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 Reichenbach & 15 others Ellen 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

Research output: Contribution to journalArticle

138 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

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

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

Cite this

Toubiana, J., Okada, S., Hiller, J., Oleastro, M., Lagos Gomez, M., Aldave Becerra, J. C., ... 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

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; International STAT1 Gain-of-Function Study Group.

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

Research output: Contribution to journalArticle

Toubiana, J, Okada, S, Hiller, J, Oleastro, M, Lagos Gomez, M, Aldave Becerra, JC, 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, Marodi, L, Morio, T, Kobayashi, M, Lilic, D, Milner, JD, Holland, S, Casanova, J-L, Puel, A & International STAT1 Gain-of-Function Study Group 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, Lagos Gomez M, Aldave Becerra JC et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood. 2016 Jun 23;127(25):3154-3164. https://doi.org/10.1182/blood-2015-11-679902
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 ; International STAT1 Gain-of-Function Study Group. / 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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T1 - Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

AU - Toubiana, Julie

AU - Okada, Satoshi

AU - Hiller, Julia

AU - Oleastro, Matias

AU - Lagos Gomez, Macarena

AU - Aldave Becerra, Juan Carlos

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 - Marodi, Laszlo

AU - Morio, Tomohiro

AU - Kobayashi, Masao

AU - Lilic, Desa

AU - Milner, Joshua D

AU - Holland, Steven

AU - Casanova, Jean-Laurent

AU - Puel, Anne

AU - International STAT1 Gain-of-Function Study Group

AU - Warris, Adilia

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N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Candidiasis, Chronic Mucocutaneous

KW - Child

KW - Child, Preschool

KW - Cohort Studies

KW - Female

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Heterozygote

KW - Humans

KW - Infant

KW - Male

KW - Middle Aged

KW - Mutation

KW - Phenotype

KW - STAT1 Transcription Factor

KW - Young Adult

KW - Journal Article

U2 - 10.1182/blood-2015-11-679902

DO - 10.1182/blood-2015-11-679902

M3 - Article

VL - 127

SP - 3154

EP - 3164

JO - Blood

JF - Blood

SN - 0006-4971

IS - 25

ER -