Woellner, CristinaGertz, Edward MichaelSchaffer, Alejandro A.Lagos, MacarenaPerro, MarioGlocker, Erik OliverPietrogrande, Maria CristinaCossu, FaustoFranko, Josè LuisMatamoros, NúriaPietrucha, Barbara MariaHeropolitańska-Pliszka, EdytaYeganeh, MehdiMoin, MostafaEspañol, TheresaEhl, StephanGennery, Andrew R.Abinun, Mario A.Brȩborowicz, AnnaNiehues, TimJunker, Anne K.Turvey, Stuart E.Plebani, AlessandroSánchez, BertaGarty, Ben ZionPignata, ClaudioCancrini, CaterinaLitzman, JiříSanal, ÖzdenBaumann, UlrichBacchetta, RosaHsu, Amy P.Davis, Joie N.Hammarström, Lennart L.G.Davis, Edward GrahamEren, EfremArkwright, Peter D.Moilanen, Jukka S.Viemann, DorotheeKhan, SujoyMáródi, László D.R.Cant, Andrew JamesFreeman, Alexandra F.Puck, Jennifer M.Holland, Steven M.Grimbacher, Bodo2022-08-242022-08-242010-02Woellner, C. vd. (2010). "Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome". Journal of Allergy and Clinical Immunology, 125(2), 424-432.0091-67491097-6825https://doi.org/10.1016/j.jaci.2009.10.059https://www.sciencedirect.com/science/article/pii/S0091674909016376http://hdl.handle.net/11452/28333Background: 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 (STAT-3) 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 STAT-3 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 folio-wing 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.eninfo:eu-repo/semantics/openAccessHyper-IgE syndromeHIESJob syndromeT(H)17 cellsSTAT3 mutationsDiagnostic guidelinesHost-defenseCellsAllergyImmunologyArticle0002747640000222-s2.0-76049116822424432125220159255AllergyImmunologyJob Syndrome; Mucocutaneous Candidiasis; MutationGamma interferonImmunoglobulin EProtein SH3STAT3 proteinTumor necrosis factor alphaAdolescentAdultAmino acid sequenceArticleCD4+ T lymphocyteChildClinical featureCytokine productionDiagnostic accuracyDNA bindingEnzyme linked immunosorbent assayFemaleFlow cytometryFractureGene mutationGenotype phenotype correlationHeterozygoteHumanHyper IgE syndromeImmunoglobulin blood levelInfantLymphocyte activationMachine learningMajor clinical studyMalePneumoniaPolymerase chain reactionPreschool childPriority journalRashSchool childTh17 cellWild type