Pulmonary Manifestations of GATA2 Deficiency

Abstract

Background: 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.

Results: 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.

Interpretation: 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.

Keywords: GATA2 deficiency; pulmonary alveolar proteinosis; pulmonary hypertension.

Figure 1

A, B, Photomicrographs showing lipoproteinaceous material filling alveolar spaces with positive periodic acid-Schiff results (A, ×200; B, ×400). C, Electron microscopic image showing BAL fluid exhibiting whorled membranous structures and amorphous osmiophilic particles. D, Higher magnification electron microscopic image showing a whorled membranous body with concentric osmiophilic membranes resembling tubular myelin.

Figure 2

CT scans with the characteristics described in GATA2 deficiency. A, Nodules: I, coronal and II, axial on 20 mm maximum intensity projection show numerous diffuse small nodules bilaterally (male patient, aged 29 years). B, Reticular infiltrate: Axial CT scan reticular shows infiltrate in left upper lobe (female patient, aged 31 years). C, Ground-glass opacities: Axial CT scan (male patient, aged 16 years). D, Paraseptal emphysema: I, Coronal multiplanar reformation 0.5 x 0.3 mm CT scan shows striking diffuse paraseptal emphysema (subpleural blebs) along all pleural surfaces (black arrows peripherally) including fissures and mediastinum (white arrows); II, Axial 0.5 x 0.3 mm CT scan diffuse paraseptal emphysema (subpleural blebs) along all pleural surfaces (black arrows peripherally) including fissures and mediastinum (white arrows) (male patient, aged 21 years). E, Consolidation: Axial CT scan (female patient, aged 21 years). F, Crazy paving: Axial CT scan shows extensive areas of ground-glass opacity within regions of interstitial markings resembling a “crazy paving” pattern (female patient, aged 37 years).

Figure 3

A, B, Distribution of pulmonary function test patterns at first visit. A, Pie chart showing pattern of impairment. B, Scatterplots showing pulmonary function test findings at first visit in probands and relatives (median and interquartile range). 6MWT = 6-min walk test; Dlco = diffusing capacity for carbon monoxide.

Figure 4

Graph showing pulmonary arterial hypertension findings: right ventricular systolic pressure measured by echocardiography before and after bone marrow transplantation. HSCT = hematopoietic stem cell transplantation; PAP = pulmonary alveolar proteinosis.