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Autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency
A rare, genetic variant of mendelian susceptibility to mycobacterial diseases (MSMD) characterized by a partial deficiency leading to impaired IFN-gamma immunity and, consequently, recurrent, moderately severe infections with bacillus Calmette-Guérin (BCG) and other environmental mycobacteria (EM).
ORPHA:319581Classification level: Disorder
- Autosomal dominant MSMD due to partial IFNgammaR1 deficiency
- Autosomal dominant MSMD due to partial interferon gamma receptor 1 deficiency
- Autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial interferon gamma receptor 1 deficiency
- Prevalence: <1 / 1 000 000
- Inheritance: Autosomal dominant
- Age of onset: Adolescent
- ICD-10: D84.8
- OMIM: 615978
- UMLS: -
- MeSH: -
- GARD: -
- MedDRA: -
The prevalence is unknown. Since it was first reported in 1999, more than 70 patients bearing heterozygous mutations in IFNGR1 gene have been reported.
Patients present with moderately severe mycobacterial infections at around the age of 13 years. These infections are recurrent but less severe than those seen in MSMD due to complete IFN-gammaR1 and IFN-gammaR2 deficiencies (see these terms). Infections with Mycobacterium bovis BCG or Mycobacterium avium often lead to multifocal or unifocal osteomyelitis in patients with this variant. Salmonellosis has been reported in 5% of cases and infections with other pathogens such as Histoplasma capsulatum and varicella-zoster virus have also been reported in single patients.
AD MSMD due to partial IFN-gammaR1 deficiency is caused by heterozygous mutations in the IFNGR1 gene on chromosome 6q23-q24 that encodes the IFN-gamma receptor ligand binding chain. Microdeletion 818del4 is by far the most common mutation and it corresponds to the first documented hotspot for a microdeletion in the human genome. It leads to the expression of IFN-gamma receptor on the cell surface with no signal transduction and therefore patients only show a partial response to IFN-gamma.
Diagnosis is made by laboratory analysis. Cells of patients show a residual response to IFN-gamma in terms of Stat-1 DNA-binding (GAS-binding activity) and HLA-II induction. Genetic testing reveals mutations in IFNGR1.
Other genetic etiologies of MSMD should be excluded.
This immunodeficiency is not severe and antenatal diagnosis is not necessary.
Transmission is autosomal dominant and genetic counseling is possible.
Management and treatment
BCG vaccination should be avoided in those with a known mutation in the IFNGR1 gene. Patients should be treated with antibiotics and, if necessary, with recombinant IFN-gamma.