If a patient expected by an allergist of having atopic disease associated with high to very high IgE serum levels, and if this patient has a history of frequent infections not limited to the skin, or has ?syndromic features?, the allergist has to think outside the box and consider a Primary Immune Deficiency that is associated with elevated serum IgE levels. 
Hyper IgE syndromes (HIES) comprise a group of rare primary immunodeficiency disorders characterized by a triad of atopic dermatitis, recurrent skin and lung infections along with elevated IgE levels. Job syndrome or autosomal dominant (AD) HIES due to loss of function mutations with dominant negative effect in STAT3 is the prototype of these disorders. However, several other genetically characterized immunodeficiency disorders have been identified over the past decade and joined the umbrella of HIES including autosomal recessive (AR) HIES due to mutations in DOCK8, AR mutations in ZNF431 and AD mutations with dominant negative effect in CARD11. Moreover, a number of phenotypically distinct immunodeficiency disorders (example: Wiskott-Aldrich syndrome, IPEX due to mutation in the transcription factor FOXP3, Comel-Netherton syndrome) can mimic HIES adding to the diagnostic challenge. In this presentation, we will concisely review these disorders, their molecular bases, and highlight key clinical and laboratory features.