Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome

Woellner, Cristina MSc
Gertz, Michael E. 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

^aDepartment of Immunology and Molecular Pathology, Royal Free Hospital, University College London, London, United Kingdom
^bNational Center for Biotechnology Information, National Institutes of Health, Department of Health and Human Services, Bethesda, Md
^cLaboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Md
^dCátedra de Inmunología Escuela de Medicina, Universidad de Valparaíso, Valparaíso, Chile
^eDepartment of Pediatrics, University of Milan, Fondazione Policlinico IRCCS, Milan, Italy
^fBone Marrow Transplant Unit, Ospedale Microcitemico, Cagliari, Italy
^gGroup of Primary Immunodeficiencies, University of Antioquia, Medellín, Colombia
^hImmunology Service, Son Dureta Hospital, Palma de Mallorca, Spain
ⁱGastroenterology, Hepatology and Immunology Clinic, Children's Memorial Health Institute, Warsaw, Poland
^jImmunology, Asthma and Allergy Research Institute, Children Medical Centre, Tehran University of Medical Sciences, Tehran, Iran
^kImmunology Unit, Hospital Vall d'Hebron, School of Medicine, Barcelona, Spain
^lDepartment of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany
^mChildren's Bone Marrow Transplant Unit, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
ⁿDepartment of Pediatric Pulmonology, Allergy and Clinical Immunology, 3rd Department of Pediatrics, Poznan University of Medical Sciences, Poznan, Poland
^oImmunodeficiency and Pediatric Rheumatology Centre, HELIOS Klinikum Krefeld, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany
^pDepartment of Pediatric Immunology, Faculty of Medicine, Uludag University, Bursa, Turkey
^qDepartment of Pediatrics, British Columbia's Children's Hospital and University of British Columbia, Vancouver, British Columbia, Canada
^rDepartment of Pediatrics and Institute of Molecular Medicine A. Novicelli, University of Brescia, Brescia, Italy
^sImmunology Service, University Hospital, Virgen del Rocıo, Sevilla, Spain
^tDepartment of Pediatrics, Schneider Children's Medical Center, Petah Tiqva, Israel
^uDepartment of Pediatrics, “Federico II” University of Naples, Naples, Italy
^vDivision of Immunology and Infectious Disease, Bambino Gesù Children's Hospital, University of Rome Tor Vergata, Rome, Italy
^wDepartment of Clinical Immunology and Allergology, Faculty of Medicine, Masaryk University, St Anne's University Hospital, Brno, Czech Republic
^xImmunology Division, Hacettepe University Children's Hospital, Ankara, Turkey
^yDepartment of Pediatric Pulmonology and Neonatology, Medical School Hannover, Hannover, Germany
^zSan Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy
^aaDivision of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at the Karolinska University Hospital, Stockholm, Sweden
^bbDepartment of Immunology, Great Ormond Street Hospital, London, United Kingdom
^ccImmunology Department, Southampton General Hospital, Southampton, United Kingdom
^ddPaediatric Immunology, University of Manchester, Manchester, United Kingdom
^eeDepartment of Clinical Genetics, University of Oulu and Medical School, University of Tampere, Tampere, Finland
^ffInstitute of Immunology and Department of Pediatrics, University of Münster, Münster, Germany
^ggPath Links Immunology, Scunthorpe General Hospital, Scunthorpe, United Kingdom
^hhDepartment of Infectious and Pediatric Immunology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary
ⁱⁱDepartment of Pediatrics, University of California, San Francisco, Calif

Reprint requests: Bodo Grimbacher, MD, Dept of Immunology and Molecular Pathology, Royal Free Hospital and University College London, Pond Street, London NW3 2QG, United Kingdom. E-mail: [email protected].

Supported by in part by the European grant MEXT-CT-2006-042316 to B.G., a grant of the Primary Immunodeficiency Association provided by GSK, the European consortium grant EURO-PADnet HEALTH-F2-2008-201549, the grant OTKA 49017 to L.M., the foundation C. Golgi from Brescia to A.P., the Intramural Research Program of the National Institutes of Health, NLM (E.M.G., A.A.S.), the National Institute of Allergy and Infectious Diseases (A.P.H., A.F.F., J.N.D., S.M.H.), and federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Disclosure of potential conflict of interest: B. Grimbacher has received research support from the European Union and the Primary Immunodeficiency Association, and is secretary of the European Society for Immunodeficiencies. J. L. Franco is vice president of Fundación Diana García de Olarte. T. Niehues has received consulting fees from Talecris Biotherapeutics, Octapharma, Behring ZLB, and Baxter. S. S. Kilic has received research support from Uludag University. A. Junker has received research support from the BS Children's Hospital Foundation, the Michael Smith Foundation, and the Canadian Institutes of Health Research. L. Hammarström has received research support from the National Institutes of Health, the European Union, and the Swedish Research Council. J. S. Moilanen has received research support from the Academy of Finland. A. J. Cant has received research support from the Bubble Foundation, UK, and the Medical Research Council, and has served as an expert witness on cases of bacterial meningitis and herpes simplex encephalitis. J. M. Puck has received research support from the National Institutes of Health, NICHD, and the Jeffrey Modell Foundation, and is on the Steering Committee of the Immune Deficiency Foundation and the Expert Committee on Primary Immunodeficiencies for IUIS. The rest of the authors have declared that they have no conflict of interest.

Received for publication November 13, 2008; revised October 2, 2009; accepted for publication October 8, 2009

Journal of Allergy & Clinical Immunology 125(2):p 424-432e8, February 2010.

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_H17 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 betweenSTAT3mutated andSTAT3wild-type patients.

Methods

We collected clinical data, determined T_H17 cell numbers, and sequencedSTAT3in 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 aSTAT3mutation.

Results

In 64 patients, we identified 31 differentSTAT3mutations, 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 predictedSTAT3mutations with 85% accuracy. T_H17 cells were profoundly reduced in patients harboringSTAT3mutations, whereas 10 of 13 patients without mutations had low (<1%) T_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 T_H17 cells or a family history for definitive HIES. Definitive: These characteristics plus a dominant-negative heterozygous mutation inSTAT3.