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

Karin R. Engelhardt, Michael E. Gertz, Sevgi Keles, Alejandro A. Schäffer, Elena C. Sigmund, Cristina Glocker, Shiva Saghafi, Zahra Pourpak, Ruben Ceja, Atfa Sassi, Laura E. Graham, Michel J. Massaad, Fethi Mellouli, Imen Ben-Mustapha, Monia Khemiri, Sara Sebnem Kilic, Amos Etzioni, Alexandra F. Freeman, Jens Thiel, Ilka SchulzeWaleed Al-Herz, Ayse Metin, Özden Sanal, Ilhan Tezcan, Mehdi Yeganeh, Tim Niehues, Gregor Dueckers, Sebastian Weinspach, Turkan Patiroglu, Ekrem Unal, Majed Dasouki, Mustafa Yilmaz, Ferah Genel, Caner Aytekin, Necil Kutukculer, Ayper Somer, Mehmet Kilic, Ismail Reisli, Yildiz Camcioglu, Andrew R. Gennery, Andrew J. Cant, Alison Jones, Bobby H. Gaspar, Peter D. Arkwright, Maria C. Pietrogrande, Zeina Baz, Salem Al-Tamemi, Vassilios Lougaris, Gerard Lefranc, Andre Megarbane, Jeannette Boutros, Nermeen Galal, Mohamed Bejaoui, Mohamed Ridha Barbouche, Raif S. Geha, Talal A. Chatila, Bodo Grimbacher*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

139 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)402-412
Number of pages11
JournalJournal of Allergy and Clinical Immunology
Issue number2
Publication statusPublished - Aug 1 2015


  • Molluscum contagiosum
  • Primary combined immunodeficiency
  • autosomal recessive hyper-IgE syndrome
  • dedicator of cytokinesis 8
  • hyper-IgE syndrome
  • signal transducer and activator of transcription 3

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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