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DOCK8 Deficiency Presenting as an IPEX-Like Disorder

Journal of Clinical Immunology volume 37, pages 811–819 (2017)Cite this article

Abstract

Purpose

The dedicator of cytokinesis 8 (DOCK8) deficiency is an autosomal recessive-combined immunodeficiency whose clinical spectra include recurrent infections, autoimmunity, malignancies, elevated serum IgE, eczema, and food allergies. Here, we report on patients with loss of function DOCK8 mutations with profound immune dysregulation suggestive of an immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)-like disorder.

Methods

Immunophenotyping of lymphocyte subpopulations and analysis of DOCK8 protein expression were evaluated by flow cytometry. T regulatory (Treg) cells were isolated by cell sorting, and their suppressive activity was analyzed by flow cytometry. Gene mutational analysis was performed by whole-exome and Sanger sequencing.

Results

Patient 1 (P1) presented at 10 months of age with chronic severe diarrhea and active colitis in the absence of an infectious trigger, severe eczema with elevated serum IgE, and autoimmune hemolytic anemia, suggestive of an IPEX-related disorder. Whole-exome sequencing revealed a homozygous nonsense mutation in DOCK8 at the DOCK-homology region (DHR)-1 (c.1498C>T; p. R500X). Patient P2, a cousin of P1 who carries the same DOCK8 nonsense mutation, presented with eczema and recurrent ear infections in early infancy, and she developed persistent diarrhea by 3 years of age. Patient P3 presented with lymphoproliferation, severe eczema with allergic dysregulation, and chronic diarrhea with colitis. She harbored a homozygous loss of function DOCK8 mutation (c.2402 –1G→A). Treg cell function was severely compromised by both DOCK8 mutations.

Conclusion

DOCK8 deficiency may present severe immune dysregulation with features that may overlap with those of IPEX and other IPEX-like disorders.

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Funding

This work was supported by the National Institutes of Health R01AI085090 to Talal A. Chatila and 4R01AI100315 to Raif S. Geha and by a grant from the Scientific and Technological Research Council of Turkey (1059B191300622) to Sevgi Keles.

Author information

Author notes

  1. Fayhan J. Alroqi and Louis-Marie Charbonnier are equal first co-authors; Zeina Baz, and Talal A. Chatila are equal senior co-authors.

Affiliations

  1. Division of Immunology, Boston Children’s Hospital and Department of Pediatrics, Harvard Medical School, Karp Family Building, Room 10-214. 1 Blackfan Street, Boston, MA, 02115, USA

    Fayhan J. Alroqi, Louis-Marie Charbonnier, Janet Chou, Michel J. Massaad, Raif S. Geha & Talal A. Chatila

  2. Department of Pediatrics, King Abdulaziz Medical City, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia

    Fayhan J. Alroqi, Reem Mohammed & Abduarahman Almutairi

  3. Division of Pediatric Allergy and Immunology, Necmettin Erbakan University, Konya, Turkey

    Sevgi Keles

  4. Department of Pathology, St George Hospital University Medical Center, Beirut, Lebanon

    Fatima Ghandour

  5. Department of Pediatrics, St George Hospital University Medical Center, Beirut, Lebanon

    Pierre Mouawad, Rami Sabouneh & Zeina Baz

Authors
  1. Fayhan J. Alroqi
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  2. Louis-Marie Charbonnier
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  13. Talal A. Chatila
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Correspondence to Talal A. Chatila.

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Electronic Supplementary Material

Fig. E1
figure 5

T and B cell subset analysis in patient P2. PBMC of patient P2 and those of a control subject were analyzed for CD3 and CD19 expression (A, B). CD3+ T cells were further analyzed for CD4 and CD8 expression (C, D). CD19+ B cells were further analyzed for IgD and CD27 expression (E, F). (GIF 89 kb) (GIF 89 kb)

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Table E1

Hematological and Immunological findings on DOCK8-deficient subjects. The quantitative determination of serum immunoglobulins is reported for the respective patients before starting IVIG therapy. (DOCX 25.7 kb) (DOCX 25.7 kb)

Table E2

List of nonsynonymous candidate variants identified by using WES in patient P1. The 96 candidate variants were homozygous and nonsynonymous in the patient and absent from dbSNP. The gene symbol (DOCK8) for the candidate gene identified on chromosome 9 is in boldface. (DOCX 27.2 kb) (DOCX 27.2 kb)

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Alroqi, F.J., Charbonnier, LM., Keles, S. et al. DOCK8 Deficiency Presenting as an IPEX-Like Disorder. J Clin Immunol 37, 811–819 (2017). https://doi.org/10.1007/s10875-017-0451-1

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Keywords

  • Combined Immunodeficiency
  • DOCK8
  • FOXP3
  • immune dysregulation
  • IPEX
  • IPEX-like
  • regulatory T cells
  • Treg