Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome

Cristina Woellner, E. Michael Gertz, Alejandro A. Schäffer, Macarena Lagos, Mario Perro, Erik Oliver Glocker, Maria C. Pietrogrande, Fausto Cossu, José L. Franco, Nuria Matamoros, Barbara Pietrucha, Edyta Heropolitańska-Pliszka, Mehdi Yeganeh, Mostafa Moin, Teresa Español, Stephan Ehl, Andrew R. Gennery, Mario Abinun, Anna Breborowicz, Tim Niehues & 27 others Sara Sebnem Kilic, Anne Junker, Stuart E. Turvey, Alessandro Plebani, Berta Sánchez, Ben Zion Garty, Claudio Pignata, Caterina Cancrini, Jiri Litzman, Özden Sanal, Ulrich Baumann, Rosa Bacchetta, Amy P. Hsu, Joie N. Davis, Lennart Hammarström, E. Graham Davies, Efrem Eren, Peter D. Arkwright, Jukka S. Moilanen, Dorothee Viemann, Sujoy Khan, L. Máródi, Andrew J. Cant, Alexandra F. Freeman, Jennifer M. Puck, Steven M. Holland, Bodo Grimbacher

Research output: Contribution to journalArticle

150 Citations (Scopus)

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 TH17 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 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. 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. TH17 cells were profoundly reduced in patients harboring STAT3 mutations, whereas 10 of 13 patients without mutations had low (H17 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 TH17 cells or a family history for definitive HIES. Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.

Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
Volume125
Issue number2
DOIs
Publication statusPublished - Feb 2010

Fingerprint

Job Syndrome
STAT3 Transcription Factor
Guidelines
Mutation
Th17 Cells
Immunoglobulin E
Spontaneous Fractures
src Homology Domains
Palate
Bone Fractures
Genetic Association Studies
Exanthema
Serum
Pneumonia

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Woellner, C., Gertz, E. M., Schäffer, A. A., Lagos, M., Perro, M., Glocker, E. O., ... Grimbacher, B. (2010). Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. Journal of Allergy and Clinical Immunology, 125(2). https://doi.org/10.1016/j.jaci.2009.10.059

Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. / 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; Heropolitańska-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, Özden; 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; Máródi, L.; Cant, Andrew J.; Freeman, Alexandra F.; Puck, Jennifer M.; Holland, Steven M.; Grimbacher, Bodo.

In: Journal of Allergy and Clinical Immunology, Vol. 125, No. 2, 02.2010.

Research output: Contribution to journalArticle

Woellner, C, Gertz, EM, Schäffer, AA, Lagos, M, Perro, M, Glocker, EO, Pietrogrande, MC, Cossu, F, Franco, JL, Matamoros, N, Pietrucha, B, Heropolitańska-Pliszka, E, Yeganeh, M, Moin, M, Español, T, Ehl, S, Gennery, AR, Abinun, M, Breborowicz, A, Niehues, T, Kilic, SS, Junker, A, Turvey, SE, Plebani, A, Sánchez, B, Garty, BZ, Pignata, C, Cancrini, C, Litzman, J, Sanal, Ö, Baumann, U, Bacchetta, R, Hsu, AP, Davis, JN, Hammarström, L, Davies, EG, Eren, E, Arkwright, PD, Moilanen, JS, Viemann, D, Khan, S, Máródi, L, Cant, AJ, Freeman, AF, Puck, JM, Holland, SM & Grimbacher, B 2010, 'Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome', Journal of Allergy and Clinical Immunology, vol. 125, no. 2. https://doi.org/10.1016/j.jaci.2009.10.059
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 ; Heropolitańska-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, Özden ; 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 ; Máródi, L. ; Cant, Andrew J. ; Freeman, Alexandra F. ; Puck, Jennifer M. ; Holland, Steven M. ; Grimbacher, Bodo. / Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. In: Journal of Allergy and Clinical Immunology. 2010 ; Vol. 125, No. 2.
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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 TH17 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 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. 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. TH17 cells were profoundly reduced in patients harboring STAT3 mutations, whereas 10 of 13 patients without mutations had low (H17 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 TH17 cells or a family history for definitive HIES. Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.",
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T1 - Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome

AU - Woellner, Cristina

AU - Gertz, E. Michael

AU - Schäffer, Alejandro A.

AU - Lagos, Macarena

AU - Perro, Mario

AU - Glocker, Erik Oliver

AU - Pietrogrande, Maria C.

AU - Cossu, Fausto

AU - Franco, José L.

AU - Matamoros, Nuria

AU - Pietrucha, Barbara

AU - Heropolitańska-Pliszka, Edyta

AU - Yeganeh, Mehdi

AU - Moin, Mostafa

AU - Español, Teresa

AU - Ehl, Stephan

AU - Gennery, Andrew R.

AU - Abinun, Mario

AU - Breborowicz, Anna

AU - Niehues, Tim

AU - Kilic, Sara Sebnem

AU - Junker, Anne

AU - Turvey, Stuart E.

AU - Plebani, Alessandro

AU - Sánchez, Berta

AU - Garty, Ben Zion

AU - Pignata, Claudio

AU - Cancrini, Caterina

AU - Litzman, Jiri

AU - Sanal, Özden

AU - Baumann, Ulrich

AU - Bacchetta, Rosa

AU - Hsu, Amy P.

AU - Davis, Joie N.

AU - Hammarström, Lennart

AU - Davies, E. Graham

AU - Eren, Efrem

AU - Arkwright, Peter D.

AU - Moilanen, Jukka S.

AU - Viemann, Dorothee

AU - Khan, Sujoy

AU - Máródi, L.

AU - Cant, Andrew J.

AU - Freeman, Alexandra F.

AU - Puck, Jennifer M.

AU - Holland, Steven M.

AU - Grimbacher, Bodo

PY - 2010/2

Y1 - 2010/2

N2 - 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 TH17 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 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. 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. TH17 cells were profoundly reduced in patients harboring STAT3 mutations, whereas 10 of 13 patients without mutations had low (H17 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 TH17 cells or a family history for definitive HIES. Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.

AB - 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 TH17 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 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. 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. TH17 cells were profoundly reduced in patients harboring STAT3 mutations, whereas 10 of 13 patients without mutations had low (H17 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 TH17 cells or a family history for definitive HIES. Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.

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