Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome

• Authors: WOELLNER Cristina; GERTZ E. Michael; SCHAFFER Alejandro A.; LAGOS Macarena; PERRO Mario; GLOCKER Erik-Oliver; PIETROGRANDE Maria C.; COSSU Fausto; FRANCO José L.; MATAMOROS Nuria; PIETRUCHA Barbara; HEROPOLITANSKA-PLISZKA Edyta; YEGANEH Mehdi; MOIN Mostafa; ESPAŇOL Teresa; EHL Stephan; GENNERY Andrew; ABINUM Mario; BREBOROWICZ Anna; NIEHUES Tim; KILIC Sebnem Sara; JUNKER Anna; TURVEY Stuart E.; PLEBANI Alesandro; SÁNCHEZ Berta; GARTY Ben-Zion; PIGNATA Claudio; CANCRINI Caterina; LITZMAN Jiří; SANAL Ozden; BAUMANN Ulrich; BACCHETA Rosa; HSU Amy P.; DAVIS Joie N.; HAMMARSTROM Lennart; DAVIES Graham E.; EREN Efrem; ARKWRIGHT Peter D.; MOILANEN Jukka; VIEMANN Dorothe; KHAN Sujoy; MARODI Lászlo; CANT Andrew J.; FREEMAN Alexandra F.; PUCK Jennifer M.; HOLLAND Steven M.; GRIMBACHER Bodo
• Year of publication: 2010
• Type: Article in Periodical
• Magazine / Source: J Allergy Clin Immunol
• MU Faculty or unit: Faculty of Medicine
• Field: Immunology
• Keywords: hyper-IgE syndrome; STAT3; diagnostic giudelines
• Description: 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