A number sign (#) is used with this entry because immunodeficiency-34 (IMD34) is caused by mutation in the CYBB gene (300481) on chromosome Xp11.

X-linked chronic granulomatous disease (CGD; 306400) is an allelic disorder.

IMD34 results in predisposition to infections by poorly virulent mycobacteria, such as bacillus Calmette-Guerin (BCG) vaccines and nontuberculous environmental bacteria. Affected individuals are also susceptible to the more virulent species Mycobacterium tuberculosis (Bustamante et al., 2007).

Bustamante et al. (2007) studied a large French kindred in which 4 male maternal relatives had recurrent mycobacterial disease, suggesting X-linked recessive inheritance. Three patients had recurrent disease caused by BCG, and 1 had recurrent tuberculosis. The infections showed tropism for lymph nodes, in which granulomas exhibiting caseous necrosis, but no acid-fast bacilli, were observed. The patients, aged 32 to 55 years at the time of report, all responded to antibiotic therapy and/or surgical excision. A common childless maternal aunt had been successfully treated for pulmonary tuberculosis that also involved the reproductive system. The mother of 2 patients had a history of asymptomatic, untreated latent tuberculosis.

Bustamante et al. (2011) identified a second kindred consisting of 3 French maternally related males, aged 36 to 41 years at the time of report, with susceptibility to mycobacterial disease manifesting as BCG disease after neonatal vaccination. Patients from this kindred and the one previously reported by Bustamante et al. (2007) displayed no distinguishable immunologic phenotype.

By immunologic, biochemical, genetic, and linkage analyses, Bustamante et al. (2007) excluded mutations in 5 autosomal genes and the X-linked NEMO gene as the cause of recurrent mycobacterial disease in 4 male patients from a large French kindred. Linkage analysis of the X chromosome implicated 2 candidate regions, Xp21.2-p11.4, which contains 129 genes, and Xq25-q26.3, which contains 70 genes, with a maximum lod score of 2.

In the kindred they reported with X-linked MSMD (IMD34), Bustamante et al. (2011) identified a thr178-to-pro (T178P; 300481.0023) mutation in the CYBB gene. In the kindred reported by Bustamante et al. (2007), Bustamante et al. (2011) identified a glu231-to-pro (Q231P; 300481.0022) mutation in the CYBB gene. All clinically affected males in both kindreds were hemizygous for the mutated allele, whereas other maternally related healthy males tested were not. All 11 obligate female carriers tested in the 2 kindreds were heterozygous for the mutated allele. Male founders of both kindreds did not develop mycobacterial disease, but they lived in France before the introduction of routine BCG vaccination. CYBB mutations are commonly associated with chronic granulomatous disease (CGD; 306400), but Bustamante et al. (2011) found that all affected males, as well as other family members, had normal NADPH oxidase activity in circulating neutrophils and monocytes, unlike individuals with CGD or variant CGD. However, in vitro differentiation of monocytes to macrophages in the presence of MCSF (CSF1; 120420) revealed that NADPH oxidase activity was impaired in patient macrophages, and the ability to control the growth of BCG was reduced. Impairment of NADPH oxidase activity was also demonstrable in patient B-cell lines. Immunoblot analysis showed reduced expression of CYBB in patient neutrophils and monocytes, with a much greater reduction in monocyte-derived macrophages. Immunohistochemistry showed impaired production of CYBB in patient lymph node macrophages. Bustamante et al. (2011) concluded that the CYBB mutations in these 7 adult patients with susceptibility to mycobacterial disease (including 1 patient with tuberculosis), who had no history of other granulomatous or infectious diseases, resulted in dysfunction of macrophages, but not in dysfunction of granulocytes or monocytes.