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Autosomal recessive mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency
A genetic variant of mendelian susceptibility to mycobacterial diseases (MSMD) characterized by a partial deficiency in IFN-gammaR1, leading to a residual response to IFN-gamma and, consequently, to recurrent, moderately severe infections with bacillus Calmette-Guérin (BCG) and other environmental mycobacteria (EM).
ORPHA:319569Classification level: Disorder
- Autosomal recessive MSMD due to partial IFNgammaR1 deficiency
- Autosomal recessive MSMD due to partial interferon gamma receptor 1 deficiency
- Autosomal recessive mendelian susceptibility to mycobacterial diseases due to partial interferon gamma receptor 1 deficiency
- Prevalence: <1 / 1 000 000
- Inheritance: Autosomal recessive
- Age of onset: -
- ICD-10: D84.8
- OMIM: 209950
- UMLS: -
- MeSH: -
- GARD: -
- MedDRA: -
The prevalence is unknown. The same homozygous mutations have been reported in 14 patients in 11 kindreds from Poland, Portugal, Spain and Chile, thus reflecting a founder effect.
Patients present with moderately severe mycobacterial infections, BCG or EM diseases. 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 tuberculosis have also been reported in patients with this disorder.
Autosomal recessive MSMD due to partial IFN-gammaR1 deficiency is caused by homozygous mutations in the IFNGR1 gene on chromosome 6q23-q24 that encodes the IFN-gamma receptor ligand binding chain. The most common mutation is, by far, I87T. This mutation leads to the expression of IFN-gamma receptors on the cell surface with no signal transduction capacity and they therefore only show a partial response to IFN-gamma.
Diagnosis is made by laboratory analysis. Low production of IL12p40 is detected in blood after BCG and BCG+IFN-gamma activation. Cells of patients show a residual response to IFN-gamma in terms of Stat-1 DNA-binding (GAS-binding activity) and HLA-II induction. A mutational analysis will identify a mutation in the IFNGR1 gene. Low levels of IFN-gamma were detected in the serum of the patients.
Other genetic etiologies of MSMD should be excluded.
This immunodeficiency is not severe and antenatal diagnosis is not necessary.
Transmission is autosomal recessive and genetic counseling is possible.
Management and treatment
BCG vaccinations should be avoided in those with a known mutation in IFNGR1. Patients should be treated with antibiotics and, if necessary, with recombinant IFN-gamma.
Prognosis is usually good.