Methods: Retrospective chart and literature review were conducted. Whole exome sequencing of genomic DNA from the proband and both parents was performed. STAT1 phosphorylation/dephosphorylation were assessed by flow cytometry.
Results: An 11 year old male with growth delay, requiring growth hormone, presented at 2 years of age with recurrent sinopulmonary infections despite prophylactic antibiotics, surgical interventions and then Ig replacement therapy. He had antibiotic related thrush only and no other fungal infections or autoimmunity. He developed bronchiectasis and carried one CFTR mutation. Immune evaluation demonstrated absent IgA, normal IgG and IgM, poor specific antibody responses after vaccination, mild CD4+ T cell lymphopenia with an inverted CD4+:CD8+ ratio, decreased CD4+CD45+RA+ T cells with normal lymphocyte proliferative responses to mitogens and Candida[IC1] , and decreased memory B cells. Whole exome sequencing revealed a de novo single heterozygous STAT1 GOF mutation (c.C1154T:p.T385M, NM_007315). Flow cytometry studies confirmed hyperphosphorylation of STAT1 in monocytes when stimulated with IFN-γ and in NK cells and T cells after stimulation with IFN-α.
Conclusions: Although STAT1 GOF patients typically present with CMC, the disease presents heterogenously. This case illustrates the roles genetic testing and biologic functional assays play in the diagnosis of a new clinical phenotype in a known genetic disease, which expands our knowledge of STAT biology in humans.