title: Inherited CARD9 deficiency in otherwise healthy children and adults with Candida species-induced meningoencephalitis, colitis, or both.
abstract: BACKGROUND
  Invasive infections of the central nervous system (CNS) or digestive tract caused by commensal fungi of the genus Candida are rare and life-threatening. The known risk factors include acquired and inherited immunodeficiencies, with patients often displaying a history of multiple infections. Cases of meningoencephalitis, colitis, or both caused by Candida species remain unexplained.
  
  
  OBJECTIVE
  We studied 5 previously healthy children and adults with unexplained invasive disease of the CNS, digestive tract, or both caused by Candida species. The patients were aged 39, 7, 17, 37, and 26 years at the time of infection and were unrelated, but each was born to consanguineous parents of Turkish (2 patients), Iranian, Moroccan, or Pakistani origin. Meningoencephalitis was reported in 3 patients, meningoencephalitis associated with colitis was reported in a fourth patient, and the fifth patient had colitis only.
  
  
  METHODS
  Inherited caspase recruitment domain family, member 9 (CARD9) deficiency was recently reported in otherwise healthy patients with other forms of severe disease caused by Candida, Trichophyton, Phialophora, and Exophiala species, including meningoencephalitis but not colitis caused by Candida and Exophiala species. Therefore we sequenced CARD9 in the 5 patients.
  
  
  RESULTS
  All patients were found to be homozygous for rare and deleterious mutant CARD9 alleles: R70W and Q289* for the 3 patients with Candida albicans-induced meningoencephalitis, R35Q for the patient with meningoencephalitis and colitis caused by Candida glabrata, and Q295* for the patient with Candida albicans-induced colitis. Regardless of their levels of mutant CARD9 protein, the patients' monocyte-derived dendritic cells responded poorly to CARD9-dependent fungal agonists (curdlan, heat-killed C albicans, Saccharomyces cerevisiae, and Exophiala dermatitidis).
  
  
  CONCLUSIONS
  Invasive infections of the CNS or digestive tract caused by Candida species in previously healthy children and even adults might be caused by inherited CARD9 deficiency.
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France; Necker Pasteur Infectious Diseases Center, Necker Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Imagine Institute, Paris, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Lanternier
authors.affiliation: Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Seyed Alireza
authors.initials: SA
authors.lastname: Mahdaviani
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France.
authors.forename: Elisa
authors.initials: E
authors.lastname: Barbati
authors.affiliation: Infectious Diseases Unit, Bretonneau Hospital, Tours, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Chaussade
authors.affiliation: Infectious Diseases Unit, Montpellier, France.
authors.forename: Yatrika
authors.initials: Y
authors.lastname: Koumar
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Levy
authors.affiliation: Paris Descartes University, Imagine Institute, Paris, France; Necker Pasteur Infectious Diseases Center, Necker Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Imagine Institute, Paris, France.
authors.forename: Blandine
authors.initials: B
authors.lastname: Denis
authors.affiliation: Infectious Diseases Unit, Montpellier, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Brunel
authors.affiliation: Pediatric Infectious Diseases Unit, Saint-Luc University Hospital, UCL, Brussels, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Martin
authors.affiliation: Pediatric-Neonatology Unit, Saint-Jean Hospital, Brussels, Belgium.
authors.forename: Michèle
authors.initials: M
authors.lastname: Loop
authors.affiliation: Pediatric Infectious Diseases Unit, Saint-Luc University Hospital, UCL, Brussels, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Peeters
authors.affiliation: Pediatric-Neonatology Unit, Saint-Jean Hospital, Brussels, Belgium.
authors.forename: Ariel
authors.initials: A
authors.lastname: de Selys
authors.affiliation: Pediatric-Neonatology Unit, Saint-Jean Hospital, Brussels, Belgium.
authors.forename: Jean
authors.initials: J
authors.lastname: Vanclaire
authors.affiliation: Pediatric Hematology-Oncology Unit, Saint-Luc University Hospital, UCL, Brussels, Belgium.
authors.forename: Christiane
authors.initials: C
authors.lastname: Vermylen
authors.affiliation: Pediatric Neurology Unit, Saint-Luc University Hospital, UCL, Brussels, Belgium.
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Nassogne
authors.affiliation: Pediatric Infectious Diseases Unit, Saint-Luc University Hospital, UCL, Brussels, Belgium.
authors.forename: Olga
authors.initials: O
authors.lastname: Chatzis
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France.
authors.forename: Luyan
authors.initials: L
authors.lastname: Liu
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Migaud
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Pedergnana
authors.affiliation: Parasitology-Mycology-Tropical Medicine Unit, Bretonneau Hospital, Center for the Study of Respiratory Diseases, INSERM U1100/Equipe 3 School of Medicine, Tours, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Desoubeaux
authors.affiliation: Human Histopathology and Animal Models, Infection and Epidemiology Department, Pasteur Institute, Paris, France.
authors.forename: Gregory
authors.initials: G
authors.lastname: Jouvion
authors.affiliation: Human Histopathology and Animal Models, Infection and Epidemiology Department, Pasteur Institute, Paris, France; Neuropathology Laboratory, Sainte-Anne Hospital, Paris, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Chretien
authors.affiliation: Department of Clinical Immunology and Allergy, National Research Institute of Tuberculosis and Lung Diseases, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Ilad Alavi
authors.initials: IA
authors.lastname: Darazam
authors.affiliation: National Center for Biotechnology Information, National Institutes of Health, Bethesda, Md.
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Immunology and Rheumatology Unit, Saint-Justine Hospital University Center, Montreal, Quebec, Canada.
authors.forename: Jean J
authors.initials: JJ
authors.lastname: De Bruycker
authors.affiliation: Infectious Diseases Unit, Bretonneau Hospital, Tours, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Bernard
authors.affiliation: Infectious Diseases Unit, Montpellier, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Reynes
authors.affiliation: Department of Neurosurgery, Tangier, Morocco.
authors.forename: Noureddine
authors.initials: N
authors.lastname: Amazrine
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.affiliation: Pediatric Infectious Diseases Unit, Saint-Luc University Hospital, UCL, Brussels, Belgium.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Van der Linden
authors.affiliation: Infection and Immunity Research Institute, Saint George's University of London, London, United Kingdom.
authors.forename: Tom
authors.initials: T
authors.lastname: Harrison
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France; Department of Neurosurgery, Tangier, Morocco; Study Center for Immunodeficiency, Necker Hospital, AP-HP, Paris, France; Pediatric Hematology-Immunology Unit, Necker Hospital, AP-HP, Paris, France.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Paris Descartes University, Imagine Institute, Paris, France; Necker Pasteur Infectious Diseases Center, Necker Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Imagine Institute, Paris, France; National Reference Center for Invasive Mycoses and Antifungals, Molecular Mycology Unit, Pasteur Institute, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lortholary
authors.affiliation: Department of Clinical Immunology and Allergy, National Research Institute of Tuberculosis and Lung Diseases, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Davood
authors.initials: D
authors.lastname: Mansouri
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY; Pediatric Hematology-Immunology Unit, Necker Hospital, AP-HP, Paris, France; Howard Hughes Medical Institute, New York, NY.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France. Electronic address: anne.puel@inserm.fr.
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
mesh_terms: D000293:Adolescent; D000328:Adult; D053468:CARD Signaling Adaptor Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D002175:Candida / Q000276:immunology; D058365:Candidiasis, Invasive / Q000235:genetics* / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D002490:Central Nervous System / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D002648:Child; D003092:Colitis / Q000235:genetics* / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D003241:Consanguinity; D005260:Female; D041981:Gastrointestinal Tract / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D015870:Gene Expression; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D008297:Male; D008590:Meningoencephalitis / Q000235:genetics* / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D010375:Pedigree; D017422:Sequence Analysis, DNA
chemical_list: D053468:CARD Signaling Adaptor Proteins; C505855:CARD9 protein, human
keywords: Candida species; Inborn error of immunity; central nervous system; colitis; human; inherited CARD9 deficiency; invasive fungal diseases; primary immunodeficiency