Skip Navigation
Skip to contents

Intest Res : Intestinal Research

Search
Advanced Search
IMPACT FACTOR
mobile search button mobile menu button

Articles

Page Path
HOME > Intest Res > Volume 23(4); 2025 > Article
Review
IBD Asian–Pacific perspectives on the management of very early-onset inflammatory bowel disease
Ichiro Takeuchi1orcid, Katsuhiro Arai1orcid, Pornthep Tanpowpong2orcid, Ming-Wei Lai3,4orcid, Andrew S Day5orcid, Way Seah Lee6orcid, James Guoxian Huang7,8orcid, Karen Sophia Calixto-Mercado9,10,11orcid, Rosanna Ming Sum Wong12orcid, Muhammad Arshad Alvi13orcid, Zubin Grover14orcid, Jung Ok Shim15orcid, Ujjal Poddar16orcid
Intestinal Research 2025;23(4):405-429.
DOI: https://doi.org/10.5217/ir.2025.00082
Published online: October 28, 2025

1Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan

2Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

3Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

4Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan

5Department of Paediatrics, University of Otago Christchurch, Christchurch, New Zealand

6M. Kandiah Faculty of Medicine and Health Sciences, University Tunku Abdul Rahman, Selangor, Malaysia

7Division of Paediatric Gastroenterology, Nutrition, Hepatology and Liver Transplantation, Khoo Teck Puat–National University Children’s Medical Institute, National University Hospital Singapore, Singapore

8Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

9Makati Medical Center, Metro Manila, Philippines

10Philippine Children’s Medical Center, Metro Manila, Philippines

11The Medical City, Metro Manila, Philippines

12Department of Pediatrics and Adolescent Medicine, Hong Kong Children’s Hospital, Hong Kong, China

13Department of Pediatric Gastroenterology and Hepatology, The Children’s Hospital, University of Child Health Sciences, Lahore, Pakistan

14Department of Gastroenterology, Perth Children’s Hospital, Perth, Australia

15Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea

16Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

Correspondence to Katsuhiro Arai, Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan. E-mail: arai-k@ncchd.go.jp
• Received: May 18, 2025   • Revised: July 29, 2025   • Accepted: August 12, 2025

© 2025 Korean Association for the Study of Intestinal Diseases.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

prev next
  • 945 Views
  • 46 Download
Full Article

Download PDF Download PDF

  • Children diagnosed with inflammatory bowel disease (IBD) before the age of 6 years are considered to have “very early-onset IBD (VEO-IBD),” which is challenging to diagnose and treat. Notably, many children with VEO-IBD have monogenic forms of the disease, meaning that early genetic testing is useful. However, because the prevalence of genetic variants causing VEO-IBD differs globally, the diagnosis and treatment of this disease should be tailored to each region. In the present review paper, the IBD Subcommittee of the Scientific Committee of the Asia-Pacific Society of Pediatric Gastroenterology, Hepatology and Nutrition (APSPGHAN) has summarized the epidemiology, presenting features, diagnosis, and treatment of VEO-IBD in the Asia–Pacific region, with an aim to guide clinicians and researchers who work with VEO-IBD in this area. Our 3 main messages are as follows: endoscopy is essential for VEO-IBD diagnosis; all children diagnosed with VEO-IBD should be suspected of having a monogenic form; and children with suspected monogenic IBD should undergo early genetic testing. Our messages aim to improve the early diagnosis and treatment of VEO-IBD in the Asia–Pacific region, including the early detection of monogenic IBD in this area.
  • Keywords: Asia; Child; Infant; Inflammatory bowel diseases; Age of onset
The incidence of pediatric inflammatory bowel disease (P-IBD) is rising worldwide [1]. A unique group of children has P-IBD known as “very early-onset IBD (VEO-IBD),” defined as IBD diagnosed before 6 years of age. VEO-IBD is particularly challenging to diagnose because of the inherent difficulties of gastrointestinal endoscopy in very young children. Limited access to appropriately sized endoscopic equipment and technical expertise is one such difficulty within the Asia–Pacific region. In addition, atypical endoscopic and histopathological findings in this age group compared with older children or adults make accurate diagnosis more challenging [2-10]. Optimal control of disease activity is another hurdle in the management of VEO-IBD because of its refractoriness, as well as the limited treatment options secondary to delayed drug approval for children with IBD. Although some off-label use of immunosuppressants and biologics has been administered in this age group, their efficacy and safety have yet to be established. Some children with VEO-IBD eventually require surgery [11,12]. However, a subset of children with VEO-IBD, particularly those with an underlying primary immune deficiency caused by genetic disorders or monogenic IBD, can be cured by hematopoietic cell transplantation (HCT) [13-17]. A well-structured approach for suspected monogenic IBD with early genetic testing is therefore warranted in children with VEO-IBD.
Although position papers and consensus guidelines for VEO-IBD or monogenic IBD have been published from societies in Europe and North America [18-20], regional differences in the underlying etiologies and genetic backgrounds of monogenic IBD should be considered in the management of VEO-IBD. This is the first review paper on VEO-IBD in Asia–Pacific by the Working Group of the IBD Subcommittee of the Scientific Committee of the Asia-Pacific Society of Pediatric Gastroenterology, Hepatology and Nutrition (APSPGHAN)—representing Japan, Thailand, Taiwan, New Zealand, Malaysia, Singapore, the Philippines, Hong Kong, Pakistan, Australia, the Republic of Korea, and India. In this review, we consider the unique genetic traits, racial/ethnic factors, resources, medical insurance systems, and variable challenges within the region.
This paper includes a brief review of the epidemiology and presenting features of VEO-IBD in the Asia–Pacific region. Through this review and discussions among the Working Group members, it was noted that VEO-IBD occurs at a clinically relevant frequency across the Asia–Pacific region, and some of these cases represent monogenic IBD. Although regional differences in healthcare systems and access to endoscopy, genetic testing, and biologics make unified recommendations challenging, the Working Group proposes the following 3 points: (1) endoscopy is essential for diagnosing VEO-IBD; (2) monogenic IBD should be considered in all children with VEO-IBD; and (3) children strongly suspected of having monogenic IBD should undergo appropriate and early genetic testing. In addition, the current paper offers a unique approach to ensure both the early diagnosis of monogenic IBD and the detection of novel forms of monogenic IBD, because there are many children with undiagnosed or undiscovered monogenic IBD within the region.
Trends in the global epidemiology of P-IBD in the 21st century were recently reported by Kuenzig et al. [1] following a systematic review of publications focusing on P-IBD. Although the epidemiological data for VEO-IBD were limited in this review, the incidence of VEO-IBD per 100,000 person-years was reported as 0.2–1.4 in West Asia, 0.2–1.4 in Europe, and 0.5–3.6 in Canada. Furthermore, Choe et al. [21] reported the incidence rates of infantile-onset Crohn’s disease (CD; diagnosed <2 years of age), and VEO-CD were 0.7 and 1.7 per 100,000, respectively, in a retrospective cohort study conducted in Korea from 2006 to 2015. Variable trends in VEO-IBD incidence are observed globally [1]. The review noted that a Canadian study reported a significant increase in the incidence of VEO-IBD, whereas no such changes were observed in studies from France and Saudi Arabia [1]. Moreover, the prevalence of VEO-IBD ranged from 1.9 cases per 100,000 people in Canada to 5.8 cases per 100,000 people in Scotland. Data from Israel of 2.9 cases per 100,000 people were considered representative of VEO-IBD prevalence in the West; however, prevalence rates in most Asia–Pacific countries are lacking.
The proportion of VEO-IBD in children with IBD and the distributions of disease phenotypes of CD, ulcerative colitis (UC), and IBD unclassified (IBD-U) have been reported in 22 studies in the Asia–Pacific region [2-5,12,22-38], 7 studies in Europe and North America [6,39-44], and 6 studies in other regions, including West Asia (Table 1) [45-50]. In the Asia–Pacific region, the frequency of VEO-IBD among cases of P-IBD varies by country; it is more common in Thailand (38%) and Australia (30%) and less common in Japan (11%), Korea (5%), and Malaysia (13%). VEO-IBD appears relatively common in Asia, especially compared with large studies from Canada and France, which report that VEO-IBD makes up merely 3%–6% of P-IBD cases [39,41,42]. However, this high VEO-IBD incidence in the Asia–Pacific region may be an overestimate owing to the common regional practice of older patients (especially teenagers) being cared for by adult gastroenterologists, thus excluding them from participation in P-IBD studies.
Unique features of VEO-IBD have been reported compared with older children with P-IBD diagnosed at 6 years of age and older (Table 2) [2-5,12,23,26-29,33,36,40-42,44,46,48]. The VEO-IBD characteristics reported in both Asian–Pacific and Western countries include a higher proportion of IBD-U [2,4,5,44], a lower proportion of CD [5,38,44], a higher proportion of colonic CD [2,23,29,40-42,46,48], and a higher proportion of severe disease in both UC and CD [3,28,29,33,44,46]. The most common initial symptoms of VEO-IBD are reportedly hematochezia and diarrhea [6,12,27,40,41,44,46], which may reflect the relatively high proportion of colonic involvement [2,23,29,41,42,46,48]. By contrast, the features of VEO-IBD reported specifically from Asia–Pacific countries comprise a higher proportion of pancolitis in UC [3,23], a higher proportion of perianal lesions in CD [4,36], and a higher proportion of positive family history [3,4,26,28]. Interestingly, 2 reports have indicated that disease onset is significantly younger in VEO-CD than in VEO-UC [12,46].
Both CD and UC are considered multifactorial disorders with a pathogenesis resulting from a complex interplay of factors, including genetics, environmental factors, the intestinal microbiome, dietary patterns, and host immune responses [51,52]. However, recent advances have revealed specific genetic disorders that can lead to chronic enterocolitis and are especially relevant in VEO-IBD [53]. These genetic disorders, collectively known as “monogenic IBD,” are distinct from typical IBD in that they are caused by a single gene mutation, rather than stemming from a combination of genetic and environmental factors.
A position paper from the Paediatric IBD Porto Group of the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition listed 75 genes that are linked to monogenic IBD [18]. The genes responsible for monogenic IBD encode proteins that play critical roles in intestinal homeostasis, spanning from epithelial barrier function to innate and adaptive immune responses (Fig. 1A) [54].
The human gut accommodates hundreds of trillions of microorganisms, including potential pathogens, and encounters numerous dietary/xenobiotic antigens. Thus, it possesses a competent and delicate immune system that aims to maintain immunological homeostasis. For the appropriate segregation and sampling of luminal contents by mucosal immune constituents, intestinal epithelial cells function not only as a physical and biochemical (via the secretion of mucins and antimicrobial peptides) barrier but also as an antigen-sensing/sampling port via specialized intestinal epithelial cells, known as microfold (M) cells. To orchestrate immune responses to these environmental triggers, intestinal epithelial cells and dendritic cells/intestine-resident macrophages regulate inflammatory, tolerogenic, or anti-inflammatory responses. These functions are performed through various cytokines, cell surface receptors, signal transducing molecules, transcription factors, and downstream cellular differentiation and functional specification (e.g., via T helper cells [Th]1, Th2, Th17, and regulatory T cells [Tregs]). Overreactive inflammation against pathogens or microbiota is counter-regulated by Tregs secret-ing interleukin (IL)-10, a key protective mediator, to avoid tissue damage. Molecules involved in intracellular signal transduction pathways (such as nuclear factor [NF]-κB, which is a pleiotropic transcription factor controlling immunity, differentiation, cell growth, and apoptosis; inhibitors of NF-κB [I-κB]; and its upstream regulator I-κB kinase [IKK] complex [IKKα, IKKβ, and NF-κB essential modulator (NEMO) or IKKγ]) are important for immune cell destiny after stimulation via surface receptors (Fig. 1B) [18,55-57].
Defects in crucial molecules that affect various steps in intestinal homeostasis—affecting the epithelial barrier, sensing, receptor docking, signal transduction, and immune cell differentiation, survival, and homeostasis—are responsible for many common monogenic IBDs (Fig. 1, yellow stars). Certain monogenic IBDs, such as X-linked inhibitor of apoptosis protein (XIAP) deficiency and colitis associated with IL-10 and IL-10R deficiency, can be effectively cured by HCT [13-16]. Thus, the specific genetic diagnosis of some monogenic IBDs may shift management from standard IBD treatments to disease-specific therapy, which may cure the disease.
Regional Differences in Monogenic IBD Frequencies
Despite the absence of precise epidemiological data on monogenic IBD in Asia, we first compiled and summarized the frequencies of reported monogenic IBD cases in very early onset IBD from published literature (Table 3, Fig. 2) to support a discussion of the distribution and types of monogenic IBD that are most commonly reported in the region [12,17,28,29,31,43,44,50,58-73]. Although single case reports or small series were not included, and some duplication may exist because of overlapping publications, the figures reveal that the distribution of causative genes in monogenic IBD in VEO-IBD appears to differ in frequency between the Asia–Pacific region and Western countries. Notably, colitis associated with IL-10 and IL-10R deficiency, which is frequently reported in mainland China, is encountered more commonly in the Asia–Pacific region than in the West. In a study conducted in Korea to identify monogenic variants in IL10RA, IL10RB, and IL10 in children with P-IBD, IL10RA mutations were detected in 17.5% of 40 patients diagnosed before the age of 10 years and in 50% of 14 patients diagnosed before the age of 1 year [17]. A20 haploinsufficiency (A20HI) is more frequently reported in Asia than in Europe or North America (Fig. 2). Conversely, immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX), tetratricopeptide repeat domain (TTC)7A, and TTC37 deficiencies are less frequent in Asia and more common in Europe and North America. In terms of SLCO2A1, although chronic enteropathy associated with SLCO2A1 (CEAS) is more frequently reported in Asia, the apparent underrepresentation likely occurs because CEAS typically presents in older children. These data highlight some of the regional differences that should be considered when investigating a child with VEO-IBD for potential monogenic disease.
This section provides an overview of the monogenic IBDs that are most frequently reported in the Asia–Pacific region (Fig. 2). In addition, several clinically important monogenic IBDs, such as CEAS, TTC7A deficiency, and X-linked anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), are also described.
1. Colitis Associated with IL-10 and IL-10R Deficiency (Autosomal Recessive)
IL-10 is a major anti-inflammatory cytokine that is secreted from various immune cells, including Tregs, monocytes, and Th2 cells. It regulates immune responses and maintains immune homeostasis. IL-10 signaling is initiated when the cytokine binds to a heterodimeric receptor complex composed of IL-10R1 and IL-10R2 (coded by IL10A and IL10B, respectively). When IL-10 signaling is impaired by IL10, IL10RA, or IL10RB mutations, severe intestinal inflammation with perianal lesions develops early in life [14]. This condition is usually accompanied by atopic dermatitis-like eczema, and affected patients reportedly have an increased lymphoma risk [14].
The most frequently observed variants in East Asia are IL10RA c.301C>T and c.537G >A, whereas pathogenic IL10RB variants are more frequent in patients from Central and South Asia and Europe, indicating a regional pattern in the genetic landscape of colitis associated with IL-10 and IL-10R deficiency [74]. Research with a geospatial association between infectious diseases and IL10RA variants suggests that Schistosoma japonicum infection may have been a selection pressure for pathogenic IL10RA variants [74].
Colitis associated with IL-10 and IL-10R deficiency is characterized by intractable symptoms and a poor response to conventional IBD treatments. However, Glocker et al. [14] first reported the resolution of severe colitis and destructive perianal disease associated with IL-10R deficiency using HCT in 2009. HCT is now recognized as an effective curative treatment for colitis associated with IL-10 and IL-10R deficiency [15,17]. Moreover, HCT with reduced toxicity conditioning regimens can be safely administered even at a young age [16].
2. CGD (X-Linked Recessive or Autosomal Recessive)
Chronic granulomatous disease (CGD) is caused by mutations in CYBB, CYBA, NCF1, NCF2, NCF4, or CYBC1 (encoding gp91, p22, p47, p67, p40, and CYBC1, respectively), resulting in the defective production of reactive oxygen species in neutrophils. A newly identified form of CGD caused by CYBC1 mutation has been reported in Asian countries [75,76]. The consequent dysfunction can lead to an increased susceptibility to bacterial and fungal infections and repeated abscess formation from early life. In addition, granulomata are formed in multiple organs because of excessive inflammation caused by the dysregulated immune response. Around half of all patients with CGD develop enterocolitis [77]. Although most children with CGD are boys (reflecting its X-linked recessive inheritance), autosomal recessive forms of CGD can be identified in girls or boys. CGD is diagnosed using dihydrorhodamine (DHR) and genetic testing. Although the use of anti-tumor necrosis factor (TNF) agents is contraindicated in CGD because of the high risk of severe infections, some immunosuppressants, such as thalidomide and anakinra, have been reported to be used successfully. Moreover, therapeutic evidence indicates that HCT may be a curative treatment [78].
3. XIAP Deficiency (X-Linked Recessive)
XIAP deficiency is caused by mutations in XIAP, which is a protein that regulates NF-κB activation, inhibits apoptosis, and modulates nucleotide-binding oligomerization domain-containing protein 2 (NOD2) signaling. Although XIAP has been identified as a causative gene for familial hemophagocytic syndrome, 10%–20% of patients develop enterocolitis resembling CD that is often refractory to conventional IBD treatment [79]. Moreover, despite XIAP-associated colitis being more common in early childhood, it is important to note that cases with onset in adulthood have also been reported [56]. A diagnosis of XIAP deficiency requires genetic testing and flow cytometry to assess XIAP expression. Reduced toxicity conditioning regimens of HCT therapy have been established as a safe and effective treatment for XIAP deficiency [13,78].
4. A20HI (Autosomal Dominant)
A20, encoded by TNFAIP3, regulates the intracellular signaling of inflammatory cytokines from Toll-like and TNF-α receptors. Even heterozygous loss-of-function mutations in TNFAIP3 result in the excessive production of inflammatory cytokines, which leads to Behçet’s disease-like symptoms such as gastrointestinal ulcers, arthritis, and recurrent oral aphthae [80]. Patients with A20HI in East Asia are reported to experience recurrent fever more frequently than patients in other regions, whereas typical Behçet’s disease symptoms such as skin rashes and genital ulcers, autoimmune disease complications, and autoantibody detection are reportedly less common [81]. Diagnosis of A20HI relies on genetic testing for TNFAIP3 mutations. Because A20HI is characterized by diverse treatment responses, its treatment is individualized and depends on disease severity. Although mild cases can be managed with colchicine or corticosteroids, severe or refractory cases require biologics, including anti-TNF-α agents, IL-1 or IL-6 inhibitors, and Janus kinase inhibitors. HCT has been reported to be successfully used in a few treatment-resistant cases; however, preexisting organ damage may persist and can potentially cause symptom relapse [81].
5. IPEX Syndrome (X-Linked Recessive)
IPEX syndrome is caused by mutations in FOXP3, which is essential for Treg differentiation. IPEX is characterized by severe immune dysregulation because dysfunctional Tregs lead to autoimmunity that affects multiple organs and is linked to various autoimmune diseases and allergies [82]. Clinically, the disease manifests as a triad of severe diarrhea caused by autoimmune enteropathy, endocrinopathies such as diabetes or thyroiditis, and dermatitis [83]. Diagnosis relies on the genetic confirmation of FOXP3 mutations, and Treg-specific demethylation region analysis may support an early diagnosis [84]. Treatment strategies include immunosuppressive drugs such as glucocorticoids, calcineurin inhibitors, and mammalian target of rapamycin (mTOR) inhibitors; however, HCT remains the only curative approach [78,83].
6. CTLA-4 Haploinsufficiency (Autosomal Dominant) and LRBA Deficiency (Autosomal Recessive)
Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) is a ligand for the auxiliary stimulus that negatively regulates T cells to not react to self-tissue in acquired immunity. Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) is involved in the expression of CTLA-4, and CTLA-4 haploinsufficiency and LRBA deficiency cause a variety of autoimmune diseases as well as enterocolitis [85,86]. CTLA-4 haploinsufficiency and LRBA deficiency present with enteropathy, which causes severe gastrointestinal tract symptoms, as well as autoimmune disorders such as thyroiditis, encephalitis, and cytopenia. A diagnosis of CTLA-4 haploinsufficiency and LRBA deficiency relies on genetic testing and flow cytometry for protein expression. Although the use of mTOR inhibitors, mycophenolate, and HCT in patients with CTLA-4 haploinsufficiency and LRBA deficiency has been reported, the use of abatacept (a CTLA4-Fc fusion protein) to restore CTLA4 function may be considered as a first-line therapy [85,87].
7. CEAS (Autosomal Recessive)
CEAS is exclusively reported in patients of Asian origin and causes multiple, well-demarcated, flat ulcers in the small intestine. Patients with CEAS present with anemia and malnutrition. A diagnosis of CEAS relies on genetic testing for SLCO2A1, which encodes a transporter that is primarily responsible for the intracellular transport of prostaglandin E2 [88]. SLCO2A1 is also the causative gene for pachydermoperiostosis, a condition characterized by a symptom triad of clubbing of the fingers, periostosis of long bones, and skin thickening. CEAS is more common in females, whereas pachydermoperiostosis occurs more frequently in males, suggesting that modifying factors such as sex-related hormones may affect disease onset. Standard IBD therapies are ineffective in CEAS; its management primarily involves the symptomatic treatment of anemia and nutritional deficiencies in addition to the surgical resection of affected areas [89].
8. TTC7A Deficiency (Autosomal Recessive)
TTC7A deficiency is caused by mutations in TTC7A, which is involved in synthesizing phosphoinositide 3-kinase (PI3K) substrates. PI3K-protein kinase B (AKT) signaling affects various physiological activities including intestinal epithelial cell homeostasis. Patients with TTC7A deficiency develop severe intestinal inflammation, multiple intestinal atresia, and immune abnormalities such as lymphocytopenia and hypogammaglobulinemia [90]. Although HCT addresses immune defects, it fails to resolve intestinal inflammation, highlighting the need for novel therapies that target epithelial cell dysfunction [78]. Animal model data suggest the potential therapeutic role of leflunomide in the treatment of TTC7A deficiency [91].
9. X-Linked EDA-ID (X-Linked Recessive)
NEMO, encoded by IKBKG, is critical for epithelial integrity and immune homeostasis in the gastrointestinal tract via the canonical activation of NF-κB. Its dysfunction leads to susceptibility to infection and chronic inflammation [92]. Patients with EDA-ID have a broad spectrum of clinical manifestations, including recurrent infections, severe colitis, and ectodermal dysplasia (such as dental dysplasia and abnormal hair) [93]. Genetic testing is essential for a diagnosis of EDA-ID, and immunosuppressive therapy with anti-TNF agents and HCT may be considered for treatments; however, colitis persists despite HCT [78].
Features that lead to the suspicion of monogenic IBD include a young age of onset, poor response to conventional treatment, and diverse syndromic or disease-specific findings. Abnormal findings of the skin and ectoderm, joint, and endocrine systems should raise concerns. In addition, associations with autoimmune or autoinflammatory conditions, as well as immunodeficiency (frequent infections, chronic viral infections, and opportunistic infections with malignant tendencies) should not be ignored. Thus, a mnemonic “YOUNG AGE MATTERS MOST” (young onset is the most important) was introduced by Uhlig et al. [94] to alert clinicians to consider a possible diagnosis of monogenic IBD (Table 4).
Given that colonic inflammation is relatively common in VEO-IBD, IBD should be considered when diarrhea and/or bloody stool are noted in infants or toddlers. A list of conditions that can present in a similar fashion to VEO-IBD, such as infectious enterocolitis and eosinophilic gastrointestinal disorders, is provided in Table 5 [95]. The consideration and exclusion of these conditions is critical for preventing the delayed diagnosis of VEO-IBD.
Intestinal infection is the most common cause of diarrhea and bloody stools in children [96]. Moreover, differentiating IBD from infectious enterocolitis can be particularly challenging in Asia because of the high prevalence of enteric infections [97]. Intestinal tuberculosis should be differentiated when CD is suspected in the Asia–Pacific region, where the prevalence of tuberculosis is high. In children with underlying immunodeficiencies, opportunistic infections such as cytomegalovirus enteritis should be considered. These conditions may present in a similar fashion with abdominal pain, fever, diarrhea, or weight loss [98]. Extensive history taking (including outbreaks, travel history, diet, and medication use) and appropriate diagnostic tests (such as stool culture, Gram stain, toxin assay, antigen-antibody assay, and polymerase chain reaction of endoscopic specimens) may lead to the identification of pathogens. To differentiate intestinal tuberculosis from CD, a combination of clinical, endoscopic, and histopathological findings may be required. Furthermore, the prevalent causative microorganisms differ between countries or regions, and diagnostic approaches for VEO-IBD should be tailored to differences in IBD prevalences and healthcare systems across regions. In areas with a high prevalence of IBD, early colonoscopy and IBD-focused evaluation should be prioritized in young children presenting with persistent diarrhea and hematochezia. By contrast, in regions in which enteric infections—including tuberculosis—remain common, infectious etiologies should be systematically excluded before invasive diagnostic procedures are conducted and immunosuppressive therapy is initiated.
For bloody stools, the evaluation of the amount of blood, color, stool consistency, and frequency are possible diagnostic clues. For example, a small amount of blood with mucus may indicate colonic polyps [99]. In infants, food protein-induced allergic proctocolitis of infancy (secondary to dietary antigens, including cow milk protein) is often the cause of bloody stools and diarrhea. To diagnose this condition, the response to the introduction of a hypoallergenic formula and stool eosinophil staining are often helpful. Nonetheless, endoscopy with histopathological evaluation remains the gold standard for differentiating food protein-induced allergic proctocolitis of infancy from IBD.
In newborns and young infants, severe diarrhea with unknown etiology that requires parenteral nutrition is considered to fit within a group of conditions known as congenital diarrheas and enteropathies (CODEs) [100]. Similar to monogenic IBD, recent genetic advances have revealed the causative genes of various CODEs, leading to a better understanding of the underlying pathophysiology. Some CODE-causing variants have been identified in genes that encode transporters and enzymes that are responsible for intestinal epithelial function, involving metabolism and electrolyte transport. Because CODEs do not typically involve gut inflammation, most children with CODEs do not present with bloody stools and do not have elevated C-reactive protein or fecal calprotectin levels.
History taking and physical examinations are crucial for the early detection of extraintestinal complications (EICs) or unusual immunodeficiency-associated infections, which not only raise suspicion of VEO-IBD but may also allow for the detection of specific monogenic IBDs. When conducting history taking and physical examinations, some key points are important in relation to VEO-IBD and potential monogenic IBD (Table 6).
Although most monogenic IBDs are autosomal recessive disorders, some, such as A20HI, are autosomal dominant disorders and others, such as CGD, are X-linked recessive disorders. Approximately 20% of patients with monogenic IBD have a family history of IBD within second-degree relatives [56]. However, the genotype–phenotype relationship has not yet been established for some monogenic IBDs [101]. For example, more than half of patients with XIAP deficiency develop only hemophagocytic lymphohistiocytosis, without enterocolitis [102,103]. A family history of other disorders, such as hemophagocytic lymphohistiocytosis and other autoimmune diseases, should therefore be queried. Furthermore, because many monogenic IBDs coexist with immunodeficiency or autoinflammatory diseases, they accompany EICs more frequently than non-monogenic IBD [65]. Seventy percent of patients with monogenic IBD develop EICs, including atypical infections (45%), skin diseases (38%), and autoimmune diseases (38%) [56]. Hemophagocytic lymphohistiocytosis and malignancy are also important EICs in this setting. In patients with infantile-onset monogenic IBD, enterocolitis usually precedes the onset of EICs, suggesting that monogenic IBD may initially present solely with gastrointestinal symptoms.
1. Blood and Stool Tests
When VEO-IBD is suspected, the standard approach for a diagnosis of IBD should be followed. Blood tests should include complete blood count, serum albumin, C-reactive protein, and erythrocyte sedimentation rate analyses [48,104]. The assessment of fecal calprotectin is also useful as a screening tool for IBD and for evaluating disease activity [105]. However, fecal calprotectin levels may need to be interpreted carefully because normal levels in infants and children under 4 years old are higher than those in older children or adults [106].
2. Endoscopy and Imaging Approaches
Endoscopy is the gold standard for IBD diagnosis; it is reportedly useful and safe even in children younger than 6 years [107,108]. As per the revised Porto criteria, a comprehensive evaluation of the entire gastrointestinal tract—including upper gastrointestinal endoscopy, ileo-colonoscopy, and small bowel evalu-ation—is recommended at diagnosis [109]. Histopathology is also essential; mucosal biopsies should be taken from both inflammatory and non-inflammatory sites because granulomata may also be detected in non-inflammatory sites [109]. In addition, intubation of the terminal ileum should always be performed [110]. The revised Porto criteria also recommend wireless capsule endoscopy or magnetic resonance enterography (MRE) for the evaluation of small intestinal lesions [97]. For capsule endoscopy, the prior use of a patency capsule and the trans-pyloric placement of the capsule using a capsule delivery device may minimize the risk of capsule retention, even in young children or infants who cannot swallow the capsule [111-115]. The smallest patient reported to have successfully undergone capsule endoscopy was a 10-month-old girl weighing 7.9 kg [116]. Device-assisted enteroscopy such as double-balloon enteroscopy and single-balloon enteroscopy are additional diagnostic options for small bowel evaluation in patients who are suspected to have VEO-IBD [108-110]. The smallest reported cases of successful transoral double-balloon enteroscopy and trans-anal double-balloon enteroscopy were a 12-month-old child weighing 7.9 kg and a 1.6-year-old child weighing 10.8 kg, respectively [117,118]. Although MRE is effective for assessing wall thickness and strictures in the small bowel, it may not be feasible in young children (particularly under 4 years old) because of the need for the prior administration of intestinal contrast media and the use of sedation or anesthesia [119]. Computed tomography enterography may serve as an alternative option [120]. For example, a contrast study with small bowel follow-through is useful for evaluating longitudinal ulcers, stenotic lesions, and fistula; however, it does not detect bowel wall thickening [121]. Abdominal ultrasonography is reportedly helpful for evaluating bowel wall thickening or increased blood flow [122,123]. The European Society of Paediatric Radiology Abdominal Imaging Task Force recommends that ultrasound be performed first, and that if the evaluation is inadequate or there is suspicion of small bowel involvement, MRE should follow [124]. This Task Force also recommends computed tomography enterography when MRE is not feasible, despite the associated radiation exposure.
3. Classification and Grading of Phenotypes and Severity
The revised Porto criteria and the Paris classification are widely used for the diagnosis and phenotyping, respectively, of IBD in children [109,125]. Additionally, because P-IBD tends to present in an atypical fashion, a classification of UC or CD may initially be difficult. More objective P-IBD classes have therefore been developed in an attempt to categorize the broad spectrum of P-IBD using more detailed characteristics [126]. However, because VEO-IBD has a wider range of atypical clinical presentations, applying the same diagnostic criteria or classification for VEO-IBD is likely to be challenging. It is crucial to note that a higher proportion of children diagnosed with VEO-IBD have colonic CD and IBD-U compared with older children with IBD, and the classification often changes during follow-up [2-7,24,30,41-43,47,49]. For example, in a North American cohort study, 11.5% of patients changed from UC/IBD-U to CD during follow-up [6]. It is thus essential to consider the reevaluation of disease phenotypes over time in children with VEO-IBD. Regarding histopathological findings, although apoptosis, torsion of the crypts, blunted villi, and eosinophilic infiltrate are reportedly more common in children with VEO-IBD than in older children with IBD, the observation of only nonspecific inflammatory findings is not uncommon [8].
A systematic review of monogenic IBD revealed that 34% of children are described as having CD or CD-like conditions, 6% as having UC or UC-like conditions, and more than half as having IBD or IBD-U [56]. Certain monogenic IBDs have characteristic endoscopic findings and disease extent. For example, colitis associated with IL-10 and IL-10R deficiency is characterized by colonic ulcers and pseudo-polyps, without upper gastrointestinal tract involvement. In children with A20HI, 80% of patients reportedly have colonic ulcers and 40% have ulcers in the ileum and duodenum bulb [72]. Patients with CEAS have multiple, relatively shallow ulcers with rings or oblique ulcers and intestinal stenosis [127]. Furthermore, leopard skin-like colonic mucosa, granulomata, and surrounding lymphocytic infiltrates and pigmented macrophages are features of CGD [128,129].
A report from China indicated that non-monogenic IBD exhibits more chronic architectural changes in crypts, increased apoptosis, and higher eosinophil counts compared with monogenic IBD, which predominantly included colitis associated with IL-10 and IL-10R deficiency [72]. By contrast, XIAP deficiency cannot be differentiated from CD on the basis of endoscopic and pathological findings [102]. Given the possible presence of monogenic disease in children with VEO-IBD, pattern-based approaches for classifying the pathological findings of VEO-IBD have been proposed [9,10]. A noteworthy classification system suggested by Wilkins et al. [9] categorizes VEO-IBD pathological findings into the following 5 distinct patterns: (1) chronic active enteritis, (2) apoptosis/epithelial injury pattern, (3) eosinophil-rich pattern, (4) lymphocytic pattern, and (5) granulomatous pattern.
The absence of typical endoscopic or histopathological findings of IBD upon initial examination does not completely rule out VEO-IBD or monogenic IBD. Rather, a diagnosis of VEO-IBD should rely on a combination of clinical, immunological/serological, stool, diagnostic imaging, endoscopic, histopathological, and enterographic findings. Because these features may evolve over time, re-assessment of the condition should always be considered. Given that current classifications are based on older children and adults, there is a need for a new classification that reflects the characteristics of children with VEO-IBD and monogenic IBD.
In addition to history taking, physical examination, basic blood/stool tests, imaging studies, and endoscopic/histopathological evaluations, a stepwise assessment of immune function is essential for evaluating children with VEO-IBD because most monogenic IBD is caused by inborn errors of immunity. First-line tests encompass basic immunological tests, including total leukocyte count and differentiation, immunoglobulin levels, and vaccine-derived antibodies (Table 7). These tests screen for neutropenia, lymphopenia, or defects of antibody production. For example, a low number and small size of platelets suggests Wiskott-Aldrich syndrome [130].
Second-line investigations include advanced immunological tests, such as lymphocyte subset analysis and the DHR test (Table 7). The DHR test is useful for diagnosing CGD with defective reactive oxygen species production [131]. Flow cytometric analysis can also be helpful for some monogenic IBD types involving T-cell or B-cell deficiencies, including IPEX syndrome with defects of regulatory T-cells and severe combined immunodeficiency with absent or defective cluster of differentiation 4 (CD4), CD8, natural killer cells, or B cells [132].
Third-line tests involve genetic testing. Genetic testing varies from targeted sequencing for specific genes to whole genome sequencing, and depends on test availability and the cost or range of insurance coverage by institutions and countries. Sometimes, whole genome sequencing requires participation in research studies or international collaborations. Notably, targeted or panel sequencing can be cost-effective and useful in geographical regions that are enriched in known genetic variants because of founder effects. For example, colitis associated with IL-10 and IL-10R deficiency is more common in mainland China.
Given that disease-specific clinical phenotypes may not be fully developed in early infancy, narrowing down the specific genes for Sanger sequencing can be challenging. Additionally, panel sequencing includes only known pathogenic genes, and therefore cannot identify novel causative genes. Conversely, although they are more expensive and the results take longer to obtain, whole exome and whole genome analyses hold the potential to detect rare and novel genes and variants. Even in countries or institutions where screening or genetic testing for monogenic IBD is not readily available, the preservation of blood or tissue specimens—ideally before starting treatment—may support a future genetic diagnosis and functional analysis.
In the present paper, we propose a model to summarize our recommended approach to differentiating or diagnosing monogenic IBD in children with VEO-IBD (Fig. 3). Compared with a previously recommended straightforward model from clinical data to genetic screening or confirmation [94], our model emphasizes the importance of integrating clinical and genetic data. Our model effectively integrates 3 crucial components: clinical data, functional analysis, and genetic analysis. It provides a framework for evaluating children with VEO-IBD and offers an approach for complex or atypical cases. It also highlights the potential for diagnosing monogenic IBD in a timely manner, regardless of whether the mutations are common or novel variants. The identification of a causative genetic variant may lead to the use of a specific treatment based on its function.
However, even with whole exome sequencing, the diagnostic yield was as low as 3% in one study of more than 1,000 children with IBD [65]. We must therefore consider the possibility that many unidentified forms of monogenic IBD remain. A constant review of genetic information is essential for the early detection of updated interpretations of variants of uncertain significance in both known and recently reported monogenic IBD forms. Moreover, the accumulation and review of clinical and genetic data might lead to the identification of potentially pathogenic variants in novel monogenic IBDs.
The major goals of VEO-IBD treatment include the control of intestinal inflammation, the achievement of mucosal healing, the maintenance of sufficient nutritional status, and the optimized growth and development of the child. In addition, all treatment recommendations should consider the quality of life and mental health of very young children and their families.
Treatment regimens should be multifaceted, with a combination of pharmacological, nutritional, and sometimes surgical interventions, and should also consider the disease phenotype and activity in each patient. The management of a child with VEO-IBD can be challenging because of the complexity of the condition and the lack of established standardized treatment approaches. Therefore, it is imperative to recognize and address the substantial heterogeneity in disease patterns and severities among patients. Currently, this variability in presentation and progression necessitates an individualized approach to treatment.
Standardized pharmacological therapy for VEO-IBD has yet to be established, and there are limited data that demonstrate efficacy and safety. Because few clinical trials have been conducted in children with VEO-IBD, most common medications have not yet been approved for this vulnerable group. Treatment usually proceeds in the same way as for older children; however, it should be noted that affected children may be immunodeficient. For example, the use of anti-TNF agents in CGD is not recommended because sepsis and death have been reported following infliximab use in children with CGD [133].
1. Corticosteroids and EEN
Cohort studies from Israeli and international children with VEO-IBD have revealed that corticosteroids are most frequently used (53%–77%) as induction therapy, whereas exclusive enteral nutrition (EEN) is used less frequently (3%–10%) in real-world practice [11,49]. However, EEN is a safe and good treatment option for the management of VEO-IBD. In children with suspected immunodeficiency, EEN may be preferred over corticosteroids to avoid the risk of opportunistic infection. EEN can also be a suitable option when the administration of live attenuated vaccines needs to be prioritized [134]. Nutrient deficiencies caused by the long-term predominant use of low-fat amino acid-based formulae have been reported in Japan [135]. Consequently, the adequate evaluation and supplementation of deficient micronutrients should be considered. It should also be noted that the delayed introduction of solid foods in infancy may interfere with chewing and swallowing development or lead to a feeding aversion.
2. 5-Aminosalicylates
5-Aminosalicylate drugs may be useful in children with VEO-IBD because they are relatively safe without systemic immune suppression. In North American, Israeli, and international cohort studies, 5-aminosalicylate agents have been used in 80%, 90%, and 75% of individuals with VEO-IBD, respectively [6,11,49]. In the international study, 22% of all cases were able to maintain disease remission with non-immunosuppressive therapies such as 5-aminosalicylate formulations and nutritional therapy [11]. The results of a single-center cohort study in Japan were similar; 25% of the included children maintained long-term remission with 5-aminosalicylate and partial enteral nutrition [12].
3. Immunomodulators
Immunomodulators (thiopurines and methotrexate) were used in approximately 75% of cases in the international cohort, with 27% remaining in long-term remission [11]. Azathioprine and 6-mercaptoprine are transformed into thioguanine nucleotides, which are the active metabolites. The enzymes thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) interfere with the production of active thioguanine nucleotides. Thiopurines are metabolized more quickly in children with VEO-IBD because of higher TPMT activity, resulting from age-related DNA hypomethylation [136,137]. Higher doses of azathioprine may therefore be necessary to generate therapeutic 6-thioguanine nucleotide concentrations [138]. Moreover, when thiopurines are used, doses should be optimized by monitoring 6-thioguanine nucleotide concentrations, lymphocyte counts, or red blood cell mean corpuscular volumes [139-142]. TPMT genotypes and polymorphisms in the NUDT15 gene can affect thiopurine metabolism, thus influencing the incidence of serious side effects such as life-threatening bone marrow suppression. TPMT-deficient variants cause thiopurine toxicity in individuals of European descent, whereas risk alleles in NUDT15 account for myelosuppression in Asian children [142,143]. Consequently, testing for NUDT15 polymorphisms prior to the use of thiopurines is strongly encouraged in Asian children.
4. Biologics
Despite limited data, biologics have shown promising potential in some children with VEO-IBD. This should instill hope in both patients and physicians because it may encourage further research and development of biologics for children with VEO-IBD in the Asia–Pacific region. In a North American cohort, 41% of individuals with VEO-IBD received biologics in the first 5 years after diagnosis [6]. In an international cohort, anti-TNF agents were used most frequently (48%), with vedolizumab (VED; an anti-α4β7 integrin antibody) used in 7% of patients, and ustekinumab (UST; an anti-IL-12/23 p40 antibody) used in 2% of patients [11].
In 2014, Kelsen et al. [144] reported the efficacy of infliximab, with a corticosteroid-free clinical remission rate of 9% at 1 year in 33 patients aged 7 years or younger. Since then, the use of anti-TNF agents has been reported in many countries, with some reports describing successful therapy and others detailing treatment failure (and sometimes moving to a second anti-TNF agent) [4,145-154]. A North American study reported anti-TNF treatment failure in approximately half of the 166 children studied; moreover, adverse events occurred in 23% of those treated with infliximab and 14% of those treated with adalimumab [153]. Additionally, although anti-TNF agents may be effective for improving growth retardation and perianal lesions in some children with VEO-IBD, more treatment failures (particularly with VEO-UC) and more adverse events occur in these patients than in older children [145-147,149,150]. In a single-center cohort study in Japan, 17 children were categorized into 3 groups—UC type (UCT), non-UCT with perianal disease, and non-UCT without perianal disease [145]. Infliximab appeared useful for children with VEO-IBD, with better outcomes and fewer infusion reactions observed in children with non-UCT with perianal disease (steroid sparing rate: 67%; infusion reaction rate: 60%) and non-UCT without perianal disease (steroid sparing rate: 60%; infusion reaction rate: 29%) compared with those with UCT (steroid sparing rate: 0%; infusion reaction rate: 100%) [145]. Furthermore, in a single-center cohort study in China, the rates of clinical remission and mucosal healing were compared between 15 children with VEO-CD and 50 older children [150]. In those with VEOCD, 64% and 40% of patients achieved clinical remission and mucosal healing after induction therapy, respectively. Although VEO-CD was not associated with primary non-response or mucosal non-healing, it was significantly associated with higher rates of adverse events and treatment discontinuation [150].
VED and UST are approved for use in adults [155-158]; however, they are yet to be approved in children with IBD, and there have been particularly few reports of their use in children with VEO-IBD. Because VED does not suppress systemic immunity, it may be a suitable option for children with VEO-IBD with underlying immunodeficiency or for those who require live attenuated vaccine administration.
In a single-center report from Poland, a clinical response after the fourth dose of VED was observed in 56% of 16 children with VEO-IBD [159]. A multicenter cohort study of VED in 48 Japanese children with UC, including 5 with VEO-UC, demonstrated a remission rate of 80% at week 14, similar to that seen in older children [160]. The VEDOKIDS study, a prospective multicenter cohort that included 22 children weighing less than 30 kg (out of 142 children with IBD), did not identify any severe adverse events [161]. In children under 30 kg, the findings suggested that VED should be administered at a higher dose, either based on the child’s body surface area (200 mg/m²) or weight (10 mg/kg), to achieve optimal drug concentrations. By contrast, a dose of 177 mg/m² body surface area (up to a maximum of 300 mg) is recommended by the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition and the European Crohn’s and Colitis Organization guidelines [140,161].
Although Rinawi et al. [162] reported the efficacy of UST in a child with VEO-IBD after anti-TNFα failure in 2016, cohort studies of UST from Europe or North America have not yet been reported. A single-center cohort study in Japan noted that, in 7 of 8 patients who had not responded to anti-TNF agents, UST led to a corticosteroid-free clinical remission rate of 50% at week 52 and 88% at week 88 [163]. Another Japanese single-center study that involved 10 children with VEO-IBD (out of 43 children with CD) with anti-TNF failure also reported good long-term outcomes, with a corticosteroid-free clinical remission rate of 83% at week 106 and without severe side effects requiring UST discontinuation [164]. In this study, although a higher frequency of interval shortening (to every 4–7 weeks) was required for 7 of the patients with VEO-IBD, the long-term outcomes of children with VEO-IBD were similar to those of older children, even after anti-TNF failure [164]. The Uni-Star study, a Phase 1 trial in children with CD, included 18 children weighing less than 40 kg (out of 44 participants); serious adverse events were identified in 16% of patients [165]. Exacerbation of CD was the most frequent adverse event. In this cohort, however, there was no apparent difference in the safety profile between younger or smaller participants and older participants. In children under 40 kg, even in a group that received a higher dose (9 mg/kg), serum UST concentrations were lower than in patients weighing 40 kg or more and the reference Phase 3 adult population [165]. These findings suggest that a different dosing regimen may be required for children under 40 kg to achieve optimal drug concentrations.
5. Surgical Treatment
Children with VEO-IBD with an intractable clinical course or intestinal complications, including stricture or perforation, may require surgical intervention. This may include colectomy or ostomy placement to avoid a life-threatening complication, minimize long-term corticosteroid use, or ensure optimal growth. Bowel-related surgery was performed in 15% of 243 children during follow-up in a multicenter international cohort study, and in 20% of a group of 54 Japanese children [11,12]. The severity and prognosis of VEO-IBD compared with IBD in older children are controversial and vary depending on study setti ngs [6,7,26,39,44,104,147,166-168]. Some reports noted higher rates of surgical intervention in children with VEO-IBD [5,7,104,147,166], whereas other reports indicated similar rates to those seen in older children [6,26,39,44,167,168].
In addition, for severe or complex perianal disease, the placement of a non-cutting seton is recommended as a first-line surgical intervention to allow adequate drainage, reduce inflammation, and enhance the efficacy of biologic therapy [169,170]. When the response to combined medical and surgical treatment is insufficient, fecal diversion by ostomy placement may also be required to preserve anorectal function and improve quality of life [171]. In a Japanese cohort study, over 10 years, 4 of 7 VEO-CD patients with perianal lesions (57.1%) received seton placement, and 3 (42.9%) ultimately required ostomy placement. By contrast, a seton was placed in 13 of 29 older pediatric CD patients with perianal lesions (44.8%), and none underwent ostomy placement [172].
6. Treatments for Monogenic IBD
In some children, monogenic IBD is refractory to conventional IBD treatments. In a systematic review, 27% of 750 children with monogenic IBD required surgical treatment [56]. Bowel resection was required in 63% of the group, whereas 21% underwent ostomy creation. In addition, although various biologic agents were reportedly used, their efficacy was reported to be only 26% [56]. However, the diagnosis of some monogenic IBD types may lead to targeted therapies, resulting in improved disease activity and prognosis (Table 8) [78].
The efficacy of HCT has been established in some forms of monogenic IBD. These include colitis associated with IL-10 and IL-10R deficiency and XIAP deficiency. HCT has also been considered in other types of monogenic IBD with associated immunodeficiency (Table 8) [13-16]. However, HCT is not helpful for treating mucosal barrier defects such as TTC7A deficiency and NEMO deficiency; exploratory studies of different therapeutic approaches have therefore been conducted [91,173].
As new IBD therapies become available, more reports of effective treatments for monogenic IBD, including via drug repositioning, are expected to emerge. However, problems remain in the form of a lack of uniformity when expressing efficacy. Uhlig et al. [78] recommend the use of a standardized reporting methodology—including disease activity assessment with a pediatric UC activity index, endoscopic assessment, and fecal calprotectin—to address this issue.
The various pathogeneses and unique challenges in the diagnosis and management of children with VEO-IBD necessitate a multidisciplinary approach. Pediatric gastroenterologists must be at the forefront of care and lead the multidisciplinary team. For the diagnosis of VEO-IBD, pathologists, radiologists, immunologists, geneticists, and other specialists who cover specific EICs are required to ensure optimal diagnostic accuracy. To decide on the appropriate pharmacological or surgical treatment, discussions with adult gastroenterologists and pediatric or adult surgeons are important, and hematologists should be involved when HCT is considered. Collaboration with the pharmacy department is also helpful in ensuring the correct administration of medications with limited dosing information and formulations. Nurses not only provide daily physical and emotional support for children and their families, but also enable community-based care that might involve stoma management or home intravenous hyperalimentation. Dietitians are another essential part of the team; their role may include prescribing nutritional products, managing specific nutritional interventions, and ensuring the provision of adequate age-appropriate diets. Psychosocial support for patients and their families must also be provided because VEO-IBD can adversely impact quality of life and mental health [174]. Child life specialists can also facilitate patients’ developmental and mental status-matched education and care.
Upon diagnosis of a specific form of monogenic IBD, genetic counseling by certified personnel should be offered to patients and their families. In addition, collaborations with researchers to identify novel candidate causative genes—and conduct functional analyses specific to these genes—may lead to the establishment of novel forms of monogenic IBD, which might result in the provision of better treatment options based on the underlying pathophysiology.
In settings where a multidisciplinary team is not available, the centralization of diagnostic tests at a local, national, or regional level, or collaboration within research projects, will likely facilitate diagnoses. Furthermore, consultation with specialized personnel or institutions may be helpful for developing the most effective approach with limited resources. Strengthening international and regional collaborations—through telemedicine, training programs, and shared databases—may enhance diagnostic accuracy and management, even in resource-limited settings. Mutual learning between countries with diverse experiences and systems might also support context-appropriate and sustainable care models.
Children with VEO-IBD face important diagnostic and treatment challenges in the Asia–Pacific region. The present review highlights the need for comprehensive diagnostic protocols—including endoscopy for VEO-IBD and genetic testing for monogenic IBD—to facilitate an early and accurate diagnosis and the provision of appropriate treatments. This paper also promotes a multidisciplinary approach for the holistic care of children with VEO-IBD, which we hope will lead to better clinical outcomes and a higher quality of life for affected children and their families. Given the current lack of data for many aspects of VEO-IBD and monogenic IBD, future research through regional collaborations across the Asia–Pacific region is required.

Funding Source

The authors received no financial support for the research, authorship, and/or publication of this article.

Conflict of Interest

Takeuchi I received honoraria from AbbVie GK, Takeda Pharmaceutical Co., Ltd., and EA Pharma Co., Ltd. Arai K received honoraria from AbbVie GK, Takeda Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., EA Pharma Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., Alfresa Pharma Co., Ltd., and Mochida Pharmaceutical Co., Ltd. He also received grants from AbbVie GK, Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Bristol-Myers Squibb Company, and Pfizer Inc. Calixto-Mercado KS received a travel grant from Celltrion. Shim JO received honoraria from Samsung Bioepis, Celltrion, AbbVie, and Janssen. She is also an Editorial Board member of this journal but was not involved in the peer review or decision-making process for this manuscript. The remaining authors have no conflicts of interest to declare.

Data Availability Statement

Data sharing is not applicable as no new data were created or analyzed in this study.

Author Contributions

Conceptualization: Poddar U, Shim JO, Arai K, Takeuchi I. Project administration: Poddar U, Shim JO, Arai K, Takeuchi I. Writing - original draft: Poddar U, Shim JO, Arai K, Takeuchi I. Writing - review & editing: all authors. Approval of final manuscript: all authors.

Fig. 1.
Overview of innate and adaptive immunity in monogenic inflammatory bowel disease (IBD). The key components involved in monogenic IBD are highlighted with stars. (A) Epithelial barriers consist of intestinal epithelial cells, mucins, antimicrobial peptides, and sIgA, separating luminal microbes from mucosal immunity. In adaptive immunity, naive T cells differentiate into various subsets under the influence of cytokines and antigens. (B) Signaling pathways and molecular interactions affected in some monogenic IBDs, resulting in alterations to epithelial barriers and innate and adaptive immunity. Altered signaling includes PI3K–AKT, NF-κB, NOD2, prostaglandin E2 transport, and immune checkpoint pathways, leading to barrier and immune dysregulation. IL, interleukin; TGF-β, transforming growth factor-beta; STAT, signal transducer and activator of transcription; Bcl6, B-cell lymphoma 6 protein; GATA3, GATA-binding protein 3; T-bet, T-box expressed in T cells (TBX21); RORγT, RAR-related orphan receptor gamma T; Foxp3, forkhead box P3; Tfh, T follicular helper cell; Th, T helper cell; Treg, regulatory T cell; iTreg, inducible regulatory T cell; IFN-γ, interferon-gamma; TLR, Toll-like recepto; TCR, T-cell receptor; TNFR, tumor necrosis factor receptor; TTC7A, tetratricopeptide repeat domain 7A; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; NEMO, nuclear factor κB essential modulator; IKK, I-κB kinase; NOD2, nucleotide-binding oligomerization domain-containing protein 2; SMAC, second mitochondria-derived activator of caspases; PGE2, prostaglandin E2; XIAP, X-linked inhibitor of apoptosis protein; CYBC1, cytochrome B-245 chaperone 1; XIAP, X-linked inhibitor of apoptosis protein; NF-κB, nuclear factor-κB; MHC, major histocompatibility complex; CTLA-4, cytotoxic T-lymphocyte associated protein 4; LRBA, lipopolysaccharide-responsive and beige-like anchor protein. Created in BioRender (2025, https://BioRender.com/x00f410).
ir-2025-00082f1.jpg
Fig. 2.
Distributions of monogenic inflammatory bowel disease in Asia (A) and Europe/North America (B).
ir-2025-00082f2.jpg
Fig. 3.
Diagnostic approach for monogenic inflammatory bowel disease (IBD) in very early-onset-IBD. This figure illustrates a diagnostic model that combines clinical data, functional studies, and genetic testing. IBD with onset <2 years, atypical features, or refractoriness raises suspicion for monogenic IBD. Functional analyses provide early diagnostic clues. Genetic testing follows a tiered approach, progressing from panel sequencing to whole-exome and whole-genome sequencing. Results are categorized as pathogenic variants, variants of uncertain significance (VUS) in known genes, or VUS in novel genes. Pathogenic variants support prompt diagnosis and prognosis improvement, whereas VUS requires integration with clinical and functional data to determine pathogenicity or identify novel monogenic IBD. EGID, eosinophilic gastrointestinal disorders; FGID, functional gastrointestinal disorders; IBS, irritable bowel syndrome; DHR, dihydrorhodamine.
ir-2025-00082f3.jpg
Table 1
Frequencies of VEO-IBD in Cohort Studies and Diagnostic Distributions
Country Year Author Design Pediatric IBD (n) VEO-IBD (n) VEO-IBD (%) CD (%) UC (%) IBD-U (%) Perianal lesion (%)
Asia
 Kuwait 2011 Al-Qabandi et al. [22] Single-center 130 11 8.0 45.5 54.5
 Japan 2013 Maisawa et al. [23] Multi-center 80b 28.8 58.8 7.5
 India 2014 Sathiyasekaran et al. [24] Multi-center 221 34 15.8
 Saudi Arabia 2014 El Mouzan et al. [25] Multi-center 340 54c 15.9c 42.6 57.4
 Saudi Arabia 2016 Al-Hussaini et al. [26] Multi-center 352 76 21.6 38.2 59.2 2.6
 Malaysia 2016 Lee et al. [27] Single-center 48 6e 12.5e 50.0 33.3 16.7
 Korea 2018 Kim et al. [28] Single-center 230 12 5.2 58.3 41.7 16.7
 China 2018 Wang et al. [29] Multi-center 143 34e 23.8e
 Singapore 2018 Ong et al. [30] Multi-center 228 40 17.5 45.0 50.0 5.0
 Japan 2020 Kudo et al. [31] Multi-center 225 21.3 56.0 8.0
 Japan 2020 Kudo et al. [32] Multi-center 36a 33.3 58.3 8.3
 India 2020 Srivastava et al. [2] Multi-center 325 60 19.2
 Japan 2020 Arai et al. [33] Multi-center 243 27 11.1 25.9 59.0 14.8
 India 2020 Poddar et al. [34] Single-center 105 20 19.0
 India 2021 Yewale et al. [4] Multi-center 138 23 16.7 26.1 17.4 56.5
 India 2021 Banerjee et al. [3] Single-center 292 22 7.5 59.1 36.3 4.5 22.7
 Japan 2022 Usami et al. [12] Single-center 54 64.8 35.2 20.0
 Asia–Pacific 2022 Huang et al. [35] Multi-center 311 91 29.3 33.0 56.0 11.0
 Australia 2023 Chapuy et al. [5] Single-center 95a 28 29.5 39.3 32.1 28.6 36.4
 India 2024 Mohan et al. [36] Single-center 126 16 12.7 18.8 81.2 6.2
 Thailand 2024 Tanpowpong et al. [37] Multi-center 72 27 37.5 48.6 50 1.4 31.4 in CD
 South and Southeast Asia 2025 Lee et al. [38] Multi-center 440 112 25.5 32.1 60.7 7.1 19.4
Europe/North America
 Canada 2014 Benchimol et al. [39] Multi-center 7,143 383 5.4 33.2 55.6 11.2
 Ireland 2016 Coughlan et al. [40] Single-center 190 57 30.0 52.6 35.1 12.3 10.0
 France 2017 Bequet et al. [41] Multi-center 1,412 42 3.0 60.0 33.0 7.0 17.0
 Canada 2020 Dhaliwal et al. [42] Multi-center 1,092 43 3.9 44.2 55.8 2.3
 Canada 2021 Kerur et al. [6] Multi-center 269 39.0 39.4 21.6 7.1
 US 2022 Collen et al. [43] Single-center 199 46.2 48.2 5.5 27.6
 Italy 2023 Cucinotta et al. [44] Multi-center 232 78 34.0 25.6 46.2 28.2 35.0
Other areas
 Turky 2015 Cakir et al. [45] Multi-center 127 15d 11.8d 46.7 40.0 13.3
 Brazil 2020 Penatti et al. [46] Single-center 20 35.0 65.0 30.0
 Israel 2021 Stulman et al. [47] Multi-center 1,533 31 2.0 65.0 35.0
 Egypt 2021 Mansour et al. [48] Single-center 197 106 54.0 34.0 52.0 14.0 7.7
 Israel 2023 Atia et al. [49] Multi-center 5,243 251 4.8 53.8 46.2 8.0
 Israel 2023 Krauthammer et al. [50] Multi-center 23e 56.5 43.5

a Early-onset.

b < 8 Years old.

c < 4 Years old.

d < 5 Years old.

e Infantile-onset.

VEO-IBD, very early-onset inflammatory bowel disease; IBD, inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; IBD-U, IBD unclassified.

Table 2
Characteristics of Very Early-Onset Inflammatory Bowel Disease versus Pediatric Inflammatory Bowel Disease (Diagnosed at 6–18 Years)
Characteristics References
Reported from Asia–Pacific and Western countries
 Higher proportion of inflammatory bowel disease unclassified 2,4,5,44
 Lower proportion of CD 5,38,44
 Higher proportion of colonic CD 2,23,29,40–42,46,48
 Higher proportion of severe disease in UC and CD 3,28,29,33,44,46
 Higher proportion of bloody stool and diarrhea as initial symptoms 3,4,6,12,27,29,40,41,44,46
Reported from Asia–Pacific countries
 Higher proportion of pancolitis in UC 3,23
 Higher proportion of perianal lesions in CD 4,36
 Higher proportion of positive family history 3,4,26,28
 Younger age of disease onset in CD than in UC 12,46

CD, Crohn’s disease; UC, ulcerative colitis.

Table 3
Frequencies of Monogenic Inflammatory Bowel Disease in Very Early-Onset Inflammatory Bowel Disease
Country Year Author Patients (n) Frequency (%) Disease or gene (n)
Korea 2014 Shim et al. [17] 40 17.5 IL10RA (7)
China 2017 Ye et al. [58] 38 (infantile) 63.2 IL10RA (24), EPCAM (1), TNFAIP3 (1), LRBA (1)
Korea 2018 Kim et al. [28] 230 (pediatric) 7.8 IL-10 signaling defect (8), CGD (3), IPEX syndrome (2), GSD (1), congenital neutropenia (2), hyper IgM syndrome (1), hypogammaglobulinemia (1)
International 2017 Petersen et al. [59] 54 9.3 IL-10 signaling defect (3), WAS (1), DKC (1)
Japan 2017 Suzuki et al. [60] 35 (pediatric) 14.3 IL10RA (2), XIAP (2), CYBB (1)
UK 2017 Kammermeier et al. [61] 62 (infantile) 31.0 IL10 (2), IL10RA (1), IL10RB (2), EPCAM (3), FOXP3 (3), LRBA (1), SKIV2L (2), TTC37 (2), TTC7A (3)
China 2018 Wang et al. [29] 143 (pediatric) 9.8 IL10RA (13), SLC37A4 (1)
China 2018 Fang et al. [62] 54 16.7 IL10RA (4), IL10RB (1), CYBB (2), TNFRSF13B (1), XIAP (1)
Europe 2018 Charbit-Henrion et al. [63] 185 33.5 FOXP3 (19), XIAP (10), IL10RB (7), LRBA (5), IL10RA (3), SKIV2L (3), IL2R (2), MALT1 (2), MYO5B (3), NCF1 (2), TTC7A (2), NEUROG3 (1), STAT3 (1), EPCAM1 (1), ICOS (1), NLRC4 (1), SI (1), STAT1 (1), TTC37 (1)
Italy 2019 Lega et al. [64] 87 11.5 WAS (2), CYBA (1), CYBB (1), FOXP3 (1), CD40L (2), XIAP (2), DKC1 (1)
Canada 2020 Crowley et al. [65] 142 7.7 TTC7A (1), ARPC1B (2), DKC1 (1), LRBA (1), STAT1 (1), XIAP (1), CYBB (1), FOXP3 (1), IL10RB (1), HSPA1L (1)
UK 2020 Ashton et al. [66] 401 (pediatric) 11.5 CD40LG (5), WASP (4), DKC1 (2), DCLRE1C (2), XIAP (1), NCF1 (1), NCF2 (3), TRIM22 (5), STAT1 (3), MASP2 (1), NOD2 (20)
International 2020 Serra et al. [67] 145 2.8 XIAP (1), CYBA (1), SH2D1A (1), PCSK1 (1)
Japan 2020 Uchida et al. [68] 81 9.9 XIAP (4), IL10RA (3), TNFAIP3 (2), SLCO2A1 (1), CTLA4 (1), HPS1 (1), FOXP3 (1), CYBB (1), RELA (1)
Japan 2020 Kudo et al. [31] 225 11.6 CGD (6), IL-10 signaling defect (4), A20 haploinsufficiency (3), XIAP deficiency (3), MHC class II deficiency (1), IKBA gene disorder (1), MIRAGE syndrome (1), SCID (1), Hoyeraal–Hreidarsson syndrome (1), Coffin–Siris syndrome (1), WAS (1), IPEX syndrome (1), IL-2Rα deficiency (1)
China 2021 Su et al. [69] 73 (infantile) 60.3 IL10RA (35), CYBB (2), WASP (1), IKBKG (1), SLC37A4 (1), CD40LG (1), LIG4 (1), CARD11 (1), PIK3CD (1)
India 2021 Ganesh et al. [70] 17 47.1 IL10RB (2), IL10RA (1), LRBA (2), DOCK8 (1), SKIV2L (1), GUCY2 (1)
Japan 2022 Usami et al. [12] 54 16.6 CGD (6), IL-10 signaling defect (1), XIAP deficiency (1), WAS (1)
US 2022 Collen et al. [43] 216 7.9 IL10RA (2), IL10RB (1), CYBB (1), NCF2 (1), FOXP3 (2), TTC37 (2), PLCG2 (1), SLCO2A1 (1), RTEL1 (1), SLC37A4 (1), WASP (1), BTK (1), XIAP (1), MASP2 (1)
Japan 2021 Sasahara et al. [71] 108 (pediatric) 13.9 XIAP (4), IL10RA (3), TNFAIP3 (2), CTLA4 (1), RELA (1), CYBB (1), FOXP3 (1)
Israel 2023 Krauthammer et al. [50] 23 (infantile) 8.7 IL10RA or IL10RB, CARMIL2
Italy 2023 Cucinotta et al. [44] 78 4.0 IL10RB (1), WAS (1), XIAP (1)
India 2023 Poddar et al. [73] 48 31.0 IL10RB (2), WASP (2), TTC37 (1), FGFR2 (1), PIK3CD (1), FOXP3 (1), EGFR (1), SCID (2), CGD (2), hyper IgE syndrome (1), selective IgM deficiency with IgG3 subclass deficiency (1)
China 2024 Ye et al. [72] 225 71.6 BACH2 (1), BTK (1), CARD11 (1), CD40LG (2), CYBA (1), CYBB (14), ELANE (4), FOXP3 (2), IL10RA (94), IL12RB1 (2), LIG4 (1), LRBA (2), PIK3CD (8), PLA2G4A (1), PLCG2 (1), XIAP (1), WAS (2), TNFAIP3 (10), SYK1 (1), SKIV2L (1), RAG1 (1), ITGB2 (1), MVK (1), IKBKG (1), STAT1 (1) (the causative genes in 6 patients are not shown)

IL, interleukin; CGD, chronic granulomatous disease; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked; GSD, glycogen storage disease; Ig, immunoglobulin; WAS, Wiskott-Aldrich syndrome; DKC, dyskeratosis congenita; XIAP, X-linked inhibitor of apoptosis protein; MHC, major histocompatibility complex; IKBA, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; MIRAGE, myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy; SCID, severe combined immunodeficiency.

Table 4
Phenotypes Suspected of Having Monogenic Inflammatory Bowel Disease
Phenotypes Comments
YOUNG AGE onset Under 6 years old, particularly under 2 years of age
Multiple family members Multiple familial cases of inflammatory bowel disease, particularly with a high incidence in males
Autoimmunity Complicated autoimmune diseases such as arthritis and cholangitis
Thriving failure Growth disturbance and stunting
Treatment with conventional medication fails No improvement with standard medications
Endocrine concerns Complicated endocrine disorders (such as thyroiditis)
Recurrent infections Compromised host with increased risk of intestinal and extraintestinal infections
Severe perianal disease Severe perianal fistula or abscess in early life
Macrophage activation syndrome Hemophagocytic lymphohistiocytosis induced by Epstein–Barr virus or cytomegalovirus infection
Obstruction and atresia of the intestine Multiple intestinal occlusions or stenotic lesions
Skin lesions, dental and hair abnormalities Eczema, folliculitis, dental defects, and fine and sparse hair
Tumors Increased risk of lymphoma, skin cancer, and thyroid tumors
Table 5
Differential Diagnosis of Very Early-Onset Inflammatory Bowel Disease
Infections
 Viruses (cytomegalovirus, norovirus, adenovirus, bocavirus, calcivirus)
 Bacteria (Clostridioides difficile, Clostridium botulinum, Shigella spp., Salmonella spp., Yersinia enterocolitica, Escherichia coli, Campylobacter jejuni, Mycobacterium tuberculosis)
 Parasites/protozoa (Giardia lamblia, Cryptosporidium spp., Cyclospora spp., Entamoeba histolytica)
Eosinophilic gastrointestinal disorders
Congenital diarrhea and enteropathies
 Congenital chloride diarrhea, congenital sodium diarrhea, tufting enteropathy, microvillus inclusion disease
Others
 Celiac disease, immunoglobulin A vasculitis, post-enteritis syndrome, lactose intolerance, juvenile polyps, medications (e.g., antibiotics), intestinal lymphangiectasia
Table 6
Key Points Regarding History Taking and Physical Examinations for Very Early-Onset Inflammatory Bowel Disease
Family history and past medical history
 Consanguinity
 IBD, autoimmune disorders, autoinflammation, HLH, infantile death
Extraintestinal comorbidities and signs of monogenic IBD
 Perianal disease
 Atypical infection
 HLH
 Joints
 Skin, hair, teeth
 Multiple intestinal atresia
 Early onset malignancy (< 25 yr)

IBD, inflammatory bowel disease; HLH, hemophagocytic lymphohistiocytosis.

Table 7
Tests for Monogenic Inflammatory Bowel Disease
First line: inflammatory bowel disease activity assessment and basic immunological tests
 Complete blood count, total leukocyte count/differential leukocyte count, immunoglobulins, vaccine-derived antibodies
Second line: advanced immunological tests
 Lymphocyte subset analysis
 Dihydrorhodamine test
Third line: genetic testing
 Targeted sequencing
 Panel sequencing
 Whole exome/genome sequencing

Functional analyses specific to candidate causative genes/variants may also be considered, especially for variants of uncertain significance.

Table 8
Reportedly Effective Treatments for Monogenic Inflammatory Bowel Disease
Treatment Genes
Hematopoietic stem cell IL10RB, IL10RA, IL10, XIAP, WAS, FOXP3,
transplantation CYBB, NCF1, NCF2, NCF4
Abatacept LRBA, CTLA4
Canakinumab MVK
Anakinra CARD8, MVK
Colchicine MEFV
Eculizumab CD55
Tadekinig alfa NLRC4
Empagliflozin SLC37A4
  • 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.ArticlePubMed
  • 2. Srivastava A, Sathiyasekharan M, Jagadisan B, et al. Paediatric inflammatory bowel disease in India: a prospective multicentre study. Eur J Gastroenterol Hepatol 2020;32:1305–1311.ArticlePubMed
  • 3. Banerjee R, Pal P, Nabi Z, Shava U, Ganesh G, Reddy DN. Very early onset inflammatory bowel disease in a South Asian country where inflammatory bowel disease is emerging: a distinct clinical phenotype from later onset disease. Intest Res 2021;19:398–407.ArticlePubMedPMCPDF
  • 4. Yewale RV, Natarajan K, Ubal Dhus J, et al. Inflammatory bowel diseases in Tamil Nadu: a survey of demographics, clinical profile, and practices. JGH Open 2021;5:1306–1313.ArticlePubMedPMCPDF
  • 5. Chapuy L, Leduc B, Godin D, et al. Phenotype and outcomes of very early onset and early onset inflammatory bowel diseases in a Montreal pediatric cohort. Front Pediatr 2023;11:1157025.ArticlePubMedPMC
  • 6. Kerur B, Benchimol EI, Fiedler K, et al. Natural history of very early onset inflammatory bowel disease in North America: a retrospective cohort study. Inflamm Bowel Dis 2021;27:295–302.ArticlePubMedPMCPDF
  • 7. Oliva-Hemker M, Hutfless S, Al Kazzi ES, et al. Clinical presentation and five-year therapeutic management of very early-onset inflammatory bowel disease in a large North American Cohort. J Pediatr 2015;167:527–532.ArticlePubMed
  • 8. Conrad MA, Carreon CK, Dawany N, Russo P, Kelsen JR. Distinct histopathological features at diagnosis of very early onset inflammatory bowel disease. J Crohns Colitis 2019;13:615–625.ArticlePubMedPMC
  • 9. 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.ArticlePubMedPMC
  • 10. Parente P, Macciomei MC, Buccoliero AM, et al. Application of a pattern-based approach to histological diagnosis in very early onset IBD (VEO-IBD) in a multicentric cohort of children with emphasis on monogenic disease with IBD-like morphology. Histopathology 2024;84:440–450.ArticlePubMed
  • 11. Guz-Mark A, Aloi M, Scarallo L, et al. Infantile and very early onset inflammatory bowel disease: a multicenter study. Pediatrics 2024;154:e2023064546.ArticlePubMedPDF
  • 12. Usami M, Takeuchi I, Kyodo R, et al. Clinical features of very early-onset inflammatory bowel disease in Japan: a retrospective single-center study. Intest Res 2022;20:475–481.ArticlePubMedPMCPDF
  • 13. Ono S, Takeshita K, Kiridoshi Y, et al. Hematopoietic cell transplantation rescues inflammatory bowel disease and dysbiosis of gut microbiota in XIAP Deficiency. J Allergy Clin Immunol Pract 2021;9:3767–3780.ArticlePubMed
  • 14. Glocker EO, Kotlarz D, Boztug K, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med 2009;361:2033–2045.ArticlePubMedPMC
  • 15. Engelhardt KR, Shah N, Faizura-Yeop I, et al. Clinical outcome in IL-10- and IL-10 receptor-deficient patients with or without hematopoietic stem cell transplantation. J Allergy Clin Immunol 2013;131:825–830.ArticlePubMed
  • 16. Tomomasa D, Suzuki T, Takeuchi I, et al. Successful allogeneic hematopoietic cell transplantation for patients with IL10RA deficiency in Japan. J Clin Immunol 2024;45:6.ArticlePubMedPDF
  • 17. Shim JO, Seo JK. Very early-onset inflammatory bowel disease (IBD) in infancy is a different disease entity from adultonset IBD; one form of interleukin-10 receptor mutations. J Hum Genet 2014;59:337–341.ArticlePubMedPDF
  • 18. 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;72:456–473.ArticlePubMedPMC
  • 19. 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.ArticlePubMedPMC
  • 20. 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;8:271–286.ArticlePubMed
  • 21. Choe YJ, Han K, Shim JO. Treatment patterns of anti-tumour necrosis factor-alpha and prognosis of paediatric and adultonset inflammatory bowel disease in Korea: a nationwide population-based study. Aliment Pharmacol Ther 2022;56:980–988.ArticlePubMedPDF
  • 22. Al-Qabandi WA, Buhamrah EK, Hamadi KA, Al-Osaimi SA, Al-Ruwayeh AA, Madda J. Inflammatory bowel disease in children, an evolving problem in Kuwait. Saudi J Gastroenterol 2011;17:323–327.ArticlePubMedPMC
  • 23. Maisawa S, Sasaki M, Ida S, et al. Characteristics of inflammatory bowel disease with an onset before eight years of age: a multicenter epidemiological survey in Japan. J Gastroenterol Hepatol 2013;28:499–504.PubMed
  • 24. Sathiyasekaran M, Bavanandam S, Sankaranarayanan S, et al. A questionnaire survey of pediatric inflammatory bowel disease in India. Indian J Gastroenterol 2014;33:543–549.ArticlePubMedPDF
  • 25. El Mouzan MI, Saadah O, Al-Saleem K, et al. Incidence of pediatric inflammatory bowel disease in Saudi Arabia: a multicenter national study. Inflamm Bowel Dis 2014;20:1085–1090.PubMed
  • 26. Al-Hussaini A, El Mouzan M, Hasosah M, et al. Clinical pattern of early-onset inflammatory bowel disease in Saudi Arabia: a multicenter national study. Inflamm Bowel Dis 2016;22:1961–1970.PubMed
  • 27. Lee WS, Ng RT, Chan KW, Lau YL. Variable outcome in infantile-onset inflammatory bowel disease in an Asian cohort. World J Gastroenterol 2016;22:10653–10662.ArticlePubMedPMC
  • 28. Kim KY, Lee EJ, Kim JW, et al. Higher morbidity of monogenic inflammatory bowel disease compared to the adolescent onset inflammatory bowel disease. Pediatr Gastroenterol Hepatol Nutr 2018;21:34–42.ArticlePubMedPMCPDF
  • 29. Wang XQ, Xiao Y, Xu X, et al. Study of disease phenotype and its association with prognosis of paediatric inflammatory bowel disease in China. BMC Pediatr 2018;18:229.ArticlePubMedPMCPDF
  • 30. Ong C, Aw MM, Liwanag MJ, Quak SH, Phua KB. Rapid rise in the incidence and clinical characteristics of pediatric inflammatory bowel disease in a South-East Asian cohort in Singapore, 1994-2015. J Dig Dis 2018;19:395–403.ArticlePubMedPDF
  • 31. Kudo T, Arai K, Uchida K, et al. Very early-onset inflammatory bowel disease in Japan: a nationwide survey. J Gastroenterol Hepatol 2021;36:151–155.ArticlePubMedPDF
  • 32. Kudo T, Fujii T, Maisawa SI, et al. A multicenter prospective survey on early-onset inflammatory bowel disease in Japan. Digestion 2021;102:368–376.ArticlePubMedPDF
  • 33. Arai K, Kunisaki R, Kakuta F, et al. Phenotypic characteristics of pediatric inflammatory bowel disease in Japan: results from a multicenter registry. Intest Res 2020;18:412–420.ArticlePubMedPMCPDF
  • 34. Poddar U, Yachha SK, Srivastava A, Kumari N. Pediatric inflammatory bowel disease: is it really uncommon in Asian children? JGH Open 2020;4:860–866.ArticlePubMedPMCPDF
  • 35. Huang JG, Wong YK, Chew KS, et al. Epidemiological characteristics of Asian children with inflammatory bowel disease at diagnosis: insights from an Asian-Pacific multi-centre registry network. World J Gastroenterol 2022;28:1830–1844.ArticlePubMedPMC
  • 36. Mohan N, Deswal S, Bhardwaj A. Spectrum and trend of pediatric inflammatory bowel disease: a two-decade experience from northern India. Indian J Gastroenterol 2024;43:208–214.ArticlePubMedPDF
  • 37. Tanpowpong P, Jitwongwai S, Kijmassuwan T, et al. Multicenter registry of pediatric inflammatory bowel disease from a developing country. BMC Pediatr 2024;24:225.ArticlePubMedPMCPDF
  • 38. Lee WS, Chew KS, Huang JG, et al. Disease phenotypic and outcome of very-early onset inflammatory bowel disease in Asian children: an understudied population. Front Pediatr 2025;13:1487253.ArticlePubMedPMC
  • 39. Benchimol EI, Mack DR, Nguyen GC, et al. Incidence, outcomes, and health services burden of very early onset inflammatory bowel disease. Gastroenterology 2014;147:803–813.ArticlePubMed
  • 40. Coughlan A, Wylde R, Lafferty L, et al. A rising incidence and poorer male outcomes characterise early onset paediatric inflammatory bowel disease. Aliment Pharmacol Ther 2017;45:1534–1541.ArticlePubMedPDF
  • 41. Bequet E, Sarter H, Fumery M, et al. Incidence and phenotype at diagnosis of very-early-onset compared with later-onset paediatric inflammatory bowel disease: a population-based study [1988-2011]. J Crohns Colitis 2017;11:519–526.ArticlePubMed
  • 42. Dhaliwal J, McKay HE, Deslandres C, et al. One-year outcomes with ustekinumab therapy in infliximab-refractory paediatric ulcerative colitis: a multicentre prospective study. Aliment Pharmacol Ther 2021;53:1300–1308.ArticlePubMedPDF
  • 43. 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;16:1380–1396.ArticlePubMedPMCPDF
  • 44. Cucinotta U, Arrigo S, Dipasquale V, et al. Clinical course of very early-onset inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2023;76:590–595.ArticlePubMed
  • 45. Cakir M, Unal F, Dinler G, et al. Inflammatory bowel disease in Turkish children. World J Pediatr 2015;11:331–337.ArticlePubMedPDF
  • 46. Penatti DA, Machado NC, Carvalho MA, Rodrigues MA. Clinical features and outcomes of very-early-onset inflammatory bowel disease in Brazilian Children. JPGN Rep 2021;2:e032.ArticlePubMedPMC
  • 47. Stulman MY, Asayag N, Focht G, et al. Epidemiology of inflammatory bowel diseases in Israel: a nationwide Epi-Israeli IBD Research Nucleus Study. Inflamm Bowel Dis 2021;27:1784–1794.ArticlePubMedPDF
  • 48. Mansour HH, Seddek SS, Meguid ME, Eskander AE, Galal ST. Very-early-onset inflammatory bowel disease versus late-onset inflammatory bowel disease in relation to clinical phenotype: a cross-sectional study. Indian J Gastroenterol 2023;42:185–191.ArticlePubMedPDF
  • 49. Atia O, Benchimol EI, Ledderman N, et al. Incidence, management, and outcomes of very early onset inflammatory bowel diseases and infantile-onset disease: an Epi-IIRN Study. Clin Gastroenterol Hepatol 2023;21:2639–2648.ArticlePubMed
  • 50. Krauthammer A, Weintraub I, Shaoul R, et al. Infantile-onset inflammatory bowel disease has variable long-term outcomes. Front Pediatr 2023;11:1097779.ArticlePubMedPMC
  • 51. Dolinger M, Torres J, Vermeire S. Crohn’s disease. Lancet 2024;403:1177–1191.ArticlePubMed
  • 52. Le Berre C, Honap S, Peyrin-Biroulet L. Ulcerative colitis. Lancet 2023;402:571–584.ArticlePubMed
  • 53. Uhlig HH. Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease. Gut 2013;62:1795–1805.ArticlePubMed
  • 54. Pazmandi J, Kalinichenko A, Ardy RC, Boztug K. Early-onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms. Immunol Rev 2019;287:162–185.ArticlePubMedPMCPDF
  • 55. Uhlig HH, Muise AM. Clinical genomics in inflammatory bowel disease. Trends Genet 2017;33:629–641.ArticlePubMed
  • 56. Nambu R, Warner N, Mulder DJ, et al. A systematic review of monogenic inflammatory bowel disease. Clin Gastroenterol Hepatol 2022;20:e653–e663.ArticlePubMedPMC
  • 57. Nambu R, Muise AM. Advanced understanding of monogenic inflammatory bowel disease. Front Pediatr 2020;8:618918.ArticlePubMedPMC
  • 58. 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;23:2154–2164.PubMed
  • 59. Petersen BS, August D, Abt R, et al. Targeted gene panel sequencing for early-onset inflammatory bowel disease and chronic diarrhea. Inflamm Bowel Dis 2017;23:2109–2120.PubMed
  • 60. Suzuki T, Sasahara Y, Kikuchi A, et al. Targeted sequencing and immunological analysis reveal the involvement of primary immunodeficiency genes in pediatric IBD: a Japanese Multicenter Study. J Clin Immunol 2017;37:67–79.ArticlePubMedPDF
  • 61. Kammermeier J, Dziubak R, Pescarin M, et al. Phenotypic and genotypic characterisation of inflammatory bowel disease presenting before the age of 2 years. J Crohns Colitis 2017;11:60–69.ArticlePubMedPMC
  • 62. Fang YH, Luo YY, Yu JD, Lou JG, Chen J. Phenotypic and genotypic characterization of inflammatory bowel disease in children under six years of age in China. World J Gastroenterol 2018;24:1035–1045.ArticlePubMedPMC
  • 63. Charbit-Henrion F, Bègue B, Sierra A, et al. Copy number variations and founder effect underlying complete IL-10Rβ deficiency in Portuguese kindreds. PLoS One 2018;13:e0205826.ArticlePubMedPMC
  • 64. Lega S, Pin A, Arrigo S, et al. Diagnostic approach to monogenic inflammatory bowel disease in clinical practice: a tenyear multicentric experience. Inflamm Bowel Dis 2020;26:720–727.ArticlePubMedPDF
  • 65. Crowley E, Warner N, Pan J, et al. Prevalence and clinical features of inflammatory bowel diseases associated with monogenic variants, identified by whole-exome sequencing in 1000 children at a single center. Gastroenterology 2020;158:2208–2220.ArticlePubMedPMC
  • 66. Ashton JJ, Mossotto E, Stafford IS, et al. Genetic sequencing of pediatric patients identifies mutations in monogenic inflammatory bowel disease genes that translate to distinct clinical phenotypes. Clin Transl Gastroenterol 2020;11:e00129.ArticlePubMedPMC
  • 67. Serra EG, Schwerd T, Moutsianas L, et al. Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease. Nat Commun 2020;11:995.PubMedPMC
  • 68. Uchida T, Suzuki T, Kikuchi A, et al. Comprehensive targeted sequencing identifies monogenic disorders in patients with early-onset refractory diarrhea. J Pediatr Gastroenterol Nutr 2020;71:333–339.ArticlePubMed
  • 69. Su W, Yu Y, Xu X, et al. Valuable clinical indicators for identifying infantile-onset inflammatory bowel disease patients with monogenic diseases. World J Gastroenterol 2021;27:92–106.ArticlePubMedPMC
  • 70. Ganesh R, Sathiyasekeran M, Srinivas S, Narayanan RK. Clinical spectrum of monogenic infantile-onset inflammatory bowel disease. Indian J Pediatr 2022;89:497–502.ArticlePubMedPDF
  • 71. Sasahara Y, Uchida T, Suzuki T, Abukawa D. Primary immunodeficiencies associated with early-onset inflammatory bowel disease in Southeast and East Asia. Front Immunol 2021;12:786538.ArticlePubMedPMC
  • 72. Ye Z, Wang Y, Tang Z, et al. Understanding endoscopic and clinicopathological features of patients with very early onset inflammatory bowel disease: results from a decade of study. Dig Liver Dis 2024;56:50–54.ArticlePubMed
  • 73. Poddar U, Aggarwal A, Jayalakshmi K, et al. Higher prevalence of monogenic cause among very early onset inflammatory bowel disease in children: experience from a tertiary care center from Northern India. Inflamm Bowel Dis 2023;29:1572–1578.ArticlePubMedPDF
  • 74. Aschenbrenner D, Ye Z, Zhou Y, et al. Pathogenic interleukin-10 receptor alpha variants in humans: balancing natural selection and clinical implications. J Clin Immunol 2023;43:495–511.ArticlePubMedPMCPDF
  • 75. Thomas DC, Charbonnier LM, Schejtman A, et al. EROS/CYBC1 mutations: decreased NADPH oxidase function and chronic granulomatous disease. J Allergy Clin Immunol 2019;143:782–785.ArticlePubMedPMC
  • 76. Mortimer PM, Nichols E, Thomas J, et al. A novel mutation in EROS (CYBC1) causes chronic granulomatous disease. Clin Immunol 2023;255:109761.ArticlePubMed
  • 77. Marciano BE, Rosenzweig SD, Kleiner DE, et al. Gastrointestinal involvement in chronic granulomatous disease. Pediatrics 2004;114:462–468.ArticlePubMedPDF
  • 78. Uhlig HH, Booth C, Cho J, et al. Precision medicine in monogenic inflammatory bowel disease: proposed mIBD REPORT standards. Nat Rev Gastroenterol Hepatol 2023;20:810–828.ArticlePubMedPDF
  • 79. Filipovich AH, Zhang K, Snow AL, Marsh RA. X-linked lymphoproliferative syndromes: brothers or distant cousins? Blood 2010;116:3398–3408.ArticlePubMedPMCPDF
  • 80. Ma A, Malynn BA. A20: linking a complex regulator of ubiquitylation to immunity and human disease. Nat Rev Immunol 2012;12:774–785.ArticlePubMedPMCPDF
  • 81. Kadowaki T, Kadowaki S, Ohnishi H. A20 Haploinsufficiency in East Asia. Front Immunol 2021;12:780689.ArticlePubMedPMC
  • 82. Bennett CL, Christie J, Ramsdell F, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001;27:20–21.ArticlePubMedPDF
  • 83. Bacchetta R, Roncarolo MG. IPEX syndrome from diagnosis to cure, learning along the way. J Allergy Clin Immunol 2024;153:595–605.ArticlePubMed
  • 84. Wyatt RC, Olek S, De Franco E, et al. FOXP3 TSDR measurement could assist variant classification and diagnosis of IPEX syndrome. J Clin Immunol 2023;43:662–669.ArticlePubMedPMCPDF
  • 85. Lo B, Zhang K, Lu W, et al. Autoimmune disease: patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science 2015;349:436–440.PubMed
  • 86. Gámez-Díaz L, Sigmund EC, Reiser V, Vach W, Jung S, Grimbacher B. Rapid flow cytometry-based test for the diagnosis of lipopolysaccharide responsive beige-like anchor (LRBA) deficiency. Front Immunol 2018;9:720.PubMedPMC
  • 87. Egg D, Rump IC, Mitsuiki N, et al. Therapeutic options for CTLA-4 insufficiency. J Allergy Clin Immunol 2022;149:736–746.PubMed
  • 88. Nakata R, Nakamura Y, Hosomi S, et al. Slco2a1 deficiency exacerbates experimental colitis via inflammasome activation in macrophages: a possible mechanism of chronic enteropathy associated with SLCO2A1 gene. Sci Rep 2020;10:4883.ArticlePubMedPMCPDF
  • 89. Umeno J, Hisamatsu T, Esaki M, et al. A hereditary enteropathy caused by mutations in the SLCO2A1 gene, encoding a prostaglandin transporter. PLoS Genet 2015;11:e1005581.ArticlePubMedPMC
  • 90. Jardine S, Dhingani N, Muise AM. TTC7A: steward of intestinal health. Cell Mol Gastroenterol Hepatol 2019;7:555–570.ArticlePubMedPMC
  • 91. Jardine S, Anderson S, Babcock S, et al. Drug screen identifies leflunomide for treatment of inflammatory bowel disease caused by TTC7A deficiency. Gastroenterology 2020;158:1000–1015.ArticlePubMedPMC
  • 92. Nenci A, Becker C, Wullaert A, et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 2007;446:557–561.ArticlePubMedPDF
  • 93. Kawai T, Nishikomori R, Heike T. Diagnosis and treatment in anhidrotic ectodermal dysplasia with immunodeficiency. Allergol Int 2012;61:207–217.ArticlePubMed
  • 94. Uhlig HH, Schwerd T, Koletzko S, et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology 2014;147:990–1007.ArticlePubMedPMC
  • 95. Townsend P, Fernandes M. Diarrhea. In: Wyllie R, Hyams JS, Kay M. eds. Pediatric gastrointestinal and liver disease. 6th ed. Amsterdam: Elsevier, 2021:88–97.
  • 96. Galloway D, Cohen MB. Infectious diarrhea. In: Wyllie R, Hyams JS, Kay M. eds. Pediatric gastrointestinal and liver disease. 6th ed. Amsterdam: Elsevier, 2021:398–415.
  • 97. Ng SC, Chan FK. Infections and inflammatory bowel disease: challenges in Asia. J Dig Dis 2013;14:567–573.PubMed
  • 98. Lee WS, Arai K, Alex G, et al. Management and monitoring of pediatric inflammatory bowel disease in the Asia-Pacific region: a position paper by the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition (APPSPGHAN) P-IBD Working Group: surgical management, disease monitoring, and special considerations. J Gastroenterol Hepatol 2023;38:510–522.ArticlePubMedPDF
  • 99. Sahn B, Mamula P, Friedlander JA. Gastrointestinal hemorrhage. In: Wyllie R, Hyams JS, Kay M. eds. Pediatric gastrointestinal and liver disease. 6th ed. Amsterdam: Elsevier, 2021:125–134.
  • 100. Thiagarajah JR, Kamin DS, Acra S, et al. Advances in evaluation of chronic diarrhea in infants. Gastroenterology 2018;154:2045–2059.ArticlePubMedPMC
  • 101. Noble AJ, Nowak JK, Adams AT, Uhlig HH, Satsangi J. Defining interactions between the genome, epigenome, and the environment in inflammatory bowel disease: progress and prospects. Gastroenterology 2023;165:44–60.ArticlePubMed
  • 102. Aguilar C, Lenoir C, Lambert N, et al. Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers. J Allergy Clin Immunol 2014;134:1131–1141.ArticlePubMed
  • 103. Yang X, Miyawaki T, Kanegane H. SAP and XIAP deficiency in hemophagocytic lymphohistiocytosis. Pediatr Int 2012;54:447–454.ArticlePubMed
  • 104. Ledder O, Catto-Smith AG, Oliver MR, Alex G, Cameron DJ, Hardikar W. Clinical patterns and outcome of early-onset inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2014;59:562–564.ArticlePubMed
  • 105. Shimizu H, Ebana R, Kudo T, et al. Both fecal calprotectin and fecal immunochemical tests are useful in children with inflammatory bowel disease. J Gastroenterol 2022;57:344–356.ArticlePubMedPDF
  • 106. Koninckx CR, Donat E, Benninga MA, et al. The use of fecal calprotectin testing in paediatric disorders: a position paper of the European Society for Paediatric Gastroenterology and Nutrition Gastroenterology Committee. J Pediatr Gastroenterol Nutr 2021;72:617–640.ArticlePubMed
  • 107. Nambu R, Hagiwara SI, Kakuta F, et al. Current role of colonoscopy in infants and young children: a multicenter study. BMC Gastroenterol 2019;19:149.ArticlePubMedPMCPDF
  • 108. Huang JG, Tanpowpong P. Paediatric gastrointestinal endoscopy in the Asian-Pacific region: recent advances in diagnostic and therapeutic techniques. World J Gastroenterol 2023;29:2717–2732.ArticlePubMedPMC
  • 109. 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.ArticlePubMed
  • 110. Thomson M, Eltumi M, Singh C, et al. Sub-10-minute highquality diagnostic colonoscopy with terminal ileum intubation in children is feasible and safe. J Pediatr Gastroenterol Nutr 2019;69:6–12.ArticlePubMed
  • 111. Herrerias JM, Leighton JA, Costamagna G, et al. Agile patency system eliminates risk of capsule retention in patients with known intestinal strictures who undergo capsule endoscopy. Gastrointest Endosc 2008;67:902–909.ArticlePubMed
  • 112. Cohen SA, Oliva S. Capsule endoscopy in pediatrics: a growing experience. Tech Gastrointest Endosc 2015;17:31–36.Article
  • 113. Friedlander JA, Liu QY, Sahn B, et al. NASPGHAN capsule endoscopy clinical report. J Pediatr Gastroenterol Nutr 2017;64:485–494.ArticlePubMed
  • 114. Iwama I, Shimizu H, Nambu R, et al. Efficacy and safety of a capsule endoscope delivery device in children. Eur J Gastroenterol Hepatol 2019;31:1502–1507.ArticlePubMed
  • 115. Nakamura M, Watanabe K, Ohmiya N, et al. Tag-less patency capsule for suspected small bowel stenosis: nationwide multicenter prospective study in Japan. Dig Endosc 2021;33:151–161.ArticlePubMedPDF
  • 116. Oikawa-Kawamoto M, Sogo T, Yamaguchi T, et al. Safety and utility of capsule endoscopy for infants and young children. World J Gastroenterol 2013;19:8342–8348.ArticlePubMedPMC
  • 117. Urs AN, Martinelli M, Rao P, Thomson MA. Diagnostic and therapeutic utility of double-balloon enteroscopy in children. J Pediatr Gastroenterol Nutr 2014;58:204–212.ArticlePubMed
  • 118. Hagiwara SI, Kudo T, Kakuta F, et al. Clinical safety and utility of pediatric balloon-assisted enteroscopy: a multicenter prospective study in Japan. J Pediatr Gastroenterol Nutr 2019;68:306–310.ArticlePubMed
  • 119. Courtier J, Cardenas A, Tan C, et al. Nonanesthesia magnetic resonance enterography in young children: feasibility, technique, and performance. J Pediatr Gastroenterol Nutr 2015;60:754–761.ArticlePubMed
  • 120. Taylor SA, Avni F, Cronin CG, et al. The first joint ESGAR/ESPR consensus statement on the technical performance of cross-sectional small bowel and colonic imaging. Eur Radiol 2017;27:2570–2582.ArticlePubMedPMCPDF
  • 121. Bernstein CN, Boult IF, Greenberg HM, van der Putten W, Duffy G, Grahame GR. A prospective randomized comparison between small bowel enteroclysis and small bowel follow-through in Crohn’s disease. Gastroenterology 1997;113:390–398.ArticlePubMed
  • 122. Elliott CL, Maclachlan J, Beal I. Paediatric bowel ultrasound in inflammatory bowel disease. Eur J Radiol 2018;108:21–27.ArticlePubMed
  • 123. Riccabona M, Lobo ML, Augdal TA, et al. European Society of Paediatric Radiology Abdominal Imaging Task Force recommendations in paediatric uroradiology, part X: how to perform paediatric gastrointestinal ultrasonography, use gadolinium as a contrast agent in children, follow up paediatric testicular microlithiasis, and an update on paediatric contrast-enhanced ultrasound. Pediatr Radiol 2018;48:1528–1536.ArticlePubMedPDF
  • 124. Watson TA, Petit P, Augdal TA, et al. European Society of Paediatric Radiology abdominal imaging task force: statement on imaging in very early onset inflammatory bowel disease. Pediatr Radiol 2019;49:841–848.ArticlePubMedPDF
  • 125. Levine A, Griffiths A, Markowitz J, et al. Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm Bowel Dis 2011;17:1314–1321.PubMed
  • 126. Ledder O, Sonnino M, Birimberg-Schwartz L, et al. Appraisal of the P-IBD-classes criteria: a multicentre validation. J Crohns Colitis 2020;14:1672–1679.ArticlePubMedPDF
  • 127. Umeno J, Esaki M, Hirano A, et al. Clinical features of chronic enteropathy associated with SLCO2A1 gene: a new entity clinically distinct from Crohn’s disease. J Gastroenterol 2018;53:907–915.ArticlePubMedPMCPDF
  • 128. Obayashi N, Arai K, Nakano N, et al. Leopard skin-like colonic mucosa: a novel endoscopic finding of chronic granulomatous disease-associated colitis. J Pediatr Gastroenterol Nutr 2016;62:56–59.ArticlePubMed
  • 129. Magnani A, Brosselin P, Beauté J, et al. Inflammatory manifestations in a single-center cohort of patients with chronic granulomatous disease. J Allergy Clin Immunol 2014;134:655–662.ArticlePubMed
  • 130. Candotti F. Clinical manifestations and pathophysiological mechanisms of the Wiskott-Aldrich syndrome. J Clin Immunol 2018;38:13–27.ArticlePubMedPDF
  • 131. Arnold DE, Heimall JR. A review of chronic granulomatous disease. Adv Ther 2017;34:2543–2557.ArticlePubMedPMCPDF
  • 132. Kanegane H, Hoshino A, Okano T, et al. Flow cytometry-based diagnosis of primary immunodeficiency diseases. Allergol Int 2018;67:43–54.ArticlePubMed
  • 133. Uzel G, Orange JS, Poliak N, Marciano BE, Heller T, Holland SM. Complications of tumor necrosis factor-α blockade in chronic granulomatous disease-related colitis. Clin Infect Dis 2010;51:1429–1434.ArticlePubMedPMC
  • 134. Arai K. Very early-onset inflammatory bowel disease: a challenging field for pediatric gastroenterologists. Pediatr Gastroenterol Hepatol Nutr 2020;23:411–422.ArticlePubMedPMCPDF
  • 135. Takeuchi I, Funayama R, Shoji H, et al. Evaluation of deficient nutrients in infants and toddlers mainly taking amino acidbased elemental formulas: an exploratory study. Ann Nutr Metab 2024;80:186–195.ArticlePubMedPDF
  • 136. Stocco G, Martelossi S, Arrigo S, et al. Multicentric case-control study on azathioprine dose and pharmacokinetics in early-onset pediatric inflammatory bowel disease. Inflamm Bowel Dis 2017;23:628–634.ArticlePubMed
  • 137. Selvestrel D, Stocco G, Aloi M, et al. DNA methylation of the TPMT gene and azathioprine pharmacokinetics in children with very early onset inflammatory bowel disease. Biomed Pharmacother 2023;157:113901.ArticlePubMed
  • 138. Grossman AB, Noble AJ, Mamula P, Baldassano RN. Increased dosing requirements for 6-mercaptopurine and azathioprine in inflammatory bowel disease patients six years and younger. Inflamm Bowel Dis 2008;14:750–755.ArticlePubMed
  • 139. Thomas CW, Lowry PW, Franklin CL, et al. Erythrocyte mean corpuscular volume as a surrogate marker for 6-thioguanine nucleotide concentration monitoring in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine. Inflamm Bowel Dis 2003;9:237–245.ArticlePubMed
  • 140. Turner D, Ruemmele FM, Orlanski-Meyer E, et al. Management of paediatric ulcerative colitis, Part 1: ambulatory care: an evidence-based guideline from European Crohn’s and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2018;67:257–291.ArticlePubMed
  • 141. Lee WS, Arai K, Alex G, et al. Medical management of pediatric inflammatory bowel disease in the Asia‐Pacific region: a position paper by the Asian Pan‐Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition (APPSPGHAN) P-IBD Working Group. J Gastroenterol Hepatol 2023;38:523–538.ArticlePDF
  • 142. Lee YJ, Hwang EH, Park JH, Shin JH, Kang B, Kim SY. NUDT15 variant is the most common variant associated with thiopurine-induced early leukopenia and alopecia in Korean pediatric patients with Crohn’s disease. Eur J Gastroenterol Hepatol 2016;28:475–478.ArticlePubMed
  • 143. Kakuta Y, Kinouchi Y, Shimosegawa T. Pharmacogenetics of thiopurines for inflammatory bowel disease in East Asia: prospects for clinical application of NUDT15 genotyping. J Gastroenterol 2018;53:172–180.ArticlePubMedPMCPDF
  • 144. Kelsen JR, Grossman AB, Pauly-Hubbard H, Gupta K, Baldassano RN, Mamula P. Infliximab therapy in pediatric patients 7 years of age and younger. J Pediatr Gastroenterol Nutr 2014;59:758–762.ArticlePubMed
  • 145. Takeuchi I, Kaburaki Y, Arai K, et al. Infliximab for very early-onset inflammatory bowel disease: a tertiary center experience in Japan. J Gastroenterol Hepatol 2020;35:593–600.ArticlePubMedPDF
  • 146. Bramuzzo M, Arrigo S, Romano C, et al. Efficacy and safety of infliximab in very early onset inflammatory bowel disease: a national comparative retrospective study. United European Gastroenterol J 2019;7:759–766.ArticlePubMedPMCPDF
  • 147. Kelsen JR, Conrad MA, Dawany N, et al. The unique disease course of children with very early onset-inflammatory bowel disease. Inflamm Bowel Dis 2020;26:909–918.ArticlePubMedPMCPDF
  • 148. Assa A, Dorfman L, Shouval DS, Shamir R, Cohen S. Therapeutic drug monitoring-guided high-dose infliximab for infantile-onset inflammatory bowel disease: a case series. J Pediatr Gastroenterol Nutr 2020;71:516–520.ArticlePubMed
  • 149. Shimizu H, Arai K, Takeuchi I, et al. Long-term durability of infliximab for pediatric ulcerative colitis: a retrospective data review in a tertiary children’s hospital in Japan. Pediatr Gastroenterol Hepatol Nutr 2021;24:7–18.ArticlePubMedPMCPDF
  • 150. Luo Y, Cheng Q, Fang Y, Yu J, Lou J, Chen J. Infliximab therapy in very early onset Crohn’s disease: real-world experience in China. Dig Dis Sci 2021;66:3555–3562.ArticlePubMedPDF
  • 151. Rohani P, Alimadadi H, Abdollah Gorji F, Shahrokh S, Zali MR. Efficacy of infliximab and adalimumab therapy in very early onset, severe ulcerative colitis. Gastroenterol Hepatol Bed Bench 2021;14:S75–S81.PubMedPMC
  • 152. Eindor-Abarbanel A, Meleady L, Lawrence S, et al. Progression to anti-TNF treatment in very early onset inflammatory bowel disease patients. J Pediatr Gastroenterol Nutr 2022;75:473–479.ArticlePubMed
  • 153. Collen LV, Mitsialis V, Kim DY, et al. Efficacy and safety of anti-tumor necrosis factor alpha in very early onset inflammatory bowel disease. Inflamm Bowel Dis 2024;30:1443–1453.ArticlePubMedPMCPDF
  • 154. Gillmore T, Jimenez-Rivera C, Mack DR. The benefit of early and frequent antitumor necrosis factor-alpha trough level determination in very early-onset inflammatory bowel disease. ACG Case Rep J 2023;10:e01197.ArticlePubMedPMC
  • 155. Feuerstein JD, Isaacs KL, Schneider Y, Siddique SM, Falck-Ytter Y, Singh S. AGA clinical practice guidelines on the management of moderate to severe ulcerative colitis. Gastroenterology 2020;158:1450–1461.ArticlePubMedPMC
  • 156. Raine T, Bonovas S, Burisch J, et al. ECCO guidelines on therapeutics in ulcerative colitis: medical treatment. J Crohns Colitis 2022;16:2–17.PubMed
  • 157. Feuerstein JD, Ho EY, Shmidt E, et al. AGA clinical practice guidelines on the medical management of moderate to severe luminal and perianal fistulizing Crohn’s disease. Gastroenterology 2021;160:2496–2508.PubMed
  • 158. Gordon H, Minozzi S, Kopylov U, et al. ECCO guidelines on therapeutics in Crohn’s disease: medical treatment. J Crohns Colitis 2024;18:1531–1555.PubMed
  • 159. Fabiszewska S, Derda E, Szymanska E, Osiecki M, Kierkus J. Safety and effectiveness of vedolizumab for the treatment of pediatric patients with very early onset inflammatory bowel diseases. J Clin Med 2021;10:2997.ArticlePubMedPMC
  • 160. Yokoyama K, Yamamoto Y, Nambu R, et al. Safety and efficacy of vedolizumab in pediatric patients with ulcerative colitis: multicenter study in Japan. J Gastroenterol Hepatol 2023;38:1107–1115.ArticlePubMed
  • 161. Atia O, Shavit-Brunschwig Z, Mould DR, et al. Outcomes, dosing, and predictors of vedolizumab treatment in children with inflammatory bowel disease (VEDOKIDS): a prospective, multicentre cohort study. Lancet Gastroenterol Hepatol 2023;8:31–42.ArticlePubMed
  • 162. Rinawi F, Rosenbach Y, Assa A, Shamir R. Ustekinumab for resistant pediatric Crohn disease. J Pediatr Gastroenterol Nutr 2016;62:e34–e35.ArticlePubMed
  • 163. Iwama I, Yoshida M, Miyazawa A, Hara T, Nambu R. Ustekinumab offers long-term clinical remission with safety in very early-onset inflammatory bowel disease. Inflamm Bowel Dis 2024;30:1220–1222.ArticlePubMedPMCPDF
  • 164. Yamamoto Y, Takeuchi I, Shimizu H, et al. Long-term clinical and endoscopic outcomes of ustekinumab in pediatric Crohn’s disease with anti-tumor necrosis factor failure. J Gastroenterol Hepatol 2025;40:123–132.ArticlePubMed
  • 165. Rosh JR, Turner D, Griffiths A, et al. Ustekinumab in paediatric patients with moderately to severely active Crohn’s disease: pharmacokinetics, safety, and efficacy results from UniStar, a Phase 1 Study. J Crohns Colitis 2021;15:1931–1942.ArticlePubMedPMCPDF
  • 166. Mamula P, Telega GW, Markowitz JE, et al. Inflammatory bowel disease in children 5 years of age and younger. Am J Gastroenterol 2002;97:2005–2010.ArticlePubMed
  • 167. Gupta N, Bostrom AG, Kirschner BS, et al. Presentation and disease course in early: compared to later-onset pediatric Crohn’s disease. Am J Gastroenterol 2008;103:2092–2098.ArticlePubMedPMC
  • 168. Aloi M, Lionetti P, Barabino A, et al. Phenotype and disease course of early-onset pediatric inflammatory bowel disease. Inflamm Bowel Dis 2014;20:597–605.ArticlePubMed
  • 169. Amil-Dias J, Kolacek S, Turner D, et al. Surgical management of Crohn disease in children: guidelines from the Paediatric IBD Porto Group of ESPGHAN. J Pediatr Gastroenterol Nutr 2017;64:818–835.ArticlePubMed
  • 170. Adamina M, Minozzi S, Warusavitarne J, et al. ECCO guidelines on therapeutics in Crohn’s disease: surgical treatment. J Crohns Colitis 2024;18:1556–1582.PubMed
  • 171. Simard AA, Kotamraju S, DeFazio JR, Picoraro JA. Role of ileal diversion in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2024;79:800–806.ArticlePubMed
  • 172. Lin CC, Takeuchi I, Shimizu H, et al. Characteristics and long-term outcomes of children with perianal Crohn’s disease. Intest Res 2025;Mar 5 [Epub]. https://doi.org/10.5217/ir.2024.00154.Article
  • 173. Leung G, Muise AM. Monogenic intestinal epithelium defects and the development of inflammatory bowel disease. Physiology (Bethesda) 2018;33:360–369.ArticlePubMedPMC
  • 174. Holbein CE, Plevinsky J, Patel T, Conrad MC, Kelsen JR. Pediatric global health in children with very early-onset inflammatory bowel disease. J Pediatr Psychol 2021;46:747–756.ArticlePubMedPMCPDF

Figure & Data

REFERENCES

    Citations

    Citations to this article as recorded by  

      • PubReader PubReader
      • ePub LinkePub Link
      • Cite
        CITE
        export Copy Download
        Close
        Download Citation
        Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.
        Format:
        • RIS — For EndNote, ProCite, RefWorks, and most other reference management software
        • BibTeX — For JabRef, BibDesk, and other BibTeX-specific software
        Include:
        • Citation for the content below
        Asian–Pacific perspectives on the management of very early-onset inflammatory bowel disease
        Intest Res. 2025;23(4):405-429.   Published online October 28, 2025
        DOI: https://doi.org/10.5217/ir.2025.00082
        Close
      • XML DownloadXML Download
      Figure
      • 0
      • 1
      • 2
      Related articles
      Asian–Pacific perspectives on the management of very early-onset inflammatory bowel disease
      Image Image Image
      Fig. 1. Overview of innate and adaptive immunity in monogenic inflammatory bowel disease (IBD). The key components involved in monogenic IBD are highlighted with stars. (A) Epithelial barriers consist of intestinal epithelial cells, mucins, antimicrobial peptides, and sIgA, separating luminal microbes from mucosal immunity. In adaptive immunity, naive T cells differentiate into various subsets under the influence of cytokines and antigens. (B) Signaling pathways and molecular interactions affected in some monogenic IBDs, resulting in alterations to epithelial barriers and innate and adaptive immunity. Altered signaling includes PI3K–AKT, NF-κB, NOD2, prostaglandin E2 transport, and immune checkpoint pathways, leading to barrier and immune dysregulation. IL, interleukin; TGF-β, transforming growth factor-beta; STAT, signal transducer and activator of transcription; Bcl6, B-cell lymphoma 6 protein; GATA3, GATA-binding protein 3; T-bet, T-box expressed in T cells (TBX21); RORγT, RAR-related orphan receptor gamma T; Foxp3, forkhead box P3; Tfh, T follicular helper cell; Th, T helper cell; Treg, regulatory T cell; iTreg, inducible regulatory T cell; IFN-γ, interferon-gamma; TLR, Toll-like recepto; TCR, T-cell receptor; TNFR, tumor necrosis factor receptor; TTC7A, tetratricopeptide repeat domain 7A; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; NEMO, nuclear factor κB essential modulator; IKK, I-κB kinase; NOD2, nucleotide-binding oligomerization domain-containing protein 2; SMAC, second mitochondria-derived activator of caspases; PGE2, prostaglandin E2; XIAP, X-linked inhibitor of apoptosis protein; CYBC1, cytochrome B-245 chaperone 1; XIAP, X-linked inhibitor of apoptosis protein; NF-κB, nuclear factor-κB; MHC, major histocompatibility complex; CTLA-4, cytotoxic T-lymphocyte associated protein 4; LRBA, lipopolysaccharide-responsive and beige-like anchor protein. Created in BioRender (2025, https://BioRender.com/x00f410).
      Fig. 2. Distributions of monogenic inflammatory bowel disease in Asia (A) and Europe/North America (B).
      Fig. 3. Diagnostic approach for monogenic inflammatory bowel disease (IBD) in very early-onset-IBD. This figure illustrates a diagnostic model that combines clinical data, functional studies, and genetic testing. IBD with onset <2 years, atypical features, or refractoriness raises suspicion for monogenic IBD. Functional analyses provide early diagnostic clues. Genetic testing follows a tiered approach, progressing from panel sequencing to whole-exome and whole-genome sequencing. Results are categorized as pathogenic variants, variants of uncertain significance (VUS) in known genes, or VUS in novel genes. Pathogenic variants support prompt diagnosis and prognosis improvement, whereas VUS requires integration with clinical and functional data to determine pathogenicity or identify novel monogenic IBD. EGID, eosinophilic gastrointestinal disorders; FGID, functional gastrointestinal disorders; IBS, irritable bowel syndrome; DHR, dihydrorhodamine.

      Fig. 1.

      Fig. 2.

      Fig. 3.

      Asian–Pacific perspectives on the management of very early-onset inflammatory bowel disease

      Frequencies of VEO-IBD in Cohort Studies and Diagnostic Distributions

      Country Year Author Design Pediatric IBD (n) VEO-IBD (n) VEO-IBD (%) CD (%) UC (%) IBD-U (%) Perianal lesion (%)
      Asia
       Kuwait 2011 Al-Qabandi et al. [22] Single-center 130 11 8.0 45.5 54.5
       Japan 2013 Maisawa et al. [23] Multi-center 80b 28.8 58.8 7.5
       India 2014 Sathiyasekaran et al. [24] Multi-center 221 34 15.8
       Saudi Arabia 2014 El Mouzan et al. [25] Multi-center 340 54c 15.9c 42.6 57.4
       Saudi Arabia 2016 Al-Hussaini et al. [26] Multi-center 352 76 21.6 38.2 59.2 2.6
       Malaysia 2016 Lee et al. [27] Single-center 48 6e 12.5e 50.0 33.3 16.7
       Korea 2018 Kim et al. [28] Single-center 230 12 5.2 58.3 41.7 16.7
       China 2018 Wang et al. [29] Multi-center 143 34e 23.8e
       Singapore 2018 Ong et al. [30] Multi-center 228 40 17.5 45.0 50.0 5.0
       Japan 2020 Kudo et al. [31] Multi-center 225 21.3 56.0 8.0
       Japan 2020 Kudo et al. [32] Multi-center 36a 33.3 58.3 8.3
       India 2020 Srivastava et al. [2] Multi-center 325 60 19.2
       Japan 2020 Arai et al. [33] Multi-center 243 27 11.1 25.9 59.0 14.8
       India 2020 Poddar et al. [34] Single-center 105 20 19.0
       India 2021 Yewale et al. [4] Multi-center 138 23 16.7 26.1 17.4 56.5
       India 2021 Banerjee et al. [3] Single-center 292 22 7.5 59.1 36.3 4.5 22.7
       Japan 2022 Usami et al. [12] Single-center 54 64.8 35.2 20.0
       Asia–Pacific 2022 Huang et al. [35] Multi-center 311 91 29.3 33.0 56.0 11.0
       Australia 2023 Chapuy et al. [5] Single-center 95a 28 29.5 39.3 32.1 28.6 36.4
       India 2024 Mohan et al. [36] Single-center 126 16 12.7 18.8 81.2 6.2
       Thailand 2024 Tanpowpong et al. [37] Multi-center 72 27 37.5 48.6 50 1.4 31.4 in CD
       South and Southeast Asia 2025 Lee et al. [38] Multi-center 440 112 25.5 32.1 60.7 7.1 19.4
      Europe/North America
       Canada 2014 Benchimol et al. [39] Multi-center 7,143 383 5.4 33.2 55.6 11.2
       Ireland 2016 Coughlan et al. [40] Single-center 190 57 30.0 52.6 35.1 12.3 10.0
       France 2017 Bequet et al. [41] Multi-center 1,412 42 3.0 60.0 33.0 7.0 17.0
       Canada 2020 Dhaliwal et al. [42] Multi-center 1,092 43 3.9 44.2 55.8 2.3
       Canada 2021 Kerur et al. [6] Multi-center 269 39.0 39.4 21.6 7.1
       US 2022 Collen et al. [43] Single-center 199 46.2 48.2 5.5 27.6
       Italy 2023 Cucinotta et al. [44] Multi-center 232 78 34.0 25.6 46.2 28.2 35.0
      Other areas
       Turky 2015 Cakir et al. [45] Multi-center 127 15d 11.8d 46.7 40.0 13.3
       Brazil 2020 Penatti et al. [46] Single-center 20 35.0 65.0 30.0
       Israel 2021 Stulman et al. [47] Multi-center 1,533 31 2.0 65.0 35.0
       Egypt 2021 Mansour et al. [48] Single-center 197 106 54.0 34.0 52.0 14.0 7.7
       Israel 2023 Atia et al. [49] Multi-center 5,243 251 4.8 53.8 46.2 8.0
       Israel 2023 Krauthammer et al. [50] Multi-center 23e 56.5 43.5

      aEarly-onset.

      b< 8 Years old.

      c< 4 Years old.

      d< 5 Years old.

      eInfantile-onset.

      VEO-IBD, very early-onset inflammatory bowel disease; IBD, inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; IBD-U, IBD unclassified.

      Characteristics of Very Early-Onset Inflammatory Bowel Disease versus Pediatric Inflammatory Bowel Disease (Diagnosed at 6–18 Years)

      Characteristics References
      Reported from Asia–Pacific and Western countries
       Higher proportion of inflammatory bowel disease unclassified 2,4,5,44
       Lower proportion of CD 5,38,44
       Higher proportion of colonic CD 2,23,29,40–42,46,48
       Higher proportion of severe disease in UC and CD 3,28,29,33,44,46
       Higher proportion of bloody stool and diarrhea as initial symptoms 3,4,6,12,27,29,40,41,44,46
      Reported from Asia–Pacific countries
       Higher proportion of pancolitis in UC 3,23
       Higher proportion of perianal lesions in CD 4,36
       Higher proportion of positive family history 3,4,26,28
       Younger age of disease onset in CD than in UC 12,46

      CD, Crohn’s disease; UC, ulcerative colitis.

      Frequencies of Monogenic Inflammatory Bowel Disease in Very Early-Onset Inflammatory Bowel Disease

      Country Year Author Patients (n) Frequency (%) Disease or gene (n)
      Korea 2014 Shim et al. [17] 40 17.5 IL10RA (7)
      China 2017 Ye et al. [58] 38 (infantile) 63.2 IL10RA (24), EPCAM (1), TNFAIP3 (1), LRBA (1)
      Korea 2018 Kim et al. [28] 230 (pediatric) 7.8 IL-10 signaling defect (8), CGD (3), IPEX syndrome (2), GSD (1), congenital neutropenia (2), hyper IgM syndrome (1), hypogammaglobulinemia (1)
      International 2017 Petersen et al. [59] 54 9.3 IL-10 signaling defect (3), WAS (1), DKC (1)
      Japan 2017 Suzuki et al. [60] 35 (pediatric) 14.3 IL10RA (2), XIAP (2), CYBB (1)
      UK 2017 Kammermeier et al. [61] 62 (infantile) 31.0 IL10 (2), IL10RA (1), IL10RB (2), EPCAM (3), FOXP3 (3), LRBA (1), SKIV2L (2), TTC37 (2), TTC7A (3)
      China 2018 Wang et al. [29] 143 (pediatric) 9.8 IL10RA (13), SLC37A4 (1)
      China 2018 Fang et al. [62] 54 16.7 IL10RA (4), IL10RB (1), CYBB (2), TNFRSF13B (1), XIAP (1)
      Europe 2018 Charbit-Henrion et al. [63] 185 33.5 FOXP3 (19), XIAP (10), IL10RB (7), LRBA (5), IL10RA (3), SKIV2L (3), IL2R (2), MALT1 (2), MYO5B (3), NCF1 (2), TTC7A (2), NEUROG3 (1), STAT3 (1), EPCAM1 (1), ICOS (1), NLRC4 (1), SI (1), STAT1 (1), TTC37 (1)
      Italy 2019 Lega et al. [64] 87 11.5 WAS (2), CYBA (1), CYBB (1), FOXP3 (1), CD40L (2), XIAP (2), DKC1 (1)
      Canada 2020 Crowley et al. [65] 142 7.7 TTC7A (1), ARPC1B (2), DKC1 (1), LRBA (1), STAT1 (1), XIAP (1), CYBB (1), FOXP3 (1), IL10RB (1), HSPA1L (1)
      UK 2020 Ashton et al. [66] 401 (pediatric) 11.5 CD40LG (5), WASP (4), DKC1 (2), DCLRE1C (2), XIAP (1), NCF1 (1), NCF2 (3), TRIM22 (5), STAT1 (3), MASP2 (1), NOD2 (20)
      International 2020 Serra et al. [67] 145 2.8 XIAP (1), CYBA (1), SH2D1A (1), PCSK1 (1)
      Japan 2020 Uchida et al. [68] 81 9.9 XIAP (4), IL10RA (3), TNFAIP3 (2), SLCO2A1 (1), CTLA4 (1), HPS1 (1), FOXP3 (1), CYBB (1), RELA (1)
      Japan 2020 Kudo et al. [31] 225 11.6 CGD (6), IL-10 signaling defect (4), A20 haploinsufficiency (3), XIAP deficiency (3), MHC class II deficiency (1), IKBA gene disorder (1), MIRAGE syndrome (1), SCID (1), Hoyeraal–Hreidarsson syndrome (1), Coffin–Siris syndrome (1), WAS (1), IPEX syndrome (1), IL-2Rα deficiency (1)
      China 2021 Su et al. [69] 73 (infantile) 60.3 IL10RA (35), CYBB (2), WASP (1), IKBKG (1), SLC37A4 (1), CD40LG (1), LIG4 (1), CARD11 (1), PIK3CD (1)
      India 2021 Ganesh et al. [70] 17 47.1 IL10RB (2), IL10RA (1), LRBA (2), DOCK8 (1), SKIV2L (1), GUCY2 (1)
      Japan 2022 Usami et al. [12] 54 16.6 CGD (6), IL-10 signaling defect (1), XIAP deficiency (1), WAS (1)
      US 2022 Collen et al. [43] 216 7.9 IL10RA (2), IL10RB (1), CYBB (1), NCF2 (1), FOXP3 (2), TTC37 (2), PLCG2 (1), SLCO2A1 (1), RTEL1 (1), SLC37A4 (1), WASP (1), BTK (1), XIAP (1), MASP2 (1)
      Japan 2021 Sasahara et al. [71] 108 (pediatric) 13.9 XIAP (4), IL10RA (3), TNFAIP3 (2), CTLA4 (1), RELA (1), CYBB (1), FOXP3 (1)
      Israel 2023 Krauthammer et al. [50] 23 (infantile) 8.7 IL10RA or IL10RB, CARMIL2
      Italy 2023 Cucinotta et al. [44] 78 4.0 IL10RB (1), WAS (1), XIAP (1)
      India 2023 Poddar et al. [73] 48 31.0 IL10RB (2), WASP (2), TTC37 (1), FGFR2 (1), PIK3CD (1), FOXP3 (1), EGFR (1), SCID (2), CGD (2), hyper IgE syndrome (1), selective IgM deficiency with IgG3 subclass deficiency (1)
      China 2024 Ye et al. [72] 225 71.6 BACH2 (1), BTK (1), CARD11 (1), CD40LG (2), CYBA (1), CYBB (14), ELANE (4), FOXP3 (2), IL10RA (94), IL12RB1 (2), LIG4 (1), LRBA (2), PIK3CD (8), PLA2G4A (1), PLCG2 (1), XIAP (1), WAS (2), TNFAIP3 (10), SYK1 (1), SKIV2L (1), RAG1 (1), ITGB2 (1), MVK (1), IKBKG (1), STAT1 (1) (the causative genes in 6 patients are not shown)

      IL, interleukin; CGD, chronic granulomatous disease; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked; GSD, glycogen storage disease; Ig, immunoglobulin; WAS, Wiskott-Aldrich syndrome; DKC, dyskeratosis congenita; XIAP, X-linked inhibitor of apoptosis protein; MHC, major histocompatibility complex; IKBA, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; MIRAGE, myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy; SCID, severe combined immunodeficiency.

      Phenotypes Suspected of Having Monogenic Inflammatory Bowel Disease

      Phenotypes Comments
      YOUNG AGE onset Under 6 years old, particularly under 2 years of age
      Multiple family members Multiple familial cases of inflammatory bowel disease, particularly with a high incidence in males
      Autoimmunity Complicated autoimmune diseases such as arthritis and cholangitis
      Thriving failure Growth disturbance and stunting
      Treatment with conventional medication fails No improvement with standard medications
      Endocrine concerns Complicated endocrine disorders (such as thyroiditis)
      Recurrent infections Compromised host with increased risk of intestinal and extraintestinal infections
      Severe perianal disease Severe perianal fistula or abscess in early life
      Macrophage activation syndrome Hemophagocytic lymphohistiocytosis induced by Epstein–Barr virus or cytomegalovirus infection
      Obstruction and atresia of the intestine Multiple intestinal occlusions or stenotic lesions
      Skin lesions, dental and hair abnormalities Eczema, folliculitis, dental defects, and fine and sparse hair
      Tumors Increased risk of lymphoma, skin cancer, and thyroid tumors

      Differential Diagnosis of Very Early-Onset Inflammatory Bowel Disease

      Infections
       Viruses (cytomegalovirus, norovirus, adenovirus, bocavirus, calcivirus)
       Bacteria (Clostridioides difficile, Clostridium botulinum, Shigella spp., Salmonella spp., Yersinia enterocolitica, Escherichia coli, Campylobacter jejuni, Mycobacterium tuberculosis)
       Parasites/protozoa (Giardia lamblia, Cryptosporidium spp., Cyclospora spp., Entamoeba histolytica)
      Eosinophilic gastrointestinal disorders
      Congenital diarrhea and enteropathies
       Congenital chloride diarrhea, congenital sodium diarrhea, tufting enteropathy, microvillus inclusion disease
      Others
       Celiac disease, immunoglobulin A vasculitis, post-enteritis syndrome, lactose intolerance, juvenile polyps, medications (e.g., antibiotics), intestinal lymphangiectasia

      Key Points Regarding History Taking and Physical Examinations for Very Early-Onset Inflammatory Bowel Disease

      Family history and past medical history
       Consanguinity
       IBD, autoimmune disorders, autoinflammation, HLH, infantile death
      Extraintestinal comorbidities and signs of monogenic IBD
       Perianal disease
       Atypical infection
       HLH
       Joints
       Skin, hair, teeth
       Multiple intestinal atresia
       Early onset malignancy (< 25 yr)

      IBD, inflammatory bowel disease; HLH, hemophagocytic lymphohistiocytosis.

      Tests for Monogenic Inflammatory Bowel Disease

      First line: inflammatory bowel disease activity assessment and basic immunological tests
       Complete blood count, total leukocyte count/differential leukocyte count, immunoglobulins, vaccine-derived antibodies
      Second line: advanced immunological tests
       Lymphocyte subset analysis
       Dihydrorhodamine test
      Third line: genetic testing
       Targeted sequencing
       Panel sequencing
       Whole exome/genome sequencing

      Functional analyses specific to candidate causative genes/variants may also be considered, especially for variants of uncertain significance.

      Reportedly Effective Treatments for Monogenic Inflammatory Bowel Disease

      Treatment Genes
      Hematopoietic stem cell IL10RB, IL10RA, IL10, XIAP, WAS, FOXP3,
      transplantation CYBB, NCF1, NCF2, NCF4
      Abatacept LRBA, CTLA4
      Canakinumab MVK
      Anakinra CARD8, MVK
      Colchicine MEFV
      Eculizumab CD55
      Tadekinig alfa NLRC4
      Empagliflozin SLC37A4
      Table 1 Frequencies of VEO-IBD in Cohort Studies and Diagnostic Distributions

      Early-onset.

      < 8 Years old.

      < 4 Years old.

      < 5 Years old.

      Infantile-onset.

      VEO-IBD, very early-onset inflammatory bowel disease; IBD, inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; IBD-U, IBD unclassified.

      Table 2 Characteristics of Very Early-Onset Inflammatory Bowel Disease versus Pediatric Inflammatory Bowel Disease (Diagnosed at 6–18 Years)

      CD, Crohn’s disease; UC, ulcerative colitis.

      Table 3 Frequencies of Monogenic Inflammatory Bowel Disease in Very Early-Onset Inflammatory Bowel Disease

      IL, interleukin; CGD, chronic granulomatous disease; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked; GSD, glycogen storage disease; Ig, immunoglobulin; WAS, Wiskott-Aldrich syndrome; DKC, dyskeratosis congenita; XIAP, X-linked inhibitor of apoptosis protein; MHC, major histocompatibility complex; IKBA, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; MIRAGE, myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy; SCID, severe combined immunodeficiency.

      Table 4 Phenotypes Suspected of Having Monogenic Inflammatory Bowel Disease

      Table 5 Differential Diagnosis of Very Early-Onset Inflammatory Bowel Disease

      Table 6 Key Points Regarding History Taking and Physical Examinations for Very Early-Onset Inflammatory Bowel Disease

      IBD, inflammatory bowel disease; HLH, hemophagocytic lymphohistiocytosis.

      Table 7 Tests for Monogenic Inflammatory Bowel Disease

      Functional analyses specific to candidate causative genes/variants may also be considered, especially for variants of uncertain significance.

      Table 8 Reportedly Effective Treatments for Monogenic Inflammatory Bowel Disease

      Table 1

      Table 2

      Table 3

      Table 4

      Table 5

      Table 6

      Table 7

      Table 8

      Intest Res : Intestinal Research
      © Korean Association for the Study of Intestinal Diseases.
      Close layer
      TOP