Clinical manifestations of patients with STAT1 gain-of-function variants in Mexico
TL;DR
This cohort illustrates the broad clinical spectrum of STAT1 GOF disease, including infectious, inflammatory, autoimmune, and hematological manifestations, and BCG disease and tuberculosis were observed in a subset of patients, highlighting the complexity of clinical presentation and the importance of comprehensive evaluation and follow-up.
Abstract
Background Germline Signal Transducer and Activator of Transcription 1 (STAT1) gain-of-function (GOF) variants enhance cellular responses to IL-27 and type I, II, and III interferons, predisposing to fungal, bacterial, and viral infections and immune dysregulation. Methods Mexican patients with pathogenic STAT1-GOF variants identified at referral centers were enrolled. Results Thirty patients from 17 kindreds were included. Fifteen variants were identified, including the novel C324W variant, confirmed as GOF by functional studies. All patients developed mucocutaneous candidiasis. Among 25 BCG-vaccinated patients, 24% developed BCG disease. According to the Graham criteria, seven patients (23%) with tuberculosis were classified as confirmed (n=1), possible (n=3), and probable (n=3) cases. Three patients developed both BCG disease and tuberculosis. Autoinflammatory and autoimmune manifestations occurred in 50% and 40%, respectively. Two patients developed infection-triggered macrophage activation syndrome. Seven patients (23%) died. Conclusions This cohort illustrates the broad clinical spectrum of STAT1 GOF disease, including infectious, inflammatory, autoimmune, and hematological manifestations. BCG disease and tuberculosis were observed in a subset of patients, highlighting the complexity of clinical presentation and the importance of comprehensive evaluation and follow-up.