Fieschi et al. (2001) found that children with complete IFNGR deficiency, unlike patients with other genetic defects predisposing them to mycobacterial diseases, have very high levels of IFNG in their plasma. Fieschi et al. (2001) proposed this measurement ... Fieschi et al. (2001) found that children with complete IFNGR deficiency, unlike patients with other genetic defects predisposing them to mycobacterial diseases, have very high levels of IFNG in their plasma. Fieschi et al. (2001) proposed this measurement as a simple, inexpensive, and accurate diagnostic test for complete IFNGR. They noted that early identification of such children, who do not respond to exogenous IFNG or antibiotics, may improve management by leading to the consideration of bone marrow transplantation.
Families with multiple cases of disseminated atypical mycobacteriosis, a rare disorder, were reported by Engbaek (1964) and Uchiyama et al. (1981). Uchiyama et al. (1981) reported fatal disseminated atypical mycobacteriosis in 2 young Mexican-American girls. The atypical mycobacterium ... Families with multiple cases of disseminated atypical mycobacteriosis, a rare disorder, were reported by Engbaek (1964) and Uchiyama et al. (1981). Uchiyama et al. (1981) reported fatal disseminated atypical mycobacteriosis in 2 young Mexican-American girls. The atypical mycobacterium was of a different serotype in the 2 sisters. One of the sisters died in 1964 and the other in 1977. Studies by the authors suggested a congenital defect in monocyte microbicidal activity. Fischer et al. (1980) observed defective monocyte function in a 12-month-old child with fatal disseminated BCG infection. Heyne (1976) described a brother and sister with generalized BCG infection after inoculation in the newborn period. The boy later had enteric salmonellosis, Salmonella osteomyelitis, and 'intestinal pseudotuberculosis.' A defect of macrophages was postulated. Levin et al. (1995) described 6 children with disseminated atypical mycobacterial infection and no recognized form of immunodeficiency. Four, including 2 brothers, came from a village in Malta, and 2 were brothers of Greek Cypriot origin. They presented with fever, weight loss, lymphadenopathy, and hepatosplenomegaly. They had anemia and an acute phase response. A range of different mycobacteria (Mycobacterium fortuitum, M. chelonei, and 4 strains of M. avium intracellulare) were isolated. Treatment with multiple antibiotics failed to eradicate the infection, although treatment with gamma-interferon was associated with improvement. Three of the children had died and the 3 survivors had chronic infection. TNF-alpha (191160) production in response to endotoxin and gamma-interferon was found to be defective in the patients and their parents. T-cell proliferative responses to mycobacterial and recall antigens were reduced in parents of affected children, and gamma-interferon production was diminished in the patients and their parents. Levin et al. (1995) suggested that these patients are phenotypically similar to Lsh/Ity/Bcg susceptible mice (see ANIMAL MODEL). Toyoda et al. (2004) examined the immunologic abnormality of a patient with recurrent Mycobacterium avium infection. The patient had reduced expression of IL12RB1 and IL12RB2 and a decreased ability to produce IFNG (147570) and to proliferate in response to IL12. However, the patient exhibited no deficiency in IL12-induced tyrosine and serine phosphorylation of STAT4 (600558) in mitogen-activated T cells. EMSA, confocal laser microscopy, and Western blot analysis demonstrated that nuclear translocation of STAT4 in response to IL12 was reduced in the patient compared with healthy control subjects. Pharmacologic treatment indicated that the defect was not due to upregulated STAT4 export from the nucleus. No mutations in IL12RB1, IL12RB2, STAT4, or the IFNG STAT4-binding sequence were identified, and the exact mechanism for the defect could not be determined.
Newport et al. (1996) and Jouanguy et al. (1996) demonstrated that mutations in the interferon-gamma-receptor-1 gene (107470) conferred susceptibility to mycobacterium infection.
Heyne (2002) noted that the family reported by Heyne ... - IFNGR1 Deficiency Newport et al. (1996) and Jouanguy et al. (1996) demonstrated that mutations in the interferon-gamma-receptor-1 gene (107470) conferred susceptibility to mycobacterium infection. Heyne (2002) noted that the family reported by Heyne (1976), later reported as family C by Jouanguy et al. (1999), had an autosomal dominant form of partial interferon gamma receptor-1 deficiency and deletion of 4 nucleotides in the IFNGR1 gene (107470.0006). - IFNGR2 Deficiency Vogt et al. (2005) studied 4 children with severe mycobacterial disease from 3 unrelated families, all consanguineous. One was from an Austrian family, 1 from an Iranian family, and 2 were from a Saudi Arabian family. The severity of the clinical phenotype and the absence of detectable mutations in IFNGR1 led to a study of IFNGR2 (147569). The Iranian patient and the 2 Saudi Arabian patients were homozygous with respect to a missense mutation in the IFNGR2 gene (147569.0002). The Austrian patient was homozygous for an in-frame 27-bp microdeletion of nucleotides 663-689 (147569.0003). The parents of the 4 children were healthy and were heterozygous with respect to the corresponding mutations. All 4 children with the disorder referred to by Vogt et al. (2005) as mendelian susceptibility to mycobacterial disease had complete IFN-gamma-R2 deficiency. Vogt et al. (2008) reported a child of consanguineous parents with M. avium disease who was homozygous for an in-frame 6-bp duplication in IFNGR2, resulting in duplication thr128 and met129 (147569.0004). Both parents and 1 of 2 sibs were heterozygous for the mutation, but they did not develop disease. The affected child died at age 5 years of disseminated M. avium disease in spite of treatment with multiple antimycobacterial drugs. Vogt et al. (2008) found that the mutant IFNGR2 protein was predominantly retained intracellularly, and that the fraction expressed on the surface had a high molecular mass, was abnormally folded, was N-glycosylated, was resistant to endoglycosidase H, and did not respond to IFNG. Treating cells expressing the mutant protein with 13 of 29 compounds affecting protein maturation by N-glycosylation reduced the molecular mass of surface-expressed mutant IFNGR2 and restored cellular responsiveness to IFNG. Vogt et al. (2008) proposed that modifiers of N-glycosylation, some of which are available for clinical use, may complement human cells carrying in-frame and misfolding mutations in genes encoding proteins subject to trafficking via the secretory pathway. - IL12RB1 Deficiency Altare et al. (1998) and de Jong et al. (1998) found that severe atypical mycobacterial infections, as well as Salmonella infections, occurred in patients with mutations in the gene for the beta-1 chain of the interleukin-12 receptor (601604.0001-601604.0004). By SSCP and sequence analysis of the IL12RB1 gene in 120 unrelated probands, including 100 with atypical mycobacteriosis, Fieschi et al. (2003) identified 41 patients in 29 kindreds from 17 countries in Africa, America, Europe, and Asia with complete IL12RB1 surface expression deficiency. The patients were homozygous or compound heterozygous for 4 nonsense mutations, 4 splice site mutations, 6 missense mutations, 1 small insertion, 2 large deletions, and 4 deletion/insertions, for a total of 21 mutant alleles. None of the mutations were found in 50 unrelated healthy individuals from corresponding ethnic groups. Opportunistic childhood infections with weakly virulent Salmonella and Mycobacteria were observed in 34 patients, but 3 patients had clinical tuberculosis, including 1 with salmonellosis. Salmonellosis, but not the mycobacterial infections, was recurrent. BCG vaccination and disease protected against environmental mycobacteriosis but not against salmonellosis. BCG disease occurred in only 9 of 27 inoculated children. Fatality before age 8 occurred in 5 patients, 3 due to M. avium in non-BCG-vaccinated children and 2 due to disseminated BCG; the remaining patients were alive and well. Fieschi et al. (2003) proposed that IL12RB1 deficiency should be considered in children with opportunistic mycobacteriosis or salmonellosis and that the diagnosis should be pursued in healthy sibs of probands and in selected cases of tuberculosis. They concluded that the overall prognosis is good due to broad resistance to infection, low clinical penetrance, and the favorable outcome of the infections. Fieschi et al. (2003) noted the unexpected finding that IL12 is redundant in protective immunity against most microorganisms other than Mycobacteria and Salmonella, possibly reflecting the difference in the natural course of infection in humans as opposed to the courses of experimental infections in animal models. Ozbek et al. (2005) reported an 11-year-old Turkish girl with severe abdominal tuberculosis. She was the fourth child of healthy, consanguineous parents. Like her parents and sibs, she had had no adverse effect from BCG vaccination, and there was no family history of mycobacterial disease or other intracellular infectious diseases. The patient did not show augmented production of IFNG in response to antigen plus IL12. Ozbek et al. (2005) identified a homozygous splice site mutation in the IL12RB1 gene that led to skipping of exon 9 (601604.0006). They concluded that a diagnosis of IL12RB1 deficiency should be considered for children with unusually severe tuberculosis, even if they have no personal or family history of infection with weakly virulent Mycobacterium or Salmonella species. - STAT1 Deficiency In cells from a French patient with a history of disseminated BCG infection with no mutations in the IL12, IL12RB, or IFNGR genes, Dupuis et al. (2001) observed severely impaired nuclear protein binding to IFNG (147570)-activating sequences when the cells were stimulated with IFNG or IFNA (147660). Sequence analysis identified a mutation in the STAT1 gene (600555.0001). The patient's daughter, who was not vaccinated with BCG, had a similar cellular phenotype in vitro and carried the same mutation. An unrelated American patient with a history of M. avium infection was heterozygous for the same mutation. The mutation was not detected in healthy cohorts or in patients with mycobacterial disease.