From CVID to PIRD: Genetic Testing Leading to Signal Transducer and Activator of Transcription 3 Gain-of-Function Diagnosis and Directed Therapy.

Abstract

Genetic testing to evaluate for monogenic inborn errors of immunity is considered the standard of care in newly diagnosed common variable immunodeficiency (CVID) patients; however, not all patients receive it for a variety of clinical and access reasons. Similarly, patients with a longstanding diagnosis of CVID diagnosed before the wide availability of genetic testing may not be considered for genetic testing as readily as those with new diagnoses. Here we present a case illustrating diagnostic and management dilemmas in a patient with a longstanding diagnosis of CVID who ultimately was found to have a STAT3 gain-of-function (GOF) variant more than 10 years after his initial CVID diagnosis. Genetic testing was prompted not only by the unusual infection history (lymphadenitis due to nontuberculous mycobacteria) but also by worsening clinical status and the presence of noninfectious features, including enteropathy, chronic cough, lymphoproliferation, and autoimmune cytopenias. The genetic diagnosis led to more precise treatments and allowed for diagnosis and improved management strategies for several affected family members. The pathophysiology, clinical presentation, and management options for STAT3 GOF are reviewed.