Understanding very early onset inflammatory bowel disease (VEOIBD) in relation to inborn errors of immunity.

Inflammatory bowel diseases (IBD) are multifactorial diseases which are caused by the combination of genetic predisposition, exposure factors (environmental and dietary), immune status, and dysbiosis. IBD is a disease which presents at any age, ranging from newborns to the elderly. The youngest of the pediatric IBD population have a more unique presentation and clinical course and may have a different etiology. Very early onset IBD (VEOIBD) patients, designated as those diagnosed prior the age of 6, have distinct features which are more frequent in this patient population including increased incidence of monogenetic causes for IBD (0%-33% depending on the study). This proportion is increased in the youngest subsets, which is diagnosed prior to the age of 2. To date, there are approximately 80 monogenic causes of VEOIBD that have been identified and published. Many of these monogenic causes are inborn errors of immunity yet the majority of VEOIBD patients do not have an identifiable genetic cause for their disease. In this review, we will focus on the clinical presentation, evaluation, and monogenic categories which have been associated with VEOIBD including (1) Epithelial cell defects (2) Adaptive immune defects, (3) Innate Immune/Bacterial Clearance and Recognition defects, and (4) Hyperinflammatory and autoinflammatory disorders. We will highlight differential diagnosis of VEOIBD presentations, as well as evaluation and treatment, which will be helpful for those who study and care for VEOIBD patients outside of the pediatric gastroenterology field. This is a fast-moving field of research which has grown significantly based on knowledge that we gain from our patients. These scientific findings have identified novel mucosal biology pathways and will continue to inform our understanding of gastrointestinal biology.

Very-early-onset Inflammatory Bowel Disease in an Infant with a Partial RIPK1 Deletion.

The monogenic causes of very-early-onset inflammatory bowel disease (VEO-IBD) have been defined by genetic studies, which were usually related to primary immunodeficiencies. Receptor-interacting serine/threonine-protein kinase-1 (RIPK1) protein is an important signalling molecule in inflammation and cell death pathways. Its deficiency may lead to various clinical features linked to immunodeficiency and/or inflammation, including IBD. Here, we discuss an infant with malnutrition, VEO-IBD, recurrent infections and polyathritis who has a homozygous partial deletion in RIPK1 gene.

Bowel-associated dermatosis-arthritis syndrome, a diagnostic challenge in a young child with very early-onset inflammatory bowel disease.

A 14-month-old girl with very early-onset inflammatory bowel disease (VEO-IBD) was admitted with a flare of her bowel disease and subsequently developed high fevers, joint pain, and skin lesions during her hospitalization. Workup demonstrated bowel-associated dermatosis-arthritis syndrome in the setting of VEO-IBD, a neutrophilic dermatosis rarely reported in children that can be challenging to diagnose and treat, with limited literature for patients under 2 years of age.

Long-term outcomes after enterostomy for very early-onset inflammatory bowel disease with interleukin-10 signaling deficiency.

BACKGROUND: Very early-onset inflammatory bowel disease (VEOIBD) with interleukin-10 (IL10R) signaling deficiency usually requires enterostomy in patients who are refractory to traditional treatment. This study aimed to evaluate long-term outcomes after enterostomy for VEOIBD patients with IL10R signaling deficiency. METHODS: The medical records of all patients undergoing enterostomy for signaling deficiency were retrospectively assessed during 2012.1-2022.7 in a tertiary teaching hospital, Children's Hospital of Fudan University, Shanghai, China. Data on disease history, diagnosis and details of enterostomy and stoma closure and follow-up were collected. Univariate and multivariate logistic regression analyses were used to evaluate the risk factors associated with the long-term outcome of delayed stoma closure. RESULTS: A total of 46 patients underwent an enterostomy, 19 who required emergency enterostomy and 27 with selective enterostomy. After ten years of follow-up, 35 patients underwent hematopoietic stem cell transplantation (HSCT), and 25 patients were alive after HSCT. The median timeframe between HSCT and stoma closure was 19.6 [15.9,26.2] months. Nineteen patients underwent stoma closure and had an average age of 3.9 ± 1.5 years; 6 patients were waiting for stoma closure. Based on a univariate logistic model, risk factors significantly associated with late stoma closure were age at enterostomy and age at HSCT. However, multivariate logistic regression showed no statistically significant factor associated with late stoma closure. There was no significant difference between the stoma closure group and delay closure group in the z scores of weight for age at follow up. CONCLUSIONS: This study determined the long-term outcomes after enterostomy for VEOIBD with interleukin-10 signaling deficiency. The appropriate time point of enterostomy and HSCT may improve quality of life in the long term.

Hematopoietic stem cell transplantation for CYBB heterozygous mutation resulting in very early onset inflammatory bowel disease in children: a case report.

BACKGROUND: Inflammatory bowel disease (IBD) is a heterogeneous group of disorders associated with environmental triggers and dysregulated immune responses resulting in chronic, recurrent intestinal inflammation. Very early-onset IBD (VEO-IBD) refers to patients with symptoms or diagnosis before the age of 6 years and is widely thought to be associated with monogenic mutations. Traditional drug therapy is often ineffective in this patient population, while hematopoietic stem cell transplantation (HSCT) represents the definitive cure for patients with gene mutations. CASE PRESENTATION: We report a case of VEO-IBD associated with a monogenic mutation in a 2-year-old girl presenting mainly with gastrointestinal symptoms, including recurrent hematochezia and abdominal pain for more than 3 months. A gastroscopy revealed erosive gastritis and bulbar duodenitis, while a colonoscopy indicated erosive colitis. Abnormal results were obtained from the dihydrohodamine (DHR) assay and immunoglobulin testing. Whole-exome sequencing identified a heterozygous and de novo nonsense mutation (c.388 C > T; p.R130X) in the CYBB gene leading to deficiency of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) (encoded by CYBB), a critical component of phagocytes. HSCT was performed successfully, and the DHR assay showed that normal neutrophil function was restored. Six months after HSCT, clinical remission was observed, and a repeat colonoscopy revealed intestinal mucosal healing was attained. CONCLUSIONS: Patients with CYBB mutations often develop recurrent or severe bacterial or fungal infections, mostly in the lungs, skin, lymph nodes, and liver. Here, we report on a young female child with CYBB mutations presenting predominantly with gastrointestinal symptoms. This study explores the mechanisms of inflammatory bowel disease caused by a monogenic mutation in CYBB to improve early diagnosis and effective treatment rates of this patient population.

Mucosal immune systems of pediatric inflammatory bowel disease: A review.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract in chronic or recurrent remission phase and is classified as Crohn's disease (CD) and ulcerative colitis (UC). IBD is a multifactorial disease that results from genetic and environmental factors, immunological disorders, and gut microbiota dysregulation called dysbiosis. Recently, the number of patients with IBD in Japan has been increasing. This review describes studies of T cells, such as type 1 helper T (Th1) and type 1 cytotoxic T (Tc1) cells, and cytokines, such as IL-17 and IL-21, as representatives of mucosal immunity in IBD. Th1 cells and Tc1 cells are involved in Peyer's patches of CD. IL-12 significantly reduced the production of IL-17 but significantly increased in that of IFN-γ, and IL-21 reduced IL-17 production. It also describes genetic analysis studies on the cause of very early-onset IBD (VEO-IBD). Furthermore, 11.6% of patients with VEO-IBD presented with monogenic IBD in Japan. Genetic analysis for patients with VEO-IBD and suspected monogenic IBD was investigated. XIAP and heterozygous SLCO2A1 were detected owing to the result of functional confirmation, and several candidate genes were detected. Cytokine analysis and genetic analysis studies have revealed several pathophysiologies of IBD. Clinical and basic studies on mucosal immunity as well as immunological and genetic analyses are currently ongoing and are anticipated to provide an elaborate understanding of the pathophysiology of IBD.

Use of mechanical thrombectomy in very early-onset inflammatory bowel disease patient with extensive venous thrombosis.

Mechanical thrombectomy is generally used in adult patients with pulmonary embolism or extensive venous thromboembolism, but it is starting to become more prevalent in the children. We present a unique case of a 3-year-old female with very early-onset inflammatory bowel disease with extensive venous thromboembolism who underwent successful mechanical thrombectomy.

[Diagnosis of a rare and severe inflammatory bowel disease in an infant with peri-orificial ulcerations]. / Diagnostic d'une maladie inflammatoire rare et sévère de l'intestin chez un nourrisson présentant des ulcérations péri-orificielles.

We report the case of an infant aged 8 and a half months, who had an apparent life-threatening event and died despite optimal resuscitation management. The medical history was marked by mild symptoms, mainly feeding difficulties and progressively settling skin lesions. Parents were related (first cousins) and the patient had two healthy older sisters. Autopsy showed growth delay, symmetrical erythematous and ulcerated periorificial lesions associated with punctiform erythematous lesions of the face and alopecia. Microscopic examination revealed deep bronchial inhalation with the onset of infectious pneumopathy, major inflammatory ulceration of the gastrointestinal tract, hepatic steatosis, brain stem and pancreas abnormalities. We conclude that the cause of death was a multi-visceral failure with inhalation pneumopathy, in a context of very early onset inflammatory bowel disease (VEO-IBD). Genetic consultation, into a rare disease reference center, allowed to orient the analysis, to identify a homozygous pathogenic variant in the IL10RA gene, confirming the diagnostic of an autosomal recessive very early onset inflammatory bowel disease (inflammatory bowel disease 28, early-onset, autosomal recessive, #613148).

Characterization of novel and large fragment deletions in exon 1 of the IL10RA gene in Chinese children with very early onset inflammatory bowel diseases.

BACKGROUND: Defects in interleukin 10 (IL10) and its receptors are particularly involved in very early onset inflammatory bowel disease (VEOIBD). However, large fragment deletions of IL10 receptor A (IL10RA) are rare. METHODS: VEOIBD patients with confirmed mutations in the IL10RA gene were enrolled from January 1, 2019 to June 30, 2020. The clinical features and endoscopic-radiological findings of the patients with large fragment deletions of the IL10RA gene were determined and followed up. RESULTS: Thirty-five patients with IL10RA gene mutations, namely, 28 compound heterozygous mutations and 7 homozygote mutations, were enrolled in this study. Six patients carried the reported point mutation c.301C > T (p. R101RW) or c.537 G > A (p. T179T) in one locus and a large fragment deletion in exon 1 in another locus, which were novel mutations in this gene. A 333-bp deletion of exon 1 (117857034-11857366 del) was the main mutation in this locus in 85.7% of the patients with large fragment deletions. The time of disease onset ranged from birth to 4 years, and diarrhea was the main initial symptom. In total, 6/7 patients had perianal complications, including perianal abscess, fistula and skin tags. Six patients accepted thalidomide treatment, 5/7 accepted mesalamine, 3/7 accepted hematopoietic stem cell transplantation (HSCT), and 3/7 were waiting for HSCT. CONCLUSIONS: We identified a novel large deletion of exon 1 involving the IL10RA gene for the first time and showed the characteristics of VEOIBD patients. This study expands the spectrum of Chinese VEOIBD patients with IL0RA gene mutations.

Clinical and Mutation Description of the First Iranian Cohort of Infantile Inflammatory Bowel Disease: The Iranian Primary Immunodeficiency Registry (IPIDR).

We describe a cohort of 25 Iranian patients with infantile inflammatory bowel disease (IBD), 14 (56%) of whom had monogenic defects. After proper screening, patients were referred for whole exome sequencing (WES). Four patients had missense mutations in the IL10 RA, and one had a large deletion in the IL10 RB. Four patients had mutations in genes implicated in host:microbiome homeostasis, including TTC7A deficiency, and two patients with novel mutations in the TTC37 and NOX1. We found a novel homozygous mutation in the SRP54 in a deceased patient and the heterozygous variant in his sibling with a milder phenotype. Three patients had combined immunodeficiency: one with ZAP-70 deficiency (T+B+NK-), and two with atypical SCID due to mutations in RAG1 and LIG4. One patient had a G6PC3 mutation without neutropenia. Eleven of the 14 patients with monogenic defects were results of consanguinity and only 4 of them were alive to this date.

Ustekinumab for children and adolescents with inflammatory bowel disease at a tertiary children's hospital in Japan.

BACKGROUND AND AIM: Ustekinumab is a human monoclonal antibody targeting the p40 subunit of both interleukin-12 and interleukin-23 with reported efficacy to treat Crohn's disease. However, few studies have reported the use of ustekinumab for pediatric inflammatory bowel disease. This study aimed to assess the clinical efficacy and safety of ustekinumab in children and adolescents with inflammatory bowel disease. METHODS: Medical records of patients aged under 20 years with Crohn's disease or Crohn's disease-like inflammatory bowel disease who had received ustekinumab at a Japanese pediatric inflammatory bowel disease center were retrospectively reviewed for efficacy and safety. The primary outcome was the steroid-free clinical remission rate at weeks 26 and 52. The steroid-free remission rate beyond week 52 was also evaluated. Weighted pediatric Crohn's disease activity index and simple endoscopic score for Crohn's disease were used to assess disease activity. RESULTS: Seventeen patients were included (male : female = 8:9, A1a [diagnosed < 10 years old]:A1b [diagnosed ≥ 10 years old] = 8:9). All patients were on ustekinumab at week 26, and 9/10 continued treatment over 1 year. The steroid-free clinical remission rates were 59% at week 26, 50% at week 52, and 70% over 1 year. Three of eight children who underwent endoscopy after ustekinumab introduction achieved endoscopic remission. No serious adverse events were recorded during the study period. CONCLUSIONS: Ustekinumab may be an effective and safe treatment option for pediatric and adolescent Crohn's disease and Crohn's disease-like inflammatory bowel disease patients having nonresponse or adverse reactions to anti-tumor necrosis factor agents.

Very early-onset inflammatory bowel disease in Japan: A nationwide survey.

BACKGROUND AND AIM: Very early-onset inflammatory bowel disease is defined as inflammatory bowel disease diagnosed before 6 years of age. Very early-onset inflammatory bowel disease has various differential diagnoses, including primary immunodeficiency disorders, and is known to be resistant to conventional treatment. Therefore, global attention is required to manage this challenging condition. We conducted a retrospective epidemiological survey of the number of patients, final diagnosis, and examinations performed to diagnose very early-onset inflammatory bowel disease in Japan. METHODS: A primary questionnaire about the number of very early-onset bowel disease cases and its diagnosis was administered to 630 pediatric facilities nationwide in Japan. A secondary survey about the examinations performed to achieve diagnosis was sent to the facilities that responded to the first survey. RESULTS: The answering rate was 92.2% (581/630 facilities); 81 facilities had 225 very early-onset bowel disease patients undergoing their care during the past 68 months. Twenty-six patients (11.6%) were diagnosed with immunodeficiency-associated inflammatory bowel disease. The answering rate of the secondary survey was 70.4% (57/81 facilities). Colonoscopy, esophagogastroduodenoscopy, and small bowel imaging were performed for 99.4%, 67.5%, and 28.8% of patients, respectively. Genetic analysis was performed for 26.9% (43/160 patients) of patients, and 51.2% (22/43) of patients were diagnosed with immunodeficiency-associated inflammatory bowel disease. CONCLUSIONS: Approximately 40 patients are diagnosed yearly in Japan. Imaging studies, especially for small bowel lesions, can be challenging for this unique group of patients. However, a comprehensive approach including immunological and genetic analyses appears useful for diagnosing immunodeficiency-associated inflammatory bowel disease.

Very early onset inflammatory bowel disease: Spectrum of clinical presentation, diagnostic tools and outcome in children.

OBJECTIVE: To explore the spectrum of presentation, underlying monogenetic defects and outcome in very early onset inflammatory bowel disease (VEO-IBD). METHOD: The prospective, observational study was conducted at the Children's Hospital, Lahore, Pakistan, from January 2017 to December 2018, and comprised children developing features of inflammatory bowel disease aged <6 years. Data included demography, clinical presentation, diagnostic tools and outcome. Data was analysed using SPSS 21. RESULTS: Of the 60 children with relevant symptoms, 26(43.3%) were diagnosed as having very early onset inflammatory bowel disease. Of them, 13(50%) had underlying monogenic defect, and 16(61.5%) had ulcerative colitis. There were 22(84.6%) males with median age of 1.5(11) months in monogenic inflammatory bowel disease versus 24(43) months for non-monogenic inflammatory bowel disease (p<0.05). In the monogenic group, isolated rectal bleeding was the major presentation 13(100%) versus non-monogenic who presented mainly with failure to thrive 13(100%). Upper and lower endoscopies with histopathology had good diagnostic yield and inflammatory infiltrates on the biopsied tissues were the major findings. Mutations detected among the subjects were XIAP, PRKDC, PIK3CD, RAG-1, LRBA, DOCK8, TTC7, MEFV and EPCAM. Mortality was significantly higher in the monogenic group 7(54%) than in the non-monogenic group 2(15%) (p<0.05). CONCLUSIONS: Very early onset inflammatory bowel disease should be suspected when conventional management fails to rectify common disease mimickers. Testing for underlying immunological defect and genetic mutation would be helpful for managing these rare disorders.

Complications of enterostomy and related risk factor analysis of very early onset inflammatory bowel disease with interleukin-10 signalling deficiency: a single-centre retrospective analysis.

BACKGROUND: Interleukin-10 (IL10) signalling pathway deficiency results in severe very early onset inflammatory bowel disease (VEOIBD), and enterostomy is often inevitable. However, studies in these surgical populations are lacking. This study aims to determine the enterostomy characteristics, postoperative complications and related risk factors in enterostomy patients. METHODS: From March 1, 2015, to December 31, 2018, patients with IL10R-mutation who underwent enterostomy were recruited for analysis. We collected data on the patients' clinical characteristics, enterostomy characteristics, postoperative complications and related risk factors. RESULTS: Twelve patients required emergency enterostomy, and 10 patients underwent elective enterostomy. Twelve patients experienced postoperative complications, including wound infection (27.3%), wound dehiscence (18.2%), reoperation (18.2%), etc. Compared with the pre-enterostomy values, there was a decrease in C-reactive protein (CRP) (P = 0.001), an increase in albumin (P = 0.001) and an improvement in the weight-for-age (P = 0.029) and body mass index (BMI) Z-scores (P = 0.004) after enterostomy. There was a significant difference between the pre-operation and postoperation medicine expenses (P = 0.002). Univariate binary logistic regression analysis revealed a statistically significant influence of CRP (OR: 1.43, 95% CI: 1.07-1.91, P = 0.016) and a tendency towards a significant influence of intestinal perforation, albumin level, BMI Z-score and weighted paediatric Crohn's disease activity index (wPCDAI). Multivariate logistic regression analysis showed that CRP (OR: 1.40), wPCDAI (OR: 2.88) and perforation (OR: 1.72) showed a tendency to behave as independent risk factors for postoperative complications, but the results were not significant (all P > 0.05). CONCLUSIONS: Surgery and enterostomy showed benefits for VEOIBD with IL-10 signalling deficiency. The timing of intervention, potential postoperative complications, economic burden and other related problems should be considered.

Infliximab for very early-onset inflammatory bowel disease: A tertiary center experience in Japan.

BACKGROUND AND AIM: Very early-onset inflammatory bowel disease (VEO-IBD), defined as IBD diagnosed before 6 years of age, tends to be refractory to conventional treatment for IBD. However, there have been a few reports about the usage of infliximab for VEO-IBD. This study aimed to evaluate the efficacy and safety of infliximab for VEO-IBD. METHODS: Medical records of a cohort of children with VEO-IBD who had received infliximab in a Japanese tertiary children's hospital were retrospectively reviewed for their disease characteristics and clinical course. Subjects were categorized into three groups for the descriptive comparison: ulcerative colitis type (UCT), non-UCT with perianal disease (NUC-PD), and non-UCT without perianal disease (NUC-NPD). RESULTS: Seventeen VEO-IBD patients (five UCT, five NUC-PD, and seven NUC-NPD) had received infliximab as their first biologic. In the UCT group, infliximab was continued over 54 weeks in two patients, and three eventually required surgery. In contrast, all patients in the NUC-PD and NUC-NPD groups followed up over 54 weeks remained on infliximab, and two of three patients and three of five patients were in remission at week 54, respectively. Infusion reactions occurred in all five UCT, three of five NUC-PD, and two of seven NUC-NPD patients; however, except for two patients with severe reactions, infliximab was continued with premedication and slow infusions. CONCLUSIONS: Infliximab appeared useful for children with VEO-IBD. Children with NUC-PD and NUC-NPD responded better with less infusion reaction compared with that with UCT.

A Unique Presentation of Infantile-Onset Colitis and Eosinophilic Disease without Recurrent Infections Resulting from a Novel Homozygous CARMIL2 Variant.

PURPOSE: This study aimed to characterize the clinical phenotype, genetic basis, and consequent immunological phenotype of a boy with severe infantile-onset colitis and eosinophilic gastrointestinal disease, and no evidence of recurrent or severe infections. METHODS: Trio whole-exome sequencing (WES) was utilized for pathogenic variant discovery. Western blot (WB) and immunohistochemical (IHC) staining were used for protein expression analyses. Immunological workup included in vitro T cell studies, flow cytometry, and CyTOF analysis. RESULTS: WES revealed a homozygous variant in the capping protein regulator and myosin 1 linker 2 (CARMIL2) gene: c.1590C>A; p.Asn530Lys which co-segregated with the disease in the nuclear family. WB and IHC analyses demonstrated reduced protein levels in patient's cells compared with controls. Moreover, comprehensive immunological workup revealed severely diminished blood-borne regulatory T cell (Treg) frequency and impaired in vitro CD4+ T cell proliferation and Treg generation. CyTOF analysis showed significant shifts in the patient's innate and adaptive immune cells compared with healthy controls and ulcerative colitis patients. CONCLUSIONS: Pathogenic variants in CARMIL2 have been implicated in an immunodeficiency syndrome characterized by recurrent infections, occasionally with concurrent chronic diarrhea. We show that CARMIL2-immunodeficiency is associated with significant alterations in the landscape of immune populations in a patient with prominent gastrointestinal disease. This case provides evidence that CARMIL2 should be a candidate gene when diagnosing children with very early onset inflammatory and eosinophilic gastrointestinal disorders, even when signs of immunodeficiency are not observed.

Genomic and Immunologic Drivers of Very Early-Onset Inflammatory Bowel Disease.

PURPOSE OF REVIEW: Inflammatory bowel disease (IBD) is a multifactorial disease caused by dysregulated immune responses to commensal or pathogenic intestinal microbes, resulting in chronic intestinal inflammation. However, a subset of patients with IBD diagnosed <6 years of age, known as very early-onset (VEO)-IBD, can be phenotypically and genetically distinct from older onset IBD. We aim to review the clinical presentation of children with VEO-IBD and recent discoveries that point to the underlying genomic and immunologic drivers of disease, and the significant impact on our therapeutic decisions. RECENT FINDINGS: VEO-IBD is increasing in incidence and is associated with more severe disease, aggressive progression, and poor response to most conventional therapies. This article will review some of the genetic findings in this population and the subsequent impact on therapy, with targeted approaches. SUMMARY: Children with VEO-IBD may present with a different phenotype and more severe disease than older children and adults. An integrated approach combining genetics, immunology, and traditional IBD evaluations can lead to the identification of causal defects that directly impact management. These strategies can also be employed in older onset refractory IBD.

Targeted Sequencing and Immunological Analysis Reveal the Involvement of Primary Immunodeficiency Genes in Pediatric IBD: a Japanese Multicenter Study.

PURPOSE: Pediatric inflammatory bowel disease (IBD) is a heterogeneous disorder caused by multiple factors. Although genetic and immunological analyses are required for a definitive diagnosis, no reports of a comprehensive genetic study of a Japanese population are available. METHODS: In total, 35 Japanese patients <16 years of age suffering from IBD, including 27 patients aged <6 years with very early-onset IBD, were enrolled in this multicenter study. Exome and targeted gene panel sequencing was performed for all patients. Mutations in genes responsible for primary immunodeficiency diseases (PID) and clinical and immunological parameters were evaluated according to disease type. RESULTS: We identified monogenic mutations in 5 of the 35 patients (14.3 %). We identified compound heterozygous and homozygous splice-site mutations in interleukin-10 receptor A (IL-10RA) in two patients, nonsense mutations in X-linked inhibitor of apoptosis protein (XIAP) in two patients, and a missense mutation in cytochrome b beta chain in one patient. Using assays for protein expression levels, IL-10 signaling, and cytokine production, we confirmed that the mutations resulted in loss of function. For each patient, genotype was significantly associated with clinical findings. We successfully treated a patient with a XIAP mutation by allogeneic cord blood hematopoietic stem cell transplantation, and his symptoms were ameliorated completely. CONCLUSIONS: Targeted sequencing and immunological analysis are useful for screening monogenic disorders and selecting curative therapies in pediatric patients with IBD. The genes responsible for PID are frequently involved in pediatric IBD and play critical roles in normal immune homeostasis in the gastrointestinal tract.

Inflammatory bowel disease caused by primary immunodeficiencies-Clinical presentations, review of literature, and proposal of a rational diagnostic algorithm.

Inflammatory bowel diseases (IBD) including Crohn's disease (CD) and ulcerative colitis have a multifactorial pathogenesis with complex interactions between polygenetic predispositions and environmental factors. However, IBD can also be caused by monogenic diseases, such as primary immunodeficiencies (PID). Recently, an increasing number of these altogether rare diseases have been described to present often primarily, or solely, as IBD. Early recognition of these conditions enables adaption of therapies and thus directly benefits the course of IBDs. Here, we discuss the different clinical presentations in IBD and characteristic features of patient's history, clinical findings, and diagnostic results indicative for a causative PID. Possible predictors are early onset of disease, necessity of parenteral nutrition, failure to respond to standard immunosuppressive therapy, parental consanguinity, increased susceptibility for infections, certain histopathologic findings, and blood tests that are atypical for classic IBD. We illustrate this with exemplary case studies of IBD due to NEMO deficiency, chronic granulomatous disease, common variable immunodeficiency, CTLA-4 and LRBA deficiency. Taking these factors into account, we propose a diagnostic pathway to enable early diagnosis of IBD due to PID.

Understanding endoscopic and clinicopathological features of patients with very early onset inflammatory bowel disease: Results from a decade of study.

BACKGROUND: Very early onset inflammatory bowel disease (VEOIBD) is associated with a unique disease course and distinct endoscopic features. AIMS: This study aims to provide a comprehensive description of the endoscopic and histologic features observed in a large cohort of patients with VEOIBD from a tertiary medical center. METHODS: A retrospective review of medical records from 2011 to 2021 was conducted to analyze clinical data, including disease phenotypes, endoscopic and histologic findings. Next generation sequencing was performed. RESULTS: A total of 225 VEOIBD subjects were included in this study. Monogenic defects were identified in 161 patients. Monogenic IBD patients more commonly had CD-like disease. Colonic involvement was more prevalent among those with monogenic IBD (P<0.001). Pseudo-polyps were significantly more common in the monogenic IBD group (P<0.001), while ileal edema and ulcers were significantly more prevalent in non-monogenic IBD cases. IL10RA deficiency were characterized by colonic ulcers and pseudo-polyps without upper gastrointestinal tract lesions, while patients with TNFAIP3 mutations demonstrated both upper and lower gastrointestinal tract involvement. The non-monogenic IBD patients showed a higher incidence of chronic architectural changes of crypt, increased apoptosis and eosinophils infiltration. CONCLUSIONS: Endoscopic and histologic analysis of children with VEOIBD plays a crucial role in facilitating accurate diagnosis. Various forms of monogenic IBD exhibit distinct endoscopic and pathologic changes.