomonocytic leukemia. Pediatr Res 65(3):334–340

    Article  CAS  Google Scholar 

  112. Locatelli F, Niemeyer CM (2015) How I treat juvenile myelomonocytic leukemia. Blood 125(7):1083–1090

    Article  CAS  Google Scholar 

  113. Mayerhofer C, Niemeyer CM, Flotho C (2021) Current treatment of juvenile myelomonocytic leukemia. J Clin Med 10(14).

  114. Calvo KR, Price S, Braylan RC et al (2015) JMML and RALD (Ras-associated autoimmune leukoproliferative disorder): common genetic etiology yet clinically distinct entities. Blood 125(18):2753–2758

    Article  CAS  Google Scholar 

  115. Rottgers S, Gombert M, Teigler-Schlegel A et al (2010) ALK fusion genes in children with atypical myeloproliferative leukemia. Leukemia 24(6):1197–1200

    Article  CAS  Google Scholar 

  116. Murakami N, Okuno Y, Yoshida K et al (2018) Integrated molecular profiling of juvenile myelomonocytic leukemia. Blood 131(14):1576–1586

    Article  CAS  Google Scholar 

  117. Buijs A, Bruin M (2007) Fusion of FIP1L1 and RARA as a result of a novel t(4;17)(q12;q21) in a case of juvenile myelomonocytic leukemia. Leukemia 21(5):1104–1108

    Article  CAS  Google Scholar 

  118. Miltiadous O, Petrova-Drus K, Kaicker S et al (2022) Successful treatment and integrated genomic analysis of an infant with FIP1L1-RARA fusion-associated myeloid neoplasm. Blood Adv 6(4):1137–1142

    Article  CAS  Google Scholar 

  119. Bown N, Yule SM, Evans J, Kernahan J, Reid MM (1992) Chronic myelomonocytic leukemia with t(13;14) in a child. Cancer Genet Cytogenet 60(2):190–192

    Article  CAS  Google Scholar 

  120. Chao AK, Meyer JA, Lee AG et al (2020) Fusion driven JMML: a novel CCDC88C-FLT3 fusion responsive to sorafenib identified by RNA sequencing. Leukemia 34(2):662–666

    Article  Google Scholar 

  121. Strullu M, Caye A, Lachenaud J et al (2014) Juvenile myelomonocytic leukaemia and Noonan syndrome. J Med Genet 51(10):689–697

    Article  CAS  Google Scholar 

  122. O'Halloran K, Ritchey AK, Djokic M, Friehling E (2017) Transient juvenile myelomonocytic leukemia in the setting of PTPN11 mutation and Noonan syndrome with secondary development of monosomy 7. Pediatr Blood Cancer 64(7).

  123. Hofmans M, Schroder R, Lammens T et al (2019) Noonan syndrome-associated myeloproliferative disorder with somatically acquired monosomy 7: impact on clinical decision making. Br J Haematol 187(4):E83–E86

    Article  Google Scholar 

Download references

Acknowledgements

This work was in part supported by the National Institutes of Health Division of Intramural Research of the NIH Clinical Center.

Author information

Author notes

  1. Martina Rudelius and Olga K. Weinberg contributed equally.

Authors and Affiliations

  1. Institute of Pathology, Ludwig-Maximilians-University of Munich, Munich, Germany

    Martina Rudelius

  2. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Olga K. Weinberg

  3. Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Charlotte M. Niemeyer

  4. German Cancer Consortium (DKTK), Heidelberg, Germany

    Charlotte M. Niemeyer

  5. Dana-Farber/Boston Children’s Hospital Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA

    Akiko Shimamura

  6. Hematology Section, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, 20814, USA

    Katherine R. Calvo

Authors
  1. Martina Rudelius
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Olga K. Weinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Charlotte M. Niemeyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akiko Shimamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Katherine R. Calvo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the gathering of supporting data for the ICC and this manuscript. MR, OKW, AS, CMN, and KRC wrote the manuscript. MR and KRC made the figures. All authors edited the manuscript and contributed to the tables. The first two authors contributed equally.

Corresponding author

Correspondence to Katherine R. Calvo.

Ethics declarations

Compliance with all ethical standards was undertaken for this work. No research involving human participants and/or animals was performed for this work. No informed consent was required.

Conflict of interest

The authors declare no competing interests.

Disclaimer

The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the views of the NIH.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rudelius, M., Weinberg, O.K., Niemeyer, C.M. et al. The International Consensus Classification (ICC) of hematologic neoplasms with germline predisposition, pediatric myelodysplastic syndrome, and juvenile myelomonocytic leukemia. Virchows Arch 482, 113–130 (2023). https://doi.org/10.1007/s00428-022-03447-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-022-03447-9

Keywords

Search

Navigation