Official reprint from UpToDate®
www.uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Transient myeloproliferative disorder of Down syndrome

Johann Hitzler, MD, FRCP(C), FAAP
Moira Garraus, MD
Section Editor
Julie R Park, MD
Deputy Editor
Alan G Rosmarin, MD


Down syndrome (DS, constitutional trisomy 21, OMIM #190685) is the most common chromosome abnormality among live born infants. It is the most frequent form of intellectual disability caused by a microscopically demonstrable chromosomal aberration.

The syndrome manifests as developmental delay and a spectrum of congenital malformations that may include the heart (eg, atrioventricular septal defect), gastrointestinal tract (eg, duodenal stenosis or atresia, imperforate anus, Hirschsprung disease), musculoskeletal system, and other organs. (See "Down syndrome: Clinical features and diagnosis".)

Hematologic abnormalities affecting red blood cells, white blood cells, and platelets are common in DS, particularly during childhood. Population-based studies show that risk for leukemia is 10 to 20 times higher in individuals with DS compared with the overall population, with a particularly striking increase of the incidence of acute myeloid leukemia (AML) in young children with DS (approximately 150-fold). (See "Down syndrome: Clinical features and diagnosis", section on 'Hematologic disorders'.)

In addition, children with DS frequently develop a transient myeloproliferative disorder (TMD) during the newborn period and early infancy (also termed transient leukemia and transient abnormal myelopoiesis). This pre-leukemic disorder poses diagnostic challenges, requires a differentiated approach to management, and plays an important pathogenetic role in the development of AML in children with DS.

The clinical features, diagnosis, and management of TMD of DS will be presented here. The epidemiology, clinical features, diagnosis, and general management of children with DS are discussed separately. (See "Down syndrome: Clinical features and diagnosis" and "Down syndrome: Management".)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Dec 2017. | This topic last updated: Aug 28, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2018 UpToDate, Inc.
  1. Zipursky A, Brown E, Christensen H, et al. Leukemia and/or myeloproliferative syndrome in neonates with Down syndrome. Semin Perinatol 1997; 21:97.
  2. Zipursky A. Transient leukaemia--a benign form of leukaemia in newborn infants with trisomy 21. Br J Haematol 2003; 120:930.
  3. Roberts I, Alford K, Hall G, et al. GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia. Blood 2013; 122:3908.
  4. Klusmann JH, Creutzig U, Zimmermann M, et al. Treatment and prognostic impact of transient leukemia in neonates with Down syndrome. Blood 2008; 111:2991.
  5. Massey GV, Zipursky A, Chang MN, et al. 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 2006; 107:4606.
  6. Gamis AS, Alonzo TA, Gerbing RB, et al. Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971. Blood 2011; 118:6752.
  7. Gamis AS, Smith FO. Transient myeloproliferative disorder in children with Down syndrome: clarity to this enigmatic disorder. Br J Haematol 2012; 159:277.
  8. Rozen L, Huybrechts S, Dedeken L, et al. Transient leukemia in a newborn without Down syndrome: case report and review of the literature. Eur J Pediatr 2014; 173:1643.
  9. Tsai MH, Hou JW, Yang CP, et al. Transient myeloproliferative disorder and GATA1 mutation in neonates with and without Down syndrome. Indian J Pediatr 2011; 78:826.
  10. Apollonsky N, Shende A, Ouansafi I, et al. Transient myeloproliferative disorder in neonates with and without Down syndrome: a tale of 2 syndromes. J Pediatr Hematol Oncol 2008; 30:860.
  11. Ono R, Hasegawa D, Hirabayashi S, et al. Acute megakaryoblastic leukemia with acquired trisomy 21 and GATA1 mutations in phenotypically normal children. Eur J Pediatr 2015; 174:525.
  12. Schifferli A, Hitzler J, Bartholdi D, et al. Transient myeloproliferative disorder in neonates without Down syndrome: case report and review. Eur J Haematol 2015; 94:456.
  13. Roberts I, Izraeli S. Haematopoietic development and leukaemia in Down syndrome. Br J Haematol 2014; 167:587.
  14. Tunstall-Pedoe O, Roy A, Karadimitris A, et al. Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations. Blood 2008; 112:4507.
  15. Chou ST, Opalinska JB, Yao Y, et al. Trisomy 21 enhances human fetal erythro-megakaryocytic development. Blood 2008; 112:4503.
  16. Wechsler J, Greene M, McDevitt MA, et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 2002; 32:148.
  17. Groet J, McElwaine S, Spinelli M, et al. Acquired mutations in GATA1 in neonates with Down's syndrome with transient myeloid disorder. Lancet 2003; 361:1617.
  18. Hitzler JK, Cheung J, Li Y, et al. GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood 2003; 101:4301.
  19. Rainis L, Bercovich D, Strehl S, et al. Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. Blood 2003; 102:981.
  20. Xu G, Nagano M, Kanezaki R, et al. Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome. Blood 2003; 102:2960.
  21. Ahmed M, Sternberg A, Hall G, et al. Natural history of GATA1 mutations in Down syndrome. Blood 2004; 103:2480.
  22. Ogawa J, Kanegane H, Tsuneyama K, et al. Platelet-derived growth factor may be associated with fibrosis in a Down syndrome patient with transient myeloproliferative disorder. Eur J Haematol 2008; 81:58.
  23. Kobayashi K, Yoshioka T, Miyauchi J, et al. Monocyte Chemoattractant Protein-1 (MCP-1) as a Potential Therapeutic Target and a Noninvasive Biomarker of Liver Fibrosis Associated With Transient Myeloproliferative Disorder in Down Syndrome. J Pediatr Hematol Oncol 2017; 39:e285.
  24. Rainis L, Toki T, Pimanda JE, et al. The proto-oncogene ERG in megakaryoblastic leukemias. Cancer Res 2005; 65:7596.
  25. Hitzler JK, Zipursky A. Origins of leukaemia in children with Down syndrome. Nat Rev Cancer 2005; 5:11.
  26. van den Berg H, Hopman AH, Kraakman KC, de Jong D. Spontaneous remission in congenital leukemia is not related to (mosaic) trisomy 21: case presentation and literature review. Pediatr Hematol Oncol 2004; 21:135.
  27. Yoshida K, Toki T, Okuno Y, et al. The landscape of somatic mutations in Down syndrome-related myeloid disorders. Nat Genet 2013; 45:1293.
  28. Nikolaev SI, Santoni F, Vannier A, et al. Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome. Blood 2013; 122:554.
  29. Al-Kasim F, Doyle JJ, Massey GV, et al. Incidence and treatment of potentially lethal diseases in transient leukemia of Down syndrome: Pediatric Oncology Group Study. J Pediatr Hematol Oncol 2002; 24:9.
  30. Heald B, Hilden JM, Zbuk K, et al. Severe TMD/AMKL with GATA1 mutation in a stillborn fetus with Down syndrome. Nat Clin Pract Oncol 2007; 4:433.
  31. Ansari DO, Lapping-Carr G, Alikhan M, et al. A neonate with a vesiculopustular rash. Pediatr Ann 2015; 44:e1.
  32. Winckworth LC, Chonat S, Uthaya S. Cutaneous lesions in transient abnormal myelopoiesis. J Paediatr Child Health 2012; 48:184.
  33. Narvaez-Rosales V, de-Ocariz MS, Carrasco-Daza D, et al. Neonatal vesiculopustular eruption associated with transient myeloproliferative disorder: report of four cases. Int J Dermatol 2013; 52:1202.
  34. Nornhold E, Li A, Rothman IL, et al. Vesiculopustular eruption associated with transient myeloproliferative disorder. Cutis 2009; 83:234.
  35. Zipursky A, Rose T, Skidmore M, et al. Hydrops fetalis and neonatal leukemia in Down syndrome. Pediatr Hematol Oncol 1996; 13:81.
  36. Roy A, Roberts I, Vyas P. Biology and management of transient abnormal myelopoiesis (TAM) in children with Down syndrome. Semin Fetal Neonatal Med 2012; 17:196.
  37. Bombery M, Vergilio JA. Transient abnormal myelopoiesis in neonates: GATA get the diagnosis. Arch Pathol Lab Med 2014; 138:1302.
  38. Williams BA, Meyn MS, Hitzler JK. Transient leukemia in newborns without down syndrome: diagnostic and management challenges. J Pediatr Hematol Oncol 2011; 33:e261.
  39. Buitenkamp TD, Izraeli S, Zimmermann M, et al. Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group. Blood 2014; 123:70.
  40. Sorrell AD, Alonzo TA, Hilden JM, et al. Favorable survival maintained in children who have myeloid leukemia associated with Down syndrome using reduced-dose chemotherapy on Children's Oncology Group trial A2971: a report from the Children's Oncology Group. Cancer 2012; 118:4806.
  41. Creutzig U, Reinhardt D, Diekamp S, et al. AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity. Leukemia 2005; 19:1355.
  42. Kudo K, Kojima S, Tabuchi K, et al. 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 2007; 25:5442.
  43. Taub JW, Berman JN, Hitzler JK, et al. Improved outcomes for myeloid leukemia of Down syndrome: a report from the Children's Oncology Group AAML0431 trial. Blood 2017; 129:3304.
  44. Uffmann M, Rasche M, Zimmermann M, et al. Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial. Blood 2017; 129:3314.
  45. Massey GV. Transient leukemia in newborns with Down syndrome. Pediatr Blood Cancer 2005; 44:29.
  46. Tragiannidis A, Pana ZD, Papageorgiou T, et al. Transient myeloproliferative disorder in a newborn with down syndrome treated with rasburicase for the risk of development of tumor lysis syndrome: A case report. J Med Case Rep 2011; 5:407.
  47. Tamblyn JA, Norton A, Spurgeon L, et al. Prenatal therapy in transient abnormal myelopoiesis: a systematic review. Arch Dis Child Fetal Neonatal Ed 2016; 101:F67.
  48. Yasuoka K, Inoue H, Tanaka K, et al. Successful Liver Transplantation for Transient Abnormal Myelopoiesis-Associated Liver Failure. Neonatology 2017; 112:159.
  49. Hayasaka I, Cho K, Morioka K, et al. Exchange transfusion in patients with Down syndrome and severe transient leukemia. Pediatr Int 2015; 57:620.
  50. Bastida Vilá P, Olivé Oliveras T, Díaz de Heredia Rubio C, Ortega Aramburu JJ. [Transient neonatal myeloproliferative disorder in the absence of Down syndrome]. An Pediatr (Barc) 2004; 61:546.