A Nationwide Study of GATA2 Deficiency in Norway-the Majority of Patients Have Undergone Allo-HSCT

Silje F Jørgensen, Jochen Buechner, Anders E Myhre, Eivind Galteland, Signe Spetalen, Mari Ann Kulseth, Hanne S Sorte, Øystein L Holla, Emma Lundman, Charlotte Alme, Ingvild Heier, Trond Flægstad, Yngvar Fløisand, Andreas Benneche, Børre Fevang, Pål Aukrust, Asbjørg Stray-Pedersen, Tobias Gedde-Dahl, Ingvild Nordøy, Silje F Jørgensen, Jochen Buechner, Anders E Myhre, Eivind Galteland, Signe Spetalen, Mari Ann Kulseth, Hanne S Sorte, Øystein L Holla, Emma Lundman, Charlotte Alme, Ingvild Heier, Trond Flægstad, Yngvar Fløisand, Andreas Benneche, Børre Fevang, Pål Aukrust, Asbjørg Stray-Pedersen, Tobias Gedde-Dahl, Ingvild Nordøy

Abstract

Purpose: GATA2 deficiency is a rare primary immunodeficiency that has become increasingly recognized due to improved molecular diagnostics and clinical awareness. The only cure for GATA2 deficiency is allogeneic hematopoietic stem cell transplantation (allo-HSCT). The inconsistency of genotype-phenotype correlations makes the decision regarding "who and when" to transplant challenging. Despite considerable morbidity and mortality, the reported proportion of patients with GATA2 deficiency that has undergone allo-HSCT is low (~ 35%). The purpose of this study was to explore if detailed clinical, genetic, and bone marrow characteristics could predict end-point outcome, i.e., death and allo-HSCT.

Methods: All medical genetics departments in Norway were contacted to identify GATA2 deficient individuals. Clinical information, genetic variants, treatment, and outcome were subsequently retrieved from the patients' medical records.

Results: Between 2013 and 2020, we identified 10 index cases or probands, four additional symptomatic patients, and no asymptomatic patients with germline GATA2 variants. These patients had a diverse clinical phenotype dominated by cytopenia (13/14), myeloid neoplasia (10/14), warts (8/14), and hearing loss (7/14). No valid genotype-phenotype correlations were found in our data set, and the phenotypes varied also within families. We found that 11/14 patients (79%), with known GATA2 deficiency, had already undergone allo-HSCT. In addition, one patient is awaiting allo-HSCT. The indications to perform allo-HSCT were myeloid neoplasia, disseminated viral infection, severe obliterating bronchiolitis, and/or HPV-associated in situ carcinoma. Two patients died, 8 months and 7 years after allo-HSCT, respectively.

Conclusion: Our main conclusion is that the majority of patients with symptomatic GATA2 deficiency will need allo-HSCT, and a close surveillance of these patients is important to find the "optimal window" for allo-HSCT. We advocate a more offensive approach to allo-HSCT than previously described.

Trial registration: ClinicalTrials.gov NCT00662090.

Keywords: GATA2 deficiency; Germline mutation; Hematologic neoplasms; Hematopoietic stem cell transplantation; Primary immunodeficiency.

Conflict of interest statement

The authors declare no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Pedigrees of the ten families, including 14 patients, with known GATA2 deficiency. Solid symbols denote affected status. Individuals marked in gray are deceased and not tested for GATA2 deficiency but are suspected to carry the disease-causing variant. In family G, the mother of Patients 10 and 11 died at age 30 of acute respiratory distress syndrome, 27 years ago. She also had lymphedema since birth. In light of their mother’s medical history, the GATA2 variant is probably maternally inherited. The father is alive and healthy. In family J, the mother of Patient 14 had a combined B and T cell defect, warts, myelodysplastic syndrome, lymphedema, and recurrent respiratory tract infections. She died of vulval cancer at the age of 38. The maternal grandfather of Patient 14 died of acute leukemia at the age of 33. WT, wild-type

References

    1. Hsu AP, Sampaio EP, Khan J, Calvo KR, Lemieux JE, Patel SY, et al. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood. 2011;118(10):2653–2655. doi: 10.1182/blood-2011-05-356352.
    1. Dickinson RE, Griffin H, Bigley V, Reynard LN, Hussain R, Haniffa M, 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.
    1. Ostergaard P, Simpson MA, Connell FC, Steward CG, Brice G, Woollard WJ, 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. doi: 10.1038/ng.923.
    1. Bresnick EH, Katsumura KR, Lee HY, Johnson KD, Perkins AS. Master regulatory GATA transcription factors: mechanistic principles and emerging links to hematologic malignancies. Nucleic Acids Res. 2012;40(13):5819–5831. doi: 10.1093/nar/gks281.
    1. Bresnick EH, Jung MM, Katsumura KR. Human GATA2 mutations and hematologic disease: how many paths to pathogenesis? Blood Adv. 2020;4(18):4584–4592. doi: 10.1182/bloodadvances.2020002953.
    1. Haugas M, Lilleväli K, Hakanen J, Salminen M. Gata2 is required for the development of inner ear semicircular ducts and the surrounding perilymphatic space. Dev Dyn. 2010;239(9):2452–2469. doi: 10.1002/dvdy.22373.
    1. Hickstein D. HSCT for GATA2 deficiency across the pond. Blood. 2018;131(12):1272–1274. doi: 10.1182/blood-2018-02-826461.
    1. Fasan A, Eder C, Haferlach C, Grossmann V, Kohlmann A, Dicker F, et al. GATA2 mutations are frequent in intermediate-risk karyotype AML with biallelic CEBPA mutations and are associated with favorable prognosis. Leukemia. 2013;27(2):482–485. doi: 10.1038/leu.2012.174.
    1. Spinner MA, Sanchez LA, Hsu AP, Shaw PA, Zerbe CS, Calvo KR, et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood. 2014;123(6):809–821. doi: 10.1182/blood-2013-07-515528.
    1. Cohen JI. GATA2 deficiency and Epstein-Barr virus disease. Front Immunol. 2017;8:1869. doi: 10.3389/fimmu.2017.01869.
    1. Oleaga-Quintas C, de Oliveira-Júnior EB, Rosain J, Rapaport F, Deswarte C, Guérin A, et al. Inherited GATA2 deficiency is dominant by haploinsufficiency and displays incomplete clinical penetrance. J Clin Immunol. 2021;41(3):639–57.
    1. Mardahl M, Jørgensen SE, Schneider A, Raaschou-Jensen K, Holm M, Veirum J, et al. Impaired immune responses to herpesviruses and microbial ligands in patients with MonoMAC. Br J Haematol. 2019;186(3):471–476.
    1. Hirabayashi S, Wlodarski MW, Kozyra E, Niemeyer CM. Heterogeneity of GATA2-related myeloid neoplasms. Int J Hematol. 2017;106(2):175–182. doi: 10.1007/s12185-017-2285-2.
    1. Donadieu J, Lamant M, Fieschi C, de Fontbrune FS, Caye A, Ouachee M, et al. Natural history of GATA2 deficiency in a survey of 79 French and Belgian patients. Haematologica. 2018;103(8):1278–1287. doi: 10.3324/haematol.2017.181909.
    1. Wlodarski MW, Hirabayashi S, Pastor V, Stary J, Hasle H, Masetti R, et al. Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood. 2016;127(11):1387–97. doi: 10.1182/blood-2015-09-669937.
    1. Parta M, Shah NN, Baird K, Rafei H, Calvo KR, Hughes T, et al. Allogeneic hematopoietic stem cell transplantation for GATA2 deficiency using a Busulfan-based regimen. Biol Blood Marrow Transplant. 2018;24(6):1250–1259. doi: 10.1016/j.bbmt.2018.01.030.
    1. Bogaert DJ, Laureys G, Naesens L, Mazure D, De Bruyne M, Hsu AP, et al. GATA2 deficiency and haematopoietic stem cell transplantation: challenges for the clinical practitioner. Br J Haematol. 2020;188(5):768–773. doi: 10.1111/bjh.16247.
    1. Tholouli E, Sturgess K, Dickinson RE, Gennery A, Cant AJ, Jackson G, et al. In vivo T-depleted reduced-intensity transplantation for GATA2-related immune dysfunction. Blood. 2018;131(12):1383–1387. doi: 10.1182/blood-2017-10-811489.
    1. Moraes-Fontes MF, Caramalho I, Hsu AP, Holland SM, Abecasis M. MonoMAC syndrome caused by a novel GATA2 mutation successfully treated by allogeneic hematopoietic stem cell transplantation. J Clin Immunol. 2019;39(1):4–6. doi: 10.1007/s10875-018-0576-x.
    1. Bortnick R, Wlodarski M, de Haas V, De Moerloose B, Dworzak M, Hasle H, et al. Hematopoietic stem cell transplantation in children and adolescents with GATA2-related myelodysplastic syndrome. Bone Marrow Transplant. 2021;56(11):2732–41.
    1. Stray-Pedersen A, Sorte HS, Samarakoon P, Gambin T, Chinn IK, Coban Akdemir ZH, et al. Primary immunodeficiency diseases: genomic approaches delineate heterogeneous Mendelian disorders. J Allergy Clin Immunol. 2017;139(1):232–245. doi: 10.1016/j.jaci.2016.05.042.
    1. Strand J, Gul KA, Erichsen HC, Lundman E, Berge MC, Tromborg AK, et al. Second-tier next generation sequencing integrated in nationwide newborn screening provides rapid molecular diagnostics of severe combined immunodeficiency. Front Immunol. 2020;11:1417. doi: 10.3389/fimmu.2020.01417.
    1. Zhang MY, Keel SB, Walsh T, Lee MK, Gulsuner S, Watts AC, et al. Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity. Haematologica. 2015;100(1):42–48. doi: 10.3324/haematol.2014.113456.
    1. Hahn CN, Chong CE, Carmichael CL, Wilkins EJ, Brautigan PJ, Li XC, et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet. 2011;43(10):1012–1017. doi: 10.1038/ng.913.
    1. Dickinson RE, Milne P, Jardine L, Zandi S, Swierczek SI, McGovern N, et al. The evolution of cellular deficiency in GATA2 mutation. Blood. 2014;123(6):863–874. doi: 10.1182/blood-2013-07-517151.
    1. Rio-Machin A, Vulliamy T, Hug N, Walne A, Tawana K, Cardoso S, et al. The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants. Nat Commun. 2020;11(1):1044. doi: 10.1038/s41467-020-14829-5.
    1. Polat A, Dinulescu M, Fraitag S, Nimubona S, Toutain F, Jouneau S, et al. Skin manifestations among GATA2-deficient patients. Br J Dermatol. 2018;178(3):781–785. doi: 10.1111/bjd.15548.
    1. Saida S, Umeda K, Yasumi T, Matsumoto A, Kato I, Hiramatsu H, et al. Successful reduced-intensity stem cell transplantation for GATA2 deficiency before progression of advanced MDS. Pediatr Transplant. 2016;20(2):333–336. doi: 10.1111/petr.12667.
    1. Mace EM, Hsu AP, Monaco-Shawver L, Makedonas G, Rosen JB, Dropulic L, et al. Mutations in GATA2 cause human NK cell deficiency with specific loss of the CD56bright subset. Blood. 2013;121(14):2669–2677. doi: 10.1182/blood-2012-09-453969.
    1. Vinh DC, Patel SY, Uzel G, Anderson VL, Freeman AF, Olivier KN, et al. Autosomal dominant and sporadic monocytopenia with susceptibility to mycobacteria, fungi, papillomaviruses, and myelodysplasia. Blood. 2010;115(8):1519–1529. doi: 10.1182/blood-2009-03-208629.
    1. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434–443. doi: 10.1038/s41586-020-2308-7.
    1. Mir MA, Kochuparambil ST, Abraham RS, Rodriguez V, Howard M, Hsu AP, et al. Spectrum of myeloid neoplasms and immune deficiency associated with germline GATA2 mutations. Cancer Med. 2015;4(4):490–499. doi: 10.1002/cam4.384.
    1. Ogawa S. Genetics of MDS. Blood. 2019;133(10):1049–1059. doi: 10.1182/blood-2018-10-844621.
    1. Hsu AP, Johnson KD, Falcone EL, Sanalkumar R, Sanchez L, Hickstein DD, et al. GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome. Blood. 2013;121(19):3830–7. doi: 10.1182/blood-2012-08-452763.
    1. Kozyra EJ, Pastor VB, Lefkopoulos S, Sahoo SS, Busch H, Voss RK, et al. Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency. Leukemia. 2020;34(10):2673–2687. doi: 10.1038/s41375-020-0899-5.
    1. Johnson KD, Hsu AP, Ryu MJ, Wang J, Gao X, Boyer ME, et al. Cis-element mutated in GATA2-dependent immunodeficiency governs hematopoiesis and vascular integrity. J Clin Invest. 2012;122(10):3692–3704. doi: 10.1172/JCI61623.
    1. Baliakas P, Tesi B, Wartiovaara-Kautto U, Stray-Pedersen Ar, Friis LS, Dybedal I, et al. Nordic guidelines for germline predisposition to myeloid neoplasms in adults: recommendations for genetic diagnosis, clinical management and follow-up. HemaSphere. 2019;3(6):e321. doi: 10.1097/HS9.0000000000000321.
    1. Grossman J, Cuellar-Rodriguez J, Gea-Banacloche J, Zerbe C, Calvo K, Hughes T, et al. Nonmyeloablative allogeneic hematopoietic stem cell transplantation for GATA2 deficiency. 2014;20(12):1940–8.
    1. McReynolds LJ, Yang Y, Yuen Wong H, Tang J, Zhang Y, Mulé MP, et al. MDS-associated mutations in germline GATA2 mutated patients with hematologic manifestations. Leuk Res. 2019;76:70–75. doi: 10.1016/j.leukres.2018.11.013.
    1. West RR, Hsu AP, Holland SM, Cuellar-Rodriguez J, Hickstein DD. Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation. Haematologica. 2014;99(2):276–281. doi: 10.3324/haematol.2013.090217.
    1. Pastor Loyola VB, Hirabayashi S, Pohl S, Kozyra EJ, Catala A, De Moerloose B, et al. Somatic genetic and epigenetic architecture of myelodysplastic syndromes arising from GATA2 deficiency. Blood. 2015;126(23):299. doi: 10.1182/blood.V126.23.299.299.
    1. Pastor V, Hirabayashi S, Karow A, Wehrle J, Kozyra EJ, Nienhold R, et al. Mutational landscape in children with myelodysplastic syndromes is distinct from adults: specific somatic drivers and novel germline variants. Leukemia. 2017;31(3):759–762. doi: 10.1038/leu.2016.342.
    1. Kozyra EJ, Gohring G, Hickstein DD, Calvo KR, DiNardo CD, Dworzak M, et al. Association of unbalanced translocation der(1;7) with germline GATA2 mutations. Blood. 2021.

Source: PubMed

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