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Disorders

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

Testing Approach

 TESTCOMMENTS
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.
OTHER
  • Complete blood count with differential: Eosinophilia is common.
  • Immunoglobulin levels: IgE are highly elevated while other immunoglobulin classes are typically normal.
  • Chest X-ray or CT scan to evaluate for pneumatoceles.
 
 

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