GATA-2 deficiency was recently described as common cause of overlapping syndromes of immunodeficiency, lymphedema, familiar myelodysplastic syndrome or acute myeloid leukemia. The aim of our study was to analyze bone marrow and peripheral blood samples of children with myelodysplastic syndrome or aplastic anemia to define prevalence of the GATA2 mutation and to assess whether mutations in GATA-2 transcription factor exhibit specific immunophenotypic features. The prevalence of a GATA2 mutation in a consecutively diagnosed cohort of children was 14% in advanced forms of myelodysplastic syndrome (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and myelodysplasia-related acute myeloid leukemia), 17% in refractory cytopenia of childhood, and 0% in aplastic anemia. In GATA-2-deficient cases, we found the most profound B-cell lymphopenia, including its progenitors in blood and bone marrow, which correlated with significantly diminished intronRSS-Kde recombination excision circles in comparison to other myelodysplastic syndrome/aplastic anemia cases. The other typical features of GATA-2 deficiency (monocytopenia and natural killer cell lymphopenia) were less discriminative. In conclusion, we suggest screening for GATA2 mutations in pediatric myelodysplastic syndrome, preferentially in patients with impaired B-cell homeostasis in bone marrow and peripheral blood (low number of progenitors, intronRSS-Kde recombination excision circles and naïve cells).

Center for Pediatrics and Adolescent Medicine University Medical Center Freiburg Germany

Centre of Oncocytogenetics Institute of Clinical Biochemistry and Laboratory Diagnostics 1 Faculty of Medicine and General University Hospital and Charles University Prague Czech Republic

CLIP Department of Pediatric Hematology and Oncology 2 Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

CLIP Department of Pediatric Hematology and Oncology 2 Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic Department of Pediatric Hematology and Oncology 2 Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Immunology Erasmus MC Rotterdam the Netherlands

Department of Pathology Aarhus University Hospital Denmark

Department of Pathology and Molecular Medicine University Hospital Motol Prague Czech Republic

Department of Pediatric Hematology and Oncology 2 Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Pediatric Hematology and Oncology University Hospital Bratislava Slovakia

Department of Pediatric Hematology Children's University Hospital Brno Czech Republic

Department of Pediatric Oncology Princess Máxima Centre for Paediatric Oncology Utrecht the Netherlands

Department of Pediatrics Charles University University Hospital Hradec Králové Czech Republic

Department of Pediatrics Ostrava University Hospital Ostrava Czech Republic

Department of Pediatrics Palacky University and University Hospital Olomouc Czech Republic

Department of Pediatrics University Hospital Pilsen Czech Republic

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Hasle H, Wadsworth LD, Massing BG, McBride M, Schultz KR. A population-based study of childhood myelodysplastic syndrome in British Columbia, Canada. Br J Haematol. 1999;106(4):1027–1032. PubMed

Baumann I, Niemeyer CM, Bennett JM, Shannon K. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: International Agency of Research on Cancer (IARC); 2008. p 104–107.

Baumann I, Führer M, Behrendt S, et al. Morphological differentiation of severe aplastic anaemia from hypocellular refractory cytopenia of childhood: reproducibility of histopathological diagnostic criteria. Histopathology. 2012;61(1):10–17. PubMed

Strahm B, Nöllke P, Zecca M, et al. Hematopoietic stem cell transplantation for advanced myelodysplastic syndrome in children: results of the EWOG-MDS 98 study. Leukemia. 2011;25(3):455–462. PubMed

Shimamura A, Alter BP. Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev. 2010; 24(3):101–122. PubMed PMC

Ostergaard P, Simpson MA, Connell FC, et al. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat Genet. 2011;43(10):929–931. PubMed

Dickinson RE, Griffin H, Bigley V, et al. Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency. Blood. 2011;118(10):2656–2658. PubMed PMC

Hahn CN, Chong C-E, Carmichael CL, et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet. 2011;43(10):1012–1017. PubMed PMC

Hsu AP, Johnson KD, Falcone EL, et al. GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome. Blood. 2013;121(19):3830–3837, S1–S7. PubMed PMC

Ganapathi KA, Townsley DM, Hsu AP, et al. GATA2 deficiency-associated bone marrow disorder differs from idiopathic aplastic anemia. Blood. 2015;125(1):56–70. PubMed PMC

Dickinson RE, Milne P, Jardine L, et al. The evolution of cellular deficiency in GATA2 mutation. Blood. 2014;123(6):863–874. PubMed PMC

Calvo KR, Vinh DC, Maric I, et al. Myelodysplasia in autosomal dominant and sporadic monocytopenia immunodeficiency syndrome: diagnostic features and clinical implications. Haematologica. 2011; 96(8):1221–1225. PubMed PMC

Hirabayashi S, Strahm B, Urbaniak S, et al. Unexpected High Frequency of GATA2 Mutations in Children with Non-Familial MDS and Monosomy 7. ASH Annual Meeting Abstracts. 2012;120(21):1699.

Westers TM, Ireland R, Kern W, et al. Standardization of flow cytometry in myelodysplastic syndromes: a report from an international consortium and the European LeukemiaNet Working Group. Leukemia. 2012;26(7):1730–1741. PubMed

Della Porta MG, Picone C, Pascutto C, et al. Multicenter validation of a reproducible flow cytometric score for the diagnosis of low-grade myelodysplastic syndromes: results of a European LeukemiaNET study. Haematologica. 2012;97(8):1209–1217. PubMed PMC

van de Loosdrecht AA, Westers TM, Westra AH, et al. Identification of distinct prognostic subgroups in low- and intermediate-1-risk myelodysplastic syndromes by flow cytometry. Blood. 2008;111(3):1067–1077. PubMed

Aalbers AM, van den Heuvel-Eibrink MM, de Haas V, et al. Applicability of a reproducible flow cytometry scoring system in the diagnosis of refractory cytopenia of childhood. Leukemia. 2013;27(9):1923–1925. PubMed

Aalbers AM, van den Heuvel-Eibrink MM, Baumann I, et al. Bone marrow immunophenotyping by flow cytometry in refractory cytopenia of childhood. Haematologica. 2015;100(3):315–323. PubMed PMC

van Zelm MC, Szczepanski T, van der Burg M, van Dongen JJM. Replication history of B lymphocytes reveals homeostatic proliferation and extensive antigen-induced B cell expansion. J Exp Med. 2007;204(3):645–655. PubMed PMC

Weinberg K, Blazar BR, Wagner JE, et al. Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. Blood. 2001;97(5):1458–1466. PubMed

Fronková E, Klocperk A, Svatoñ M, et al. The TREC/KREC assay for the diagnosis and monitoring of patients with DiGeorge syndrome. PLoS One. 2014;9(12):e114514. PubMed PMC

Fronkova E, Muzikova K, Mejstrikova E, et al. B-cell reconstitution after allogeneic SCT impairs minimal residual disease monitoring in children with ALL. Bone Marrow Transplant. 2008;42(3):187–196. PubMed

Veltroni M, Sainati L, Zecca M, et al. Advanced pediatric myelodysplastic syndromes: can immunophenotypic characterization of blast cells be a diagnostic and prognostic tool? Pediatr Blood Cancer. 2009;52(3):357–363. PubMed

Bras AE, van den Heuvel-Eibrink MM, van der Sluijs-Gelling AJ, et al. No significant prognostic value of normal precursor B-cell regeneration in paediatric acute myeloid leukaemia after induction treatment. Br J Haematol. 2013;161(6):861–864. PubMed

Piatosa B, Wolska-Kušnierz B, Pac M, et al. B cell subsets in healthy children: reference values for evaluation of B cell maturation process in peripheral blood. Cytometry B Clin Cytom. 2010;78(6):372–381. PubMed

Svobodova T, Mejstrikova E, Salzer U, et al. Diffuse parenchymal lung disease as first clinical manifestation of GATA-2 deficiency in childhood. BMC Pulm Med. 2015;15:8. PubMed PMC

Chou J, Lutskiy M, Tsitsikov E, et al. Presence of hypogammaglobulinemia and abnormal antibody responses in GATA2 deficiency. J Allergy Clin Immunol. 2014; 134(1):223–226. PubMed PMC

Spinner MA, Sanchez LA, Hsu AP, et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood. 2014;123(6):809–821. PubMed PMC

Dotta L, Badolato R. Primary immunodeficiencies appearing as combined lymphopenia, neutropenia, and monocytopenia. Immunol Lett. 2014;161(2):222–225. PubMed

Pasquet M, Bellanné-Chantelot C, Tavitian S, et al. High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia. Blood. 2013;121(5):822–829. PubMed PMC

Mejstrikova E, Pelkova V, Reiterova M, et al. Composition of Cellular Subsets by Flow Cytometry Identifies Differences Between MDS Subtypes and Aplastic Anemia but No Differences Are Identified Between Cases with and without Monosomy 7. ASH Annual Meeting Abstracts. 2009;114(22):3802.

Reiterova M, Kramarzova K, Sukova M, et al. Changes Identified by Flow Cytometry and WT1 Expression in Consecutive Bone Marrow Samples in Refractory Cytopenia of Childhood and Aplastic Anemia Before Start of the Therapy. ASH Annual Meeting Abstracts. 2011;118(21):1342.

Yoshimi A, van den Heuvel-Eibrink MM, Baumann I, et al. Comparison of horse and rabbit antithymocyte globulin in immunosuppressive therapy for refractory cytopenia of childhood. Haematologica. 2014; 99(4):656–663. PubMed PMC

Führer M, Rampf U, Baumann I, et al. Immunosuppressive therapy for aplastic anemia in children: a more severe disease predicts better survival. Blood. 2005; 106(6):2102–2104. PubMed

Forester C, Sartain S, Guo D, et al. Pediatric aplastic anemia and refractory cytopenia: A retrospective analysis assessing outcomes and histomorphologic predictors. Am J Hematol. 2015;90(4):320–326. PubMed PMC

Association of unbalanced translocation der(1;7) with germline GATA2 mutations

Hematopoietic stem cell transplantation in children and adolescents with GATA2-related myelodysplastic syndrome

Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency