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, L. Máródi, Tomohiro Morio, Masao Kobayashi, Desa Lilic, Joshua D. Milner, Steven Holland, Jean Laurent Casanova, Anne Puel

Research output: Article

137 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 - jún. 23 2016

Fingerprint

Skin
Chronic Mucocutaneous Candidiasis
BCG Vaccine
Phenotype
Mutation
T-cells
Interleukin-17
Candida
Medical problems
Blood
Intracranial Aneurysm
Herpesviridae
Virus Diseases
Mycobacterium
Hypothyroidism
Type 1 Diabetes Mellitus
Age of Onset
Mycobacterium tuberculosis
Bacterial Infections
Systemic Lupus Erythematosus

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Toubiana, J., Okada, S., Hiller, J., Oleastro, M., Gomez, M. L., Becerra, J. C. A., ... Puel, A. (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

Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. / Toubiana, Julie; Okada, Satoshi; Hiller, Julia; Oleastro, Matias; Gomez, Macarena Lagos; Becerra, Juan Carlos Aldave; 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; Máródi, L.; Morio, Tomohiro; Kobayashi, Masao; Lilic, Desa; Milner, Joshua D.; Holland, Steven; Casanova, Jean Laurent; Puel, Anne.

In: Blood, Vol. 127, No. 25, 23.06.2016, p. 3154-3164.

Research output: Article

Toubiana, J, Okada, S, Hiller, J, Oleastro, M, Gomez, ML, Becerra, JCA, Ouachée-Chardin, M, Fouyssac, F, Girisha, KM, Etzioni, A, Van Montfrans, J, Camcioglu, Y, Kerns, LA, Belohradsky, B, Blanche, S, Bousfiha, A, Rodriguez-Gallego, C, Meyts, I, Kisand, K, Reichenbach, J, Renner, ED, Rosenzweig, S, Grimbacher, B, Van De Veerdonk, FL, Traidl-Hoffmann, C, Picard, C, Máródi, L, Morio, T, Kobayashi, M, Lilic, D, Milner, JD, Holland, S, Casanova, JL & Puel, A 2016, 'Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype', Blood, vol. 127, no. 25, pp. 3154-3164. https://doi.org/10.1182/blood-2015-11-679902
Toubiana J, Okada S, Hiller J, Oleastro M, Gomez ML, Becerra JCA et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood. 2016 jún. 23;127(25):3154-3164. https://doi.org/10.1182/blood-2015-11-679902
Toubiana, Julie ; Okada, Satoshi ; Hiller, Julia ; Oleastro, Matias ; Gomez, Macarena Lagos ; Becerra, Juan Carlos Aldave ; 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 ; Máródi, L. ; Morio, Tomohiro ; Kobayashi, Masao ; Lilic, Desa ; Milner, Joshua D. ; Holland, Steven ; Casanova, Jean Laurent ; Puel, Anne. / Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. In: Blood. 2016 ; Vol. 127, No. 25. pp. 3154-3164.
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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-Gu{\'e}rin 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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AU - Okada, Satoshi

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AU - Gomez, Macarena Lagos

AU - Becerra, Juan Carlos Aldave

AU - Ouachée-Chardin, Marie

AU - Fouyssac, Fanny

AU - Girisha, Katta Mohan

AU - Etzioni, Amos

AU - Van Montfrans, Joris

AU - Camcioglu, Yildiz

AU - Kerns, Leigh Ann

AU - Belohradsky, Bernd

AU - Blanche, Stéphane

AU - Bousfiha, Aziz

AU - Rodriguez-Gallego, Carlos

AU - Meyts, Isabelle

AU - Kisand, Kai

AU - Reichenbach, Janine

AU - Renner, Ellen D.

AU - Rosenzweig, Sergio

AU - Grimbacher, Bodo

AU - Van De Veerdonk, Frank L.

AU - Traidl-Hoffmann, Claudia

AU - Picard, Capucine

AU - Máródi, L.

AU - Morio, Tomohiro

AU - Kobayashi, Masao

AU - Lilic, Desa

AU - Milner, Joshua D.

AU - Holland, Steven

AU - Casanova, Jean Laurent

AU - Puel, Anne

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