Pulmonary Manifestations of GATA2 Deficiency


      GATA2 deficiency is a genetic disorder of hematopoiesis, lymphatics, and immunity caused by autosomal dominant or sporadic mutations in GATA2. The disease has a broad phenotype encompassing immunodeficiency, myelodysplasia, leukemia, and vascular or lymphatic dysfunction as well as prominent pulmonary manifestations.

      Research Question

      What are the pulmonary manifestations of GATA2 deficiency?

      Study Design and Methods

      A retrospective review was conducted of clinical medical records, diagnostic imaging, pulmonary pathologic specimens, and tests of pulmonary function.


      Of 124 patients (95 probands and 29 ascertained), the lung was affected in 56%. In addition to chronic infections, pulmonary alveolar proteinosis (11 probands) and pulmonary arterial hypertension (nine probands) were present. Thoracic CT imaging found small nodules in 54% (54 probands and 12 relatives), reticular infiltrates in 40% (45 probands and four relatives), paraseptal emphysema in 25% (30 probands and one relative), ground-glass opacities in 35% (41 probands and two relatives), consolidation in 21% (23 probands and two relatives), and a typical crazy-paving pattern in 7% (eight probands and no relatives). Nontuberculous mycobacteria were the most frequent organisms associated with chronic infection. Allogeneic hematopoietic stem cell transplantation successfully reversed myelodysplasia and immune deficiency and also improved pulmonary hypertension and pulmonary alveolar proteinosis in most patients.


      GATA2 deficiency has prominent pulmonary manifestations. These clinical observations confirm the essential role of hematopoietic cells in many aspects of pulmonary function, including infections, alveolar proteinosis, and pulmonary hypertension, many of which precede the formal diagnosis, and many of which respond to stem cell transplantation.

      Key Words


      GM-CSF (granulocyte-macrophage colony-stimulating factor), HSCT (hematopoietic stem cell transplantation), NK (natural killer), PAH (pulmonary arterial hypertension), PAP (pulmonary alveolar proteinosis)
      To read this article in full you will need to make a payment
      Subscribe to CHEST
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Spinner M.A.
        • Sanchez L.A.
        • Hsu A.P.
        • et al.
        GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity.
        Blood. 2014; 123: 809-821
        • Ishida H.
        • Honma K.
        • Tamura S.-I.
        • Imamura T.
        • Ito M.
        • Nonoyama S.
        GATA-2 anomaly and clinical phenotype of a sporadic case of lymphedema, dendritic cell, monocyte, B- and NK-cell (DCML) deficiency, and myelodysplasia.
        Eur J Pediatr. 2012; 171: 1273-1276
        • Wlodarski M.W.
        • Collin M.
        • Horwitz M.S.
        GATA2 deficiency and related myeloid neoplasms.
        Semin Hematol. 2017; 54: 81-86
        • Collin M.
        • Bigley V.
        • McClain K.L.
        • Allen C.E.
        Cell(s) of origin of Langerhans cell histiocytosis.
        Hematol Oncol Clin North Am. 2015; 29: 825-838
        • Ostergaard P.
        • Simpson M.A.
        • Connell F.C.
        • et al.
        Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome).
        Nat Genet. 2011; 43: 929-931
        • Vicente C.
        • Conchillo A.
        • Garcia-Sanchez M.A.
        • Odero M.D.
        The role of the GATA2 transcription factor in normal and malignant hematopoiesis.
        Crit Rev Oncol Hematol. 2012; 82: 1-17
        • Kitajima K.
        • Tanaka M.
        • Zheng J.
        • et al.
        Redirecting differentiation of hematopoietic progenitors by a transcription factor, GATA-2.
        Blood. 2006; 107: 1857-1863
        • Rodrigues N.P.
        • Boyd A.S.
        • Fugazza C.
        • et al.
        GATA-2 regulates granulocyte-macrophage progenitor cell function.
        Blood. 2008; 112: 4862-4873
        • Vinh D.C.
        • Patel S.Y.
        • Uzel G.
        • et al.
        Autosomal dominant and sporadic monocytopenia with susceptibility to mycobacteria, fungi, papillomaviruses, and myelodysplasia.
        Blood. 2010; 115: 1519-1529
        • Griese M.
        • Zarbock R.
        • Costabel U.
        • et al.
        GATA2 deficiency in children and adults with severe pulmonary alveolar proteinosis and hematologic disorders.
        BMC Pulm Med. 2015; 15: 87
        • Trapnell B.C.
        • Carey B.C.
        • Uchida K.
        • Suzuki T.
        Pulmonary alveolar proteinosis, a primary immunodeficiency of impaired GM-CSF stimulation of macrophages.
        Curr Opin Immunol. 2009; 21: 514-521
        • Jouneau S.
        • Ballerie AA-Ohoo
        • Kerjouan M.
        • Demant X.
        • Blanchard E.
        • Lederlin M.
        Haemodynamically proven pulmonary hypertension in a patient with GATA2 deficiency-associated pulmonary alveolar proteinosis and fibrosis.
        Eur Respir J. 2017; 49: 1700407
        • Cuellar-Rodriguez J.
        • Gea-Banacloche J.
        • Freeman A.F.
        • et al.
        Successful allogeneic hematopoietic stem cell transplantation for GATA2 deficiency.
        Blood. 2011; 118: 3715-3720
        • Parta M.
        • Shah N.N.
        • Baird K.
        • et al.
        Allogeneic hematopoietic stem cell transplantation for GATA2 deficiency using a busulfan-based regimen.
        Biol Blood Marrow Transplant. 2018; 24: 1250-1259
        • Cole K.
        • Avila D.
        • Parta M.
        • et al.
        GATA2 deficiency: early identification for improved clinical outcomes.
        Clin J Oncol Nurs. 2019; 23: 417-422
        • 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
        • Griffith De
        • Aksamit T.
        • Brown-Elliott B.A.
        • et al.
        An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med.
        2007 (175(4):367-416.)
        • Pellegrino R.
        • Viegi G.
        • Brusasco V.
        • et al.
        Interpretative strategies for lung function tests.
        Eur Respir J. 2005; 26: 948-968
        • Johnson J.D.
        • Theurer W.M.
        A stepwise approach to the interpretation of pulmonary function tests.
        Am Fam Physician. 2014; 89: 359-366
        • Lee K.N.
        • Levin D.L.
        • Webb W.R.
        • Chen D.
        • Storto M.L.
        • Golden J.A.
        Pulmonary alveolar proteinosis: high-resolution CT, chest radiographic, and functional correlations.
        Chest. 1997; 111: 989-995
        • Hsu A.P.
        • Johnson K.D.
        • Falcone E.L.
        • et al.
        GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome.
        Blood. 2013; 121 (s3831-s3837): 3830-3837
        • Wang B.M.
        • Stern E.J.
        • Schmidt R.A.
        • Pierson D.J.
        Diagnosing pulmonary alveolar proteinosis. A review and an update.
        Chest. 1997; 111: 460-466
        • Papiris S.A.
        • Tsirigotis P.
        • Kolilekas L.
        • et al.
        Pulmonary alveolar proteinosis: time to shift?.
        Expert Rev Respir Med. 2015; 9: 337-349
        • Maygarden S.J.
        • Iacocca M.V.
        • Funkhouser W.K.
        • Novotny D.B.
        Pulmonary alveolar proteinosis: a spectrum of cytologic, histochemical, and ultrastructural findings in bronchoalveolar lavage fluid.
        Diagn Cytopathol. 2001; 24: 389-395
        • Galiè N.
        • Hoeper M.M.
        • Humbert M.
        • et al.
        • Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC)
        • European Respiratory Society (ERS)
        • International Society of Heart and Lung Transplantation (ISHLT)
        Guidelines for the diagnosis and treatment of pulmonary hypertension..
        Eur Respir J. 2009; 34: 1219-1263
        • Summer R.
        • Kotton D.N.
        • Sun X.
        • Fitzsimmons K.
        • Fine A.
        Translational physiology: origin and phenotype of lung side population cells..
        Am J Physiol Lung Cell Mol Physiol. 2004; 287
        • Tang X.
        • Lasbury M.E.
        • Davidson D.D.
        • Bartlett M.S.
        • Smith J.W.
        • Lee C.H.
        Down-regulation of GATA-2 transcription during Pneumocystis carinii infection.
        Infect Immun. 2000; 68: 4720-4724
        • Lasbury M.E.
        • Tang X.
        • Durant P.J.
        • Lee C.-H.
        Effect of transcription factor GATA-2 on phagocytic activity of alveolar macrophages from Pneumocystis carinii-infected hosts.
        Infect Immun. 2003; 71: 4943-4952
        • Nishinakamura R.
        • Wiler R.
        • Dirksen U.
        • et al.
        The pulmonary alveolar proteinosis in granulocyte macrophage colony-stimulating factor/interleukins 3/5 beta c receptor-deficient mice is reversed by bone marrow transplantation.
        J Exp Med. 1996; 183: 2657-2662
        • Zhang P.
        • Behre G.
        • Pan J.
        • et al.
        Negative cross-talk between hematopoietic regulators: GATA proteins repress PU.1.
        Proc Natl Acad Sci U S A. 1999; 96: 8705-8710
        • Shibata Y.
        • Berclaz P.Y.
        • Chroneos Z.C.
        • Yoshida M.
        • Whitsett J.A.
        • Trapnell B.C.
        GM-CSF regulates alveolar macrophage differentiation and innate immunity in the lung through PU.1.
        Immunity. 2001; 15: 557-567
        • Bonfield T.L.
        • Raychaudhuri B.
        • Malur A.
        • et al.
        PU.1 regulation of human alveolar macrophage differentiation requires granulocyte-macrophage colony-stimulating factor.
        Am J Physiol Lung Cell Mol Physiol. 2003; 285: L1132-L1136
        • Berclaz P.Y.
        • Shibata Y.
        • Whitsett J.A.
        • Trapnell B.C.
        GM-CSF, via PU.1, regulates alveolar macrophage Fcgamma R-mediated phagocytosis and the IL-18/IFN-gamma-mediated molecular connection between innate and adaptive immunity in the lung.
        Blood. 2002; 100: 4193-4200
        • Perdiguero E.G.
        • Geissmann F.
        The development and maintenance of resident macrophages.
        Nat Immunol. 2016; 17: 2-8
        • Srinivasan A.
        • Sunkara A.
        • Mitchell W.
        • et al.
        Recovery of pulmonary function after allogeneic hematopoietic cell transplantation in children is associated with improved survival.
        Biol Blood Marrow Transplant. 2017; 23: 2102-2109
        • Lázár Z.
        • Mészáros M.
        • Bikov A.
        The nitric oxide pathway in pulmonary arterial hypertension: pathomechanism, biomarkers and drug targets.
        Curr Med Chem. 2020; 27: 7168-7188
        • German Z.
        • Chambliss K.L.
        • Pace M.C.
        • Arnet U.A.
        • Lowenstein C.J.
        • Shaul P.W.
        Molecular basis of cell-specific endothelial nitric-oxide synthase expression in airway epithelium.
        J Biol Chem. 2000; (275(11):8183-8189.)
        • Lanzola E.
        • Farha S.
        • Erzurum S.C.
        • Asosingh K.
        Bone marrow-derived vascular modulatory cells in pulmonary arterial hypertension.
        Pulm Circ. 2013; 3: 781-791
        • Pu X.
        • Du L.
        • Hu Y.
        • Fan Y.
        • Xu Q.
        Stem/progenitor cells and pulmonary arterial hypertension.
        Arterioscler Thromb Vasc Biol. 2021; 41: 167-178
        • Faiz S.A.
        • Iliescu C.
        • Lopez-Mattei J.
        • Patel B.
        • Bashoura L.
        • Popat U.
        Resolution of myelofibrosis-associated pulmonary arterial hypertension following allogeneic hematopoietic stem cell transplantation.
        Pulm Circ. 2016; 6: 611-613
        • Umar S.
        • de Visser Y.P.
        • Steendijk P.
        • et al.
        Allogenic stem cell therapy improves right ventricular function by improving lung pathology in rats with pulmonary hypertension.
        Am J Physiol Heart Circ Physiol. 2009; 297: H1606-H1616
        • Pittman C.
        • Hsieh M.M.
        • Coles W.
        • Tisdale J.F.
        • Weir N.A.
        • Fitzhugh C.D.
        Reversal of pre-capillary pulmonary hypertension in a patient with sickle cell anemia who underwent haploidentical peripheral blood stem cell transplantation.
        Bone Marrow Transplant. 2017; 52: 641-642