European Journal of Pediatrics

, Volume 171, Issue 9, pp 1301–1307 | Cite as

Hematological disorders and leukemia in children with Down syndrome

  • Annelyse Bruwier
  • Christophe F. ChantrainEmail author


Constitutional trisomy 21 inherent to Down syndrome (DS) is associated with several hematological disorders occurring at different ages. Neonates with DS may present with transient asymptomatic blood count abnormalities such as neutrophilia, thrombocytopenia and polycythemia. Within 1–2 months of life, 3–10% of DS infants develop transient myeloproliferative disease. Despite a spontaneous regression in most of the cases, TMD can be fatal or lead to the subsequent development of myeloid leukemia in 20% of DS children (DS ML). DS ML has clinical and biological features that define a unique entity with a high sensitivity to chemotherapy and a favorable outcome. Children with DS also have an increased risk of developing acute lymphoblastic leukemia (ALL) characterized by a more heterogeneous pattern of genetic findings and by a higher rate of treatment-related toxicities. These features highlight the role of trisomy 21 in leukemogenesis and confirm the need of specific and adapted therapeutic approach for DS children with leukemia.


Down syndrome Myeloid leukemia Acute lymphoblastic leukemia Transient myeloproliferative disorder GATA1 Trisomy 21 



Down syndrome


Transient myeloproliferative disease


Acute myeloid leukemia


Acute lymphoblastic leukemia


Myeloid leukemia of Down syndrome


Hematopoietic stem cell transplantation


  1. 1.
    Brichard B, Vermylen C, De Potter P, Casteels I (2003) Down syndrome: possible predisposition to retinoblastoma. Med Pediatr Oncol 41:73–74PubMedCrossRefGoogle Scholar
  2. 2.
    Cabelof DC, Patel HV, Chen Q, van Remmen H, Matherly LH, Ge Y, Taub JW (2009) Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome. Blood 114:2753–2763PubMedCrossRefGoogle Scholar
  3. 3.
    de Hingh YC, van der Vossen PW, Gemen EF, Mulder AB, Hop WC, Brus F, de Vries E (2005) Intrinsic abnormalities of lymphocyte counts in children with down syndrome. J Pediatr 147:744–747PubMedCrossRefGoogle Scholar
  4. 4.
    Elagib KE, Racke FK, Mogass M, Khetawat R, Delehanty LL, Goldfarb AN (2003) RUNX1 and GATA-1 coexpression and cooperation in megakaryocytic differentiation. Blood 101:4333–4341PubMedCrossRefGoogle Scholar
  5. 5.
    Ensor HM, Schwab C, Russell LJ, Richards SM, Morrison H, Masic D, Jones L, Kinsey SE, Vora AJ, Mitchell CD, Harrison CJ, Moorman AV (2011) Demographic, clinical, and outcome features of children with acute lymphoblastic leukemia and CRLF2 deregulation: results from the MRC ALL97 clinical trial. Blood 117:2129–2136PubMedCrossRefGoogle Scholar
  6. 6.
    Fonatsch C (2010) The role of chromosome 21 in hematology and oncology. Genes Chromosomes Cancer 49:497–508PubMedGoogle Scholar
  7. 7.
    Forestier E, Izraeli S, Beverloo B, Haas O, Pession A, Michalová K, Stark B, Harrison CJ, Teigler-Schlegel A, Johansson B (2008) Cytogenetic features of acute lymphoblastic and myeloid leukemias in pediatric patients with Down syndrome: an iBFM-SG study. Blood 111:1575–1583PubMedCrossRefGoogle Scholar
  8. 8.
    Gaikwad A, Rye CL, Devidas M, Heerema NA, Carroll AJ, Izraeli S, Plon SE, Basso G, Pession A, Rabin KR (2009) Prevalence and clinical correlates of JAK2 mutations in Down syndrome acute lymphoblastic leukaemia. Br J Haematol 144:930–932PubMedCrossRefGoogle Scholar
  9. 9.
    Hasle H (2001) Pattern of malignant disorders in individuals with Down’s syndrome. Lancet Oncol 2:429–436PubMedCrossRefGoogle Scholar
  10. 10.
    Hasle H, Niemeyer CM, Chessells JM, Baumann I, Bennett JM, Kerndrup G, Head DR (2003) A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases. Leukemia 17:277–282PubMedCrossRefGoogle Scholar
  11. 11.
    Hastings C, Whithlock JA, La MK, and Seibel N (2007) Improved outcome of children with Down syndrome (DS) and high risk acute lymphocytic leukemia (HR-ALL): a report of CCG-1961. Blood 110:Abstract 586Google Scholar
  12. 12.
    Henry E, Walker D, Wiedmeier SE, Christensen RD (2007) Hematological abnormalities during the first week of life among neonates with Down syndrome: data from a multihospital healthcare system. Am J Med Genet A 143:42–50PubMedGoogle Scholar
  13. 13.
    Hertzberg L, Vendramini E, Ganmore I, Cazzaniga G, Schmitz M, Chalker J, Shiloh R, Iacobucci I, Shochat C, Zeligson S, Cario G, Stanulla M, Strehl S, Russell LJ, Harrison CJ, Bornhauser B, Yoda A, Rechavi G, Bercovich D, Borkhardt A, Kempski H, te Kronnie G, Bourquin JP, Domany E, Izraeli S (2010) Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group. Blood 115:1006–1017PubMedCrossRefGoogle Scholar
  14. 14.
    Izraeli S (2010) The acute lymphoblastic leukemias of Down syndrome. 42nd Congress of the International Society of Pediatric Oncology. Boston 2010. SIOP Education Book 2010:72–76Google Scholar
  15. 15.
    Kalwinsky DK, Raimondi SC, Bunin NJ, Fairclough D, Pui CH, Relling MV, Ribeiro R, Rivera GK (1990) Clinical and biological characteristics of acute lymphocytic leukemia in children with Down syndrome. Am J Med Genet Suppl 7:267–271PubMedGoogle Scholar
  16. 16.
    Kanezaki R, Toki T, Terui K, Xu G, Wang R, Shimada A, Hama A, Kanegane H, Kawakami K, Endo M, Hasegawa D, Kogawa K, Adachi S, Ikeda Y, Iwamoto S, Taga T, Kosaka Y, Kojima S, Hayashi Y, Ito E (2010) Down syndrome and GATA1 mutations in transient abnormal myeloproliferative disorder: mutation classes correlate with progression to myeloid leukemia. BloodGoogle Scholar
  17. 17.
    Kivivuori SM, Rajantie J, Siimes MA (1996) Peripheral blood cell counts in infants with Down’s syndrome. Clin Genet 49:15–19PubMedCrossRefGoogle Scholar
  18. 18.
    Klusmann JH, Creutzig U, Zimmermann M, Dworzak M, Jorch N, Langebrake C, Pekrun A, Macakova-Reinhardt K, Reinhardt D (2008) Treatment and prognostic impact of transient leukemia in neonates with Down syndrome. Blood 111:2991–2998PubMedCrossRefGoogle Scholar
  19. 19.
    Kudo K, Kojima S, Tabuchi K, Yabe H, Tawa A, Imaizumi M, Hanada R, Hamamoto K, Kobayashi R, Morimoto A, Nakayama H, Tsuchida M, Horibe K, Kigasawa H, Tsukimoto I, and Japanese Childhood AML Cooperative Study Group (2007) Prospective study of a pirarubicin, intermediate-dose cytarabine, and etoposide regimen in children with Down syndrome and acute myeloid leukemia: the Japanese Childhood AML Cooperative Study Group. J Clin Oncol 25:5442–5447PubMedCrossRefGoogle Scholar
  20. 20.
    Lange BJ, Kobrinsky N, Barnard DR, Arthur DC, Buckley JD, Howells WB, Gold S, Sanders J, Neudorf S, Smith FO, Woods WG (1998) Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: Children’s Cancer Group studies 2861 and 2891. Blood 91:608–615PubMedGoogle Scholar
  21. 21.
    Malinge S, Izraeli S, Crispino JD (2009) Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome. Blood 113:2619–2628PubMedCrossRefGoogle Scholar
  22. 22.
    Maloney KW, Carroll WL, Carroll AJ, Devidas M, Borowitz MJ, Martin PL, Pullen J, Whitlock JA, Willman CL, Winick NJ, Camitta BM, Hunger SP (2010) Down syndrome childhood acute lymphoblastic leukemia has a unique spectrum of sentinel cytogenetic lesions that influences treatment outcome: a report from the Children’s Oncology Group. Blood 116:1045–1050PubMedCrossRefGoogle Scholar
  23. 23.
    Massey GV, Zipursky A, Chang MN, Doyle JJ, Nasim S, Taub JW, Ravindranath Y, Dahl G, Weinstein HJ, and Children’s Oncology Group (COG) (2006) A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children’s Oncology Group (COG) study POG-9481. Blood 107:4606–4613PubMedCrossRefGoogle Scholar
  24. 24.
    Meissner B, Borkhardt A, Dilloo D, Fuchs D, Friedrich W, Handgretinger R, Peters C, Schrauder A, Schuster FR, Vormoor J, Maecker B, Sykora KW, Zintl F, Welte K, Sauer M (2007) Relapse, not regimen-related toxicity, was the major cause of treatment failure in 11 children with Down syndrome undergoing haematopoietic stem cell transplantation for acute leukaemia. Bone Marrow Transplant 40:945–949PubMedCrossRefGoogle Scholar
  25. 25.
    Mullighan CG, Collins-Underwood JR, Phillips LA, Loudin MG, Liu W, Zhang J, Ma J, Coustan-Smith E, Harvey RC, Willman CL, Mikhail FM, Meyer J, Carroll AJ, Williams RT, Cheng J, Heerema NA, Basso G, Pession A, Pui CH, Raimondi SC, Hunger SP, Downing JR, Carroll WL, Rabin KR (2009) Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia. Nat Genet 41:1243–1246PubMedCrossRefGoogle Scholar
  26. 26.
    Muramatsu H, Kato K, Watanabe N, Matsumoto K, Nakamura T, Horikoshi Y, Mimaya J, Suzuki C, Hayakawa M, Kojima S (2008) Risk factors for early death in neonates with Down syndrome and transient leukaemia. Br J Haematol 142:610–615PubMedCrossRefGoogle Scholar
  27. 27.
    Roll JD, Reuther GW (2010) CRLF2 and JAK2 in B-progenitor acute lymphoblastic leukemia: a novel association in oncogenesis. Cancer Res 70:7347–7352PubMedCrossRefGoogle Scholar
  28. 28.
    Rubin CM, Mick R, Johnson FL (1996) Bone marrow transplantation for the treatment of haematological disorders in Down’s syndrome: toxicity and outcome. Bone Marrow Transplant 18:533–540PubMedGoogle Scholar
  29. 29.
    Tandonnet J, Clavel J, Baruchel A, Nacka F, Pérel Y (2010) Myeloid leukaemia in children with Down syndrome: report of the registry-based French experience between 1990 and 2003. Pediatr Blood Cancer 54:927–933PubMedCrossRefGoogle Scholar
  30. 30.
    Tchernia G, Lejeune F, Boccara JF, Denavit MF, Dommergues JP, Bernaudin F (1996) Erythroblastic and/or megakaryoblastic leukemia in Down syndrome: treatment with low-dose arabinosyl cytosine. J Pediatr Hematol Oncol 18:59–62PubMedCrossRefGoogle Scholar
  31. 31.
    Tunstall-Pedoe O, Roy A, Karadimitris A, de la Fuente J, Fisk NM, Bennett P, Norton A, Vyas P, Roberts I (2008) Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations. Blood 112:4507–4511PubMedCrossRefGoogle Scholar
  32. 32.
    Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, Le Beau MM, Crispino JD (2002) Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 32:148–152PubMedCrossRefGoogle Scholar
  33. 33.
    Weijerman ME, de Winter JP (2010) Clinical practice. the care of children with Down syndrome. Eur J Pediatr 169:1445–1452PubMedCrossRefGoogle Scholar
  34. 34.
    Whitlock JA, Sather HN, Gaynon P, Robison LL, Wells RJ, Trigg M, Heerema NA, Bhatia S (2005) Clinical characteristics and outcome of children with Down syndrome and acute lymphoblastic leukemia: a Children’s Cancer Group study. Blood 106:4043–4049PubMedCrossRefGoogle Scholar
  35. 35.
    Xavier AC, Ge Y, Taub J (2010) Unique clinical and biological features of leukemia in Down syndrome children. Expert Rev Hematol 3:175–186PubMedCrossRefGoogle Scholar
  36. 36.
    Zwaan CM, Kaspers GJ, Pieters R, Hählen K, Janka-Schaub GE, van Zantwijk CH, Huismans DR, de Vries E, Rots MG, Peters GJ, Jansen G, Creutzig U, Veerman AJ (2002) Different drug sensitivity profiles of acute myeloid and lymphoblastic leukemia and normal peripheral blood mononuclear cells in children with and without Down syndrome. Blood 99:245–251PubMedCrossRefGoogle Scholar
  37. 37.
    Zwaan CM, Reinhardt D, Hitzler J, Vyas P (2010) Acute leukemias in children with Down syndrome. Hematol Oncol Clin North Am 24:19–34PubMedCrossRefGoogle Scholar
  38. 38.
    Zwaan MC, Reinhardt D, Hitzler J, Vyas P (2008) Acute leukemias in children with Down syndrome. Pediatr Clin North Am 55:53–70PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Department of Pediatric Hematology Oncology, Cliniques Universitaires Saint-LucUniversité Catholique de LouvainBrusselsBelgium

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