While 118 mutations are attributed to “hyper-IgE syndrome” or “STAT3 deficiency” in the Human Gene Mutation Database, few variants had been functionally demonstrated to impair STAT3 function; however, a recent report examined all variants described to cause STAT3-HIES and found functionally that the mutations, including both in-frame and out-of-frame, were indeed dominant negative [109]. This evidence concerns the gene STAT3 and hyperinsulinemic hypoglycemia, familial, 4.