title: Key findings to expedite the diagnosis of hyper-IgE syndromes in infants and young children.
abstract: BACKGROUND
  Hyper-IgE syndromes (HIES) are primary immunodeficiency disorders characterized by elevated serum IgE, eczema, and recurrent infections. Despite the availability of confirmatory molecular diagnosis of several distinct HIES entities, the differentiation of HIES particularly from severe forms of atopic dermatitis remains a challenge. The two most common forms of HIES are caused by mutations in the genes STAT3 and DOCK8.
  
  
  METHODS
  Here, we assess the clinical and immunologic phenotype of DOCK8- and STAT3-HIES patients including the cell activation, proliferation, and cytokine release after stimulation.
  
  
  RESULTS
  Existing HIES scoring systems are helpful to identify HIES patients. However, those scores may fail in infants and young children due to the age-related lack of clinical symptoms. Furthermore, our long-term observations showed a striking variation of laboratory results over time in the individual patient. Reduced memory B-cell counts in concert with low specific antibody production are the most consistent findings likely contributing to the high susceptibility to bacterial and fungal infection. In DOCK8-HIES, T-cell lymphopenia and low IFN-gamma secretion after stimulation were common, likely promoting viral infections. In contrast to STAT3-HIES, DOCK8-HIES patients showed more severe inflammation with regard to allergic manifestations, elevated activation markers (HLA-DR, CD69, CD86, and CD154), and significantly increased inflammatory cytokines (IL1-beta, IL4, IL6, and IFN-gamma).
  
  
  CONCLUSIONS
  Differentiating HIES from other diseases such as atopic dermatitis early in life is essential for patients because treatment modalities differ. To expedite the diagnosis process, we propose here a diagnostic workflow.
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Hagl
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany.
authors.forename: Valerie
authors.initials: V
authors.lastname: Heinz
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany.|Dermatology Hospital, Ludwig Maximilian University, Munich, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Schlesinger
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany.
authors.forename: Benedikt D
authors.initials: BD
authors.lastname: Spielberger
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany.
authors.forename: Julie
authors.initials: J
authors.lastname: Sawalle-Belohradsky
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Senn-Rauh
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Magg
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany.|Dermatology Hospital, Ludwig Maximilian University, Munich, Germany.
authors.forename: Annette C
authors.initials: AC
authors.lastname: Boos
authors.affiliation: University Children's Hospital, University Ulm, Ulm, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Hönig
authors.affiliation: Institute for Transfusion Medicine, University of Ulm and Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service, Ulm, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwarz
authors.affiliation: HELIOS Children's Hospital, Krefeld, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Dückers
authors.affiliation: University Children's Hospital, Charité, Berlin, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: von Bernuth
authors.affiliation: Oral and Maxillofacial Surgery, Ludwig Maximilian University, Munich, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Pache
authors.affiliation: Department of Pediatrics, Hospital Dornbirn, Dornbirn, Austria.
authors.forename: Cäcilia
authors.initials: C
authors.lastname: Karitnig-Weiss
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany.
authors.forename: Bernd H
authors.initials: BH
authors.lastname: Belohradsky
authors.affiliation: Department of Transfusion Medicine, Cell Therapeutics and Haemostaseology, Ludwig Maximilian University, Munich, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Frank
authors.affiliation: HELIOS Children's Hospital, Krefeld, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Niehues
authors.affiliation: University Children's Hospital, Charité, Berlin, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Wahn
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Albert
authors.affiliation: Dermatology Hospital, Ludwig Maximilian University, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Wollenberg
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany.
authors.forename: Annette F
authors.initials: AF
authors.lastname: Jansson
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany.
authors.forename: Ellen D
authors.initials: ED
authors.lastname: Renner
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000175:diagnosis*; D003937:Diagnosis, Differential; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007156:Immunologic Memory; D007223:Infant; D007589:Job Syndrome / Q000175:diagnosis* / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D016207:Cytokines; C516591:DOCK8 protein, human; D020662:Guanine Nucleotide Exchange Factors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D007073:Immunoglobulin E
keywords: dedicator of cytokinesis 8; host defense; hyper-IgE syndrome; immune dysregulation; signal transducer and activator of transcription 3