Hyper IgE syndrome 1 D82.4

Davis, 1966; Buckley, 1972

Rare, genetically heterogeneous immunodeficiency syndrome (multisystem disease, see below Immunodeficiencies primary congenital/classification) with the clinical triad:

• Recurrent skin infections mainly by staphylococci (skin abscesses, with low inflammation(cold abscesses).
• Upper and lower respiratory tract infections (bronchopneumonia-J18.0)
• excessive elevation of serum IgE level and recurrent blood eosinophilia (D72.1).

Rare; about 300 cases have been described in the literature to date.

The phenotype"Hyper-IgE syndrome" is characterized by a variable genoype. Hyper IgE syndrome 1/ HIES1 (147060) is characterized by autosomal dominant mutations in the STAT3 gene. This IgE variant is the most common!

Milner et al (2008) showed that production of interleukin-17 by T cells is absent in individuals with hyper IgE syndrome (HIES). They observed that ex vivo T cells from individuals with HIES do not produce IL17 upon mitogenic stimulation with staphylococcal enterotoxin B or antigenic stimulation with Candida albicans or streptokinase, but also do not produce IL2 (147680), TNF (191160), or IFNG (147570).

Purified naive T cells were unable to differentiate into IL17-producing (TH17) T helper cells in vitro and exhibited lower expression of ROR-gamma-t (602943), suggesting a critical role of STAT3 (102582) signaling in TH17 cell formation. TH17 cells are an important subset of T helper cells thought to play a critical role in clearing fungal and bacterial infections. Milner et al (2008) concluded that the inability to generate TH17 cells is causative for the susceptibility to recurrent infections in HIES 1.

Occurring in infancy or early childhood. Both sexes are affected equally often.

Mostly manifestation as superinfected atopic dermatitis with recurrent abscessing infections of the skin (face, neck region), mucous membranes of the upper (sinusitis, otitis media) and lower (pneumonia) airways as well as lung cysts.Recurrent, bacterial infections with characteristic distribution pattern: skin (face, hairy head, neck region), mucous membranes of the upper airways (sinusitis, otitis media) and lungs (pneumonia). The pathogen is predominantly Staphylococcus aureus, but other gram-positive and gram-negative pathogens are also frequently detected. Abscesses often form with or without clinical signs of inflammation (often "cold abscesses", but not obligatory).

Mycotic infections are common, usually progressing as chronic chronic mucocutaneous candidiasis , with severe nail dystrophies.

Dental changes: Persistent deciduous teeth due to non-attachment or delayed eruption, high arched palate.

Isolated cases with associated cutis verticis gyrata have been described.

In most cases, excessive polyclonal IgE elevation (values up to 40,000 IU/ml) is detectable in the serum, with staphylococcal and Candida-specific IgE in high titers. Furthermore, eosinophilia may be present in blood (about 90% of all cases), sputum, and pus. Chemotaxis of neutrophil granulocytes is inconstantly decreased.

IgE (polyclonal increase usually > 5000 IU/ml)

RAST (frequently Staphylococcus and Candida specific IgE)

Blood count (recurrent eosinophilia)

In infections often absent or low increase of acute phase proteins

Differentially, the rarer autosomal recessive variants of hyper-IgE syndrome should be considered:

• Hyper-IgE syndrome 2 due to mutations in the DOCK8 gene/HIES2 (243700)/(DOCK8=Dedicator of cytokinesis 8 protein
• Hyper-IgE syndrome 3 due to mutations in the ZNF431 gene/HIES3 (618282)/ZNF431=Zinc finger 431 gene
• Hyper IgE syndrome4a/4b due to mutations in the IL6ST gene/HIES4A (619752) and HIES4B (618523)/IL6ST=Interleukin 6 Cytokine Family Signal Transducer
• Hyper IgE syndrome 5 due to mutations in the IL6R gene/ HIES5 (618944)/(IL6R = Interleukin6 receptor)

Cause of death is usually pulmonary insufficiency due to recurrent lower respiratory tract infections (causative agent: Pseudomonas aeruginosa or fungal species, mostly Aspergillus species). Cerebral mycotic infections may also be a possible cause of death. Malignant lymphoma and systemic lupus erythematosus (single case reports) may occur concomitantly.

Davis et al (1966) reported on two unrelated girls with lifelong histories of indolent staphylococcal abscesses. Both had eczema shortly after birth and had persistent weeping lesions on the ears and face. The abscesses were described as "cold" because the surrounding area was not warm, red, or tender. Both girls had red hair and were fair-skinned. The authors suspected a defect in local resistance to staphylococcal infection. Further examination of these girls by White et al (1969) revealed normal leukocyte functions. However, Hill et al. (1974) and Hill and Quie (1974) found a defect in neutrophil granulocyte chemotaxis and very high serum IgE levels in four girls with this disorder; two of the girls had already been described by Davis et al. (1966).

Buckley et al (1972) described 2 male patients with features of the Job syndrome as originally described by Davis et al (1966). Both boys had extremely high serum IgE levels and immediate skin hypersensitivity reactions to Staphylococcus aureus and Candida albicans. The authors also noted hyperextensibility of the joints and an asymmetric facial shape.

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