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Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome

2010; Elsevier BV; Volume: 125; Issue: 2 Linguagem: Inglês

10.1016/j.jaci.2009.10.059

1097-6825

Cristina Woellner, E. Michael Gertz, Alejandro A. Schäffer, Macarena Lagos, Mario Perro, Erik-Oliver Glocker, Maria Cristina Pietrogrande, Fausto Cossu, José Luis Franco, N Matamoros, Barbara Pietrucha, Edyta Heropolitańska–Pliszka, Mehdi Yeganeh, Mostafa Moin, Teresa Español, Stephan Ehl, Andrew R. Gennery, Mario Abinun, Anna Bręborowicz, Tim Niehues, Sara Şebnem Kılıç, Anne Junker, Stuart E. Turvey, Alessandro Plebani, Berta Sánchez, Ben-Zion Garty, Claudio Pignata, Caterina Cancrini, Jiří Litzman, Özden Sanal, Ulrich Baumann, Rosa Bacchetta, Amy P. Hsu, Joie Davis, Lennart Hammarström, E. Graham Davies, Efrem Eren, Peter D. Arkwright, Jukka S. Moilanen, Dorothee Viemann, Sujoy Khan, László Maródi, Andrew J. Cant, Alexandra F. Freeman, Jennifer M. Puck, Steven M. Holland, Bodo Grimbacher,

T-cell and B-cell Immunology

BackgroundThe 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 TH17 cells.ObjectiveTo 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.MethodsWe collected clinical data, determined TH17 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.ResultsIn 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. TH17 cells were profoundly reduced in patients harboring STAT3 mutations, whereas 10 of 13 patients without mutations had low ( 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 TH17 cells or a family history for definitive HIES. Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3. 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 TH17 cells. 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. We collected clinical data, determined TH17 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. 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. TH17 cells were profoundly reduced in patients harboring STAT3 mutations, whereas 10 of 13 patients without mutations had low ( 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 TH17 cells or a family history for definitive HIES. Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.