Annals of Hematology

, Volume 90, Issue 3, pp 301–306

Long-term outcome of hemizygous and heterozygous carriers of a germline GATA1G208R mutation

  • Ulrich Dührsen
  • Christian P. Kratz
  • Christian Flotho
  • Thomas Lauenstein
  • Martin Bommer
  • Erika König
  • Günter Brittinger
  • Hermann Heimpel
Original Article

Abstract

The transcriptional regulator GATA1 is crucially involved in megakaryocytopoiesis and erythropoiesis. Mutations of the gene which is located on the X chromosome have been associated with platelet and red blood cell abnormalities. We identified a family with a GATA1G208R mutation in whom a low male birth rate and frequent miscarriages among heterozygous females suggested increased fetal death in male hemizygotes. Female mutation carriers had normal or near normal hemoglobin levels and platelet counts ranging from normal to severely reduced, probably reflecting skewed X chromosome inactivation. Platelets were dimorphous, and thrombocytopenia was associated with erythroblastosis. The only living male mutation carrier had severe macrothrombocytopenia with life-threatening bleeding episodes, moderate to severe anemia, eosinopenia, skeletal abnormalities, and abundant extramedullary hematopoiesis. Long-term sequelae in the 50-year-old patient included unilateral nephrectomy following misinterpretation of paraspinal hematopoiesis as renal cancer, spinal stenosis which was possibly favored by progressive bone marrow expansion, and severe secondary gout.

Keywords

Anemia Erythroblastosis Extramedullary hematopoiesis GATA1 Thrombocytopenia 

References

  1. 1.
    Ciovacco WA, Raskind WH, Kacena MA (2008) Human phenotypes associated with GATA-1 mutations. Gene 427:1–6CrossRefPubMedGoogle Scholar
  2. 2.
    Del Vecchio GC, Giordani L, De Santis A, De Mattia D (2005) Dyserythropoietic anemia and thrombocytopenia due to a novel mutation in GATA-1. Acta Haematol 114:113–116CrossRefPubMedGoogle Scholar
  3. 3.
    Kratz CP, Niemeyer CM, Karow A, Volz-Fleckenstein M, Schmitt-Gräff A, Strahm B (2008) Congenital transfusion-dependent anemia and thrombocytopenia with myelodysplasia due to a recurrent GATA1 G208R germline mutation. Leukemia 22:432–434CrossRefPubMedGoogle Scholar
  4. 4.
    König E, Osieka R, Brittinger G (1973) Atypische kongenitale dyserythropoietische Anämie mit Thrombocytopenie. Verh Dtsch Ges Inn Med 79:490–492PubMedGoogle Scholar
  5. 5.
    Schmidt U, Richter HJ, Samandari S (1987) Atypische kongenitale dyserythropoietische Anämie. Schweiz med Wschr 117:1776–1780PubMedGoogle Scholar
  6. 6.
    Heimpel H, Dührsen U, Hofbauer P, Rigamonti-Wermlinger V, Kreuser ED, Schwarz K, Solenthaler M, Pauls S (2009) Bulky extramedullary hematopoiesis is not a rare complication of congenital dyserythropoietic anemia. Ann Hematol 88:937–941CrossRefPubMedGoogle Scholar
  7. 7.
    Nichols KE, Crispino JD, Poncz M, White JG, Orkin SH, Maris JM, Weiss MJ (2000) Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1. Nat Genet 24:266–270CrossRefPubMedGoogle Scholar
  8. 8.
    Hollanda LM, Lima CS, Cunha AF, Albuquerque DM, Vassallo J, Ozelo MC, Joazeiro PP, Saad ST, Costa FF (2006) An inherited mutation leading to production of only the short isoform of GATA-1 is associated with impaired erythropoiesis. Nat Genet 38:807–812CrossRefPubMedGoogle Scholar
  9. 9.
    Balduini CL, Pecci A, Loffredo G, Izzo P, Noris P, Grosso M, Bergamaschi G, Rosti V, Magrini U, Ceresa IF, Conti V, Poggi V, Savoia A (2004) Effects of the R216Q mutation of GATA-1 on erythropoiesis and megakaryocytopoiesis. Thromb Haemost 91:129–140PubMedGoogle Scholar
  10. 10.
    Abkowitz JL, Taboada M, Shelton GH, Catlin SN, Guttorp P, Kiklevich JV (1998) An X chromosome gene regulates hematopoietic stem cell kinetics. Proc Natl Acad Sci U S A 95:3862–3866CrossRefPubMedGoogle Scholar
  11. 11.
    Busque L, Paquette Y, Provost S, Roy DC, Levine RL, Mollica L, Gilliland DG (2009) Skewing of X-inactivation ratios in blood cells of aging women is confirmed by independent methodologies. Blood 113:3472–3474CrossRefPubMedGoogle Scholar
  12. 12.
    Mehaffey MG, Newton AL, Gandhi MJ, Crossley M, Drachman JG (2001) X-linked thrombocytopenia caused by a novel mutation of GATA-1. Blood 98:2681–2688CrossRefPubMedGoogle Scholar
  13. 13.
    Rund D, Rachmilewitz E (2005) Beta-thalassemia. N Engl J Med 353:1135–1146CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Ulrich Dührsen
    • 1
  • Christian P. Kratz
    • 2
    • 5
  • Christian Flotho
    • 2
  • Thomas Lauenstein
    • 3
  • Martin Bommer
    • 4
  • Erika König
    • 1
  • Günter Brittinger
    • 1
  • Hermann Heimpel
    • 4
  1. 1.Klinik für HämatologieUniversitätsklinikum EssenEssenGermany
  2. 2.Klinik IV: Hämatologie und OnkologieZentrum für Kinderheilkunde und Jugendmedizin der Universität FreiburgFreiburgGermany
  3. 3.Institut für Diagnostische und Interventionelle Radiologie und NeuroradiologieUniversitätsklinikum EssenEssenGermany
  4. 4.Zentrum für Innere MedizinUniversitätsklinikum UlmUlmGermany
  5. 5.Clinical Genetics Branch, Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaUSA

Personalised recommendations