MonoMAC Syndrome

MonoMAC syndrome (monocytopenia and Mycobacterium avium complex infection) is the adult clinical presentation of GATA2 deficiency. It combines severe monocytopenia, B cell and NK cell lymphopenia, and disseminated non-tuberculous mycobacterial infection, with a high risk of myelodysplasia.

Pathophysiology. Heterozygous GATA2 loss removes monocytes and dendritic cells, which are needed to activate the IL-12 and interferon gamma axis against mycobacteria. B cells, NK cells and CD4 cells fall, and the marrow slowly fails.

It presents in adolescents and adults, usually in the third or fourth decade, and may be sporadic or familial.

Pulmonary alveolar proteinosis, warts, and myelodysplasia often follow.

• Disseminated Mycobacterium avium complex infection, with fever, weight loss, cough and lymphadenopathy
• Other non-tuberculous mycobacteria and, less often, BCG disease
• Severe warts and genital HPV disease
• Histoplasmosis, aspergillosis and candidiasis
• Pulmonary alveolar proteinosis
• Myelodysplastic syndrome or acute myeloid leukaemia
• Lymphoedema, deafness, thrombosis, panniculitis
• Cytopenias

• Full blood count and flow cytometry: monocytes under 0.1 x 109/L, with low B cells, NK cells and CD4 T cells.
• Mycobacterial blood cultures, sputum, lymph node and marrow cultures with species identification and susceptibility testing.
• Bone marrow aspirate and trephine with cytogenetics (monosomy 7, trisomy 8).
• Genetic testing of GATA2, with family testing.
• HIV test and immunoglobulins.
• High resolution CT chest for infection or alveolar proteinosis, and abdominal imaging for nodes.
• Audiometry.

Differential diagnosis.

• Disseminated mycobacterial infection in HIV infection
• Other defects of the interferon gamma and IL-12 axis
• Idiopathic CD4 lymphocytopenia
• Hairy cell leukaemia (monocytopenia)
• Acquired myelodysplastic syndrome and aplastic anaemia
• Common variable immunodeficiency

• Disseminated Mycobacterium avium complex: clarithromycin 500 mg orally twice daily (or azithromycin 250 to 500 mg once daily), ethambutol 15 mg/kg orally once daily (maximum 1.6 g) and rifampicin 10 mg/kg orally once daily (maximum 600 mg), continued for at least 12 months after cultures turn negative. For severe disease add amikacin 15 mg/kg intravenously once daily for the first 2 to 3 months, adjusted to levels and renal function.
• Safety monitoring: liver enzymes monthly at first; visual acuity and colour vision before ethambutol and monthly (stop for visual change); ECG for QTc under 450 ms on macrolides; audiometry and creatinine on amikacin. Rifampicin induces many drugs, including azoles and anticoagulants, so adjust doses.
• Long term secondary prophylaxis after treatment: azithromycin 500 mg orally three times weekly or 250 mg daily, for as long as monocytopenia persists.
• Haematopoietic stem cell transplantation is the only cure, and should be done before myelodysplasia progresses and before refractory infection. Related donors must be tested for the variant.
• Interferon gamma 1b (50 microgram/m2 subcutaneously three times weekly) is used as an adjunct in refractory mycobacterial disease in specialist centres, with limited evidence.
• Pulmonary alveolar proteinosis: whole lung lavage in symptomatic patients.
• HPV disease: 9-valent HPV vaccine, cryotherapy or imiquimod 5% cream three times weekly at night for up to 16 weeks, and yearly cervical or anal cytology.
• Fungal prophylaxis during severe neutropenia: posaconazole modified release tablets 300 mg twice daily on day 1 then 300 mg once daily with food.
• Vaccines: inactivated only; no BCG or other live vaccines.

Special groups.

• Patients on rifampicin who use hormonal contraception need an alternative method, since rifampicin reduces its effect.

Monitoring. Mycobacterial cultures monthly during treatment. Full blood count every 3 months. Bone marrow examination with cytogenetics yearly, or sooner for new cytopenia. Audiometry yearly.

Referral and escalation. Refer to infectious diseases, haematology and immunology. Urgent for fever, new cytopenia, or respiratory failure.