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.

Mediastinal and Disseminated Mycobacterium kansasii Disease in GATA2 Deficiency

“…In contrast, patients with GATA2 deficiency develop disseminated disease beginning in their early 20s. The levels of B, NK, and CD4 1 T cells, and of monocytes, are variable in GATA2 deficiency; however, infectious complications increase as cytopenias evolve, which typically begins in late adolescence or adulthood (11). The absence of disseminated M. kansasii disease in childhood likely results from intact T-cell and monocyte compartments in GATA2 deficiency early in life.…”

“…GATA2 is a transcription factor required for the differentiation and proliferation of hematopoietic stem cells (HSCs). Deficiency of GATA2 contributes susceptibility to severe and disseminated viral (e.g., human papillomavirus), fungal, and NTM infections, pulmonary alveolar proteinosis, and myelodysplastic syndrome (MDS) (11). The hematologic profile of patients includes deficiencies of NK cells, monocytes, and B cells, and down-regulation of GATA2 has also been associated with impaired phagocytic activity of alveolar macrophages (12).…”

Heterogeneity of GATA2-related myeloid neoplasms

“…Overall, non-curative therapies should be limited and because of the high risk for evolution of advanced MDS with unfavorable karyotypes, timely HSCT should be suggested as a curative approach. Overall survival (OS) of GATA2-mutated patients transplanted for immunodeficiency was shown to be 54% at 4 years after transplantation in a NIHbased study [23]. In pediatric GATA2 cohorts, 5-year OS was 66% in patients transplanted for MDS with monosomy 7.…”

“…Generalized warts related to HPV infection were common viral complication, in addition to severe HSV, VZV, EBV and CMV infections. Disseminated non-tuberculous mycobacteria (NTM) infections were observed in about half of cases with MonoMAC syndrome [23]. Severe bacterial or fungal infections, and pulmonary alveolar proteinosis (PAP) were also prevalent in MonoMAC syndrome.…”

“…GATA2 protein is expressed at high levels in endothelial cells and lymphatic vessel valves [26,27] and controls the expression of PROX1 and FOXC2 genes important for programming lymphatic valve development [28]. In one study, it has been suggested that N-terminal frameshift mutations or larger deletions of GATA2 are more likely to cause lymphedema [23]; however, this association could not be confirmed in other patient cohorts [6]. Congenital deafness is presumed to result from failure of generation of the perilymphatic space surrounding the semicircular ducts in inner ear [29].…”