1. The Extended Clinical Phenotype Of 64 Patients With Dedicator Of Cytokinesis 8 Deficiency
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Tim Niehues, Karin R. Engelhardt, Mehmet Kilic, Raif S. Geha, Necil Kutukculer, Zeina Baz, Sevgi Keles, Cristina Glocker, Caner Aytekin, Ozden Sanal, Ismail Reisli, Zahra Pourpak, Ferah Genel, Mustafa Yilmaz, Alison Jones, B Gaspar, Elena C. Sigmund, Nermeen Galal, Yildiz Camcioglu, Michel J. Massaad, Amos Etzioni, Turkan Patiroglu, Laura E. Graham, Maria Cristina Pietrogrande, Majed Dasouki, Andrew R. Gennery, S Weinspach, G Dueckers, Michael E. Gertz, Monia Khemiri, M. R. Barbouche, Mehdi Yeganeh, Imen Ben-Mustapha, Shiva Saghafi, Bodo Grimbacher, Salem Al-Tamemi, Andrew J. Cant, A. Sassi, Gérard Lefranc, Ayse Metin, Vassilios Lougaris, Ayper Somer, Fethi Mellouli, Ekrem Unal, Alexandra F. Freeman, Jeannette Boutros, Ruben Ceja, Jens Thiel, André Mégarbané, Sara Sebnem Kilic, Talal A. Chatila, Mohamed Bejaoui, Alejandro A. Schäffer, Ilhan Tezcan, Waleed Al-Herz, Peter D. Arkwright, Ilka Schulze, Çocuk Sağlığı ve Hastalıkları, University College of London [London] (UCL), National Center for Biotechnology Information (NCBI), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, Freiburg University Medical Center, Institute of Mechanical Systems, Department of Mechanical and Process Engineering, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Tehran University of Medical Sciences (TUMS), Laboratoire d'Immunopathologie, Vaccinologie et Génétique Moléculaire (LVGM), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Laboratory for the Study of Skeletal Disorders and Rehabilitation (Boston, USA), Harvard Combined Orthopaedic Residency (USA), Department of Peadiatric Immuno-Haematology, National Bone Marrow Transplantation, Laboratoire d'immunologie clinique [Institut Pasteur de Tunis], Pediatrics Department A, Children's Hospital of Tunis, Tunis, Tunisia, National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, Kuwait University, the Pediatric Immunology Unit, SB Ankara Diskapi Children’s Hospital, Ankara University School of Medicine [Turkey], Tehran University of Medical Sciences, School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-Tehran University of Medical Sciences, Helios Klinikum Krefeld - Helios Klinikum Krefeld, Center of Child and Adolescent Medicine, Heinrich-Heine-University Dusseldorf, Department of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, Kayseri, Turkey, Department of Pediatrics, Division of Pediatric Immunology, Faculty of Medicine, Erciyes University, Kayseri, Turkey, Department of Oncology, Aalborg Hospital, Aarhus University [Aarhus], Behcet Uz State Hospital Division of Pediatric Immunology, Izmir, Dis Training & Res Ctr, Department of Pediatrics, Ege University, Istanbul University, Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), Necmettin Erbakan Univ, Cerrahpasa Medical School, Université d' Istanbul, Newcastle General Hospital, the Department of Maternal and Pediatric Sciences, University of Milan, Fondazione IRCCS Policlinico Milano, the Department of Pediatrics, St George Hospital University Medical Center, Beirut, Sultan Qaboos University (SQU), Université Montpellier 2 - Sciences et Techniques (UM2), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Primary Immunodeficiency Clinic, Cairo University Specialized Pediatric Hospital, Pediatrics Department, Bone Marrow Transplantation Center, Tunis, Tunisia., Laboratoire de Transmission, Contrôle et Immunobiologie des Infections - Laboratory of Transmission, Control and Immunobiology of Infection (LR11IPT02), and Çukurova Üniversitesi
- Subjects
CD4-Positive T-Lymphocytes ,Male ,Allergy ,Support Vector Machine ,[SDV]Life Sciences [q-bio] ,medicine.medical_treatment ,Hypereosinophilia ,Hematopoietic stem cell transplantation ,CD8-Positive T-Lymphocytes ,autosomal recessive hyper-IgE syndrome ,dedicator of cytokinesis 8 ,hyper-IgE syndrome ,Molluscum contagiosum ,Primary combined immunodeficiency ,signal transducer and activator of transcription 3 ,Adolescent ,Adult ,Antigens, Bacterial ,Antigens, Viral ,Bacterial Infections ,Child ,Child, Preschool ,Eosinophils ,Female ,Guanine Nucleotide Exchange Factors ,Humans ,Immunoglobulin E ,Immunoglobulin M ,Infant ,Job Syndrome ,Lymphocyte Count ,Middle Aged ,Mutation ,STAT3 Transcription Factor ,Skin Diseases ,Survival Analysis ,Virus Diseases ,Phenotype ,Immunology and Allergy ,Immunology ,0302 clinical medicine ,MESH: Child ,MESH: Guanine Nucleotide Exchange Factors ,Viral ,Immunodeficiency ,0303 health sciences ,MESH: Middle Aged ,Respiratory tract infections ,Progressive multifocal leukoencephalopathy ,MESH: Immunoglobulin E ,MESH: Support Vector Machine ,Bacterial ,MESH: STAT3 Transcription Factor ,MESH: CD4-Positive T-Lymphocytes ,MESH: Infant ,MESH: CD8-Positive T-Lymphocytes ,MESH: Immunoglobulin M ,3. Good health ,MESH: Virus Diseases ,MESH: Survival Analysis ,Dock8 ,medicine.symptom ,MESH: Antigens, Viral ,MESH: Lymphocyte Count ,MESH: Mutation ,MESH: Bacterial Infections ,MESH: Skin Diseases ,Biology ,MESH: Phenotype ,03 medical and health sciences ,MESH: Eosinophils ,medicine ,Antigens ,Preschool ,030304 developmental biology ,MESH: Adolescent ,MESH: Humans ,MESH: Job Syndrome ,MESH: Child, Preschool ,MESH: Adult ,medicine.disease ,MESH: Male ,DOCK8 Deficiency ,MESH: Female ,MESH: Antigens, Bacterial ,030215 immunology - Abstract
PubMedID: 25724123 Background Mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency (CID) also classified as autosomal recessive (AR) hyper-IgE syndrome (HIES). Recognizing patients with CID/HIES is of clinical importance because of the difference in prognosis and management. Objectives We sought to define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs, study the mutational spectrum of DOCK8 deficiency, and report on the frequency of specific clinical findings. Methods Eighty-two patients from 60 families with CID and the phenotype of AR-HIES with (64 patients) and without (18 patients) DOCK8 mutations were studied. Support vector machines were used to compare clinical data from 35 patients with DOCK8 deficiency with those from 10 patients with AR-HIES without a DOCK8 mutation and 64 patients with signal transducer and activator of transcription 3 (STAT3) mutations. Results DOCK8-deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/µL (92% of patients), and low IgM levels (62%). About 20% of patients were lymphopenic, mainly because of low CD4+ and CD8+ T-cell counts. Fewer than half of the patients tested produced normal specific antibody responses to recall antigens. Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed. Skin abscesses (60%) and allergies (73%) were common clinical problems. In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems. Mortality was high (34%). A combination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations. Conclusions DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures. © 2015 American Academy of Allergy, Asthma & Immunology. National Institutes of Health: R01AI065617 National Institutes of Health: R21AI087627
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- 2015