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Toubiana, J.* ; Okada, S.* ; Hiller, J. ; Oleastro, M.* ; Lagos Gomez, M.* ; Aldave Becerra, J.C.* ; Ouachée-Chardin, M.* ; Fouyssac, F.* ; Girisha, K.M.* ; Etzioni, A.* ; van Montfrans, J.* ; Camcioglu, Y.* ; Kerns, L.A.* ; Belohradsky, B.* ; Blanche, S.* ; Bousfiha, A.* ; Rodriguez-Gallego, C.* ; Meyts, I.* ; Kisand, K.* ; Reichenbach, J.* ; Renner, E.D.* ; Rosenzweig, S.* ; Grimbacher, B.* ; van de Veerdonk, F.L.* ; Traidl-Hoffmann, C. ; Picard, C.* ; Maródi, L.* ; Morio, T.* ; Kobayashi, M.* ; Lilic, D.* ; Milner, J.D.* ; Holland, S.* ; Casanova, J.L.* ; Puel, A.*

Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype: An international survey of 274 patients from 167 kindreds.

Blood 127, 3154-3164 (2016)
Publ. Version/Full Text Postprint DOI PMC
Open Access Green
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 five 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 one year (range: 0 - 24 years). Patients often displayed bacterial (74%) infections, mostly due to Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly due to 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 BCG 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 IL-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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Chronic Mucocutaneous Candidiasis; Hyper-ige Syndrome; Progressive Multifocal Leukoencephalopathy; Aicardi-goutieres-syndrome; Function Signal Transducer; Homozygous Card9 Mutation; Autosomal-dominant Gain; Cytokine Gm-csf; Syndrome Type-i; Inborn-errors
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Journal Blood
Quellenangaben Volume: 127, Issue: 25, Pages: 3154-3164 Article Number: , Supplement: ,
Publisher American Society of Hematology
Publishing Place Washington
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute for Allergy Research (IAF)
Institute of Environmental Medicine (IEM)