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Blood. 2016 Jun 23;127(25):3154-64. doi: 10.1182/blood-2015-11-679902. Epub 2016 Apr 25.

Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype.

Collaborators (138)

Cypowyj S, Thumerelle C, Toulon A, Bustamante J, Tahuil N, Salhi A, Boiu S, Chopra C, Di Giovanni D, Bezrodnik L, Boutros J, Thomas C, Lacuesta G, Jannier S, Korganow AS, Paillard C, Boutboul, Bué M, Marie-Cardine A, Bayart S, Migaud M, Weiss, Karmochkine M, Garcia-Martinez JM, Stephan JL, Bensaid P, Jeannoel GP, Witte T, Baumann U, Harrer T, Navarrete C, Benjamin AT, Firinu, Pignata C, Picco P, Mendoza D, Lugo Reyes SO, Torres Lozano C, Ortega-Cisneros M, Cortina M, Mesdaghi M, Nabavi M, Español T, Martínez-Saavedra MT, Rezaei N, Zoghi S, Pac M, Barlogis V, Revon-Rivière G, Haimi-Cohen Y, Spiegel R, Miron D, Bouchaib J, Blancas-Galicia L, Toth B, Drexel B, Rohrlich PS, Lesens O, Hoernes M, Drewe E, Abinum M, Sawalle-Belohradsky J, Kindle G, Depner M, Milani L, Nikopensius T, Remm M, Talas UG, Tucker M, Willis M, Leonard S, Meuwissen H, Ferdman RM, Wallace M, Desai MM, Taur P, Badolato R, Soltesz B, Schnopp C, Jansson AF, Ayvaz D, Shabashova N, Chernyshova L, Bondarenko A, Moshous D, Neven B, Boubidi C, Ailal F, Giardino G, Del Giacco S, Bougnoux ME, Imai K, Okawa T, Mizoguchi Y, Ozaki Y, Takeuchi M, Hayakawa A, Lögering B, Reich K, Buhl T, Eyerich K, Schaller M, Arkwright PD, Gennery AR, Cant AJ, Warris A, Henriet S, Mekki N, Barbouche R, Ben Mustapha I, Bodemer, Polak M, Grimprel E, Burgel PR, Fischer A, Hermine O, Debré M, Kocacyk D, Dhalla F, Patel SY, Moens L, Haerynck F, Dullaers, Hoste L, Sanal O, Kilic SS, Roesler J, Lanternier F, Lortholary O, Fieschi C, Church JA, Roifman C, Yuenyongviwat A, Peterson P, Boisson-Dupuis S, Abel L, Marciano BE, Netea MG.

Author information

1
Department of General Pediatrics and Pediatric Infectious Diseases, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker-Enfants Malades Hospital, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Institut Imagine, Paris, France; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Necker Medical School, Paris, France; Pediatric Hematology-Immunology-Rheumatology Unit, AP-HP, Necker-Enfants Malades Hospital, Paris, France;
2
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY; Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan;
3
Institute of Environmental Medicine, UNIKA-T, Technical University and Helmholtz Center Munich, Augsburg, Germany; Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland;
4
Immunology and Reumatholoy Department, Juan Pedro Garrahan National Hospital of Pediatrics, Buenos Aires, Argentina;
5
Department of Preclinics, School of Medicine, Valparaíso University and Department of Pediatrics, Padre Hurtado-Clinica Alemana de Santiago Hospital, Valparaíso, Chile;
6
Allergy and Immunology Division, Edgardo Rebagliati Martins National Hospital, Lima, Peru;
7
Pediatric Hematology-Oncology Unit, AP-HP, Robert Debré Hospital, Paris, France;
8
Pediatric Oncology and Hematology Unit, Children Hospital, Vandoeuvre-les-Nancy, France;
9
Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India;
10
Meyer Children's Hospital, Haifa, Israel;
11
Department of Pediatric Immunology, Hematology and Infectious Diseases, Utrecht University Medical Center, Utrecht, The Netherlands;
12
Department of Pediatrics, Infectious Disease, Clinical Immunology and Allergy Division, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey;
13
Division of Pediatric Pulmonology, Allergy, Immunology, and Sleep Medicine, Rainbow Babies and Children's Hospital, Case Medical Center, Cleveland, OH;
14
Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany;
15
Paris Descartes University, Sorbonne Paris Cité, Institut Imagine, Paris, France; Pediatric Hematology-Immunology-Rheumatology Unit, AP-HP, Necker-Enfants Malades Hospital, Paris, France;
16
Clinical Immunology Unit, Department of Pediatric Infectious Diseases, Ibn Rochd Hospital, King Hassan II University, Casablanca, Morocco;
17
Department of Immunology, Son Espases University Hospital, Palma de Mallorca, Spain;
18
Department of Pediatrics, Leuven University Hospitals, Leuven, Belgium;
19
Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia;
20
Division of Immunology, University Children's Hospital and Children's Research Centre, University of Zurich, Zurich, Switzerland;
21
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
22
Center for Chronic Immunodeficiency, Freiburg University Medical Center and University of Freiburg, Freiburg, Germany;
23
Department of Internal Medicine, Radboud University Medical Center, Radboud Center for Infectious Diseases, Nijmegen, The Netherlands;
24
Paris Descartes University, Sorbonne Paris Cité, Institut Imagine, Paris, France; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Necker Medical School, Paris, France; Pediatric Hematology-Immunology-Rheumatology Unit, AP-HP, Necker-Enfants Malades Hospital, Paris, France; Study Center for Immunodeficiencies, Necker-Enfants Malades Hospital, AP-HP, Paris, France;
25
Department of Infectious Diseases and Pediatric Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary;
26
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan;
27
Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan;
28
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom;
29
Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
30
Paris Descartes University, Sorbonne Paris Cité, Institut Imagine, Paris, France; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Necker Medical School, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY; Howard Hughes Medical Institute, New York, NY; and.
31
Paris Descartes University, Sorbonne Paris Cité, Institut Imagine, Paris, France; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Necker Medical School, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY; Department of Infectious and Tropical Diseases, Necker-Enfants Malades Hospital, AP-HP, Paris, France.

Abstract

Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from 5 continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years). Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or Bacille Calmette-Guérin vaccines were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis.

Comment in

PMID:
27114460
PMCID:
PMC4920021
DOI:
10.1182/blood-2015-11-679902
[Indexed for MEDLINE]
Free PMC Article

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