Immunodeficiency 27a

A number sign (#) is used with this entry because of evidence that immunodeficiency-27A (IMD27A), an autosomal recessive disorder, is caused by homozygous or compound heterozygous mutation in the IFNGR1 gene (107470) on chromosome 6q23.

Immunodeficiency-27B (IMD27B; 615978), an autosomal dominant disorder, is allelic.

Description

Immunodeficiency-27A results from autosomal recessive (AR) IFNGR1 deficiency. Patients with complete IFNGR1 deficiency have a severe clinical phenotype characterized by early and often fatal mycobacterial infections. bacillus Calmette-Guerin (BCG) and environmental mycobacteria are the most frequent pathogens, and infection typically begins before the age of 3 years. Plasma from patients with complete AR IFNGR1 deficiency usually contains large amounts of IFNG (147570), and their cells do not respond to IFNG in vitro. In contrast, cells from patients with partial AR IFNGR1 deficiency, which is caused by a specific mutation in IFNGR1, retain residual responses to high IFNG concentrations. Patients with partial AR IFNGR1 deficiency are susceptible to BCG and environmental mycobacteria, but they have a milder clinical disease and better prognosis than patients with complete AR IFNGR1 deficiency. The clinical features of children with complete AR IFNGR1 deficiency are usually more severe than those in individuals with AD IFNGR1 deficiency (IMD27B), and mycobacterial infection often occurs earlier (mean age of 1.3 years vs 13.4 years), with patients having shorter mean disease-free survival. Salmonellosis is present in about 5% of patients with AR or AD IFNGR1 deficiency, and other infections have been reported in single patients (review by Al-Muhsen and Casanova, 2008).

Clinical Features

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.

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.

Diagnosis

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 deficiency. 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.

Molecular Genetics

Newport et al. (1996) and Jouanguy et al. (1996) demonstrated that mutations in the interferon-gamma-receptor-1 gene (IFNGR1; 107470) conferred autosomal recessive susceptibility to mycobacterium infection.

Al-Muhsen and Casanova (2008) and Cottle (2011) reviewed genetic heterogeneity of susceptibility to mycobacterial disease.

Genotype/Phenotype Correlations

Dorman et al. (2004) compared the clinical features of recessive and dominant IFNGR1 deficiencies using a worldwide cohort of patients. They assessed the patients by medical histories and genetic and immunologic studies. Recessive deficiency, which Dorman et al. (2004) identified in 22 patients, results in complete loss of cellular response to IFNG and absence of surface IFNGR1 expression. Dominant deficiency, which they identified in 38 patients, is typically due to cytoplasmic domain truncations resulting in accumulation of nonfunctional IFNGR1 proteins that may impede the function of molecules encoded by the wildtype allele, thereby leading to diminished but not absent responsiveness to IFNG. Although the clinical phenotypes are related, Dorman et al. (2004) found that patients with the recessive form had an earlier age of onset (3 vs 13 years), more mycobacterial disease episodes (19 vs 8 per 100 person years of observation), more severe mycobacterial disease (involvement of 4 vs 2 organs), shorter mean disease-free intervals (1.6 vs 7.2 years), and lower Kaplan-Meier survival probability. Recessive patients also had more frequent disease from rapidly growing mycobacteria. Patients with a dominant mutation, however, were more likely to have M. avium complex osteomyelitis, and only dominant patients had osteomyelitis without other organ involvement. Dorman et al. (2004) concluded that there is a strong correlation between the IFNGR1 genotype, clinical disease features, and the cellular responsiveness to IFNG. They suggested that subtle defects in IFNG production, signaling, or related pathways may predispose to diseases caused by virulent mycobacteria, including M. tuberculosis.

Animal Model

There is a mouse gene, variously symbolized Lsh, Ity, and Bcg, on murine chromosome 1 which encodes resistance to bacterial and parasitic infections and affects the function of macrophages (Skamene et al., 1982; Brown et al., 1982; Goto et al., 1984; Plant et al., 1982; Swanson and O'Brien, 1983; Nickol and Bonventre, 1985). Bcg is expressed in 2 allelic forms, the dominant resistance allele and the recessive susceptibility allele. The Bcg region on proximal mouse chromosome 1 shows homology of synteny with the telomeric portion of human 2q; a 35-cM fragment around the murine Bcg locus (from Col3a1 (120180) to Col6a3 (120250)), has been conserved between the 2 species, the human region being 2q32-q37.

History

Schurr et al. (1991) studied linkage of genetic markers on distal chromosome 2q with susceptibility to tuberculosis and found a lod score of 2.4. Shaw et al. (1993), however, could not confirm this finding. They performed linkage analysis using a panel of markers from the 2q33-q37 region in 35 multicase families with infection by Mycobacterium leprae, M. tuberculosis, and Leishmania sp. Data from all 3 types of families were pooled to produce a detailed RFLP map of the region. The order of genes in the human was consistent with that determined for the same loci in the mouse. Nonetheless, Shaw et al. (1993) could not demonstrate linkage of infection susceptibility to this region.

Newport et al. (1995) excluded NRAMP (600266) as the site of the mutation causing this disorder, which they referred to as familial disseminated atypical mycobacterial infection, in a Maltese kindred. They typed 8 markers in the region of 2q34-q37 where NRAMP maps.