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Nambu, R., N. Warner, D. J. Mulder, and A. Muise. "A26 A SYSTEMTIC REVIEW OF MONOGENIC INFLAMMATORY BOWEL DISEASE: CLINICAL PHENOTYPE AND GENOTYPE." Journal of the Canadian Association of Gastroenterology 4, Supplement_1 (March 1, 2021): 145–47. http://dx.doi.org/10.1093/jcag/gwab002.025.
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Abstract Background Advances in genomic technologies have led to an increase in reports of monogenic inflammatory bowel disease (IBD). The majority of the studies on monogenic IBD have focused only on young children aged <6 years. There are no detailed reports containing a comprehensive picture of monogenic IBD with specific numbers on the clinical features, genetic profiles and disease course. Since each gene-specific cause of monogenic IBD is rare, it is difficult to collect cases in a single study even with international cohort studies. Aims To elucidate a comprehensive picture of monogenic IBD, we conducted a systematic review of all reported cases of monogenic IBD. Methods A systematic review of MEDLINE articles published between January 2000 and December 2019 was conducted. 662 monogenic IBD cases were identified from 273 eligible articles. Data on clinical manifestation, genotype, and management were collected. Results The most frequently reported genes causative of monogenic IBD patients were IL10RA, CYBB, IL10RB, and TTC7A (Figure). In total, 64.8% of patients developed IBD before six years old, 15.6% between ages 10 and 17.9 years, and 11.6% at age 18 years or older. Only 32.7% had any history of extra-intestinal manifestation (EIM) before IBD onset. There was substantial difference in the onset age groups and the underlying monogenic disorders. 74.4% developed at least one EIM during their clinical course. The most common EIMs were atypical infection (44.1%), dermatologic abnormality (39.2%), autoimmunity (22.7%) and lymphoid organ abnormality (11.5%). Autosomal recessive (62.8%) was the most common inheritance pattern, and missense-variants (44.3%) were the most identified type of genetic variants. Deletions including CNVs, intronic, synonymous and inversion, which have the possibility to be overlooked by whole exome sequencing were shown in some cases. Bowel surgery, biologics, and hematopoietic stem cell transplantation were performed in 28.3%, 32.8%, and 24.4% of patients, respectively. Conclusions Monogenic IBD diagnosis and management is a challenging clinical problem across age groups; the EIMs are more diverse and the management is evidently more difficult compared to non-monogenic IBD. An improved understanding of the characteristics of the genes and underlying disease processes in monogenic IBD is necessary for effective management. Funding Agencies CAG, CIHRUehara Memorial Foundation Fellowship
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Jezernik, Gregor, Dušanka Mičetić-Turk, and Uroš Potočnik. "Molecular Genetic Architecture of Monogenic Pediatric IBD Differs from Complex Pediatric and Adult IBD." Journal of Personalized Medicine 10, no. 4 (November 26, 2020): 243. http://dx.doi.org/10.3390/jpm10040243.
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Inflammatory bowel disease (IBD) manifests as a complex disease resulting from gene–environment interactions or as a monogenic disease resulting from deleterious mutations. While monogenic IBD is predominantly pediatric, only one-quarter of complex IBD is pediatric. In this study, we were the first to systematically compare genetic architecture between monogenic and complex pediatric and adult IBD on genetic and molecular pathway levels. Genes reported as causal for monogenic pediatric IBD and related syndromes and as risk factors for pediatric and adult complex IBD were analyzed using CytoScape and ClueGO software tools to elucidate significantly enriched Gene Ontology (GO) terms. Despite the small overlap (seven genes) between monogenic IBD genes (85) and complex IBD loci (240), GO analysis revealed several enriched GO terms shared between subgroups (13.9%). Terms Th17 cell differentiation and Jak/STAT signaling were enriched in both monogenic and complex IBD subgroups. However, primary immunodeficiency and B-cell receptor signaling pathway were specifically enriched only for pediatric subgroups, confirming existing clinical observations and experimental evidence of primary immunodeficiency in pediatric IBD patients. In addition, comparative analysis identified patients below 6 years of age to significantly differ from complex pediatric and adult IBD and could be considered a separate entity.
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Ouahed, Jodie, Elizabeth Spencer, Daniel Kotlarz, Dror S. Shouval, Matthew Kowalik, Kaiyue Peng, Michael Field, et al. "Very Early Onset Inflammatory Bowel Disease: A Clinical Approach With a Focus on the Role of Genetics and Underlying Immune Deficiencies." Inflammatory Bowel Diseases 26, no. 6 (December 3, 2019): 820–42. http://dx.doi.org/10.1093/ibd/izz259.
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Abstract Very early onset inflammatory bowel disease (VEO-IBD) is defined as IBD presenting before 6 years of age. When compared with IBD diagnosed in older children, VEO-IBD has some distinct characteristics such as a higher likelihood of an underlying monogenic etiology or primary immune deficiency. In addition, patients with VEO-IBD have a higher incidence of inflammatory bowel disease unclassified (IBD-U) as compared with older-onset IBD. In some populations, VEO-IBD represents the age group with the fastest growing incidence of IBD. There are contradicting reports on whether VEO-IBD is more resistant to conventional medical interventions. There is a strong need for ongoing research in the field of VEO-IBD to provide optimized management of these complex patients. Here, we provide an approach to diagnosis and management of patients with VEO-IBD. These recommendations are based on expert opinion from members of the VEO-IBD Consortium (www.VEOIBD.org). We highlight the importance of monogenic etiologies, underlying immune deficiencies, and provide a comprehensive description of monogenic etiologies identified to date that are responsible for VEO-IBD.
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Lega, Sara, Alessia Pin, Serena Arrigo, Cristina Cifaldi, Martina Girardelli, Anna Monica Bianco, Monica Malamisura, et al. "Diagnostic Approach to Monogenic Inflammatory Bowel Disease in Clinical Practice: A Ten-Year Multicentric Experience." Inflammatory Bowel Diseases 26, no. 5 (August 3, 2019): 720–27. http://dx.doi.org/10.1093/ibd/izz178.
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Abstract Background and aims Multiple monogenic disorders present as very early onset inflammatory bowel disease (VEO-IBD) or as IBD with severe and atypical features. Establishing a genetic diagnosis may change patients’ management and prognosis. In this study, we describe the diagnostic approach to suspected monogenic IBD in a real clinical setting, discussing genetic and phenotypic findings and therapeutic implications of molecular diagnosis. Methods Information of patients with VEO-IBD and early onset IBD with severe/atypical phenotypes (EO-IBD s/a) managed between 2008–2017 who underwent a genetic workup were collected. Results Ninety-three patients were included, and 12 (13%) reached a genetic diagnosis. Candidate sequencing (CS) was performed in 47 patients (50%), and next generation sequencing (NGS) was performed in 84 patients (90%). Candidate sequencing had a good diagnostic performance only when guided by clinical features specific for known monogenic diseases, whereas NGS helped finding new causative genetic variants and would have anticipated one monogenic diagnosis (XIAP) and consequent bone marrow transplant (BMT). Patients with monogenic IBD more frequently were male (92% vs 54%; P = 0.02), had extraintestinal findings (100% vs 34%; P < 0.001), and had disease onset ≤1 month of life (25% vs 1%; P = 0.006). Genetic diagnosis impacted patient management in 11 patients (92%), 7 of whom underwent BMT. Conclusion A genetic diagnosis can be established in a significant proportion of suspected monogenic IBD and has an impact on patients’ management. Candidate sequencing may be deployed when clinical findings orientate toward a specific diagnosis. Next generation sequencing should be preferred in patients with nonspecific phenotypes.
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Levine, Anne E., Dominique Mark, Laila Smith, Hengqi B. Zheng, and David L. Suskind. "Pharmacologic Management of Monogenic and Very Early Onset Inflammatory Bowel Diseases." Pharmaceutics 15, no. 3 (March 17, 2023): 969. http://dx.doi.org/10.3390/pharmaceutics15030969.
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Inflammatory bowel disease (IBD) is treated with a variety of immunomodulating and immunosuppressive therapies; however, for the majority of cases, these therapies are not targeted for specific disease phenotypes. Monogenic IBD with causative genetic defect is the exception and represents a disease cohort where precision therapeutics can be applied. With the advent of rapid genetic sequencing platforms, these monogenic immunodeficiencies that cause inflammatory bowel disease are increasingly being identified. This subpopulation of IBD called very early onset inflammatory bowel disease (VEO-IBD) is defined by an age of onset of less than six years of age. Twenty percent of VEO-IBDs have an identifiable monogenic defect. The culprit genes are often involved in pro-inflammatory immune pathways, which represent potential avenues for targeted pharmacologic treatments. This review will provide an overview of the current state of disease-specific targeted therapies, as well as empiric treatment for undifferentiated causes of VEO-IBD.
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Leung, Gabriella, and Aleixo M. Muise. "Monogenic Intestinal Epithelium Defects and the Development of Inflammatory Bowel Disease." Physiology 33, no. 5 (September 1, 2018): 360–69. http://dx.doi.org/10.1152/physiol.00020.2018.
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The incidence of inflammatory bowel disease (IBD) is increasing worldwide, most notably in young children. The development of disease is a combination of several factors, including genetics, environment, the microbiota, and immune system. Recently, next-generation sequencing has allowed for the identification of novel genetic causes for intestinal disease, including pediatric inflammatory bowel disease (IBD). These IBD genes can generally be grouped into genes causing either primary immunodeficiency or intestinal epithelial defects (the focus of this review). Most of these genes have been functionally validated with in vitro and/or animal models, and have been demonstrated to cause intestinal disease. Intestinal epithelial IBD genes are of particular interest since they are the least amenable to current therapies; therefore, further research is warranted to develop potential therapies. A number of cellular pathways are impacted with intestinal epithelial IBD genes, including intestinal epithelial cell adhesion and generation of reactive oxygen species. Here, we describe the currently known IBD risk alleles and monogenic causal intestinal epithelial genes, their putative roles in preserving intestinal epithelial cell homeostasis, and their implications for IBD pathophysiology.
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Charbit-Henrion, Fabienne, Marianna Parlato, Sylvain Hanein, Rémi Duclaux-Loras, Jan Nowak, Bernadette Begue, Sabine Rakotobe, et al. "Diagnostic Yield of Next-generation Sequencing in Very Early-onset Inflammatory Bowel Diseases: A Multicentre Study." Journal of Crohn's and Colitis 12, no. 9 (May 18, 2018): 1104–12. http://dx.doi.org/10.1093/ecco-jcc/jjy068.
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Abstract Background and Aims An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment. Methods A total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally. Results Molecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES. Conclusions Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.
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Gramaglia, S. M. C., U. Cucinotta, V. Dipasquale, A. Serena, P. Gandullia, and C. Romano. "P300 Very early onset Inflammatory Bowel Diseases: Review of the Genoa-Messina joint clinical experience. Therapeutic approach: Part II." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i330. http://dx.doi.org/10.1093/ecco-jcc/jjab232.427.
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Abstract Background Pediatric inflammatory bowel diseases (pIBD) have specific phenotypes compared to Inflammatory Bowel Diseases (IBD) in adults. The Very Early Onset-IBD (VEO-IBD) is considered a diagnosis of IBD in children before age, 6 years old with, 15% of prevalence. Methods The objective of this study was to compare the clinical and endoscopic features of VEO-IBD compared to pediatric IBD (diagnosis >, 6 years old) also in terms of natural history and response to treatment. The VEO patients followed at the IBD-Centers of Messina and Gaslini were enrolled retrospectively. We compared the results of this population with what is reported in the literature in terms of therapeutic approach and surgery. Percentage comparison of data was performed. Results 74 VEO-IBD patients were enrolled. At the onset of the disease, during induction therapy, we found, 15–21% of VEO-IBDs are corticoresistant, remission was with Infliximab (table 1). During disease follow-up of at least, 5 years from onset: CD, 47,4% and CU, 61,1% of VEO-IBDs remain in therapeutic maintenance with, 1st line drugs (Mesalazine and Azathioprine; table 2). This result highlights how the VEO-IBDs also maintain clinical, histological and endoscopic remission even with, 1st line drugs, the only exception being the monogenic forms that may also require HSC transplantation. The surgical approach, according to our data, is far superior to that reported in the literature, although there are several conflicting studies in this regard. Patients undergoing major surgery (colectomy, ileostomy, ileorectoanastomosis, J pouch) are CD, 36.8% and CU, 18.5%, if we also consider minor surgery (perianal surgery; CD, 36.8%) the percentage of patients with Crohn’s disease undergoing surgery increases to, 52.6%. These numbers are far above what is reported in the literature:, 14–15% after, 5 years from diagnosis. It is likely that this result is due to the high numbers of procedures performed at Gaslini Institute, National Center for these diseases. A monogenic form of VEO-IBD was found in, 5.4% frequently linked to immunedeficiency, 2 cases (2,7%) required allogeneic HSC transplantation (XIAP, WAS) with complete recovery from disease. Conclusion VEO-IBDs represent a challenge for the pediatric gastroenterologist. Therapy is no different in terms of response from pediatric inflammatory bowel diseases, with the exception of monogenic forms who may need HSC transplant. Many VEO IBDs maintain remission with, 1st line drugs. Further studies will be needed to define the best therapeutic and diagnostic approach for these diseases.
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Collen, Lauren, Michael Field, Alal Eran, Vanessa Mitsialis, Jared Barends, Gwen Saccocia, Mairead Bresnahan, et al. "BULK RNA-SEQUENCING OF BLOOD INFORMS MOLECULAR DIAGNOSES IN VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE." Inflammatory Bowel Diseases 29, Supplement_1 (January 26, 2023): S56. http://dx.doi.org/10.1093/ibd/izac247.108.
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Abstract BACKGROUND Very early onset inflammatory bowel disease (VEOIBD) is defined as disease onset prior to age 6. VEOIBD is monogenic in >5% of cases; however, in the remaining cases, molecular basis of disease is unknown. We aimed to utilize bulk RNA-seq of blood to 1) define transcriptional signatures in established monogenic IBD and 2) to inform novel molecular diagnoses. METHODS We sequenced the transcriptomes of 115 whole blood samples, comprising patients with VEOIBD of a known monogenic cause (n=35), VEOIBD without a known monogenic cause (n=70), and healthy controls (n=10). We focused on genes whose normalized expression was at least 5 standard deviations away from the population mean in at least one sample. We comprehensively characterized clinical phenotypes, to assess concordance with known pathway and gene function, and compared to whole exome sequencing data where available. We interrogated Bayesian IBD networks to assess for enrichment of genes of interest. RESULTS First, we report on a novel transcriptional signature shared by two patients with VEOIBD secondary to X-linked agammaglobulinemia (pathogenic BTK mutations). The signature is defined by under-expression of CXCR5 and FCRL5 (Fig 1) and suggests reduced transcripts secondary to B-cell depletion or novel BTK-dependent mechanisms of gene transcription. Second, we report on three novel candidate VEOIBD genes identified through our approach: MSN, SLC39A4, and BTN3A2 (Fig 2). MSN expression was below threshold in one patient with VEOIBD complicated by fistulae, recurrent infections, and death from pneumonia at age 62. Review of his exome revealed a novel loss of function mutation in MSN. MSN encodes moesin, an actin cytoskeleton modulator, which regulates lymphocyte migration and adhesion. Mutations in MSN are associated with X-linked moesin-associated immunodeficiency, which was first reported in a patient with IBD this year. SLC39A4, which encodes an intestinal zinc transporter, was below threshold in two patients. Mutations in SLC39A4 are associated with acrodermatitis enteropathica, characterized by dermatitis and diarrhea. One patient has VEOIBD with dermatitis; the second has VEOIBD complicated by toxic megacolon and colectomy. Coding mutations in SLC39A4 have not been identified. Further molecular assessment of zinc transporter function is underway. Lastly, BTN3A2 expression was below threshold in two patients with infantile-onset IBD. BTN3A2 plays a role in T cell receptor interactions and NF-KB signaling. Bayesian IBD networks, built from independent cohorts, revealed BTN3A2 and SLC39A4 subnetworks to be enriched in predicted key driver genes of inflammation, further supporting these genes’ potential disease association. CONCLUSIONS Bulk RNA-seq in blood can be used as a diagnostic tool to aid in identifying novel molecular pathways and monogenic diagnoses in VEOIBD.
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Gramaglia, S. M. C., U. Cucinotta, V. Dipasquale, S. Arrigo, P. Gandullia, and C. Romano. "P263 Very early onset Inflammatory Bowel Diseases: Review of the Genoa-Messina joint clinical experience. Clinical history: Part I." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i304. http://dx.doi.org/10.1093/ecco-jcc/jjab232.390.
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Abstract Background Pediatric inflammatory bowel diseases (pIBD) have specific phenotypes compared to Inflammatory Bowel Diseases (IBD) in adults. The Very Early Onset-IBD (VEO-IBD) is considered a diagnosis of IBD in children before age 6 years old with 15% of prevalence. Methods The objective of this study was to compare the clinical and endoscopic features of VEO-IBD compared to pediatric IBD (diagnosis > 6 years old) also in terms of natural history and response to treatment. The VEO patients followed at the IBD-Centers of Messina and Gaslini were enrolled retrospectively. We compared the results of this population with what is reported in the literature in terms of clinical characteristics at onset (symptoms, age at onset, age at diagnosis), comorbidities, complications, associated immunodeficiencies, endoscopic models. Percentage comparison and chi-square test of data was performed. Results 74 VEO-IBD patients were enrolled. The onset is around 3 years, a predominantly colonic localization, inflammatory pattern. Positive family history for IBD in 8.1%. Histology is very nonspecific and is characterized above all by basal plasmacytosis (CD 68,4%; CU 72,7%) and hypereosinophilia (CD 36,8%; CU 40%). At diagnosis, IBD-U (= Unclassified) is prevalent (47,2%), the frequency of which will decrease over the years (3 years after onset, 32.4%), differentiating into CU and CD (table 1). The main clinical manifestations at onset are chronic diarrhea (CD 89,5%; CU 91%), blood in the stool and / or hematochezia (CD 78,9%; CU 96,4%; table 2). Sensitive onset tests for IBD are ESR, fecal calprotectin and iron deficiency anemia (positive respectively in CD 75-60-71,4%%; CU 58,8-84,6-66,7%). The most frequent extraintestinal manifestations are arthritis (CD 22,2%) and sclerosing cholangitis (CU 7,3%). To highlight the significant statistical association (p <0.05) between VEO-IBD and neuro / nephrological diseases (major renal malformations and nephropathies, autism and neuropsychiatric disorders; table 3). Among the most common complications are severe anemia (CD 31,6%; CU 42,6%), acute attack of severe colitis, malnutrition and fistulization. A monogenic form of VEO-IBD was found in 5.4% frequently linked to immunedeficiency, 2 cases required allogenic HSC transplantation (XIAP, WAS). Conclusion VEO-IBDs represent a challenge for the pediatric gastroenterologist. The clinical course is no more severe than pediatric inflammatory bowel diseases, with the exception of monogenic forms. A genetic association between nephro / neurological comorbidities and VEO-IBDs is likely, the genetics is still to be discovered. Further studies will be needed to define the best therapeutic and diagnostic approach for these diseases.
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Schwärzler, J. P., A. Zollner, T. Dolejsi, B. Enrich, L. Mayr, W. Sturm, I. Tancevski, J. Zschocke, T. E. Adolph, and H. Tilg. "P302 Precision medicine for a case with monogenic inflammatory bowel disease." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i446—i448. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0432.
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Abstract Background Here we report the case of a 33-year-old patient suffering from recurring infections since childhood, and Crohn’s disease (CD)-like inflammation in the ileum and colon for 5 years. The patient was transferred to our hospital due to severe pneumonia with Pseudomonas aeruginosa and Mycobacterium chimaera infection, recurrent fever, bronchiectasis, cachexia (BMI 12.9) and severe gastrointestinal symptoms (diarrhoea with blood 15 times per day). Colonoscopy revealed a peculiar inflammatory pattern in the ileum and the colon without healthy sections and deep punched lesions which did not fit to a diagnosis of CD. Methods Exome sequencing was performed and pathogenic variants identified by in silico prediction. Peripheral blood mononuclear cells (PBMCs) were isolated and Signal Transducer And Activator Of Transcription 1 (STAT1) activation was assessed by immunoblot after treatment with JAK-inhibitors. STAT1 activation was quantified in leukocytes of whole blood samples by flow cytometry. Mucosal sections were used to quantify STAT1 activation within mucosal cells by multicolour immunofluorescence. Two healthy individuals served as controls. Results Exome sequencing revealed a pathogenic mutation (c.1256C>G) in the STAT1 gene, which was predicted to cause a gain-of-function. STAT1 is part of the JAK/STAT1 pathway which is induced by different stimuli and orchestrates proliferation and responses of immune cells as a transcription factor. Isolated PBMCs from the patient exhibited increased STAT1 activation, and in whole blood samples increased levels were particularly observed in Monocytes and T-helper cells. In mucosal sections activated STAT1 was especially expressed in immune cells but also epithelial cells. Stimulation of PBMCs with Upadacitinib or Tofacitinib and partially with Filgotinib decreased STAT1 levels. We initiated treatment with Tofacitinib due to the in vitro results and its approval to treat ulcerative colitis. After two weeks, clinical symptoms improved drastically and endoscopy performed after 3 month indicated full remission, which was paralleled by a normalisation of STAT1 in PBMCs. Conclusion We present a case with a rare form of Inflammatory bowel disease (IBD) caused by a gain-of-function mutation affecting the STAT1 gene. IBD-like symptoms are unusual for STAT1 mutations, which usually present as immunodeficiency, and this specific mutation was only identified twice before and listed in data bases without describing the clinical phenotype. Our results and approach demonstrate how delineating the specific pathomechanism of a case with IBD enables targeted and precision treatment, a currently intensively investigated concept which might be implemented into clinical routine to treat IBD in the future.
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Magg, Thomas, Anna Shcherbina, Duran Arslan, Mukesh M. Desai, Sarah Wall, Vanessa Mitsialis, Raffaele Conca, et al. "CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease." Inflammatory Bowel Diseases 25, no. 11 (May 22, 2019): 1788–95. http://dx.doi.org/10.1093/ibd/izz103.
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Abstract Background Children with very early onset inflammatory bowel diseases (VEO-IBD) often have a refractory and severe disease course. A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes. The diagnosis of the underlying primary immunodeficiency (PID) often has critical implications for the treatment of patients with IBD-like phenotypes. Methods To identify the molecular etiology in 5 patients from 3 unrelated kindred with IBD-like symptoms, we conducted whole exome sequencing. Immune workup confirmed an underlying PID. Results Whole exome sequencing revealed 3 novel CARMIL2 loss-of-function mutations in our patients. Immunophenotyping of peripheral blood mononuclear cells showed reduction of regulatory and effector memory T cells and impaired B cell class switching. The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency. Conclusion Our study highlights that human CARMIL2 deficiency can manifest with IBD-like symptoms. This example illustrates that early diagnosis of underlying PID is crucial for the treatment and prognosis of children with VEO-IBD.
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Shumilov, P. V., and A. E. Shchigoleva. "Features of very early-onset inflammatory bowel disease: the experience of the Federal Pediatric Center." Voprosy detskoj dietologii 19, no. 3 (2021): 5–13. http://dx.doi.org/10.20953/1727-5784-2021-3-5-13.
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Objective. To clarify the incidence of monogenic IBD-like diseases and the features of clinical course and response to therapy of major types of inflammatory bowel diseases (IBD) among children under the age of 6 with manifestation of the disease. Patients and methods. The study included 135 children under the age of 6 with manifestation of IBD; in the comparison group, there were 128 children after the age of 6 with manifestation of IBD (97 children with ulcerative colitis (UC) and 31 children with Crohn’s disease (CD)) who were observed for at least 1 year. All children underwent a standard examination, including calprotectin and antineutrophil antibodies testing, determination of activity by the Pediatric Ulcerative Colitis Activity Index (PUCAI) or the Pediatric Crohn’s Disease Activity Index (PCDAI), depending on the nosology. Children with the onset of IBD under 6 years of age underwent a genetic testing using Primary Immunodeficiency Panel by next-generation sequencing. All children were analyzed for efficacy of therapy during catamnestic observation. Results. It was revealed that in the study group the incidence of monogenic IBD-like diseases was 6.7%, of UC – 71.1%, of CD – 22.2%. Major types of IBD with very early onset differed little in their clinical, endoscopic and laboratory features from the forms with manifestation at an older age. In most cases, both CD (57%) and UC (71%) were characterized by low activity. Very earlyonset CD was characterized by isolated localization of the colon (53%, p = 0.037) and a non-stenotic and non-penetrating behaviour of the disease (60% of cases). The leading clinical symptoms were diarrhea (67%) and blood in the stool (63%, p = 0.04). Very early-onset UC was characterized by total lesion of the colon (84%, p = 0.001) and the development of anemia (48%, p = 0.01). Among children with very early-onset UC, the percentage of glucocorticosteroid-dependence and glucocorticosteroid-resistance was high, but anti-TNFα therapy was prescribed late. Conclusion. It is advisable to observe children with very early-onset IBD in federal multidisciplinary clinics, where there is experience in managing patients with this pathology. Key words: inflammatory bowel disease, very early onset, Crohn’s disease, ulcerative colitis, primary immunodeficiency, treatment, children
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Alghoul, Zahra, Chunhua Yang, and Didier Merlin. "The Current Status of Molecular Biomarkers for Inflammatory Bowel Disease." Biomedicines 10, no. 7 (June 24, 2022): 1492. http://dx.doi.org/10.3390/biomedicines10071492.
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Diagnosis and prognosis of inflammatory bowel disease (IBD)—a chronic inflammation that affects the gastrointestinal tract of patients—are challenging, as most clinical symptoms are not specific to IBD, and are often seen in other inflammatory diseases, such as intestinal infections, drug-induced colitis, and monogenic diseases. To date, there is no gold-standard test for monitoring IBD. Endoscopy and imaging are essential diagnostic tools that provide information about the disease’s state, location, and severity. However, the invasive nature and high cost of endoscopy make it unsuitable for frequent monitoring of disease activity in IBD patients, and even when it is possible to replace endoscopy with imaging, high cost remains a concern. Laboratory testing of blood or feces has the advantage of being non-invasive, rapid, cost-effective, and standardizable. Although the specificity and accuracy of laboratory testing alone need to be improved, it is increasingly used to monitor disease activity or to diagnose suspected IBD cases in combination with endoscopy and/or imaging. The literature survey indicates a dearth of summarization of biomarkers for IBD testing. This review introduces currently available non-invasive biomarkers of clinical importance in laboratory testing for IBD, and discusses the trends and challenges in the IBD biomarker studies.
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Crowley, E., N. Warner, K. Fiedler, R. Murchie, P. Church, T. D. Walters, A. Griffiths, and A. Muise. "A13 WHOLE EXOME SEQUENCING OF OVER 1000 PEDIATRIC IBD PATIENTS FROM A SINGLE CENTRE IDENTIFIES MONOGENIC FORMS OF IBD." Journal of the Canadian Association of Gastroenterology 1, suppl_2 (February 2018): 21. http://dx.doi.org/10.1093/jcag/gwy009.013.
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Mateos, B., A. Gaite, I. Rodríguez-Lago, and U. M. Marigorta. "DOP79 Alternative polygenic forms of Inflammatory Bowel Disease are not captured by current generations of polygenic risk scores." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i155—i157. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0119.
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Abstract Background Polygenic risk scores (PRSs) have emerged as a promising tool to ascertain individuals at high risk of developing IBD. However, the sensitivity of current PRSs is limited, and will likely remain so in the immediate future. The default expectation is that patients not captured by PRSs must be enriched for rare variants with strong effects and/or environmental risk factors. We set out to investigate an alternative scenario, namely that combinations of common variants in non-GWAS genes conform population of patients that are missed by large genetic studies for the main forms of the disease. Methods MAGMA was used to identify genes from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) GWAS. We selected a sort of monogenic IBD genes1 which were significant for IBD (pval ≈ 10-4) but do not overlap with polygenic IBD genes. These genes were compared using DESeq tool on two transcriptomic databases: RISK (Crohn’s disease (CD) onset vs non-IBD) and PROTECT (ulcerative colitis (UC) onset vs 52 weeks). A second DESeq analysis was performed between patients with high against low expression of these 13 genes. We explored these genes using in-silico predicted expression based on eQTL in 9 different tissues for UK Biobank (UKBB) population, comparing UKBB individuals according to disease and polygenic risk score status. Results The starting point based on MAGMA analysis led to the detection of 13 monogenic IBD genes which may partially participate in polygenic forms of the disease. The transcriptomic analyses, based on stratification according to the levels of these 13 genes, implied that these genes participate in regulatory programmes that are particularly heterogeneous and variable among cases. The detected differentially expressed genes are associated with immune processes and receptors, inflammation transporters, and digestive problems, as well as skin development, humoral response, extracellular matrix, and mitochondrial component. The TWAS-based estimation analyses hint that low-PRS patients are indeed enriched for common variants associated with higher pathogenic levels at the 13 selected genes. Conclusion Although polygenic risk scores may play a valuable role in patient management, our study hints at the presence of patients with common polygenic forms that are not captured by current genetic risk estimators. 1. Chrissy B. et al, 2022. Gastroenterology.
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Bolton, Chrissy, Nicola Burch, James Morgan, Beth Harrison, Sumeet Pandey, Alistair T. Pagnamenta, Carolina Arancibia, et al. "Remission of Inflammatory Bowel Disease in Glucose-6-Phosphatase 3 Deficiency by Allogeneic Haematopoietic Stem Cell Transplantation." Journal of Crohn's and Colitis 14, no. 1 (June 3, 2019): 142–47. http://dx.doi.org/10.1093/ecco-jcc/jjz112.
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Abstract Mendelian disorders in glucose-6-phosphate metabolism can present with inflammatory bowel disease [IBD]. Using whole genome sequencing we identified a homozygous variant in the glucose-6-phosphatase G6PC3 gene [c.911dupC; p.Q305fs*82] in an adult patient with congenital neutropenia, lymphopenia and childhood-onset, therapy-refractory Crohn’s disease. Because G6PC3 is expressed in several haematopoietic and non-haematopoietic cells it was unclear whether allogeneic stem cell transplantation [HSCT] would benefit this patient with intestinal inflammation. We show that HSCT resolves G6PC3-associated immunodeficiency and the Crohn’s disease phenotype. It illustrates how even in adulthood, next-generation sequencing can have a significant impact on clinical practice and healthcare utilization in patients with immunodeficiency and monogenic IBD.
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Ensari, Arzu, Judith Kelsen, and Pierre Russo. "Newcomers in paediatric GI pathology: childhood enteropathies including very early onset monogenic IBD." Virchows Archiv 472, no. 1 (July 17, 2017): 111–23. http://dx.doi.org/10.1007/s00428-017-2197-9.
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Alahmari, A. A., A. M. Al-Bahlani, B. Frenette, A. Xuan-Lan Nguyen, N. Ahmed, and A. Sant’Anna. "A251 VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE IN CHILDREN: A SINGLE CENTER EXPERIENCE OVER 15 YEARS." Journal of the Canadian Association of Gastroenterology 3, Supplement_1 (February 2020): 128–29. http://dx.doi.org/10.1093/jcag/gwz047.250.
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Abstract Background Very-early-onset inflammatory bowel disease (VEOIBD) refers to an IBD diagnosis established before the 6th year of life, including a subset of patients with disease onset before the age of 2 years, known as infantile-onset IBD (IO-IBD) (1). VEO-IBD accounts for 15% of pediatric IBD and infantile IBD in approximately 1% (2,3). VEOIBD is considered to be a unique entity, and compared to adults with IBD, VEO-IBD children are more likely to present with extensive and treatment-resistant disease (4). Aims To analyze the clinical characteristics and management of patients diagnosed with very early onset inflammatory bowel disease (VEO-IBD). Methods A retrospective analysis of children diagnosed with VEO-IBD (age <6 years) at the Montreal Children’s Hospital from 2003–2018 was performed. Clinical data for VEO-IBD patients was collected to identify the clinical, biochemical, endoscopic and histological features of these patients and their clinical course until 2018. Results A total of 28 VEO-IBD patients (71% male) were included in this study. The median age of disease onset was 52 months. A diagnosis of Crohn’s disease (CD) or CD-like intestinal manifestations accounted for 89% of the VEO-IBD cases. Most patients had Crohn’s colitis (36%) of whom 50% had evidence of granulomatous Crohn’s disease; 11 patients[NAD1] [AQAB2] (39%) had upper gastrointestinal involvement. Over their progress of the disease, 4 patients (14%) required surgical intervention, while 11 patients (39%) required biologic therapy for maintenance therapy. Genetic[NAD3] [AQAB4] results were available for 5 patients out of 28 (18%) and 3 of them were identified to have monogenic IBD. Conclusions In our center, the majority of patients with VEO-IBD had typical Crohn’s disease presentation. Most of the VEO-IBD patients responded well to the standard IBD treatment. Genetic studies were not done regularly for all of our patients, however, among those who had this testing performed 3/5 had an identifiable cause, suggesting that these patients should be investigated for an underlying genetic abnormality. Funding Agencies None
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Ahamed, Nazmul, Mukesh Khadga, Wahiduzzaman Majumder, and Md Rukunuzzaman. "An Eleven Months Old Infant with Very Early Onset Inflammatory Bowel Diseases (IBD): A Rare Case Report." Bangladesh Medical Journal 50, no. 2 (August 14, 2022): 45–49. http://dx.doi.org/10.3329/bmj.v50i2.61220.
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Inflammatory bowel disease (IBD) in pediatric cases has been seen rapidly increasing in number over the last decade. Now a days four types of pediatric IBD has been identified: less than ten years of age - early onset IBD, less than six years of age - very early onset IBD, less than two years of age- infantile IBD and less than twenty eight days of age - neonatal onset IBD. Young children presented with more aggressive clinical features and severity is more than the older children and adults. Early onset disease presenting in children may have a monogenic basis. Infantile IBD or neonatal IBD having the high rates to affect the first-degree relatives and there is very high chance to develop resistance against immunosuppressive treatment. Very early onset IBD (VEO-IBD) most commonly presenting per rectal bleeding with or without mucous stools, isolated colonic disease, perianal involvement, skin lesions, whereas early onset IBD (EO-IBD) commonly presented with abdominal pain and weight loss. A thorough history, physical examination, biochemical markers, endoscopic evaluation with macroscop and microscopic findings are the only way to reach the diagnosis. The treatment of VEO-IBD is the same as that given to the adolescents and adults with IBD (eg, anti-inflammatory agents, immunomodulators, biologics, antibiotics, and surgical approaches). Here, we report a rare case of very early onset IBD of a 11 months old male infant, who presented with the complaints of blood and mucus mixed loose watery stool for 10 days, having similar episodes for last five months. He was mildly pale, and had thrombocytosis with raised C reactive protein (CRP), features of colitis in stool routine microscopic test. The diagnosis was confirmed by colonoscopy and histopathology study, which showed features of Crohn’s colitis. He was treated by anti-inflammatory drugs (steroid and mesalazine) with a significant improvement in a short time. Bangladesh Med J. 2021 May; 50(2) : 45-49
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Mehta, M., L. Wang, C. Guo, N. Warner, Q. Li, J. Pan, K. Boztug, H. Uhlig, and A. Muise. "A39 NOVEL GAIN OF FUNCTION NON-RECEPTOR TYROSINE KINASE MUTATIONS ARE LINKED TO THE PATHOGENESIS OF VEOIBD." Journal of the Canadian Association of Gastroenterology 3, Supplement_1 (February 2020): 46–48. http://dx.doi.org/10.1093/jcag/gwz047.038.
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Abstract Background Very early-onset inflammatory bowel disease (VEOIBD) is an emerging global disease, that results in inflammation of the digestive tract. Severe forms of VEOIBD can be caused by mutations in a single gene (monogenic variants) and, can result in death. A candidate gene which codes for a non-receptor tyrosine kinase (nRTK) has recently been implicated as a monogenic cause of IBD (unpublished). Whole exome sequencing was performed in two unrelated children who presented with symptoms of IBD identifying two distinct de novo gain of function mutations (S550Y and P342T). Both mutations are located in the highly conserved region of the nRTK, and were predicted to have similar downstream effects. Furthermore, four other patients with a variety of adult-onset immune disorders have recently been identified with rare variants in the same gene (M450I, R42P, A353T, V433M, S550F) but, their potential gain of function status remains to be determined. Studies show that this nRTK is an essential mediator in inflammation. It is expressed in both intestinal epithelial and immune cells however, its role in infantile IBD is unclear. This protein is first activated by phosphorylation and is linked to activating downstream transcription factors such as ERK and JNK. All these target proteins play a meaningful role in intestinal inflammation in patients with IBD. Aims Since we identified P342T and S550Y to be gain of function, we wanted to determine if the new variants exhibit a similar downstream impact on target protein expression levels when compared with S550Y and P342T. We also wanted to identify if all variants can be rescued with a known nRTK inhibitor. It is hypothesized that the new variants are gain of function and that all variants can be rescued with the inhibitor. Methods Using western blot analysis, the activation of ERK, JNK and nRTK was compared between wildtype (WT) and mutants. This in vitro method helped identify the degree of activation. For the second part of the study, HEK293T cells were treated with inhibitor to test for a rescue of phenotypes via western blot analysis. Results Results show an increased activation of nRTK, ERK and JNK in all variants with S550Y and S550F having the highest activation. Furthermore, pharmacological inhibition using small molecular kinase inhibitors resulted in decreased activation of nRTK, ERK and JNK suggesting a rescue of phenotypes. Conclusions Characterizing the downstream functional impact of these nRTK variants is an important first step to determine if gain of function nRTK mutations drive IBD. With a rising prevalence of IBD worldwide, these findings may lead to the development of pharmacological nRTK inhibitors as a novel personalized therapeutic approach for these patients and possibly for the broader IBD population. Funding Agencies CIHR
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Eisenbarth, George S. "Etiology of Organ-Specific Autoimmunity: Basic Research and Clinical Implications in IBD." Canadian Journal of Gastroenterology 10, no. 2 (1996): 121–25. http://dx.doi.org/10.1155/1996/909212.
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Autoimmunity develops in the setting of genetic susceptibility and can be monogenic (eg, autoimmune polyendocrine syndrome type I with Addison’s disease, mucocutaneous candidiasis and hypoparathyroidism, which is autosomal recessive with the causative gene on the tip of chromosome 21) or polygenic (usually with important alleles within the major histocompatibility complex [eg, type I diabetes]). In addition to genetic susceptibility, many autoimmune disorders can be classified into etiological categories (oncogenic, drug-induced, diet-induced, infectious or idiopathic). For most autoimmune disorders there are multiple target autoantigens and, for type I diabetes, a combinatorial approach (eg, expression of at least two autoantibodies of insulin, glutamic acid decarboxylase and/or ICA512/IA-2) is the best predictor of diabetes risk. Finally, antigen-specific therapies hold promise for the prevention and therapy of autoimmunity, eg, parenteral or oral therapy with insulin delays or prevents type I diabetes in animal models, and a small pilot trial of parenteral insulin in humans suggests that such therapy may similarly prevent diabetes in humans.
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Feakins, R. M., J. Torres, P. Borralho-Nunes, J. Burisch, T. Cúrdia Gonçalves, L. De Ridder, A. Driessen, et al. "DOP78 The differential diagnosis and clinicopathological spectrum of Inflammatory Bowel Disease: An interesting and informative ECCO topical review." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S110—S111. http://dx.doi.org/10.1093/ecco-jcc/jjab073.117.
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Abstract Background A wide variety of intestinal and non-intestinal diseases can resemble chronic idiopathic inflammatory bowel disease (IBD) clinically and/or pathologically. The aim of the current Topical Review was to explore the differential diagnosis of IBD and to discuss clinical, histomorphological features and ancillary techniques that help distinguish between IBD and its mimics. Methods An open ECCO call led to the selection of 12 participants who formed three working groups (WG) to study the mimics of IBD. WG 1 comprised gastroenterologists, who explored mainly the clinical features. WG 2 consisted of histopathologists, who focused on macroscopic and microscopic pathological aspects. WG 3 was a mixed group of pathologists and clinicians who studied the value of additional investigative techniques such as imaging, serology and molecular markers. A systematic literature search allowed exploration of these topics and the identification of the most helpful and relevant distinguishing features. The process led to the development of Current Practice Position (CPP) statements and supporting text. Consensus meetings with voting by all participants facilitated modification and finalisation of CPP statements. Results The project highlighted several points. Firstly, there is a wide and sometimes overwhelming variety of potential mimics of new and established IBD, both in adults and in children. Secondly, some mimics are more important clinically and others pathologically, meaning that the emphasis on the mimics of IBD is different for clinicians and pathologists. Thirdly, close attention to all clinical features, pathological findings and other evidence optimises accuracy. Finally, newer techniques sometimes have a role, e.g., in distinguishing monogenic IBD-like disorders from IBD in young children, and the value of many novel techniques is as yet uncertain. A practical message is that constant awareness by clinicians and pathologists of the possibility of mimics is particularly important. Conclusion Discussions between pathologists and clinicians were particularly useful during this process and were a reminder of the importance of clinicopathological correlation. There is a wide variety of mimics of IBD, including infections, diverticular disease, drug effect, radiation damage, immune disorders, vascular disorders and diversion proctocolitis. An important, relatively new, and sometimes very close mimic of IBD is immune checkpoint inhibitor colitis. In turn, reliable distinction between IBD and other entities requires a multidisciplinary approach with a full clinical history (including duration of disease), and with appropriate investigations that may include endoscopy, pathology, imaging, microbiological tests, serology, and newer molecular tests.
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Abdel-Motal, Ussama M., Ahmad Al-Shaibi, Mamoun Elawad, and Bernice Lo. "Zero tolerance! A perspective on monogenic disorders with defective regulatory T cells and IBD-like disease." Immunological Reviews 287, no. 1 (December 18, 2018): 236–40. http://dx.doi.org/10.1111/imr.12717.
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Lindoso, Livia, Mariana Deboni, Mayra Barros Dorna, Ana Paula Moschione Castro, Antonio Carlos Pastorino, and Ricardo Toma. "P053 Activated PI3K-Delta Syndrome (APDS): A Monogenic Cause of VEO-IBD That Impacts on Treatment." American Journal of Gastroenterology 114, no. 1 (December 2019): S14. http://dx.doi.org/10.14309/01.ajg.0000613180.48811.fe.
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Crowley, Eileen, Neil E. Warner, K. Fiedler, Ryan Murchie, S. Khalouei, Justin Foong, Arun Ramani, et al. "587 - Whole Exome Sequencing of over 1000 Pediatric IBD Patients from a Single Centre on an Expanded Gene Panel Identifies Monogenic Forms of IBD." Gastroenterology 154, no. 6 (May 2018): S—123. http://dx.doi.org/10.1016/s0016-5085(18)30840-0.
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Zhang, Zinan Z., Yu Zhang, Tingyan He, Colin L. Sweeney, Safa Baris, Elif Karakoc-Aydiner, Yikun Yao, et al. "Homozygous IL37 mutation associated with infantile inflammatory bowel disease." Proceedings of the National Academy of Sciences 118, no. 10 (March 4, 2021): e2009217118. http://dx.doi.org/10.1073/pnas.2009217118.
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Interleukin (IL)-37, an antiinflammatory IL-1 family cytokine, is a key suppressor of innate immunity. IL-37 signaling requires the heterodimeric IL-18R1 and IL-1R8 receptor, which is abundantly expressed in the gastrointestinal tract. Here we report a 4-mo-old male from a consanguineous family with a homozygous loss-of-function IL37 mutation. The patient presented with persistent diarrhea and was found to have infantile inflammatory bowel disease (I-IBD). Patient cells showed increased intracellular IL-37 expression and increased proinflammatory cytokine production. In cell lines, mutant IL-37 was not stably expressed or properly secreted and was thus unable to functionally suppress proinflammatory cytokine expression. Furthermore, induced pluripotent stem cell–derived macrophages from the patient revealed an activated macrophage phenotype, which is more prone to lipopolysaccharide and IL-1β stimulation, resulting in hyperinflammatory tumor necrosis factor production. Insights from this patient will not only shed light on monogenic contributions of I-IBD but may also reveal the significance of the IL-18 and IL-37 axis in colonic homeostasis.
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Jabandžiev, Petr, Eva Hlaváčková, Viktor Bílý, Eva Karásková, Lumír Kunovský, Hana Grombiříková, Romana Kozumplíková, et al. "Trichohepatoenteric syndrome in a patient with TTC37 mutations – a case report." Gastroenterologie a hepatologie 74, no. 6 (December 22, 2020): 481–87. http://dx.doi.org/10.48095/ccgh2020481.
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We report a patient with somatic retardation and woolly hair appearance who suffered from recurring episodes of watery mucous diarrhea, impaired liver functions, and failure to thrive. He manifested with severe infection courses, including hepatitis of unknown origin complicated by liver failure at 4 months, bronchopneumonia at 4 years, and life-threatening sepsis with septic shock at 8 years of age. Esophagogastroduodenoscopy and colonoscopy were performed at 4 years to rule out inflammatory bowel disease (IBD), and only signs of nonspecific colitis were evident. Immunology workup revealed slight reduction in CD4+ naive subsets and impaired T cell response to mitogens. Massive parallel sequencing (also termed next-generation sequencing – NGS) targeting a panel of primary immunodeficiency-related genes was used to examine the patient’s DNA. NGS analysis revealed two heterozygous variants in the TTC37 gene. Nonsense p.Arg1201* and missense p.Leu1505Ser variants in exons 34 and 42, respectively, were evaluated as pathogenic based on in silico predictions, their rare occurrence in the general population, and the fact that both mutations had already been described in patients with trichohepatoenteric syndrome (THES). As clinical features in our patient were in accordance with this diagnosis, we consider our findings as causative. THES could be a life-threatening condition, particularly in children who develop liver disease or severe infection courses. THES can have a similar clinical presentation as does very early-onset inflammatory bowel disease (VEO-IBD) and is often assigned to this group. Although IBD is generally regarded as a polygenic disease, some children with VEO-IBD are known also to have diseases with monogenic etiologies, as in THES. Targeted NGS is an efficient tool for establishing an accurate dia gnosis in VEO-IBD patients.
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Fachal, L. "OP11 Expanded genome-wide association study of Inflammatory Bowel Disease identifies 174 novel loci and directly implicates new genes in disease susceptibility." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i011—i013. http://dx.doi.org/10.1093/ecco-jcc/jjab232.010.
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Abstract Background Genome-wide association studies (GWASs) have identified 243 loci associated with inflammatory bowel disease (IBD). However, the mapping of additional disease loci and causal variants is still limited by sample size. Larger GWAS can provide further insights into causal biology. Methods We performed a GWAS meta-analysis of 33 cohorts, totalling 54,439 IBD patients (N=30,574 with Crohn’s disease (CD), 21,193 with Ulcerative Colitis (UC)) and 37,054 European controls. Genotype imputation was undertaken using the TOPMed diverse population panel and association tests were performed using REGENIE. These results were meta-analysed with summary statistics from 4 additional studies, a Danish cohort, the UK Biobank, deCODE, and FinnGen, totalling 73,030 IBD patients and 1 million controls, Fig1. Results We identified 174 novel genome-wide significant signals (32 associated with CD, 36 with UC, 106 with IBD, Fig2). Of these, 79 are located >1Mb from any known GWAS loci. We also identified two new population specific genetic associations, Fig3. Six new loci contain genes implicated in monogenic syndromes that include colitis: CARMIL2, DOCK8, G6PC3, HPS4, NCF1, PIK3CD. Several new loci alter the expression of nearby genes, suggesting that aberrant expression of these genes underpins the association. For instance, a new variant associated with decreased risk of IBD increases the expression of VSIR in colon Fig4. VSIR knockout mice have increased expression of IL23 and develop chronic inflammation in multiple tissues. Fine-mapping analyses identified likely causal missense variants at three new loci. DOK2 (ORCD=1.3, 27p=2x10-12) encodes a protein expressed in macrophages and T cells. Loss of Dok2 in mice causes severe DSS-induced colitis with reduced IL17A and IL22 expression. The same variant has been recently associated with CD in a sequencing study. SHARPIN (ORCD=1.2, p=1x10-16) is part of the linear ubiquitin chain assembly complex that modulates activation of the NF-κB pathway. Loss-of-function (LOF) mutations in other proteins in the complex are associated with immunodeficiency and systemic autoinflammation. CARMIL2 (ORUC=1.2, p=1x10-10) is required for NF-κB signalling in both B and T cells. LOF mutations are associated with primary immunodeficiencies and paediatric forms of IBD. Conclusion The greatly expanded sample size in our latest GWAS meta-analysis has enabled the identification of low frequency variants with larger effects on IBD susceptibility than the more common variants typically identified by previous GWAS. The biological overlap between Mendelian and complex forms of IBD is demonstrated by the discovery of common non-coding variants associated with complex forms of IBD that dysregulate the function of a Mendelian IBD gene.
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Amininejad, Leila, Benoit Charloteaux, Emilie Theatre, Jacques Van Cauter, Pierre Hayard, Vinciane Muls, Jean Marc Maisin, et al. "389 A Candidate Gene Study of Rare Monogenic Disorders With IBD-Like Phenotype Identified Rare Variants in XIAP Gene in a Cohort of Early-Onset IBD Patients." Gastroenterology 148, no. 4 (April 2015): S—81—S—82. http://dx.doi.org/10.1016/s0016-5085(15)30283-3.
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De castelbajac, F., F. Charbit-Henrion, O. Goulet, N. Cerf-Bensussan, X. Treton, C. Stefanescu, D. Cazals-Hatem, et al. "P672 A tertiary multicenter cohort of patients with chronic intestinal pseudo-obstruction and Crohn’s disease: a rare association with a high prevalence of monogenic disorders." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S593—S594. http://dx.doi.org/10.1093/ecco-jcc/jjab076.792.
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Abstract Background Chronic intestinal pseudo-obstruction (CIPO) is a rare condition that is not commonly associated with Crohn’s disease (CD). We performed a cohort study aiming at identifying clinical, immunological and genetic features as well as response to conventional CD treatments of patients co-affected with CIPO and CD. Methods We conducted an observational retrospective cohort study in two tertiary CIPO and IBD centers. Patients with parenteral nutrition-dependent CIPO and features of CD including large intestinal or perianal ulcers, strictures, abscesses and fistula with pathology findings compatible with CD, were included. We used flow-cytometry and targeted-next generation sequencing to identify immune defects and monogenic causes in 129 predefined genes responsible for monogenic enteropathies Results Eight unrelated patients were studied. 5 had a myogenic phenotype and 3 had a neurogenic form with histological exam for all patients. CD involved small bowel in all cases whereas one patient had ileocolonic involvement. Two patients had perianal complex fistula. Seven patients had a stricturing form and 1 had an inflammatory-only behavior. No patient had a penetrating form. All patients were diagnosed with CIPO prior to CD. Median age at CIPO diagnosis was 11.5 years old (IQR 0,31.5) while it was 22.5 (IQR 19,29) at CD diagnosis. At CD diagnosis, mean fecal calprotectin level was 551 ug/g (range 390 - 1200) and citrulline averaged 23.6 umol/l (range 15–35 umol/l). Histopathological analyses of intestinal specimens revealed ulcerations for half of the patients, increase in intraepithelial lymphocytes in 3, granuloma and cryptitis in 1 patient. Abnormalities in peripheral lymphocytes’ subsets were found in 2 patients. 5 patients were ultimately diagnosed with monogenic forms of enteropathy: 2 in ACTG2, with an autosomal dominant inheritance, 1 with a STAT1gain of function, (GOF) and two with recessive inheritance: TYMP. All patients received steroids with clinical response in 2. 6 patients received antiTNF, with only one sustained remission. Two patients received vedolizumab and 2 were treated with ustekinumab. Except for antiTNF in 1 patient, common CD treatments did not lead to any improvement. Of note, antiJAK therapy in a patient with STAT1GOF failed to induce remission. Conclusion Herein is described the first cohort of extensively genetically and immunologically explored patients co-affected with CIPO and CD. Immune defects were common and monogenic forms were found with a high prevalence. Rates of response to biologic treatment were very low. Identification of monogenic cause through immunological and genetic explorations is warranted in patient with CIPO-CD association as it could lead to targeted therapy and genetic counseling.
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Guz Mark, A., M. Aloi, L. Scarallo, M. Bramuzzo, J. C. Escher, P. Alvisi, P. Henderson, et al. "DOP69 Long-term outcome of infantile and very early onset IBD: A multi-center study from the IBD Porto group of ESPGHAN." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i112—i113. http://dx.doi.org/10.1093/ecco-jcc/jjab232.108.
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Abstract Background Very early-onset inflammatory bowel disease (VEOIBD) is diagnosed before the age of 6 years while infantile IBD occurs before the age of 2 years. We aimed to assess disease characteristics and long-term outcomes in these populations. Methods We conducted a retrospective longitudinal cohort study in 21 pediatric centers worldwide. Patients diagnosed with VEOIBD between the years 2008–2018 with at least 2 years of follow-up were included. Results The cohort included 243 patients (52% males), with median follow-up of 5.8 (IQR 3.2–8.4) years. Median age at diagnosis was 3.3 (IQR 1.8–4.5) years, with 69 (28%) diagnosed before the age of 2 years. Disease was classified as Crohn’s disease (CD), ulcerative colitis (UC) and IBD-unclassified (IBDU) in 30%, 59% and 11%, respectively. In patients with UC or IBDU, 75% presented with pancolitis. In patients with CD, 62% presented with isolated colonic disease and 32% with ileo-colonic disease, while 19% had perianal involvement. Genetic testing was performed in 96 (40%) patients [40 (58%) <2 years, 56 (32%) 2–6 years, p=0.001], with monogenic diagnosis identified in 23% (33% and 16%, respectively, p=0.08). The most common findings were mutations in IL10-receptor (5 cases, 23%). Stricturing or penetrating disease was observed in 9 cases (4%). First induction therapies were corticosteroids, 5-aminosalicylic acid (5ASA) and nutritional therapy in 53%, 30% and 11%, respectively. Corticosteroids were more common as first induction in infantile vs. non-infantile IBD (64% vs. 49% respectively, p=0.003). Maintenance therapies included deep immune-suppression (mainly biologics and corticosteroids) in 51%, immunomodulators in 27%, and non-immunosuppressive agents (5-ASA, nutritional therapy and antibiotics) in 22% of patients, with no significant differences between age groups. Compared to patients diagnosed after 2 years of age, patients with infantile IBD presented with higher rates of IBDU, lower levels of hemoglobin and albumin and higher levels of CRP, lower weight (but not height) z-scores, had lower rates of response to first induction therapy and shorter time to hospitalization during follow-up (p<0.05 for all). Colectomy was performed in 11% and diversion surgery in 4% of the cohort, with no significant differences between age groups. No malignancies and nor deaths were observed. At end of follow-up, 85% of patients were in corticosteroid free clinical remission. Conclusion Patients with VEOIBD, including infantile IBD, have fair long-term outcome with low rates of complications and surgical interventions. Nevertheless, patients with infantile IBD demonstrated more severe clinical features at presentation and a lower response to induction therapy.
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Sultan, M., P. Millman, B. McCourt, N. Kol, A. Lev, M. Matar, O. Barel, et al. "DOP64 Pathogenic RIPK1 Mutations Cause Infantile-onset IBD with Inflammatory and Fistulizing Features." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i109. http://dx.doi.org/10.1093/ecco-jcc/jjab232.103.
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Abstract Background Genetics plays a key role in the pathogenesis of inflammatory bowel disease (IBD). With the expanding use of next-generation sequencing, >70 different monogenic disorders associated with IBD have been identified, and most of them present in the first years of life. Recently, several patients with severe IBD were identified to harbor pathogenic mutations in Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) gene, which regulates necroptosis, a necrotic cell death mechanism. We present the clinical features, genetic analysis and immune work-up of three patients with infantile-onset IBD resulting from novel RIPK1 mutations. Methods Whole exome sequencing was performed in three patients with severe infantile-onset IBD, along with sanger sequencing for conformation. Mass cytometry time of flight was conducted for in-depth immunophenotyping, including cytokine secretion analysis following lipopolysaccharide (LPS) or Phorbol myristate acetate with ionomycin (PMA-I), on one of the patient’s peripheral blood mononuclear cells, and compared to control subjects and patients with Crohn’s disease. Results All patients, born to consanguineous Muslim families, presented with severe colitis and multiple perianal fistulas in the first months of life, without severe or atypical infections. One of the patients had a partial response to high doses of inlfliximab and azathioprine, while another one failed to respond to adaliumab and later to low dose anakinra, an IL-1 receptor antagonist. Genetic studies identified novel and pathogenic genetic variants in the RIPK1 gene in all patients, that were confirmed by Sanger sequencing. Using mass cytometry time of flight unbiased clustering analysis, we identified peripheral immune dysregulation in one of these patients, characterized by an increase in IFNγ CD8+ T cells along with a decrease in monocytes, dendritic cells and B cells. Moreover, RIPK1-deficient patient’s immune cells exhibited decreased IL-6 production in response to LPS across multiple cell types including T cells B cells and innate immune cells. Conclusion Mutations in RIPK1 should be considered in very young patients presenting with colitis and perianal fistulas. Given RIPK1’s role in both immune cells (and specifically in inflammasome activation), and epithelial cells, it is unclear whether immunosuppressive medications (including IL1 blockade) as well as allogeneic hematopoietic stem cell transplantation can suppress or cure the hyper-inflammatory response in these patients. Additional studies in humans are required to better define the role of RIPK1 in regulating intestinal immune responses, and how treatment can be optimized for patients with RIPK1 deficiency.
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Huma Arshad Cheema, Nadia Waheed, Anjum Saeed, Zafar Fayyaz, Muhammad Nadeem Anjum, Muhammad Arshad Alvi, and Syeda Sara Batool. "Very early onset inflammatory bowel disease (VEO-IBD); spectrum of clinical presentation, diagnostic tools and outcome in children." Journal of the Pakistan Medical Association 71, no. 10 (July 26, 2021): 2350–54. http://dx.doi.org/10.47391/jpma.05-725.
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Background: Very early-onset inflammatory bowel disease (VEO-IBD) is defined as diagnosis of Ulcerative Colitis (UC) or Crohn’s Disease (CD) in children under six years of age. Genome wide association studies have linked a strong genetic component responsible for VEO-IBD. Approximately, 30-40% children of VEO-IBD have underlying immunodeficiency states. We aimed to study the spectrum of presentation, underlying monogenetic defects and outcome in VEO-IBD. Methods: This is a prospective, observational study conducted at division of Gastroenterology, the Children's Hospital & the Institute of Child Health, Lahore, over 2 years. Children developing features of IBD under six-years of age were included. Data included demography, clinical presentation, diagnostic tools and outcome. Gastroscopy and colonoscopy were performed in all patients in addition to basic work up done for associatedimmunodeficiency states and molecular genetics. SPSS version 21 was used for analysis. Continuous...
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Beier, Rita, Daniel Kotlarz, Kaan Boztug, Erik Glocker, Eva Doreen Pfister, Jana Diestelhorst, Dhaarini Murugan, et al. "Successful Allogeneic Hematopoietic Stem Cell Transplantation for Severe Inflammatory Bowel Disease – IL10 Receptor Deficiency May Serve as a Novel Therapeutic Paradigm." Blood 116, no. 21 (November 19, 2010): 2379. http://dx.doi.org/10.1182/blood.v116.21.2379.2379.
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Abstract Abstract 2379 Inflammatory bowel diseases (IBDs) comprise a heterogeneous group of disorders, classically defined as Crohn's disease, ulcerative colitis, and indeterminate colitis. The molecular pathophysiology of enterocolitis is still largely unknown. Recently, we identified monogenic mutations in the IL10 receptor genes, providing novel insights into the role of IL10-mediated immune homeostasis in the human gut. Here, we report a series of 8 patients with mutations in the IL10RA or IL10RB gene. All patients presented within the first three months of life with severe enterocolitis and rectal fistulations. Patients were unresponsive to immunosuppressive and immunomodulatory therapies. Deleterious mutations in IL10 receptor genes abrogated IL10-induced signaling, as demonstrated by deficient STAT3 phosphorylation at the tyrosine 705 residue upon IL10 stimulation. As a consequence of defective STAT3 signal transduction in response to IL10 stimulation, IL10R-deficient mononuclear cells showed increased secretion of TNFα and various other proinflammatory cytokines unresponsive to IL10-dependent negative feedback regulation (TGFβ1, IL1α, IL1β, IL2, IL6, IL6sR, RANTES, MCP1, MIP1α, and MIP1β). In view of the critical immunomodulatory role of IL10, we designed a protocol for allogeneic hematopoietic stem cell transplantation for patients with IL10R-mutations. The conditioning regimen includes treosulfan, fludarabin, thiotepa, and campath-1A. A strict gut decontamination regime was chosen to reduce intestinal bacterial load. Ciclosporin A, mycophenolatemofetil, and campath-1A was used for graft versus host disease prophylaxis. 4 patients (age at HSCT 0.9–13.8yrs, 3 male, 1 female) were transplanted from a HLA-identical matched sibling (n=2) or a matched unrelated donor (MUD, HLA match 9/10) (n=2). All patients engrafted(neutrophil engraftment 10–26 days). In 3/4 patients displayed full chimerism after the first HSCT. One patient developed mixed chimerism on day 69 after HSCT and consecutively lost his graft. He was successfully re-transplanted from a different 9/10 MUD successfully achieving full donor chimerism. Acute GvHD II° and III° (skin) occurred in one patient each and was treated successfully, no chronic GvHD was observed. Regimen related toxicity was low and included mucositis I-II° and skin toxicity I-II°. Viral infections were diagnosed and successfully treated in 3/4 children (1 CMV, 1 adenovirus, 1 rotavirus). These patients responded well to the antiviral treatment or reduction of immunsuppression (follow up after HSCT 6 months-2 yrs). Intestinal inflammation resolved as proven by clinical examination, colonoscopy and histological analysis. All children improved their growth rate following the bone marrow transplantation. Post transplant samples taken after transplant showed a restored response to IL10 in mononuclear cells. These data suggest that allogeneic HSCT may represent a novel, effective, and safe therapeutic approach to treat defined subgroups of IBD patients. Disclosures: No relevant conflicts of interest to declare.
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Boztug, Kaan, Daniel Kotlarz, Erik Glocker, Mike E. Gertz, Alejandro A. Schäffer, Fatih Noyan, Mario Perro, et al. "Severe Early-Onset Inflammatory Bowel Disease Caused by IL10 Receptor Deficiency Can Be Cured by Allogeneic Hematopoietic Stem Cell Transplantation." Blood 114, no. 22 (November 20, 2009): 713. http://dx.doi.org/10.1182/blood.v114.22.713.713.
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Abstract Abstract 713 In spite of recent genome-wide association studies, the molecular pathophysiology of many human auto-inflammatory diseases such as enterocolitis remains largely unknown. Here, we discover the first fully penetrant monogenetic defect causing inflammatory bowel disease (IBD) in humans. Using homozygosity mapping and candidate gene sequencing, we identified three distinct, homozygous mutations in IL10RA, encoding the IL10R1 protein, and IL10RB, encoding the IL10R2 protein, in patients with severe and refractory enterocolitis. IL10R1 is a specific receptor for IL10, whereas IL10R2 is a shared cytokine receptor unit for IL10, IL22, IL26, and IFNλ. The striking similarity of the clinical phenotype between patients with IL10RA and IL10RB deficiency, respectively, suggests that defective IL10-mediated signaling, and not IL22, IL26, or IFNλ dependent effects, is the critical reason for disease. Deleterious missense mutations in IL10RA abrogate IL10-induced signaling, as shown by deficient phosphorylation of STAT3 at the residue tyrosine 705 in primary patient cells and in HeLa cells engineered to express mutant IL10R1. Mutations in IL10RB introduced a premature stop codon. Defective expression of IL10R2 on the cell surface and deficient STAT3 signaling could be reconstituted by lentiviral gene transfer. As a consequence of defective STAT3 signal transduction in response to IL10 stimulation, IL10R-deficient primary cells showed increased secretion of TNFαa and various other proinflammatory cytokines unresponsive to IL10-dependent negative feedback regulation (TGFβ1, IL1αa, IL1β, IL2, IL6, IL6sR, RANTES, MCP1, MIP1αa, and MIP1β). We are currently assessing whether other IBD patients with early-onset IBD show defects in IL10-mediated signal transduction. In view of the therapy refractory course of disease and the critical role of IL10 signaling on cells of the hematopoietic system, we have successfully treated two IBD patients with IL10 receptor deficiency by hematopoietic stem cell transplantation (HSCT) without overt side effects. This proof-of-principle suggests that allogeneic HSCT may represent a novel therapeutic approach to treat defined subgroups of IBD patients. In summary, our results suggest that IL10 receptor defects constitute monogenetic causes for severe, early-onset IBD patients, proving that a lack of IL10-mediated negative feedback signaling perturbs homeostasis of the intestinal immune system. Disclosures: No relevant conflicts of interest to declare.
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Young, Sarah, Keely McDonald, Rodney Newberry, and Lane Clarke. "EVALUATING THE ROLE OF GOBLET CELL ASSOCIATED ANTIGEN PASSAGES (GAPS) IN THE DEVELOPMENT OF MUCOSAL IMMUNE TOLERANCE IN THE CFTR KO INTESTINE." Inflammatory Bowel Diseases 27, Supplement_1 (January 1, 2021): S33. http://dx.doi.org/10.1093/ibd/izaa347.077.
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Abstract Greater than 70,000 individuals worldwide are living with the monogenetic disease cystic fibrosis (CF). The development of chronic intestinal inflammation, with clinical signs resembling inflammatory bowel disease-like conditions, is a common yet poorly understood occurrence in CF patients. This inflammation is typically neutrophilic in human and animal models with a heightened basal pro-inflammatory cytokine release. Prior research utilizing intestinal organoids (enteroids) cultured from Cftr knockout mice has shown that goblet cells in the CF mouse intestine demonstrate defective clearance of mucin granules and abnormal mucus retention. Goblet cell-associated antigen passages (GAPs), located in the small intestine and colon, deliver intraluminal antigens to antigen-presenting dendritic cells in the submucosa. This mechanism serves as an important step in the development and maintenance of tolerogenic dendritic cell populations expressing receptors to luminal antigens with involvement of regulatory T cell activation and release of IL-10. We hypothesized that mucus plugging of goblet cells in the CF intestine leads to defective GAP formation and a consequent decrease in the expansion of tolerogenic dendritic cells. To test this hypothesis, Cftrtm1Unc (Cftr KO) and wild type (WT) sex-matched littermate pairs (n=2) maintained on a commercially available liquid diet (Peptamen®) were anesthetized with ketamine/xylazine for a laparotomy to inject a luminal fluorescent 10kD dextran dye into the mid-jejunum. After 30 min, the mice were euthanized with CO2, and the intestine was collected for immunofluorescent staining to evaluate GAP formation. In the WT intestine, the dextran dye was observed within goblet cells outlined by CK18 immunofluorescence, a goblet cell marker. Punctate dextran dye was observed in the submucosa, suggestive of dendritic cell uptake. In contrast, the Cftr KO mice demonstrated defective GAP formation, i.e., without dye penetration of goblet cells, and the lack of punctate dextran fluorescence in the submucosa. To evaluate the population of tolerogenic dendritic cells, small intestinal segments from Cftr KO-WT sex-matched littermate pairs (3-female and 2-male pairs) were collected for FACS sorting of submucosal CD103+ (tolerogenic) and CD103- (pro-inflammatory) dendritic cells. The WT mice had a significantly higher population of CD103+ tolerogenic dendritic cells compared to the CF mice (WT: 20.5+/-2, CF: 9.2+/-3, P < 0.006). A trend towards an increase in CD103- dendritic cells was seen in the CF intestine. In summary, the CF mice were found to have defective intraluminal antigen transfer through the GAP pathway and a significant decrease in tolerogenic dendritic cells in the intestine.
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Poddar, Ujjal, Amita Aggarwal, Krishnegowda Jayalakshmi, Moinak Sen Sarma, Anshu Srivastava, Amit Rawat, and Surender Kumar Yachha. "Higher Prevalence of Monogenic Cause Among Very Early Onset Inflammatory Bowel Disease in Children: Experience From a Tertiary Care Center From Northern India." Inflammatory Bowel Diseases, January 3, 2023. http://dx.doi.org/10.1093/ibd/izac254.
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Abstract Background Very early-onset inflammatory bowel disease (VEO-IBD) is generally defined as onset of IBD at <6 years of age. Up to 20% of VEO-IBD may have a monogenic cause; hence, next-generation sequencing is highly recommended for diagnostic accuracy. There remains a paucity of data on VEO-IBD and the proportion of monogeneic causes in South Asia. We analyzed our tertiary care center experience of monogenic VEO-IBD from Northern India and compared them with nonmonogenic VEO-IBD to find out the factors that differentiate monogenic from nonmonogenic VEO-IBD. Methods All children (<18 years of age) diagnosed with IBD between January 2010 to July 2021 were analyzed along with the next-generation sequencing data and functional assays when available. Clinical features and outcomes between monogenic and nonmonogenic VEO-IBD were compared. Results A total of 200 children with a median age of 15.3 (range, 0.17-17) years, 125 of whom were boys, were diagnosed to have IBD during the study period. VEO-IBD was seen in 48 (24%) children. Monogenic IBD was diagnosed in 15 (31%) children with VEO-IBD and 7.5% of all IBD cases. The causes of monogenic VEO-IBD included disorders of the immune system (including interleukin-10 receptor mutations) in 12 and epithelial barrier dysfunction in 3. Features that differentiated monogenic from nonmonogenic VEO-IBD were neonatal IBD, presence of perianal disease, IBD unclassified, history of consanguinity and sibling death, wasting, and stunting (P < .05). There were 6 deaths. Conclusions One-third of participants were monogenic among Indian children with VEO-IBD, the highest proportion reported to date in the world. Next-generation (either exome or whole genome) sequencing should be recommended in a subset of VEO-IBD with neonatal onset, perianal disease, history of consanguinity and siblings’ death, wasting, stunting, and IBD unclassified phenotype for an early diagnosis and referral to an appropriate center for hematopoietic stem cell transplantation for a better outcome.
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Nambu, Ryusuke, and Aleixo M. Muise. "Advanced Understanding of Monogenic Inflammatory Bowel Disease." Frontiers in Pediatrics 8 (January 22, 2021). http://dx.doi.org/10.3389/fped.2020.618918.
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Inflammatory bowel disease (IBD) is a group of chronic disorders that cause relapsing inflammation in the gastrointestinal tract and comprise three major subgroups of Crohn's disease (CD), ulcerative colitis (UC), and IBD-unclassified (IBDU). Recent advances in genomic technologies have furthered our understanding of IBD pathogenesis. It includes differentiation rare monogenic disorders exhibiting IBD and IBD-like inflammation (monogenic IBD) from patients with the common polygenic form of IBD. Several novel genes responsible for monogenic IBD have been elucidated, and the number of reports has increased due to advancements in molecular functional analysis. Identification of these pathogenic genetic mutations has helped in elucidating the details of the immune response associated with gastrointestinal inflammation and in providing individualized treatments for patients with severe IBD that is often unresponsive to conventional therapy. The majority of monogenic IBD studies have focused on young children diagnosed <6 years of age (very early-onset IBD); however, a recent study revealed high prevalence of monogenic IBD in older children aged >6 years of age as well. Meanwhile, although patients with monogenic IBD generally show co-morbidities and/or extraintestinal manifestation at the time of diagnosis, cases of IBD developing as the initial symptom with unremarkable prodromal symptoms have been reported. It is crucial that the physicians properly match genetic analytical data with clinical diagnosis and/or differential diagnosis. In this review, we summarize the essential clues that may physicians make a correct diagnosis of monogenic disease, including classification, prevalence and clinical phenotype based on available literatures.
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Zheng, Hengqi B., M. Teresa de la Morena, and David L. Suskind. "The Growing Need to Understand Very Early Onset Inflammatory Bowel Disease." Frontiers in Immunology 12 (May 26, 2021). http://dx.doi.org/10.3389/fimmu.2021.675186.
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Very Early Onset Inflammatory Bowel Disease (VEO-IBD) represents a cohort of inflammatory bowel disease (IBD) patients diagnosed before 6 years of age. Unlike IBD diagnosed at older ages, VEO-IBD can be associated with underlying primary immunodeficiencies. VEO-IBD has been linked to monogenic variations in over 70 genes involved in multiple pathways of immunity. As sequencing technologies and platforms evolve and become readily available, an increasing number of genes linked to VEO-IBD have emerged. Although monogenic defects are rare in VEO-IBD, diagnosis of these variants can often dictate specific treatment. In this mini-review, we set out to describe monogenic variants previously characterized in multiple patients in the literature that contribute to VEO-IBD, diagnostic tools, unique treatment modalities for specific genetic diagnoses, and future directions in the field of VEO-IBD. Although this mini-review is by no means comprehensive of all the novel monogenic variants linked to VEO-IBD, we hope to provide relevant information that is readily accessible to clinicians and educators.
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Jans, Deborah, and Isabelle Cleynen. "The genetics of non-monogenic IBD." Human Genetics, January 31, 2023. http://dx.doi.org/10.1007/s00439-023-02521-9.
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Illig, David, and Daniel Kotlarz. "Dysregulated inflammasome activity in intestinal inflammation – Insights from patients with very early onset IBD." Frontiers in Immunology 13 (November 29, 2022). http://dx.doi.org/10.3389/fimmu.2022.1027289.
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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.
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Hosokawa, Takahiro, Yutaka Tanami, Yumiko Sato, Ryusuke Nambu, Itaru Iwama, and Eiji Oguma. "Role of ultrasound in the diagnosis of very early-onset inflammatory bowel disease in children: a report of three cases." Medical Ultrasonography, November 3, 2021. http://dx.doi.org/10.11152/mu-3273.
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Very early-onset inflammatory bowel disease (VEO-IBD) is defined as IBD onset before 6 years of age and some cases are caused by unique monogenic disorders that require specific treatments such as stem cell transplantation. We identified three children with VEO-IBD of whom two had monogenic disorders. In cases 1 and 2, ultrasound revealed isolated colonic distribution and the loss of wall stratification. In case 3, mesentery inflammation was evident. Bowel ultrasound showed variable findings due to differences in the inflammation distribution within the bowel. In order to diagnose VEO-IBD, sonographersshould carefully evaluate the intestinal wall thickness and stratification and the distribution of inflammation in the intestine and mesentery. These findings may aid the diagnosis of VEO-IBD.
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Collen, Lauren V., David Y. Kim, Michael Field, Ibeawuchi Okoroafor, Gwen Saccocia, Sydney Driscoll Whitcomb, Julia Green, et al. "Clinical Phenotypes and Outcomes in Monogenic versus Non-Monogenic Very Early Onset Inflammatory Bowel Disease." Journal of Crohn's and Colitis, April 2, 2022. http://dx.doi.org/10.1093/ecco-jcc/jjac045.
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Abstract Background and Aims Over 80 monogenic causes of very early onset inflammatory bowel disease (VEOIBD) have been identified. Prior reports of the natural history of VEOIBD have not considered monogenic disease status. The objective of this study is to describe clinical phenotypes and outcomes in a large single-center cohort of patients with VEOIBD and universal access to whole exome sequencing (WES). Methods Patients receiving IBD care at a single center were prospectively enrolled in a longitudinal data repository starting in 2012. WES was offered with enrollment. Enrolled patients were filtered by age of diagnosis <6 years to comprise VEOIBD cohort. Monogenic disease was identified by filtering proband variants for rare, loss-of-function or missense variants in known VEOIBD genes inherited according to standard Mendelian inheritance patterns. Results This analysis included 216 VEOIBD patients, followed for a median of 5.8 years. Seventeen patients (7.9%) had monogenic disease. Patients with monogenic IBD were younger at diagnosis and were more likely to have Crohn’s disease phenotype with higher rates of stricturing and penetrating disease and extraintestinal manifestations. Patients with monogenic disease were also more likely to experience outcomes of ICU hospitalization, gastrostomy tube, total parenteral nutrition use, stunting at 3-year follow-up, hematopoietic stem cell transplant, and death. Forty-one patients (19.0%) had infantile-onset disease. After controlling for monogenic disease, patients with infantile-onset IBD did not have increased risk for most severity outcomes. Conclusions Monogenic disease is an important driver of disease severity in VEOIBD. WES is a valuable tool in prognostication and management of VEOIBD.
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Sasahara, Yoji, Takashi Uchida, Tasuku Suzuki, and Daiki Abukawa. "Primary Immunodeficiencies Associated With Early-Onset Inflammatory Bowel Disease in Southeast and East Asia." Frontiers in Immunology 12 (January 13, 2022). http://dx.doi.org/10.3389/fimmu.2021.786538.
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BackgroundCauses of early-onset inflammatory bowel disease (IBD) vary, and primary immunodeficiency diseases (PIDs) are associated with early-onset IBD as monogenic disorders.AimThis review investigates the prevalence, clinical manifestation, genetic profile, and treatment of patients with early-onset IBD in Southeast and East Asia.MethodsA systemic review of articles reporting PID patients associated with early-onset IBD in Southeast and East Asia was conducted.ResultsThe prevalence of PID associated with IBD was higher than that reported in western nations, and the frequency of patients with bloody stools as an early symptom was relatively higher in monogenic diseases. A total 13 (12.0%) of 108 patients with early-onset IBD were diagnosed as PID by exome sequencing and targeted gene panel analysis in Japan, including four patients with XIAP, three with IL10RA, and two or one patient with other gene mutations. In addition, ten patients were reported as having IL-10 receptor alpha (IL-10RA) deficiency in China and Hong Kong. Allogeneic hematopoietic stem cell transplantation was performed in patients with X-linked inhibitor of apoptosis deficiency, IL-10RA deficiency, or other PID as a curative treatment, and the preferable outcome of reduced-intensity conditioning and complete resolution of IBD symptoms and dysbiosis were achieved.ConclusionComprehensive molecular diagnosis has been widely applied to screen for patients with PID-associated IBD in Southeast and East Asia. These results contributed to the awareness of monogenic PID in early-onset IBD patients and their differences in clinical manifestations and genetic profiles compared to the patients in western counties.
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Bader-Meunier, Brigitte, Andreia Luís Martins, Fabienne Charbit-Henrion, Ulrich Meinzer, Alexandre Belot, Laurence Cuisset, Albert Faye, et al. "Mevalonate Kinase Deficiency: A Cause of Severe Very-Early-Onset Inflammatory Bowel Disease." Inflammatory Bowel Diseases, September 15, 2021. http://dx.doi.org/10.1093/ibd/izab139.
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Abstract Mevalonate kinase deficiency should be considered in patients with severe very-early-onset inflammatory bowel disease (IBD), especially in patients with a history of recurrent or chronic fever, peritoneal adhesions, and atypical IBD pathology. Anti-interleukin-1 therapy may be efficacious in these patients with monogenic very-early-onset IBD.
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Ouahed, Jodie. "Expanding Contributions of Monogenic Very Early Onset Inflammatory Bowel Disease." Inflammatory Bowel Diseases, September 15, 2021. http://dx.doi.org/10.1093/ibd/izab145.
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Abstract Currently over 70 genes known to be causative in very early onset inflammatory bowel disease (VEOIBD) have been identified. In the current issue of Inflammatory Bowel Diseases, 2 articles describing monogenetic forms of VEOIBD are highlighted. One describes a patient with life-threatening VEOIBD and a mutation in ITGA6, illustrating the importance of the epithelial barrier in maintaining mucosal homeostasis. The other describes the presentation and management of 10 patients with VEOIBD secondary to damaging mutations in MVK, resulting in mevalonate kinase deficiency. Though most monogenic causes of VEOIBD remain “private,” understanding the different categories of pathways affected in children with VEOIBD is critical and has already resulted in invaluable insight in the management of patients with VEOIBD and may hold strong implications for the care of IBD overall.
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Krawiec, Paulina, Agnieszka Pawłowska-Kamieniak, and Elżbieta Pac-Kożuchowska. "Interleukin 10 and interleukin 10 receptor in paediatric inflammatory bowel disease: from bench to bedside lesson." Journal of Inflammation 18, no. 1 (March 10, 2021). http://dx.doi.org/10.1186/s12950-021-00279-3.
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Abstract Background The differences between adults and children in inflammatory bowel disease (IBD) phenotype, severity, complications, co-morbidities, and response to the therapy resulted in the extraction of paediatric IBD. It has been revealed that the substantial role in the development of IBD in children under 6 years of age plays a single genetic mutation (monogenic IBD). On the other hand, in older children and adolescents IBD is usually associated with number of interactions between susceptibility loci (polygenic IBD). Main body Until now there have been described about 60 monogenic defects which affect the variety of immune mechanisms in IBD pathogenesis including epithelial barrier, function of neutrophil granulocytes and phagocytes, T- and B-cell selection and activation, immune inhibitory mechanisms, or apoptosis. Il-10 is an anti-inflammatory cytokine which modulates innate and adaptive immunity affecting expression of pro-inflammatory molecules and function of the variety of immune cells. Patients with identified defects in Il-10 pathway manifest with life-threating colitis with perianal lesions which occurs within first months of life. Allogenic hematopoietic stem cell transplantation is curative therapy in children with Il-10 signalling defects. Conclusion Clinical awareness of Il-10 signalling defects enables early recognition and prompt management of the disease.
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Ouahed, Jodie Deborah. "Understanding inborn errors of immunity: A lens into the pathophysiology of monogenic inflammatory bowel disease." Frontiers in Immunology 13 (September 29, 2022). http://dx.doi.org/10.3389/fimmu.2022.1026511.
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Inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the gastrointestinal tract, including Crohn’s disease, ulcerative colitis and inflammatory bowel disease-undefined (IBD-U). IBD are understood to be multifactorial, involving genetic, immune, microbial and environmental factors. Advances in next generation sequencing facilitated the growing identification of over 80 monogenic causes of IBD, many of which overlap with Inborn errors of immunity (IEI); Approximately a third of currently identified IEI result in gastrointestinal manifestations, many of which are inflammatory in nature, such as IBD. Indeed, the gastrointestinal tract represents an opportune system to study IEI as it consists of the largest mass of lymphoid tissue in the body and employs a thin layer of intestinal epithelial cells as the critical barrier between the intestinal lumen and the host. In this mini-review, a selection of pertinent IEI resulting in monogenic IBD is described involving disorders in the intestinal epithelial barrier, phagocytosis, T and B cell defects, as well as those impairing central and peripheral tolerance. The contribution of disrupted gut-microbiota-host interactions in disturbing intestinal homeostasis among patients with intestinal disease is also discussed. The molecular mechanisms driving pathogenesis are reviewed along with the personalized therapeutic interventions and investigational avenues this growing knowledge has enabled.
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Shaul, Eliana, Máire A. Conrad, Noor Dawany, Trusha Patel, Megan C. Canavan, Alyssa Baccarella, Sarah Weinbrom, Daniel Aleynick, Kathleen E. Sullivan, and Judith R. Kelsen. "Canakinumab for the treatment of autoinflammatory very early onset- inflammatory bowel disease." Frontiers in Immunology 13 (September 20, 2022). http://dx.doi.org/10.3389/fimmu.2022.972114.
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IntroductionTherapeutic 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.MethodsThis 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.ResultsNineteen 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.ConclusionCanakinumab 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.