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

Toubiana, Julie; Okada, Satoshi; Hiller, Julia; Oleastro, Matias; Lagos Gomez, Macarena; Aldave Becerra, Juan Carlos; Ouachée-Chardin, Marie; Fouyssac, Fanny; Girisha, Katta Mohan; Etzioni, Amos; Van Montfrans, Joris; Camcioglu, Yildiz; Kerns, Leigh Ann; Belohradsky, Bernd; Blanche, Stéphane; 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, Claudia; Picard, Capucine; Marodi, Laszlo; Morio, Tomohiro; Kobayashi, Masao; Lilic, Desa; Milner, Joshua D; Holland, Steven; Casanova, Jean-Laurent; Puel, Anne

doi:10.1182/blood-2015-11-679902

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

Author:

Toubiana, Julie

Okada, Satoshi ; Hiller, Julia ; Oleastro, Matias ; Lagos Gomez, Macarena ; Aldave Becerra, Juan Carlos ; Ouachée-Chardin, Marie ; Fouyssac, Fanny ; Girisha, Katta Mohan ; Etzioni, Amos ; Van Montfrans, Joris ; Camcioglu, Yildiz ; Kerns, Leigh Ann ; Belohradsky, Bernd ; Blanche, Stéphane ; 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, Claudia ; Picard, Capucine ; Marodi, Laszlo ; Morio, Tomohiro ; Kobayashi, Masao ; Lilic, Desa ; Milner, Joshua D ; Holland, Steven ; Casanova, Jean-Laurent ; Puel, Anne

Keywords:

Science & Technology, Life Sciences & Biomedicine, Hematology, CHRONIC MUCOCUTANEOUS CANDIDIASIS, PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY, FUNCTION SIGNAL TRANSDUCER, HOMOZYGOUS CARD9 MUTATION, AUTOSOMAL-DOMINANT GAIN, HYPER-IGE SYNDROME, INBORN-ERRORS, IL-17 IMMUNITY, T-CELLS, EX-VIVO, Adolescent, Adult, Aged, Candidiasis, Chronic Mucocutaneous, Child, Child, Preschool, Cohort Studies, Female, Genetic Association Studies, Genetic Predisposition to Disease, Heterozygote, Humans, Infant, Male, Middle Aged, Mutation, Phenotype, STAT1 Transcription Factor, Young Adult, International STAT1 Gain-of-Function Study Group, 1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences, 1114 Paediatrics and Reproductive Medicine, Immunology, 3101 Biochemistry and cell biology, 3201 Cardiovascular medicine and haematology, 3213 Paediatrics

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 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.