BACKGROUND & AIMS:Monogenic inflammatory bowel disease (IBD) can result in inborn errors of immunity and intestinal epithelial cell dysfunction, more commonly seen in patients with very early onset IBD (VEO-IBD). Hematopoietic stem cell transplant (HSCT) has emerged as an effective treatment for a subset of patients with monogenic IBD. We sought to evaluate the efficacy and safety of HSCT in these patients. We hypothesized that HSCT will lead to IBD medication-free remission or significant improvement of disease. METHODS:This was a single-center, retrospective study of children with monogenic IBD who underwent HSCT at The Children's Hospital of Philadelphia from 2012 to 2022. The primary outcome was IBD medication-free sustained remission, measured by disease activity index. Secondary outcomes included all-cause mortality, growth, hospitalizations, infections, and HSCT-associated complications. RESULTS:Thirty-eight patients with monogenic IBD were identified as eligible for HSCT, with 25 undergoing HSCT as therapy for IBD during the study period. There was 100% survival at a median follow-up of 3 years. Prior to transplant, 76% of patients received immunosuppression, and 20% underwent IBD-related surgery. At most recent follow-up, 92% of patients achieved sustained medication-free remission of IBD and 60% with prior ostomy underwent re-anastomosis. There was significant improvement in growth, hospital days, and severe infections. CONCLUSIONS:HSCT resulted in IBD medication-free remission and reduction in disease-associated complications. This highlights the strength of genetic evaluation in patients with VEO-IBD or refractory IBD and consideration of HSCT, which can be curative and lifesaving in patients with monogenic defects involving immune dysfunction.

X-linked inhibitor of apoptosis (XIAP) deficiency is a rare inborn error of immunity with particularly pleiomorphic spectrum of manifestations. These include hemophagocytic lymphohistiocytosis (HLH) with and without primary EBV infection, inflammatory bowel disease (IBD), uveitis, and episodic fevers. Liver manifestations have been rarely reported. Herein we describe severe acute liver failure (ALF) in a patient with very early-onset IBD found to have XIAP deficiency. The patient presented at 5 years of age with intermittent bloody stools, a perianal skin tag, and a history of intermittent fevers since infancy. Endoscopic evaluation at 6 years of age showed ulcerations and histologic colitis and granulomas. He was initiated on infliximab with good clinical response. Concurrent with his IBD evaluation, he was noted to have elevated liver enzymes. Twenty-one months after diagnosis, he developed fever, right upper quadrant pain, nausea, scleral icterus, liver enzymes to the 2000s, and cholestasis without synthetic dysfunction. EBV serologies were IgM positive. Transaminases improved spontaneously, but five days later, he re-presented with marked transaminitis, worsened cholestasis, and new synthetic dysfunction. He was transferred to a tertiary academic referral center ICU with high fevers and encephalopathy for management of ALF. HLH biomarkers were only modestly elevated: ferritin 290, Hgb 9.2, Plts 177, ANC 1620, fibrinogen 103, sIL-2Ra 1500, IFNg 128, and CXCL9 2959. EBV serologies and serial PCRs were negative. IL-18 was 12079. He was treated with IV glucocorticoids and emapalumab with stabilization. Flow cytometry showed XIAP deficiency, and anakinra was added with gradual resolution of liver dysfunction. Whole-genome sequencing revealed an XIAP frameshift variant (c.1021_1022del, p.(N341Yfs*8)). Emapalumab was replaced with ruxolitinib as the patient was preparing for hematopoietic stem cell transplant. XIAP-deficiency is remarkable for its range and severity of inflammatory phenotypes, including HLH and refractory IBD. Here we present a rare case of ALF in XIAP-deficiency. Antecedent, transient EBV infection was a likely trigger. His ALF improved with steroids, emapalumab, and IL-1 blockade. A high index of suspicion for immune dysregulation should be employed in all cases of VEO-IBD and/or liver failure. Figure 1. Laboratory trends and therapeutics. Day 0 represents initial hospitalization for acute liver failure.

Very early-onset inflammatory bowel disease (VEO-IBD), diagnosed before the age of 6, is a severe IBD subtype often associated with monogenic causes. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of inflammation and cell death. Biallelic pathogenic variants in the RIPK1 gene lead to RIPK1 deficiency, which disrupts these processes, causing immunodeficiency and autoinflammation, such as recurrent infections, early-onset IBD, and polyarthritis. Here, we report a VEO-IBD case associated with a novel variant in the RIPK1 gene. A 3-month-old male with suspected milk protein allergy presented with a 3-week history of hematochezia, intermittent fevers, vomiting, poor feeding, irritability, and large oral ulcers. Initial evaluation revealed anemia, elevated fecal calprotectin (>3000 µg/g), and gastritis with erosions, lymphocytic infiltrates in the duodenum, crypt abscesses in the sigmoid colon, focal active colitis, and colon ulcers. Imaging demonstrated splenomegaly, and an infectious workup was negative. Initial management included nasogastric tube feeds, total parenteral nutrition, RBC transfusions, iron supplementation, metronidazole, and anti-inflammatory therapy with an IL-1 receptor antagonist. Despite treatment, the patient was readmitted 1 week later with worsening symptoms. Repeat endoscopy revealed severe ulcerations and a cobblestone appearance in the stomach, along with ulcers and cobblestoning in the duodenum and the colon. In response, therapy was transitioned to infliximab, to which the patient thus far has shown a good response. The patient underwent genome sequencing, which identified a homozygous c.460-5C>A variant in the RIPK1 gene, inherited from consanguineous unaffected parents. Reported as a variant of uncertain significance (VUS), it was predicted to disrupt the splice acceptor site of exon 5, likely resulting in aberrant splicing and loss of function. The pathogenicity of this previously unreported variant was validated through western blot analysis, which served as a crucial diagnostic tool in confirming the deficiency of RIPK1 in the patient. RIPK1 deficiency causes severe VEO-IBD. Western blot analysis confirmed a novel pathogenic variant. Anti-TNF therapy stabilized symptoms. Early diagnosis and personalized treatment are critical for management. A novel RIPK1 variant highlights the importance of genetic testing and functional studies in VEO-IBD. Early recognition and targeted therapies improve outcomes in severe cases.

Background: Lymphocytic colitis (LC) in the pediatric population has been associated with immune dysregulation. Methods: Single-center retrospective study of pediatric LC. Results: 50 patients (35 female, 70%) with a median age of 12 years at diagnosis (interquartile range: 5.7–15.8) of LC were identified. At presentation, 11 patients (22%) had malnutrition, 16 (32%) had a known underlying immune dysregulation, 4 (8%) had celiac disease (CD), and none had a diagnosis of inflammatory bowel disease. The most common medications prior to diagnosis were non-steroidal anti-inflammatory drugs, proton pump inhibitor, and selective serotonin reuptake inhibitors (10% each). Colonic biopsies showed a median number of intraepithelial lymphocytes (IELs)/100 epithelial cells of 48 (range: 25–85), and only 10% of cases had neutrophilic cryptitis. Upper gastrointestinal tract findings included lymphocytic esophagitis (4%), and duodenal IELs without and with villous blunting (9% each) (n: 47). Ten patients (23%) had increased IELs in the terminal ileum (n: 43). Treatments including 5-ASA, budesonide, prednisone, and gluten-free diet improved symptoms in <50% of patients (n: 42), and all follow-up colonoscopies showed persistent LC (n: 13). Conclusion: Our study supports the association of LC with immune-mediated conditions, most commonly celiac disease. Symptomatic improvement was seen in <50% of patients with none of the patients with repeat colonoscopy showing histologic improvement.

BACKGROUND:Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract. Treatment for patients who have a monogenic cause of their IBD, often the youngest children, known as very early onset IBD (VEO-IBD), can be different from standard treatment for polygenic cases. Yet, ascertainment of these patients is difficult. METHODS:We analyzed cases of VEO-IBD to understand the breadth of monogenic etiology and to identify clinical, laboratory, and flow cytometric correlates of this subpopulation. RESULTS:Genetic causes of very early onset inflammatory bowel disease are highly diverse ranging from pure epithelial defects to classic T cell defects. Flow cytometry, other than testing for chronic granulomatous disease, has a low sensitivity for monogenic etiologies. Poor growth was a clinical feature associated with monogenic causality. CONCLUSIONS:Genetic testing is, at this moment, the most robust method for the identification of monogenic cases of very early onset IBD.

Very early onset inflammatory bowel disease (VEO-IBD), diagnosed <6 years old, can be genetically and phenotypically distinct and more refractory than older-onset IBD. Identified causal monogenic defects have been targeted therapeutically in a small subset of VEO-IBD1; however, for most of these children, treatment strategies, such as phenotypic profiles, are critically needed to improve outcomes.

Introduction Therapeutic options are critically needed for children with refractory very early onset inflammatory bowel disease (VEO-IBD). Our aim was to evaluate clinical response to canakinumab, an anti-IL-1β monoclonal antibody, in patients with VEO-IBD whose phenotype resembles those with monogenic autoinflammatory disease. Methods This is a single center retrospective study of patients with VEO-IBD with autoinflammatory phenotype (AIP) in the absence of identified monogenic disease treated with canakinumab for >6 months. AIP was defined as confirmed IBD with associated signs of systemic inflammation in the absence of infection, including leukocytosis, markedly elevated inflammatory markers, and extraintestinal manifestations (recurrent fevers, oral ulcers, arthritis). Primary outcomes included clinical response in disease activity indices after 6 months of therapy. Secondary outcomes included rate of AIP signs and symptoms, growth, surgery, steroid use, hospitalizations, and adverse events. Results Nineteen patients were included: 47% with infantile onset, 58% classified as IBD-U, and 42% classified as CD. At baseline, 37% were biologic naïve, and canakinumab was used as dual therapy in 74% of patients. Clinical response was achieved in 89% with statistically significant improvement in PCDAI and PUCAI. Clinical remission was achieved in 32% of patients. There was significant improvement in the clinical manifestations of AIP and the biochemical markers of disease. Number of hospitalizations (p<0.01) and length of stay (p<0.05) decreased. Growth improved with median weight-for-length Z-score increasing from -1.01 to 1.1 in children less than 2 years old. There were minimal adverse events identified during the study period. Conclusion Canakinumab may be an effective and safe treatment for a subset of children with VEO-IBD with AIP, as well as older patients with IBD. This study highlights the importance of a precision medicine approach in children with VEO-IBD.

OBJECTIVE Children with very early-onset inflammatory bowel disease (VEO-IBD) represent a distinct group of patients with IBD with unique phenotypic and genetic characteristics; however, they are frequently omitted from psychosocial research. This study used a novel, brief measure of pediatric global health to assess (1) overall health-related quality of life (HRQOL) in children with VEO-IBD, (2) HRQOL compared to healthy children, and (3) whether gastrointestinal symptoms account for the differences in HRQOL between these groups. METHODS Caregivers of 51 children with VEO-IBD (Mage = 4.26 years, 75% male) and 54 healthy children (Mage = 3.50 years, 54% male) completed the PROMIS Pediatric Global Health Scale (PGH-7) parent-proxy form to assess HRQOL and a questionnaire assessing gastrointestinal symptoms. Descriptive statistics, analysis of variance with covariates (ANCOVA), and meditation analyses with bootstrapping were conducted. RESULTS Caregivers of children with VEO-IBD rated their HRQOL as relatively positive, although children with greater disease yielded lower ratings on some PGH-7 items (e.g., fun with friends, physical health, sadness). Compared to healthy youth, children with VEO-IBD scored lower on the PGH-7, with significantly lower item-level scores on overall health, physical health, mental health, and quality of life. Gastrointestinal symptoms mediated the association between health status (i.e., VEO-IBD vs. healthy) and HRQOL, αβ = -2.84, 95% CI = -5.70, -0.34. CONCLUSIONS While some children with VEO-IBD are at risk for deficits in HRQOL, many are quite resilient. Psychosocial screening is necessary for providing appropriate referrals to behavioral health services and learning more about psychosocial adjustment in children with VEO-IBD.

BACKGROUND:Mutations in ITCH, which encodes an E3 ubiquitin-protein ligase, can result in systemic autoimmunity and immunodeficiency. The clinical phenotype and mechanism of disease have not been fully characterized, resulting in a paucity of therapeutic options for this potentially fatal disease. OBJECTIVE:We aimed to (1) expand the understanding about the phenotype of human ITCH deficiency (2) further characterize the associated immune dysregulation, and (3) report the first successful hematopoietic cell transplant (HCT) in a patient with ITCH deficiency. METHODS:Disease profiling was performed in a patient with multisystem immune dysregulation. Whole exome sequencing with trio analysis and functional validation of candidate disease variants were performed, including mRNA and protein expression. Analyses to further delineate the immunophenotype included quantitative evaluation of lymphoid and myeloid subsets with flow cytometry and mass cytometry. RESULTS:A patient with multisystem immune dysregulation presenting with growth failure, very-early-onset inflammatory bowel disease, arthritis, uveitis, psoriasis, and type 1 diabetes mellitus underwent whole exome sequencing, which identified novel compound heterozygous mutations in ITCH. Reduced expression of ITCH mRNA and absent ITCH protein were found. Abnormalities in both lymphoid and myeloid lineages were identified. The patient underwent HCT. He demonstrated excellent immune reconstitution and resolution of many manifestations of his systemic disease. CONCLUSIONS:Here we report ITCH deficiency with unique clinical features of colonic very-early-onset inflammatory bowel disease, arthritis, and uveitis in the setting of immune dysregulation and further characterize the underlying immune dysregulation. We demonstrate that HCT can be an effective, and potentially curative, therapy for ITCH deficiency.

Anemia is a common complication of inflammatory bowel disease (IBD), with studies reporting an even greater prevalence among children (49-70%) than adults (20-39%) at any given time during disease course. In the majority of cases, anemia is a result of iron deficiency (ID), chronic inflammation, or a combination of both. Both anemia and ID itself have been associated with high rates of IBD-related complications, resource utilization, and impaired quality of life. However, ID and anemia remain under-recognized and undertreated. To align clinical practice with guideline recommendations, we developed a clinical care pathway for screening, management, and follow-up of ID and anemia among pediatric patients with IBD. In the absence of specific pediatric guidance, these recommendations are based on international adult clinical guidelines and evidence-based pediatric publications. We aim to achieve a 70% screening and intervention rate by June 2019. This QI initiative was started at the CHOP IBD Center in November 2017. PDSA cycles included review of our current performance with all IBD providers (11/2017), educational sessions given in the inpatient and outpatient setting (01/2018), modification of the divisional IV iron therapy order set (02/2018), development of a new clinical pathway for active screening and management of iron deficiency and anemia (1st version available 2/2018 and open access online 11/2018), and creation of individualized monthly reports for all of our GI providers identifying patients with anemia (12/2018). In parallel, ferric carboxymaltose was made available for outpatient management of iron deficiency as of November 2017. Baseline data from July 2016 was compared to data after initiation of the QI initiative. Prior to this QI initiative, review of our performance at CHOP, revealed that 35.7% of our active outpatient IBD population was anemic, however only a minority of these patients were being screened for iron deficiency (20%) and appropriately treated with supplementation (18.4%). Following the implementation of this QI project, improvement was observed with screening and treatment rate increasing to 54.6% and 36.9% respectively by February 2019 (Figures 1 and 2). Iron deficiency and anemia is commonly underdiagnosed and undertreated in children with IBD. An evidence and expert based pathway may help increase screening and intervention. We expect to show continued improvement once this pathway is fully incorporated into clinical practice.