Patients with very early-onset inflammatory bowel disease (VEO-IBD) may present because of underlying monogenic inborn errors of immunity (IEI). Strong differences have been observed in the causes of monogenic IBD among ethnic populations. This multicenter study was carried out on 16 Iranian patients with VEO-IBD. We reviewed clinical and basic immunologic evaluation including flow cytometry and immunoglobulin levels. All patients underwent clinical whole exome sequencing (WES). Sixteen patients (8 females and 8 males) with a median age of 43.5 months were enrolled. The median age at the onset of symptoms was 4 months. Most patients (12, 75%) had consanguineous parents. Chronic non-bloody diarrhea (13, 81.3%) and perianal diseases including perianal abscess (6, 37.5%), anal fissure (6, 37.5%), or anal fistula (2, 12.5%) were the most common manifestations. WES identified a spectrum of genetic variants in 13 patients (81.3%): IL10RB (6, 37.5%), MVK (3, 18.8%), and CASP8, SLC35C1, G6PC3, and IKBKB in 1 patient, respectively. In 3 patients (18.7%), no variant was identified. Flow cytometry identified a spectrum of abnormalities that helped to assess the evidence of genetic diagnosis. At the end of the survey, 3 (18.8%) patients were deceased. This high rate of monogenic defects with a broad spectrum of genes reiterates the importance of investigating IEI in patients with infantile-onset IBD.

Infantile inflammatory bowel disease (IBD) is a very rare subgroup of IBD that develops in children younger than two years with genetic susceptibility, especially in those with monogenic defects. This type, when compared with IBD in older children, is more resistant to conventional medical treatment and presents with more complications that require more surgical interventions. Our patient is a male with first-degree consanguineous parents. He was 16 months old when he presented with multiple perianal fistulas, fissures, abscesses, diarrhea, fever, and failure to thrive. He underwent a protective double-barrel ileostomy and surgical repair of the perianal disease. Crohn\'s disease was confirmed after endoscopy and biopsy. A genetic workup was done and revealed receptor-interacting protein kinase 1 (RIPK1) mutations. Conventional pediatric IBD treatment was initiated after surgery, including tumor necrosis factor antagonist adalimumab 40 mg subcutaneously weekly for five months. Despite treatment, he presented with dysuria and a colovesical fistula. The patient underwent secondary surgical repair.

Very Early Onset Inflammatory Bowel Disease (VEO-IBD) is potentially associated with genetic disorders of the intestinal epithelial barrier or inborn errors of immunity (IEI). Dual oxidase 2 (DUOX2), an H2O2-producing NADPH oxidase expressed at apical enterocyte membranes, plays a crucial role in innate defense response. Biallelic DUOX2 mutations have been described only in two patients with VEO-IBD to date. We report the case of a 1-month-old female infant who presented persistent high C-reactive protein (CRP) levels from birth and anemia. Positive occult blood and very high calprotectin in the stool were detected and abdominal ultrasound showed thickened last ileal loop. Full endoscopy evaluation revealed important colon stenosis with multiple pseudo-polyploidy formations that resulted refractory to steroid therapy, requiring a partial colic resection. Histological examination of biopsy samples showed morphological features of IBD. Whole Exome Sequencing (WES) disclosed compound heterozygous variants in the DUOX2 gene: the pathogenic c.2524C>T; p.Arg842Ter and the variant of uncertain significance (VUS) c.3175C>T; p.Arg1059Cys. Molecular and functional studies showed the presence of mutant DUOX2 in the intestinal epithelium of the patient, albeit with at least 50% decreased catalytic activity. In conclusion, we describe the third patient to date with compound heterozygous variants of DUOX2, responsible for monogenic neonatal-IBD. This case expands the knowledge about Mendelian causes of VEO-IBD and DUOX2 deficiency. We suggest that DUOX2 should be part of the diagnostic evaluation of patients with suspected monogenic VEO-IBD.

UNASSIGNED: The COVID-19 pandemic has introduced new challenges to the diagnosis and management of pediatric inflammatory bowel disease (IBD). Many patients have had only limited access to their providers through telemedicine, and many chose to delay nonemergent treatment.
UNASSIGNED: A retrospective chart review of patients with IBD seen by the Pediatric Gastroenterology Division at Doernbecher Children\'s Hospital from January 2018 to August 2021 was conducted. The study cohort was divided into 2 groups: those presenting before the onset of the COVID-19 pandemic (January 1, 2018 to February 28, 2020) and those presenting during the pandemic (March 1, 2020 to August 1, 2021). Variables collected included: age, sex, race, ethnicity, IBD type, insurance type, location of residence. Primary outcome measures selected focused on disease severity, initial type of treatment, or surgical intervention offered. A subgroup analysis of the new diagnosis patients was performed. Data were analyzed using independent t-tests, chi-squared analysis, and Wilcoxon rank sum tests.
UNASSIGNED: Two hundred and eleven patients met inclusion criteria, 107 (72 new diagnoses, 35 admissions) within the pre-COVID epoch and 104 (67 new diagnoses, 37 admissions) within the during-COVID epoch. Patients in the during-COVID epoch had higher fecal calprotectin level and were more likely to be started on a biologic as initial treatment. Patients admitted during COVID for IBD flare were more likely to require surgical intervention. Subgroup analysis of newly diagnosed patients revealed higher incidence of comorbid depression and anxiety.
UNASSIGNED: Our review identified increased disease severity in newly diagnosed pediatric patients with IBD as well as pediatric patients admitted for flare during COVID. Increases in anxiety and depression rates during COVID may have contributed to worsened disease severity.

OBJECTIVE: Very early-onset inflammatory bowel disease (VEO-IBD) is a clinical umbrella term referring to IBD-like symptoms arising in children before the age of 6 years, encompassing both \'pure\' IBD, such as ulcerative colitis (UC) and Crohn\'s disease (CD) and monogenic diseases (MDs), the latter often involving genes associated with primary immunodeficiencies. Moreover, histological features in gastrointestinal (GI) biopsies in MD can also have IBD-like morphology, making differential diagnosis difficult. Correct diagnosis is fundamental, as MDs show a more severe clinical course and their inadequate/untimely recognition leads to inappropriate therapy.
RESULTS: Biopsy samples from the lower and upper GI tract of 93 clinically diagnosed VEO-IBD children were retrospectively selected in a multicentre cohort and histologically re-evaluated by 10 pathologists blinded to clinical information. Each case was classified according to morphological patterns, including UC-like; CD-like; enterocolitis-like; apoptotic; eosinophil-rich; and IBD-unclassified (IBD-U). Nine (69%) MD children showed IBD-like morphology; only the IBD-U pattern correlated with MD diagnosis (P = 0.02) (available in 64 cases: 51 non-MD, true early-onset IBD/other; 13 MD cases). MD patients showed earlier GI symptom onset (18.7 versus 26.9 months) and were sent to endoscopy earlier (22 versus 37 months), these differences were statistically significant (P < 0.05). Upper GI histology was informative in 37 biopsies.
CONCLUSIONS: The diagnosis of the underlying cause of VEO-IBD requires a multidisciplinary setting, and pathology, while being one of the fundamental puzzle pieces, is often difficult to interpret. A pattern-based histological approach is therefore suggested, thus aiding the pathologist in VEO-IBD reporting and multidisciplinary discussion.

Inflammatory bowel diseases (IBD) are chronic intestinal disorders that result from an inappropriate inflammatory response to the microbiota in genetically susceptible individuals, often triggered by environmental stressors. Part of this response is the persistent inflammation and tissue injury associated with deficiency or excess of reactive oxygen species (ROS). The NADPH oxidase NOX1 is highly expressed in the intestinal epithelium, and inactivating NOX1 missense mutations are considered a risk factor for developing very early onset IBD. Albeit NOX1 has been linked to wound healing and host defence, many questions remain about its role in intestinal homeostasis and acute inflammatory conditions. Here, we used in vivo imaging in combination with inhibitor studies and germ-free conditions to conclusively identify NOX1 as essential superoxide generator for microbiota-dependent peroxynitrite production in homeostasis and during early endotoxemia. NOX1 loss-of-function variants cannot support peroxynitrite production, suggesting that the gut barrier is persistently weakened in these patients. One of the loss-of-function NOX1 variants, NOX1 p. Asn122His, features replacement of an asparagine residue located in a highly conserved HxxxHxxN motif. Modelling the NOX1-p22phox complex revealed near the distal heme an internal pocket restricted by His119 and Asn122 that is part of the oxygen reduction site. Functional studies in several human NADPH oxidases show that substitution of asparagine with amino acids with larger side chains is not tolerated, while smaller side chains can support catalytic activity. Thus, we identified a previously unrecognized structural feature required for the electron transfer mechanism in human NADPH oxidases.

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Patients with very early onset inflammatory bowel disease (VEO-IBD) have a higher incidence of monogenic disease compared to older age groups. Age, alone, is a strong predictor for monogenic disease. We discuss a case of VEO-IBD in which the patient presented with severe and refractory enteropathy, leading to diagnosis of CTLA-4 haploinsufficiency. Genetic workup showed de novo heterozygous deletions of the CTLA-4 and ICOS genes. This case was unique, as the patient did not have the other manifestations commonly present with the disease. We advocate for early and routine genetic workup of VEO-IBD, as patients with monogenic IBD have high morbidity and mortality, if inadequately treated. Our patient did not respond to conventional treatment modalities and required targeted treatment with Abatacept, a CTLA-4 agonist.

Inflammatory bowel disease (IBD) is a multifactorial disorder triggered by imbalances of the microbiome and immune dysregulations in genetically susceptible individuals. Several mouse and human studies have demonstrated that multimeric inflammasomes are critical regulators of host defense and gut homeostasis by modulating immune responses to pathogen- or damage-associated molecular patterns. In the context of IBD, excessive production of pro-inflammatory Interleukin-1β has been detected in patient-derived intestinal tissues and correlated with the disease severity or failure to respond to anti-tumor necrosis factor therapy. Correspondingly, genome-wide association studies have suggested that single nucleotide polymorphisms in inflammasome components might be associated with risk of IBD development. The relevance of inflammasomes in controlling human intestinal homeostasis has been further exemplified by the discovery of very early onset IBD (VEO-IBD) patients with monogenic defects affecting different molecules in the complex regulatory network of inflammasome activity. This review provides an overview of known causative monogenic entities of VEO-IBD associated with altered inflammasome activity. A better understanding of the molecular mechanisms controlling inflammasomes in monogenic VEO-IBD may open novel therapeutic avenues for rare and common inflammatory diseases.

OBJECTIVE: Failure of optimal growth and lack of appropriate weight gain are major nutritional problems in children with inflammatory bowel disease (IBD). Therefore, this study was designed to assess the nutritional and growth status of patients with very-early-onset IBD (VEO-IBD) before and after individual-based nutritional interventions.
METHODS: This prospective cohort study assessed the nutritional status of 30 pediatric patients with VEO-IBD by performing comprehensive clinical examinations and evaluating anthropometric and biochemical parameters. The latter included the initial evaluation of serum albumin, prealbumin, minerals, and 25-hydroxyvitamin D. A 24-month nutritional strategy was designed for each patient. Patients who completed the study were reassessed after 6 months and their growth rate was calculated 2 years later.
RESULTS: The initial assessment of malnutrition severity using the World Health Organization\'s z-score revealed that 36.7%, 43.3%, and 26.7% of the study group were underweight, stunted, and wasted, respectively. Among the study population, Crohn\'s disease has the highest prevalence. Almost all patients had micronutrient deficiencies (i.e., iron, calcium, zinc, magnesium, and vitamin D) and subnormal serum levels of nutritional markers (i.e., prealbumin and albumin). Six months after the intervention, a significant improvement in anthropometric and biochemical parameters was detected (p < 0.05); nevertheless, the calculated growth rate revealed a considerable decrease after 2 years.
CONCLUSIONS: The early detection of nutritional impairment in patients with VEO-IBD remains a major challenge. Therefore, nutritional support and constant monitoring of these patients are necessary to ensure the improvement in their nutritional status and achieve an acceptable growth rate. Furthermore, we found that prealbumin could be a good discriminative tool for screening malnutrition in such patients.