Successful bone marrow transplantation for DOCK8 deficient hyper IgE syndrome

Background Mutations in DOCK8 cause a combined immunodeficiency (CID) also classified as autosomal-recessive hyper-IgE syndrome (HIES). Recognizing patients with CID / HIES is of clinical importance due to a difference in prognosis and management. Objectives 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 autosomal-recessive 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 10 AR-HIES patients without a DOCK8 mutation and 64 patients with STAT3 mutations. Results DOCK8-deficient patients had a median IgE of 5,201 IU, high eosinophil levels of usually at least 800/µl (92% of patients), and low levels of IgM (62%). About 20% of patients were lymphopenic, mainly due to low CD4+ and CD8+ T cells. 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 five 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.

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“…Early diagnosis of DOCK8 deficiency is important to facilitate an adequate treatment such as HSCT. 11–15 …”

Section: Discussionmentioning

confidence: 99%

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

Engelhardt

Gertz

Keleş

et al. 2015

Journal of Allergy and Clinical Immunology

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162

157

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“…36 Certainly, besides defective glycan biosynthesis, other pathogenic mechanisms such as abrogated membrane transport or gain of glycosylation sites can also account for immune deficiencies. 37–38 Whether hematopoietic stem cell transplantation, a successful treatment option in DOCK8-deficiency, 39 is also effective for patients with PGM3 mutations has not yet been confirmed.…”

Section: Discussionmentioning

confidence: 99%

Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels

Sassi

Lazaroski

et al. 2014

Journal of Allergy and Clinical Immunology

161

195

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Background Recurrent bacterial and fungal infections, eczema and elevated serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes for HIES are mutations in STAT3 and DOCK8, involved in signal transduction pathways. However, glycosylation defects have not been described in HIES. One crucial enzyme in the glycosylation pathway is Phosphoglucomutase 3 (PGM3), which catalyzes a key step in the synthesis of UDP-GlcNAc which is required for the biosynthesis of N-glycans. Objective To elucidate the genetic cause in HIES patients who do not carry mutations in STAT3 or DOCK8. Methods After establishing a linkage interval by SNP-chip genotyping and homozygosity mapping in two HIES families from Tunisia, mutational analysis was performed with selector-based, high-throughput sequencing. Protein expression was analyzed by Western blotting and glycosylation was profiled by mass spectrometry. Results Mutational analysis of candidate genes in a 11.9 Mb linkage region on chromosome 6 shared by two multiplex families identified two homozygous mutations in PGM3 which segregated with the disease status and followed a recessive inheritance trait. The mutations predict amino acid changes in Phosphoglucomutase-3; PGM3 (p.Glu340del and p.Leu83Ser). A third homozygous mutation (p.Asp502Tyr) and the p.Leu83Ser variant were identified in two other affected families, respectively. These hypomorphic mutations have impact on the biosynthetic reactions involving UDP-GlcNAc. Glycomic analysis revealed an aberrant glycosylation pattern in leukocytes demonstrated by a reduced level of tri-/tetra-antennary N-glycans. T cell proliferation and differentiation was impaired in patients. Most patients showed developmental delay and many had psychomotor retardation. Conclusion Impairment of PGM3 function leads to a novel primary (inborn) error of development and immunity, as biallelic hypomorphic mutations are associated with impaired glycosylation and a hyper-IgE-like phenotype.

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“…The development of overt autoimmune disease is likely regulated by modifier genes or/and triggered by recurrent infections. The standard of care for treatment of DOCK8 deficient patients is hematopoietic stem cell transplant (HSCT) 39–45 . HSCT is expected to restore the Treg cell compartment; however, autoantibody producing plasma cells may persist for a long time after HSCT as they are relatively resistant to the immunosuppressive regimens used in the conditioning of the recipients 46, 47 .…”

Section: Discussionmentioning

confidence: 99%

Dedicator of cytokinesis 8–deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells

Janssen

Morbach

Ullas

et al. 2014

Journal of Allergy and Clinical Immunology

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Background Dedicator of Cytokinesis 8 (DOCK8) deficiency is typified by recurrent infections, elevated serum IgE levels, eosinophilia, and a high incidence of allergic and autoimmune manifestations. Objective We sought to determine the role of DOCK8 in the establishment and maintenance of human B cell tolerance. Methods Autoantibodies were measured in the plasma of DOCK8 deficient patients. The antibody coding genes from new emigrant/transitional and mature naive B cells were cloned and assessed for their ability to bind self-antigens. Regulatory T (Treg) cells in the blood were analyzed by flow cytometry, and their function was tested by examining their capacity to inhibit the proliferation of CD4+CD25− T effector (Teff) cells. Results DOCK8 deficient patients had increased levels of autoantibodies in their plasma. We determined that central B cell tolerance did not require DOCK8 as evidenced by the normal low frequency of polyreactive new emigrant/transitional B cells in DOCK8 deficient patients. In contrast, autoreactive B cells were enriched in the mature naïve B cell compartment, revealing a defective peripheral B cell tolerance checkpoint. In addition, we found that Treg cells were decreased and exhibited impaired suppressive activity in DOCK8 deficient patients. Conclusions Our data support a critical role for DOCK8 in Treg cell homeostasis and function and the enforcement of peripheral B cell tolerance. Clinical Implications DOCK8 deficient patients should be evaluated for autoantibodies, the possible emergence of autoimmunity, and end organ damage.

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Successful bone marrow transplantation for DOCK8 deficient hyper IgE syndrome

Cited by 45 publications

References 7 publications

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

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

Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels

Dedicator of cytokinesis 8–deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells

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