A De Novo STAT6 p.D419G Variant Causing Severe Multi-Organ Allergic Disease: Case Report on a Transformative Response with Dupilumab

Background: Signal transducer and activator of transcription 6 (STAT6) gain-of-function (GOF) variants cause severe, early-onset multi-organ allergic disease through IL-4/IL-13-mediated type 2 immunity. We report a patient with a de novo STAT6 p.D419G variant and her remarkable response to targeted therapy. Case Presentation: A 39-year-old woman of Middle Eastern origin presented with lifelong severe atopic disease beginning before age 2, including treatment-refractory atopic dermatitis, severe asthma requiring intubation, IgE-mediated food allergies, eosinophilic gastrointestinal disease, and recurrent infections. She demonstrated persistently elevated serum IgE (peak >17,000 kU/L, consistently >5,000 kU/L) and eosinophilia (peak 1.5 × 10⁹/L). Whole exome sequencing identified a de novo heterozygous STAT6 variant (NM_001178079.2) c.1256A>G (p.D419G). Notably, brain MRI revealed vascular malformations in the circle of Willis, including hypoplastic vertebrobasilar arteries and persistent trigeminal artery. She required daily prednisone (average 20 mg) for years, resulting in cataracts and low bone mineral density. At age 34, dupilumab (300 mg subcutaneously every 2 weeks) was initiated, targeting the dysregulated IL-4/IL-13 pathway. Over five years of treatment, she achieved complete corticosteroid cessation, with her Eczema Area and Severity Index declining from 65 (very severe) to 2.2 (mild), normalization of spirometry, and improvement in biomarkers (IgE decreased to 3,263 kU/L, eosinophils to 0.2 × 10⁹/L). Her quality of life improved dramatically, enabling the pursuit of personal, academic, and professional goals. Conclusion: This case demonstrates the severe phenotype of STAT6-GOF and highlights the transformative potential of precision medicine using IL-4Rα-blocking therapy. Early recognition of STAT6-GOF clinical "red flags" and genetic testing enables targeted treatment, avoiding prolonged corticosteroid exposure and its complications. The presence of cerebrovascular malformations warrants further investigation into potential associations with STAT6-GOF.