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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
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
References
Davis S, Schaller J, Wedgwood R, Harvard MD. Job’s syndrome. Lancet. 1966;287(7445):1013–5.
Buckley RH, Wray BB, Belmaker EZ. Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. Pediatrics. 1972;49(1):59–70.
Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, et al. Hyper-IgE syndrome with recurrent infections–an autosomal dominant multisystem disorder. N Engl J Med. 1999;340(9):692–702.
Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, et al. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med. 2007;357(16):1608–19.
Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature. 2007;448(7157):1058–62.
Renner ED, Torgerson TR, Rylaarsdam S, Anover-Sombke S, Golob K, LaFlam T, et al. STAT3 mutation in the original patient with job’s syndrome. N Engl J Med. 2007;357(16):1667–8.
Renner ED, Puck JM, Holland SM, Schmitt M, Weiss M, Frosch M, et al. Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity. J Pediatr. 2004;144(1):93–9.
Engelhardt KR, McGhee S, Winkler S, Sassi A, Woellner C, Lopez-Herrera G, et al. Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. J Allergy Clin Immunol. 2009;124(6):1289--1302.
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.
Al-Zahrani D, Raddadi A, Massaad M, Keles S, Jabara HH, Chatila TA, et al. Successful interferon-alpha 2b therapy for unremitting warts in a patient with DOCK8 deficiency. Clin Immunol. 2014;153(1):104–8.
Keles S, Jabara HH, Reisli I, McDonald DR, Barlan I, Hanna-Wakim R, et al. Plasmacytoid dendritic cell depletion in DOCK8 deficiency: rescue of severe herpetic infections with IFN-alpha 2b therapy. J Allergy Clin Immunol. 2014;133(6):1753–1755.
Papan C, Hagl B, Heinz V, Albert MH, Ehrt O, Sawalle-Belohradsky J, et al. Beneficial IFN-alpha treatment of tumorous herpes simplex blepharoconjunctivitis in dedicator of cytokinesis 8 deficiency. J Allergy Clin Immunol. 2014;133(5):1456–8.
Bittner TC, Pannicke U, Renner ED, Notheis G, Hoffmann F, Belohradsky BH, et al. Successful long-term correction of autosomal recessive hyper-IgE syndrome due to DOCK8 deficiency by hematopoietic stem cell transplantation. Klin Pädiatr. 2010;222(6):351–5.
Gatz SA, Benninghoff U, Schutz C, Schulz A, Honig M, Pannicke U, et al. Curative treatment of autosomal-recessive hyper-IgE syndrome by hematopoietic cell transplantation. Bone Marrow Transplant. 2011;46(4):552–6.
Boztug H, Karitnig-Weiss C, Ausserer B, Renner ED, Albert MH, Sawalle-Belohradsky J, et al. Clinical and immunological correction of DOCK8 deficiency by allogeneic hematopoietic stem cell transplantation following a reduced toxicity conditioning regimen. Pediatr Hematol Oncol. 2012;29(7):585–94.
Barlogis V, Galambrun C, Chambost H, Lamoureux-Toth S, Petit P, Stephan JL, et al. Successful allogeneic hematopoietic stem cell transplantation for DOCK8 deficiency. J Allergy Clin Immunol. 2011;128(2):420--422.
Ghosh S, Schuster FR, Adams O, Babor F, Borkhardt A, Comoli P, et al. Haploidentical stem cell transplantation in DOCK8 deficiency - successful control of pre-existing severe viremia with a TCRass/CD19-depleted graft and antiviral treatment. Clin Immunol. 2014;152(1–2):111–4.
Metin A, Tavil B, Azik F, Azkur D, Ok-Bozkaya I, Kocabas C, et al. Successful bone marrow transplantation for DOCK8 deficient hyper IgE syndrome. Pediatr Transplant. 2012;16(4):398–9.
Sassi A, Lazaroski S, Wu G, Haslam SM, Fliegauf M, Mellouli F, et al. Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels. J Allergy Clin Immunol. 2014;133(5):1410--1419.
Crawford G, Enders A, Gileadi U, Stankovic S, Zhang Q, Lambe T, et al. DOCK8 is critical for the survival and function of NKT cells. Blood. 2013;122(12):2052–61.
Ham H, Guerrier S, Kim J, Schoon RA, Anderson EL, Hamann MJ, et al. Dedicator of cytokinesis 8 interacts with talin and Wiskott-Aldrich syndrome protein to regulate NK cell cytotoxicity. J Immunol. 2013;190(7):3661–9.
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.
Chu EY, Freeman AF, Jing H, Cowen EW, Davis J, Su HC, et al. Cutaneous manifestations of DOCK8 deficiency syndrome. Arch Dermatol. 2012;148(1):79–84.
Dasouki M, Okonkwo KC, Ray A, Folmsbeel CK, Gozales D, Keles S, et al. Deficient T cell receptor excision circles (TRECs) in autosomal recessive hyper IgE syndrome caused by DOCK8 mutation: implications for pathogenesis and potential detection by newborn screening. Clin Immunol. 2011;141(2):128–32.
McDonald DR, Massaad MJ, Johnston A, Keles S, Chatila T, Geha RS, et al. Successful engraftment of donor marrow after allogeneic hematopoietic cell transplantation in autosomal-recessive hyper-IgE syndrome caused by dedicator of cytokinesis 8 deficiency. J Allergy Clin Immunol. 2010;126(6):1304--1305.
Randall KL, Chan SS, Ma CS, Fung I, Mei Y, Yabas M, et al. DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice. J Exp Med. 2011;208(11):2305–20.
Sanal O, Jing H, Ozgur T, Ayvaz D, Strauss-Albee DM, Ersoy-Evans S, et al. Additional diverse findings expand the clinical presentation of DOCK8 deficiency. J Clin Immunol. 2012;32(4):698–708.
Gray R. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16(3):1141–54.
Alsum Z, Hawwari A, Alsmadi O, Al-Hissi S, Borrero E, Abu-Staiteh A, et al. Clinical, immunological and molecular characterization of DOCK8 and DOCK8-like deficient patients: single center experience of twenty-five patients. J Clin Immunol. 2013;33(1):55–67.
Al-Herz W, Ragupathy R, Massaad MJ, Al-Attiyah R, Nanda A, Engelhardt KR, et al. Clinical, immunologic and genetic profiles of DOCK8-deficient patients in Kuwait. Clin Immunol. 2012;143(3):266–72.
Nehme NT, Pachlopnik Schmid J, Debeurme F, Andre-Schmutz I, Lim A, Nitschke P, et al. MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival. Blood. 2012;119(15):3458–68.
Jing H, Zhang Q, Zhang Y, Hill BJ, Dove CG, Gelfand EW, et al. Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype. J Allergy Clin Immunol. 2014;133(6):1667–75.
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.–223.
Nijman IJ, van Montfrans JM, Hoogstraat M, Boes ML, van de Corput L, Renner ED, et al. Targeted next-generation sequencing: a novel diagnostic tool for primary immunodeficiencies. J Allergy Clin Immunol. 2014;133(2):529–34.
Kane A, Deenick EK, Ma CS, Cook MC, Uzel G, Tangye SG. STAT3 is a central regulator of lymphocyte differentiation and function. Curr Opin Immunol. 2014;28C:49–57.
Albert MH, Notarangelo LD, Ochs HD. Clinical spectrum, pathophysiology and treatment of the Wiskott-Aldrich syndrome. Curr Opin Hematol. 2011;18(1):42–8.
Aan de Kerk DJ, van Leeuwen EM, Jansen MH, van den Berg JM, Alders M, Vermont CL, et al. Aberrant humoral immune reactivity in DOCK8 deficiency with follicular hyperplasia and nodal plasmacytosis. Clin Immunol. 2013;149(1):25–31.
Harada Y, Tanaka Y, Terasawa M, Pieczyk M, Habiro K, Katakai T, et al. DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses. Blood. 2012;119(19):4451–61.
Jabara HH, McDonald DR, Janssen E, Massaad MJ, Ramesh N, Borzutzky A, et al. DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation. Nat Immunol. 2012;13(6):612–20.
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.
Author information
Authors and Affiliations
Consortia
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
ESM 1
(DOCX 66 kb)
Rights and permissions
About this article
Cite this article
Aydin, S.E., Kilic, S.S., Aytekin, C. et al. DOCK8 Deficiency: Clinical and Immunological Phenotype and Treatment Options - a Review of 136 Patients. J Clin Immunol 35, 189–198 (2015). https://doi.org/10.1007/s10875-014-0126-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10875-014-0126-0