Clinical Phenotypes and Outcomes in Monogenic Versus Non-monogenic Very Early Onset Inflammatory Bowel Disease

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.

Phenotype and outcomes of very early onset and early onset inflammatory bowel diseases in a Montreal pediatric cohort

“…This is in line with most published cohorts where VEO-IBD consisted of 3%-5.8% of patients under 18-year-old (8)(9)(10). The frequency of CD was higher in older patients, whereas VEO-IBD patients were more frequently diagnosed with IBD-U, which also compared with the published cohorts (8,10,12,13).…”

“…Thus, most cases of VEO-IBD are not associated with the identification of monogenic disorders and are underreported in the literature compared to monogenic IBD. Only a few cohorts have described the phenotype at diagnosis and treatments of VEO-IBD (4,(8)(9)(10)(11)(12)(13). Detailed histological and radiologic findings are even more sparsely reported in the literature (14,15).…”

Infantile-onset inflammatory bowel disease has variable long-term outcomes

“…This is similar to the proportion of 59% (10/17), in the Japanese cohort of VEO-IBD (15) but lower than 90% (9/10), reported among patients who were diagnosed with IBD during their first year of life (5). Notably, patients with monogenic disease were also described to have higher TPN requirements (34). In studies of older IBD patients at older ages (35), the TPN requirement for TPN was much lower.…”

Understanding inborn errors of immunity: A lens into the pathophysiology of monogenic inflammatory bowel disease

“…Indeed, biologics are only effective in 25.5% of patients with monogenic IBD ( 9 ). Moreover, among VEOIBD patients, monogenic disease is a driver of disease severity, including death ( 10 ). The growing number of IEI manifesting with IBD, and interaction with the microbiome permits a deeper understanding of the molecular mechanisms driving intestinal inflammation.…”

“…Monogenic IBD is predominantly identified in patients diagnosed prior to 6 years old, known as very early onset IBD (VEOIBD) ( 9 ). Two large North American centers identified the prevalence of monogenic VEOIBD to be roughly 8% ( 10 , 11 ), but this varies depending on the population studied ( 12 , 13 ).…”