期刊
BLOOD
卷 127, 期 25, 页码 3154-3164出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-11-679902
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资金
- French National Research Agency (ANR) under the Investments for the future program [ANR-10-IAHU-01]
- French National Research Agency (ANR) under GENCMCD grant [ANR-11-BSV3-005-01]
- French National Research Agency (ANR) under HGDIFD [ANR-14-CE15-0006]
- French National Research Agency (ANR) under Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases [ANR-10-LABX-62-IBEID]
- INSERM
- University Paris Descartes
- Jeffrey Modell Foundation-Translational Research Program
- Jeffrey Modell Centers Network
- Rockefeller University
- St. Giles Foundation
- National Institute of Allergy and Infectious Diseases, National Institutes of Health [U01AI109697]
- ERA-Net for Research Programmes on Rare Diseases E-RARE EURO CMC [ANR-14-RARE-0005-02]
- Helmholtz Center grant DZIF [8000805-3_TTU_IICH 07.801]
- Gebert Ruf Stiftung-programme Rare Diseases-New Approaches, EUFP7 CELL-PID, EUFP7 NET4CGD, ZIHP
- Ministerio de Sanidad, Spain from the Regional Development Fund-European Social Fund (FEDER-FSE) [PI13/1456]
- MRC [MR/N006364/1] Funding Source: UKRI
- Grants-in-Aid for Scientific Research [16K15528, 16H05355] Funding Source: KAKEN
- Agence Nationale de la Recherche (ANR) [ANR-14-CE15-0006] Funding Source: Agence Nationale de la Recherche (ANR)
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-Guerin 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.
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