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. 2022 Sep 8;16(9):1380-1396.
doi: 10.1093/ecco-jcc/jjac045.

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

Lauren V Collen  1 , David Y Kim  1 , Michael Field  1 , Ibeawuchi Okoroafor  1 , Gwen Saccocia  1 , Sydney Driscoll Whitcomb  1 , Julia Green  1 , Michelle Dao Dong  1 , Jared Barends  1 , Bridget Carey  1 , Madison E Weatherly  1 ; Regeneron Genetics centre; Shira Rockowitz  2 , Piotr Sliz  2   3 , Enju Liu  1   4 , Alal Eran  5   6   7 , Leslie Grushkin-Lerner  1 , Athos Bousvaros  1 , Aleixo M Muise  8   9   10 , Christoph Klein  11 , Vanessa Mitsialis  1   12 , Jodie Ouahed  1 , Scott B Snapper  1   12
Affiliations

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

Lauren V Collen et al. J Crohns Colitis. .

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-centre cohort of patients with VEOIBD and universal access to whole exome sequencing [WES].

Methods: Patients receiving IBD care at a single centre 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 a 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 intensive care unit [ICU] hospitalisation, gastrostomy tube, total parenteral nutrition use, stunting at 3-year follow-up, haematopoietic stem cell transplant, and death. A total of 41 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.

Keywords: Very early onset inflammatory bowel disease; disease course; whole exome sequencing.

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Figures

Figure 1.
Figure 1.
Distribution of monogenic VEOIBD by age of diagnosis and monogenic aetiology identified. [A] Proportion of patients with monogenic VEOIBD by age at diagnosis. Monogenic VEOIBD was identified in 22.0% of patients with infantile-onset IBD compared with 4.6% of patients with IBD diagnosed at age 2 to <6 years. [B] Further stratification of infantile-onset disease group identified monogenic VEOIBD in 42.9% of patients diagnosed at <6 months, 41.7% diagnosed from 6 months to <12 months, and 4.5% diagnosed from 12 to <24 months. [C] Distribution of the 17 cases of monogenic VEOIBD identified in this cohort. IL10 signaling defects were most common, followed by chronic granulomatous disease, IPEX syndrome, and trichohepatoenteric syndrome. VEOIBD, very early onset inflammatory bowel disease.
Figure 1.
Figure 1.
Distribution of monogenic VEOIBD by age of diagnosis and monogenic aetiology identified. [A] Proportion of patients with monogenic VEOIBD by age at diagnosis. Monogenic VEOIBD was identified in 22.0% of patients with infantile-onset IBD compared with 4.6% of patients with IBD diagnosed at age 2 to <6 years. [B] Further stratification of infantile-onset disease group identified monogenic VEOIBD in 42.9% of patients diagnosed at <6 months, 41.7% diagnosed from 6 months to <12 months, and 4.5% diagnosed from 12 to <24 months. [C] Distribution of the 17 cases of monogenic VEOIBD identified in this cohort. IL10 signaling defects were most common, followed by chronic granulomatous disease, IPEX syndrome, and trichohepatoenteric syndrome. VEOIBD, very early onset inflammatory bowel disease.
Figure 1.
Figure 1.
Distribution of monogenic VEOIBD by age of diagnosis and monogenic aetiology identified. [A] Proportion of patients with monogenic VEOIBD by age at diagnosis. Monogenic VEOIBD was identified in 22.0% of patients with infantile-onset IBD compared with 4.6% of patients with IBD diagnosed at age 2 to <6 years. [B] Further stratification of infantile-onset disease group identified monogenic VEOIBD in 42.9% of patients diagnosed at <6 months, 41.7% diagnosed from 6 months to <12 months, and 4.5% diagnosed from 12 to <24 months. [C] Distribution of the 17 cases of monogenic VEOIBD identified in this cohort. IL10 signaling defects were most common, followed by chronic granulomatous disease, IPEX syndrome, and trichohepatoenteric syndrome. VEOIBD, very early onset inflammatory bowel disease.
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