Mutations in STAT3 and Diagnostic Guidelines for hyper-IgE Syndrome

J Allergy Clin Immunol. 2010 Feb;125(2):424-432.e8. doi: 10.1016/j.jaci.2009.10.059.

Abstract

Background: The hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by infections of the lung and skin, elevated serum IgE, and involvement of the soft and bony tissues. Recently, HIES has been associated with heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3) and severe reductions of T(H)17 cells.

Objective: To determine whether there is a correlation between the genotype and the phenotype of patients with HIES and to establish diagnostic criteria to distinguish between STAT3 mutated and STAT3 wild-type patients.

Methods: We collected clinical data, determined T(H)17 cell numbers, and sequenced STAT3 in 100 patients with a strong clinical suspicion of HIES and serum IgE >1000 IU/mL. We explored diagnostic criteria by using a machine-learning approach to identify which features best predict a STAT3 mutation.

Results: In 64 patients, we identified 31 different STAT3 mutations, 18 of which were novel. These included mutations at splice sites and outside the previously implicated DNA-binding and Src homology 2 domains. A combination of 5 clinical features predicted STAT3 mutations with 85% accuracy. T(H)17 cells were profoundly reduced in patients harboring STAT3 mutations, whereas 10 of 13 patients without mutations had low (<1%) T(H)17 cells but were distinct by markedly reduced IFN-gamma-producing CD4(+)T cells.

Conclusion: We propose the following diagnostic guidelines for STAT3-deficient HIES. Possible: IgE >1000IU/mL plus a weighted score of clinical features >30 based on recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic face, and high palate. Probable: These characteristics plus lack of T(H)17 cells or a family history for definitive HIES. Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Cell Separation
  • Child
  • Child, Preschool
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Humans
  • Immunoglobulin E / blood
  • Infant
  • Interleukin-17 / immunology
  • Job Syndrome / diagnosis*
  • Job Syndrome / genetics*
  • Job Syndrome / immunology
  • Male
  • Middle Aged
  • Mutation
  • Polymerase Chain Reaction
  • Practice Guidelines as Topic
  • STAT3 Transcription Factor / genetics*
  • T-Lymphocytes, Helper-Inducer / immunology
  • Young Adult

Substances

  • Interleukin-17
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Immunoglobulin E