Seminars in Hematology
Volume 43, Issue 3 , Pages 196-203 , July 2006

Inherited Thrombocytopenia: Congenital Amegakaryocytic Thrombocytopenia and Thrombocytopenia With Absent Radii

  • Amy E. Geddis

      Affiliations

    • Corresponding Author InformationAddress correspondence to Amy E. Geddis, MD, PhD, 9500 Gilman Dr, Mailcode 0726, La Jolla, CA 92093-0726.

References 

  1. Geddis AE , Kaushansky K . Inherited thrombocytopenias (Toward a molecular understanding of disorders of platelet production) . Curr Opin Pediatr . 2004;16:15–22
  2. Balduini CL , Iolascon A , Savoia A . Inherited thrombocytopenias (From genes to therapy) . Haematologica . 2002;87:860–880
  3. Roberts IA , Murray NA . Thrombocytopenia in the newborn . Curr Opin Pediatr . 2003;15:17–23
  4. Saxonhouse MA , Christensen RD , Walker DM , Hutson AD , Sola MC . The concentration of circulating megakaryocyte progenitors in preterm neonates is a function of post-conceptional age . Early Hum Dev . 2004;78:119–124
  5. van den Oudenrijn S , Bruin M , Folman CC , Bussel J , de Haas M , von dem Borne AE . Three parameters, plasma thrombopoietin levels, plasma glycocalicin levels and megakaryocyte culture, distinguish between different causes of congenital thrombocytopenia . Br J Haematol . 2002;117:390–398
  6. Ballmaier M , Germeshausen M , Schulze H , Cherkaoui K , Lang S , Gaudig A , et al.  c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia . Blood . 2001;97:139–146
  7. Ballmaier M , Germeshausen M , Krukemeier S , Welte K . Thrombopoietin is essential for the maintenance of normal hematopoiesis in humans (Development of aplastic anemia in patients with congenital amegakaryocytic thrombocytopenia) . Ann N Y Acad Sci . 2003;996:17–25
  8. Geddis AE , Linden HM , Kaushansky K . Thrombopoietin (A pan-hematopoietic cytokine) . Cytokine Growth Factor Rev . 2002;13:61–73
  9. Murone M , Carpenter DA , de Sauvage FJ . Hematopoietic deficiencies in c-mpl and TPO knockout mice . Stem Cells . 1998;16:1–6
  10. Alexander WS , Roberts AW , Nicola NA , Li R , Metcalf D . Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic receptor c-Mpl . Blood . 1996;87:2162–2170
  11. Nagata Y , Shozaki Y , Nagahisa H , Nagasawa T , Abe T , Todokoro K . Serum thrombopoietin level is not regulated by transcription but by the total counts of both megakaryocytes and platelets during thrombocytopenia and thrombocytosis . Thromb Haemost . 1997;77:808–814
  12. McCarty JM , Sprugel KH , Fox NE , Sabath DE , Kaushansky K . Murine thrombopoietin mRNA levels are modulated by platelet count . Blood . 1995;86:3668–3675
  13. Wiestner A , Schlemper RJ , van der Maas AP , Skoda RC . An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia . Nat Genet . 1998;18:49–52
  14. Shivdasani RA . Molecular and transcriptional regulation of megakaryocyte differentiation . Stem Cells . 2001;19:397–407
  15. Yergeau DA , Hetherington CJ , Wang Q , Zhang P , Sharpe AH , Binder M , et al.  Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene . Nat Genet . 1997;15:303–306
  16. Crispino JD . GATA1 in normal and malignant hematopoiesis . Semin Cell Dev Biol . 2005;16:137–147
  17. Kawada H , Ito T , Pharr PN , Spyropoulos DD , Watson DK , Ogawa M . Defective megakaryopoiesis and abnormal erythroid development in Fli-1 gene-targeted mice . Int J Hematol . 2001;73:463–468
  18. 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;23:166–175
  19. Deveaux S , Filipe A , Lemarchandel V , Ghysdael J , Romeo PH , Mignotte V . Analysis of the thrombopoietin receptor (MPL) promoter implicates GATA and Ets proteins in the coregulation of megakaryocyte-specific genes . Blood . 1996;87:4678–4685
  20. Italiano JE , Lecine P , Shivdasani RA , Hartwig JH . Blood platelets are assembled principally at the ends of proplatelet processes produced by differentiated megakaryocytes . J Cell Biol . 1999;47:1299–1312
  21. Richardson JL , Shivdasani RA , Boers C , Hartwig JH , Italiano JE . Mechanisms of organelle transport and capture along proplatelets during platelet production . Blood . 2005;106:4066–4075
  22. Italiano JE , Bergmeier W , Tiwari S , Falet H , Hartwig JH , Hoffmeister KM , et al.  Mechanisms and implications of platelet discoid shape . Blood . 2003;101:4789–4796
  23. King S , Germeshausen M , Strauss G , Welte K , Ballmaier M . Congenital amegakaryocytic thrombocytopenia (A retrospective clinical analysis of 20 patients) . Br J Haematol . 2005;131:636–644
  24. Cines DB , Bussel JB , McMillan RB , Zehnder JL . Congenital and acquired thrombocytopenia . Hematology (Am Soc Hematol Educ Program) . 2004;390–406
  25. Ihara K , Ishii E , Eguchi M , Takada H , Suminoe A , Good RA , et al.  Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia . Proc Natl Acad Sci U S A . 1999;96:3132–3136
  26. Gandhi MJ , Pendergrass TW , Cummings CC , Ihara K , Blau CA , Drachman JG . Congenital amegakaryocytic thrombocytopenia in three siblings (Molecular analysis of atypical clinical presentation) . Exp Hematol . 2005;33:1215–1221
  27. Tonelli R , Scardovi AL , Pession A , Strippoli P , Bonsi L , Vitale L , et al.  Compound heterozygosity for two different amino-acid substitution mutations in the thrombopoietin receptor (c-mpl gene) in congenital amegakaryocytic thrombocytopenia (CAMT) . Hum Genet . 2000;107:225–233
  28. Gandhi MJ , Cummings CL , Drachman JG . FLJ14813 missense mutation (a candidate for autosomal dominant thrombocytopenia on human chromosome 10) . Hum Hered . 2003;55:66–70
  29. Krishnamurti L , Neglia JP , Nagarajan R , Berry SA , Lohr J , Hirsch B , et al.  Paris-Trousseau syndrome platelets in a child with Jacobsen’s syndrome . Am J Hematol . 2001;66:295–299
  30. Rengan R , Ochs HD . Molecular biology of the Wiskott-Aldrich syndrome . Rev Immunogenet . 2000;2:243–255
  31. Nichols KE , Crispino JD , Poncz M , White JG , Orkin SH , Maris JM , et al.  Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1 . Nat Genet . 2000;24:266–270
  32. Balduini CL , Pecci A , Loffredo G , Izzo P , Noris P , Grosso M , et al.  Effects of the R216Q mutation of GATA-1 on erythropoiesis and megakaryocytopoiesis . Thromb Haemost . 2004;91:129–140
  33. Seri M , Cusano R , Gangarossa S , Caridi G , Bordo D , Lo Nigro C , et al.  Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. The May-Heggllin/Fechtner Syndrome Consortium . Nat Genet . 2000;26:103–105
  34. Caen JP , Nurden AT , Jeanneau C , Michel H , Tobelem G , Levy-Toledano S , et al.  Bernard-Soulier syndrome: A new platelet glycoprotein abnormality. Its relationship with platelet adhesion to subendothelium and with the factor VIII von Willebrand protein . J Lab Clin Med . 1976;87:586–596
  35. Carver-Moore K , Broxmeyer HE , Luoh SM , Cooper S , Peng J , Burstein SA , et al.  Low levels of erythroid and myeloid progenitors in thrombopoietin-and c-mpl-deficient mice . Blood . 1996;88:803–808
  36. Basser RL , O’Flaherty E , Green M , Edmonds M , Nichol J , Menchaca DM , et al.  Development of pancytopenia with neutralizing antibodies to thrombopoietin after multicycle chemotherapy supported by megakaryocyte growth and development factor . Blood . 2002;99:2599–2602
  37. 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
  38. Germeshausen M , Ballmaier M , Welte K . Implications of mutations in hematopoietic growth factor receptor genes in congenital cytopenias . Ann N Y Acad Sci . 2001;938:305–320
  39. Taylor DS , Lee Y , Sieff CA , Homans A , Garrison L , Guinan EC . Phase I/II trial of PIXY321 (granulocyte-macrophage colony stimulating factor/interleukin-3 fusion protein) for treatment of inherited and acquired marrow failure syndromes . Br J Haematol . 1998;103:304–307
  40. Guinan EC , Lee YS , Lopez KD , Kohler S , Oette DH , Bruno E , et al.  Effects of interleukin-3 and granulocyte-macrophage colony-stimulating factor on thrombopoiesis in congenital amegakaryocytic thrombocytopenia . Blood . 1993;81:1691–1698
  41. Muraoka K , Ishii E , Ihara K , Imayoshi M , Miyazaki S , Hara T , et al.  Successful bone marrow transplantation in a patient with c-mpl-mutated congenital amegakaryocytic thrombocytopenia from a carrier donor . Pediatr Transplant . 2005;9:101–103
  42. Lackner A , Basu O , Bierings M , Lassay L , Schaefer UW , Revesz T , et al.  Haematopoietic stem cell transplantation for amegakaryocytic thrombocytopenia . Br J Haematol . 2000;109:773–775
  43. MacMillan ML , Davies SM , Wagner JE , Ramsay NK . Engraftment of unrelated donor stem cells in children with familial amegakaryocytic thrombocytopenia . Bone Marrow Transplant . 1998;21:735–737
  44. Steele M , Hitzler J , Doyle JJ , Germeshausen M , Fernandez CV , Yuille K , et al.  Reduced intensity hematopoietic stem-cell transplantation across human leukocyte antigen barriers in a patient with congenital amegakaryocytic thrombocytopenia and monosomy 7 . Pediatr Blood Cancer . 2005;45:212–216
  45. Orita T , Tsunoda H , Yabuta N , Nakano K , Yoshino T , Hirata Y , et al.  A novel therapeutic approach for thrombocytopenia by minibody agonist of the thrombopoietin receptor . Blood . 2005;105:562–566
  46. Wang B , Nichol JL , Sullivan JT . Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand . Clin Pharmacol Ther . 2004;76:628–638
  47. Richard RE , Blau CA . Small-molecule-directed mpl signaling can complement growth factors to selectively expand genetically modified cord blood cells . Stem Cells . 2003;21:71–78
  48. Zahavi J , Gale R , Kakkar VV . Storage pool disease of platelets in an infant with thrombocytopenic absent radii (TAR) syndrome simulating Fanconi’s anaemia . Haemostasis . 1981;10:121–133
  49. Day HJ , Holmsen H . Platelet adenine nucleotide “storage pool deficiency” in thrombocytopenic absent radii syndrome . JAMA . 1972;221:1053–1054
  50. Hedberg VA , Lipton JM . Thrombocytopenia with absent radii. A review of 100 cases . Am J Pediatr Hematol Oncol . 1988;10:51–64
  51. Ballmaier M , Schulze H , Strauss G , Cherkaoui K , Wittner N , Lynen S , et al.  Thrombopoietin in patients with congenital thrombocytopenia and absent radii (Elevated serum levels, normal receptor expression, but defective reactivity to thrombopoietin) . Blood . 1997;90:612–619
  52. Greenhalgh KL , Howell RT , Bottani A , Ancliff PJ , Brunner HG , Verschuuren-Bemelmans CC , et al.  Thrombocytopenia-absent radius syndrome (A clinical genetic study) . J Med Genet . 2002;39:876–881
  53. Ray R , Zorn E , Kelly T , Hall JG , Sommer A . Lower limb anomalies in the thrombocytopenia absent-radius (TAR) syndrome . Am J Med Genet . 1980;7:523–528
  54. Schoenecker PL , Cohn AK , Sedgwick WG , Manske PR , Salafsky I , Millar EA . Dysplasia of the knee associated with the syndrome of thrombocytopenia and absent radius . J Bone Joint Surg Am . 1984;66:421–427
  55. Whitfield MF , Barr DG . Cows’ milk allergy in the syndrome of thrombocytopenia with absent radius . Arch Dis Child . 1976;51:337–343
  56. Bagby GC . Genetic basis of Fanconi anemia . Curr Opin Hematol . 2003;10:68–76
  57. Sola MC , Slayton WB , Rimsza LM , Perez JA , Fuchs D , Calhoun DA , et al.  A neonate with severe thrombocytopenia and radio-ulnar synostosis . J Perinatol . 2004;24:528–530
  58. Dokal I , Ganly P , Riebero I , Marsh J , Steed A , Kendra J , et al.  Late onset bone marrow failure associated with proximal fusion of radius and ulna (A new syndrome) . Br J Haematol . 1989;71:277–280
  59. Thompson AA , Nguyen LT . Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation . Nat Genet . 2000;26:397–398
  60. Fujino T , Suzuki A , Ito Y , Ohyashiki K , Hatano Y , Miura I , et al.  Single-translocation and double-chimeric transcripts (Detection of NUP98-HOXA9 in myeloid leukemias with HOXA11 or HOXA13 breaks of the chromosomal translocation t(7;11)(p15;p15)) . Blood . 2002;99:1428–1433
  61. Speleman F , Cauwelier B , Dastugue N , Cools J , Verhasselt B , Poppe B , et al.  A new recurrent inversion, inv(7)(p15q34), leads to transcriptional activation of HOXA10 and HOXA11 in a subset of T-cell acute lymphoblastic leukemias . Leukemia . 2005;19:358–366
  62. Boulet AM , Capecchi MR . Multiple roles of Hoxa11 and Hoxd11 in the formation of the mammalian forelimb zeugopod . Development . 2004;131:299–309
  63. Rabinowitz JG , Moseley JE , Mitty HA , Hirschhorn K . Trisomy 18, esophageal atresia, anomalies of the radius, and congenital hypoplastic thrombocytopenia . Radiology . 1967;89:488–491
  64. Bajaj R , Jain M , Kasat L , Naregal A , Borwankar SS . Tar syndrome with unilateral absent radius and associated esophageal atresia (A variant?) . Indian J Pediatr . 1999;66:460–463
  65. Vega H , Waisfisz Q , Gordillo M , Sakai N , Yanagihara I , Yamada M , et al.  Roberts syndrome is caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion . Nat Genet . 2005;37:468–470
  66. Hall JG . Thrombocytopenia and absent radius (TAR) syndrome . J Med Genet . 1987;24:79–83
  67. Van Maldergem L , Siitonen HA , Jalkh N , Chouery E , De Roy M , Delague V , et al.  Revisiting the craniosynostosis-radial ray hypoplasia association (Baller-Gerold syndrome caused by mutations in RECQL4 gene) . J Med Genet . 2005;43:148–152
  68. Li QY , Newbury-Ecob RA , Terrett JA , Wilson DI , Curtis AR , Yi CH , et al.  Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family . Nat Genet . 1997;15:21–29
  69. Basson CT , Bachinsky DR , Lin RC , Levi T , Elkins JA , Soults J , et al.  Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome . Nat Genet . 1997;15:30–35
  70. Castilla EE , Ashton-Prolla P , Barreda-Mejia E , Brunoni D , Cavalcanti DP , Correa-Neto J , et al.  Thalidomide, a current teratogen in South America . Teratology . 1996;54:273–277
  71. Schnur RE , Eunpu DL , Zackai EH . Thrombocytopenia with absent radius in a boy and his uncle . Am J Med Genet . 1987;28:117–123
  72. Adeyokunnu AA . Radial aplasia and amegakaryocytic thrombocytopenia (TAR syndrome) among Nigerian children . Am J Dis Child . 1984;138:346–348
  73. Edelberg SB , Cohn J , Brandt NJ . Congenital hypomegakaryocytic thrombocytopenia associated with bilateral absence of the radius—The TAR syndrome . Hum Hered . 1977;27:147–152
  74. Ceballos-Quintal JM , Pinto-Escalante D , Gongora-Biachi RA . TAR-like syndrome in a consanguineous Mayan girl . Am J Med Genet . 1992;43:805–807
  75. Teufel M , Enders H , Dopfer R . Consanguinity in a Turkish family with thrombocytopenia with absent radii (TAR) syndrome . Hum Genet . 1983;64:94–96
  76. Hall JG , Levin J , Kuhn JP , Ottenheimer EJ , van Berkum KA , McKusick VA . Thrombocytopenia with absent radius (TAR) . Medicine (Baltimore) . 1969;48:411–439
  77. Homans AC , Cohen JL , Mazur EM . Defective megakaryocytopoiesis in the syndrome of thrombocytopenia with absent radii . Br J Haematol . 1988;70:205–210
  78. Ballmaier M , Schulze H , Cremer M , Folman CC , Strauss G , Weite K . Defective c-Mpl signaling in the syndrome of thrombocytopenia with absent radii . Stem Cells . 1998;16(suppl 2):177–184
  79. Strippoli P , Savoia A , Iolascon A , Tonelli R , Savino M , Giordano P , et al.  Mutational screening of thrombopoietin receptor gene (c-mpl) in patients with congenital thrombocytopenia and absent radii (TAR) . Br J Haematol . 1998;103:311–314
  80. Fleischman RA , Letestu R , Mi X , Stevens D , Winters J , Debili N , et al.  Absence of mutations in the HoxA10, HoxA11 and HoxD11 nucleotide coding sequences in thrombocytopenia with absent radius syndrome . Br J Haematol . 2002;116:367–375
  81. Go RS , Johnston KL . Acute myelogenous leukemia in an adult with thrombocytopenia with absent radii syndrome . Eur J Haematol . 2003;70:246–248
  82. Camitta BM , Rock A . Acute lymphoidic leukemia in a patient with thrombocytopenia/absent radii (Tar) syndrome . Am J Pediatr Hematol Oncol . 1993;15:335–337
  83. Fadoo Z , Naqvi SM . Acute myeloid leukemia in a patient with thrombocytopenia with absent radii syndrome . J Pediatr Hematol Oncol . 2002;24:134–135
  84. Symonds RP , Clark BJ , George WD , Bryant PE , Liu N , Connor JM . Thrombocytopenia with absent radii (TAR) syndrome (A new increased cellular radiosensitivity syndrome) . Clin Oncol (R Coll Radiol) . 1995;7:56–58
  85. Brochstein JA , Shank B , Kernan NA , Terwilliger JW , O’Reilly RJ . Marrow transplantation for thrombocytopenia-absent radii syndrome . J Pediatr . 1992;121:587–589
  86. Armitage JO , Hoak JC , Elliott TE , Fry GL . Syndrome of thrombocytopenia and absent radii (Qualitatively normal platelets with remission following spenectomy) . Scand J Haematol . 1978;20:25–28
  87. Aquino VM , Mustafa MM , Vaickus L , Wooley R , Buchanan GR . Recombinant interleukin-6 in the treatment of congenital thrombocytopenia associated with absent radii . J Pediatr Hematol Oncol . 1998;20:474–476

 The author receives funding from K08 HL04470-06 and Cindy Matters.

PII: S0037-1963(06)00077-1

doi: 10.1053/j.seminhematol.2006.04.003

Seminars in Hematology
Volume 43, Issue 3 , Pages 196-203 , July 2006

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