Hyper-IGE Recurrent Infection Syndrome


The STAT3 gene encodes the transcription factor protein, STAT3. STAT3 plays a crucial role in immunologic pathways by signaling cytokines which induce T helper cells (TH17 lineage). TH17 cells upregulate chemokine receptors that release cytokines with antifungal and antimicrobial properties. Deficient STAT3 signals lead to recurrent infection and immune deficiency, as seen in Hyper IgE syndrome.

Hyper IgE Syndrome (AD-HIES) is an autosomal dominant primary immune deficiency characterized by elevated serum IgE, eczema, recurrent skin and respiratory tract infections, and connective tissue and skeletal abnormalities. Generally, recurrent infections and skin findings manifest in the first few years of life. Survival is usually into adulthood, but a shortened life span is typical. Death is often caused by complications associated with infections. A diagnosis of this AD-HIES is made using a clinical scoring system with molecular genetic testing of STAT3. More than 95% of individuals with typical findings are found to have a STAT3 mutation.

Infantile-onset multisystem autoimmune disease is characterized by early childhood onset of a spectrum of autoimmune disorders affecting multiple organs. The most common manifestations are insulin-dependent diabetes mellitus and autoimmune enteropathy, or celiac disease. Other features include short stature and nonspecific dermatitis. More variable features include hypothyroidism, autoimmune arthritis, and delayed puberty. STAT3 gain of function mutations have been described in this multiorgan autoimmunity.


Confirmation of diagnosis in a patient with the following:

  • Job Syndrome / Autosomal Dominant Hyper IgE Syndrome/ Hyper IgE recurrent infection Syndrome
  • Multisystem autoimmune disease, infantile onset
  • Family members with previously identified STAT3 mutation

Testing Methodology

Testing is performed by Sanger sequencing of the entire coding regions and intron/exon boundaries of the STAT3 gene. 

Test Sensitivity

Clinical Sensitivity

More than 95% of individuals with findings typical of signal hyper IgE syndrome have a STAT3 mutation encoding an altered, expressed protein (Holland et al 2007; Woellner et al 2010).

Analytical Sensitivity

The sensitivity of DNA sequencing is over 99% for the detection of nucleotide base changes, small deletions and insertions in the regions analyzed.

Mutations in regulatory regions or other untranslated regions are not detected by this test. Large deletions involving entire single exons or multiple exons, large insertions and other complex genetic events have been reported in many of these genes and will not be identified using this test methodology. Rare primer site variants may lead to erroneous results.

Turnaround Time

28 days


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Renner, E.D., et al. (2008). “Novel signal transducer and activator of transcription 3 (STAT3) mutations, reduced Th17 cell numbers, and defective STAT3 phosphorylation in hyper-IgE syndrome.” Journal of Allergy and Clinical Immunology, 122(1), 181-187.

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