Myelodysplasia and Myeloid Proliferations

  • Zeba N. SinghEmail author
  • Margaret L. Gulley
Part of the Molecular and Translational Medicine book series (MOLEMED)


Myelodysplastic syndrome (MDS) and myeloproliferative disorders are uncommon in the pediatric age group, each constituting less than 5 % of all hematological malignancies. The annual incidence of MDS per million for children up to 14 years of age is 1.8. There are several differences in MDS observed in children and those in adults (discussed later) due to which the classification systems developed for adult MDS (Leukemia 18(12):2008–2014, 2004; Blood 100(7):2292–2302, 2002) are less relevant in children. In the 2008 WHO classification childhood MDS is classified as a separate group. A provisional category of refractory cytopenia of childhood has been introduced to accommodate the significant proportion of children who present with persistent, idiopathic neutropenia or thrombocytopenia in the absence of anemia (Pathology and genetics of tumours of haematopoietic and lymphoid tissues. World Health Organization classification of tumours, 2008). MDS associated with Down syndrome is categorized separately by the WHO as “myeloid proliferations related to Down syndrome.” Philadelphia chromosome positive chronic myelogenous leukemia is rare in children, comprising 1–3 % of all childhood leukemias (Pediatrics 116(1):140–143, 2005). Juvenile myelomonocytic leukemia is a MDS/MPN overlap neoplasm that occurs in children and adolescents with an annual incidence of 1.2 per million children up to 14 years of age.


JMML Refractory cytopenia Down syndrome Transient myeloproliferative disorder Acute megakaryoblastic leukemia 


  1. 1.
    Hasle H, Baumann I, Bergstrasser E, Fenu S, Fischer A, Kardos G, et al. The international prognostic scoring system (IPSS) for childhood myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML). Leukemia. 2004;18(12):2008–14.PubMedGoogle Scholar
  2. 2.
    Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100(7):2292–302.PubMedGoogle Scholar
  3. 3.
    Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. World Health Organization classification of tumours. 4th ed. Lyon, France: IARC Press; 2008. p. 262.Google Scholar
  4. 4.
    Millot F, Traore P, Guilhot J, Nelken B, Leblanc T, Leverger G, et al. Clinical and biological features at diagnosis in 40 children with chronic myeloid leukemia. Pediatrics. 2005;116(1):140–3.PubMedGoogle Scholar
  5. 5.
    Hasle H. Myelodysplastic and myeloproliferative disorders in children. Curr Opin Pediatr. 2007;19(1):1–8.PubMedGoogle Scholar
  6. 6.
    Luna-Fineman S, Shannon KM, Atwater SK, Davis J, Masterson M, Ortega J, et al. Myelodysplastic and myeloproliferative disorders of childhood: a study of 167 patients. Blood. 1999;93(2):459–66.PubMedGoogle Scholar
  7. 7.
    Niemeyer CM, Arico M, Basso G, Biondi A, Cantu Rajnoldi A, Creutzig U, et al. Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European working group on myelodysplastic syndromes in childhood (EWOG-MDS). Blood. 1997;89(10):3534–43.PubMedGoogle Scholar
  8. 8.
    Emanuel PD, Bates L, Castleberry RP, Gualtieri RJ, Zuckerman KS. Selective hypersensitivity to granulocyte-macrophage colony-stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors. Blood. 1991;77(5):925–9.PubMedGoogle Scholar
  9. 9.
    Emanuel PD. RAS pathway mutations in juvenile myelomonocytic leukemia. Acta Haematol. 2008;119(4):207–11.PubMedGoogle Scholar
  10. 10.
    Flotho C, Valcamonica S, Mach-Pascual S, Schmahl G, Corral L, Ritterbach J, et al. RAS mutations and clonality analysis in children with juvenile myelomonocytic leukemia (JMML). Leukemia. 1999;13(1):32–7.PubMedGoogle Scholar
  11. 11.
    Miyauchi J, Asada M, Sasaki M, Tsunematsu Y, Kojima S, Mizutani S. Mutations of the N-ras gene in juvenile chronic myelogenous leukemia. Blood. 1994;83(8997):2248–54.PubMedGoogle Scholar
  12. 12.
    Shen M, Harper PS, Upadhyaya M. Molecular genetics of neurofibromatosis type 1 (NF1). J Med Genet. 1996;33(1):2–17.PubMedGoogle Scholar
  13. 13.
    Side L, Taylor B, Cayouette M, Conner E, Thompson P, Luce M, et al. Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders. N Engl J Med. 1997;336(24):1713–20.PubMedGoogle Scholar
  14. 14.
    Maris JM, Wiersma SR, Mahgoub N, Thompson P, Geyer RJ, Hurwitz CG, et al. Monosomy 7 myelodysplastic syndrome and other second malignant neoplasms in children with neurofibromatosis type 1. Cancer. 1997;79(7):1438–46.PubMedGoogle Scholar
  15. 15.
    Side LE, Emanuel PD, Taylor B, Franklin J, Thompson P, Castleberry RP, et al. Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1. Blood. 1998;92(1):267–72.PubMedGoogle Scholar
  16. 16.
    Bastida P, Garcia-Minaur S, Ezquieta B, Dapena JL, Sanchez de Toledo J. Myeloproliferative disorder in Noonan syndrome. J Pediatr Hematol Oncol. 2011;33(1):e43–5.PubMedGoogle Scholar
  17. 17.
    Tartaglia M, Zampino G, Gelb BD. Noonan syndrome: clinical aspects and molecular pathogenesis. Mol Syndromol. 2010;1(1):2–26.PubMedGoogle Scholar
  18. 18.
    Cirstea IC, Kutsche K, Dvorsky R, Gremer L, Carta C, Horn D, et al. A restricted spectrum of NRAS mutations causes Noonan syndrome. Nat Genet. 2010;42(1):27–9.PubMedGoogle Scholar
  19. 19.
    Martinelli S, De Luca A, Stellacci E, Rossi C, Checquolo S, Lepri F, et al. Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype. Am J Hum Genet. 2010;87(2):250–7.PubMedGoogle Scholar
  20. 20.
    Roberts AE, Araki T, Swanson KD, Montgomery KT, Schiripo TA, Joshi VA, et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet. 2007;39(1):70–4.PubMedGoogle Scholar
  21. 21.
    Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003;34(2):148–50.PubMedGoogle Scholar
  22. 22.
    Loh ML, Vattikuti S, Schubbert S, Reynolds MG, Carlson E, Lieuw KH, et al. Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood. 2004;103(6):2325–31.PubMedGoogle Scholar
  23. 23.
    Kratz CP, Niemeyer CM, Castleberry RP, Cetin M, et. al. The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood. 2005;106(6): 2183–85.PubMedGoogle Scholar
  24. 24.
    Liu YL, Castleberry RP, Emanuel PD. PTEN deficiency is a common defect in juvenile myelomonocytic leukemia. Leuk Res. 2009;33(5):671–7.PubMedGoogle Scholar
  25. 25.
    Loh ML, Sakai DS, Flotho C, Kang M, Fliegauf M, Archambeault S, et al. Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood. 2009;114(9):1859–63.PubMedGoogle Scholar
  26. 26.
    Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissue (IARC WHO classification of tumours). 4th ed. Lyon, France: IARC press; 2008.Google Scholar
  27. 27.
    Pinkel D. Differentiating juvenile myelomonocytic leukemia from infectious disease. Blood. 1998;91(171):365–7.PubMedGoogle Scholar
  28. 28.
    Cioc AM, Wagner JE, MacMillan ML, DeFor T, Hirsch B. Diagnosis of myelodysplastic syndrome among a cohort of 119 patients with fanconi anemia: morphologic and cytogenetic characteristics. Am J Clin Pathol. 2010;133(1):92–100.PubMedGoogle Scholar
  29. 29.
    Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the world health organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5):937–51.PubMedGoogle Scholar
  30. 30.
    Manabe A, Yoshimasu T, Ebihara Y, Yagasaki H, Wada M, Ishikawa K, et al. Viral infections in juvenile myelomonocytic leukemia: prevalence and clinical implications. J Pediatr Hematol Oncol. 2004;26(10):636–41.PubMedGoogle Scholar
  31. 31.
    Watanabe N, Yoshimi A, Kamachi Y, Kawabe T, Muramatsu H, Matsumoto K, et al. Wiskott-Aldrich syndrome is an important differential diagnosis in male infants with juvenile myelomonocytic leukemialike features. J Pediatr Hematol Oncol. 2007;29(12):836–8.PubMedGoogle Scholar
  32. 32.
    Archambeault S, Flores NJ, Yoshimi A, Kratz CP, Reising M, Fischer A, et al. Development of an allele-specific minimal residual disease assay for patients with juvenile myelomonocytic leukemia. Blood. 2008;111(3):1124–7.PubMedGoogle Scholar
  33. 33.
    Yoshida N, Yagasaki H, Xu Y, Matsuda K, Yoshimi A, Takahashi Y, et al. Correlation of clinical features with the mutational status of GM-CSF signaling pathway-related genes in juvenile myelomonocytic leukemia. Pediatr Res. 2009;65(3):334–40.PubMedGoogle Scholar
  34. 34.
    Haferlach T, Kohlmann A, Wieczorek L, Basso G, Kronnie GT, Bene MC, et al. Clinical utility of microarray-based gene expression profiling in the diagnosis and subclassification of leukemia: report from the international microarray innovations in leukemia study group. J Clin Oncol. 2010;28(15):2529–37.PubMedGoogle Scholar
  35. 35.
    Mills KI, Kohlmann A, Williams PM, Wieczorek L, Liu WM, Li R, et al. Microarray-based classifiers and prognosis models identify subgroups with distinct clinical outcomes and high risk of AML transformation of myelodysplastic syndrome. Blood. 2009;114(5):1063–72.PubMedGoogle Scholar
  36. 36.
    Bresolin S, Zecca M, Flotho C, Trentin L, Zangrando A, Sainati L, et al. Gene expression-based classification as an independent predictor of clinical outcome in juvenile myelomonocytic leukemia. J Clin Oncol. 2010;28(11):1919–27.PubMedGoogle Scholar
  37. 37.
    Chang YH, Jou ST, Lin DT, Lu MY, Lin KH. Differentiating juvenile myelomonocytic leukemia from chronic myeloid leukemia in childhood. J Pediatr Hematol Oncol. 2004;26(4):236–42.PubMedGoogle Scholar
  38. 38.
    Gupta N, Gupta R, Sharawat SK, Bakhshi S. Childhood chronic myeloid leukemia with monocytosis. Indian J Pediatr. 2010;77(10):1143–5.PubMedGoogle Scholar
  39. 39.
    Aurer I, Butturini A, Gale RP. BCR-ABL rearrangements in children with Philadelphia chromosome-positive chronic myelogenous leukemia. Blood. 1991;78(9):2407–10.PubMedGoogle Scholar
  40. 40.
    Scrideli CA, de Oliveira FM, Brassesco MS, de Paula QR, Bernardes JE, Valera ET, et al. Is p190 bcr-abl rearrangement necessary for acute transformation in some p210 CML of childhood? Leuk Res. 2009;33(3):495–9.PubMedGoogle Scholar
  41. 41.
    Hasle H, Kerndrup G, Jacobsen BB. Childhood myelodysplastic syndrome in Denmark: incidence and predisposing conditions. Leukemia. 1995;9(9):1569–72.PubMedGoogle Scholar
  42. 42.
    Rytting ME. Pediatric myelodysplastic syndromes. Curr Hematol Rep. 2004;3(3):173–7.PubMedGoogle Scholar
  43. 43.
    Niemeyer CM, Kratz CP, Hasle H. Pediatric myelodysplastic syndromes. Curr Treat Options Oncol. 2005;6(3):209–14.PubMedGoogle Scholar
  44. 44.
    McKenna RW. Myelodysplasia and myeloproliferative disorders in children. Am J Clin Pathol. 2004;122(Suppl):S58–69.PubMedGoogle Scholar
  45. 45.
    Mueller BU, Tannenbaum S, Pizzo PA. Bone marrow aspirates and biopsies in children with human immunodeficiency virus infection. J Pediatr Hematol Oncol. 1996;18:266–71.PubMedGoogle Scholar
  46. 46.
    Alter BP. Bone marrow failure: a child is not just a small adult (but an adult can have a childhood disease). Hematology Am Soc Hematol Educ Program. 2005:96–103.Google Scholar
  47. 47.
    Alter BP. Diagnosis, genetics, and management of inherited bone marrow failure syndromes. Hematology Am Soc Hematol Educ Program. 2007:29–39.Google Scholar
  48. 48.
    Clinton C, Gazda HT. Diamond-Blackfan anemia. In: Pagon RA, Bird TC, Dolan CR, et al., editors. GeneReviews. Seattle: University of Washington; 1993.Google Scholar
  49. 49.
    Dror Y. Shwachman-Diamond syndrome: implications for understanding the molecular basis of leukaemia. Expert Rev Mol Med. 2008;10:e38.PubMedGoogle Scholar
  50. 50.
    Kearns WG, Sutton JF, Maciejewski JP, Young NS, Liu JM. Genomic instability in bone marrow failure syndromes. Am J Hematol. 2004;76(3):220–4.PubMedGoogle Scholar
  51. 51.
    Morrissette JJD, de Chadarevian JP, Kolb EA. Familial mosaic monosomy 7 syndrome. In: Pagon RA, Bird TC, Dolan CR, et al., editors. GeneReviews. Seattle: University of Washington; 1993.Google Scholar
  52. 52.
    Shimamura A. Inherited bone marrow failure syndromes: molecular features. Hematology Am Soc Hematol Educ Program. 2006:63–71.Google Scholar
  53. 53.
    Bader-Meunier B, Rötig A, Mielot F, Lavergne JM, Croisille L, Rustin P, et al. Refractory anaemia and mitochondrial cytopathy in childhood. Br J Haematol. 1994;87(2):381–5.PubMedGoogle Scholar
  54. 54.
    Hasle H. Myelodysplastic syndromes in childhood–classification, epidemiology, and treatment. Leuk Lymphoma. 1994;13(1–2):11–26.PubMedGoogle Scholar
  55. 55.
    Polychronopoulou S, Panagiotou JP, Kossiva L, Mavrou A, Anagnostou D, Haidas S. Clinical and morphological features of paediatric myelodysplastic syndromes: a review of 34 cases. Acta Paediatr. 2004;93(8):1015–23.PubMedGoogle Scholar
  56. 56.
    Tuncer MA, Pagliuca A, Hicsonmez G, Yetgin S, Ozsoylu S, Mufti GJ. Primary myelodysplastic syndrome in children: the clinical experience in 33 cases. Br J Haematol. 1992;82(2):347–53.PubMedGoogle Scholar
  57. 57.
    Angelidis P, Kojouri K, Lee J, Kern W, Mulvihill JJ, Li S. Trisomy 1q in a patient with severe aplastic anemia. Cancer Genet Cytogenet. 2006;169(1):73–5.PubMedGoogle Scholar
  58. 58.
    Maciejewski JP, Selleri C. Evolution of clonal cytogenetic abnormalities in aplastic anemia. Leuk Lymphoma. 2004;45(3):433–40.PubMedGoogle Scholar
  59. 59.
    Koh Y, Lee HR, Song EY, Kim HK, Kim I, Park S, et al. Hypoplastic myelodysplastic syndrome (h-MDS) is a distinctive clinical entity with poorer prognosis and frequent karyotypic and FISH abnormalities compared to aplastic anemia (AA). Leuk Res. 2010;34(10):1344–50.PubMedGoogle Scholar
  60. 60.
    Ohshima K, Karube K, Shimazaki K, Kamma H, Suzumiya J, Hamasaki M, et al. Imbalance between apoptosis and telomerase activity in myelodysplastic syndromes: possible role in ineffective hemopoiesis. Leuk Lymphoma. 2003;44(8):1339–46.PubMedGoogle Scholar
  61. 61.
    Parker JE, Mufti GJ, Rasool F, Mijovic A, Devereux S, Pagliuca A. The role of apoptosis, proliferation, and the bcl-2-related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS. Blood. 2000;96(12):3932–8.PubMedGoogle Scholar
  62. 62.
    Papadaki HA, Eliopoulos GD. The role of apoptosis in the pathophysiology of chronic neutropenias associated with bone marrow failure. Cell Cycle (Georgetown, Tex). 2003;2(5):447–51.Google Scholar
  63. 63.
    Rosselli F. Fanconi anaemia syndrome and apoptosis: state of the art. Apoptosis. 1998;3:229–36.PubMedGoogle Scholar
  64. 64.
    Parikh S, Bessler M. Recent insights into inherited bone marrow failure syndromes. Curr Opin Pediatr. 2012;24(1):23–32.PubMedGoogle Scholar
  65. 65.
    D’Andrea AD, Grompe M. The fanconi anaemia/BRCA pathway. Nat Rev Cancer. 2003;3:23–34.PubMedGoogle Scholar
  66. 66.
    Carlsson G, Aprikyan AA, Tehranchi R, Dale DC, Porwit A, Hellström-Lindberg E, et al. Kostmann syndrome: severe congenital neutropenia associated with defective expression of Bcl-2, constitutive mitochondrial release of cytochrome c, and excessive apoptosis of myeloid progenitor cells. Blood. 2004;103(9):3355–61.PubMedGoogle Scholar
  67. 67.
    Liu JM, Ellis SR. Ribosomes and marrow failure: coincidental association or molecular paradigm? Blood. 2006;107:4583–8.PubMedGoogle Scholar
  68. 68.
    Dokal I. Fanconi’s anaemia and related bone marrow failure syndromes. Br Med Bull. 2006;77–78:37–53.PubMedGoogle Scholar
  69. 69.
    Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D, et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet. 1999;23:166–75.PubMedGoogle Scholar
  70. 70.
    Antillon F, Raimondi SC, Fairman J, Liang H, Nagarajan L, Head D, et al. 5q- in a child with refractory anemia with excess blasts: similarities to 5q- syndrome in adults. Cancer Genet Cytogenet. 1998;105(2):119–22.PubMedGoogle Scholar
  71. 71.
    Kardos G, Baumann I, Passmore SJ, Locatelli F, Hasle H, Schultz KR, et al. Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7. Blood. 2003;102(6):1997–2003.PubMedGoogle Scholar
  72. 72.
    Touliatou V, Kolialexi A, Tsangaris GT, Moschovi M, Polychronopoulou S, Mavrou A. Conventional cytogenetics and fluorescence in situ hybridization in persistent cytopenias and myelodysplastic syndromes in childhood. Anticancer Res. 2004;24(6):3945–9.PubMedGoogle Scholar
  73. 73.
    Tsurusawa M, Manabe A, Hayashi Y, Akiyama Y, Kigasawa H, Inada H, et al. Therapy-related myelodysplastic syndrome in childhood: a retrospective study of 36 patients in Japan. Leuk Res. 2005;29(6):625–32.PubMedGoogle Scholar
  74. 74.
    Mehta PA, Harris RE, Davies SM, Kim MO, Mueller R, Lampkin B, et al. Numerical chromosomal changes and risk of development of myelodysplastic syndrome—acute myeloid leukemia in patients with fanconi anemia. Cancer Genet Cytogenet. 2010;203(2):180–6.PubMedGoogle Scholar
  75. 75.
    Lasky J, Sakamoto KM. Topics in pediatric leukemia—myelodysplastic and myeloproliferative disorders of childhood. MedGenMed. 2005;7(1):21.PubMedGoogle Scholar
  76. 76.
    Pitman SD, Victorio A, Rowsell E, Morris J, Wang J. 5q- syndrome in a child with slowly progressive pancytopenia: a case report and review of the literature. J Pediatr Hematol Oncol. 2006;28(3):115–9.PubMedGoogle Scholar
  77. 77.
    Shikano T, Ishikawa Y, Anakura M. Myelodysplastic syndrome with partial deletion of the long arm of chromosome 5: first report of a case in a child. Acta Paediatr Jpn. 1992;34(5):539–42.PubMedGoogle Scholar
  78. 78.
    Uyttebroeck A, Brock P, De Groote B, Renard M, Dal Cin P, Van den Berghe H, et al. 5q- syndrome in a child. Cancer Genet Cytogenet. 1995;80(2):121–3.PubMedGoogle Scholar
  79. 79.
    Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89(6):2079–88.PubMedGoogle Scholar
  80. 80.
    Passmore SJ, Hann IM, Stiller CA, Ramani P, Swansbury GJ, Gibbons B, et al. Pediatric myelodysplasia: a study of 68 children and a new prognostic scoring system. Blood. 1995;85(7):1742–50.PubMedGoogle Scholar
  81. 81.
    Mandel K, Dror Y, Poon A, Freedman MH. A practical, comprehensive classification for pediatric myelodysplastic syndromes: the CCC system. J Pediatr Hematol Oncol. 2002;24(5):343–52.PubMedGoogle Scholar
  82. 82.
    Mrozek K, Prior TW, Edwards C, Marcucci G, Carroll AJ, Snyder PJ, et al. Comparison of cytogenetic and molecular genetic detection of t(8;21) and inv(16) in a prospective series of adults with de novo acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol. 2001;19(9):2482–92.PubMedGoogle Scholar
  83. 83.
    Bernasconi P, Cavigliano PM, Boni M, Calatroni S, Klersy C, Giardini I, et al. Is FISH a relevant prognostic tool in myelodysplastic syndromes with a normal chromosome pattern on conventional cytogenetics? A study on 57 patients. Leukemia. 2003;17(11):2107–12.PubMedGoogle Scholar
  84. 84.
    Costa D, Valera S, Carrio A, Arias A, Munoz C, Rozman M, et al. Do we need to do fluorescence in situ hybridization analysis in myelodysplastic syndromes as often as we do? Leuk Res. 2010;34(11):1437–41.PubMedGoogle Scholar
  85. 85.
    Cuneo A, Bigoni R, Cavazzini F, Bardi A, Roberti MG, Agostini P, et al. Incidence and significance of cryptic chromosome aberrations detected by fluorescence in situ hybridization in acute myeloid leukemia with normal karyotype. Leukemia. 2002;16(9):1745–51.PubMedGoogle Scholar
  86. 86.
    Flactif M, Lai JL, Preudhomme C, Fenaux P. Fluorescence in situ hybridization improves the detection of monosomy 7 in myelodysplastic syndromes. Leukemia. 1994;8(6):1012–8.PubMedGoogle Scholar
  87. 87.
    Jakovleva K, Ogard I, Arvidsson I, Jacobsson B, Swolin B, Hast R. Masked monosomy 7 in myelodysplastic syndromes is uncommon and of undetermined clinical significance. Leuk Res. 2001;25(3):197–203.PubMedGoogle Scholar
  88. 88.
    Mallo M, Arenillas L, Espinet B, Salido M, Hernandez JM, Lumbreras E, et al. Fluorescence in situ hybridization improves the detection of 5q31 deletion in myelodysplastic syndromes without cytogenetic evidence of 5q-. Haematologica. 2008;93(7):1001–8.PubMedGoogle Scholar
  89. 89.
    Panani AD, Pappa V. Hidden chromosome 8 abnormalities detected by FISH in adult primary myelodysplastic syndromes. In Vivo. 2005;19(6):979–81.PubMedGoogle Scholar
  90. 90.
    Rigolin GM, Bigoni R, Milani R, Cavazzini F, Roberti MG, Bardi A, et al. Clinical importance of interphase cytogenetics detecting occult chromosome lesions in myelodysplastic syndromes with normal karyotype. Leukemia. 2001;15(12):1841–7.PubMedGoogle Scholar
  91. 91.
    Romeo M, Chauffaille Mde L, Silva MR, Bahia DM, Kerbauy J. Comparison of cytogenetics with FISH in 40 myelodysplastic syndrome patients. Leuk Res. 2002;26(11):993–6.PubMedGoogle Scholar
  92. 92.
    Wilkens L, Tchinda J, Burkhardt D, Nolte M, Werner M, Georgii A. Analysis of hematologic diseases using conventional karyotyping, fluorescence in situ hybridization (FISH), and comparative genomic hybridization (CGH). Hum Pathol. 1998;29(8):833–9.PubMedGoogle Scholar
  93. 93.
    Wilkens L, Burkhardt D, Tchinda J, Busche G, Werner M, Nolte M, et al. Cytogenetic aberrations in myelodysplastic syndrome detected by comparative genomic hybridization and fluorescence in situ hybridization. Diagn Mol Pathol. 1999;8(1):47–53.PubMedGoogle Scholar
  94. 94.
    Cherry AM, Brockman SR, Paternoster SF, Hicks GA, Neuberg D, Higgins RR, et al. Comparison of interphase FISH and metaphase cytogenetics to study myelodysplastic syndrome: an eastern cooperative oncology group (ECOG) study. Leuk Res. 2003;27(12):1085–90.PubMedGoogle Scholar
  95. 95.
    Ketterling RP, Wyatt WA, VanWier SA, Law M, Hodnefield JM, Hanson CA, et al. Primary myelodysplastic syndrome with normal cytogenetics: utility of ‘FISH panel testing’ and M-FISH. Leuk Res. 2002;26(3):235–40.PubMedGoogle Scholar
  96. 96.
    Pitchford CW, Hettinga AC, Reichard KK. Fluorescence in situ hybridization testing for −5/5q, -7/7q, +8, and del(20q) in primary myelodysplastic syndrome correlates with conventional cytogenetics in the setting of an adequate study. Am J Clin Pathol. 2010;133(2):260–4.PubMedGoogle Scholar
  97. 97.
    Douet-Guilbert N, Herry A, LE Bris MJ, Gueganic N, Bovo C, Morel F, et al. Interphase FISH does not improve the detection of DEL(5q) and DEL(20q) in myelodysplastic syndromes. Anticancer Res. 2011;31(3):1007–10.PubMedGoogle Scholar
  98. 98.
    Bench AJ, Nacheva EP, Hood TL, Holden JL, French L, Swanton S, et al. Chromosome 20 deletions in myeloid malignancies: reduction of the common deleted region, generation of a PAC/BAC contig and identification of candidate genes. UK cancer cytogenetics group (UKCCG). Oncogene. 2000;19(34):3902–13.PubMedGoogle Scholar
  99. 99.
    Hackanson B, Robbel C, Wijermans P, Lübbert M. In vivo effects of decitabine in myelodysplasia and acute myeloid leukemia: review of cytogenetic and molecular studies. Ann Hematol. 2005;84(1):32–8.PubMedGoogle Scholar
  100. 100.
    Zhao N, Stoffel A, Wang PW, Eisenbart JD, Espinosa III R, Larson RA, et al. Molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases to 1–1.5 mb and preparation of a PAC-based physical map. Proc Natl Acad Sci USA. 1997;94(13):6948–53.PubMedGoogle Scholar
  101. 101.
    Anastasi J, Vardiman JW, Rudinsky R, Patel M, Nachman J, Rubin CM, et al. Direct correlation of cytogenetic findings with cell morphology using in situ hybridization: an analysis of suspicious cells in bone marrow specimens of two patients completing therapy for acute lymphoblastic leukemia. Blood. 1991;77(11):2456–62.PubMedGoogle Scholar
  102. 102.
    Anderson K, Arvidsson I, Jacobsson B, Hast R. Fluorescence in situ hybridization for the study of cell lineage involvement in myelodysplastic syndromes with chromosome 5 anomalies. Cancer Genet Cytogenet. 2002;136(2):101–7.PubMedGoogle Scholar
  103. 103.
    Lockwood WW, Chari R, Chi B, Lam WL. Recent advances in array comparative genomic hybridization technologies and their applications in human genetics. Eur J Hum Genet. 2006;14:139–48.PubMedGoogle Scholar
  104. 104.
    Gondek LP, Haddad AS, O’Keefe CL, Tiu R, Wlodarski MW, Sekeres MA, et al. Detection of cryptic chromosomal lesions including acquired segmental uniparental disomy in advanced and low-risk myelodysplastic syndromes. Exp Hematol. 2007;35(11):1728–38.PubMedGoogle Scholar
  105. 105.
    Gondek LP, Tiu R, O’Keefe CL, Sekeres MA, Theil KS, Maciejewski JP. Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD, and MDS-derived AML. Blood. 2008;111(3):1534–42.PubMedGoogle Scholar
  106. 106.
    Makishima H, Rataul M, Gondek LP, Huh J, Cook JR, Theil KS, et al. FISH and SNP-A karyotyping in myelodysplastic syndromes: improving cytogenetic detection of del(5q), monosomy 7, del(7q), trisomy 8 and del(20q). Leuk Res. 2010;34(4):447–53.PubMedGoogle Scholar
  107. 107.
    O’Keefe CL, Tiu R, Gondek LP, Powers J, Theil KS, Kalaycio M, et al. High-resolution genomic arrays facilitate detection of novel cryptic chromosomal lesions in myelodysplastic syndromes. Exp Hematol. 2007;35(2):240–51.PubMedGoogle Scholar
  108. 108.
    Tiu RV, Gondek LP, O’Keefe CL, Elson P, Huh J, Mohamedali A, et al. Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Blood. 2011;117(17):4552–60.PubMedGoogle Scholar
  109. 109.
    Cannon HE. Acute lymphatic leukemia: report of a case in an eleventh month Mongolian idiot. New Orleans Med Surg J. 1930;94(3):289–93.Google Scholar
  110. 110.
    Kivivuori SM, Rajantie J, Siimes MA. Peripheral blood cell counts in infants with Down’s syndrome. Clin Genet. 1996;49:15–9.PubMedGoogle Scholar
  111. 111.
    Hasle H, Clemmensen IH, Mikkelsen M. Risks of leukaemia and solid tumors in individuals with Down’s syndrome. Lancet. 2000;355:165–9.PubMedGoogle Scholar
  112. 112.
    Xavier AC, Ge Y, Taub JW. Down syndrome and malignancies: a unique clinical relationship: a paper from the 2008 William Beaumont Hospital symposium on molecular pathology. J Mol Diagn. 2009;11(5):371–80.PubMedGoogle Scholar
  113. 113.
    Yang Q, Rasmussen SA, Friedman JM. Mortality associated with Down’s syndrome in the USA from 1983 to 1997: a population-based study. Lancet. 2002;359(9311):1019–25.PubMedGoogle Scholar
  114. 114.
    Fonatsch C. The role of chromosome 21 in hematology and oncology. Genes Chromosomes Cancer. 2010;49(6):497–508.PubMedGoogle Scholar
  115. 115.
    Roy A, Roberts I, Norton A, Vyas P. Acute megakaryoblastic leukaemia (AMKL) and transient myeloproliferative disorder (TMD) in Down syndrome: a multi-step model of myeloid leukaemogenesis. Br J Haematol. 2009;147(1):3–12.PubMedGoogle Scholar
  116. 116.
    Xavier AC, Ge Y, Taub J. Unique clinical and biological features of leukemia in Down syndrome children. Expert Rev Hematol. 2010;3(2):175–86.PubMedGoogle Scholar
  117. 117.
    Zipursky A. Transient leukemia-a benign form of leukemia in ewborn infants with trisomy 21. Br J Haematol. 2003;120:930–8.PubMedGoogle Scholar
  118. 118.
    Zwaan CM, Reinhardt D, Hitzler J, Vyas P. Acute leukemias in children with Down syndrome. Hematol Oncol Clin North Am. 2010;24(1):19–34.PubMedGoogle Scholar
  119. 119.
    Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, Le Beau MM, et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet. 2002;32(1):148–52.PubMedGoogle Scholar
  120. 120.
    Ahmed M, Sternberg A, Hall G, Thomas A, Smith O, O’Marcaigh A, et al. Natural history of GATA1 mutations in Down syndrome. Blood. 2004;103(7):2480–9.PubMedGoogle Scholar
  121. 121.
    Crispino JD. GATA1 mutations in Down syndrome: implications for biology and diagnosis of children with transient myeloproliferative disorder and acute megakaryoblastic leukemia. Pediatr Blood Cancer. 2005;44(1):40–4.PubMedGoogle Scholar
  122. 122.
    Greene ME, Mundschau G, Wechsler J, McDevitt M, Gamis A, Karp J, et al. Mutations in GATA1 in both transient myeloproliferative disorder and acute megakaryoblastic leukemia of Down syndrome. Blood Cells Mol Dis. 2003;31(3):351–6.PubMedGoogle Scholar
  123. 123.
    Mundschau G, Gurbuxani S, Gamis AS, Greene ME, Arceci RJ, Crispino JD. Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis. Blood. 2003;101(11):4298–300.PubMedGoogle Scholar
  124. 124.
    Xu G, Nagano M, Kanezaki R, Toki T, Hayashi Y, Taketani T, et al. Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome. Blood. 2003;102(8):2960–8.PubMedGoogle Scholar
  125. 125.
    Cabelof DC, Patel HV, Chen Q, van Remmen H, Matherly LH, Ge Y, et al. Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome. Blood. 2009;114(13):2753–63.PubMedGoogle Scholar
  126. 126.
    Baschat AA, Wagner T, Malisius R, Gembruch U. Prenatal diagnosis of a transient myeloproliferative disorder in trisomy 21. Prenat Diagn. 1998;18(7):731–6.PubMedGoogle Scholar
  127. 127.
    Robertson M, De Jong G, Mansvelt E. Prenatal diagnosis of congenital leukemia in a fetus at 25 weeks’ gestation with Down syndrome: case report and review of the literature. Ultrasound Obstet Gynecol. 2003;21(5):486–9.PubMedGoogle Scholar
  128. 128.
    Smrcek JM, Baschat AA, Germer U, Gloeckner-Hofmann K, Gembruch U. Fetal hydrops and hepatosplenomegaly in the second half of pregnancy: a sign of myeloproliferative disorder in fetuses with trisomy 21. Ultrasound Obstet Gynecol. 2001;17(5):403–9.PubMedGoogle Scholar
  129. 129.
    Ge Y, Stout ML, Tatman DA, Jensen TL, Buck S, Thomas RL, et al. GATA1, cytidine deaminase, and the high cure rate of Down syndrome children with acute megakaryocytic leukemia. J Natl Cancer Inst. 2005;97(3):226–31.PubMedGoogle Scholar
  130. 130.
    Lange B. The management of neoplastic disorders of haematopoiesis in children with Down’s syndrome. Br J Haematol. 2000;110(3):512–24.PubMedGoogle Scholar
  131. 131.
    Lange BJ, Kobrinsky N, Barnard DR, Arthur DC, Buckley JD, Howells WB, et al. 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. 1998;91(2):608–15.PubMedGoogle Scholar
  132. 132.
    Ravindranath Y, Abella E, Krischer JP, Wiley J, Inoue S, Harris M, et al. Acute myeloid leukemia (AML) in Down’s syndrome is highly responsive to chemotherapy: experience on pediatric oncology group AML study 8498. Blood. 1992;80(9):2210–4.PubMedGoogle Scholar
  133. 133.
    Taub JW, Huang X, Matherly LH, Stout ML, Buck SA, Massey GV, et al. Expression of chromosome 21-localized genes in acute myeloid leukemia: differences between Down syndrome and non-Down syndrome blast cells and relationship to in vitro sensitivity to cytosine arabinoside and daunorubicin. Blood. 1999;94(4):1393–400.PubMedGoogle Scholar
  134. 134.
    Maloney KW, Carroll WL, Carroll AJ, Devidas M, Borowitz MJ, Martin PL, et al. 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. 2010;116(7):1045–50.PubMedGoogle Scholar
  135. 135.
    Tigay JH. A comparison of acute lymphoblastic leukemia in Down syndrome and non-Down syndrome children: the role of trisomy 21. J Pediatr Oncol Nurs. 2009;26(6):362–8.PubMedGoogle Scholar
  136. 136.
    Whitlock JA, Sather HN, Gaynon P, Robison LL, Wells RJ, Trigg M, et al. Clinical characteristics and outcome of children with Down syndrome and acute lymphoblastic leukemia: a children’s cancer group study. Blood. 2005;106(13):4043–9.PubMedGoogle Scholar
  137. 137.
    Whitlock JA. Down syndrome and acute lymphoblastic leukaemia. Br J Haematol. 2006;135:595–602.PubMedGoogle Scholar
  138. 138.
    Bercovich D, Ganmore I, Scott LM, Wainreb G, Birger Y, Elimelech A, et al. Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down’s syndrome. Lancet. 2008;372(9648):1484–91.PubMedGoogle Scholar
  139. 139.
    Kearney L, Gonzalez De Castro D, Yeung J, Procter J, Horsley SW, Eguchi-Ishimae M, et al. Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia. Blood. 2009;113(3):646–8.PubMedGoogle Scholar
  140. 140.
    Hertzberg L, Vendramini E, Ganmore I, Cazzaniga G, Schmitz M, Chalker J, et al. 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. 2010;115(5):1006–17.PubMedGoogle Scholar
  141. 141.
    Russell LJ, Capasso M, Vater I, Akasaka T, Bernard OA, Calasanz MJ, et al. Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia. Blood. 2009;114(13):2688–98.PubMedGoogle Scholar
  142. 142.
    Izraeli S. Similar yet different. Blood. 2010;116(7):1019–20.PubMedGoogle Scholar
  143. 143.
    Kudo K, Hama A, Kojima S, Ishii R, Morimoto A, Bessho F, et al. Mosaic Down syndrome-associated acute myeloid leukemia does not require high-dose cytarabine treatment for induction and consolidation therapy. Int J Hematol. 2010;91(4):630–5.PubMedGoogle Scholar
  144. 144.
    Stepensky P, Brooks R, Waldman E, Revel-Vilk S, Izraeli S, Resnick I, et al. A rare case of GATA1 negative chemoresistant acute megakaryocytic leukemia in an 8-month-old infant with trisomy 21. Pediatr Blood Cancer. 2010;54(7):1048–9.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Department of PathologyUniversity of Arkansas for Medical SciencesLittle RockUSA
  2. 2.Department of Pathology and Laboratory MedicineUniversity of North Carolina at Chapel HillChapel HillUSA

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