Clinical, immunologic and genetic profiles of DOCK8-deficient patients in Kuwait
Highlights
► DOCK8-deficient patients have selective TH2 bias. ► DOCK8 deficiency is characterized by progressive lymphopenia. ► DOCK8 deficiency is characterized by poor T-lymphocyte stimulation to mitogens. ► Hypermelanosis of oral mucosa is a new finding in DOCK8-deficient patients.
Introduction
Deficiency of dedicator of cytokinesis 8 (DOCK8) is a newly described combined primary immunodeficiency disease (PID) characterized by susceptibility to viral infections, recurrent sinopulmonary infections, atopy, early onset malignancies and autoimmunity [1], [2], [3], [4]. Reported immunologic abnormalities include T-cell lymphopenia, defective T-cell proliferation, decreased IgM, elevated IgE, eosinophilia and a variable IgG antibody response [5]. The disease is caused by biallelic loss-of-function mutations in the DOCK8 gene, most of which lead to absent or trace amounts of expressed DOCK8 protein [6].
Autosomal recessive primary immunodeficiency diseases are more prevalent in Kuwait compared to other populations, because of a high rate of consanguinity [7]. The present study presents the clinical, immunologic and molecular characteristics of 9 Kuwaiti patients who presented with DOCK8 deficiency between the years 2004 and 2011.
Section snippets
Patients data
The patients data were retrieved from the Kuwait National Primary Immunodeficiency Disorders Registry (KNPIDR), which began recruiting patients in 2004. The project was approved by the Human Subjects Research and Ethics Committee of the Ministry of Health, Kuwait.
Mutation analysis of the DOCK8 gene
Genomic DNA was extracted from whole blood using QIAamp DNA Blood Kit (Qiagen, Valencia, CA). For some patients and family members, total RNA was prepared from blood using QIAamp RNA Blood Kit (Qiagen), and cDNA was synthesized as
Patient characteristics and clinical presentations
A total of 9 DOCK8-deficient patients (3 males and 6 females) from 4 families are presented in this report. They represent 3.73% of all patients with PID and 15% of the patients with combined T- and B-cell immunodeficiencies registered in the KNPIDR. All of the patients were born to consanguineous parents. The details of the clinical presentations are shown in Table 1. One patient (A49) was screened and diagnosed early in life because of family history of the disease. All of the patients
Discussion
Combined immunodeficiency due to DOCK8 deficiency is an autosomal recessive disease, which appears to be common in populations where the frequency of consanguineous marriages is high. In Kuwait, where the incidence of consanguinity is 54% [11], DOCK8 deficiency accounted for a significant proportion (15%) of patients who suffer from combined T- and B-cell immunodeficiencies.
The clinical phenotype in the present group of patients is consistent with that in the two initial reports of DOCK8
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgments
We are very grateful to the patients and their families for participation in this study. The project was supported by the Kuwait Foundation for Advancement of Sciences (2010-1302-05) and by a grant from the Dubai Harvard Foundation for Medical Research (RSG and LDN).
References (16)
- et al.
Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study
J. Allergy Clin. Immunol.
(2003) - et al.
Major histocompatibility complex class II expression deficiency caused by a RFXANK founder mutation: a survey of 35 patients
Blood
(2011) - et al.
Large deletions and pointmutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome
J. Allergy Clin. Immunol.
(2009) - et al.
Combined immunodeficiency associated with DOCK8 mutations
N. Engl. J. Med.
(2009) - et al.
DOCK8 deficiency
Ann. N. Y. Acad. Sci.
(2011) - et al.
Clinical manifestations of hyper IgE syndromes
Dis. Markers
(2010) Dedicator of cytokinesis 8 (DOCK8) deficiency
Curr. Opin Allergy Clin. Immunol.
(2010)- et al.
Genetic, clinical, and laboratory markers for DOCK8 immunodeficiency syndrome
Dis. Markers
(2010)
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