Hyperimmunoglobulin E

Hyperimmunoglobulin E syndrome (HIES) was first described as Job syndrome in 1966, when 2 patients were reported with eczematous dermatitis, recurrent staphylococcal boils, hyperextensible joints/recurrent bone fractures, and distinctive coarse faces. See the images below.

Father and daughter with autosomal dominant (AD) h
Father and daughter with autosomal dominant (AD) hyperimmunoglobulin E syndrome (HIES). Note the father's distinctive facies with prominent forehead, deep-set eyes, broad nasal bridge, and wide interalar distance.
Mother and son with autosomal dominant (AD) hyperi
Mother and son with autosomal dominant (AD) hyperimmunoglobulin E syndrome (HIES). Note the mother's distinctive facies. She had a history of multiple deep-seated abscesses that took months to heal after incision and drainage.
Buckley et al expanded the clinical picture in 1972 and reported the association with elevated immunoglobulin E (IgE) in patients with hyperimmunoglobulin E syndrome.[1] Hyperimmunoglobulin E syndrome is now recognized as a primary immunodeficiency disease characterized by recurrent skin abscesses, recurrent pneumonica with pneumotocele, eczematous dermatitis, and elevated serum IgE levels. HIES was initially reported to have an autosomal dominant (AD) inheritance pattern, but cases with autosomal recessive (AR) inheritance and sporadic cases have been reported.

Mutations of the signal transducer and activator of transcription 3 (STAT3) gene were shown to cause the AD HIES by 2 groups independently.[2, 3] In addition, tyrosine kinase 2 deficiency (tyk2) deficiency was reported in 2 patients with HIES, but tyk2 deficiency is also characterized by severe viral and bacterial infections.[4, 5] A fair numbers of patients with AD HIES have STAT3 mutations (around 70%); however, some patients have AD HIES-like disease without STAT3 mutations.

In AD HIES and sporadic cases, HIES manifests as a disease that affects multiple organ systems, including the skeleton, connective tissue, and dentition. AD HIES is inherited as a single-locus trait with various expressivity in some families. In contrast, patients with AR HIES lack skeletal or dental involvement and do not develop cystic lung disease. However, patients with AR HIES are susceptible to viral infection characterized by severe Molluscum contagiosum and may develop severe neurological complications for unknown reasons.[6] Some patients with AR HIES have mutations in DOCK8.[7] Subsequent studies in animals and affected humans revealed an important role in DOCK8 in T and B cell development and functions; DOCK8 deficiency is now known to cause a combined immunodeficiency rendering the affected patients susceptible to viral, fungal, and bacterial infections.[8]