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Woellner, Cristina, MSc; Gertz, E. Michael, PhD; Schäffer, Alejandro A., PhD; Lagos, Macarena, MD; Perro, Mario, MSc; Glocker, Erik-Oliver, MD; Pietrogrande, Maria C., MD; Cossu, Fausto, MD; Franco, José L., MD, PhD; Matamoros, Nuria, MD; Pietrucha, Barbara, MD, PhD; Heropolitańska-Pliszka, Edyta, MD; Yeganeh, Mehdi, MD; Moin, Mostafa, MD; Español, Teresa, MD, PhD; Ehl, Stephan, MD; Gennery, Andrew R., MD; Abinun, Mario, MD, PhD; Bręborowicz, Anna, MD; Niehues, Tim, MD; Kilic, Sara Sebnem, MD; Junker, Anne, MD; Turvey, Stuart E., MD, PhD; Plebani, Alessandro, MD; Sánchez, Berta, PhD; Garty, Ben-Zion, MD; Pignata, Claudio, MD; Cancrini, Caterina, MD; Litzman, Jiri, MD; Sanal, Özden, MD; Baumann, Ulrich, MD; Bacchetta, Rosa, MD; Hsu, Amy P., BA; Davis, Joie N., CRNP; Hammarström, Lennart, MD; Davies, E. Graham, MD; Eren, Efrem, MD; Arkwright, Peter D., MD, PhD; Moilanen, Jukka S., MD, PhD; Viemann, Dorothee, MD; Khan, Sujoy, MRCP; Maródi, László, MD; Cant, Andrew J., MD; Freeman, Alexandra F., MD; Puck, Jennifer M., MD; Holland, Steven M., MD; Grimbacher, Bodo, MD
Journal of allergy and clinical immunology, 02/2010, Letnik: 125, Številka: 2Journal Article
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 TH 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 TH 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. TH 17 cells were profoundly reduced in patients harboring STAT3 mutations, whereas 10 of 13 patients without mutations had low (<1%) TH 17 cells but were distinct by markedly reduced IFN-γ–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 TH 17 cells or a family history for definitive HIES. Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.
