title: Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency.
abstract: Chronic mucocutaneous candidiasis (CMC) is defined as recurrent or persistent infection of the skin, nails, and/or mucosae with commensal Candida species. The first genetic etiology of isolated CMC-autosomal recessive (AR) IL-17 receptor A (IL-17RA) deficiency-was reported in 2011, in a single patient. We report here 21 patients with complete AR IL-17RA deficiency, including this first patient. Each patient is homozygous for 1 of 12 different IL-17RA alleles, 8 of which create a premature stop codon upstream from the transmembrane domain and have been predicted and/or shown to prevent expression of the receptor on the surface of circulating leukocytes and dermal fibroblasts. Three other mutant alleles create a premature stop codon downstream from the transmembrane domain, one of which encodes a surface-expressed receptor. Finally, the only known missense allele (p.D387N) also encodes a surface-expressed receptor. All of the alleles tested abolish cellular responses to IL-17A and -17F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes. The patients are currently aged from 2 to 35 y and originate from 12 unrelated kindreds. All had their first CMC episode by 6 mo of age. Fourteen patients presented various forms of staphylococcal skin disease. Eight were also prone to various bacterial infections of the respiratory tract. Human IL-17RA is, thus, essential for mucocutaneous immunity to Candida and Staphylococcus, but otherwise largely redundant. A diagnosis of AR IL-17RA deficiency should be considered in children or adults with CMC, cutaneous staphylococcal disease, or both, even if IL-17RA is detected on the cell surface.
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, 75015 Paris, France.|Imagine Institute, Paris Descartes University, 75015 Paris, France.|St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors.forename: Romain
authors.initials: R
authors.lastname: Lévy
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.|Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, 734-8551, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okada
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, 75015 Paris, France.|Imagine Institute, Paris Descartes University, 75015 Paris, France.
authors.forename: Vivien
authors.initials: V
authors.lastname: Béziat
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, 75015 Paris, France.|Imagine Institute, Paris Descartes University, 75015 Paris, France.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Moriya
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195.
authors.forename: Caini
authors.initials: C
authors.lastname: Liu
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, 75015 Paris, France.|Imagine Institute, Paris Descartes University, 75015 Paris, France.
authors.forename: Louis Yi Ann
authors.initials: LY
authors.lastname: Chai
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, 75015 Paris, France.|Imagine Institute, Paris Descartes University, 75015 Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Migaud
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Hauck
authors.affiliation: Institute for Research and Medical Consultation, University of Dammam, Dammam 31441, Saudi Arabia.
authors.forename: Amein
authors.initials: A
authors.lastname: Al Ali
authors.affiliation: Institute for Research and Medical Consultation, University of Dammam, Dammam 31441, Saudi Arabia.
authors.forename: Cyril
authors.initials: C
authors.lastname: Cyrus
authors.affiliation: Institute for Research and Medical Consultation, University of Dammam, Dammam 31441, Saudi Arabia.
authors.forename: Chittibabu
authors.initials: C
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authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, 38030 Kayseri, Turkey.
authors.forename: Turkan
authors.initials: T
authors.lastname: Patiroglu
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, 38030 Kayseri, Turkey.
authors.forename: Ekrem
authors.initials: E
authors.lastname: Unal
authors.affiliation: Department of Dermatology, Necker Hospital for Sick Children, 75015 Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Ferneiny
authors.affiliation: Center of Bone Marrow Transplantation, Faculty of Medicine, University of the Ryukyus, Okinawa 903-0213, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Hyakuna
authors.affiliation: Division of Infectious Diseases, Clinical Immunology and Allergy, Department of Pediatrics, Cerrahpasa Medical Faculty, Istanbul University, 34452 Istanbul, Turkey.
authors.forename: Serdar
authors.initials: S
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authors.affiliation: Department of Immunology and Rheumatology, Juan P. Garrahan National Pediatric Hospital, C1245AAM Buenos Aires, Argentina.
authors.forename: Matias
authors.initials: M
authors.lastname: Oleastro
authors.affiliation: Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, 06100 Ankara, Turkey.
authors.forename: Aydan
authors.initials: A
authors.lastname: Ikinciogullari
authors.affiliation: Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, 06100 Ankara, Turkey.
authors.forename: Figen
authors.initials: F
authors.lastname: Dogu
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, 734-8551, Japan.
authors.forename: Takaki
authors.initials: T
authors.lastname: Asano
authors.affiliation: Department of Technology Development, Kazusa DNA Research Institute, Chiba 292-0818, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, 75015 Paris, France.|Imagine Institute, Paris Descartes University, 75015 Paris, France.
authors.forename: Ling
authors.initials: L
authors.lastname: Yun
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, 75015 Paris, France.|Imagine Institute, Paris Descartes University, 75015 Paris, France.
authors.forename: Erika
authors.initials: E
authors.lastname: Della Mina
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, 75015 Paris, France.|Imagine Institute, Paris Descartes University, 75015 Paris, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Bronnimann
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Itan
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Gothe
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, 75015 Paris, France.|Imagine Institute, Paris Descartes University, 75015 Paris, France.|St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.|Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, 75015 Paris, France.
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, 75015 Paris, France.|Imagine Institute, Paris Descartes University, 75015 Paris, France.|St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Boisson-Dupuis
authors.affiliation: Department of Immunology, Hospital Del Niño Jesus, 4000 San Miguel de Tucumán, Tucumán, Argentina.
authors.forename: Natalia
authors.initials: N
authors.lastname: Tahuil
authors.affiliation: Department of Pediatric Immunology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, 06080 Ankara, Turkey.
authors.forename: Caner
authors.initials: C
authors.lastname: Aytekin
authors.affiliation: Department of Dermatology, Algiers Faculty of Medicine, University of Algiers, Algiers 16030, Algeria.
authors.forename: Aicha
authors.initials: A
authors.lastname: Salhi
authors.affiliation: Prince Naif Center for Immunology Research, King Saud University, Riyadh 12372, Saudi Arabia.
authors.forename: Saleh
authors.initials: S
authors.lastname: Al Muhsen
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, 734-8551, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Department of General Pediatrics and Pediatric Infectious Diseases, Assistance Publique-Hôpitaux de Paris, Necker Hospital for Sick Children, 75015 Paris, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Toubiana
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, 75015 Paris, France.|Imagine Institute, Paris Descartes University, 75015 Paris, France.|St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.affiliation: Division of Infectious Diseases, Clinical Immunology and Allergy, Department of Pediatrics, Cerrahpasa Medical Faculty, Istanbul University, 34452 Istanbul, Turkey.
authors.forename: Yildiz
authors.initials: Y
authors.lastname: Camcioglu
authors.affiliation: Department of Pediatric Immunology and Allergy, Antalya Education and Research Hospital, 07070 Antalya, Turkey.
authors.forename: Fatih
authors.initials: F
authors.lastname: Celmeli
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
authors.affiliation: Department of Pediatrics, College of Medicine, King Fahad Hospital of the University, University of Dammam, Al-Khobar 31952, Saudi Arabia.
authors.forename: Suzan A
authors.initials: SA
authors.lastname: AlKhater
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, 75015 Paris, France; casanova@rockefeller.edu anne.puel@inserm.fr.|Imagine Institute, Paris Descartes University, 75015 Paris, France.|St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.|Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France.|Howard Hughes Medical Institute, New York, NY 10065.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, 75015 Paris, France; casanova@rockefeller.edu anne.puel@inserm.fr.|Imagine Institute, Paris Descartes University, 75015 Paris, France.|St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
mesh_terms: D000483:Alleles; D001424:Bacterial Infections / Q000276:immunology*; D002175:Candida; D002177:Candidiasis / Q000276:immunology*; D002462:Cell Membrane; D002648:Child; D002675:Child, Preschool; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005808:Genes, Recessive; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D007231:Infant, Newborn; D020381:Interleukin-17 / Q000378:metabolism; D008297:Male; D009154:Mutation; D009181:Mycoses / Q000276:immunology*; D016366:Open Reading Frames; D010375:Pedigree; D053722:Receptors, Interleukin-17 / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000382:microbiology; D013601:T-Lymphocytes / Q000166:cytology
chemical_list: C508717:IL17A protein, human; C440021:IL17F protein, human; C109985:IL17RA protein, human; C486701:IL25 protein, human; D020381:Interleukin-17; D053722:Receptors, Interleukin-17
keywords: candidiasis; genetics; immunodeficiency