Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype.
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.
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;
Julie
0000-0001-9561-669X
J
Toubiana
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;
Satoshi
0000-0002-4622-5657
S
Okada
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;
Julia
J
Hiller
Immunology and Reumatholoy Department, Juan Pedro Garrahan National Hospital of Pediatrics, Buenos Aires, Argentina;
Matias
M
Oleastro
Department of Preclinics, School of Medicine, Valparaíso University and Department of Pediatrics, Padre Hurtado-Clinica Alemana de Santiago Hospital, Valparaíso, Chile;
Macarena
M
Lagos Gomez
Allergy and Immunology Division, Edgardo Rebagliati Martins National Hospital, Lima, Peru;
Juan Carlos
JC
Aldave Becerra
Pediatric Hematology-Oncology Unit, AP-HP, Robert Debré Hospital, Paris, France;
Marie
M
Ouachée-Chardin
Pediatric Oncology and Hematology Unit, Children Hospital, Vandoeuvre-les-Nancy, France;
Fanny
F
Fouyssac
Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India;
Katta Mohan
KM
Girisha
Meyer Children's Hospital, Haifa, Israel;
Amos
A
Etzioni
Department of Pediatric Immunology, Hematology and Infectious Diseases, Utrecht University Medical Center, Utrecht, The Netherlands;
Joris
J
Van Montfrans
Department of Pediatrics, Infectious Disease, Clinical Immunology and Allergy Division, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey;
Yildiz
Y
Camcioglu
Division of Pediatric Pulmonology, Allergy, Immunology, and Sleep Medicine, Rainbow Babies and Children's Hospital, Case Medical Center, Cleveland, OH;
Leigh Ann
LA
Kerns
Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany;
Bernd
B
Belohradsky
Paris Descartes University, Sorbonne Paris Cité, Institut Imagine, Paris, France; Pediatric Hematology-Immunology-Rheumatology Unit, AP-HP, Necker-Enfants Malades Hospital, Paris, France;
Stéphane
S
Blanche
Clinical Immunology Unit, Department of Pediatric Infectious Diseases, Ibn Rochd Hospital, King Hassan II University, Casablanca, Morocco;
Aziz
A
Bousfiha
Department of Immunology, Son Espases University Hospital, Palma de Mallorca, Spain;
Carlos
C
Rodriguez-Gallego
Department of Pediatrics, Leuven University Hospitals, Leuven, Belgium;
Isabelle
I
Meyts
Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia;
Kai
K
Kisand
Division of Immunology, University Children's Hospital and Children's Research Centre, University of Zurich, Zurich, Switzerland;
Janine
J
Reichenbach
Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany;
Ellen D
ED
Renner
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
Sergio
S
Rosenzweig
Center for Chronic Immunodeficiency, Freiburg University Medical Center and University of Freiburg, Freiburg, Germany;
Bodo
B
Grimbacher
Department of Internal Medicine, Radboud University Medical Center, Radboud Center for Infectious Diseases, Nijmegen, The Netherlands;
Frank L
FL
van de Veerdonk
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;
Claudia
C
Traidl-Hoffmann
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;
Capucine
C
Picard
Department of Infectious Diseases and Pediatric Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary;
Laszlo
L
Marodi
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan;
Tomohiro
T
Morio
Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan;
Masao
M
Kobayashi
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom;
Desa
D
Lilic
Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
Joshua D
JD
Milner
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
Steven
S
Holland
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.
Jean-Laurent
JL
Casanova
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.
Anne
0000-0003-2603-0323
A
Puel
D000293:Adolescent; D000328:Adult; D000368:Aged; D002178:Candidiasis, Chronic Mucocutaneous / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D050794:STAT1 Transcription Factor / Q000235:genetics*; D055815:Young Adult
D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human