The Diagnostic Approach to Monogenic Very Early Onset Inflammatory Bowel Disease

Patients with a diverse spectrum of rare genetic disorders can present with inflammatory bowel disease (monogenic IBD). Patients with these disorders often develop symptoms during infancy or early childhood, along with endoscopic or histological features of Crohn’s disease, ulcerative colitis, or IBD unclassified. Defects in interleukin-10 signaling have a Mendelian inheritance pattern with complete penetrance of intestinal inflammation. Several genetic defects that disturb intestinal epithelial barrier function or affect innate and adaptive immune function have incomplete penetrance of the IBD-like phenotype. Several of these monogenic conditions do not respond to conventional therapy and are associated with high morbidity and mortality. Due to the broad spectrum of these extremely rare diseases, a correct diagnosis is frequently a challenge and often delayed. In many cases, these diseases cannot be categorized based on standard histological and immunologic features of IBD. Genetic analysis is required to identify the cause of the disorder and offer the patient appropriate treatment options, which include medical therapy, surgery, or allogeneic hematopoietic stem cell transplantation. In addition, diagnosis based on genetic analysis can lead to genetic counseling for family members of patients. We describe key intestinal, extraintestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation. In addition, we provide approaches for identifying patients likely to have these disorders. We also discuss classic approaches to identify these variants in patients, starting with phenotypic and functional assessments that lead to analysis of candidate genes. As a complementary approach, we discuss parallel genetic screening using next-generation sequencing followed by functional confirmation of genetic defects

NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease.

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes

Phenotypic stratification and molecular characterisation of inflammatory bowel disease presenting in early childhood

Genome wide association studies in inflammatory bowel disease (IBD) highlighted the contribution of common genetic variants to the disease pathogenicity of IBD. Overall combined genetic variation in IBD across the age spectrum however still fails to explain the majority of IBD heritability. First publications of young children with IBD-like phenotype due to underlying monogenic diseases affecting the immune system raised the awareness of Mendelian disorder associated IBD (MDIBD). Although overall rare, the clinical impact of a timely molecular diagnosis was evident for individual patients with immune deficiencies amenable to curative haematopoietic stem cell transplantation. In my research, I investigated the phenotype of IBD presenting in early childhood and evaluated novel next generation sequencing (NGS) platforms to screen for MDIBD. My research led to the first publication of targeted gene panel sequencing (TGPS) for children with suspected MDIBD. The North-East Thames Regional Genetic Laboratory has since integrated TGPS into the routine clinical work up for young children with IBD. I have subsequently analysed transcriptomic data from peripheral blood mononuclear cells and gut biopsies. My results suggest that transcriptomics can highlight the biological compartment affected by a pathogenic variant in patients with MDIBD. Being part of an international working group, we were able to curate and publish the first comprehensive list of MDIBD genes and to establish phenotypic features suggestive of underlying monogenic disease. The main emphasis for the future is to ensure genomic screening is made available for all patients with suspected MDIBD. This will require optimised work flows and the development of national expert hubs to interpret genetic results and feedback clinically relevant information to enable best possible clinical outcome for our patients. Furthermore, we need to strengthen international MDIBD initiatives, to develop a unified nomenclature and facilitate multicentre research into rare monogenic conditions with IBD-like phenotype

Kakutani property of the polytopes implies Kakutani property of the whole space

SIGLECopy held by FIZ Karlsruhe; available from UB/TIB Hannover / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Variation in access and prescription of vedolizumab and ustekinumab in paediatric inflammatory bowel disease patients: a UK-wide study

Background: therapeutic options for paediatric inflammatory bowel disease (IBD) are limited, especially for younger children. Unlike in adults, vedolizumab and ustekinumab are not licensed for paediatric use in the UK. We aimed to understand the real-world access to, and use of, these therapies in the paediatric population.Methods: we surveyed UK IBD centres to assess the incident use of vedolizumab and ustekinumab from 1 January 2021 to 31 December 2021. We collected information on funding, dose escalations and therapeutic drug monitoring.Results: 18 of 21 centres responded, covering an estimated 5260 patients. One hundred and thirteen were started on vedolizumab, prescription incidence 2.2%, median prescriptions per centre was 4 (range 1–20). Considering ustekinumab, 73 patients were commenced, prescription incidence 1.4%. Median prescription per centre was 3.5 (range 1–13). Prescription rates at each centre were not predicted by patient number cared for at that centre (p=0.2). Dose escalation was common in vedolizumab (66.7% centres) and ustekinumab (55.5%).Funding strategies varied substantially, and multiple funding sources were used; 12 of 18 centres (66.7%) reported funding through routine National Health Service (NHS) England/Scottish arrangements. There was local NHS trust funding in 8 of 18 centres (44.4%). Individual funding requests (IFRs) were used in 5 of 18 (27.8%), although IFRs are reserved for patients with unique additional characteristics. Four centres were unable to achieve funding in pre-pubescent children.Conclusions: there is widespread use of vedolizumab and ustekinumab across the UK, although practice is highly variable. Access to therapy appeared to differ substantially. There is a growing disparity between international guidelines and real-world practice. Establishing early and effective therapy in all patients remains a priority

Impact of COVID-19 on diagnosis and management of paediatric inflammatory bowel disease during lockdown:a UK nationwide study

Background: COVID-19 has impacted on healthcare provision. Anecdotally, investigations for children with inflammatory bowel disease (IBD) have been restricted, resulting in diagnosis with no histological confirmation and potential secondary morbidity. In this study, we detail practice across the UK to assess impact on services and document the impact of the pandemic. Methods: For the month of April 2020, 20 tertiary paediatric IBD centres were invited to contribute data detailing: (1) diagnosis/management of suspected new patients with IBD; (2) facilities available; (3) ongoing management of IBD; and (4) direct impact of COVID-19 on patients with IBD. Results: All centres contributed. Two centres retained routine endoscopy, with three unable to perform even urgent IBD endoscopy. 122 patients were diagnosed with IBD, and 53.3% (n=65) were presumed diagnoses and had not undergone endoscopy with histological confirmation. The most common induction was exclusive enteral nutrition (44.6%). No patients with a presumed rather than confirmed diagnosis were started on anti-tumour necrosis factor (TNF) therapy. Most IBD follow-up appointments were able to occur using phone/webcam or face to face. No biologics/immunomodulators were stopped. All centres were able to continue IBD surgery if required, with 14 procedures occurring across seven centres. Conclusions: Diagnostic IBD practice has been hugely impacted by COVID-19, with &gt;50% of new diagnoses not having endoscopy. To date, therapy and review of known paediatric patients with IBD has continued. Planning and resourcing for recovery is crucial to minimise continued secondary morbidity.</p

Phenotypic and genotypic characterisation of inflammatory bowel disease presenting before the age of two years.

Inflammatory bowel disease presenting in early childhood is extremely rare. More recently, progress has been made to identify children with monogenic forms of IBD predominantly presenting very early in life. In this study, we describe the heterogeneous phenotypes and genotypes of patients with IBD presenting before the age of two years and establish phenotypic features associated with underlying monogenicity.Phenotype data of 62 children with disease-onset before the age of two years presenting over the last 20 years were reviewed. Children without previously established genetic diagnosis were prospectively recruited for next-generation sequencing.62 patients (55% male) were identified. The median disease-onset was three months of age [IQR: 1 to 11]. Conventional IBD classification only applied to 15 patients with Crohn's disease-like (24%) and three with ulcerative colitis-like (5%) phenotype. Forty-four patients (71%) were diagnosed with otherwise unclassifiable IBD. Patients frequently required parenteral nutrition (40%), extensive immunosuppression (31%), hematopoietic stem-cell transplantation (29%) and abdominal surgery (19%). In 31% of patients underlying monogenic diseases were established (EPCAM, IL10, IL10RA, IL10RB, FOXP3, LRBA, SKIV2L, TTC37, TTC7A). Phenotypic features significantly more prevalent in monogenic IBD were: consanguinity, disease-onset before the 6(th) month of life, stunting, extensive intestinal disease and histological evidence of epithelial abnormalities.IBD in children with disease-onset before the age of two years is frequently unclassifiable into Crohn's disease and ulcerative colitis, particularly treatment resistant and can be indistinguishable from monogenic diseases with IBD-like phenotype

Transition services for paediatric inflammatory bowel disease; a multicentre study of practice in the United Kingdom

Objectives: patients with paediatric inflammatory bowel disease (IBD) constitute one of the largest cohorts requiring transition from paediatric to adult services. Standardised transition care improves short and long-term patient outcomes. This study aimed to detail the current state of transition services for IBD in the United Kingdom (UK). Methods: we performed a nationwide study to ascertain current practice, facilities and resources for children and young people with IBD. Specialist paediatric IBD centres were invited to contribute data on: timing of transition/transfer of care; transition resources available including clinics, staff and patient information; planning for future improvement. Results: twenty of 21 (95%) of invited centres responded. Over 90% of centres began the transition process below 16 years of age and all had completed transfer to adult care at 18 years of age. The proportion of patients in the transition process at individual centres varied from 10% to 50%. Joint clinics were held in every centre, with a mean of 12.9 clinics per year. Adult and paediatric gastroenterologists attended at all sites. Availability of additional team members was patchy across the UK, with dietetic, psychological and surgical attendance available in &lt;50% centres. A structured transition tool was used in 75% of centres. Sexual health, contraception and pregnancy were discussed by &lt;60% of teams. Conclusions: this study provides real-world clinical data on UK-wide transition services. These data can be used to develop a national strategy to complement current transition guidelines, focused on standardising services whilst allowing for local implementation