Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome.

Area of Science:

• Immunology
• Genetics
• Clinical Diagnostics

Background:

• Hyper-IgE syndrome (HIES) is a primary immunodeficiency with recurrent infections, high IgE, and tissue abnormalities.
• HIES is increasingly linked to dominant-negative mutations in STAT3, leading to reduced T(H)17 cells.

Purpose of the Study:

• To correlate genotype with phenotype in HIES patients.
• To establish diagnostic criteria differentiating STAT3 mutated from wild-type HIES.
• To identify predictive clinical features for STAT3 mutations.

Main Methods:

• Clinical data, T(H)17 cell counts, and STAT3 sequencing were performed on 100 suspected HIES patients.
• A machine-learning approach was used to identify features predicting STAT3 mutations.
• Diagnostic criteria were developed based on clinical features and laboratory findings.

Main Results:

• 31 STAT3 mutations were identified in 64 patients, including novel mutations.
• A combination of 5 clinical features predicted STAT3 mutations with 85% accuracy.
• STAT3-mutated patients showed profound T(H)17 reduction; non-mutated patients had reduced IFN-gamma-producing CD4(+)T cells.

Conclusions:

• Proposed diagnostic guidelines for STAT3-deficient HIES: Possible, Probable, and Definitive.
• Criteria include elevated IgE, specific clinical features, T(H)17 cell counts, and STAT3 mutation status.
• These guidelines aid in distinguishing STAT3-mutated HIES, facilitating timely intervention.