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Haematologica. 2018 Aug;103(8):1278-1287. doi: 10.3324/haematol.2017.181909. Epub 2018 May 3.

Natural history of GATA2 deficiency in a survey of 79 French and Belgian patients.

Author information

1
Department of Paediatric Haematology and Oncology, Registre National des Neutropénies Chroniques, AP-HP Trousseau Hospital, Paris, France.
2
Department of Paediatric Haematology and Immunology, CHU Toulouse, France.
3
Department of Clinical Immunology Assistance Publique - Hôpitaux de Paris (AP-HP) Saint-Louis Hospital, France.
4
INSERM UMR1126, Centre Hayem, Université Paris Denis Diderot, Sorbonne Paris Cité, France.
5
Department of Haematology and Bone Marrow Transplantation, AP-HP Saint-Louis Hospital, Paris, France.
6
Genetic Laboratory, AP-HP Robert Debré Hospital, Paris, France.
7
Department of Haematology, AP-HP Robert Debré Hospital, Paris, France.
8
French Neutropenia Registry, AP-HP Trousseau Hospital, Paris, France.
9
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker-Enfants Malades Hospital, Paris, France.
10
Centre for the Study of Primary Immunodeficiencies, Necker-Enfants Malades Hospital, AP-HP, Paris, France.
11
St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, New York, NY, USA.
12
Paris Descartes University, Imagine Institute, Paris, France.
13
Centre for Human Genetics, Cliniques Universitaires Saint-Luc & Human Molecular Genetics (GEHU), de Duve Institute -Université Catholique de Louvain, Brussels, Belgium.
14
Department of Genetics, CHU Nantes, France.
15
Department of Haematology, St Luc Hospital, Brussels, Belgium.
16
Department of Internal Medicine, CHU Nantes, France.
17
Department of Haematology, CHU de Rennes, France.
18
Department of Paediatric Haematology and Oncology, CHU de Rennes, France.
19
Department of Paediatric Haematology, CHU de Marseille, Hopital La Timone, Université Aix-Marseille, France.
20
Internal Medicine, CHU de Marseille, Hopital La Timone, Université Aix-Marseille, France.
21
Department of Haematology, CHU de Besançon, France.
22
Department of Haematology, AP-HP Necker-Enfants Malades, INSERM UMR 1163 and CNRS ERL 8254 Institut Imagine, Sorbonne Paris Cité, Université Paris Descartes, France.
23
Department of Haematology, CHU de Nancy, France.
24
Department of Paediatric Haematology, CHU de Lille, France.
25
Department of Internal Medicine and Immunology, CHU Lille, France.
26
Department of Haematology, CHU d'Angers, France.
27
Department of Haematology, CHU de Strasbourg, France.
28
Department of Neurology, Hôpitaux Civils de Colmar, France.
29
Inflammation Chimiokines et Immunopathologie, INSERM, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Clamart, France.
30
Laboratory of Haematology, CHU de Lille, France.
31
Laboratory of Haematology, IUCT-Oncopole, Toulouse, France.
32
Centre of Research in Oncology, INSERM U1037, Team 16, IUCT-Oncopole, Toulouse, France.
33
Department of Genetics, AP-HP Pitié Salpêtrière Hospital, Faculté de Médecine Sorbonne Université, Paris, France.
34
Department of Paediatric Haematology and Immunology, CHU Toulouse, France pasquet.m@chu-toulouse.fr.

Abstract

Heterozygous germline GATA2 mutations strongly predispose to leukemia, immunodeficiency, and/or lymphoedema. We describe a series of 79 patients (53 families) diagnosed since 2011, made up of all patients in France and Belgium, with a follow up of 2249 patients/years. Median age at first clinical symptoms was 18.6 years (range, 0-61 years). Severe infectious diseases (mycobacteria, fungus, and human papilloma virus) and hematologic malignancies were the most common first manifestations. The probability of remaining symptom-free was 8% at 40 years old. Among the 53 probands, 24 had missense mutations including 4 recurrent alleles, 21 had nonsense or frameshift mutations, 4 had a whole-gene deletion, 2 had splice defects, and 2 patients had complex mutations. There were significantly more cases of leukemia in patients with missense mutations (n=14 of 34) than in patients with nonsense or frameshift mutations (n=2 of 28). We also identify new features of the disease: acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, fatal progressive multifocal leukoencephalopathy related to the JC virus, and immune/inflammatory diseases. A revised International Prognostic Scoring System (IPSS) score allowed a distinction to be made between a stable disease and hematologic transformation. Chemotherapy is of limited efficacy, and has a high toxicity with severe infectious complications. As the mortality rate is high in our cohort (up to 35% at the age of 40), hematopoietic stem cell transplantation (HSCT) remains the best choice of treatment to avoid severe infectious and/or hematologic complications. The timing of HSCT remains difficult to determine, but the earlier it is performed, the better the outcome.

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