Impaired control of multiple viral infections in a family with complete IRF9 deficiency

Because STAT1 was phosphorylated after IFN-α stimulation of primary fibroblasts from healthy control subjects and patients, the initial steps of the signaling cascade were conserved in the setting of IRF9 deficiency, but no induction of ISGs, including MX1, IFIT3, or ISG15, was observed (Fig 1, E). [...]PCR analysis of freshly isolated PBMCs treated or not with IFN-αβ revealed that IRF9-deficient cells were profoundly defective in induction of multiple ISGs (Fig 1, H). Because IFN-α induction of ISG expression in the mother's PBMCs was comparable with the average of 4 healthy donors, IRF9 p.Glu166LeufsTer80 does not exert any dominant negative effect on IFN-αβ stimulation. At presentation, the patient was profoundly lymphopenic, with an inverted CD4/CD8 ratio and diminished lymphocyte proliferation in response to mitogens. Because immunologic studies also revealed IgG and IgM hypogammaglobulinemia (IgG, 252 mg/dL; IgM, 24 mg/dL) with undetectable antibodies to tetanus and diphtheria toxins or pneumococci, treatment with IVIG replacement therapy was instituted. At birth, she was given a diagnosis of clubfoot (left) and congenital (left) hip dysplasia. Because of her family history, immunologic analyses were carried out when she was 3 days old, and these studies revealed normal levels of IgG and IgM and normal lymphocyte proliferation in response to PHA but a B-cell and natural killer cell lymphopenia.