Video capsule endoscopy in very early onset inflammatory bowel disease: a multicenter retrospective study from the Chinese Pediatric VCE Study Group

Introduction

The incidence of inflammatory bowel disease (IBD) is increasing internationally (1). Very early onset IBD (VEOIBD) refers to patients who have disease onset before 6 years of age (2). A recent systemic review showed that the incidence of VEOIBD per 100,000 person-years ranged from 0.2–1.2 in Asia, and 0.4–3.3 in Europe (1). Studies in VEOIBD showed that monogenic cause was identified in 0–33% patients based on genetic testing (3). Due to its unique etiology, VEOIBD patients present with more severe and refractory phenotype than pediatric or young adult IBD (4). Therefore, it is crucial to identify patients with VEOIBD as management may be different from classical IBD (3). Hematopoietic stem cell transplantation and personalized targeted therapy can be applied to VEOIBD patients with certain genetic defects (5,6).

Our prior work described phenotype and genotype of VEOIBD patients, and patients with certain monogenic defects (7,8). Endoscopic and histologic evaluations are required to establish IBD diagnosis, and to assess disease behavior and inflammatory activity (2). Video capsule endoscopy (VCE) is a noninvasive modality in pediatrics to assess small bowel lesions without anesthesia. VCE has been approved for children older than 2 years of age in 2009 (9). VCE has been widely used among pediatric IBD in diagnosis and management (10,11). There are some case reports and case series describing upper and lower endoscopy findings of patients with monogenic defects in PIK3CD, XIAP, PRKDC, and LRBA (12,13). The literature on large cohort of VEOIBD patients on the VCE findings is still limited due to the younger age of these groups of patients and relatively rarity of the entities. The purpose of our study is to investigate features of small bowel lesions and explore the safety of VCE among VEOIBD based on a multicenter study. We present this article in accordance with the STROBE reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-22/rc).

Methods

Study design and patients

This was a retrospective multicenter study in China to examine the features of VCE among VEOIBD patients. We asked the pediatric gastroenterologist specialists whether they have performed VCE and genetic sequencing among VEOIBD patients using an internet-based questionnaire. The questionnaire was sent to eleven tertiary care centers in China. The clinical records of consecutive patients with all identified patients were retrospectively reviewed. Patients were diagnosed according to previously reported criteria on VEOIBD (14,15). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. All participating hospitals were informed and agreed the study. The study was approved by the Ethical Committees of Children’s Hospital of Fudan University (ethics No. [2015]-130), Shenzhen Children’s Hospital (ethics No. 2022-167), Chengdu Women’s and Children’s Central Hospital [ethics No. 2022(72)], Children’s Hospital of Hebei Province (ethics No. 202407-81), and Qilu Children’s Hospital of Shandong University (ethics No. 2020038). Written informed consents were obtained from parents or guardians of all patients before the procedure.

Procedures

VCEs were performed using either OMOM capsule CE-2012 (Jinshan Science & Technology, Chongqing, China), ANKON capsule (Anhan Science & Technology, Wuhan, China), or MiroCam capsule (Intromedic, Seoul, South Korea). The computed tomography enterography was performed to evaluate the patency of small bowel prior to subsequent VCE. Patients were given a clear liquid diet one day prior to VCE and were fast after midnight. If the patient cannot swallow the capsule or prolonged lodging in the stomach for more than 2.5 hours post-ingestion, a gastroscopy would be performed to deliver it into the duodenum.

Clinical data

Demographics, clinical manifestations and treatment were extracted from medical records. Original endoscopy reports were reviewed retrospectively for the distribution of lesions and pattern. If the patient has follow-up VCE, the result will also be collected. The gross description included the presence of mucosal ulcerations (ulcers of any size), nonulcerative inflammation (edema, pseudo-polyps), and strictures in the duodenum, jejunum and ileum. Gastric transit time (GTT) was defined as time of first duodenal image minus the time of the first gastric image. Small bowel transit time (SBTT) was defined as time of first cecal image minus the first duodenal image. Upper and lower endoscopy findings were also described. The histologic pattern was reported according to previous studies on pathologic findings in VEOIBD (15). Next-generation sequencing, including whole exome sequencing or capture-based targeted sequencing were performed.

Statistical analysis

Data were analyzed using SPSS 24.0 for Windows (SPSS Inc., Chicago, IL, USA). Continuous data were presented as the mean and standard deviation or median and interquartile range (IQR). Categorical variables were reported as the frequency and percentage.

Results

All specialists from eleven centers responded to the survey. A total of 37 VEOIBD patients who undergone both VCE and genetic sequencing were retrospectively identified from 5 centers. The total number of VCE procedures performed was 58 between 2012 and 2022. Among all subjects, 29 were male (78.4%). The demographic features of the patients are summarized in Table S1.

Perianal disease was found in 7 (18.9%) patients and 4 (10.8%) patients had recurrent infections. Both upper and lower endoscopy have been conducted in all patients. In this study, 27 (73.0%) were diagnosed with Crohn’s disease (CD)-like, 5 (13.5%) were identified as ulcerative colitis (UC)-like, and 5 (13.5%) fell under IBD-unclassified (IBD-U). Histologic evaluations of the lower endoscopy were performed for 35 patients. The most common findings were active enteritis, lymphocytic pattern and eosinophil-pattern. The VCE features, upper/lower endoscopy and histology are summarized in Table S1.

Gastroscopy-assisted delivery was performed for six times because of prolonged lodging in the stomach and for three times when the patients cannot swallow the capsule. The VCE were performed at an average age of 7.8±3.2 years. Median GTT was 78.5 minutes (IQR, 29.3–170.0 minutes) and median SBTT was 318.0 minutes (IQR, 231.3–423.0 minutes) among all procedures. VCE detected erosions, edema, ulcers and pus formation in the duodenum, jejunum and ileum. The numbers and percentages of various lesions are summarized in Table 1. The most frequent findings were duodenal ulcers, jejunal ulcers, ileal ulcers and pseudo-polyps. Stenosis, blunting and lymphoid changes had also been identified. There was no statistical difference in the proportion of various lesions between monogenic (number of VCE procedures =26) and non-monogenic patients (number of VCE procedures =29).

Next-generation sequencing confirmed the known monogenic IBD in 18 patients (48.6%) (Figure 1). The frequent mutations were found in TNFAIP3 (n=5), BTK (n=3), FOXP3 (n=2), PIK3CD (n=2), and XIAP (n=2). All patients with TNFAIP3 mutations except one suffered from ileal ulcers, and ileal blunting was noted in one patient with BTK mutation (Figure 2). Patients with TNFAIP3 mutations also had colonic erosions and ulcers identified by colonoscopy. Notably, patients with TNFAIP3 mutations tended to have persistent diseases, as the lesions did not improve during follow-up VCEs (Figure 2). Patients with PIK3CD mutations showed nodular lymphoid hyperplasia in terminal ileum (Figure 2). Ulceration was discovered in one patient with FOXP3 mutation, while for patients with XIAP mutation, pseudo-polyps were identified (Figure 2). For patient with SLC37A4 mutation, ulceration was noted in the terminal ileum (Figure 2).

Figure 1 Number of patients with identified pathogenic variants based on next-generation sequencing.

Figure 2 VCE findings of VEOIBD patients. (A,B) Erosion and ileal ulcer found in one patient with SLC37A4 mutations. (C,D) Ulcers and pseudo-polyps found in one patient with XIAP mutations. (E,F) Ileal blunting found in patient with BTK mutation. (G,H) Multiple ulcers and erosions found in two patients with TNFAIP3 mutations. (I,J) Ulcers and lymphoid changes found in one patient with PIK3CD mutation. (K,L) Ulcers found in one patient with ELANE mutation. (M) Nodules with ulcers found in one patient with BACH2 mutation. (N) Multiple ulcers found in this patient during follow up. (O,P) Multiple ulcers found in two patients without known pathogenic mutations. White arrows: lesions found on VCE. VCE, video capsule endoscopy; VEOIBD, very early onset inflammatory bowel disease.

Monogenic IBD can be classified according to the taxonomy of defective genes (16). The monogenic disease syndrome might be caused by different gene defects and each gene cluster is associated with a specific IBD mechanism (16). In this cohort, the predominant cellular compartment of the defective genes involved hematopoietic cells, phagocytes, Treg, and mixed cell types. VCE features of monogenic IBD patients based on defective gene cluster and cellular compartment were shown in Figure 3.

Figure 3 Endoscopic phenotypes on VCE of patients based on the taxonomy model of monogenic IBD including defective gene, cellular compartment in the heatmap. G-CSF, granulocyte colony-stimulating factor; HSCT, hematopoietic stem cell transplantation; IBD, inflammatory bowel disease; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome; IVIG, intravenous immunoglobulin; Treg, regulatory T cells; VCE, video capsule endoscopy.

Twelve patients underwent follow-up VCE investigations, of whom one patient received four tests, five patients received three tests and the rest five of them had two tests. Only three patients showed improvements in the small bowel lesions showed in VCE (Figure 4). No adverse effect including capsule retention or endoscopic delivery procedures related adverse effects including perforation, aspiration pneumonia, gastrointestinal bleeding, mucosal trauma in the pharynx, esophagus, stomach or duodenum have been observed in this study.

Figure 4 Follow-up VCE of VEOIBD patients. (A-C) Patient without known pathogenic variants, the lesions showed improvement during follow-up. (D-F) Another patient with TNFAIP3 mutations, her small lesions did not improve during 4 years of follow-up. (G-I) Patient with no known pathogenic variants, the initial VCE finding was negative, while she developed ulcers in the terminal ileum and jejunum during later follow-up. White arrows: lesions found on VCE. VCE, video capsule endoscopy; VEOIBD, very early onset inflammatory bowel disease.

In this cohort, 26 patients (70.3%) received mesalamine, 22 patients (59.5%) received exclusive enteral nutrition, 20 patients (54.1%) received steroid as induction therapy, 14 patients (37.8%) received infliximab, and two patients (5.4%) received adalimumab. Two patients with refractory disease after infliximab tried ustekinumab. For maintenance treatment, 3 patients (8.1%) were treated with methotrexate, 10 patients (27.0%) were treated with azathioprine, 10 (27.0%) with thalidomide, one with tofacitinib. For genetic defect-specific treatment, two patients with PIK3CD mutations received sirolimus, one patient with CARD11 mutation, one with PIK3CD mutations and one with XIAP mutations underwent successful hematopoietic stem cell transplantations, six patients required regular immunoglobulin infusion (three patients with BTK mutations, two with PIK3CD mutations and one with BACH2 mutations). One patient with SLC37A4 mutations received granulocyte colony-stimulating factor. Eighteen patients (48.6%) achieved clinical remission based on physician’s evaluation.

Discussion

VEOIBD is a heterogenous disease by nature both in phenotype and genotype (4). Among this population, the disease onset is generally early in life and the disease course can be more aggressive (17). The incidence of VEOIBD is rapidly increasing, thus timely recognition and diagnosis are of importance (1). The recent position paper from the Pediatric IBD Porto Group of European Society of Pediatric Gastroenterology, Hepatology and Nutrition included 75 genes based on specialist reviews and consensus (3). There are also verified novel VEOIBD causative genes which are expanding the lists (18-20). Genetic investigations in VEOIBD patients to identify monogenic IBD is crucial to guide appropriate targeted therapies and decision makings (3). Allogeneic hemopoietic stem cell transplant has been shown as standard of care in patients with primary immunodeficiencies, while this therapy is not effective in patients with exclusively epithelial defects, such as TTC7A and IKBKG defects (6,21,22). However, the definite causative genetic defect can be only identified in less than 33% VEOIBD patients depending on the preselected patient cohorts (3). Therefore, an integrated diagnostic evaluation is significant in guiding therapy and follow-up in VEOIBD. This multicenter, retrospective study presents the VCE findings and follow-up of small bowel lesions of patients from a large cohort of VEOIBD patients.

VCE is a minimally invasive approach to monitor the entire intestinal tract with single procedure, which can be used in a treat to target strategy to manage pediatric CD (23). VCE has been shown to monitor mucosal healing and deep remission in a treat to strategy for pediatric CD (24). The most common indication for VCE among pediatric patients is hemorrhage. An 8-month-old patient have undergone VCE without complications (25,26). Swallowing the capsule might be difficult for patients at any age, for they are unable or unwilling to ingest the capsule. It could be a challenging issue especially in VEOIBD patients, considering the younger age. Under these circumstances, a capsule would be directly placed into duodenum during endoscopy under general anesthesia (27). Consistent with other literatures, VCE is a safe procedure for infants and young children with VEOIBD. However, known stenosis and obstruction are contraindications, while some monogenic VEOIBD are associated with gastrointestinal strictures, including patients with IL10RA and RTEL1 mutations (8,28).

In a cohort of 57 VEOIBD 10 monogenic IBD patients tended to have colonic linear ulcers and duodenitis when compared with non-monogenic IBD (4). In our study, 45% of patients had monogenic IBD. The rate of monogenic IBD is associated with age of onset, as earlier onset is strong predictor for the risk of monogenic IBD (2). We showed that a majority of VEOIBD had small bowel lesions. Monogenic IBD overwhelmingly showed a CD phenotype during follow-up, and more likely to have primarily colonic disease (29). However, there is a scarcity of study focusing on the features and severity of small bowel involvement in VEOIBD. Only some patients had small bowel abnormality on imaging studies (29). Because of the limited number of patients with specific genetic defects, it would be difficult to conclude specific defect-dependent pattern of lesions among patients. However, there is a tendency that patients with TNFAIP3 mutations showed multiple ulcers in the small bowel. Previous studies showed that these patients had ulcers both found in the upper and lower endoscopy, and the lesions tend to persist, which partially explained their refractory disease course despite treatment with mesalazine, steroids, infliximab and thalidomide (30). Since its first description, no targeted treatment has been identified so far. Most patients received symptomatic treatment and immunosuppressive therapies including steroids, colchicine, tacrolimus and infliximab (31,32). Therefore, VCE can be chosen as an effective and noninvasive investigation during follow-up. For other monogenic IBD patients, including FOXP3, PIK3CD and SLC37A4 mutations, some showed ulcers in the terminal ileum but not involving the ileum or jejunum. BTK deficiency patients showed only ileal blunting instead of ulcers. Location-specific signatures of Crohn’s Disease have identified at a multi-omics scale (33). Integrated taxonomy showed distinct cellular landscape and networks of monogenic IBD (16). Considering there is gene specific pathway among monogenic IBD, the features, location and pattern of the lesions might also be closely related to the defective pathway.

VCE features have been compared with upper and lower endoscopy, and histologic evaluations in this cohort. The misalignment between endoscopic findings and histology in VEOIBD is reported as nearly 30% (34). Most of the VEOIBD patients had abnormal endoscopic and histologic features in this study. Therefore, it would be essential to perform genetic sequencing for patients with high suspicion of VEOIBD besides endoscopy and histology (35).

We included a large cohort of VEOIBD patients from multiple centers in this study. One possible limitation could be a small proportion of monogenic IBD patients might be mistakenly identified as non-monogenic IBD, for it might take years for the identification of novel causative genetic defects. Considering the extremely low incidence of monogenic defects, the number would not be large. As more monogenic IBD is to be reported, future studies will facilitate the full description of patients with associated pathways.

Conclusions

The endoscopic analysis of children with VEOIBD are crucial to guide the diagnosis and application of timely genomic testing. VEOIBD patients frequently suffer from small bowel lesions. VCE can serve as a noninvasive modality in follow-up and management of disease. We also showed the safety of VCE among VEOIBD patient population based on a multi-center study.

Acknowledgments

Authors thank all the patients and families who participated in the study. The authors would like to thank the dedicated IBD nurses in each participating hospital. This article is an extension of the e-Poster presented in the 55th Annual meeting of the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-22/rc

Data Sharing Statement: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-22/dss

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-22/prf

Funding: This work was supported by the National Natural Science Foundation of China (No. 82300597 to Z.Y.), Shanghai Sailing Program (No. 22YF1403800 to Z.Y.) and Shanghai Municipal Health and Family Planning Commission (No. 20224Y0283 to Z.Y.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-22/coif). Z.Y. reports that this work was supported by the National Natural Science Foundation of China (No. 82300597), Shanghai Sailing Program (No. 22YF1403800) and Shanghai Municipal Health and Family Planning Commission (No. 20224Y0283). D.D. is the Director of the Pediatric Gastroenterology, Hepatology and Nutrition Group of the Shenzhen Medical Association. X.X. is the Vice Director of the Pediatric Gastroenterology Group of the Sichuan Medical Association. R.Z. serves as the Chair of the Digestive Diseases Committee of the Hebei Pediatric Society. J.X. is the Director of the Digestive and Infectious Diseases Group of the 9th Committee of the Pediatric Branch of the Shandong Medical Association. Y.H. is the Chair of the Pediatric Digestive Endoscopy Group of the Chinese Medical Doctor Association. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. All participating hospitals were informed and agreed the study. The study was approved by the Ethical Committees of Children’s Hospital of Fudan University (ethics No. [2015]-130), Shenzhen Children’s Hospital (ethics No. 2022-167), Chengdu Women’s and Children’s Central Hospital [ethics No. 2022(72)], Children’s Hospital of Hebei Province (ethics No. 202407-81), and Qilu Children’s Hospital of Shandong University (ethics No. 2020038). Written informed consents were obtained from parents or guardians of all patients before the procedure.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Kuenzig ME, Fung SG, Marderfeld L, et al. Twenty-first Century Trends in the Global Epidemiology of Pediatric-Onset Inflammatory Bowel Disease: Systematic Review. Gastroenterology 2022;162:1147-1159.e4. [Crossref] [PubMed]
2. Uhlig HH, Schwerd T, Koletzko S, et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology 2014;147:990-1007.e3. [Crossref] [PubMed]
3. Uhlig HH, Charbit-Henrion F, Kotlarz D, et al. Clinical Genomics for the Diagnosis of Monogenic Forms of Inflammatory Bowel Disease: A Position Paper From the Paediatric IBD Porto Group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2021;72:456-73. [Crossref] [PubMed]
4. Conrad MA, Carreon CK, Dawany N, et al. Distinct Histopathological Features at Diagnosis of Very Early Onset Inflammatory Bowel Disease. J Crohns Colitis 2019;13:615-25. [Crossref] [PubMed]
5. Uhlig HH, Muise AM. Clinical Genomics in Inflammatory Bowel Disease. Trends Genet 2017;33:629-41. [Crossref] [PubMed]
6. Jardine S, Anderson S, Babcock S, et al. Drug Screen Identifies Leflunomide for Treatment of Inflammatory Bowel Disease Caused by TTC7A Deficiency. Gastroenterology 2020;158:1000-15. [Crossref] [PubMed]
7. Ye Z, Zhou Y, Huang Y, et al. Phenotype and Management of Infantile-onset Inflammatory Bowel Disease: Experience from a Tertiary Care Center in China. Inflamm Bowel Dis 2017;23:2154-64. [Crossref] [PubMed]
8. Ye Z, Qian L, Hu W, et al. Clinical outcome of infantile-onset inflammatory bowel disease in 102 patients with interleukin-10 signalling deficiency. Aliment Pharmacol Ther 2022;55:1414-22. [Crossref] [PubMed]
9. Friedlander JA, Liu QY, Sahn B, et al. NASPGHAN Capsule Endoscopy Clinical Report. J Pediatr Gastroenterol Nutr 2017;64:485-94. [Crossref] [PubMed]
10. Gralnek IM, Cohen SA, Ephrath H, et al. Small bowel capsule endoscopy impacts diagnosis and management of pediatric inflammatory bowel disease: a prospective study. Dig Dis Sci 2012;57:465-71. [Crossref] [PubMed]
11. Min SB, Le-Carlson M, Singh N, et al. Video capsule endoscopy impacts decision making in pediatric IBD: a single tertiary care center experience. Inflamm Bowel Dis 2013;19:2139-45. [Crossref] [PubMed]
12. Cheema HA, Waheed N, Saeed A, et al. Very early onset inflammatory bowel disease: Spectrum of clinical presentation, diagnostic tools and outcome in children. J Pak Med Assoc 2021;71:2350-4. [Crossref] [PubMed]
13. Marzollo A, Bresolin S, Colavito D, et al. Case Report: Intestinal Nodular Lymphoid Hyperplasia as First Manifestation of Activated PI3Kδ Syndrome Due to a Novel PIK3CD Variant. Front Pediatr 2021;9:703056. [Crossref] [PubMed]
14. Levine A, Koletzko S, Turner D, et al. ESPGHAN revised porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents. J Pediatr Gastroenterol Nutr 2014;58:795-806. [Crossref] [PubMed]
15. Wilkins BJ, Kelsen JR, Conrad MA. A Pattern-based Pathology Approach to Very Early-onset Inflammatory Bowel Disease: Thinking Beyond Crohn Disease and Ulcerative Colitis. Adv Anat Pathol 2022;29:62-70.
16. Bolton C, Smillie CS, Pandey S, et al. An Integrated Taxonomy for Monogenic Inflammatory Bowel Disease. Gastroenterology 2022;162:859-76. [Crossref] [PubMed]
17. Kelsen JR, Sullivan KE, Rabizadeh S, et al. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Position Paper on the Evaluation and Management for Patients With Very Early-onset Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr 2020;70:389-403. [Crossref] [PubMed]
18. Wang L, Aschenbrenner D, Zeng Z, et al. Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice. Nat Genet 2021;53:500-10. [Crossref] [PubMed]
19. Salter CG, Cai Y, Lo B, et al. Biallelic PI4KA variants cause neurological, intestinal and immunological disease. Brain 2021;144:3597-610. [Crossref] [PubMed]
20. Magg T, Shcherbina A, Arslan D, et al. CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease. Inflamm Bowel Dis 2019;25:1788-95. [Crossref] [PubMed]
21. Miot C, Imai K, Imai C, et al. Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations. Blood 2017;130:1456-67. [Crossref] [PubMed]
22. Burroughs LM, Petrovic A, Brazauskas R, et al. Excellent outcomes following hematopoietic cell transplantation for Wiskott-Aldrich syndrome: a PIDTC report. Blood 2020;135:2094-105. [Crossref] [PubMed]
23. Bruining DH, Oliva S, Fleisher MR, et al. Panenteric capsule endoscopy versus ileocolonoscopy plus magnetic resonance enterography in Crohn's disease: a multicentre, prospective study. BMJ Open Gastroenterol 2020;7:e000365. [Crossref] [PubMed]
24. Oliva S, Aloi M, Viola F, et al. A Treat to Target Strategy Using Panenteric Capsule Endoscopy in Pediatric Patients With Crohn's Disease. Clin Gastroenterol Hepatol 2019;17:2060-2067.e1. [Crossref] [PubMed]
25. Oikawa-Kawamoto M, Sogo T, Yamaguchi T, et al. Safety and utility of capsule endoscopy for infants and young children. World J Gastroenterol 2013;19:8342-8. [Crossref] [PubMed]
26. Nuutinen H, Kolho KL, Salminen P, et al. Capsule endoscopy in pediatric patients: technique and results in our first 100 consecutive children. Scand J Gastroenterol 2011;46:1138-43. [Crossref] [PubMed]
27. Cohen SA, Oliva S. Capsule Endoscopy in Children. Front Pediatr 2021;9:664722. [Crossref] [PubMed]
28. Ziv A, Werner L, Konnikova L, et al. An RTEL1 Mutation Links to Infantile-Onset Ulcerative Colitis and Severe Immunodeficiency. J Clin Immunol 2020;40:1010-9. [Crossref] [PubMed]
29. Collen LV, Kim DY, Field M, et al. Clinical Phenotypes and Outcomes in Monogenic Versus Non-monogenic Very Early Onset Inflammatory Bowel Disease. J Crohns Colitis 2022;16:1380-96. [Crossref] [PubMed]
30. Zheng C, Huang Y, Ye Z, et al. Infantile Onset Intractable Inflammatory Bowel Disease Due to Novel Heterozygous Mutations in TNFAIP3 (A20). Inflamm Bowel Dis 2018;24:2613-20. [Crossref] [PubMed]
31. Liu J, Lin Y, Li X, et al. Haploinsufficiency of A20 in a Chinese child caused by loss-of-function mutations in TNFAIP3: A case report and review of the literature. Front Pediatr 2022;10:990008. [Crossref] [PubMed]
32. Yu MP, Xu XS, Zhou Q, et al. Haploinsufficiency of A20 (HA20): updates on the genetics, phenotype, pathogenesis and treatment. World J Pediatr 2020;16:575-84. [Crossref] [PubMed]
33. Gonzalez CG, Mills RH, Zhu Q, et al. Location-specific signatures of Crohn's disease at a multi-omics scale. Microbiome 2022;10:133. [Crossref] [PubMed]
34. Ferro J, Francalanci P, Angerilli V, et al. Histologic alterations are common in Monogenic Disease patients with 'healthy' endoscopy: Results from a GIPAD-GIPPI multicenter study. Hum Pathol 2025;157:105763. [Crossref] [PubMed]
35. Kammermeier J, Lamb CA, Jones KDJ, et al. Genomic diagnosis and care co-ordination for monogenic inflammatory bowel disease in children and adults: consensus guideline on behalf of the British Society of Gastroenterology and British Society of Paediatric Gastroenterology, Hepatology and Nutrition. Lancet Gastroenterol Hepatol 2023;8:271-86. [Crossref] [PubMed]