GATA2 Deficiency Syndrome (PDQ®): Genetics - Health Professional Information [NCI]

Introduction to GATA2 Deficiency Syndrome

Germline loss-of-function variants in the master hematopoietic transcription factor, GATA2, can cause cellular deficiencies that have a high propensity to develop into myeloid malignancies. Initial reports identified GATA2 deficiency in cohorts of patients with the following conditions:

• Familial myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML).[1]
• Autosomal dominant and sporadic monocytopenias and mycobacterial infection (MonoMAC) syndrome.[2]
• D endritic c ell, m onocyte, and B and natural killer (NK) l ymphoid (DCML) deficiency.[3]
• Lymphedema and anogenital dysplasia (WILD) syndrome.[4]
• Primary lymphedema associated with a predisposition to AML (Emberger syndrome).[5]
• Unexplained chronic neutropenia.[6]
• Primary childhood MDS.[7]

Following these initial reports, it became well accepted that all of these clinical phenotypes represent the broad spectrum of GATA2 deficiency, a single genetic disease.

References:

1. Hahn CN, Chong CE, Carmichael CL, et al.: Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet 43 (10): 1012-7, 2011.
2. Hsu AP, Sampaio EP, Khan J, et al.: Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood 118 (10): 2653-5, 2011.
3. 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 118 (10): 2656-8, 2011.
4. Dorn JM, Patnaik MS, Van Hee M, et al.: WILD syndrome is GATA2 deficiency: A novel deletion in the GATA2 gene. J Allergy Clin Immunol Pract 5 (4): 1149-1152.e1, 2017 Jul - Aug.
5. 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 43 (10): 929-31, 2011.
6. 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 121 (5): 822-9, 2013.
7. Wlodarski MW, Hirabayashi S, Pastor V, et al.: Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood 127 (11): 1387-97; quiz 1518, 2016.

Genetics and Molecular Biology of GATA2 Deficiency Syndrome

GATA2 deficiency is caused by de novo or inherited, heterozygous, germline pathogenic variants in the GATA2gene, which result in a loss of GATA2 expression or abnormal GATA2 transcription factor function.[1] Most patients with GATA2 deficiency carry null GATA2 variants (i.e., splice-site variants, nonsense variants, frameshift variants, whole-gene deletions, or synonymous variants that affect RNA splicing) or GATA2missense variants that affect the zinc finger 2 domain. Approximately 10% of patients have noncoding substitutions in the EBOX-GATA-ETS enhancer element in intron 4 of GATA2, or occasionally, tandem duplications of the entire GATA2locus.[1,2]

Variable expressivity is common in GATA2 deficiency. Some patients present early in life with one of the following: 1) cytopenias and bone marrow failure that progress to myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), or 2) severe immunodeficiency with recurrent bacterial, viral, and fungal infections.[3,4,5,6,7,8,9] Other patients with GATA2 deficiency develop MDS with excess blasts without preexisting clinical features.[10,11,12] Immunodeficiency is common in patients with GATA2 deficiency and manifests with mycobacterial infections, human papillomavirus (HPV) infections (i.e., generalized warts, intraepithelial neoplasia), Epstein-Barr virus (EBV)–related disease, herpes virus–related disease, and fungal infections. Some patients may also develop pulmonary disease (anti-granulocyte–macrophage colony stimulating factor [GM-CSF] antibody-negative pulmonary alveolar proteinosis), thrombosis, and autoimmune features like autoimmune cytopenias, hepatitis, colitis, panniculitis, and arthritis. Immunological laboratory findings can include deficiencies of the following: dendritic cells, monocytes, transitional B cells, and natural killer cells. Patients with GATA2 deficiency can also have inverted CD4:CD8 ratios and hypogammaglobulinemia. Loss of B cells and their precursors was shown to be the most common feature in GATA2-deficient patients with MDS.[12] Although not all patients with GATA2 deficiency present with immunological changes, a history of immunodeficiency in a patient with MDS/AML may be a strong indicator that a germline GATA2 pathogenic variant is present.[3,8,13]

References:

1. Homan CC, Venugopal P, Arts P, et al.: GATA2 deficiency syndrome: A decade of discovery. Hum Mutat 42 (11): 1399-1421, 2021.
2. Singh P, Heer M, Resteu A, et al.: GATA2 deficiency phenotype associated with tandem duplication of GATA2 and overexpression of GATA2-AS1. Blood Adv 5 (24): 5631-5635, 2021.
3. Hsu AP, Sampaio EP, Khan J, et al.: Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood 118 (10): 2653-5, 2011.
4. 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 121 (5): 822-9, 2013.
5. Dickinson RE, Milne P, Jardine L, et al.: The evolution of cellular deficiency in GATA2 mutation. Blood 123 (6): 863-74, 2014.
6. Kazenwadel J, Secker GA, Liu YJ, et al.: Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature. Blood 119 (5): 1283-91, 2012.
7. Mir MA, Kochuparambil ST, Abraham RS, et al.: Spectrum of myeloid neoplasms and immune deficiency associated with germline GATA2 mutations. Cancer Med 4 (4): 490-9, 2015.
8. Calvo KR, Vinh DC, Maric I, et al.: Myelodysplasia in autosomal dominant and sporadic monocytopenia immunodeficiency syndrome: diagnostic features and clinical implications. Haematologica 96 (8): 1221-5, 2011.
9. Ganapathi KA, Townsley DM, Hsu AP, et al.: GATA2 deficiency-associated bone marrow disorder differs from idiopathic aplastic anemia. Blood 125 (1): 56-70, 2015.
10. Hahn CN, Chong CE, Carmichael CL, et al.: Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet 43 (10): 1012-7, 2011.
11. Wlodarski MW, Hirabayashi S, Pastor V, et al.: Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood 127 (11): 1387-97; quiz 1518, 2016.
12. Nováková M, Žaliová M, Suková M, et al.: Loss of B cells and their precursors is the most constant feature of GATA-2 deficiency in childhood myelodysplastic syndrome. Haematologica 101 (6): 707-16, 2016.
13. 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 118 (10): 2656-8, 2011.

Clinical Phenotypes in GATA2 Deficiency Syndrome

Approximately half of reported patients with GATA2pathogenic variants have constitutional features of GATA2 deficiency. Constitutional features of GATA2 deficiency include the following:[1,2]

• Congenital sensorineural deafness.
• Lymphedema.
• Hydrocele.
• Urogenital malformations.
• Attention deficit hyperactivity disorder (ADHD) spectrum disorders.

GATA2 deficiency prevalence is dependent upon several factors, including a patient's age and clinical manifestations. A myelodysplastic syndrome (MDS) cohort study estimated that germline GATA2 pathogenic variants were present in approximately 0.5% of adults and 7% of children.[1] Commonly acquired genetic lesions in GATA2 deficiency-related MDS include the following:[3,4,5,6,7,8]

• Abnormal karyotypes (monosomy 7, der(1;7) translocation, and trisomy 8).
• Somatic variants, particularly in the ASXL1, SETBP1, STAG2, and RUNX1genes.

In children with GATA2-related MDS, monosomy 7 has been reported in up to 70% to 80% of cases. However, in adults, the frequencies of both trisomy 8 and monosomy 7 were approximately 20% to 40%.[9] It is recommended that monosomy 7 in a young patient trigger GATA2 germline testing, since up to 72% of adolescents with an MDS diagnosis and monosomy 7 carry germline GATA2 pathogenic variants.[1] The der (1;7) chromosomal abnormality is a cytogenetic lesion that is also enriched in patients with GATA2 deficiency.[10]

The lifetime risk of developing myeloid neoplasms (MDS, myeloproliferative neoplasms, acute myeloid leukemia [AML]) is very high in individuals with GATA2 deficiency. The median age of myeloid neoplasm diagnosis was estimated to be 12 years in pediatric cohorts [1] and 35 years in adult cohorts.[5] Consolidated data from several studies suggest that the average age of myeloid neoplasm diagnosis was 20 years,[9] and the median age of diagnosis is 17 years (range, 0–78 y).[11] Infants and young children are typically not affected with myeloid malignancy or clinically relevant immunodeficiencies. However, these symptoms can manifest as early as age 4 to 5 years.[1] The lifetime penetrance of GATA2 deficiency is high (estimated as >80%), and thus far, only a small proportion of GATA2 carriers reported not having symptoms.

Genotype /phenotype correlative studies found that lymphedema is associated with GATA2 null pathogenic variants.[11] However, correlations between GATA2 variant type and hematopoietic malignancy development have not yet been established. Additional research is required to investigate whether different types of GATA2 variants have differing penetrance rates.

References:

1. Wlodarski MW, Hirabayashi S, Pastor V, et al.: Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood 127 (11): 1387-97; quiz 1518, 2016.
2. Spinner MA, Sanchez LA, Hsu AP, et al.: GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood 123 (6): 809-21, 2014.
3. Homan CC, Drazer MW, Yu K, et al.: Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX41. Blood Adv 7 (20): 6092-6107, 2023.
4. Largeaud L, Collin M, Monselet N, et al.: Somatic genetic alterations predict hematological progression in GATA2 deficiency. Haematologica 108 (6): 1515-1529, 2023.
5. West RR, Hsu AP, Holland SM, et al.: Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation. Haematologica 99 (2): 276-81, 2014.
6. Pastor V, Hirabayashi S, Karow A, et al.: Mutational landscape in children with myelodysplastic syndromes is distinct from adults: specific somatic drivers and novel germline variants. Leukemia 31 (3): 759-762, 2017.
7. Fisher KE, Hsu AP, Williams CL, et al.: Somatic mutations in children with GATA2-associated myelodysplastic syndrome who lack other features of GATA2 deficiency. Blood Adv 1 (7): 443-448, 2017.
8. McReynolds LJ, Yang Y, Yuen Wong H, et al.: MDS-associated mutations in germline GATA2 mutated patients with hematologic manifestations. Leuk Res 76: 70-75, 2019.
9. Wlodarski MW, Collin M, Horwitz MS: GATA2 deficiency and related myeloid neoplasms. Semin Hematol 54 (2): 81-86, 2017.
10. Kozyra EJ, Göhring G, Hickstein DD, et al.: Association of unbalanced translocation der(1;7) with germline GATA2 mutations. Blood 138 (23): 2441-2445, 2021.
11. Homan CC, Venugopal P, Arts P, et al.: GATA2 deficiency syndrome: A decade of discovery. Hum Mutat 42 (11): 1399-1421, 2021.

Management and Prognosis for GATA2 Deficiency Syndrome

Consensus guidelines on the management of GATA2 deficiency do not yet exist, and hence, surveillance strategies are individually tailored for each patient. Most patients are followed by hematologists, immunologists, or transplant physicians. General GATA2 deficiency management recommendations include the following: periodic analysis of peripheral blood counts and immune status, yearly bone marrow evaluation with cytogenetics and somatic variant testing, and screening for human papillomavirus (HPV)–related cancers.[1,2] Patients with severe cellular deficiencies may require antimicrobial prophylaxis.[3] Due to the risk of clonal evolution, treatment with granulocyte colony-stimulating factor (G-CSF) is generally avoided in neutropenic patients with GATA2 deficiency.

It is widely accepted that timely hematopoietic stem cell transplantation (HSCT) is the only curative approach for symptomatic GATA2-deficient patients. HSCT outcomes are influenced by several patient factors, including myelodysplastic syndrome (MDS) subtype and the presence of a preexisting immunodeficiency. Overall survival (OS) rates for patients who underwent HSCT for various indications were reported as follows: 54% for MDS/acute myeloid leukemia (AML) or immunodeficiency,[4] 66% in children with MDS and monosomy 7,[5] 88% in children with refractory cytopenia of childhood (RCC) and normal karyotypes,[6] and 86% in young adults with immunodeficiency.[7] Difficulty in predicting the disease's course complicates decision making regarding the optimal timing of HSCT. In 2021, researchers examined HSCT outcomes in 65 patients with GATA2-related MDS.[8] Five years after HSCT, the probability of OS and disease-free survival (DFS) was 75% and 70%, respectively. Nonrelapse mortality and relapse equally contributed to treatment failure. There was no evidence of increased graft-versus-host-disease incidence, excessive rates of infections, or organ toxicities. Advanced MDS and monosomy 7 were associated with worse outcomes. Patients who had RCC with normal karyotypes had better outcomes (DFS rate, 90%) when compared with those who had RCC and monosomy 7 (DFS rate, 67%).

HSCT is indicated in GATA2-deficient patients with the following: recurrent infections, transfusion dependency, or clonal evolution into a myeloid malignancy.[9,10,11] Several cases of donor-derived MDS/AML have been reported after HSCT in families with GATA2 deficiency.[12,13] This emphasizes the need for genetic counseling, assessment for the presence of GATA2-specific clinical features, and genetic testing in potential familial donors.

References:

1. Collin M, Dickinson R, Bigley V: Haematopoietic and immune defects associated with GATA2 mutation. Br J Haematol 169 (2): 173-87, 2015.
2. Davies SM: Monitoring and treatment of MDS in genetically susceptible persons. Hematology Am Soc Hematol Educ Program 2019 (1): 105-109, 2019.
3. Hsu AP, McReynolds LJ, Holland SM: GATA2 deficiency. Curr Opin Allergy Clin Immunol 15 (1): 104-9, 2015.
4. Spinner MA, Sanchez LA, Hsu AP, et al.: GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood 123 (6): 809-21, 2014.
5. Wlodarski MW, Hirabayashi S, Pastor V, et al.: Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood 127 (11): 1387-97; quiz 1518, 2016.
6. Sahoo SS, Pastor VB, Goodings C, et al.: Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes. Nat Med 27 (10): 1806-1817, 2021.
7. Parta M, Shah NN, Baird K, et al.: Allogeneic Hematopoietic Stem Cell Transplantation for GATA2 Deficiency Using a Busulfan-Based Regimen. Biol Blood Marrow Transplant 24 (6): 1250-1259, 2018.
8. Bortnick R, Wlodarski M, de Haas V, et al.: Hematopoietic stem cell transplantation in children and adolescents with GATA2-related myelodysplastic syndrome. Bone Marrow Transplant 56 (11): 2732-2741, 2021.
9. Förster A, Davenport C, Duployez N, et al.: European standard clinical practice - Key issues for the medical care of individuals with familial leukemia. Eur J Med Genet 66 (4): 104727, 2023.
10. Clark A, Thomas S, Hamblin A, et al.: Management of patients with germline predisposition to haematological malignancies considered for allogeneic blood and marrow transplantation: Best practice consensus guidelines from the UK Cancer Genetics Group (UKCGG), CanGene-CanVar, NHS England Genomic Laboratory Hub (GLH) Haematological Malignancies Working Group and the British Society of Blood and Marrow Transplantation and cellular therapy (BSBMTCT). Br J Haematol 201 (1): 35-44, 2023.
11. Parta M, Cole K, Avila D, et al.: Hematopoietic Cell Transplantation and Outcomes Related to Human Papillomavirus Disease in GATA2 Deficiency. Transplant Cell Ther 27 (5): 435.e1-435.e11, 2021.
12. Galera P, Hsu AP, Wang W, et al.: Donor-derived MDS/AML in families with germline GATA2 mutation. Blood 132 (18): 1994-1998, 2018.
13. Sakata N, Okano M, Masako R, et al.: Donor-derived myelodysplastic syndrome after allogeneic stem cell transplantation in a family with germline GATA2 mutation. Int J Hematol 113 (2): 290-296, 2021.

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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about GATA2 deficiency syndrome. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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• Courtney DiNardo, MD, MSC (University of Texas, M.D. Anderson Cancer Center)
• Marcin Wlodarski, MD, PhD (St. Jude Children's Research Hospital)

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Last Revised: 2024-08-22