Disorders of neutrophils: GATA2 Deficiency (also known as MonoMAC, DCML, Emberger, familial AML/MDS, classical NK cell deficiency)

What every physician needs to know:

GATA2 is a critical transcription factor in early hematopoietic ontogeny. Haploinsufficiency for GATA2 causes conditions ranging from deafness to lymphedema to acute myelogenous leukemia to disseminated mycobacterial infection, with ages of onset ranging from childhood to adulthood. Most patients eventually develop marrow dysfunction with monocytopenia, as well B and NK cell lymphopenia.

Are you sure your patient has GATA2 Deficiency? What should you expect to find?

Disseminated nontuberculous mycobacterial infection with absent monocytes, NK cells and B cells in the peripheral blood suggests the diagnosis. Other findings include: diffuse or severe warts, including perineal and cervical, pulmonary alveolar proteinosis, and clubbing. The bone marrow may show myelodysplasia, aplasia, or dysmorphic megakaryocytes. Karyotypic abnormalities (monosomy 7, trisomy 8) are common.

Beware of other conditions that can mimic GATA2 Deficiency:

Common considerations in the differential are advanced HIV infection, defects in the interferon gamma/IL-12 pathway, NEMO deficiency and myelodysplasia. However, the constellation of unusual cytopenias and infections is relatively specific to GATA2 deficiency. Despite the absence of circulating monocytes and B cells, there are normal numbers of tissue macrophages and plasma cells. Typical myelodysplasia is hypercellular, whereas that seen in GATA2 deficiency is hypocellular.

Continue Reading

Immunoglobulin levels are usually normal to high.

Which individuals are most at risk for developing GATA2 Deficiency:

There are no known environmental factors for development of the mutation, but the patients are susceptible to environmental infections, such as histoplasmosis, which has a finite geographic distribution. Nontuberculous mycobacteria are relatively ubiquitous, as are Aspergillus and warts.

There is as yet, no known racial or gender effect.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Inspection of the complete blood count (CBC) is informative, even if rarely performed. The leukocyte number is usually mildly low, but the monocyte number is usually below 40cells/mcl. On flow cytometry, both B cells and NK cells are dramatically reduced or absent. T cell numbers are variable. Definitive diagnosis depends on sequence of GATA2, and should include intronic regions as well as exons.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of GATA2 Deficiency?

Subpleural and paraseptal emphysematous changes are common and can be seen in children and young adults. Pulmonary alveolar proteinosis is eventually seen in up to 50% of patients. Necrotizing mediastinal adenopathy in GATA2 Deficiency is characteristically caused by Mycobacterium kansasii.

If you decide the patient has GATA2 Deficiency, what therapies should you initiate immediately?

Consider whether the patient has active mycobacterial infection and obtain bone marrow examination, including bone marrow biopsy and cytogenetics.

Most of the infections in GATA2 deficiency are slow-growing and do not require urgent therapy. However, the myelodysplasia in this disease can convert to acute leukemia.

More definitive therapies?

Hematopoietic stem cell transplantation is effective and well tolerated, ideally before extensive infection or leukemic transformation. The pulmonary alveolar proteinosis resolves with transplantation. Antibiotic prophylaxis for nontuberculous mycobacteria with daily azithromycin or clarithromycin is desirable.

What other therapies are helpful for reducing complications?

In the setting of refractory mycobacterial infection: interferon gamma 50 mcg/m2 subcutaneously three times weekly, has been effective.

What should you tell the patient and the family about prognosis?

Patients usually are normal in childhood, but may have more warts in adolescence, including difficult perineal warts or cervical dysplasia. Serious problems begin in adolescence or adulthood with recurrent severe infections, accompanied by abnormal bone marrow function and hypocellular bone marrow with characteristic megakaryocyte morphology. With the development of disseminated nontuberculous mycobacteria disease (often Mycobacterium kansasii), the cytopenias are noticed and the diagnosis is made.

Other scenarios in this disease are: severe varicella zoster infection, marrow aplasia, myelodysplasia, and leukemia. Currently, the penetrance appears to be complete with highly variable expression, especially with the milder mutations. Transplant success rates are high and appear to correct the infection and leukemic susceptibilities, as well as the pulmonary problems. The rate of progression of the disease is unknown, but it is likely that marrow function declines over time.

"What if" scenarios.

Pulmonary infiltrates should lead to consideration of both pulmonary alveolar proteinosis as well as infection with mycobacteria or fungi. Pulmonary hypertension has been seen in those with severe pulmonary alveolar proteinosis, and should be considered in the setting of hypoxemia. Marrow failure can be associated with disseminated infection, or be part of the underlying process; therefore, cultures and stains of the bone marrow should be performed, along with cytogenetics in any case in which this diagnosis is being considered. GATA2 deficiency can present in several ways, so should also be considered in cases of lymphedema, leukemia, myelodysplasia, pulmonary alveolar proteinosis and disseminated warts or mycobacterial infection.


GATA2 regulates early hematopoiesis, vascular and lymphatic formation, and some activities of mature cells, including regulation of endothelial factors and mature macrophage functions. Therefore, GATA2 deficiency has a wide range of clinical and pathologic consequences. The most likely mechanism of action is haploinsufficiency, since a large number of the mutations identified are deletions or protein-destabilizing.

The disease occurs spontaneously but is transmitted in a dominant pattern. There are many different mutations identified. Deletions have higher rates of lymphedema and deafness.

The likely explanation for the relatively normal hematopoietic function early in life, followed by cytopenias and marrow failure is that the haploinsufficient state allows an initial, and in some cases prolonged period of apparently normal hematopoiesis, followed by cytopenias, preferentially involving the monocytes, B cells, and NK cells. Whether these cytopenias are accompanied by pre-existing dysfunction is currently unresolved.

What other clinical manifestations may help me to diagnose GATA2 Deficiency?

Important aspects of the history include: unusual severity of chicken pox, frequency and severity of warts, miscarriages, cervical smear results, history of panniculitis.

Significant findings on physical exam may include warts, including flat warts on the arms and face, clubbing, and lymphedema. Patients may also present with cutaneous lesions (purplish, palpable) that might be consistent with disseminated mycobacterial or fungal infection.

What other additional laboratory studies may be ordered?

CBC with differential, flow cytometric testing of B and NK cell number, cytogenetics of bone marrow, GATA2 sequencing.