Signal transducer and activator of transcription 1 (STAT1) plays a key role in gene expression for immune regulation. It receives signals from cytokines/interferons and growth factors and activates transcription of pathways involved in immune responses to viral, fungal, and mycobacterial infections. Pathogenic variants in STAT1 are associated with inborn errors of immunity. Loss-of-function variants have been linked to severe infections and increased susceptibility to mycobacterial disease, while gain-of-function (GOF) variants are associated with chronic mucocutaneous candidiasis and autoimmune diseases. In this presentation, we will discuss the finding of a novel STAT1 GOF variant associated with difficult-to-treat histoplasmosis.
A 58-year-old female presented to adult immunology clinic for relapsed and difficult-to-treat histoplasmosis infection. Her medical history is significant for recurrent sinopulmonary infections, sarcoidosis, and cervical lymph node histoplasmosis. Her infectious history includes frequent diagnoses of pneumonia as a child and adolescent and frequent ear and sinus infections in adulthood that all resolved with oral antibiotics. She was initially diagnosed with cervical lymph node histoplasmosis while on a TNF-alpha inhibitor for sarcoidosis that was discontinued with the onset of her symptoms. She received treatment with itraconazole. However, she developed a relapse of her histoplasmosis. Initial immunologic testing revealed normal B and T cell panels with normal immunoglobulin levels. However, her relapsed and difficult-to-treat histoplasmosis infection with her history of granulomatous inflammation suggesting immune dysregulation raised concern for a primary immunodeficiency for which genetic testing was pursued. A next-generation sequencing primary immunodeficiency panel revealed a VUS in STAT1: c.736G>A (p.Ala246Thr). Commercially available studies assessing STAT1 GOF activity and Th17 levels were normal. However, a research functional assay of STAT1 performed at the National Institute of Health was consistent with GOF. This case highlights the importance of broad panel-based sequencing in unusual presentations of endemic fungal disease, as well as the limits of commercially available functional testing in assessing subtle missense variants.
