GATA2 Deficiency

GATA2 deficiency is an autosomal dominant haploinsufficiency of GATA2 that causes immunodeficiency, bone marrow failure and a high risk of myelodysplastic syndrome and acute myeloid leukaemia. It was once described as separate syndromes (MonoMAC, Emberger, DCML deficiency) that share the same cause.

Pathophysiology. GATA2 is a transcription factor for blood stem cells. Loss lowers monocytes, dendritic cells, B cells and NK cells, and the marrow becomes hypocellular and dysplastic.

It is rare. Onset ranges from childhood to the fourth decade, and penetrance is high by adult life.

Most patients present with infection, myelodysplasia, or a family history.

• Recurrent or disseminated non-tuberculous mycobacterial infection
• Severe or recalcitrant warts (HPV), genital HPV disease and cervical or anal neoplasia
• Fungal infection: Aspergillus, histoplasmosis, candidiasis
• Myelodysplastic syndrome and acute myeloid leukaemia, often with monosomy 7 or trisomy 8
• Pulmonary alveolar proteinosis
• Lymphoedema of limbs or genitals (Emberger syndrome) and hydrocele
• Sensorineural deafness
• Thrombosis, panniculitis, and recurrent miscarriage
• Cytopenias

• Full blood count with differential and flow cytometry: profound monocytopenia, with low B cells, NK cells and CD4 T cells.
• Bone marrow aspirate and trephine with cytogenetics: hypocellular marrow, dysplasia, and clonal changes (monosomy 7, trisomy 8).
• Genetic testing of GATA2 (coding variants, enhancer and large deletions), with family testing.
• Immunoglobulins (usually normal) and specific antibody responses.
• Infection workup: mycobacterial cultures from blood, marrow and tissue, fungal studies, HPV testing.
• High resolution CT chest (alveolar proteinosis, infection) and audiometry.

Differential diagnosis.

• Acquired myelodysplastic syndrome and aplastic anaemia
• Severe congenital neutropenia
• WHIM syndrome
• Interferon gamma and IL-12 axis defects
• Common variable immunodeficiency
• Idiopathic CD4 lymphocytopenia
• Primary lymphoedema (other genes)

• Haematopoietic stem cell transplantation is the only cure, and is advised for all with marrow failure, myelodysplasia, recurrent severe infection or leukaemia. Do it before leukaemia or end organ damage. Do not use a related donor who carries the variant.
• Infection prevention:
  • Azithromycin 250 mg orally daily or 500 mg three times weekly in adults (children 10 mg/kg three times weekly, maximum 500 mg) for mycobacterial prophylaxis, after ECG shows QTc under 450 ms and blood cultures are negative for mycobacteria.
  • Antifungal prophylaxis during severe neutropenia: posaconazole modified release tablets 300 mg twice daily on day 1 then 300 mg once daily with food; check trough level and liver enzymes.
  • 9-valent HPV vaccine, yearly cervical or anal cytology, and treatment of warts (cryotherapy, or imiquimod 5% cream three times weekly at night for up to 16 weeks).
• Disseminated mycobacterial infection: combination treatment for at least 12 months after cultures turn negative, for example clarithromycin 500 mg orally twice daily (or azithromycin 250 to 500 mg daily), ethambutol 15 mg/kg daily and rifampicin 10 mg/kg daily (maximum 600 mg), with amikacin 15 mg/kg intravenously once daily for severe disease for the first 2 to 3 months (adjust to renal function and levels; monitor hearing).
• Pulmonary alveolar proteinosis: whole lung lavage in symptomatic patients.
• Lymphoedema: compression, skin care, and treatment of cellulitis.
• Thrombosis and pregnancy: specialist haematology input.
• Vaccines: inactivated only; avoid live vaccines.

Special groups.

• Family members: test siblings and parents before donor selection.
• Women: obstetric and haematology review, because of recurrent miscarriage.

Monitoring. Full blood count every 3 months. Bone marrow examination with cytogenetics yearly, or sooner for new cytopenia. Audiometry yearly. CT chest if respiratory symptoms.

Referral and escalation. Refer to haematology and immunology. Urgent for new cytopenia, blasts on the film, fever, or respiratory symptoms.