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

doi:10.1016/j.jaci.2014.12.1945

Journal of Allergy and Clinical Immunology

Volume 136, Issue 2, August 2015, Pages 402-412

, , , , , , , , , , , , , , , , , , , …

https://doi.org/10.1016/j.jaci.2014.12.1945 Get rights and content

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.

Section snippets

Patients and control subjects

We enrolled a cohort of 82 patients from 60 families in a worldwide collaboration. All patients fulfilled the following inclusion criteria for this study: signed informed consent forms, strong clinical suspicion of AR-HIES according to the referring immunologist, and available samples of genomic DNA or RNA. Of the 82 patients, 40 were male, and 42 were female. Forty-seven of the patients were also described by Aydin et al in a separate study (accepted for publication in the Journal of Clinical

Identification of DOCK8 deficiency

Of the 82 subjects studied in 60 families, we diagnosed DOCK8 deficiency in 64 patients from 50 families (see Fig E1). For 60 patients from 46 unrelated families, a homozygous or compound heterozygous mutation was identified in DOCK8 (Fig 1 and see Table E3 in this article's Online Repository at www.jacionline.org), for a total of 40 distinct mutations. For 4 patients from 4 families (ARH018, ARH019, ARH006, and ARH007), the DOCK8 mutation could not be identified by means of sequencing because

Discussion

Here we report 25 new mutations causing human DOCK8 deficiency and symptoms that were previously unrecognized to occur in patients with DOCK8 deficiency. Early diagnosis of DOCK8 deficiency is important to facilitate an adequate treatment, such as hematopoietic stem cell transplantation (HSCT).16, 17, 18, 19, 20

DOCK8 deficiency has a high mortality at a young age, with more frequent severe infections and malignancy, and therefore HSCT should be considered. In contrast, conflicting results have

References (34)

K.R. Engelhardt 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)
A. Stray-Pedersen et al.
PGM3 mutations cause a congenital disorder of glycosylation with severe immunodeficiency and skeletal dysplasia
Am J Hum Genet
(2014)
B. Grimbacher et al.
Genetic linkage of hyper-IgE syndrome to chromosome 4
Am J Hum Genet
(1999)
W.M. Comans-Bitter et al.
Immunophenotyping of blood lymphocytes in childhood. Reference values for lymphocyte subpopulations
J Pediatr
(1997)
W. Al-Herz et al.
Clinical, immunologic and genetic profiles of DOCK8-deficient patients in Kuwait
Clin Immunol
(2012)
D.R. McDonald 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)
V. Barlogis et al.
Successful allogeneic hematopoietic stem cell transplantation for DOCK8 deficiency
J Allergy Clin Immunol
(2011)
E. Goussetis et al.
Successful long-term immunologic reconstitution by allogeneic hematopoietic stem cell transplantation cures patients with autosomal dominant hyper-IgE syndrome
J Allergy Clin Immunol
(2010)
S.Y. Pai et al.
Flow cytometry diagnosis of dedicator of cytokinesis 8 (DOCK8) deficiency
J Allergy Clin Immunol
(2014)
H. Jing et al.
Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype
J Allergy Clin Immunol
(2014)

S.J. Vowells et al.

Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in patients with chronic granulomatous disease

J Pediatr

(1996)

Y. Harada et al.

DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses

Blood

(2012)

M. Dasouki 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)

E. Janssen et al.

Flow cytometry biomarkers distinguish DOCK8 deficiency from severe atopic dermatitis

Clin Immunol

(2014)

Q. Zhang et al.

Combined immunodeficiency associated with DOCK8 mutations

N Engl J Med

(2009)

B. Grimbacher et al.

Hyper-IgE syndrome with recurrent infections—an autosomal dominant multisystem disorder

N Engl J Med

(1999)

S.M. Holland et al.

STAT3 mutations in the hyper-IgE syndrome

N Engl J Med

(2007)

Cited by (158)

Metabolic fitness of IgA<sup>+</sup> plasma cells in the gut requires DOCK8
2024, Mucosal Immunology
Dedicator of cytokinesis 8 (DOCK8) mutations lead to a primary immunodeficiency associated with recurrent gastrointestinal infections and poor antibody responses but, paradoxically, heightened IgE to food antigens, suggesting that DOCK8 is central to immune homeostasis in the gut. Using Dock8-deficient mice, we found that DOCK8 was necessary for mucosal IgA production to multiple T cell-dependent antigens, including peanut and cholera toxin. Yet DOCK8 was not necessary in T cells for this phenotype. Instead, B cell-intrinsic DOCK8 was required for maintenance of antigen-specific IgA-secreting plasma cells (PCs) in the gut lamina propria. Unexpectedly, DOCK8 was not required for early B cell activation, migration, or IgA class switching. An unbiased interactome screen revealed novel protein partners involved in metabolism and apoptosis. Dock8-deficient IgA⁺ B cells had impaired cellular respiration and failed to engage glycolysis appropriately. These results demonstrate that maintenance of the IgA⁺ PC compartment requires DOCK8 and suggest that gut IgA⁺ PCs have unique metabolic requirements for long-term survival in the lamina propria.
Relevance of Coding Variation in FLG And DOCK8 in Finnish Pediatric Patients with Early-Onset Moderate-To-Severe Atopic Dermatitis
2023, JID Innovations
Early-onset, persistent atopic dermatitis (AD) is proposed as a distinct subgroup that may have specific genotypic features. FLG gene loss-of-function variants are the best known genetic factors contributing to epidermal barrier impairment and eczema severity. In a cohort of 140 Finnish children with early-onset moderate-to-severe AD, we investigated the effect of coding variation in FLG and 13 other genes with epidermal barrier or immune function through the use of targeted amplicon sequencing and genotyping. A FLG loss-of-function variant (Arg501Ter, Ser761fs, Arg2447Ter, or Ser3247Ter) was identified in 20 of 140 patients showing higher transepidermal water loss values than patients without these variants. Total FLG loss-of-function variant frequency (7.14%) was significantly higher than in the general Finnish population (2.34%). When tested separately, only Arg2447Ter showed a significant association with AD (P = 0.003104). In addition, a modest association with moderate-to-severe pediatric AD was seen for rs12730241 and rs6587667 (FLG2:Gly137Glu). Loss-of-function variants, previously reported pathogenic variants, or statistically significant enrichment of nonsynonymous coding region variants were not found in the 13 candidate genes studied by amplicon sequencing. However, higher IgE and eosinophil counts were found in carriers of potentially pathogenic DOCK8 missense variants, suggesting that the role of DOCK8 variation in AD should be further investigated in larger cohorts.
DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity
2023, Blood
Dedicator of cytokinesis (DOCK) proteins play a central role in actin cytoskeleton regulation. This is highlighted by the DOCK2 and DOCK8 deficiencies leading to actinopathies and immune deficiencies. DOCK8 and DOCK11 activate CDC42, a Rho–guanosine triphosphate hydrolases involved in actin cytoskeleton dynamics, among many cellular functions. The role of DOCK11 in human immune disease has been long suspected but, to the best of our knowledge, has never been described to date. We studied 8 male patients, from 7 unrelated families, with hemizygous DOCK11 missense variants leading to reduced DOCK11 expression. The patients were presenting with early-onset autoimmunity, including cytopenia, systemic lupus erythematosus, skin, and digestive manifestations. Patients' platelets exhibited abnormal ultrastructural morphology and spreading as well as impaired CDC42 activity. In vitro activated T cells and B-lymphoblastoid cell lines from patients exhibited aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. Knock down of DOCK11 recapitulated these abnormal cellular phenotypes in monocytes-derived dendritic cells and primary activated T cells from healthy controls. Lastly, in line with the patients’ autoimmune manifestations, we also observed abnormal regulatory T-cell (Treg) phenotype with profoundly reduced FOXP3 and IKZF2 expression. Moreover, we found reduced T-cell proliferation and impaired STAT5B phosphorylation upon interleukin-2 stimulation of the patients’ lymphocytes. In conclusion, DOCK11 deficiency is a new X-linked immune-related actinopathy leading to impaired CDC42 activity and STAT5 activation, and is associated with abnormal actin cytoskeleton remodeling as well as Treg phenotype, culminating in immune dysregulation and severe early-onset autoimmunity.
Eosinophilia Associated With Immune Deficiency
2022, Journal of Allergy and Clinical Immunology: In Practice
The differential diagnosis of eosinophilia is broad and includes infections, malignancies, and atopy as well as inborn errors of immunity (IEI). Certain types of IEIs are known to be associated with elevated numbers of eosinophils and frequently elevated serum IgE, whereas for others the degree and frequency of eosinophilia are less established. The molecular defects underlying IEI are heterogeneous and affect different pathways, which highlights the complex regulations of this cell population within the immune system. In this review, we list and discuss clinical manifestations and therapies of immune deficiency or immune dysregulation disorders associated with peripheral blood or tissue eosinophilia with or without raised IgE levels. We present illustrative case vignettes for the most common entities and propose a diagnostic algorithm aiming to help physicians systematically to evaluate patients with eosinophilia and suspicion of an underlying IEI.
Hyper IgE syndromes: A clinical approach
2022, Clinical Immunology
Hyper IgE syndromes (HIESs) are a group of rare inborn errors of immunity with a triad of eczema, increase susceptibility to sinopulmonary and skin infections with high level of IgE serum. Although most of HIESs are sporadic, hereditary types of these disorders have been studied well. There are several distinct immunodeficiency disorders which are phenotypically similar to HIES, and thus make the diagnosis of HIES challenging. In fact, the diagnosis of HIES is typically based on the clinical suspicion and immunological assessments. There is yet no specific curative treatment for most of HIESs at present, and the treatments are mostly standing on early diagnosis and preventive therapies. For instance, the genetic diagnosis is an important module, while, due to DOCK8 mutations, the hematopoietic stem cell transplantation is necessary for patients with autosomal recessive form of HIESs. Herein, we overview HIESs, highlight their peculiar clinical and laboratory features, and finally suggest a practical forthright diagnostic chart for clinical purposes.
Cell architecture defect and autoimmunity : DOCK11 deficiency
2024, Medecine/Sciences

View all citing articles on Scopus

: Supported by the German Federal Ministry of Education and Research (BMBF 01EO1303). The research was funded in part by the European Community's 7th Framework Programmes FP7/2007-2013 under grant agreement Health-F5-2008-223292 (Euro Gene Scan), by a Marie Curie Excellence Grant (to B.G.; MEXT-CT-2006-042316-PIAID), and by National Institutes of Health grants 5R01AI065617 and 1R21AI087627 (to T.A.C.). This research was supported in part by a grant from the Scientific and Technological Research Council of Turkey (Tubitak, grant no. 1059B191300622). This research was supported in part by the Intramural Research program of the National Institutes of Health, NLM, and NIAID.

: Disclosure of potential conflict of interest: K. R. Engelhardt has received research support from BMBF (BMBF 01EO1303) and the European Union (EU; MEXT-CT-2006-042316-PIAID). E. M. Gertz and Alejandro A. Schäffer are employed by the National Institutes of Health (NIH). R. Ceja is employed by Children's Hospital Boston. I. Schulze has received lecture fees from CSL Behring and Octapharma. T. Niehues has received lecture fees from CSL Behring, Infectopharma, and Novartis. M. Dasouki has received research support from Genzyme Corporation and Amicus Therapeutics. A. Jones has received lecture fees and support for attending meetings from CSL Behring. M.-R. Barbouche is employed by the Ministry of Health of Tunisia. R. S. Geha is employed by Boston Children's Hospital, has received research support from the NIH (5R01AI100315), and received grant support from the Dubai-Harvard Foundation for Medical Research. T. A. Chatila has received research support from the NIH (5R01AI065617 and 1R21AI087627). B. Grimbacher has received research support from BMBF (BMBF 01EO1303), the EU (MEXT-CT-2006-042316-PIAID), and Helmholtz (DZIF 8000805-3); is employed by UCL and UKL-FR; and has received lecture fees from CSL, Baxter, and Biotest. The rest of the authors declare that they have no relevant conflicts of interest.

^∗: These authors contributed equally to this work.

View full text

Immune deficiencies, infection, and systemic immune disordersThe extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency

Background

Objectives

Methods

Results

Conclusions

Section snippets

Patients and control subjects

Identification of DOCK8 deficiency

Discussion

J Allergy Clin Immunol

Am J Hum Genet

Am J Hum Genet

J Pediatr

Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Pediatr

Blood

Clin Immunol

Clin Immunol

Combined immunodeficiency associated with DOCK8 mutations

N Engl J Med

Hyper-IgE syndrome with recurrent infections—an autosomal dominant multisystem disorder

N Engl J Med

STAT3 mutations in the hyper-IgE syndrome

N Engl J Med

Immune deficiencies, infection, and systemic immune disorders
The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency