DOCK8 Deficiency Presenting as an IPEX-Like Disorder

Abstract

Purpose 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.

Clinical, Immunological, and Molecular Heterogeneity of 173 Patients With the Phenotype of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome

“…Mutations in the dedicator of cytokinesis 8 ( DOCK8 ) gene cause a combined immunodeficiency extending beyond recurrent infections to include atopy, autoimmunity and cancer ( 97 , 98 ). DOCK8 deficiency has recently been identified in a patient with an IPEX-like disorder ( 99 ). Three brothers with IPEX-like phenotype were originally evaluated in our Centers and found to have wild type FOXP3 .…”

“…Mutations in TTC7A ( 83 , 113 ) and TTC37 ( 100 , 114 ) have been associated with severe diarrhea, villous atrophy, recurrent infections and (in TTC7A) a SCID-like phenotype with multiple intestinal atresia. DOCK8 deficiency shares with IPEX some features such as atopic dermatitis, autoimmunity, recurrent infections including muco-cutaneous candidiasis but, with few exceptions ( 99 ), not inflammatory bowel disease. While the clinical phenotypes of these conditions are generally quite dissimilar from IPEX and IPEX-like disorders, they should be considered in the differential diagnosis.…”

Primary atopic disorders

“…Rltpr encoded by Carmil2 which is downstream of CD28 and participates in actin polymerization, has likewise been demonstrated as indispensable for T reg development in mice ( Liang et al, 2013 ), and humans with CARMIL2 deficiency have been shown to have a significant reduction of T regs in circulation ( Wang et al, 2016 ; Schober et al, 2017 ). DOCK8-deficient and STAT1 GOF patients can also present with IPEX-like phenotypes: the former appears to cause T reg dysfunction principally by limiting IL-2–mediated STAT5 activation, whereas direct effects of STAT1 GOF mutations on T regs have not been established ( Uzel et al, 2013 ; Janssen et al, 2014 , 2017 ; Alroqi et al, 2017 ; Singh et al, 2017 ). Finally, T reg disruption has also been demonstrated in LDS patients, as might be expected in a disease associated with abnormal TGF-β pathway signaling.…”

Primary immunodeficiencies caused by mutations in actin regulatory proteins

“…128 Like WIP and WASP deficient patients, DOCK8 deficient patients are predisposed toward developing autoimmunity. 131,133,[148][149][150] They have increased antibodies against self-antigens. 150…”