Multisystem autoimmune disease caused by increased STAT3 phosphorylation, and dysregulated gene expression

Signal transducer and activator of transcription (STAT) 3 is a member of the STAT family, and plays a major role in various immunological mechanisms.1 Mutations in STAT3 are associated with a broad spectrum of manifestations, including immunodeficiency, autoimmunity, and malignancy.2 In particular, heterozygous germline loss-of-function (LOF) mutations cause Hyper-IgE syndrome (HIES),3–5 while heterozygous germline gain-of-function (GOF) mutations have recently been associated to multi-organ autoimmune manifestations (i.e. type 1 diabetes, enteropathy, cytopenia, interstitial lung disease, hypothyroidism), lymphoproliferation, short stature, and recurrent infections (OMIM #615952).6–8 We report a 7-year-old boy who presented with early-onset severe enteropathy, and diffuse eczematous dermatitis since birth. During the first weeks of life, Hirschsprung disease was also suspected and surgically treated. Gastrointestinal and cutaneous manifestations were first ascribed to food allergy with quite a good response to amino acid-based formula. In the following months, the patient failed to thrive, and developed respiratory tract infections. At two years, the patient presented with progressive interstitial lung disease characterized by lymphocytic interstitial infiltration leading to pulmonary hypertension, tricuspid insufficiency, and right ventricular heart failure with hepatomegaly. Because of the increased risk of infections, he received intravenous (IV) immunoglobulin infusions (400 mg/kg), prophylaxis with cotrimoxazole and fluconazole. Methylprednisolone at 0.3 mg/kg/day was also given to treat autoimmune manifestations.