GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity

Abstract

Haploinsufficiency of the hematopoietic transcription factor GATA2 underlies monocytopenia and mycobacterial infections; dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency; familial myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML); and Emberger syndrome (primary lymphedema with MDS). A comprehensive examination of the clinical features of GATA2 deficiency is currently lacking. We reviewed the medical records of 57 patients with GATA2 deficiency evaluated at the National Institutes of Health from January 1, 1992, to March 1, 2013, and categorized mutations as missense, null, or regulatory to identify genotype-phenotype associations. We identified a broad spectrum of disease: hematologic (MDS 84%, AML 14%, chronic myelomonocytic leukemia 8%), infectious (severe viral 70%, disseminated mycobacterial 53%, and invasive fungal infections 16%), pulmonary (diffusion 79% and ventilatory defects 63%, pulmonary alveolar proteinosis 18%, pulmonary arterial hypertension 9%), dermatologic (warts 53%, panniculitis 30%), neoplastic (human papillomavirus+ tumors 35%, Epstein-Barr virus+ tumors 4%), vascular/lymphatic (venous thrombosis 25%, lymphedema 11%), sensorineural hearing loss 76%, miscarriage 33%, and hypothyroidism 14%. Viral infections and lymphedema were more common in individuals with null mutations (P = .038 and P = .006, respectively). Monocytopenia, B, NK, and CD4 lymphocytopenia correlated with the presence of disease (P < .001). GATA2 deficiency unites susceptibility to MDS/AML, immunodeficiency, pulmonary disease, and vascular/lymphatic dysfunction. Early genetic diagnosis is critical to direct clinical management, preventive care, and family screening.

Figure 1

GATA2 mutations. (A) Genomic organization of GATA2 showing the 2 5′-untranslated and 5 coding exons. Larger boxes represent coding regions. Insertion/deletion and nonsense mutations predicted to result in null alleles are shown above in red. Regulatory mutations in intron 5 are shown in blue. (B) Protein domains of GATA2, showing N- and C-terminal zinc fingers (ZF-1, ZF-2) and nuclear localization signal (N). (C) Missense mutations, in-frame deletions, and frameshift mutations predicted to escape nonsense-mediated decay are shown in green. Superscript numerals indicate the number of independent mutations.

Figure 2

Onset of illness, survival, and transplantation. Kaplan-Meier curves are shown for onset of illness (first severe infection, myelodysplasia/leukemia, PAP, or lymphedema), survival after onset of illness, overall survival, and transplant-free survival for 57 individuals. Cumulative incidence of transplantation is shown accounting for death as a competing event. Posttransplant survival is shown for 21 individuals who underwent transplantation. The number of individuals under follow-up is indicated under the X axis. Confidence intervals of 95% are shaded in gray.

Figure 3

Clinical, pathologic, and radiographic features of GATA2 deficiency. (A) Hypocellular bone marrow with trilineage hypoplasia (36-year-old woman), bone marrow core biopsy hematoxylin and eosin stain. (B-D) Atypical megakaryocytes, small mononuclear (B), and dysplastic forms with separated nuclear lobes (B-D); taken from bone marrow core biopsies (B,C) and aspirate smear (D). (E) Cutaneous M abscessus infection and (F) skin biopsy AFB smear showing abundant mycobacteria. (G) Computed tomography scan of the chest showing the typical crazy paving pattern of PAP and (H) lung biopsy hematoxylin and eosin stain showing alveolar filling with lipoproteinaceous material. (I) Recalcitrant periungual warts, (J) perineal condyloma, and vulvar/anal intraepithelial neoplasia. (K) Panniculitis/erythema nodosum involving the anterior shins. (L) Computed tomography scan of the abdomen with multiple hypodense liver lesions (arrows) and (M) liver biopsy showing EBV-related spindle cell tumor with in situ hybridization of EBV-encoded messenger RNA using EBV probe antifluorescein antibody and bond polymer refine detection. (N) Unilateral lymphedema of the right lower extremity. (O) Magnetic resonance imaging of the brain with embolic infarcts in the right occipital and left parietal lobes (arrows) in the setting of culture-negative endocarditis.

Figure 4

Genotype-phenotype associations. Kaplan-Meier curves are shown for patients with missense (green, N = 33), null (red, N = 12), and regulatory mutations (blue, N = 9). Patients with uniallelic expression (N = 3) are not shown. Mutation group was associated with the risk for viral infection (P = .038) and lymphedema (exact log-rank test P = .006). No other end points differed by mutation group. Unless otherwise noted, P values were calculated using Cox regression stratified on proband status, with robust standard errors to adjust for kindred clusters.

Figure 5

Blood counts and disease severity. Absolute B cell, NK cell, monocyte, and CD4⁺ T cell count at first NIH visit for patients with 0, 1, 2, 3, or 4 of the following major complications: MDS/leukemia, severe viral infection, disseminated mycobacterial or fungal infection, and PAP. Monocyte counts and lymphocyte phenotyping were available for 55 and 51 patients, respectively. Shaded regions indicate normal blood count ranges from the NIH Department of Laboratory Medicine: absolute CD20⁺ B cell count 60 to 539 cells/μL; absolute NK cell count 126 to 729 cells/μL; absolute monocyte count 0.24 to 0.86 x10³ cells/μL; and absolute CD4⁺ T-cell count 362 to 1275 cells/μL. Diamonds indicate individuals with monocytosis in the setting of CMML. Horizontal bars indicate medians. Vertical bars indicate interquartile ranges. Blood counts were significantly associated with the number of major complications (P < .001). P values were obtained using linear regression with robust standard errors to adjust for kindred clusters. Analysis was done for the log-transformed cell counts, with offsets of half the lower limit of detection for B cells, NK cells, and monocytes to account for those cases in which the numbers were zero.

Figure 6

Clinical features of GATA2 deficiency by organ system. Common clinical findings are shown by the affected organ system. Primary disease features are indicated in bold.