title: Intermediate phenotypes in patients with autosomal dominant hyper-IgE syndrome caused by somatic mosaicism.
abstract: BACKGROUND
  Autosomal dominant hyper-IgE syndrome (AD-HIES) is caused by mutations in signal transducer and activator of transcription 3 (STAT3). We describe 2 subjects in whom somatic mosaicism was associated with intermediate phenotypes.
  
  
  OBJECTIVE
  Somatic mosaics might shed light on the pathogenesis of dominant STAT3 mutations and the mechanisms behind the immunologic and nonimmunologic features of the disease.
  
  
  METHODS
  Clinical evaluations were conducted. Mutant STAT3 was amplified from different tissues and sequenced, and the percentage of mosaicism in various cell types was calculated. Flow cytometry was performed to determine percentages of IL-17(+) cells, IL-22(+) cells, or both. Suction blisters were induced in 1 subject, and exudate fluid was analyzed for whether emigrating neutrophils were STAT3 mutant or wild-type; neutrophils from peripheral blood were simultaneously examined.
  
  
  RESULTS
  The 2 subjects with STAT3 somatic mosaicism had intermediate phenotypes and were found to have preserved TH17 cell compartments and apparently normal CD8 cells. However, they still had infections, including mucocutaneous candidiasis. The percentage of STAT3 mutant neutrophils migrating into blisters at 16 hours was the same as in peripheral blood, suggesting normal chemotaxis.
  
  
  CONCLUSIONS
  STAT3 mosaicism accounts for a milder phenotype and allows for further investigation into the pathogenesis of AD-HIES. Despite having a preserved TH17 cell compartment, both subjects with mosaicism had chronic mucocutaneous candidiasis, suggesting that candidiasis in subjects with AD-HIES is not driven solely by low TH17 cell numbers. The percentage of STAT3 mutant neutrophils emigrating into a suction blister at 16 hours was the same as the percentage in peripheral blood, suggesting that early chemotaxis of STAT3 neutrophils is normal in vivo.
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md., USA.
authors.forename: Amy P
authors.initials: AP
authors.lastname: Hsu
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Sowerwine
authors.forename: Monica G
authors.initials: MG
authors.lastname: Lawrence
authors.forename: Joie
authors.initials: J
authors.lastname: Davis
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Henderson
authors.forename: Kol A
authors.initials: KA
authors.lastname: Zarember
authors.forename: Mary
authors.initials: M
authors.lastname: Garofalo
authors.forename: John I
authors.initials: JI
authors.lastname: Gallin
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kuhns
authors.forename: Theo
authors.initials: T
authors.lastname: Heller
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Milner
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Puck
authors.forename: Alexandra F
authors.initials: AF
authors.lastname: Freeman
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
mesh_terms: D000328:Adult; D000483:Alleles; D001483:Base Sequence; D005091:Exons; D006801:Humans; D007589:Job Syndrome / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009030:Mosaicism; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D050796:STAT3 Transcription Factor / Q000235:genetics; D058504:Th17 Cells / Q000378:metabolism
chemical_list: D050796:STAT3 Transcription Factor