SUMMARY

 

1. GATA2 deficiency is an autosomal dominant disease characterized by monocytopenia and susceptibility to mycobacterial infections (MonoMAC).

 

2. GATA2 is a zinc finger transcription factor required for proper development of hematopoietic cells including myeloid cells.

 

3. Patients typically have onset of disseminated nontuberculous mycobacterial disease in late adolescence or early adulthood. Patients also suffer from viral infections (molluscum contagiosum, HPV) and fungal infections (histoplasmosis, aspergillus).

 

4. The immunologic abnormalities include monocytopenia, NK cell lymphopenia and B cell lymphopenia. T cell lymphopenia may also be present in some patients. Immunoglobulin levels are typically normal or elevated despite the B cell lymphopenia.

 

5. Other clinical features of this disease include aplastic anemia/pancytopenia, myelodysplasia and an increased risk for myeloid leukemias (AML and CML). Pulmonary alveolar proteinosis and pulmonary hypertension occurs in approximately one-third of patients.

 

6. The diagnosis is suggested by a history of severe mycobacterial or fungal infections and characteristic immune abnormalities. Bone marrow is typically hypocellular. Sequencing of the GATA2 gene can confirm the diagnosis.

 

7. Hematopoietic stem cell transplantation has been successful in a small number of patients with GATA2 deficiency.

 

 

 

 

OVERVIEW

 

          GATA2 deficiency is an autosomal dominant disease characterized by monocytopenia and susceptibility to mycobacterial infections (MonoMAC).

 

          Patients typically have onset of disseminated nontuberculous mycobacterial disease in late adolescence or early adulthood. Patients also suffer from viral infections (molluscum contagiosum, HPV) and fungal infections (histoplasmosis, aspergillus).

 

          The key immunologic abnormalities include the following:

- Monocytopenia

- NK cell lymphopenia

- B cell lymphopenia

         

          T cell lymphopenia may also be present in some patients. Immunoglobulin levels are typically normal or elevated despite the B cell lymphopenia.

 

          Other clinical features of this disease include aplastic anemia/pancytopenia, myelodysplasia and an increased risk for myeloid leukemias (AML and CML). Pulmonary alveolar proteinosis and pulmonary hypertension occurs in approximately one-third of patients.

 

 

 

PATHOGENESIS

 

         GATA2 is a zinc finger transcription factor required for proper development of hematopoietic cells including myeloid cells. Missense, frameshift, splice site, and large intragenic deletions in GATA2 have been reported to date.

 

          GATA2 also plays a role in the transcriptional regulation of endothelial nitric oxide synthetase (eNOS). The pulmonary complications reported in this disease may be the result of pulmonary alveolar macrophage dysfunction and defective eNOS espression in the pulmonary epithelium.

 

 

EVALUATION

 

GATA2 deficiency should be suspected in patients with invasive non-tuberculous mycobacteria, viral, or fungal infections. Aplastic anemia/pancytopenia, myelodysplasia, myeloid leukemias, and pulmonary alveolar proteinosis may also occur. A dominant inheritance pattern in the clinical history would also be supportive of the diagnosis.

 

 

 

Step 1: Immune Evaluation

         

                      - CBC with Differential

-Quantitative immunoglobulins (IgG, IgM, IgA)

-Antibody titers to vaccine antigens

-Flow cytometry for B cell, T cell, and NK cell enumeration

 

-Severe monocytopenia is typically present.  CBC with differential may also be significant for pancytopenia due to aplastic anemia.

 

-IgG is typically normal or elevated. IgA levels have been reduced in some patients.

 

-B and NK cell lymphopenia is typically present. T cell may be normal or reduced.

 

 

Step 2:  Additional Studies

 

-Bone Marrow Biopsy

 

-Patients typically have hypocellular marrow

 

 

Step 3: Genetic confirmation

 

-GATA2 gene sequencing

 

-Sequencing of the GATA2 gene provides a definitive diagnosis.  Genetic confirmation can be achieved by sanger sequencing, whole exome sequencing or whole genome sequencing.

 

 

 

 

MANAGEMENT

 

          Hematopoietic stem cell transplantation (non-myeloablative) has been successful in a small number of patients with GATA2 deficiency.

 

 

 

 

                                                                           

RESOURCES

 

Diagnostic Resources         

 

1. Seattle Children's - GATA2 gene sequencing

 

 

Literature Resources

 

1. Hsu 2011

    GATA2 deficiency

 

2. Cuellar-Rodriguez 2011

    Successful HSCT for GATA2 Deficiency (6 patients)

 

3. Vinh 2010

    AD monocytopenia with susceptibility to mycobacteria, fungi, papillomavirus, and myelodysplasia