STAT3 Infantile-Onset Multi-System Autoimmune Disease: A 27-Year Follow-Up of a Rare Entity

Background: Signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) disease is a rare autosomal dominant primary immunoregulatory disorder characterized by early-onset autoimmunity, lymphoproliferation, recurrent infections, and multisystem involvement. Marked phenotypic heterogeneity and overlap with other immune dysregulation occasionally result in delayed diagnosis with detrimental prognostic implications. Case Presentation: We report a 27-year longitudinal follow-up of a male patient who first presented at 18 months of age with recurrent pyrexia, failure to thrive, pallor, hepatosplenomegaly, and generalized lymphadenopathy. Initial investigations revealed persistent pancytopenia, impaired vaccine responsiveness, and hypergammaglobulinemia with a monoclonal spike. In the absence of a definitive diagnosis, the patient was treated with monthly intravenous immunoglobulin (IVIG) for 26 years and remained largely infection-free for 26 years. Over time, the patient developed progressive multisystem disease including short stature refractory to growth hormone therapy, end-stage renal disease, portal hypertension, and neuropsychiatric deterioration. Genetic testing performed in adulthood identified a heterozygous likely pathogenic STAT3 variant (c.1974G > T; p.Lys658Asn), consistent with STAT3 GOF disease. The patient died shortly after elective splenectomy performed for portal hypertension and refractory cytopenias. Discussion: This case illustrates the protean manifestations and diagnostic complexity of STAT3 GOF disease. The clinical course was consistent with known features—autoimmune cytopenias, lymphoproliferation, growth failure, and impaired vaccine responses—while also expanding the phenotypic spectrum to include pronounced dysmorphic features and severe growth impairment. Notably, therapy with prophylactic IVIG was particularly effective in preventing severe infection. STAT3 GOF is a relevant diagnostic consideration in patients with early-onset multisystem autoimmune disease, persistent lymphoproliferation, recurrent infections, and abnormal vaccine responses.