Immunodeficiency 45 D81.4

Immunodeficiency-45 (IMD45/ OMIM: 616669) is an autosomal recessively inherited immunological disorder with specific clinical features. Two affected children reported to date developed an acute and severe reaction to vaccination with live MMR vaccines.

Features included fever, exanthema, lymphadenopathy, irritability or encephalopathy , and seizures.

One patient developed hemophagocytic lymphohistiocytosis (HLH), from which he later recovered, while the other eventually died.

In an immunodeficient-45 male infant who developed fatal encephalitis after routine MMR vaccination, Duncan et al (2015) identified a homozygous truncating mutation in the IFNAR2 gene (602376.0002). The patients' cells lacked IFNAR2 expression and did not respond to IFNA1/IFNB1 signaling, resulting in increased susceptibility to viral infection. Unaffected parents were heterozygous for the mutation.

In a 2-year-old Italian boy with IMD45, Passarelli et al (2020) identified heterozygous frameshift mutations in the IFNAR2 gene (602376,0003 and 602376,0004). The mutations were found by clinical exome sequencing and confirmed by Sanger sequencing. In vitro studies showed that the patients' monocytes and NK cells did not respond to IFN-alpha. The patients' NK cells exhibited other functional deficits, including a lack of inhibition of gamma-IFN production after exposure to type I IFN.

Impaired response to alpha-IFN (see 147660) and an impaired type I interferon signature after stimulation (summary of Duncan et al., 2015 and Passarelli et al. 2020).

1. Duncan CJA et al (2015) Human IFNAR2 deficiency: lessons for antiviral immunity. Sci Transl Med 7: 307ra154.
2. Passarelli C et al (2020) IFNAR2 deficiency causing dysregulation of NK cell functions and presenting with hemophagocytic lymphohistiocytosis. Front Genet 11: 937.