| Author |
Woellner, Cristina Gertz, E. Michael Schäffer, 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 Español, Teresa Ehl, Stephan Gennery, Andrew R. Abinun, Mario Breborowicz, Anna Niehues, Tim Kilic, Sara Sebnem Junker, Anne Turvey, Stuart E. Plebani, Alessandro Sánchez, Berta Garty, Ben-Zion Pignata, Claudio Cancrini, Caterina Litzman, Jiri Sanal, Ozden Baumann, Ulrich Bacchetta, Rosa Hsu, Amy P. Davis, Joie N. Hammarström, Lennart Davies, E. Graham Eren, Efrem Arkwright, Peter D. Moilanen, Jukka S. Viemann, Dorothee Khan, Sujoy Maródi, László Cant, Andrew J. Freeman, Alexandra F. Puck, Jennifer M. Holland, Steven M. Grimbacher, Bodo |
| Abstract |
BACKGROUND: 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. |
| Subject Keyword |
Discipline Immunology Job Syndrome Diagnosis Genetics Stat3 Transcription Factor Adolescent Cell Separation Child, Preschool Enzyme-linked Immunosorbent Assay Flow Cytometry Immunoglobulin E Blood Infant Interleukin-17 Immunology Mutation Polymerase Chain Reaction Practice Guidelines As Topic T-lymphocytes, Helper-inducer Multicenter Study Research Support, N.i.h., Extramural Research Support, N.i.h., Intramural Research Support, Non-u.s. Gov't |
