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


OBJECTIVE
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.
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.
Karin R
KR
Engelhardt
National Center for Biotechnology Information, National Institutes of Health, Department of Health and Human Services, Bethesda, Md.
Michael E
ME
Gertz
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.
Sevgi
S
Keles
National Center for Biotechnology Information, National Institutes of Health, Department of Health and Human Services, Bethesda, Md.
Alejandro A
AA
Schäffer
Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany.
Elena C
EC
Sigmund
Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany.
Cristina
C
Glocker
Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
Shiva
S
Saghafi
Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
Zahra
Z
Pourpak
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.
Ruben
R
Ceja
Laboratory of Immunology, Vaccinology, and Molecular Genetics, Pasteur Institute of Tunis and University of Tunis el Manar, Tunis, Tunisia.
Atfa
A
Sassi
Department of Immunology and Molecular Pathology, Royal Free Hospital and University College London, London, United Kingdom.
Laura E
LE
Graham
Division of Immunology, Children's Hospital, Boston, Mass.
Michel J
MJ
Massaad
Department of Pediatrics, Bone Marrow Transplantation Center, Tunis, Tunisia.
Fethi
F
Mellouli
Laboratory of Immunology, Vaccinology, and Molecular Genetics, Pasteur Institute of Tunis and University of Tunis el Manar, Tunis, Tunisia.
Imen
I
Ben-Mustapha
Department of Pediatrics, Children's Hospital, Tunis, Tunisia.
Monia
M
Khemiri
Department of Pediatric Immunology, Faculty of Medicine, Uludag University, Bursa, Turkey.
Sara Sebnem
SS
Kilic
Meyer's Children Hospital, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Amos
A
Etzioni
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Md.
Alexandra F
AF
Freeman
Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany.
Jens
J
Thiel
Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany.
Ilka
I
Schulze
Department of Pediatrics, Faculty of Medicine, Kuwait University and Allergy and Clinical Immunology Unit, Department of Pediatrics, Al-Sabah Hospital, Kuwait City, Kuwait.
Waleed
W
Al-Herz
Pediatric Immunology Unit, SB Ankara Diskapi Children's Hospital, Ankara, Turkey.
Ayse
A
Metin
Immunology Division, Hacettepe University, Children's Hospital, Ankara, Turkey.
Özden
Ö
Sanal
Immunology Division, Hacettepe University, Children's Hospital, Ankara, Turkey.
Ilhan
I
Tezcan
Immunology Asthma and Allergy Research Institute, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
Mehdi
M
Yeganeh
HELIOS Klinikum Krefeld, Zentrum für Kinder- und Jugendmedizin, Krefeld, Germany.
Tim
T
Niehues
HELIOS Klinikum Krefeld, Zentrum für Kinder- und Jugendmedizin, Krefeld, Germany.
Gregor
G
Dueckers
Department of Pediatric Oncology, Hematology and Clinical Immunology, Center of Child and Adolescent Medicine, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
Sebastian
S
Weinspach
Department of Pediatrics, Division of Pediatric Hematology and Immunology, Erciyes University, Faculty of Medicine, Kayseri, Turkey.
Turkan
T
Patiroglu
Department of Pediatrics, Division of Pediatric Hematology and Oncology, Erciyes University, Faculty of Medicine, Kayseri, Turkey.
Ekrem
E
Unal
Department of Pediatrics, University of Kansas Medical Center, Kansas City, Mo.
Majed
M
Dasouki
Cukurova University, Adana, Turkey.
Mustafa
M
Yilmaz
Division of Pediatric Immunology, Behcet Uz State Hospital, Izmir, Turkey.
Ferah
F
Genel
Department of Pediatric Immunology, Dr Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.
Caner
C
Aytekin
Department of Pediatrics, Ege University Faculty of Medicine, Izmir, Turkey.
Necil
N
Kutukculer
Division of Infectious Diseases and Immunology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
Ayper
A
Somer
Firat University, Elazig, Turkey.
Mehmet
M
Kilic
Division of Pediatric Allergy and Immunology, Konya Necmettin Erbakan University, Konya, Turkey.
Ismail
I
Reisli
Division of Pediatric Allergy-Immunology and Infectious Diseases, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.
Yildiz
Y
Camcioglu
Institute of Cellular Medicine, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom.
Andrew R
AR
Gennery
Institute of Cellular Medicine, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom.
Andrew J
AJ
Cant
Department of Immunology, Great Ormond Street Hospital, London, United Kingdom.
Alison
A
Jones
Department of Immunology, Great Ormond Street Hospital, London, United Kingdom.
Bobby H
BH
Gaspar
University of Manchester, Royal Manchester Children's Hospital, Manchester, United Kingdom.
Peter D
PD
Arkwright
Department of Pediatrics, University of Milan, Fondazione Policlinico IRCCS, Milan, Italy.
Maria C
MC
Pietrogrande
Department of Pediatrics, St George Hospital University Medical Center, Beirut, Lebanon.
Zeina
Z
Baz
Department of Pediatrics, Sultan Qaboos University, Muscat, Oman.
Salem
S
Al-Tamemi
Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Brescia, Italy.
Vassilios
V
Lougaris
University Montpellier 2 and CNRS Institute of Human Genetics, Montpellier, France.
Gerard
G
Lefranc
Medical Genetics Unit, Saint Joseph University, Beirut, Lebanon.
Andre
A
Megarbane
Cairo University, Specialized Pediatric Hospital, Primary Immunodeficiency Clinic, Cairo, Egypt.
Jeannette
J
Boutros
Cairo University, Specialized Pediatric Hospital, Primary Immunodeficiency Clinic, Cairo, Egypt.
Nermeen
N
Galal
Department of Pediatrics, Bone Marrow Transplantation Center, Tunis, Tunisia.
Mohamed
M
Bejaoui
Laboratory of Immunology, Vaccinology, and Molecular Genetics, Pasteur Institute of Tunis and University of Tunis el Manar, Tunis, Tunisia.
Mohamed-Ridha
MR
Barbouche
Division of Immunology, Children's Hospital, Boston, Mass.
Raif S
RS
Geha
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.
Talal A
TA
Chatila
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.
Bodo
B
Grimbacher
D000293:Adolescent; D000328:Adult; D000942:Antigens, Bacterial / Q000097:blood / Q000276:immunology; D000956:Antigens, Viral / Q000097:blood / Q000276:immunology; D001424:Bacterial Infections / Q000150:complications* / Q000235:genetics / Q000276:immunology / Q000401:mortality; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004804:Eosinophils / Q000276:immunology / Q000473:pathology; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood / Q000235:genetics; D007075:Immunoglobulin M / Q000097:blood / Q000235:genetics; D007223:Infant; D007589:Job Syndrome / Q000150:complications* / Q000235:genetics / Q000276:immunology / Q000401:mortality; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D012871:Skin Diseases / Q000150:complications* / Q000235:genetics / Q000276:immunology / Q000401:mortality; D060388:Support Vector Machine; D016019:Survival Analysis; D014777:Virus Diseases / Q000150:complications* / Q000235:genetics / Q000276:immunology / Q000401:mortality
D000942:Antigens, Bacterial; D000956:Antigens, Viral; C516591:DOCK8 protein, human; D020662:Guanine Nucleotide Exchange Factors; D007075:Immunoglobulin M; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D007073:Immunoglobulin E
Molluscum contagiosum; Primary combined immunodeficiency; autosomal recessive hyper-IgE syndrome; dedicator of cytokinesis 8; hyper-IgE syndrome; signal transducer and activator of transcription 3