title: Novel STAT3 mutation causing hyper-IgE syndrome: studies of the clinical course and immunopathology.
abstract: OBJECTIVE
  Reporting a clinical case with a novel mutation in the signal transducer and activator of transcription 3 (STAT3) gene resulting in autosomal dominant hyper-immunoglobulin E syndrome (AD-HIES). Here we also had the opportunity to perform in-depth immunologic investigations to further understand the immunopathology of this primary immunodeficiency.
  
  
  METHODS
  The patient, a baby boy, was clinically assessed according to the scoring system developed by Grimbacher et al. and STAT3 was investigated by DNA sequencing. Immunologic work-up consisted of lymphocyte phenotyping and proliferation assays, measurement of soluble mediators and routine investigations.
  
  
  RESULTS
  According to the Grimbacher score the patient was likely to have AD-HIES and a novel heterozygous STAT3 mutation (c.1110-3C>A), causing a splice error, was identified. Lymphocyte phenotyping revealed decreased numbers of interleukin (IL)-17 producing T-helper lymphocytes and aberrant B-lymphocyte subsets. Proliferative in vitro lymphocyte responses against C. albicans, staphylococcal enterotoxins and pokeweed mitogen were supernormal at presentation, whereas only the elevated response to pokeweed mitogen persisted. The soluble mediators IL-5, -10, -12, -13, -15 and granulocyte colony stimulatory factor were elevated in serum.
  
  
  CONCLUSIONS
  A novel heterozygous STAT3 mutation causing defective splicing of exon 12 was identified. Lymphocyte phenotyping revealed deranged subpopulations. Despite the clinical picture with severe C. albicans and staphylococcal infections, the patient's lymphocytes mounted responses to these pathogens. The hypereosinophilia and high immunoglobulin E levels might partly be explained by elevated IL-5 and -13 as a result of lack of negative feedback from defective STAT3 signaling.
authors.affiliation: Hematology/Immunology/SCT Section, Astrid Lindgren Children's, Karolinska University Hospital, Stockholm, Sweden, mikael.sundin@ki.se.
authors.forename: Mikael
authors.initials: M
authors.lastname: Sundin
authors.forename: Bianca
authors.initials: B
authors.lastname: Tesi
authors.forename: Maria
authors.initials: M
authors.lastname: Sund Böhme
authors.forename: Yenan T
authors.initials: YT
authors.lastname: Bryceson
authors.forename: Katrin
authors.initials: K
authors.lastname: Pütsep
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Chiang
authors.forename: Sarah
authors.initials: S
authors.lastname: Thunberg
authors.forename: Jacek
authors.initials: J
authors.lastname: Winiarski
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Wikström
mesh_terms: D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D001483:Base Sequence; D002177:Candidiasis / Q000150:complications / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D007073:Immunoglobulin E / Q000235:genetics*; D007223:Infant; D007589:Job Syndrome / Q000150:complications / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D018655:Lymphocyte Count; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D050796:STAT3 Transcription Factor / Q000235:genetics*; D013203:Staphylococcal Infections / Q000150:complications / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000473:pathology
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D007073:Immunoglobulin E