The study of inborn errors of immunity (IEI) has made a crucial contribution to understanding the regulatory and effector mechanisms of immunity. Here we present 2 cases involving variants in the IFNAR1 and IFNAR2 genes, both associated with increased susceptibility to severe viral infections. Clinical presentation, history of deceased siblings, and parental consanguinity suggested a potential genetic etiology.
7-year-old female with consanguineous parents (first cousins). Bilateral sensorineural deafness after severe case of chickenpox at age 1. At age 3, acute hepatitis and stroke after yellow fever vaccine (YFV). Two deceased siblings, one from diarrhea of unknown etiology and the other from acute liver failure after YFV. Blood counts, immunoglobulins, lymphocyte subpopulations, and vaccine response were normal. Immunodeficiency (PID) panel without candidate variants. Whole-genome sequencing (WGS) revealed a homozygous 8-kb deletion (exons 3–5) in the IFNAR1 gene. IDP panel did not yet include the IFNAR1/2 genes.
14-year-old female, consanguineous parents (first cousins). Suspected hemophagocytic lymphohistiocytosis (HLH) after MMR vaccination at age 1, viral meningitis at 20 months, chickenpox at age 3, and disseminated herpes at age 4, with corneal ulcer and bilateral visual loss. Normal blood count, immunoglobulins, lymphocyte immunophenotyping, and vaccine response. Normal NK cell cytotoxic activity. HLH panel and Exome with no candidate variants. WGS revealed a homozygous missense variant (c.840+1G>T) in a splicing region following exon 8 in the IFNAR2 gene.
The impact of variants in these genes and their effects on the type I IFN signaling pathway have been more widely studied in recent years, particularly after COVID-19 pandemic. The presented cases highlight the importance of expanding the investigation of IEI in patients with infectious complications involving a restricted pattern of microorganisms, especially those with a family history and consanguinity. Reanalysis of molecular data, in light of ongoing advances in genetic research, is crucial. Early and accurate diagnosis is essential for optimizing patient care.
