Congenital Transfusion-Dependent Anemia and Thrombocytopenia with Myelodysplasia Due to a Recurrent GATA1G208R Germline Mutation
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Letters to the Editor 432 high-dose cytarabine are administered. J Clin Oncol 1999; 17: constitute a distinctive subtype of t(8;21) AML. Leukemia 2003; 17: 3767–3775. 731–737. 3 Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, 6 Nguyen S, Leblanc T, Fenaux P, Witz F, Blaise D, Pigneux A et al. A Harrison G et al. The importance of diagnostic cytogenetics on white blood cell index as the main prognostic factor in t(8;21) acute outcome in AML: analysis of 1612 patients entered into the MRC myeloid leukemia (AML): a survey of 161 cases from the French AML 10 trial. The Medical Research Council Adult and Children’s AML Intergroup. Blood 2002; 99: 3517–3523. Leukaemia Working Parties. Blood 1998; 92: 2322–2333. 7 Schlenk RF, Benner A, Krauter J, Buchner T, Sauerland C, Ehninger 4 Marcucci G, Mrozek K, Ruppert AS, Maharry K, Kolitz JE, Moore JO G et al. Individual patient data-based meta-analysis of patients aged et al. 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Appendix Meitetsu Hospital, Nagoya; Fujita Health University Hospital, Toyoake; Komaki City Hospital, Komaki; Yokkaichi This study was conducted at the following institu- Municipal Hospital, Yokkaichi; Yamanashi Prefectural tions: National Hospital Organization Nagoya Medical Central Hospital, Yamanashi; Okazaki City Hospital, Okazaki, Center, Nagoya; Toyohashi Municipal Hospital, Toyohashi; Japan. Congenital transfusion-dependent anemia and thrombocytopenia with myelodysplasia due to a recurrent GATA1G208R germline mutation Leukemia (2008) 22, 432–434; doi:10.1038/sj.leu.2404904; We identified a second family with a GATA1G208R mutation. published online 23 August 2007 The index patient was a male neonate born at term to healthy European non-consanguineous parents. Family history was unremarkable and the mother previously gave birth to a healthy The X-linked gene GATA1 encodes a 414-amino-acid hemato- boy. At birth, petechiae and ecchymoses on skin and mucosa as poietic transcription factor that controls erythroid and mega- well as enlargement of liver and spleen were noted. Hemoglobin karyocytic differentiation. Virtually all cases of transient measured 8.9 g/dl, leukocytes 54 900/ml and thrombocytes myeloproliferative disease and acute megakaryoblastic leuke- 54 000/ml. Repeated platelet and packed red blood cell transfu- mia in children with Down syndrome harbor somatic GATA1 sions were administered. A bone marrow smear revealed mutations typically affecting exon 2 and leading to expression of dyserythropoiesis (Figure 1) and dysmegakaryopoiesis but no the short isoform, GATA-1s, which lacks the transcriptional increase in blasts. A liver biopsy taken at the age of 16 days activation domain. Moreover, germline missense mutations in revealed siderosis, cholestasis and extramedullary hematopoi- exon 4 of GATA1 that predict alterations of amino acids Val205, esis. Mutation analysis with published methods,1,10 uncovered a Gly208, Arg216 or Asp218 of the N-terminal zinc-finger domain hemizygous G to A transition at nucleotide position c.622 in (residues 204–228) have been reported in nine families.1–9 One exon 4 of GATA1 predicting a p.G208R change in the highly additional family has been found to harbor a germline mutation, conserved N-terminal zinc-finger domain of GATA-1. The GATA1 c.322G4C, which leads to expression of GATA-1s.10 patient inherited this allele from his heterozygous mother Consistent with X-linked inheritance and full penetrance, (Figure 1), who had a hemoglobin level of 11.3 g/dl, mean germline GATA1 mutations disrupt hematopoiesis in males erythrocyte volume 81 fl, leukocytes 12 700/ml and thrombocytes who harbor a hemizygous mutant GATA1 allele. In contrast, 172 000/ml. At the time of this report, the patient was 6 months of female heterozygous carriers have no or minor hematopoietic age and was in stable condition requiring platelet transfusions defects such as mild chronic thrombocytopenia.1–10 The every week and red packed cell transfusions every second to spectrum of abnormalities caused by different GATA1 mutations third week. To obtain the option of hematopoietic stem cells probably depends on the function of the predicted mutant transplantation (HSCT) a donor search has been initiated. The protein such as the ability to associate with cofactor FOG-1.9 same mutation, GATA1G208R has been described in another Hematologic abnormalities include dyserythropoietic anemia individual with dyserythropoietic anemia and thrombocytopenia and thrombocythemia (V205M, G208R, D218Y and GATA- who was found to have anemia and thrombocytopenia at birth 1s),1,3,9,10 thrombocytopenia with mild dyserythropoiesis requiring transfusions.3 This patient received his last red packed (D218G, G208S),2,8 thrombocytopenia with thalassemia cell transfusion at 5 years of age and the frequency of mucosal (R216Q),4,5 congenital erythropoietic porphyria (R216W),7 and severe bleeding decreased in adulthood. At the age of 17 and gray platelet syndrome (R216Q).6 Splenomegaly is noted years he had a hemoglobin level of 9.6 g/dl, mean erythrocyte in some cases5,7 and is likely to be due to ineffective and volume 103 fl and thrombocytes 12 000/ml.3 Notably, this consecutive extramedullary hematopoiesis. To date, only the patient’s mother was mildly thrombocytopenic with platelets GATA1R216Q mutation has been identified in more than one measuring 140 000/ml.3 The similar clinical presentation with family,4–6 hampering phenotype–genotype correlation. transfusion-dependent cytopenia at birth underscores the notion Leukemia Letters to the Editor 433 7.7 Kb 1 2 3 4 5 6 GATA1WT/mut GATA1WT TD NC 414 aa TGCGGA TGCGGA A N terminal zinc finger …204 CVNCGATATPLWRRDRTGHYLCNACG 228 … G208R c GATA1mut TGCAGA Figure 1 The recurrent GATA1G208R mutation causes congenital dyserythropoietic anemia and thrombocytopenia. A heterozygous germline GATA1 mutation, c.622G4A, is detected in the patient’s mother. The patient harbors a hemizygous mutant allele (a). This alteration in exon 4 predicts a G208R change in the N-terminal zinc finger (N) of the protein (TD: transcriptional activation domain; C: C-terminal zinc finger). This mutation locates near residues that are altered by other known germline mutations (red) (b). A bone marrow slide shows severe dyserythropoietic changes (arrows) (c). of a genotype–phenotype relationship of different GATA1 Hedwig/Pa¨diatrische Onkologie und Ha¨matologie, Regensburg, Germany and defects. However, in addition to dyserythropoietic anemia and 3 thrombocytopenia, our patient presented with marked organo- Department of Pathology, University of Freiburg, Freiburg, megaly. Although bleeding complications in patients with Germany E-mail: [email protected] germline GATA1 mutations may decrease with age,3 this disorder may lead to early death.2,9 Notably, in one family with a GATA1D218Y allele, six affected boys died before the age of 2 9 References years. In cases of GATA1 defects with significant thrombo- cytopenia and severe bleeding diathesis, HSCT may be warranted. Indeed, related or unrelated HSCT has been performed in a small 1 Nichols KE, Crispino JD, Poncz M, White JG, Orkin SH, Maris JM 1,7,10 et al. Familial dyserythropoietic anaemia and thrombocytopenia number of cases. In conclusion, we describe the second due to an inherited mutation in GATA1. Nat Genet 2000; 24: G208R family with a GATA1 allele causing congenital dyserythro- 266–270. poietic anemia and thrombocytopenia. Additionally, the affected 2 Mehaffey MG, Newton AL, Gandhi MJ, Crossley M, Drachman JG. male showed marked organomegaly. Besides GATA1G216Q,the X-linked thrombocytopenia caused by a novel mutation of GATA1G208R allele is the only mutation that has been identified in GATA-1. Blood 2001; 98: 2681–2688. more than one family. The identification of a larger number of 3 Del Vecchio GC, Giordani L, De Santis A, De Mattia D. Dyserythropoietic anemia and thrombocytopenia due to a novel families with these rare mutations that lead to a spectrum of mild mutation in GATA-1. Acta Haematol 2005; 114: 113–116. to severe hematologic defects will help to perform phenotype– 4 Yu C, Niakan KK, Matsushita M, Stamatoyannopoulos G, Orkin genotype correlations that eventually will facilitate treatment SH, Raskind WH. X-linked thrombocytopenia with thalassemia decisions and patient care. from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interaction. Blood 2002; 100: 2040–2045. Acknowledgements 5 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. We thank Cornelia Klein for technical assistance. 6 Tubman VN, Levine JE, Campagna DR, Monahan-Earley R, 1 1 1 2 Dvorak AM, Neufeld EJ et al. X-linked gray platelet syndrome CP Kratz , CM Niemeyer , A Karow , M Volz-Fleckenstein , due to a GATA1 Arg216Gln mutation. Blood 2007; 109: A Schmitt-Gra¨ff3 and B Strahm1 1 3297–3299. Department of Pediatrics and Adolescent Medicine, Pediatric 7 Phillips JD, Steensma DP, Pulsipher MA, Spangrude GJ, Kushner JP. Hematology/Oncology, University of Freiburg, Freiburg, Congenital erythropoietic porphyria due to a mutation in GATA1: Germany; the first trans-acting mutation causative for a human porphyria.