Journal of Clinical Immunology

, Volume 39, Issue 6, pp 592–595 | Cite as

Compound Heterozygous DOCK8 Mutations in a Patient with B Lymphoblastic Leukemia and EBV-Associated Diffuse Large B Cell Lymphoma

  • David BuchbinderEmail author
  • Ivan Kirov
  • Jeffrey Danielson
  • Nirali N. Shah
  • Alexandra F. Freeman
  • Rishikesh S. Chavan
  • Helen C. Su
Original Article


Mutations in Dedicator of cytokinesis 8 (DOCK8) are a rare cause of combined immunodeficiency associated with atopy, infectious susceptibility, and risk for malignancy. We describe a 22-year-old male with a diagnosis of B cell lymphoblastic leukemia followed by Epstein-Barr virus (EBV)-associated diffuse large B cell lymphoma (DLBCL) with compound heterozygous mutations in DOCK8 and normal intracellular DOCK8 protein expression. Here, B cell lymphoblastic leukemia followed by EBV-associated DLBCL led to the discovery of DOCK8 deficiency. For instances of high clinical suspicion despite normal DOCK8 protein expression, additional functional testing is critical to make a diagnosis. Understanding the spectrum of DOCK8 mutants and their phenotypes will improve our understanding of DOCK8 deficiency.


B cell lymphoblastic leukemia diffuse large B cell lymphoma combined immunodeficiency dedicator of cytokinesis 8 



Children’s Oncology Group


diffuse large B cell lymphoma


Dedicator of cytokinesis 8


Epstein-Barr virus


graft-versus-host disease


Human Papilloma Virus


hematopoietic stem cell transplantation




Varicella Zoster Virus


whole exome sequencing



We thank the patient and his family for participating in our research studies, and Pam Angelus for research support. Patient blood samples were obtained after provision of written informed consent under an NIH IRB–approved protocol. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases.

Authorship Contributions

All authors helped draft and approved the submitted manuscript. HCS and DB coordinated investigation of the patient’s immunological analyses and creation of the manuscript. DB, IK, and RSC diagnosed and treated the patient’s immune disorder. JD and HCS helped characterize the immunological disturbance. NNS, AFF, and HCS helped review the literature and illustrate the manuscript. DB, IK, and RSC recognized the patient’s enigmatic presentation, initiated diagnostic studies, and made possible his multi-institutional investigation.

Compliance with Ethical Standards

Conflict of Interest

The authors declared that have no conflict of interest.

Supplementary material

10875_2019_663_MOESM1_ESM.docx (30 kb)
ESM 1 (DOCX 29 kb)


  1. 1.
    Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing H, Favreau AJ, et al. Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med. 2009;361(21):2046–55.CrossRefGoogle Scholar
  2. 2.
    Mizesko MC, Banerjee PP, Monaco-Shawver L, Mace EM, Bernal WE, Sawalle-Belohradsky J, et al. Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency. J Allergy Clin Immunol. 2013;131(3):840–8.CrossRefGoogle Scholar
  3. 3.
    Zhang Q, Dove CG, Hor JL, Murdock HM, Strauss-Albee DM, Garcia JA, et al. DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity. J Exp Med. 2014;211(13):2549–66.CrossRefGoogle Scholar
  4. 4.
    Lambe T, Crawford G, Johnson A, et al. DOCK8 is essential for T-cell survival and the maintenance of CD8+ T-cell memory. Eur J Immunol. 2011;41(12):3423–35.CrossRefGoogle Scholar
  5. 5.
    Aydin SE, Kilic SS, Aytekin C, et al. DOCK8 deficiency: clinical and immunological phenotype and treatment options - a review of 136 patients. J Clin Immunol. 2015;35(2):189–98.CrossRefGoogle Scholar
  6. 6.
    Engelhardt KR, Gertz ME, Keles S, Schäffer AA, Sigmund EC, Glocker C, et al. The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency. J Allergy Clin Immunol. 2015;136(2):402–12.CrossRefGoogle Scholar
  7. 7.
    Su HC, Jing H, Angelus P, Freeman AF. Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome. Immunol Rev. 2019;287(1):9–19.CrossRefGoogle Scholar
  8. 8.
    Zhang Q, Jing H, Su HC. Recent advances in DOCK8 immunodeficiency syndrome. J Clin Immunol. 2016;36(5):441–9.CrossRefGoogle Scholar
  9. 9.
    Pai SY, de Boer H, Massaad MJ, Chatila TA, Keles S, Jabara HH, et al. Flow cytometry diagnosis of dedicator of cytokinesis 8 (DOCK8) deficiency. J Allergy Clin Immunol. 2014;134(1):221–3.CrossRefGoogle Scholar
  10. 10.
    Shah NN, Freeman AF, Su H, Cole K, Parta M, Moutsopoulos NM, et al. Haploidentical related donor hematopoietic stem cell transplantation for dedicator-of-cytokinesis 8 deficiency using post-transplantation cyclophosphamide. Biol Blood Marrow Transplant. 2017;23(6):980–90.CrossRefGoogle Scholar
  11. 11.
    Aydin SE, Freeman AF, Al-Herz W, et al. Hematopoietic stem cell transplantation as treatment for patients with DOCK8 deficiency. J Allergy Clin Immunol Pract. 2019;7(3):848–55.CrossRefGoogle Scholar
  12. 12.
    Jing H, Zhang Q, Zhang Y, Hill BJ, Dove CG, Gelfand EW, et al. Somatic reversion in DOCK8 immunodeficiency modulates disease phenotypes. J Allergy Clin Immunol. 2014;133(6):1667–75.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of HematologyChildren’s Hospital of Orange CountyOrangeUSA
  2. 2.Department of PediatricsUniversity of California at IrvineOrangeUSA
  3. 3.Department of OncologyChildren’s Hospital of Orange CountyOrangeUSA
  4. 4.Laboratory of Clinical Immunology and MicrobiologyNIAID, NIHBethesdaUSA
  5. 5.Pediatric Oncology BranchNCI, NIHBethesdaUSA

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