Characteristics of monogenic inflammatory bowel disease in very early-onset cases: a Japanese multicenter registry study

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Intest Res. 2026;.ir.2025.00203

Publication date (electronic) : 2026 February 24

doi : https://doi.org/10.5217/ir.2025.00203

Natsuki Ito¹, Takahiro Kudo^,1, Keisuke Jimbo¹, Ryusuke Nambu², Fumihiko Kakuta³, Tatsuki Mizuochi⁴, Takeshi Saito⁵, Shin-ichiro Hagiwara⁶, Naomi Iwata⁷, Nao Tachibana⁸, Hideki Kumagai⁹, Takashi Ishige¹⁰, Toshifumi Yodoshi¹¹, Mikihiro Inoue¹², Shigeo Nishimata¹³, Hitoshi Tajiri¹⁴, Eitaro Hiejima¹⁵, Mika Sasaki¹⁶, Sawako Kato¹⁷, Hirotaka Shimizu¹⁸, Yuri Hirano¹⁸, Toshiaki Shimizu¹, Katsuhiro Arai¹⁸, Japanese Pediatric Inflammatory Bowel Disease Registry (JPIBD-R)

¹Department of Pediatrics, Faculty of Medicine, Juntendo University, Tokyo, Japan

²Division of Gastroenterology and Hepatology, Saitama Children’s Medical Center, Saitama, Japan

³Department of General Pediatrics and Gastroenterology, Miyagi Children’s Hospital, Miyagi, Japan

⁴Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan

⁵Division of Pediatric Surgery, Chiba Children’s Hospital, Chiba, Japan

⁶Department of Gastroenterology, Nutrition and Endocrinology, Osaka Women’s and Children’s Hospital, Osaka, Japan

⁷Department of Infection and Immunology, Aichi Children’s Health and Medical Center, Aichi, Japan

⁸Department of Gastroenterology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan

⁹Department of Pediatrics, Jichi Medical University, Tochigi, Japan

¹⁰Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan

¹¹Department of Pediatrics, Okinawa Chubu Hospital, Okinawa, Japan

¹²Department of Pediatric Surgery, Fujita Health University, Aichi, Japan

¹³Department of Pediatrics and Adolescent Medicine, Tokyo Medical University, Tokyo, Japan

¹⁴Department of Pediatrics, Osaka General Medical Center, Osaka, Japan

¹⁵Department of Pediatrics, Kyoto University Hospital, Kyoto, Japan

¹⁶Department of Pediatrics, National Hospital Organization Morioka Medical Center, Iwate, Japan

¹⁷Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan

¹⁸Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan

Correspondence to Takahiro Kudo, Department of Pediatrics, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. E-mail: t-kudo@juntendo.ac.jp

Received 2025 September 1; Revised 2025 December 3; Accepted 2025 December 22.

Abstract

Graphical abstract

INTRODUCTION

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic conditions that cause recurrent inflammation of the digestive tract. IBD arises from the interactions between environmental factors, the immune system, changes in the gut microbiome, and genetic factors. Because of its complex management, this disease poses significant challenges in pediatric healthcare.

Very early-onset IBD (VEO-IBD), defined as IBD diagnosed before 6 years of age, accounts for approximately 5% to 15% of pediatric IBD cases, with its prevalence varying across studies and populations [1,2]. This subgroup has drawn attention to the potential genetic backgrounds, especially with monogenic IBD, which is caused by a single pathogenic variant [3,4]. Pathogenic variants often relate to innate immune dysfunctions, such as T and B cell functional abnormalities, heightened inflammation, autoinflammatory disorders, or epithelial barrier dysfunctions [5]. Due to these varieties, monogenic IBD may not be classifiable by standard clinical, endoscopic, or histological characteristics. They most often present with unique features such as severe disease progression and refractoriness to conventional treatments. However, patients refractory to conventional treatments may respond to bone marrow transplantation or targeted molecular therapies, highlighting the importance of the early detection of underlying inborn errors of immunity or genetic anomalies [6].

Despite the identification of more than 80 causative genes for monogenic IBD through global genetic research, specific genetic backgrounds and their implications for disease management in Asia have been underreported [7,8]. VEO-IBD is a heterogeneous group of diseases, and elucidating the clinical characteristics and disease progression across different regions and ethnicities could improve clinical understanding of the disease [9]. Therefore, this study aimed to understand the clinical characteristics of VEO-IBD in non-monogenic and monogenic Japanese patients.

METHODS

RESULTS

1. Patient Characteristics and Genetic Analysis

During the observation period, among 703 pediatric IBD patients in the registry, 68 (9.7%) had VEO-IBD. Of these, 26 (38.2%) were diagnosed with UC, 16 (23.5%) with CD, 23 (33.8%) with unclassified IBD (IBD-U), and 3 (4.4%) with Behçet’s disease. Genetic testing was performed in 25 patients (36.8% of the VEO-IBD cohort), resulting in genetic diagnoses in 6 cases (8.8%). Monogenic IBD was identified in 5 of the 23 patients with IBD-U (7.4% of the overall cohort). Notably, all 5 monogenic IBD cases exhibited an IBD-U phenotype at presentation, and none were initially classified as typical UC or CD. In addition, 1 patient with Behçet’s disease was found to have trisomy 8 on genetic analysis; this case was not classified as monogenic IBD. Twenty-five patients (36.8%) underwent genetic testing, and because some patients received more than one test, a total of 26 tests were performed. The modalities included targeted gene panel sequencing in 11 patients, whole-exome sequencing in 10, whole genome sequencing in 2, and disease-specific Sanger sequencing in 3 patients. Among the 68 patients with VEO-IBD, the median follow-up duration was 5.6 years. At diagnosis, growth failure (defined as height Z-score <–2 standard deviation) was present in 23.5% of the cohort (16 out of 68 patients). An additional 8 patients developed new-onset growth failure during the follow-up period (median 5.6 years). Specifically, 6 of these patients developed growth failure within 6 months of diagnosis, 1 patient at 12 months, and 1 patient at 24 months post-diagnosis. In total, 24 patients (35.3%) experienced growth failure at or during follow-up. The median ages at symptom onset and diagnosis were 22 months and 34 months, respectively, and 42.6% of patients were male. The clinical phenotypes and genetic findings of the cohort are summarized in Table 1.

Table 1.

VEO-IBD Phenotype and Genetic Analysis (n=68)

2. Clinical Characteristics of Monogenic IBD

The clinical profiles of the patients diagnosed with monogenic IBD are described in Tables 2 and 3. The predominant clinical manifestations were diarrhea, growth failure, and perianal disease, each observed in 3 cases (60%). Disease phenotyping revealed IBD-U in all 5 cases (100%), severe disease (characterized by a mean Pediatric Ulcerative Colitis Activity Index >65 and Pediatric Crohn’s Disease Activity Index >40) in 2 (40%), and small intestinal lesions in 3 (60%). A notable history of severe infections before 1 year of age, indicative of systemic symptoms attributable to immune dysregulation, was observed in 3 cases (60%). No fatalities occurred during the median follow-up period. Various therapeutic interventions led to remission in all patients with monogenic IBD. HSCT has been curative for patients with interleukin-10 receptor subunit alpha (IL-10RA) deficiency, chronic granulomatous disease, and Wiskott–Aldrich syndrome. Patients with A20 haploinsufficiency and Hermansky–Pudlak syndrome show sustained remission with immunosuppressive agents and biologics.

Table 2.

Monogenic Inflammatory Bowel Disease

Table 3.

IBD Phenotype in Monogenic versus Non-Monogenic Disease

3. Clinical Features and Treatment in Monogenic versus Non-Monogenic IBD

Tables 3 and 4 summarize the phenotypic comparisons between monogenic and non-monogenic IBD. Since genetic testing was not performed for all patients clinically classified as non-monogenic IBD, only those who underwent genetic evaluation were included in the comparison—5 patients with monogenic IBD and 20 patients without pathogenic variants. The onset of monogenic IBD was earlier (17.6 months) than was non-monogenic IBD (24.3 months), although this difference was not statistically significant (P=0.563). Additionally, a higher percentage of males was observed in the monogenic IBD group (80.0%) than in the non-monogenic IBD group (30.0%) (P=0.121). The follow-up duration did not differ significantly between the 2 groups (monogenic IBD: 30.6 ± 18.29 months; non-monogenic IBD: 48.55 ± 30.02 months; P=0.277). Phenotypically, all monogenic IBD cases were significantly more frequently classified as IBD-U (P=0.015), in contrast to the balanced distribution of CD, UC, and IBD-U observed in non-monogenic IBD. Regarding lesion distribution, non-monogenic IBD predominantly presented with CD as isolated colitis (L2, 56.2%), with upper gastrointestinal lesions observed as L4a (37.5%) and L4b (25.0%), and perianal disease in 25.0% of the cases. UC cases commonly presented with pancolitis (E4, 84.6%). Although perianal disease was more frequent in monogenic IBD (60.0%) than in non-monogenic IBD (20.0%), the difference was not statistically significant (P=0.113). The prevalence of severe disease at diagnosis was higher in patients with monogenic IBD (40.0%) than in those with non-monogenic IBD (30.0%) (P=1.000). At diagnosis, patients with monogenic IBD tended to have lower mean Z-scores for both weight (–2.2) and height (–2.5) compared with those with non-monogenic IBD (–1.2 for weight and –1.4 for height). However, these differences did not reach statistical significance (weight: P=0.074; height: P=0.080). A history of severe infections before 1 year of age was significantly more common in the monogenic IBD group (60.0%) than in the non-monogenic IBD group (0%) (P=0.004). A family history of IBD was reported in 20.0% of the monogenic IBD cases versus 15.0% of the non-monogenic IBD cases (P=1.000). Milk allergies were reported more frequently in patients with monogenic IBD (20.0%) than in those with non-monogenic IBD (5.0%) (P=0.367). The remission maintenance rates achieved through drug therapy, including biologics, were 40.0% and 40.0% for non-monogenic and monogenic IBD, respectively (P=1.000). Steroids were administered to 80.0% of the patients with monogenic IBD and 85.0% of the patients with non-monogenic IBD (P=1.000). Biologics were used in 20.0% of patients with monogenic IBD and 60.0% of patients with non-monogenic IBD (P=0.160). In the monogenic IBD group, only 1 patient was treated with infliximab. Various biologics have been used to treat non-monogenic IBD, including infliximab, adalimumab, ustekinumab, golimumab, and vedolizumab. Tumor necrosis factor failure was observed in 5 cases (25.0%) of non-monogenic IBD, leading to the use of subsequent biological therapies. Surgical interventions were reported in 10.0% of non-monogenic IBD cases, but not in monogenic IBD cases. HSCT was performed in 3 cases (60.0%) of monogenic IBD, all of which achieved a curative outcome. No fatalities were reported in either group. Given the very small number of monogenic IBD cases (n=5) and the presence of complete separation in some variables, multivariate logistic regression was not performed. Therefore, we presented only univariate analyses.

Table 4.

Comparison of Treatments between Monogenic and Non-Monogenic Diseases

Among the 68 patients with VEO-IBD, genetic testing was performed in 25 (36.8%). As expected, patients selected for genetic testing tended to have more severe clinical features, including a higher frequency of growth failure, perianal lesions, and severe disease activity.

DISCUSSION

This study investigated the clinical and genetic features of VEO-IBD and monogenic IBD in Japanese children. The results highlight the significant role of genetic factors in the onset and progression of these conditions. Based on our findings, a genetically guided approach to diagnosis and treatment may improve clinical outcomes in pediatric IBD. Early genetic screening could enable the use of more precise and potentially safer therapies compared to standard treatment options. The prevalence of VEO-IBD in our study (9.7%) was comparable to that reported by other institutions, which ranged from 2.9% to 13.9% [6,13]. Given that the prevalence of VEO-IBD in the pediatric population is significant, accurate diagnosis is essential. Although the proportions of UC and CD in VEO-IBD are comparable to those in older children, the incidence of IBD-U and monogenic IBD is higher [4]. Moreover, comparing monogenic and non-monogenic IBD cases offers insights into the clinical phenotype, providing a clearer understanding of the disease’s heterogeneity.

The initial major finding of our study was that the prevalence of genetic variants associated with monogenic IBD in the Japanese pediatric population diagnosed with VEO-IBD was comparable to the previously reported global average. The literature indicates that the prevalence of monogenic IBD in VEO-IBD cases ranges from <1% to >30% [7,14,15]. Our discovery that 7.4% of the VEO-IBD cohort was diagnosed with monogenic IBD aligns closely with the outcomes of cohort studies conducted in Canada and the United States. In Canada, whole-exome sequencing was performed on 1,005 pediatric IBD cases, of which 140 were diagnosed with VEO-IBD and 7.8%, with monogenic IBD [6]. Similarly, a U.S. cohort study involving 216 patients with VEO-IBD identified 17 patients (7.9%) with monogenic IBD [14].

Gene diagnosis plays a crucial role in determining the prognosis and treatment strategies for various genetic disorders. For conditions such as IL-10RA deficiency, chronic granulomatous disease, and Wiskott–Aldrich syndrome, bone marrow transplantation has proven to be a curative treatment [15-17]. Conversely, for disorders such as A20 haploinsufficiency and Hermansky–Pudlak syndrome, understanding the underlying pathogenesis markedly enhances treatment prospects [18,19]. The limited number of reported cases of monogenic IBD, totaling only 5, can be attributed to factors such as the registry-based nature of the study and the historically low rates of genetic testing in earlier years. Although genetic testing has advanced in Japan with the introduction of panels and diagnostic guidelines, many countries still lack access to these tests. Therefore, meticulous patient selection is essential.

The second important observation is that patients with monogenic IBD, compared to those with non-monogenic IBD, tend to have more IBD-U phenotype, and a history of severe infections before 1 year of age. This clinical course aligns with that presented in the literature, such as studies showing that patients with IL-10RA mutations, a common cause of monogenic IBD, are prone to serious perianal disease and early-onset severe infections [20]. A cohort study in India diagnosed 15 of 48 children with VEO-IBD (31%) as having monogenic IBD [21]. Compared to non-monogenic IBD, monogenic IBD was characterized by neonatal IBD, the presence of perianal disease, IBD-U, a history of consanguinity and sibling death, as well as wasting and stunting. In a cohort study from the U.S., compared to patients with non-monogenic IBD, those with monogenic IBD were diagnosed at a younger age and were more likely to experience CD phenotype with higher rates of stricturing and penetrating disease and extraintestinal manifestations [12]. Patients with monogenic IBD were also more likely to experience intensive care unit hospitalization, gastrostomy tube use, total parenteral nutrition use, stunting at the 3-year follow-up, HSCT, and death. These patients often require aggressive treatment strategies, including advanced biological therapies and, in some cases, surgical interventions. This finding is in line with those of previous studies that have documented the challenging management and prognosis of monogenic IBD owing to its aggressive nature. However, our study highlights the critical need for early and precise genetic diagnosis to guide the management of these patients effectively.

In this study, patients who underwent genetic testing showed higher rates of growth failure, perianal lesions, and severe disease; however, this pattern likely reflects the clinical tendency to test patients with more severe presentations rather than a true biological difference. Therefore, these findings should not be interpreted as evidence of phenotype–genotype associations. The European Society for Paediatric Gastroenterology Hepatology and Nutrition recommends genetic testing for all patients with infantile-onset IBD and consideration of testing for those with VEO-IBD [6]. Identifying an underlying monogenic cause can directly guide treatment strategies, including the potential use of targeted therapies or HSCT.

This study also offers several novel contributions. First, it is one of the largest multicenter, registry-based analyses of VEO-IBD and monogenic IBD in Japanese children, conducted in a context where comprehensive genetic testing is still relatively uncommon. Second, our findings highlight the relevance of ethnic and regional genetic differences. For example, IL-10RA mutations and other monogenic variants appear more frequently in East Asian populations [20], emphasizing the need for diagnostic and therapeutic approaches tailored to specific genetic backgrounds. Third, we quantitatively compared clinical features at diagnosis between patients with and without monogenic IBD. IBD-U phenotype and a history of severe infections before 1 year of age were significantly associated with monogenic IBD, suggesting that these features may be useful indicators for selecting candidates for genetic testing. Finally, our data reflect a temporal trend in genetic testing practices in Japan: while a previous national report indicated that only 26.9% of VEO-IBD cases had undergone genetic testing up to 2016 [11], our cohort showed a higher rate of 36.8%, suggesting increasing clinical recognition of its utility.

Although this study provides valuable insights into the genetic underpinnings of VEO-IBD, it has some limitations. First, genetic analysis was performed in only a portion of VEO-IBD cases, which may not fully represent the spectrum of genetic diversity within this population. Importantly, the absence of genetic testing does not exclude the possibility of monogenic IBD, and some patients who were not tested may still harbor monogenic etiologies. Second, given that the study involved multiple institutions and that not all diagnosed patients meeting the inclusion criteria were subjected to genetic analysis during the study period, there is a potential for selection bias. Third, our focus on the Japanese pediatric population may limit the generalizability of our findings to other ethnic groups, necessitating further studies in diverse populations. Fourth, the relatively small number of patients diagnosed with monogenic IBD may affect the generalizability of our findings. Future studies with larger cohorts will be necessary to validate and extend these observations. To address these limitations, we plan to perform additional genetic testing for patients with refractory disease among those who were not genetically analyzed, as this may uncover previously unrecognized monogenic cases. We are also considering an extended follow-up study with a larger cohort, which will help validate and expand upon our findings.

In conclusion, our multicenter analysis highlights that certain clinical features in VEO-IBD (IBD-U phenotype and early severe infections) should prompt early genetic evaluation for monogenic IBD, as timely identification of a monogenic etiology can critically inform optimal treatment (including curative therapies like HSCT) and improve patient outcomes.

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