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Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome Woellner C; Gertz EM; Schaffer AA; Lagos M; Perro M; Glocker EO; Pietrogrande MC; Cossu F; Franco JL; Matamoros N; Pietrucha B; Heropolitanska-Pliszka E; Yeganeh M; Moin M; Espanol T; Ehl S; Gennery AR; Abinun M; Breborowicz A; Niehues T; Kilic SS; Junker A; Turvey SE; Plebani A; Sanchez B; Garty BZ; Pignata C; Cancrini C; Litzman J; Sanal O; Baumann U; Bacchetta R; Hsu AP; Davis JN; Hammarstrom L; Davies EG; Eren E; Arkwright PD; Moilanen JS; Viemann D; Khan S; Marodi L; Cant AJ; Freeman AF; Puck JM; Holland SM; Grimbacher BJ Allergy Clin Immunol 2010[Feb]; 125 (2): 424-432.e8BACKGROUND: 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 (STAT3) 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 STAT3 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 following 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.|Adolescent[MESH]|Adult[MESH]|Cell Separation[MESH]|Child[MESH]|Child, Preschool[MESH]|Enzyme-Linked Immunosorbent Assay[MESH]|Female[MESH]|Flow Cytometry[MESH]|Humans[MESH]|Immunoglobulin E/blood[MESH]|Infant[MESH]|Interleukin-17/immunology[MESH]|Job Syndrome/*diagnosis/*genetics/immunology[MESH]|Male[MESH]|Middle Aged[MESH]|Mutation[MESH]|Polymerase Chain Reaction[MESH]|Practice Guidelines as Topic[MESH]|STAT3 Transcription Factor/*genetics[MESH]|T-Lymphocytes, Helper-Inducer/immunology[MESH]|Young Adult[MESH] |
