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1266 Prospective and Retrospective Observational Study in Adult and Pediatric Patients with GATA2 Variants (GATA2 Deficiency)Clinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 509. Bone Marrow Failure and Cancer Predisposition Syndromes: Congenital: Poster I
Hematology Disease Topics & Pathways:
Research, Clinical Research, hematopoiesis, Diseases, immunology, registries, Biological Processes
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Samuele Roncareggi1*, Katia Girardi, MD2*, Francesca Fioredda, MD3*, Francesca Conti4*, Erika Borlenghi, M.D.5*, Concetta Micalizzi6*, Gaia Mancuso7*, Fabiola Guerra, MD, PhD8*, Emilia Cirillo9*, Antonio Marzollo, MD10*, Piero Farruggia, MD11*, Daniela Onofrillo12*, Riccardo Masetti, Prof., MD, PhD13*, Raffaele Badolato, MD, PhD14*, Luca Arcuri15*, Tiziana Angela Coliva, MD16*, Francesca Vendemini, MD17*, Claudio Pignata18*, Sonia Bonanomi19*, Andrea Biondi, MD20 and Francesco Saettini, MD21*

1Milano Bicocca University, Monza, Italy
2Department of Hematology/Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
3Hematology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)-Istituto Giannina Gaslini, Genova, Italy
4Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ITA
5Department of Hematology, ASST Spedali Civili di Brescia, Brescia, Italy
6Haematology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
7Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Scientific Institute, Milan, Italy., Milan, Italy
8University of Milano Bicocca, Monza, Italy, Monza, AL, Italy
9"federico II" University of Naples, Naples, ITA
10U.O.C. Oncoematologia Pediatrica, Padova, ITA
11Pediatric Hematology and Oncology Unit, A.R.N.A.S. Ospedale Civico, Palermo, Italy
12Ospedale Civile, Pescara, Italy
13Pediatric Oncology and Hematology "Lalla Seràgnoli", IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
14Department of Pediatrics, Institute of Molecular Medicine "Angelo Nocivelli," University of Brescia, Brescia, Italy
15Haematology Unit, Istituto Giannina Gaslini, Genoa, Italy., Genoa, Italy
16Department of Paediatrics, Paediatric Haematology-Oncology Unit, Fondazione MBBM/San Gerardo Hospital, Monza, Italy., Monza, ITA
17Department of Paediatrics, Paediatric Haematology-Oncology Unit, Fondazione MBBM/San Gerardo Hospital, Monza, Italy., Monza, AL, ITA
18Federico II University, Naples, NA, ITA
19Ospedale San Gerardo, Monza, MB, ITA
20Centro Ricerca Tettamanti, Pediatric Department, University of Milano-Bicocca, Fondazione MBBM, Monza, MI, Italy
21Tettamanti Research Centre, Department of Paediatrics, University of Milano-Bicocca, Monza, Italy., Monza, ITA

Heterozygous germline GATA2 variants are associated with a broad spectrum of manifestations, encompassing immuno-haematological alterations, severe/recurrent infections and extra-haematological phenomena.

We here describe 25 patients (11 males) with molecular diagnosis of GATA2 deficiency identified in 9 AIEOP (Associazione Italiana di Ematologia Oncologia Pediatrica) centers in Italy (Table 1). Patients’ median age at onset of symptoms was 12.5 years. The main signs/symptoms at onset were severe/recurrent infections (40%), cytopenias (20%) and myelodysplasia (MDS)/acute myeloid leukemia (AML) (20%). The prevalence of these manifestations increased during the follow-up and further clinical manifestations, i.e.hepatosplenomegaly, haemorrhagic diathesis, thrombosis, bone marrow failure, lymphedema, pulmonary alveolar proteinosis and sensorineural deafness, occurred. Once the diagnosis was established, congenital deafness was considered part of the clinical picture of GATA2 deficiency in two individuals. We identified a rare (myelofibrosis) and two possible new manifestations (pilonidal cyst/sacro-coccygeal fistula and cholangiocarcinoma). Complete blood count with differential and lymphocyte subsests revealed that monocytopenia (83%) and CD19+ lymphocytopenia (70%) were the most frequent and distinctive changes in patients without hematological malignancies or in whom we obtained data before the onset of MDS/AML (Table 2).

Different myeloid neoplasms were observed: refractory cytopenia in childhood (RCC) (24%), AML (12%), MDS with excess blasts (MDS-EB) (12%), MDS-EB in transformation (MDS-EBt) (4%) and MDS with multilineage dysplasia(MDS-MLD) (8%). Monosomy 7 (8%) and trisomy 8 (16%) were the two most frequent karyotype abnormalities. Targeted next-generation sequencing (NGS) analysis for somatic mutations associated with myeloid neoplasms was performed in 48% of the patients, resulting positive in 8% of cases (i.e. EZH2 and MECOM in one individual each).

The majority of GATA2 variants were located at zinc-finger 2 (ZF2) domain of the GATA2 protein. Missense and null mutations were the most frequent (46% each). Intronic variants were found in 8% of the cohort. We report 3 missense mutations out of the 4 cases of lymphedema described.Median age at molecular diagnosis was 18 years.

The diagnostic delay (time between age at onset of symptoms and molecular diagnosis) had a median of 4 years, but, excluding who had onset of the disease before the first description of GATA2 deficiency (2011) the median was 1 year.

Hematopoietic stem cell transplantation (HSCT) was the most widely used therapeutic option (52%). HSCT was performed in case of myeloid neoplasia (8/13) and bone marrow failure (3/13), but also in patients with immunodeficiency (i.e. hypogammaglobulinemia with immunoglobulin replacement therapy, immunodeficiency with previous severe infections). Time between molecular diagnosis and HSCT was1 year. The event free survival (EFS) was 20% at the age of 20 and 15% at the age of 40. The overall survival (OS) was 90% at the age of 20 and 70% at the age of 40. Family screening was essential to identify asymptomatic patients (8% in our series).

In conclusion, our series represents the third largest national cohort after the ones described by Donadieu and Spinner (79 and 57 patients, respectively)1,2. GATA2 deficiency should be included in targeted gene panels for congenital deafness and we recommend to perform the sequencing of the regulatory region. Our data disproves the hypothesis that lymphedema is exclusively associated with null and regulatory mutations3, as we here describe three patients with lymphedema and missense mutations. HSCT should be considered in case of patients with immunodeficiency without myeloid neoplasms. Family screening should be offered to first degree relatives, as identification of asymptomatic GATA2 deficient patients could allow to exclude potential HSC donors and to investigate risk factors that may explain the phenotypic difference.


1. Donadieu J, et al. Natural history of GATA2 deficiency in a survey of 79 French and Belgian patients. Haematologica. 2018;103(8):1278-1287

2. Spinner MA, et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood. 2014;123(6):809-821.

3. Homan CC, et al. GATA2 deficiency syndrome: A decade of discovery. Human Mutation. 2021;42(11):1399-1421.

Disclosures: Fioredda: X4 Pharmaceutics: Consultancy. Biondi: Incyte: Consultancy, Other: Advisory Board; Bluebird: Other: Advisory Board; Novartis: Honoraria; Amgen: Honoraria.

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