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Mucosal manifestations of immunodeficiencies
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Scott Snapper, Jodie Ouahed, Luigi D. Notarangelo
Over the past decade, an international effort focused on next-generation sequencing approaches has led to a marked increase in the identification of monogenic causes for inflammatory bowel diseases in infants and very young children (https:// veoibd.org). The majority of these monogenic defects result from a primary or secondary immune defect (with or without concomitant involvement of other affected cell populations). A summary of genes identified with mutations leading to very early onset inflammatory bowel disease (VEOIBD) is outlined in Table 33.4.
Introduction to the special issue on gastroenterology
Published in Paediatrics and International Child Health, 2019
Very early-onset inflammatory bowel disease (VEO-IBD) is defined as that occurring in children under 6 years of age and a subset are those who develop symptoms when under 2 years of age. Xu Teng and co-authors present a case series of six infants under 2 years of age who presented with VEO-IBD in Liaoning Province, China. The age range at diagnosis was 1–3 months and the clinical features were compatible with Crohn disease. Interleukin-10 receptor mutations were detected in five patients. Three patients had compound mutations and two of them died of suspected septicaemia. Haematopoietic stem cell transplantation is considered life-saving in severe cases and one infant who was being prepared for it unfortunately died before it could be administered.
Very-Early Onset Chronic Active Colitis with Heterozygous Variants in LRBA1 and CARD11, a Case of “Immune TOR-Opathies”
Published in Fetal and Pediatric Pathology, 2023
Mai He, Amanda Wong, Kimberly Sutton, Mercia Jeanne Bezerra Gondim, Charles Samson
Colitis has a broad spectrum of etiologies. In pediatric patients, causes of colitis include inflammatory bowel disease (IBD), infection, autoimmune disease, immununodeficiency, drug effects and ischemia [1]. IBD is a chronic inflammatory condition caused by complex interactions between the host immune system and intestinal microbiota in genetically susceptible individuals [2]. Conventional IBD presents as a polygenic, multifactorial disease whose etiology involves a genetic predisposition and environmental factors. Genome-wide associated studies have identified over 163 genetic loci associated with IBD with each gene conferring a minor contribution toward disease development [3]. A small subset of IBD cases, typically seen in young or very young pediatric patients (very early onset inflammatory bowel disease (VEO-IBD)), occurs as a result of single gene defects [4]. The gene variants leading to so-called “monogenic IBD” are often associated with primary immunodeficiency syndromes [4]. As these variants may not be detected by genome-wide association studies, their identification and characterization often relies on case reports or series [5]. Here we report a case of VEO-IBD in a patient harboring mutations in the immune-related genes LRBA1 and CARD11. Variants of these 2 genes were reported to be involved in primary immune deficiency. Determining which pathologic variants are involved may allow potential targeted therapy. Recently, some primary immunodeficiency were grouped together as “immune TOR-opathies” by the shared abnormal mTOR signal transduction pathway due to pathogenic variants of genes involving in this pathway leading to immune dysfunction, such as LRBA and CARD11 as seen in current case [6]. Targeted therapy could be directed to the pathway in addition to individual genes with pathogenic variants.
A 2020 update on the use of genetic testing for patients with primary immunodeficiency
Published in Expert Review of Clinical Immunology, 2020
Ivan K. Chinn, Jordan S. Orange
A few studies (all from LC cohorts) in children with very early onset inflammatory bowel disease (VEO-IBD) [56] suggest noninferiority between gene panel testing and WES in terms of diagnostic rates. One study from France sequenced 177 children using gene panels or WES [57]. Of these 177 cases, 51 received WES first, achieving molecular diagnoses for 10 (20%). All 51 patients had been prescreened with functional testing to exclude obvious diagnoses. The 41 undiagnosed patients were then tested using a gene panel. Interestingly, this additional step secured further genetic diagnoses (LRBA deficiency and 2 cases of NCF1 deficiency). In these 3 patients, gene panel testing captured large deletions in the genes that were not identified by WES. Meanwhile, the remaining 126 patients were evaluated using only gene panel testing. Altogether, the diagnostic rate for the 66 gene panel test was 14% (24 of 167). The authors noted that the performance of the gene panel was even greater (13/49 = 27%) when conducted without functional test prescreening and argued that the panel testing outperformed WES. The WES and gene panel data are allocated in separate rows in Figures 1 and 4. Meanwhile, in a small VEO-IBD cohort from China, 16 patients were tested by ‘Mendeliome’ or full WES analyses [58]. The diagnostic rate was observed to be 56% (9 cases), the highest reported to date. On the other hand, 2 separate studies originating from the United Kingdom show disparate diagnostic rates with use of WES for VEO-IBD. The first studied 62 infants and used single gene sequencing, a 40 gene panel, and then WES, if necessary [59]. This approach led to molecular diagnoses in 19 individuals (31%). Alternately, in the second study, all 145 children were assessed using only WES, resulting in a diagnostic rate of 4% (6 likely genetic explanations) [60]. The large discrepancy could be partially explained by the differences in testing algorithms and in the fact that the first study investigated solely patients less than 2 years of age (infantile onset) while the second included children up to 6 years old.