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Journal of Clinical Immunology

, Volume 35, Issue 2, pp 189–198 | Cite as

DOCK8 Deficiency: Clinical and Immunological Phenotype and Treatment Options - a Review of 136 Patients

  • Susanne E. Aydin
  • Sara Sebnem Kilic
  • Caner Aytekin
  • Ashish Kumar
  • Oscar Porras
  • Leena Kainulainen
  • Larysa Kostyuchenko
  • Ferah Genel
  • Necil Kütükcüler
  • Neslihan Karaca
  • Luis Gonzalez-Granado
  • Jordan Abbott
  • Daifulah Al-Zahrani
  • Nima Rezaei
  • Zeina Baz
  • Jens Thiel
  • Stephan Ehl
  • László Marodi
  • Jordan S. Orange
  • Julie Sawalle-Belohradsky
  • Sevgi Keles
  • Steven M. Holland
  • Özden Sanal
  • Deniz C. Ayvaz
  • Ilhan Tezcan
  • Hamoud Al-Mousa
  • Zobaida Alsum
  • Abbas Hawwari
  • Ayse Metin
  • Susanne Matthes-Martin
  • Manfred Hönig
  • Ansgar Schulz
  • Capucine Picard
  • Vincent Barlogis
  • Andrew Gennery
  • Marianne Ifversen
  • Joris van Montfrans
  • Taco Kuijpers
  • Robbert Bredius
  • Gregor Dückers
  • Waleed Al-Herz
  • Sung-Yun Pai
  • Raif Geha
  • Gundula Notheis
  • Carl-Philipp Schwarze
  • Betül Tavil
  • Fatih Azik
  • Kirsten Bienemann
  • Bodo Grimbacher
  • Valerie Heinz
  • H. Bobby Gaspar
  • Roland Aydin
  • Beate Hagl
  • Benjamin Gathmann
  • Bernd H. Belohradsky
  • Hans D. Ochs
  • Talal Chatila
  • Ellen D. Renner
  • Helen Su
  • Alexandra F. Freeman
  • Karin Engelhardt
  • Michael H. Albert
  • On behalf of the inborn errors working party of EBMT
Original Research

Abstract

Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3–47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.

Keywords

DOCK8 deficiency combined immunodeficiency hyper-IgE syndrome natural outcome 

Abbreviations

DOCK8

Dedicator of cytokinesis 8

CID

Combined immunodeficiency

HIES

Hyper-IgE syndrome

HSCT

Hematopoietic stem cell transplantation

STAT3

Signal transducer and activator of transcription 3

Ig replacement

Immunoglobulin replacement

Notes

Acknowledgments

This work was supported in part by the Division of Intramural Research, NIAID, NIH (SH, HS, AF).

Conflict of Interest

The authors declare that they have no conflicts of interest.

Supplementary material

10875_2014_126_MOESM1_ESM.docx (67 kb)
ESM 1 (DOCX 66 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Susanne E. Aydin
    • 1
  • Sara Sebnem Kilic
    • 2
  • Caner Aytekin
    • 3
  • Ashish Kumar
    • 4
  • Oscar Porras
    • 5
  • Leena Kainulainen
    • 6
  • Larysa Kostyuchenko
    • 7
  • Ferah Genel
    • 8
  • Necil Kütükcüler
    • 9
  • Neslihan Karaca
    • 9
  • Luis Gonzalez-Granado
    • 10
  • Jordan Abbott
    • 11
  • Daifulah Al-Zahrani
    • 12
  • Nima Rezaei
    • 13
    • 14
  • Zeina Baz
    • 15
  • Jens Thiel
    • 16
    • 17
  • Stephan Ehl
    • 17
  • László Marodi
    • 18
  • Jordan S. Orange
    • 19
  • Julie Sawalle-Belohradsky
    • 1
  • Sevgi Keles
    • 20
  • Steven M. Holland
    • 21
  • Özden Sanal
    • 22
  • Deniz C. Ayvaz
    • 22
  • Ilhan Tezcan
    • 22
  • Hamoud Al-Mousa
    • 23
  • Zobaida Alsum
    • 24
  • Abbas Hawwari
    • 24
  • Ayse Metin
    • 25
  • Susanne Matthes-Martin
    • 26
  • Manfred Hönig
    • 27
  • Ansgar Schulz
    • 27
  • Capucine Picard
    • 28
    • 29
    • 30
  • Vincent Barlogis
    • 31
  • Andrew Gennery
    • 32
  • Marianne Ifversen
    • 33
  • Joris van Montfrans
    • 34
  • Taco Kuijpers
    • 35
  • Robbert Bredius
    • 36
  • Gregor Dückers
    • 37
  • Waleed Al-Herz
    • 38
    • 39
  • Sung-Yun Pai
    • 40
    • 41
  • Raif Geha
    • 42
  • Gundula Notheis
    • 1
  • Carl-Philipp Schwarze
    • 43
  • Betül Tavil
    • 44
  • Fatih Azik
    • 44
  • Kirsten Bienemann
    • 45
  • Bodo Grimbacher
    • 16
    • 17
  • Valerie Heinz
    • 1
  • H. Bobby Gaspar
    • 46
  • Roland Aydin
    • 1
  • Beate Hagl
    • 1
  • Benjamin Gathmann
    • 17
  • Bernd H. Belohradsky
    • 1
  • Hans D. Ochs
    • 47
  • Talal Chatila
    • 42
  • Ellen D. Renner
    • 1
  • Helen Su
    • 16
  • Alexandra F. Freeman
    • 16
  • Karin Engelhardt
    • 16
    • 17
  • Michael H. Albert
    • 1
    • 48
  • On behalf of the inborn errors working party of EBMT
  1. 1.Dr. von Haunersches Children’s HospitalLudwig-Maximilians-UniversityMunichGermany
  2. 2.Department of Pediatric Immunology, Faculty of MedicineUludag UniversityBursaTurkey
  3. 3.Department of Pediatric ImmunologyDr. Sami Ulus Maternity and Children’s Health and Diseases Training and Research HospitalAnkaraTurkey
  4. 4.BMT/Immune DeficiencyCincinnati Children’s HospitalCincinattiUSA
  5. 5.Hospital Nacional De Ninos Dr. Carlos Saenz Herrera Servicio de Immunologia y Reumatologia PediatricaSan JoseCosta Rica
  6. 6.Department of PediatricsTurku University HospitalTurkuFinland
  7. 7.Pediatric ImmunologyWestern Ukrainian Specialized Children’s Medical CentreLvivUkraine
  8. 8.Division of Pediatric ImmunologyBehcet Uz State HospitalIzmirTurkey
  9. 9.Department of PediatricsEge University Faculty of MedicineIzmirTurkey
  10. 10.Pedriatrics, Immunodeficiencies UnitHospital 12 OctubreMadridSpain
  11. 11.Fellow, Allergy and Immunology Department of Pediatrics National Jewish HealthUniversity of ColoradoDenverUSA
  12. 12.Pediatric allergy and immunology, King Saud Bin Abdulaziz University for Health Sciences and Department of Pediatrics, National Guard HospitalKing Abdulaziz Medical City–WRJeddahSaudi Arabia
  13. 13.Research Center for ImmunodeficienciesChildren’s Medical CenterTehranIran
  14. 14.Department of Immunology, School of MedicineTehran University of Medical SciencesTehranIran
  15. 15.Department of PediatricsSt George Hospital University Medical CenterBeirutLebanon
  16. 16.Department of Rheumatology and Clinical ImmunologyUniversity Hospital FreiburgFreiburgGermany
  17. 17.Center for Chronic Immunodeficiency (CCI)University Medical Centre Freiburg and University of FreiburgFreiburgGermany
  18. 18.Faculty of Medicine Department of Infectious Diseases and Pediatric ImmunologyUniversity of DebrecenDebrecenHungary
  19. 19.Texas Children’s Hospital Center for Human ImmunobiologyHoustonUSA
  20. 20.Division of Pediatric Allergy and ImmunologyKonya Necmettin Erbakan UniversityKonyaTurkey
  21. 21.Laboratory of Clinical Infectious DiseasesNIAID, National Institutes of HealthBethesdaUSA
  22. 22.Immunology Division, Children’s HospitalHacettepe UniversityAnkaraTurkey
  23. 23.Pediatric Allergy & Immunology, Department of PediatricsKing Faisal Specialist Hospital & Research Center RiyadhRiyadhSaudi Arabia
  24. 24.Department of Genetics, Research Center, MBC 03King Faisal Specialist Hospital and Research CenterRiyadhSaudi Arabia
  25. 25.Pediatric Immunology UnitSB Ankara Diskapi Children’s HospitalAnkaraTurkey
  26. 26.St. Anna Children’s HospitalViennaAustria
  27. 27.Department of Pediatric Hematology/OncologyUniversity Childrens HospitalUlmGermany
  28. 28.Study Center for Primary Immunodeficiencies, Necker-Enfant Malades HospitalAssistance Publique - Hôpitaux de Paris (AP-HP)ParisFrance
  29. 29.Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Imagine Institut, Sorbonne Paris CitéParis Descartes UniversityParisFrance
  30. 30.Pediatric Hematology-Immunology UnitNecker Enfant Malades Hospital, AP-HPParisFrance
  31. 31.Department of Paediatric Haematology-Oncology, APHM, La Timone HospitalAix-Marseille UniversityMarseilleFrance
  32. 32.Institute of Cellular MedicineUniversity of Newcastle upon TyneNewcastle upon TyneUK
  33. 33.RigshospitaletCopenhagenDenmark
  34. 34.University Medical CenterUtrechtThe Netherlands
  35. 35.Division of Pediatric Hematology, Immunology & Infectious DiseasesHead Emma Children’s Hospital Academic Medical Center (AMC)AmsterdamThe Netherlands
  36. 36.Pediatric SCT Unit and Laboratory for Immunology, Department of PediatricsLUMCLeidenThe Netherlands
  37. 37.HELIOS Children’s Hospital KrefeldKrefeldGermany
  38. 38.Department of Pediatrics, Faculty of MedicineKuwait University and Allergy and Clinical Immunology UnitKuwait CityKuwait
  39. 39.Department of PediatricsAl-Sabah HospitalKuwait CityKuwait
  40. 40.Division of Hematology-OncologyBoston Children’s HospitalBostonUSA
  41. 41.Department of Pediatric Hematology-OncologyDana-Farber Cancer InstituteBostonUSA
  42. 42.Division of ImmunologyBoston Children’s HospitalBostonUSA
  43. 43.Department of Pediatric Hematology/OncologyUniversity Childrens HospitalTuebingenGermany
  44. 44.Department of Pediatric HematologyAnkara Children’s Hematology Oncology HospitalAnkaraTurkey
  45. 45.Department of Pediatric Hematology/OncologyUniversity Childrens HospitalDuesseldorfGermany
  46. 46.Infection, Immunity, Inflammation and Physiological Medicine, Molecular and Cellular Section, Institute of Child HealthUniversity College LondonLondonUK
  47. 47.Center for Immunity and Immunotherapies Seattle Children’s Research InstituteUniversity of WashingtonSeattleUSA
  48. 48.Hauner University Childrens HospitalMunichGermany

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