Both LOF and GOF STAT3 mutations have significant clinical consequences. Whereas STAT3 LOF is responsible for autosomal-dominant hyper–immunoglobulin E syndrome (AD-HIES) with increased susceptibility to infection via reduced Th17 and B-cell function, STAT3 GOF is responsible for both immune dysregulation and immune deficiency. The clinical phenotype of STAT3 GOF-induced immune dysregulation is very diverse and can be seen as a mix of IPEX-like, ALPS-like, and STAT5b-deficiency–like symptoms. IgE, immunoglobulin E; IgG, immunoglobulin G.