Holland SM, DeLeo FR, Elloumi HZ, et al. N Engl J Med. 2007;357(16):1608–1619
PURPOSE OF THE STUDY. To identify the genetic defect underlying the hyper–immunoglobulin E (IgE) (Job) syndrome.
STUDY POPULATION. Patients with hyper-IgE syndrome were ranked by a clinical scoring system. Fifty patients over the age of 16 years who had the highest scores (most features of the disease) were selected. Forty-eight family members also underwent genetic analysis.
METHODS. The authors used a combination of microarray screening of gene expression and analysis of cytokine production in vitro from lymphocytes subjected to various stimuli.
RESULTS. Lymphocytes from patients were found to have diminished response to the cytokine interleukin 6. The authors systematically analyzed the intracellular signaling molecules involved in the response to interleukin 6 and found that patients carried a mutation in 1 of the 2 copies of the gene encoding signal transducer and activator of transcription 3 (STAT3). They confirmed the biological importance of the mutations by showing that the STAT3 protein did not function normally within the cell.
CONCLUSIONS. STAT3 mutations are the genetic basis of the hyper-IgE syndrome.
REVIEWER COMMENTS. The first clinical description of hyper-IgE syndrome as a distinct entity was published in 1966. It was given the eponym “Job syndrome” as a biblical allusion because of the many severe skin abscesses that afflict patients with the condition. This report is the culmination of >40 years of investigation by many groups around the world to find the molecular basis of this disease. A similar report was published by another group around the same time (Minegishi Y, Saito M, Tsuchiya S, et al. Nature. 2007;448:1058–1062). We are reminded again of the power of modern molecular biological methods and the tremendous insights we gain when such diseases are finally understood at their “source.”
- Copyright © 2008 by the American Academy of Pediatrics