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Hyper IgE syndrome (HIES) is a primary immunodeficiency characterized by eczema, recurrent skin and lung infections, elevated serum IgE, and connective tissue and skeletal abnormalities. We present newly recognized aspects of the clinical phenotype and discuss recent genetic and immunologic findings.In 2007, mutations in signal transducer and activator of transcription 3 (STAT3) were determined to be the cause of autosomal-dominant HIES. Mutations lead to disruption of STAT3-dependent pathways, which are crucial for signaling of many cytokines, including IL-6 and IL-10. On the one hand, cells from STAT3-defective patients have a proinflammatory profile with elevated TNFα and IFNγ; on the other hand, STAT3 mutations result in the inability to produce IL-17 or form Th17 cells.HIES was previously defined on the basis of clinical manifestations and laboratory markers that were not specific to the disease. With the identification of STAT3 mutations as the cause of HIES, we can definitively characterize the disease at molecular and immunologic levels. Future study of HIES and STAT3 will help us understand eczema, IgE regulation, infection susceptibility, coronary artery disease, scoliosis, and bronchiectasis as well as provide mechanistic insights into treatment.