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The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency

Engelhardt KR 1 , Gertz ME 2 , Keles S 3 , Schäffer AA 2 , Sigmund EC 4 , Glocker C 4 Show all authors , Saghafi S 5 , Pourpak Z 5 , Ceja R 6 , Sassi A 7 , Graham LE 8 , Massaad MJ 9 , Mellouli F 10 , Ben-Mustapha I 7 , Khemiri M 11 , Kilic SS 12 , Etzioni A 13 , Freeman AF 14 , Thiel J 4 , Schulze I 4 , Al-Herz W 15 , Metin A 16 , Sanal Ö 17 , Tezcan I 17 , Yeganeh M 18 , Niehues T 19 , Dueckers G 19 , Weinspach S 20 , Patiroglu T 21 , Unal E 22 , Dasouki M 23 , Yilmaz M 24 , Genel F 25 , Aytekin C 26 , Kutukculer N 27 , Somer A 28 , Kilic M 29 , Reisli I 30 , Camcioglu Y 31 , Gennery AR 32 , Cant AJ 32 , Jones A 33 , Gaspar BH 33 , Arkwright PD 34 , Pietrogrande MC 35 , Baz Z 36 , Al-Tamemi S 37 , Lougaris V 38 , Lefranc G 39 , Megarbane A 40 , Boutros J 41 , Galal N 41 , Bejaoui M 10 , Barbouche MR 7 , Geha RS 9 , Chatila TA 6 , Grimbacher B 42

Affiliations 

  • 1 Department of Immunology and Molecular Pathology, Royal Free Hospital and University College London, London, United Kingdom; Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany; Institute of Cellular Medicine, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
  • 2 National Center for Biotechnology Information, National Institutes of Health, Department of Health and Human Services, Bethesda, Md
  • 3 Division of Immunology, Allergy and Rheumatology, Department of Pediatrics, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, Calif; Division of Pediatric Allergy and Immunology, Konya Necmettin Erbakan University, Konya, Turkey; Division of Immunology, Children's Hospital, Boston, Mass
  • 4 Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany
  • 5 Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
  • 6 Division of Immunology, Allergy and Rheumatology, Department of Pediatrics, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, Calif; Division of Immunology, Children's Hospital, Boston, Mass
  • 7 Laboratory of Immunology, Vaccinology, and Molecular Genetics, Pasteur Institute of Tunis and University of Tunis el Manar, Tunis, Tunisia
  • 8 Department of Immunology and Molecular Pathology, Royal Free Hospital and University College London, London, United Kingdom
  • 9 Division of Immunology, Children's Hospital, Boston, Mass
  • 10 Department of Pediatrics, Bone Marrow Transplantation Center, Tunis, Tunisia
  • 11 Department of Pediatrics, Children's Hospital, Tunis, Tunisia
  • 12 Department of Pediatric Immunology, Faculty of Medicine, Uludag University, Bursa, Turkey
  • 13 Meyer's Children Hospital, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
  • 14 Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Md
  • 15 Department of Pediatrics, Faculty of Medicine, Kuwait University and Allergy and Clinical Immunology Unit, Department of Pediatrics, Al-Sabah Hospital, Kuwait City, Kuwait
  • 16 Pediatric Immunology Unit, SB Ankara Diskapi Children's Hospital, Ankara, Turkey
  • 17 Immunology Division, Hacettepe University, Children's Hospital, Ankara, Turkey
  • 18 Immunology Asthma and Allergy Research Institute, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
  • 19 HELIOS Klinikum Krefeld, Zentrum für Kinder- und Jugendmedizin, Krefeld, Germany
  • 20 Department of Pediatric Oncology, Hematology and Clinical Immunology, Center of Child and Adolescent Medicine, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
  • 21 Department of Pediatrics, Division of Pediatric Hematology and Immunology, Erciyes University, Faculty of Medicine, Kayseri, Turkey
  • 22 Department of Pediatrics, Division of Pediatric Hematology and Oncology, Erciyes University, Faculty of Medicine, Kayseri, Turkey
  • 23 Department of Pediatrics, University of Kansas Medical Center, Kansas City, Mo
  • 24 Cukurova University, Adana, Turkey
  • 25 Division of Pediatric Immunology, Behcet Uz State Hospital, Izmir, Turkey
  • 26 Department of Pediatric Immunology, Dr Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey
  • 27 Department of Pediatrics, Ege University Faculty of Medicine, Izmir, Turkey
  • 28 Division of Infectious Diseases and Immunology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
  • 29 Firat University, Elazig, Turkey
  • 30 Division of Pediatric Allergy and Immunology, Konya Necmettin Erbakan University, Konya, Turkey
  • 31 Division of Pediatric Allergy-Immunology and Infectious Diseases, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
  • 32 Institute of Cellular Medicine, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
  • 33 Department of Immunology, Great Ormond Street Hospital, London, United Kingdom
  • 34 University of Manchester, Royal Manchester Children's Hospital, Manchester, United Kingdom
  • 35 Department of Pediatrics, University of Milan, Fondazione Policlinico IRCCS, Milan, Italy
  • 36 Department of Pediatrics, St George Hospital University Medical Center, Beirut, Lebanon
  • 37 Department of Pediatrics, Sultan Qaboos University, Muscat, Oman
  • 38 Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Brescia, Italy
  • 39 University Montpellier 2 and CNRS Institute of Human Genetics, Montpellier, France
  • 40 Medical Genetics Unit, Saint Joseph University, Beirut, Lebanon
  • 41 Cairo University, Specialized Pediatric Hospital, Primary Immunodeficiency Clinic, Cairo, Egypt
  • 42 Department of Immunology and Molecular Pathology, Royal Free Hospital and University College London, London, United Kingdom; Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany. Electronic address: bodo.grimbacher@uniklinik-freiburg.de
J Allergy Clin Immunol, 2015 Aug;136(2):402-12.
PMID: 25724123 DOI: 10.1016/j.jaci.2014.12.1945

Abstract

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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