Very early onset inflammatory bowel disease with compound heterozygous variants in Nuclear Factor of Activated T cell 5

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.

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

10.21203/rs.3.rs-34174/v1 ◽

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.

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

Frontiers in Pediatrics ◽

10.3389/fped.2021.678390 ◽

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.

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The E3 ubiquitin ligase UBR5 interacts with TTC7A and may be associated with very early onset inflammatory bowel disease

Scientific Reports ◽

10.1038/s41598-020-73482-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Neel Dhingani ◽

Conghui Guo ◽

Jie Pan ◽

Qi Li ◽

Neil Warner ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Early Onset ◽

Intestinal Atresia ◽

Compound Heterozygous ◽

Functional Studies ◽

Monogenic Disorders ◽

Whole Exome ◽

Inflammatory Bowel ◽

Tetratricopeptide Repeat Domain

Abstract Very early onset inflammatory bowel disease (VEOIBD) denotes children with onset of IBD before six years of age. A number of monogenic disorders are associated with VEOIBD including tetratricopeptide repeat domain 7A (TTC7A) deficiency. TTC7A-deficiency is characterized by apoptotic colitis in milder cases with severe intestinal atresia and immunodeficiency in cases with complete loss of protein. We used whole exome sequencing in a VEOIBD patient presenting with colitis characterized by colonic apoptosis and no identified known VEOIBD variants, to identify compound heterozygous deleterious variants in the Ubiquitin protein ligase E3 component N-recognin 5 (UBR5) gene. Functional studies demonstrated that UBR5 co-immunoprecipitates with the TTC7A and the UBR5 variants had reduced interaction between UBR5 and TTC7A. Together this implicates UBR5 in regulating TTC7A signaling in VEOIBD patients with apoptotic colitis.

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