scholarly journals Case Report: A Novel Compound Heterozygous Mutation in IL-10RA in a Chinese Child With Very Early-Onset Inflammatory Bowel Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Fang Dong ◽  
Fangfei Xiao ◽  
Ting Ge ◽  
Xiaolu Li ◽  
Wuhen Xu ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Peripheral Blood ◽  
Early Onset ◽  
Compound Heterozygote ◽  
Chinese Child ◽  
Compound Heterozygous ◽  
Primary Immune Deficiency ◽  
Hematopoietic Stem ◽  
Inflammatory Bowel

Very early-onset inflammatory bowel disease (VEO-IBD) is defined as IBD diagnosed in children younger than 6 years of age. VEO-IBD is often associated with a monogenic etiology or primary immune deficiency. Here, we report the case of a 7-month-old Chinese girl diagnosed with VEO-IBD who had a variant in the interleukin-10 receptor A (IL-10-RA) gene. The patient presented with recurrent fevers, abdominal pain, diarrhea, perianal abscesses, and oral ulcers. Whole-exome sequencing (WES) identified a novel compound heterozygote mutation, c.395T>G (p.Leu132Arg)/ex.1del (p.?), in the IL-10RA gene of the patient. The missense mutation c.395T>G (p.Leu132Arg) was inherited from her mother, and ex.1del (p.?) was inherited from her father. Neither mutation has been reported previously. The IL-10RA function of the patient was defective, as demonstrated by a failure of signal transducer and activator of transcription 3 (STAT3) activation in peripheral blood mononuclear cells (PBMCs) stimulated with recombinant IL-10. The patient underwent matched unrelated peripheral blood hematopoietic stem cell transplantation (HSCT), and the clinical manifestations were dramatically improved. In summary, we identified a novel compound heterozygote mutation, c.395T>G (p.Leu132Arg)/ex.1del (p.?), in IL-10RA that caused VEO-IBD in a Chinese child, which further expands the mutational spectrum of IL-10RA.

Compound Heterozygous IL10RA Mutations in Brothers with Very Early Onset Inflammatory Bowel Disease

2012 ◽  
Vol 18 ◽  
pp. S81
Author(s):  
Julia Bracken ◽  
Darrel Dinwiddie ◽  
Kathy Christenson ◽  
Charles Roberts ◽  
Carol Saunders ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Early Onset ◽  
Compound Heterozygous ◽  
Inflammatory Bowel

scholarly journals Sequence Analysis of TNFRSF13b, Encoding TACI, in a Patient with Very Early Onset Inflammatory Bowel Disease: a Case Report

2018 ◽  
Vol 1 (4) ◽  
pp. 110
Author(s):  
Jiaying Shen
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Early Onset ◽  
Clinical Laboratory ◽  
Histopathological Examination ◽  
Immunosuppressive Treatment ◽  
Poor Response ◽  
Compound Heterozygous ◽  
Inflammatory Bowel ◽  
Compound Heterozygous Mutations

Very early onset inflammatory bowel disease (VEO-IBD), IBD diagnosed before 6 years of age, frequently presents with increased severity, aggressive progression, and often poor response to conventional treatments. Although the cause of IBD is generally considered to be intestinal immune dysfunction induced by polygenic mutations and environment and other factors, VEO-IBD has a stronger genetic susceptibility specifically the neonatal- or infantile-onset IBD. Herein we report compound heterozygous mutations in the tumor necrosis factor receptor superfamily member 13b (TNFRSF13B) gene in a 3-year-old male that was admitted to our hospital with lasted jaundice, repeated fever and diarrhea in May 2014 at 2-month-old. He was diagnosed with VEO-IBD based on clinical, laboratory and histopathological examination. However, he was unresponsive to the conventional therapy, including the nutritional support therapy, antibiotic and immunosuppressive treatment, and surgical release of neonatal intestinal obstruction. Novel compound heterozygous mutations, c.[365G>A];[452C>T](p.[R122Q];[P151L]), were discovered in TNFRSF13B, encoding TACI, for this patient.

scholarly journals Phenotype of Very-Early-Onset Inflammatory Bowel Disease with Interleukin-10 Receptor A Mutations in 22 Chinese Children

2020 ◽  
Author(s):  
Dexiu Guan ◽  
Jing Zhang ◽  
Shu Guo ◽  
Feihong Yu ◽  
Jin Zhou ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Early Onset ◽  
Cord Blood Transplantation ◽  
Gene Mutations ◽  
Onset Time ◽  
Interleukin 10 ◽  
Compound Heterozygous ◽  
Genetic Characteristics ◽  
Inflammatory Bowel

Abstract Backgroud: Very-early-onset inflammatory bowel disease (VEO-IBD) with onset in infancy may be caused by genetic mutation. We collected the VEO-IBD patients with interleukin-10 receptor A (IL-10RA) gene mutations to investigate the clinical phenotype and genetic characteristics.Methods: The data of 22 patients with VEO-IBD with IL-10RA gene mutations were retrospectively analyzed, and high-throughput sequencing was used to identify IL-10RA gene mutations.Results: All 22 patients in this study had IL-10RA gene mutations, including 4 (18.2%) homozygous mutations and 18 (81.8%) compound heterozygous mutations. Among these mutations, 10 mutations had been previously described and 1 novel mutation was identified. In these patients, c.C301T (p.R101W) (86.4%, 19/22) and c.G537A (p.T179T) (36.4%, 8/22) mutations were the most common mutations. This study showed that the patients had extremely early onset of symptoms, about 81.8% (18/22) of the patients had onset within 1 month after birth, and the onset time was 8.5 (IQR: 3.0–24.0) days. In addition, 77.3% (17/22) of patients had recurrent perianal lesions. Oral ulcers and skin rash were common extra-intestinal manifestations, accounting for 72.7% (16/22) and 63.6% (14/22), respectively. In this study, 3 patients underwent enterostomy and 1 patient experienced intestinal perforation repair. Umbilical cord blood transplantation (UCBT) and thalidomide proved efficacious. Follow-up showed the mortality rate was as high as 45% (9/20).Conclusions: We should consider the genetic defects in the IL-10 signaling pathway in VEO-IBD patients, particularly when they had early onset of symptoms, perianal lesions and severe colitis.

Severe Early-Onset Inflammatory Bowel Disease Caused by IL10 Receptor Deficiency Can Be Cured by Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 713-713
Author(s):  
Kaan Boztug ◽  
Daniel Kotlarz ◽  
Erik Glocker ◽  
Mike E Gertz ◽  
Alejandro A Schäffer ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Inflammatory Bowel Disease ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Negative Feedback ◽  
Bowel Disease ◽  
Early Onset ◽  
Hematopoietic Stem ◽  
Inflammatory Bowel

Abstract Abstract 713 In spite of recent genome-wide association studies, the molecular pathophysiology of many human auto-inflammatory diseases such as enterocolitis remains largely unknown. Here, we discover the first fully penetrant monogenetic defect causing inflammatory bowel disease (IBD) in humans. Using homozygosity mapping and candidate gene sequencing, we identified three distinct, homozygous mutations in IL10RA, encoding the IL10R1 protein, and IL10RB, encoding the IL10R2 protein, in patients with severe and refractory enterocolitis. IL10R1 is a specific receptor for IL10, whereas IL10R2 is a shared cytokine receptor unit for IL10, IL22, IL26, and IFNλ. The striking similarity of the clinical phenotype between patients with IL10RA and IL10RB deficiency, respectively, suggests that defective IL10-mediated signaling, and not IL22, IL26, or IFNλ dependent effects, is the critical reason for disease. Deleterious missense mutations in IL10RA abrogate IL10-induced signaling, as shown by deficient phosphorylation of STAT3 at the residue tyrosine 705 in primary patient cells and in HeLa cells engineered to express mutant IL10R1. Mutations in IL10RB introduced a premature stop codon. Defective expression of IL10R2 on the cell surface and deficient STAT3 signaling could be reconstituted by lentiviral gene transfer. As a consequence of defective STAT3 signal transduction in response to IL10 stimulation, IL10R-deficient primary cells showed increased secretion of TNFαa and various other proinflammatory cytokines unresponsive to IL10-dependent negative feedback regulation (TGFβ1, IL1αa, IL1β, IL2, IL6, IL6sR, RANTES, MCP1, MIP1αa, and MIP1β). We are currently assessing whether other IBD patients with early-onset IBD show defects in IL10-mediated signal transduction. In view of the therapy refractory course of disease and the critical role of IL10 signaling on cells of the hematopoietic system, we have successfully treated two IBD patients with IL10 receptor deficiency by hematopoietic stem cell transplantation (HSCT) without overt side effects. This proof-of-principle suggests that allogeneic HSCT may represent a novel therapeutic approach to treat defined subgroups of IBD patients. In summary, our results suggest that IL10 receptor defects constitute monogenetic causes for severe, early-onset IBD patients, proving that a lack of IL10-mediated negative feedback signaling perturbs homeostasis of the intestinal immune system. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Early Diagnosis and Hematopoietic Stem Cell Transplantation for IL10R Deficiency Leading to Very Early-Onset Inflammatory Bowel Disease Are Essential in Familial Cases

2016 ◽  
Vol 2016 ◽  
pp. 1-5 ◽  
Author(s):  
Neslihan Edeer Karaca ◽  
Guzide Aksu ◽  
Ezgi Ulusoy ◽  
Serap Aksoylar ◽  
Salih Gozmen ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Bowel Disease ◽  
Early Onset ◽  
Chronic Diarrhea ◽  
Hematopoietic Stem ◽  
Inflammatory Bowel

Alterations of immune homeostasis in the gut may result in development of inflammatory bowel disease. A five-month-old girl was referred for recurrent respiratory and genitourinary tract infections, sepsis in neonatal period, chronic diarrhea, perianal abscess, rectovaginal fistula, and hyperemic skin lesions. She was born to second-degree consanguineous, healthy parents. Her elder siblings were lost at 4 months of age due to sepsis and 1 year of age due to inflammatory bowel disease, respectively. Absolute neutrophil and lymphocyte counts, immunoglobulin levels, and lymphocyte subsets were normal ruling out severe congenital neutropenia and classic severe combined immunodeficiencies. Quantitative determination of oxidative burst was normal, excluding chronic granulomatous disease. Colonoscopy revealed granulation, ulceration, and pseudopolyps, compatible with colitis. Very early-onset colitis and perianal disease leading to fistula formation suggested probability of inherited deficiencies of IL-10 or IL-10 receptor. A mutation at position c.G477A in exon of the IL10RB gene, resulting in a stop codon at position p.W159X, was identified. The patient underwent myeloablative hematopoietic stem cell transplantation from full matched father at 11 months of age. Perianal lesions, chronic diarrhea, and recurrent infections resolved after transplantation. IL-10/IL-10R deficiencies must be considered in patients with early-onset enterocolitis.

Novel Compound Heterozygote Mutation in IL10RA in a Patient With Very Early-Onset Inflammatory Bowel Disease

2018 ◽  
Vol 25 (3) ◽  
pp. 498-509
Author(s):  
Seak Hee Oh ◽  
Young Hoon Sung ◽  
Inki Kim ◽  
Chan Kyu Sim ◽  
Jung Hoon Lee ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Early Onset ◽  
Compound Heterozygote ◽  
Inflammatory Bowel

scholarly journals Very Early Onset Inflammatory Bowel Disease: A Clinical Approach With a Focus on the Role of Genetics and Underlying Immune Deficiencies

2019 ◽  
Vol 26 (6) ◽  
pp. 820-842 ◽  
Author(s):  
Jodie Ouahed ◽  
Elizabeth Spencer ◽  
Daniel Kotlarz ◽  
Dror S Shouval ◽  
Matthew Kowalik ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Early Onset ◽  
Primary Immune Deficiency ◽  
Clinical Approach ◽  
Older Children ◽  
Ongoing Research ◽  
Complex Patients ◽  
Immune Deficiencies ◽  
Inflammatory Bowel

Abstract Very early onset inflammatory bowel disease (VEO-IBD) is defined as IBD presenting before 6 years of age. When compared with IBD diagnosed in older children, VEO-IBD has some distinct characteristics such as a higher likelihood of an underlying monogenic etiology or primary immune deficiency. In addition, patients with VEO-IBD have a higher incidence of inflammatory bowel disease unclassified (IBD-U) as compared with older-onset IBD. In some populations, VEO-IBD represents the age group with the fastest growing incidence of IBD. There are contradicting reports on whether VEO-IBD is more resistant to conventional medical interventions. There is a strong need for ongoing research in the field of VEO-IBD to provide optimized management of these complex patients. Here, we provide an approach to diagnosis and management of patients with VEO-IBD. These recommendations are based on expert opinion from members of the VEO-IBD Consortium (www.VEOIBD.org). We highlight the importance of monogenic etiologies, underlying immune deficiencies, and provide a comprehensive description of monogenic etiologies identified to date that are responsible for VEO-IBD.

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