Background/Aims:Very early-onset inflammatory bowel disease (VEO-IBD), defined as IBD diagnosed before 6 years of age, is highly influenced by genetic factors. Monogenic IBD is a type of enterocolitis caused by a single pathogenic variant. However, information on Asian patients with VEO-IBD and monogenic IBD is limited. This study investigated real-world data on VEOIBD and monogenic IBD in Japan. Methods:We evaluated patients with VEO-IBD registered in the Japanese Pediatric Inflammatory Bowel Disease Registry, a multicenter prospective registry study conducted between 2012 and 2021. We categorized patients into monogenic and non-monogenic IBD groups and compared their clinical characteristics and outcomes. Results:Among 703 pediatric patients with IBD, 68 (9.7%) had VEO-IBD. Of these, 26 (38.2%) had ulcerative colitis, 16 (23.5%) had Crohn's disease, 23 (33.8%) had unclassified IBD (IBD-U), and 3 (4.4%) had Behçet's disease. Genetic testing was performed in 25 patients (36.8%), and monogenic IBD was identified in 5 of the 23 patients with IBD-U (7.4% of the VEO-IBD cohort). All 5 monogenic cases presented with an IBD-U phenotype. Monogenic IBD included A20 haploinsufficiency, interleukin-10 receptor subunit alpha deficiency, chronic granulomatous disease, Wiskott-Aldrich syndrome, and Hermansky-Pudlak syndrome. Monogenic IBD was significantly associated with IBD-U phenotype (P= 0.015) and severe infections before 1 year of age (P= 0.004). Conclusions:Patients with VEO-IBD who present an IBD-U phenotype and have a history of severe infections during infancy should be prioritized for genetic analysis to investigate the possibility of monogenic IBD.

BACKGROUND & AIMS:Tumor necrosis factor (TNF) is a key driver of intestinal epithelial inflammation. The baculoviral inhibitor of apoptosis protein repeat-containing 3 (BIRC3) gene encodes the cellular inhibitor of apoptosis protein 2 (cIAP2), a known regulator of TNF signaling. Although genetic variants in components of the TNF signaling pathway have been reported, no human BIRC3 variants have been previously identified. METHODS:We screened exomes obtained from Crohn's disease (CD) patients from multiple centers for BIRC3 variants. We used cellular, mouse organoids, induced pluripotent stem cells-derived intestinal organoids, knock-in and knockout mouse models, and knockout zebrafish, as well as transcriptome analysis of various samples to determine pathogenicity of BIRC3 variants. RESULTS:Rare and damaging BIRC3 variants were identified in 14 patients from 10 unrelated families with CD diagnosed between infancy and adulthood. Functional studies showed that BIRC3 deficiency caused impaired receptor-interacting protein kinase 1 (RIPK1) ubiquitylation, leading to RIPK1 autophosphorylation resulting in increased epithelial cell death. The p.H312Y cIAP2 variant identified in both our index and in another independent patient was mislocalizaed, and a knock-in mouse model of this BIRC3 variant (cIAP2H312Y/+) had exacerbation of chemically induced colitis, whereas ciap1-/+ zebrafish developed spontaneous colitis. Transcriptome analysis of mice organoids and zebrafish showed that BIRC3 deficiency led to inappropriate sustained activation of TNF-responsiveness genes in the absence of stimuli. Small molecule pharmacologic inhibition of RIPK1 or caspases attenuated intestinal inflammation in BIRC3-deficient intestinal organoids and cIAP2H312Y/+ mice. CONCLUSIONS:We establish BIRC3 deficiency as a cause of monogenic CD in both pediatric- and adult-onset patients and identify RIPK1 as a therapeutic target.

BACKGROUND/AIMS:Occasionally, pediatric Crohn's disease (CD) may develop after diagnosis of orofacial granulomatosis (OFG), which is characterized by chronic granulomatous lesions of the oral mucosa, lips, and perioral area. This study aimed to clarify clinical characteristics, treatment responses, and potential genetic contributors in pediatric patients with CD complicating OFG. METHODS:We studied pediatric patients with CD complicating OFG who were treated from 2013 to 2022 at 7 Japanese institutions specializing in pediatric inflammatory bowel disease. Their clinical courses were analyzed retrospectively, and analyses of 71 genes associated with monogenic inflammatory bowel disease were performed. RESULTS:Among 13 patients, 8 were girls. Median ages at diagnosis of OFG and CD were 9.2 (3.8-15.3) and 10.3 (6.4-15.3) years old, respectively. Upper gastrointestinal lesions were frequent in 8 cases (62%), while perianal lesions were present in 7 (54%). OFG failed to improve or relapsed despite remission of intestinal lesions in about half of the patients (n = 7, 54%). During follow-up, OFG went into remission in 7 patients, including 6 of the 9 who were treated with biologics (66%) and 1 of the 4 who were not (25%). In 8 patients, the NCF1 p.Arg90His allele was detected by genetic analysis; 7 were heterozygous and 1 homozygous, a higher prevalence than in the general Japanese population. CONCLUSIONS:Clinical features of OFG associated with pediatric CD are diverse, and biologic agents were beneficial for OFG patients. NCF1 p.Arg90His mutation may contribute to the pathogenesis of pediatric CD complicating OFG.

BackgroundNFKB1 haploinsufficiency caused by monoallelic loss-of-function variants in NFKB1 results in a CVID-like phenotype or other forms of hypogammaglobulinemia.ObjectiveThis study aims to characterize the clinical and immunological profiles of 21 individuals from nine families with this disorder.MethodsGene panel sequence and/or whole exome sequence, followed by Sanger sequencing, were used to identify and confirm NFKB1 variants. Immunophenotyping were performed by flow cytometry. The type I interferon signature was determined by quantitative PCR.ResultsOf the nine NFKB1 variants, seven novel heterozygous variants were identified in this study. Ten individuals were clinically asymptomatic, while 11 were symptomatic, resulting in clinical penetrance of 52%. However, immunologic abnormalities were observed in all asymptomatic family members tested (n=9). The main presenting symptoms in symptomatic individuals were respiratory tract infections (7/11) and autoimmune or autoinflammatory features (7/11). Interestingly, two patients had Moyamoya disease, and one patient was complicated by alopecia and rheumatoid arthritis. Immunological analyses were performed in 19 individuals, including 9 asymptomatic, and revealed that 58% had low absolute T cell counts and that 72% of individuals displayed inverted CD4/CD8 T-cell ratio. B-cell lymphopenia and decreased switch memory B cells were observed in 42% and 61% of individuals, respectively. A type I interferon signature was not observed.ConclusionsIn addition to hypogammaglobulinemia/CVID-like phenotype, NFKB1 variants have been associated with a wide range of manifestations, ranging from various organ involvements to autoimmunity. Autoinflammatory features have also been reported; however, the presence of type I interferon signatures was not specifically addressed in this study.

[This corrects the article DOI: 10.3389/fimmu.2026.1866459.].

Very-early-onset inflammatory bowel disease (VEO-IBD), representing cases diagnosed before age 6 years, is increasing in prevalence. Although VEO-IBD often presents as severe, treatment-resistant disease requiring biologic agents, studies showing the effectiveness of biologics, such as ustekinumab (UST) and vedolizumab (VDZ), remain limited. We retrospectively analyzed patients with VEO-IBD treated for at least a year from 13 institutions in Japan, evaluating clinical course including effectiveness of biologics, such as infliximab (IFX), adalimumab (ADL), UST, and VDZ. Patients with monogenic IBD were excluded. Steroid-free clinical remission (SFCR) and treatment persistence were assessed separately for first-line and for second-line or subsequent biologic therapies. We studied 101 VEO-IBD patients (56

IKAROS, encoded by IKZF1, is a crucial transcription factor regulating hematopoiesis and B cell development. While IKZF1 haploinsufficiency variants are associated with various immunological disorders, inflammatory bowel disease (IBD) has been rarely reported. We report a case of IKZF1 haploinsufficiency presenting with an atypical IBD phenotype and its response to filgotinib. The patient was previously diagnosed with IKZF1 haploinsufficiency and presented with chronic diarrhea, fatigue and anemia. Laboratory findings indicated folate deficiency-induced megaloblastic anemia and malabsorption syndrome. Endoscopic examination showed inflammation with erythema in the colon and extensive villous blunting of the small intestine. Immunohistochemical analysis revealed increased pSTAT3/5 in the colon. Considering the clinical features and increased JAK-STAT cascade, treatment with filgotinib was initiated. At 10 weeks post-treatment, we observed improvement in endoscopic findings and suppression of pSTAT3/5. This case extends the clinical spectrum of IKZF1 haploinsufficiency. A JAK1 inhibitor is considered to be useful for IKZF1 haploinsufficiency-associated IBD.

Eosinophilic gastrointestinal disorders (EGIDs) are treated with corticosteroids and food allergen elimination. However, treatment for refractory cases is not standardized. We demonstrate the efficacy of vedolizumab, an anti-α4β7 integrin agent, in 2 children with duodenal ulcers developed by non-eosinophilic esophagitis EGIDs. In both, vedolizumab was used continuously without side effects, and long-term remission has been durable. Duodenal ulcers associated with EGIDs are increasing. Vedolizumab has potential as a treatment for even upper gastrointestinal lesions in refractory EGIDs.

PURPOSE:To evaluate the diagnostic performance of ultrasound in detecting Meckel's diverticulum (MD) and duplication cysts (DC) and to identify factors influencing diagnostic accuracy. METHODS:Among 66 patients with MD or DCs, we assessed the effect of symptom presence, atypical complications (hemoperitoneum, perforation, or acute pancreatitis), and lesion shape (tubular or cystic) on initial sonographic diagnostic accuracy using Fisher's exact test. RESULTS:Initial ultrasound correctly diagnosed 49.9% (27/66) of cases. Correct diagnosis rates differed significantly between MD and DC (11/17 vs. 33/5, p < 0.001) and between tubular and cystic lesions (13/15 vs. 36/2, p < 0.001). No significant differences were observed for symptomatic versus asymptomatic cases (22/6 vs. 34/4, p = 0.302) or for cases with versus without atypical complications (1/27 vs. 5/33, p = 0.230). However, all DC cases with atypical complications were misdiagnosed on ultrasound. CONCLUSION:Ultrasound demonstrated reliable diagnostic performance for DCs; however, MDs were more challenging to identify. Consequently, when MDs are suspected on clinical grounds, additional imaging, such as Tc-99m scintigraphy, should be considered. In patients with DCs, atypical complications, such as hemoperitoneum or acute pancreatitis, may obscure sonographic diagnosis. Sonographers should therefore include DCs in the differential diagnosis when these complications arise without an apparent etiology.

OBJECTIVES:To investigate the prevalence and characteristics of growth impairment (GI) in children with inflammatory bowel disease (IBD). METHODS:In this prospective observational study, 402 children with ulcerative colitis (UC, n = 257) and Crohn's disease (CD, n = 145) were enrolled from the Japanese Pediatric IBD Registry (2012-2020). GI was defined by Paris classification criteria. Longitudinal outcomes were assessed in children with ≥2 years of follow-up (n = 307). RESULTS:At diagnosis, the GI prevalence was comparable between children with UC and CD (6.2% vs. 8.3%, p = 0.54). However, children with UC diagnosed at 0-4 years demonstrated significantly higher GI rates (35.3%) than older children (p < 0.001). All children with CD experiencing GI had small intestinal lesions. Among those with GI at diagnosis, fewer children with UC (9%) recovered growth at a 2-year follow-up than those with CD (50%). Among children with normal growth at baseline, new-onset GI occurred in 23% of UC and 16% of CD cases. Of these, 31% recovered within 2 years, while persistent GI was observed in 16% of UC and 11% of CD cases. Prolonged corticosteroid use at 1 year was more frequent in UC (31% vs. 19%, p = 0.02) and was significantly associated with persistent GI. CONCLUSIONS:Distinct growth patterns exist in Japanese children with IBD. Children with UC diagnosed at 0-4 years are particularly vulnerable and may benefit from early, steroid-sparing treatment. The association between small intestinal lesions and GI in CD emphasizes the importance of small bowel evaluation. Age-specific, patient-centered growth monitoring is crucial to optimize long-term outcomes.

OBJECTIVES:This study aimed to investigate the diagnostic performance of ultrasonography in evaluating intra-abdominal free air in pediatric patients with acute abdomen. METHODS:This retrospective study evaluated pediatric patients with abdominal symptoms who underwent ultrasonography before computed tomography (CT), the gold standard for diagnosing intra-abdominal air. The diagnostic performance of ultrasonography was determined based on this standard. In pediatric patients with intra-abdominal free air, free air sizes (massive or focal), and age were compared between those in whom free air was and was not detected on ultrasonography using Fisher's exact and Mann-Whitney U tests. RESULTS:A total of 240 patients were evaluated. Among the 14 patients with intra-abdominal free air, 10 patients were correctly diagnosed using ultrasonography. The diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of ultrasonography for detecting intra-abdominal free air were 98.3% (236/240), 71.4% (10/14), 100% (226/226), 100% (10/10), and 98.3% (226/230), respectively. Although the differences were not statistically significant, diagnosis tended to be more difficult in patients with focal free air and older age (massive versus focal free air and ages in patients with ultrasonographically detected versus undetected free air = 6/4 versus 0/4, P = .084; age: 5.2 ± 6.4 years [0-16.7 years] versus 11.6 ± 5.2 years [5.7-16.8 years], P = .089). CONCLUSIONS:Ultrasonography has satisfactory diagnostic accuracy for detecting intra-abdominal free air in pediatric patients with acute abdomen, but not all cases are detected. Examiners and physicians should consider further examinations and management for these patients.

BACKGROUND:Small bowel capsule endoscopy is a valuable modality for evaluating small intestinal lesions in children with inflammatory bowel disease. However, its application for very early-onset inflammatory bowel disease remains insufficiently documented. This study investigated the feasibility and safety of small bowel capsule endoscopy for very early-onset inflammatory bowel disease. METHODS:A cohort of patients with very early-onset inflammatory bowel disease who underwent small bowel capsule endoscopy at under 6 years of age between January 2013 and December 2022 at 7 Japanese pediatric centers was included. Their medical records were retrospectively reviewed for actual procedures, safety, and test results. RESULTS:Eighty-two patients (21 with ulcerative colitis, 25 with Crohn's, 31 with inflammatory bowel disease-unclassified, 4 with monogenic inflammatory bowel disease, and 1 with intestinal Behçet's disease) were enrolled, and 104 small bowel capsule endoscopies (median age, 3.8 years; median body weight, 13.0 kg) were analyzed. All capsules were deployed endoscopically, mostly using delivery devices (95%). Gastrointestinal patency was assessed in 95% of procedures, most commonly using patency capsules (70%). Abnormal small bowel findings were observed in 42% of patients, with aphthae being the most common (34%), followed by ulcers (18%). No serious complications, including small intestinal retention and perforation, were reported. CONCLUSIONS:Small bowel capsule endoscopy for very early-onset inflammatory bowel disease is feasible with diagnostic utility, and it can be performed safely with appropriate evaluation using patency capsules.

Introduction: This study evaluated nutrient deficiencies in infants and toddlers with inflammatory bowel disease (IBD) and eosinophilic gastrointestinal disorders (EGIDs), whose primary nutritional source is elemental formulas (EFs). Methods: The nutrient status of children with IBD and EGID aged 6 months to 6 years was evaluated. Results: Twenty-one children fed with EFs (EF group) and 25 controls (CL group) were enrolled. The selenium level in the EF group was lower than that in the CL group (2.2 μg/dL vs. 9.3 μg/dL; p < 0.01). Although fat-soluble vitamins were deficient in some EF group participants, no significant differences were observed in their concentration and insufficiency proportion. However, ascorbic acid deficiency was more frequent in the EF group, with significantly lower levels (8.6 μg/mL vs. 12.0 μg/mL; p < 0.01). The triene:tetraene ratio was significantly higher in the EF group (0.046 vs. 0.010; p < 0.01). Asparagine and taurine levels were significantly lower in the EF group (asparagine: p < 0.01; taurine: p < 0.01) and tyrosine and phenylalanine levels were higher in the EF group, resulting in a lower Fisher’s ratio (p < 0.01). Conclusion: Long-term feeding with EFs can cause deficiencies in essential fatty acids, selenium, and ascorbic acid and also carries a risk of amino acid imbalance in infants and toddlers.

This multicenter cohort study described the long-term course and prognostic factors in pediatric ulcerative proctitis. The commonest treatment, 5-ASA suppository monotherapy in 40% of patients, showed worst compliance. Immunosuppressive treatment was given to 37%; biologic agents were used for 18%.

We observed efficacy and safety of ustekinumab in very early-onset inflammatory bowel disease, which has not been previously reported. Clinical remission at 52% was 75%, often persisting beyond 2 years. Further studies including larger numbers of cases are needed to confirm this observation.

As best practices for treating children with severe-onset ulcerative colitis remain controversial in the era of biologic agents, we prospectively investigated treatments and outcomes in a multicenter cohort. Using a Web-based data registry maintained in Japan between October 2012 and March 2020, we compared management and treatment outcomes in an S1 group defined by a Pediatric Ulcerative Colitis Activity Index of 65 or more points at diagnosis with those in an S0 group defined by an index value below 65. Three hundred one children with ulcerative colitis treated at 21 institutions were included, with follow-up for 3.6 ± 1.9 years. Among them, 75 (25.0%) were in S1; their age at diagnosis was 12.3 ± 2.9 years, and 93% had pancolitis. Colectomy free rates in S1 were 89% after 1 year, 79% after 2, and 74% after 5, significantly lower than for S0 (P = 0.0003). Calcineurin inhibitors and biologic agents, respectively, were given to 53% and 56% of S1 patients, significantly more than for S0 patients (P < 0.0001). Among S1 patients treated with calcineurin inhibitors when steroids failed, 23% required neither biologic agents nor colectomy, similarly to the S0 group (P = 0.46). Children with severe ulcerative colitis are likely to require powerful agents such as calcineurin inhibitors and biologic agents; sometimes colectomy ultimately proves necessary. Need for biologic agents in steroid-resistant patients might be reduced to an extent by interposing a therapeutic trial of CI rather than turning to biologic agents or colectomy immediately.

BackgroundVedolizumab (VDZ) is a humanized monoclonal antibody that binds to alpha 4 beta 7 integrin expressed in T-lymphocytes and is gut selective. Few studies have evaluated the safety and efficacy of VDZ in pediatric ulcerative colitis (UC) patients, especially from Asia. MethodsA longitudinal multicenter retrospective study was conducted at 10 Japanese tertiary medical institutions. Patients aged <= 18 years old who received VDZ for UC between January 2019 and July 2021 were enrolled. Information on the clinical characteristics, prior/concomitant treatment, and safety during the observation period was collected. ResultsThe data obtained from 48 patients (males, n = 30; females, n = 18) were analyzed. The median age at VDZ induction was 14 (range 4-18) years old. VDZ was indicated in 73% of patients as switching from previous biologics due to primary failure, loss of response, and adverse events (AEs) and was the first biologic in 27%. Remission was achieved or maintained at weeks 14, 30, and 54 in 79.2%, 75.0%, and 65.8% of patients, respectively. There were no significant differences between the number of previous biologics exposures and VDZ effectiveness. The hematocrit, serum albumin concentrations, and erythrocyte sedimentation rate (ESR) at baseline differed significantly by VDZ effectiveness. Nine AEs, including infusion reaction, were noted in seven (14.3%) patients. There were no severe AEs related to VDZ administration. ConclusionsVDZ was safe and effective in children with UC. The hematocrit, albumin, and ESR at VDZ initiation might be predictors for VDZ effectiveness. VDZ may be an important option for pediatric patients and can be used as an alternative to immunomodulators.