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, International STAT1 Gain-of-Function Study Group

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183 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 Jun 2016

Keywords

  • 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
  • Journal Article

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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., ... International STAT1 Gain-of-Function Study Group (2016). Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood, 127(25), 3154-3164. https://doi.org/10.1182/blood-2015-11-679902