Susceptibility to mycobacterial diseases (MSMD) due to complete defect of interferon-gamma receptor 2 (IFNGR2) is a very rare autosomal recessive inherited immunodeficiency syndrome, a genetic variant of the genetically heterogeneous immunodeficiency family: Mendelian susceptibility to mycobacterial diseases, MSMD for short (see there). The consequence of complete IFN-gammaR2 deficiency with an unmeasurable IFN-gamma response is severe and often fatal infections with Bacillus Calmette-Guérin (BCG) and other environmental mycobacteria (EM).
MSDM, IFNGR2 deficiencyD84.8
DefinitionThis section has been translated automatically.
Occurrence/EpidemiologyThis section has been translated automatically.
Prevalence unknown. <20 children have been described.
EtiopathogenesisThis section has been translated automatically.
The cause is mutations in the IFNGR2 gene (21q22.1-22.2). This gene encodes the signaling chain of the IFN-gamma receptor.
ManifestationThis section has been translated automatically.
Onset in early childhood (<age 3 years).
Clinical featuresThis section has been translated automatically.
Severe and often lethal infections with BCG and other mycobacteria (EM). The most common pathogens include Mycobacterium fortuitum, Mycobacterium bovis, BCG, Mycobacterium abscessus, and Mycobacterium avium. Disseminated infections involving the soft tissues, bone marrow, lungs, skin, bones, and lymph nodes. Clinical symptoms: fever, weight loss, hepatosplenomegaly, lymphadenopathy.
DiagnosticsThis section has been translated automatically.
Detection of mutations in the IFNGR2 gene.
General therapyThis section has been translated automatically.
Stem cell transplantation (HSCT) is considered the only curative therapy for complete IFN-gammaR2 deficiency. Due to the lack of specific receptors, IFN-gamma treatment is not indicated. BCG vaccination must be avoided.
Case report(s)This section has been translated automatically.
Hoyos-Bachiloglu et al (2017) reported on a boy born to consanguineous Saudi parents who presented at two months of age with febrile illness due to Streptococcus viridans bacteremia and severe cytomegalovirus (CMV) viremia. He rapidly developed anemia, thrombocytopenia, splenomegaly, and lymphadenopathy. Laboratory tests indicated hemophagocytic lymphohistiocytosis (HLH). Bone marrow was positive for CMV and Mycobacterium abscessus. Laboratory testing revealed leukocytosis, CD4+ T cells slightly decreased, CD8+ T cells increased.
Attenuated MMR vaccination was normal. Whole-exome sequencing of this patient identified a homozygous loss-of-function mutation in the IFNGR2 gene (147569,0007), which explained the mycobacterial disease and confirmed IMD28, and a homozygous variant in the IFNAR1 gene (107450,0004), which may explain the unusual phenotype of CMV infection.
Lab: In vitro functional expression studies using patient fibroblasts revealed an impaired response to stimulation with gamma-IFN and a defect in IFN type II signaling, presumably caused by the IFNGR2 gene, and impaired downstream signaling after stimulation with alpha-IFN, suggesting a defect in IFN type I signaling, presumably caused by the IFNAR1 variant.
LiteratureThis section has been translated automatically.
- Al-Muhsen S et al (2008) The genetic heterogeneity of mendelian susceptibility to mycobacterial diseases. J Allergy Clin Immun 122: 1043-1051.
- Bustamante J (2020) Mendelian susceptibility to mycobacterial disease: recent discoveries. Hum Genet 139: 993-1000.
- Fieschi C et al (2001) High levels of interferon gamma in the plasma of children with complete interferon gamma receptor deficiency. Pediatrics 107: E48.
- Hoyos-Bachiloglu R et al (2017) A digenic human immunodeficiency characterized by IFNAR1 and IFNGR2 mutations. J Clin Invest 127: 4415-4420.
- Rosain J et al (2019) Mendelian susceptibility to mycobacterial disease: 2014-2018 update. Immunol Cell Biol 97:360-367.