MSDM, IFNGR2 deficiency D84.8

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).

Prevalence unknown. <20 children have been described.

The cause is mutations in the IFNGR2 gene (21q22.1-22.2). This gene encodes the signaling chain of the IFN-gamma receptor.

Onset in early childhood (<age 3 years).

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.

Detection of mutations in the IFNGR2 gene.

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.

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.

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