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

Julie Toubiana, Satoshi Okada, Julia Hiller, Matias Oleastro, Macarena Lagos Gomez, Juan Carlos Aldave Becerra, Marie Ouachée-Chardin, Fanny Fouyssac, Katta Mohan Girisha, Amos Etzioni, Joris Van Montfrans, Yildiz Camcioglu, Leigh Ann Kerns, Bernd Belohradsky, Stéphane Blanche, Aziz Bousfiha, Carlos Rodriguez-Gallego, Isabelle Meyts, Kai Kisand, Janine ReichenbachEllen D. Renner, Sergio Rosenzweig, Bodo Grimbacher, Frank L. Van De Veerdonk, Claudia Traidl-Hoffmann, Capucine Picard, Laszlo Marodi, Tomohiro Morio, Masao Kobayashi, Desa Lilic, Joshua D. Milner, Steven Holland, Jean Laurent Casanova, Anne Puel

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221 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)3154-3164
Number of pages11
JournalBlood
Volume127
Issue number25
DOIs
Publication statusPublished - 23-06-2016

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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