Traumatic subcutaneous emphysema following blood donation: A case report.

BACKGROUND: Subcutaneous emphysema is a condition where air becomes trapped under the skin, typically resulting from surgery or skin trauma. It is mostly localized and its occurrence in blood donors is exceedingly rare. Phlebotomy poses minimal risk of subcutaneous emphysema, but procedural errors may lead to such complications. STUDY DESIGN AND METHOD: This is a case report of 29-year-old repeat blood donor who experienced subcutaneous emphysema following blood donation. The donor was vigorously squeezing sponge ball during donation resulting in displacement of the needle which required readjustment. Post-donation, the donor reported a crackling sensation and mild swelling near phlebotomy site. Non-contrast computed tomography (NCCT) scans confirmed subcutaneous emphysema, attributing its development to air trapping in subcutaneous plane due to ball valve mechanism. RESULTS: Computed tomography (CT) imaging revealed subcutaneous emphysematous changes in the right cubital region and no evidence of hematoma. The swelling spontaneously subsided in 10-12 days without any intervention. The case underscores the importance of differentiating subcutaneous emphysema from common complications like hematoma. DISCUSSION: Subcutaneous emphysema in blood donors is exceptionally rare but should be managed with clear communication. Donors should be reassured that the condition, although rare, is benign and self-resolving. Healthcare providers should be equipped to handle such rare complications, offering appropriate care and documenting incidents for future prevention.

The Pediatric Crohn Disease Morbidity Index (PCD-MI): Development of a Tool to Assess Long-Term Disease Burden Using a Data-Driven Approach.

BACKGROUND/OBJECTIVE: Heterogeneity and chronicity of Crohn disease (CD) make prediction of outcomes difficult. To date, no longitudinal measure can quantify burden over a patient's disease course, preventing assessment and integration into predictive modeling. Here, we aimed to demonstrate the feasibility of constructing a data driven, longitudinal disease burden score. METHODS: Literature was reviewed for tools used in assessment of CD activity. Themes were identified to construct a pediatric CD morbidity index (PCD-MI). Scores were assigned to variables. Data were extracted automatically from the electronic patient records at Southampton Children's Hospital, diagnosed from 2012 to 2019 (inclusive). PCD-MI scores were calculated, adjusted for duration of follow up and assessed for variation (ANOVA) and distribution (Kolmogorov-Smirnov). RESULTS: Nineteen clinical/biological features across five themes were included in the PCD-MI including blood/fecal/radiological/endoscopic results, medication usage, surgery, growth parameters, and extraintestinal manifestations. Maximal score was 100 after accounting for follow-up duration. PCD-MI was assessed in 66 patients, mean age 12.5 years. Following quality filtering, 9528 blood/fecal test results and 1309 growth measures were included. Mean PCD-MI score was 14.95 (range 2.2-32.5); data were normally distributed ( P = 0.2) with 25% of patients having a PCD-MI < 10. There was no difference in the mean PCD-MI when split by year of diagnosis, F -statistic 1.625, P = 0.147. CONCLUSIONS: PCD-MI is a calculatable measure for a cohort of patients diagnosed over an 8-year period, integrating a wide-range of data with potential to determine high or low disease burden. Future iterations of the PCD-MI require refinement of included features, optimized scores, and validation on external cohorts.

Prediction of Crohn's Disease Stricturing Phenotype Using a NOD2-derived Genomic Biomarker.

BACKGROUND: Crohn's disease (CD) is highly heterogenous and may be complicated by stricturing behavior. Personalized prediction of stricturing will inform management. We aimed to create a stricturing risk stratification model using genomic/clinical data. METHODS: Exome sequencing was performed on CD patients, and phenotype data retrieved. Biallelic variants in NOD2 were identified. NOD2 was converted into a per-patient deleteriousness metric ("GenePy"). Using training data, patients were stratified into risk groups for fibrotic stricturing using NOD2. Findings were validated in a testing data set. Models were modified to include disease location at diagnosis. Cox proportional hazards assessed performance. RESULTS: Six hundred forty-five patients were included (373 children and 272 adults); 48 patients fulfilled criteria for monogenic NOD2-related disease (7.4%), 24 of whom had strictures. NOD2 GenePy scores stratified patients in training data into 2 risk groups. Within testing data, 30 of 161 patients (18.6%) were classified as high-risk based on the NOD2 biomarker, with stricturing in 17 of 30 (56.7%). In the low-risk group, 28 of 131 (21.4%) had stricturing behavior. Cox proportional hazards using the NOD2 risk groups demonstrated a hazard ratio (HR) of 2.092 (P = 2.4 × 10-5), between risk groups. Limiting analysis to patients diagnosed aged < 18-years improved performance (HR-3.164, P = 1 × 10-6). Models were modified to include disease location, such as terminal ileal (TI) disease or not. Inclusion of NOD2 risk groups added significant additional utility to prediction models. High-risk group pediatric patients presenting with TI disease had a HR of 4.89 (P = 2.3 × 10-5) compared with the low-risk group patients without TI disease. CONCLUSIONS: A NOD2 genomic biomarker predicts stricturing risk, with prognostic power improved in pediatric-onset CD. Implementation into a clinical setting can help personalize management.

NOD2 is a well-established risk gene for development of Crohn's disease and stricturing behavior. Here we demonstrate NOD2 can be utilized as a genomic biomarker, stratifying patients into 2 stricturing risk groups. Further refinement using disease location at diagnosis improved risk stratification.

Incidence and Prevalence of Paediatric Inflammatory Bowel Disease Continues to Increase in the South of England.

OBJECTIVE: The incidence of paediatric inflammatory bowel disease (IBD) has been increasing over 25 years; however, contemporary trends are not established and the impact of COVID-19 on case rates is unclear. METHODS: Data from Southampton Children's hospital prospective IBD database were retrieved for 2002-2021. Incidence rates were calculated based on referral area populations and temporal trends analysed. Disease prevalence for those aged <18 years was calculated for 2017-2021. Monoclonal prescriptions were reported. RESULTS: In total, 1150 patients were included (mean age at diagnosis 12.63 years, 40.5% female). An estimated 704 patients had Crohn's disease (61.2%), 385 had ulcerative colitis (33.5%), and 61 had IBD unclassified (5.3%). Overall IBD incidence increased, ß = 0.843, P = 3 × 10 -6 , driven by Crohn's disease, ß = 0.732, P = 0.00024 and ulcerative colitis, ß = 0.816, P = 0.000011. There was no change in IBDU incidence, ß = 0.230, P = 0.33. From 2002-2021, 51 patients were diagnosed <6 years of age, 160 patients aged 6 to <10 years and 939 patients aged 10 to <18 years of age. Increased incidence was observed in patients aged 10 to <18 years of age (ß = 0.888, P = 1.8 × 10 -7 ). There was no significant change in incidence of IBD in <6 years (ß = 0.124, P = 0.57), or 6 to <10 years (ß = 0.146, P = 0.54). IBD prevalence increased by an average of 1.71%/year from 2017 to 2021, ß = 0.979, P = 0.004. The number of new monoclonal prescriptions increased from 6 in 2007 to 111 in 2021. CONCLUSIONS: IBD incidence continues to increase in Southern England. Compounding prevalence and increased monoclonal usage has implications for service provision.

Time to normalisation of tissue transglutaminase in paediatric coeliac disease is dependent on initial titre and half of patients will normalise within 12 months.

BACKGROUND: Coeliac disease (CD) is common. Response to a gluten-free diet is assessed through serial measurement of tissue transglutaminase (TTG) antibody titre. However, the relationship of TTG titres to symptoms and the speed of normalisation is poorly understood. METHODS: Patients seen in 2020, and under follow-up in the Southampton CD clinic, had blood results, growth measures and symptom data collated. Time to normalisation, predictors of normalisation and relationship of TTG to growth/symptoms were assessed. RESULTS: 57 patients were included. All had TTG results from the time of diagnosis and follow-up. All families reported dietary compliance.Median TTG at diagnosis was 100 µ/L (range 0.3-4360), 94.7% of the patients had symptoms compatible with CD. At 6-12 months after diagnosis, the median TTG was 3.8 µ/mL (range 0.3-133). In terms of response, 29 of the 57 patients (50.9%) had a TTG below 4 µ/mL (upper normal limit). A further 25 patients (43.9%) had a TTG<10 times the upper limit of normal. Ten patients (17.5%) had a persistently high TTG (median=8.55 µ/mL, range 4.1-303) after >12 months.TTG at diagnosis was correlated with TTG at 6-12 months, ß=0.542, p=0.000016. Patients with TTG<10 times the upper limit of normal at diagnosis group were more likely to have normalised at 6-12 months compared with >10 times normal (85% vs 32.4%, p=0.0015). TTG titres did not correlate with growth measures (Z-scores) at diagnosis or at follow-up. CONCLUSIONS: Normalisation of TTG levels occurs within 6-12 months for around half of patients. Higher TTG levels at diagnosis take longer to normalise. The role of compliance is unclear.

Feeding children with neurodisability: challenges and practicalities.

Nutritional management for children with neurodisability can be challenging and there are an increasing number of children at risk of malnutrition. Management involves healthcare professionals in community and hospital working together with the family with the aim of optimising nutrition and quality of life. Feeding difficulties can be the result of physical causes like lack of oromotor coordination, discomfort associated with reflux oesophagitis or gastrointestinal dysmotility. Non-physical causes include parental/professional views towards feeding, altered perception of pain and discomfort, extreme sensitivity to certain textures and rigidity of feeding schedule associated with artificial feeding. Estimating nutritional needs can be difficult and is affected by comorbidities including epilepsy and abnormal movements, severity of disability and mobility. Defining malnutrition is difficult as children with neurodisability reflect a wide spectrum with disparate growth patterns and body composition and auxology is less reliable and less reproducible. Management involves selecting the type and method of feeding best suited for the patient. As artificial feeding can place a significant burden of care any decision-making should be, as much as possible, in concurrence with the family. Symptom management sometimes requires pharmacological interventions, but polypharmacy is best avoided. The article aims to discuss the pathways of identifying children at risk of malnutrition and available management options with a strong emphasis on working as a clinical team with the child and family.

Deleterious Genetic Variation Across the NOD Signaling Pathway Is Associated With Reduced NFKB Signaling Transcription and Upregulation of Alternative Inflammatory Transcripts in Pediatric Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease may arise with inadequate immune response to intestinal bacteria. NOD2 is an established gene in Crohn's disease pathogenesis, with deleterious variation associated with reduced NFKB signaling. We hypothesized that deleterious variation across the NOD2 signaling pathway impacts on transcription. METHODS: Treatment-naïve pediatric inflammatory bowel disease patients had ileal biopsies for targeted autoimmune RNA-sequencing and blood for whole exome sequencing collected at diagnostic endoscopy. Utilizing GenePy, a per-individual, per-gene score, genes within the NOD signaling pathway were assigned a quantitative score representing total variant burden. Where multiple genes formed complexes, GenePy scores were summed to create a "complex" score. Normalized transcript expression of 95 genes within this pathway was retrieved. Regression analysis was performed to determine the impact of genomic variation on gene transcription. RESULTS: Thirty-nine patients were included. Limited clustering of patients based on NOD signaling transcripts was related to underlying genomic variation. Patients harboring deleterious variation in NOD2 had reduced NOD2 (ß = -0.702, P = 4.3 × 10-5) and increased NFKBIA (ß = 0.486, P = .001), reflecting reduced NFKB signal activation. Deleterious variation in the NOD2-RIPK2 complex was associated with increased NLRP3 (ß = 0.8, P = 3.1475 × 10-8) and TXN (ß = -0.417, P = 8.4 × 10-5) transcription, components of the NLRP3 inflammasome. Deleterious variation in the TAK1-TAB complex resulted in reduced MAPK14 transcription (ß = -0.677, P = 1.7 × 10-5), a key signal transduction protein in the NOD2 signaling cascade and increased IFNA1 (ß = 0.479, P = .001), indicating reduced transcription of NFKB activators and alternative interferon transcription in these patients. CONCLUSIONS: Data integration identified perturbation of NOD2 signaling transcription correlated with genomic variation. A hypoimmune NFKB signaling transcription response was observed. Alternative inflammatory pathways were activated and may represent therapeutic targets in specific patients.

Short bowel syndrome in infancy: recent advances and practical management.

Short bowel syndrome (SBS) is a rare condition characterised by extensive loss of intestinal mass secondary to congenital or acquired disease. The outcomes are determined by dependency on parenteral nutrition (PN), its possible complications and factors that influence intestinal adaptation. In order to achieve the best results, patients should be managed by a specialised multidisciplinary team with the aims of promoting growth and development, stimulating intestinal adaptation and preventing possible complications. This involves timely surgical management aimed at rescuing maximum bowel length and eventually re-establishing intestinal continuity where appropriate. A combination of enteral and parenteral nutrition needs to be targeted towards maintaining a balance between fulfilling the nutritional and metabolic needs of the child while preventing or at least minimising potential complications. Enteral nutrition and establishment of oral feeding play a fundamental role in stimulating bowel adaptation and promoting enteral autonomy. Other measures to promote enteral autonomy include the chyme recycling in patients where bowel is not in continuity, autologous gastrointestinal reconstruction and pharmacological treatments, including promising new therapies like teduglutide. Strategies such as lipid reduction, changing the type of lipid emulsion and cycling PN are associated with a reduction in the rates of intestinal failure-associated liver disease. Even though vast improvements have been made in the surgical and medical management of SBS, there is still lack of consensus in many aspects and collaboration is essential.

Bioelectrical spectroscopy impedance phase angle is not associated with nutritional status in a stable cohort of paediatric inflammatory bowel disease patients.

BACKGROUND & AIMS: Nutritional assessment in paediatric inflammatory bowel disease (IBD) is key to supporting growth whilst minimising adiposity. Bedside assessment using bioelectrical impedance spectroscopy (BIS) has previous identified patients with declining cellular and nutritional health. We aimed to assess BIS measures in stable paediatric IBD patient. METHODS: Stable IBD patients were recruited at routine hospital visits. All patients underwent BIS, anthropometry and disease activity assessment. Multivariable regression and receiver operator curve (ROC) analyses were undertaken to assess the utility of BIS phase angle 50 KHz (PA-50) and 200/5 KHz impedance ratio (IR) in nutritional assessment. RESULTS: There were 140 study visits from 97 patients, mean age 14.49 years, 62.9% Crohn's disease. Mean BMI Z-score (BMIZ) was 0.31 (range -2.97 to 3.99), 33% of patients were overweight (BMIZ>1) and 13.8% of patients were underweight (BMIZ < -1). Crohn's disease patients had a lower mean BMIZ score 0.14, compared to ulcerative colitis, 0.68, p = 0.007. There was no relationship between PA-50 and BMIZ or disease activity. IR was not related to disease activity but was negatively related to BMIZ in a multivariable regression, accounting for age, sex and disease subtype (beta -0.331, p = 0.001). ROC analyses did not identify a clinically useful cut off for either PA-50 or IR to identify patients with active disease, biologic use or BMIZ>1 or < -1. CONCLUSION: BIS appears to have limited added value in nutritional assessment of stable paediatric IBD patients. Nearly 1/3 patients were overweight and personalised approach to supplementation is vital to avoid overnutrition.

Prevalence of home parenteral nutrition in children.

BACKGROUND: Use of HPN in paediatrics in the UK has increased rapidly over the last 20 years but the prevalence of HPN has been challenging to define. Clinicians in the UK have noted an evolving complexity of cases and perceive improved outcomes and increased acceptability of long-term PN. These factors combined have the potential to increase the burden on existing paediatric gastroenterology services in the UK. METHODS: A national database was interrogated to define the prevalence of HPN in children in the UK and to explore outcomes for patients receiving HPN. RESULTS: Since 2015, 525 children were notified to the database; of these patients, mortality was <5% and intestinal transplant occurred in 1%. In 2019, 389 children received HPN in the UK; this is nearly double the number last reported in 2012 and is a prevalence of 30 per million children. Short bowel syndrome is the largest category of these patients. However, a poorly defined group including those with multisystem disease has increased 10 fold since 2012 and is now the second largest category. CONCLUSIONS: Long term HPN in childhood is safe and associated with good survival and low risk of the need for intestinal transplantation.

Expression profile of the matricellular protein periostin in paediatric inflammatory bowel disease.

The precise role of periostin, an extra-cellular matrix protein, in inflammatory bowel disease (IBD) is unclear. Here, we investigated periostin in paediatric IBD including its relationship with disease activity, clinical outcomes, genomic variation and expression in the colonic tissue. Plasma periostin was analysed using ELISA in 144 paediatric patients and 38 controls. Plasma levels were assessed against validated disease activity indices in IBD and clinical outcomes. An immuno-fluorescence for periostin and detailed isoform-expression analysis in the colonic tissue was performed in 23 individuals. We integrated a whole-gene based burden metric 'GenePy' to assess the impact of variation in POSTN and 23 other genes functionally connected to periostin. We found that plasma periostin levels were significantly increased during remission compared to active Crohn's disease. The immuno-fluorescence analysis demonstrated enhanced peri-cryptal ring patterns in patients compared to controls, present throughout inflamed, as well as macroscopically non-inflamed colonic tissue. Interestingly, the pattern of isoforms remained unchanged during bowel inflammation compared to healthy controls. In addition to its role during the inflammatory processes in IBD, periostin may have an additional prominent role in mucosal repair. Additional studies will be necessary to understand its role in the pathogenesis, repair and fibrosis in IBD.

Growth failure is rare in a contemporary cohort of paediatric inflammatory bowel disease patients.

AIM: We assessed growth in a paediatric inflammatory bowel disease (PIBD) cohort. METHODS: Paediatric inflammatory bowel disease patients were eligible if they were diagnosed at Southampton Children's Hospital from 2011 to 2018. Weight and height standard deviation scores (SDS) were retrieved. Mean SDS values, SDS change and anti-TNF status were analysed at diagnosis and during follow-up. RESULTS: Four hundred and ninety patients were included, 313 with Crohn's disease (CD). CD patients presented with mean height SDS -0.13, -0.1 at 1-year, -0.11 at 2-years and -0.03 at 5 years, reflecting preserved linear growth. There was no significant height-SDS change from diagnosis to 5-year follow-up, +0.12, 95%-CI: 0.48 to -0.24. Mean weight-SDS at diagnosis was -0.39, driven by CD patients (-0.65). Mean weight-SDS approached 0 after 1 year and remained at the 50th centile throughout follow-up. Growth in ulcerative colitis was maintained. In multivariable regression males had worse height growth from diagnosis to transition (P = .036). Anti-TNF treatment (P = .013) and surgical resection (P = .005) were also associated with poorer linear growth. Patients treated with anti-TNF therapy had lower height-SDS compared to those never treated with anti-TNF at 1 year (-0.2 vs -0.01, P = .22), 2-years (-0.27 vs -0.01, P = .07) and 5 years (-0.21 vs 0.25, P = .051). CONCLUSION: Height was generally maintained in Crohn's disease, and impaired linear growth was rare in this cohort.

Ileal Transcriptomic Analysis in Paediatric Crohn's Disease Reveals IL17- and NOD-signalling Expression Signatures in Treatment-naïve Patients and Identifies Epithelial Cells Driving Differentially Expressed Genes.

BACKGROUND AND AIMS: Crohn's disease [CD] arises through host-environment interaction. Abnormal gene expression results from disturbed pathway activation or response to bacteria. We aimed to determine activated pathways and driving cell types in paediatric CD. METHODS: We employed contemporary targeted autoimmune RNA sequencing, in parallel to single-cell sequencing, to ileal tissue derived from paediatric CD and controls. Weighted gene co-expression network analysis [WGCNA] was performed and differentially expressed genes [DEGs] were determined. We integrated clinical data to determine co-expression modules associated with outcomes. RESULTS: In all, 27 treatment-naive CD [TN-CD], 26 established CD patients and 17 controls were included. WGCNA revealed a 31-gene signature characterising TN-CD patients, but not established CD, nor controls. The CSF3R gene is a hub within this module and is key in neutrophil expansion and differentiation. Antimicrobial genes, including S100A12 and the calprotectin subunit S100A9, were significantly upregulated in TN CD compared with controls [p = 2.61 x 10-15 and p = 9.13 x 10-14, respectively] and established CD [both p = 0.0055]. Gene-enrichment analysis confirmed upregulation of the IL17-, NOD- and Oncostatin-M-signalling pathways in TN-CD patients, identified in both WGCNA and DEG analyses. An upregulated gene signature was enriched for transcripts promoting Th17-cell differentiation and correlated with prolonged time to relapse [correlation-coefficient-0.36, p = 0.07]. Single-cell sequencing of TN-CD patients identified specialised epithelial cells driving differential expression of S100A9. Cell groups, determined by single-cell gene expression, demonstrated enrichment of IL17-signalling in monocytes and epithelial cells. CONCLUSIONS: Ileal tissue from treatment-naïve paediatric patients is significantly upregulated for genes driving IL17-, NOD- and Oncostatin-M-signalling. This signal is driven by a distinct subset of epithelial cells expressing antimicrobial gene transcripts.

Emotional Wellbeing in Parents of Children on Home Parenteral Nutrition.

OBJECTIVES: Caring for a child on home parenteral nutrition (HPN) is stressful, and its emotional impact not fully appreciated. This study explored the emotional wellbeing and coping styles of parents and children on HPN. METHODS: Questionnaire data were collected for parents of children (0-18 years) on HPN. Children 8 years and older completed the revised children's anxiety and depression scale. Parents completed the Hospital Anxiety and Depression Scale, Paediatric Inventory for Parents (PIP) and brief COPE. RESULTS: A total of 14 children were included, 20 parents (13 females) and 4 children completed the survey. Parents had mean PIP difficulty and frequency score of 117.9 and 124, respectively, higher compared to parents of children with other chronic illness. PIP scores were significantly higher where children were also enterally tube fed (P < 0.05). Thirty-five per cent parents scored above clinical threshold on anxiety subscale of Hospital Anxiety and Depression Scale and 30% in borderline range. On depression subscale 15% scored above clinical threshold range and 15% in borderline range. Mean anxiety and depression scores in parents of children with short bowel syndrome (11.8, 7.8) were significantly higher than those with neuromuscular disease (5.8, 1.6) P < 0.05. Coping styles differed according to health condition and whether child was enterally fed. CONCLUSIONS: There is a significant emotional impact of caring for a child on HPN, assessment and treatment of anxiety, depression, and stress should be a routine part of care. Individual needs of the child and parent need to be taken into account in providing the most appropriate psychological support.

Immunological Profiling of Paediatric Inflammatory Bowel Disease Using Unsupervised Machine Learning.

OBJECTIVES: The current classification of inflammatory bowel disease (IBD) is based on clinical phenotypes, which is blind to the molecular basis of the disease. The aim of this study was to stratify a treatment-naïve paediatric IBD cohort through specific innate immunity pathway profiling and application of unsupervised machine learning (UML). METHODS: In order to test the molecular integrity of biological pathways implicated in IBD, innate immune responses were assessed at diagnosis in 22 paediatric patients and 10 age-matched controls. Peripheral blood mononuclear cells (PBMCs) were selectively stimulated for assessing the functionality of upstream activation receptors including NOD2, toll-like receptor (TLR) 1-2 and TLR4, and the downstream cytokine responses (IL-10, IL-1ß, IL-6, and TNF-α) using multiplex assays. Cytokine data generated were subjected to hierarchical clustering to assess for patient stratification. RESULTS: Combined immune responses in patients across 12 effector responses were significantly reduced compared with controls (P = 0.003) and driven primarily by "hypofunctional" TLR responses (P values 0.045, 0.010, and 0.018 for TLR4-mediated IL-10, IL-1ß, and TNF-α, respectively; 0.018 and 0.015 for TLR1-2 -mediated IL-10 and IL-1ß). Hierarchical clustering generated 3 distinct clusters of patients and a fourth group of "unclustered" individuals. No relationship was observed between the observed immune clusters and the clinical disease phenotype. CONCLUSIONS: Although a clinically useful outcome was not observed through hierarchical clustering, our study provides a rationale for using an UML approach to stratify patients. The study also highlights the predominance of hypo-inflammatory innate immune responses as a key mechanism in the pathogenesis of IBD.

Genetic Sequencing of Pediatric Patients Identifies Mutations in Monogenic Inflammatory Bowel Disease Genes that Translate to Distinct Clinical Phenotypes.

OBJECTIVES: Monogenic inflammatory bowel disease (IBD) comprises rare Mendelian causes of gut inflammation, often presenting in infants with severe and atypical disease. This study aimed to identify clinically relevant variants within 68 monogenic IBD genes in an unselected pediatric IBD cohort. METHODS: Whole exome sequencing was performed on patients with pediatric-onset disease. Variants fulfilling the American College of Medical Genetics criteria as "pathogenic" or "likely pathogenic" were assessed against phenotype at diagnosis and follow-up. Individual patient variants were assessed and processed to generate a per-gene, per-individual, deleteriousness score. RESULTS: Four hundred one patients were included, and the median age of disease-onset was 11.92 years. In total, 11.5% of patients harbored a monogenic variant. TRIM22-related disease was implicated in 5 patients. A pathogenic mutation in the Wiskott-Aldrich syndrome (WAS) gene was confirmed in 2 male children with severe pancolonic inflammation and primary sclerosing cholangitis. In total, 7.3% of patients with Crohn's disease had apparent autosomal recessive, monogenic NOD2-related disease. Compared with non-NOD2 Crohn's disease, these patients had a marked stricturing phenotype (odds ratio 11.52, significant after correction for disease location) and had undergone significantly more intestinal resections (odds ratio 10.75). Variants in ADA, FERMT1, and LRBA did not meet the criteria for monogenic disease in any patients; however, case-control analysis of mutation burden significantly implicated these genes in disease etiology. DISCUSSION: Routine whole exome sequencing in pediatric patients with IBD results in a precise molecular diagnosis for a subset of patients with IBD, providing the opportunity to personalize therapy. NOD2 status informs risk of stricturing disease requiring surgery, allowing clinicians to direct prognosis and intervention.