Hyper IgE Syndrome

Elevated IgE levels are frequently encountered in the setting of atopic diseases. However, elevated IgE levels in association with recurrent infections warrant further consideration. The hyper IgE syndromes (HIES) are a group of monogenic primary immunodeficiencies characterized by a common phenotypic triad of eczematous dermatitis, recurrent infections, and elevated IgE levels. Job syndrome, first described in 1966 by Davis et al., represents the prototype of these disorders and is caused by a dominant negative mutation in the signal transducer and activator of transcription-3 (STAT3) gene. However, since the discovery of STAT3 deficiency, several other genes have been implicated in causing HIES, including mutations in DOCK8, ZNF431, IL6R, IL6ST, PGM3, SPINK5, and CARD11 genes. Distinguishing these monogenic disorders remains challenging and requires careful attention to the clinical and immunological phenotypes and selection of the appropriate molecular diagnostic tests. Additionally, treatments and outcomes for these disorders are variable and largely dependent on the underlying molecular defect. In this chapter, we will discuss the most two common causes of HIES, namely, STAT3 deficiency and DOCK8 deficiency.