Tuberculosis in an autosomal recessive case of chronic granulomatous disease due to mutation of the NCF1 gene.

Susceptibility to infections caused by Mycobacterium tuberculosis and other Mycobacterium species has been reported in patients with acquired immunodeficiencies (e.g., acquired immunodeficiency syndrome, or AIDS) or primary immunodeficiency diseases (PIDs), including defects of the IL-12/IFNaxis, severe combined immunodeficiency (SCID), CD40L deficiency, and chronic granulomatous disease (CGD). The latter is caused by genetic defects that affect the NADPH oxidase in phagocytes, which results in the failure of neutrophils and monocytes/macrophages to generate reactive oxygen species and, hence, an inability to kill pathogens, including fungi and intracellular bacteria. The phagocyte NADPH oxidase complex consists of two membrane-bound proteins (gp91phox and p22phox), which together form cytochrome b558, and three cytosolic proteins (p47phox, p67phox, and p40phox). Upon cell activation, these proteins and the small GTPase Rac assemble at the cell membrane and at phagolysosomes and trigger the oxidative burst, which is essential for microbial killing. Mutations in genes encoding components of NADPH oxidase have been described in CGD. Among the genes encoding the NADPH oxidase subunits, mutations in CYBB, which encodes gp91phox and is located on the X chromosome, account for approximately 65% of CGD cases, whereas mutations in autosomal genes, such as CYBA (encoding p22phox), NCF1 (encoding p47phox), NCF2 (encoding p67phox), and NCF4 (encoding p40phox), cause autosomal recessive (AR)-CGD. The most common form of AR-CGD is caused by mutations in NCF1 (25% of CGD cases), followed by rare mutations in NCF2, CYBA, and NCF4. Patients with CGD suffer from recurrent, life-threatening bacterial and fungal infections that affect the skin, the lungs, the liver, the spleen, lymph nodes, and bones. In North America and Europe, the most commonly observed infections in CGD are caused by Staphylococcus aureus, Burkholderia cepacia, Salmonella sp., Serratia marcescens, Nocardia spp., and Aspergillus spp. In addition to these pathogens, CGD patients may develop TB and clinical adverse reactions following Bacille Calmette--Guerin (BCG) vaccination (BCGites or BCGosis), particularly patients in regions with a high incidence of TB, such as South America and Asia. Mycobacterial infections have been reported in patients with defects in gp91phox, p22phox, and p67phox. However,