The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency.
Karin R Engelhardt
(1)
,
Michael E Gertz
(2)
,
Sevgi Keles
(3)
,
Alejandro A Schäffer
(2)
,
Elena C Sigmund
(4)
,
Cristina Glocker
(5)
,
Shiva Saghafi
(6)
,
Zahra Pourpak
(6)
,
Ruben Ceja
,
Atfa Sassi
(7)
,
Laura E Graham
(8)
,
Michel J Massaad
,
Fethi Mellouli
(9)
,
Imen Ben-Mustapha
(10)
,
Monia Khemiri
(11)
,
Sara Sebnem Kilic
,
Amos Etzioni
,
Alexandra F Freeman
(12)
,
Jens Thiel
(13)
,
Ilka Schulze
(13)
,
Waleed Al-Herz
(14)
,
Ayse Metin
(15)
,
Özden Sanal
,
Ilhan Tezcan
(16)
,
Mehdi Yeganeh
(17)
,
Tim Niehues
(18)
,
Gregor Dueckers
,
Sebastian Weinspach
(19)
,
Turkan Patiroglu
(20, 20)
,
Ekrem Unal
(20)
,
Majed Dasouki
,
Mustafa Yilmaz
(21)
,
Ferah Genel
(22)
,
Caner Aytekin
(23)
,
Necil Kutukculer
(24)
,
Ayper Somer
(25)
,
Mehmet Kilic
(26)
,
Ismail Reisli
(27)
,
Yildiz Camcioglu
(28)
,
Andre Gennery
(29)
,
Andre Cant
,
Alison Jones
(1)
,
Bobby H Gaspar
,
Peter D Arkwright
,
Maria C Pietrogrande
(30)
,
Zeina Baz
(31)
,
Salem Al-Tamemi
(32)
,
Vassilios Lougaris
,
Gerard Lefranc
(33, 34)
,
Andre Megarbane
(35)
,
Jeannette Boutros
,
Nermeen Galal
(36)
,
Mohamed Bejaoui
(37)
,
Mohamed-Ridha Barbouche
(38)
,
Raif S Geha
,
Talal A Chatila
(3)
,
Bodo Grimbacher
(13, 1)
1
UCL -
University College of London [London]
2 NCBI - National Center for Biotechnology Information
3 David Geffen School of Medicine [Los Angeles]
4 Uniklinik - Universitäts Klinikum Freiburg = University Medical Center Freiburg
5 Institute of Mechanical Systems, Department of Mechanical and Process Engineering
6 TUMS - Tehran University of Medical Sciences
7 LVGM - Laboratoire d'Immunopathologie, Vaccinologie et Génétique Moléculaire
8 Laboratory for the Study of Skeletal Disorders and Rehabilitation (Boston, USA)
9 Department of Peadiatric Immuno-Haematology
10 Laboratoire d'immunologie clinique [Institut Pasteur de Tunis]
11 Pediatrics Department A, Children's Hospital of Tunis, Tunis, Tunisia
12 NIAID-NIH - National Institute of Allergy and Infectious Diseases [Bethesda]
13 Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany
14 Kuwait University
15 the Pediatric Immunology Unit
16 Ankara University School of Medicine [Turkey]
17 Tehran University of Medical Sciences
18 Helios Klinikum Krefeld - Helios Klinikum Krefeld
19 Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf]
20 Erciyes University
21 Department of Oncology, Aalborg Hospital
22 Behcet Uz State Hospital Division of Pediatric Immunology, Izmir
23 Dis Training & Res Ctr
24 Department of Pediatrics
25 Istanbul University
26 DEÜ - Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir]
27 Necmettin Erbakan Univ
28 Cerrahpasa Medical School
29 Department of Pediatrics
30 the Department of Maternal and Pediatric Sciences
31 the Department of Pediatrics
32 the Department of Pediatrics
33 UM2 - Université Montpellier 2 - Sciences et Techniques
34 IGH - Institut de génétique humaine
35 IBCP - Institut de biologie et chimie des protéines [Lyon]
36 Primary Immunodeficiency Clinic
37 Pediatrics Department, Bone Marrow Transplantation Center, Tunis, Tunisia.
38 LR11IPT02 - Laboratoire de Transmission, Contrôle et Immunobiologie des Infections - Laboratory of Transmission, Control and Immunobiology of Infection
2 NCBI - National Center for Biotechnology Information
3 David Geffen School of Medicine [Los Angeles]
4 Uniklinik - Universitäts Klinikum Freiburg = University Medical Center Freiburg
5 Institute of Mechanical Systems, Department of Mechanical and Process Engineering
6 TUMS - Tehran University of Medical Sciences
7 LVGM - Laboratoire d'Immunopathologie, Vaccinologie et Génétique Moléculaire
8 Laboratory for the Study of Skeletal Disorders and Rehabilitation (Boston, USA)
9 Department of Peadiatric Immuno-Haematology
10 Laboratoire d'immunologie clinique [Institut Pasteur de Tunis]
11 Pediatrics Department A, Children's Hospital of Tunis, Tunis, Tunisia
12 NIAID-NIH - National Institute of Allergy and Infectious Diseases [Bethesda]
13 Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany
14 Kuwait University
15 the Pediatric Immunology Unit
16 Ankara University School of Medicine [Turkey]
17 Tehran University of Medical Sciences
18 Helios Klinikum Krefeld - Helios Klinikum Krefeld
19 Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf]
20 Erciyes University
21 Department of Oncology, Aalborg Hospital
22 Behcet Uz State Hospital Division of Pediatric Immunology, Izmir
23 Dis Training & Res Ctr
24 Department of Pediatrics
25 Istanbul University
26 DEÜ - Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir]
27 Necmettin Erbakan Univ
28 Cerrahpasa Medical School
29 Department of Pediatrics
30 the Department of Maternal and Pediatric Sciences
31 the Department of Pediatrics
32 the Department of Pediatrics
33 UM2 - Université Montpellier 2 - Sciences et Techniques
34 IGH - Institut de génétique humaine
35 IBCP - Institut de biologie et chimie des protéines [Lyon]
36 Primary Immunodeficiency Clinic
37 Pediatrics Department, Bone Marrow Transplantation Center, Tunis, Tunisia.
38 LR11IPT02 - Laboratoire de Transmission, Contrôle et Immunobiologie des Infections - Laboratory of Transmission, Control and Immunobiology of Infection
Sevgi Keles
- Fonction : Auteur
- PersonId : 779159
- ORCID : 0000-0001-7344-8947
Ruben Ceja
- Fonction : Auteur
Michel J Massaad
- Fonction : Auteur
Sara Sebnem Kilic
- Fonction : Auteur
Amos Etzioni
- Fonction : Auteur
Özden Sanal
- Fonction : Auteur
Gregor Dueckers
- Fonction : Auteur
Majed Dasouki
- Fonction : Auteur
Andre Cant
- Fonction : Auteur
Bobby H Gaspar
- Fonction : Auteur
Peter D Arkwright
- Fonction : Auteur
Vassilios Lougaris
- Fonction : Auteur
Jeannette Boutros
- Fonction : Auteur
Raif S Geha
- Fonction : Auteur
Résumé
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.
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.
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.
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.
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.