DOCK8 Deficiency Presenting as an IPEX-Like Disorder

被引:37
|
作者
Alroqi, Fayhan J. [1 ,2 ]
Charbonnier, Louis-Marie [1 ]
Keles, Sevgi [3 ]
Ghandour, Fatima [4 ]
Mouawad, Pierre [5 ]
Sabouneh, Rami [5 ]
Mohammed, Reem [2 ]
Almutairi, Abduarahman [2 ]
Chou, Janet [1 ]
Massaad, Michel J. [1 ]
Geha, Raif S. [1 ]
Baz, Zeina [5 ]
Chatila, Talal A. [1 ]
机构
[1] Harvard Med Sch, Boston Childrens Hosp, Div Immunol, Karp Family Bldg,Room 10-214,1 Blackfan St, Boston, MA 02115 USA
[2] King Saud bin Abdulaziz Univ Hlth Sci, King Abdulaziz Med City, Dept Pediat, Riyadh, Saudi Arabia
[3] Necmettin Erbakan Univ, Div Pediat Allergy & Immunol, Konya, Turkey
[4] St George Hosp Univ, Dept Pathol, Med Ctr, Beirut, Lebanon
[5] St George Hosp Univ, Dept Pediat, Med Ctr, Beirut, Lebanon
基金
美国国家卫生研究院;
关键词
Combined Immunodeficiency; DOCK8; FOXP3; immune dysregulation; IPEX; IPEX-like; regulatory T cells; T-reg; ALDRICH-SYNDROME PROTEIN; X-LINKED IPEX; IMMUNE DYSREGULATION; GERMLINE MUTATIONS; T-CELLS; DEDICATOR; POLYENDOCRINOPATHY; ENTEROPATHY; IMMUNODYSREGULATION; ACCUMULATION;
D O I
10.1007/s10875-017-0451-1
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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. Immunophenotyping of lymphocyte subpopulations and analysis of DOCK8 protein expression were evaluated by flow cytometry. T regulatory (T-reg) 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. 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). T-reg cell function was severely compromised by both DOCK8 mutations. DOCK8 deficiency may present severe immune dysregulation with features that may overlap with those of IPEX and other IPEX-like disorders.
引用
收藏
页码:811 / 819
页数:9
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