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Summary: Background: Infantile‐onset inflammatory bowel disease can be caused by defects in interleukin‐10 signalling. The natural history and clinical outcomes of allogeneic haematopoietic stem cell transplantation, medical treatment and surgery have not been thoroughly described. Aims: This study evaluates disease progression and clinical outcome in patients with interleukin‐10 signalling deficiency. Methods: One hundred and nine patients with interleukin‐10 signalling deficiency were retrospectively reviewed from a single tertiary centre. The Kaplan‐Meier method was applied to calculate probabilities of survival and interval between transplant and stoma closure. Results: One hundred and nine patients were reviewed, and 102 patients were included in the survival analysis. One hundred and eight patients were identified with IL10RA mutations, and one patient harboured IL10RB mutation. Seventy‐three patients received haematopoietic stem cell transplantation. The overall survival after transplantation was 64.2% (95% confidence interval, 52.8 to 75.6), and without transplantation, it was 47.5% (95% confidence interval, 14.8 to 80.2, P = 0.47). The median timeframe between transplant and stoma closure was 19.6 months. The probability of survival was significantly lower in patients with perforation (P < 0.001), ileus (P = 0.038) and without thalidomide treatment (P < 0.001) among patients who did not receive haematopoietic stem cell transplantation. The survival probability was not associated with timeframe between transplant and onset, graft source and genotypes. Conclusions: The survival probability was not significantly different between patients with transplantation and the non‐transplanted patients. [ABSTRACT FROM AUTHOR]

Background: Although deleterious mutations in interleukin-10 and its receptor molecules cause severe infantile-onset inflammatory bowel disease, there are no reports of mutations affecting this signaling pathway in Japanese patients. Here we report a novel exonic mutation in the IL10RA gene that caused unique splicing aberrations in a Japanese patient with infantile-onset of inflammatory bowel disease in association with immune thrombocytopenic purpura and a transient clinical syndrome mimicking juvenile myelomonocytic leukemia.Case Presentation: A Japanese boy, who was the first child of non-consanguineous healthy parents, developed bloody diarrhea, perianal fistula, and folliculitis in early infancy and was diagnosed with inflammatory bowel disease. He also developed immune thrombocytopenic purpura and transient features mimicking juvenile myelomonocytic leukemia. The patient failed to respond to various treatments, including elemental diet, salazosulfapyridine, metronidazole, corticosteroid, infliximab, and adalimumab. We identified a novel mutation (c.537G > A, p.T179T) in exon 4 of the IL10RA gene causing unique splicing aberrations and resulting in lack of signaling through the interleukin-10 receptor. At 21 months of age, the patient underwent allogeneic hematopoietic stem cell transplantation and achieved clinical remission.Conclusions: We describe a novel exonic mutation in the IL10RA gene resulting in infantile-onset inflammatory bowel disease. This mutation might also be involved in his early-onset hematologic disorders. Physicians should be familiar with the clinical phenotype of IL-10 signaling defects in order to enable prompt diagnosis at an early age and referral for allogeneic hematopoietic stem cell transplantation. [ABSTRACT FROM AUTHOR]

Background: Infantile-onset inflammatory bowel disease (IO-IBD) occurs in very young children and causes severe clinical manifestations, which has poor responses to traditional inflammatory bowel disease (IBD) treatments. At present, there are no simple and reliable laboratory indicators for early screening IO-IBD patients, especially those in whom the disease is caused by monogenic diseases., Aim: To search for valuable indicators for early identifying IO-IBD patients, especially those in whom the disease is caused by monogenic diseases., Methods: A retrospective analysis was performed in 73 patients with IO-IBD admitted to our hospital in the past 5 years. Based on the next-generation sequencing results, they were divided into a monogenic IBD group (M-IBD) and a non-monogenic IBD group (NM-IBD). Forty age-matched patients with allergic proctocolitis (AP) were included in a control group. The clinical manifestations and the inflammatory factors in peripheral blood were evaluated. Logistic regression analysis and receiver operating characteristic (ROC) curve analysis were used to identify the screening factors and cut-off values of IO-IBD as well as monogenic IO-IBD, respectively., Results: Among the 44 M-IBD patients, 35 carried IL-10RA mutations, and the most common mutations were c.301C>T (p.R101W, 30/70) and the c.537G>A (p.T179T, 17/70). Patients with higher serum tumor necrosis factor (TNF)-α value were more likely to have IBD [odds ratio (OR) = 1.25, 95% confidence interval (CI): 1.05-1.50, P = 0.013], while higher serum albumin level was associated with lower risk of IBD (OR = 0.86, 95%CI: 0.74-1.00, P = 0.048). The cut-off values of TNF-α and albumin were 17.40 pg/mL (sensitivity: 0.78; specificity: 0.88) and 36.50 g/L (sensitivity: 0.80; specificity: 0.90), respectively. The increased ferritin level was indicative of a genetic mutation in IO-IBD patients. Its cut-off value was 28.20 ng/mL (sensitivity: 0.93; specificity: 0.92). When interleukin (IL)-10 level was higher than 33.05 pg/mL (sensitivity: 1.00; specificity: 0.84), or the onset age was earlier than 0.21 mo (sensitivity: 0.82; specificity: 0.94), the presence of disease-causing mutations in IL-10RA in IO-IBD patients was strongly suggested., Conclusion: Serum TNF-α and albumin level could differentiate IO-IBD patients from allergic proctocolitis patients, and serum ferritin and IL-10 levels are useful indicators for early diagnosing monogenic IO-IBD., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to declare., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Infantile-onset inflammatory bowel disease (IO IBD) is an invalidating illness with an onset before 2 years of age and has a complex pathophysiology in which genetic factors are important. Homozygosity mapping and whole-exome sequencing in an IO IBD patient and subsequent sequencing of the candidate gene in 12 additional IO IBD patients revealed two patients with two mutated ankyrin repeat and zinc-finger domain-containing 1 ( ANKZF1 ) alleles (homozygous ANKZF1 R585Q mutation and compound heterozygous ANKZF1 E152K and V32&#95;Q87del mutations, respectively) and two patients with one mutated ANKZF1 allele. Although the function of ANKZF1 in mammals had not been previously evaluated, we show that ANKZF1 has an indispensable role in the mitochondrial response to cellular stress. ANKZF1 is located diffusely in the cytoplasm and translocates to the mitochondria upon cellular stress. ANKZF1 depletion reduces mitochondrial integrity and mitochondrial respiration under conditions of cellular stress. The ANKZF1 mutations identified in IO IBD patients with two mutated ANKZF1 alleles result in dysfunctional ANKZF1, as shown by an increased level of apoptosis in patients' lymphocytes, a decrease in mitochondrial respiration in patient fibroblasts with a homozygous ANKZF1 R585Q mutation, and an inability of ANKZF1 R585Q and E152K to rescue the phenotype of yeast deficient in Vms1, the yeast homologue of ANKZF1. These data indicate that loss-of-function mutations in ANKZF1 result in deregulation of mitochondrial integrity, and this may play a pathogenic role in the development of IO IBD., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Aim: Infantile-onset inflammatory bowel disease (IO-IBD) with the onset of disease before 12 mo of age, is a different disease entity from childhood IBD. We aimed to describe the clinical features, outcome and role of mutation in interleukin-10 (IL-10) and interleukin-10 receptors (IL-10R) in Asian children with IO-IBD., Methods: All cases of IO-IBD, defined as onset of disease before 12 mo of age, seen at University Malaya Medical Center, Malaysia were reviewed. We performed mutational analysis for IL10 and IL10R genes in patients with presenting clinical features of Crohn's disease (CD)., Results: Six [13%; CD = 3, ulcerative colitis (UC) = 2, IBD-unclassified (IBD-U) = 1] of the 48 children (CD = 25; UC = 23) with IBD have IO-IBD. At final review [median (range) duration of follow-up: 6.5 (3.0-20) years], three patients were in remission without immunosuppression [one each for post-colostomy (IBD-U), after standard immunosuppression (CD), and after total colectomy (UC)]. Three patients were on immunosuppression: one (UC) was in remission while two (both CD) had persistent disease. As compared with later-onset disease, IO-IBD were more likely to present with bloody diarrhea (100% vs 55%, P = 0.039) but were similar in terms of an associated autoimmune liver disease (0% vs 19%, P = 0.31), requiring biologics therapy (50% vs 36%, P = 0.40), surgery (50% vs 29%, P = 0.27), or achieving remission (50% vs 64%, P = 0.40). No mutations in either IL10 or IL10R in the three patients with CD and the only patient with IBD-U were identified., Conclusion: The clinical features of IO-IBD in this Asian cohort of children who were negative for IL-10 or IL-10R mutations were variable. As compared to childhood IBD with onset of disease after 12 mo of age, IO-IBD achieved remission at a similar rate., Competing Interests: Conflict-of-interest statement: The authors have declared that no competing interests exist.