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

• Autores: Toubiana, Julie, Okada, Satoshi, Hiller, Julia, Oleastro, Matías, Lagos Gomez, Macarena, Aldave Becerra, Juan Carlos, Ouachée-Chardin, Marie, Fouyssac, Fanny, Mohan Girisha, Katta, Etzioni, Amos, Van Montfrans, Joris, Camcioglu, Yildiz, Kerns, Leigh Ann, Belohradsky, Bernd, Blanche, Stephane, Bousfiha, Aziz, Rodriguez-Gallego, Carlos, Meyts, Isabelle, Kisand, Kai, Reichenbach, Janine, Renner, Ellen D., Rosenzweig, Sergio, Grimbacher, Bodo, Van de Veerdonk, Frank L., Traidl-Hoffmann, Caludia
• Formato: artículo
• Fecha de Publicación: 2016
• Institución: Seguro Social de Salud
• Repositorio: ESSALUD-Institucional
• Lenguaje: inglés
• OAI Identifier: oai:repositorio.essalud.gob.pe:20.500.12959/259
• Enlace del recurso: https://hdl.handle.net/20.500.12959/259; https://doi.org/10.1182/blood-2015-11-679902
• Nivel de acceso: acceso abierto
• Materia: Genética humana; Mutación con Ganancia de Función; Candidiasis; Enfermedades autoinmunes; Carcinoma; Mutación; Micosis sistémica; Autoimmune diseases; Autoimmunity; Signs and symptoms; Systemic mycosis; https://purl.org/pe-repo/ocde/ford#3.05.00

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.