Hyper IgE Syndrome – Autosomal Dominant (AD-HIES)
- Inheritance: Autosomal dominant
- Gene: STAT3
- Protein: STAT3
- Tests: STAT3 Gene Sequencing, HIES Screen by Flow
Key Clinical and Laboratory Features
- Common clinical features: Staphylococcal pneumonias that lead to pneumatocele formation, staphylococcal skin boils, “cold” (non-inflammatory) soft-tissue abscesses, mucocutaneous candidiasis, delayed shedding of the primary teeth, spontaneous fractures, eczema
- Other clinical features: Cardiac and CNS aneurysms that may result in myocardial infarction and subarachnoid hemorrhage, fungal infections of the GI tract, hyperextensibility
- Physical exam: Coarse facial features that develop over time; eczema, presence of primary teeth well beyond the expected age and high-arched palate.
- Common laboratory features: Highly-elevated IgE (other immunoglobulins often normal), eosinophilia, decreased/absent Th17 cells
|GENE||STAT3 Gene Sequencing||The gold standard for confirming a diagnosis of AD-HIES. All described mutations allow expression of a mutant STAT3 protein.|
|PROTEIN AND FUNCTION||HIES Screen by Flow||This is both a protein test and a functional test that measures the presence of IL-17 producing Th17 cells in the CD4+ T-cell population and evaluates whether STAT3 is normally phosphorylated in patient cells after cytokine stimulation.
Th17 Cells: Virtually all STAT3-deficient patients have very low or absent Th17 cells so this test is very sensitive for AD-HIES. However, Th17 cells may also be low in patients with DOCK8 mutations or STAT1 gain-of-function mutations so this test is not specific for AD-HIES.
STAT3 Phosphorylation: Patients with STAT3 mutations that affect either the SH2 or Transactivation domains of the protein (approximately one-third to one-half of patients) demonstrate abnormal STAT3 phosphorylation. Patients with STAT3 mutations that affect the DNA-binding domain of the protein demonstrate normal STAT3 phosphorylation.