Case 16 Discussion
Please remember to do the post-case question after this page
Learning Objectives
- Describe the planning behind the transition and ultimate transfer of patients from pediatric to adult GI clinic.
- List the healthcare maintenance considerations for young adults with pediatric-onset IBD.
- Discuss when it is appropriate to consider genetic testing for monogenic causes of IBD.
IBD EPAs Addressed:
EPA 1: Classify Inflammatory Bowel Disease Phenotype, Disease Activity, and Extraintestinal Manifestations
EPA 7: Manage Inflammatory Bowel Disease in Special Populations
EPA 8: Recognize the Importance of Psycho-behavioral Health in Inflammatory Bowel Disease and Implement Psychosocial Support Strategies
EPA 10: Apply Preventive Health Strategies for Inflammatory Bowel Disease Patients in Accordance With Guidelines
Patients diagnosed at 6 years of age or younger are classified as having Very Early Onset-IBD (VEO-IBD). These patients require a unique set of considerations in diagnosis and treatment since a subset may have enteritis or colitis consistent with IBD, but driven by an underlying genetic variant, specifically abnormalities causing primary immunodeficiencies or epithelial defects. Causes are typically identified through targeted sequencing studies or whole exome sequencing (Kelsen et al JPGN 2020; Muise AM et al. Gastroenterology. 2012; Benchimol EI et al. Gut. 2009; Glocker E et al. Cell Mol Life Sci. 2012).
Although there is a broad phenotypic range in this population, VEO-IBD tends to follow a more severe and refractory course than older onset pediatric IBD or adult-onset IBD. Approximately 40% of children with VEO-IBD have extensive colonic disease at presentation suggestive of Ulcerative Colitis but can evolve over time to demonstrate features consistent with Crohn’s Disease, including granulomas on histology or small bowel involvement.
Several pathways have been recognized as causes of genetically driven IBD, including disorders of epithelial barrier function (ADAM17 deficiency, X-linked ectodermal dysplasia and immunodeficiency, dystrophic epidermolysis bullosa), phagocyte bacterial killing (chronic granulomatous disease), hyper- or autoimmune inflammatory pathways (IL-10/IL-10R defects; Hyper IgD syndrome, Familial Mediterranean Fever, X-linked lymphoproliferative syndrome), and development and function of the adaptive immune system (agammaglobulinemia, common variable immune deficiency (CVID), IgA deficiency, Wiskott-Adrich Syndrome) (Worthey EA et al. Genet Med. 2011; Ruemmele FM et al. J Pediatr Gastroenterol Nutr. 2006; Begue B et al. Am J Gastroenterol. 2011; Uhlig HH. Gut. 2013; Durandy A et al. Nat Rev Immunol. 2013). The testing for these immune deficiencies is now relatively straightforward and should be performed on all VEO-IBD patients to assess for safety of common IBD treatments (such as avoiding anti-TNFs in chronic granulomatous disease), and understanding risk of sequelae (such as high risk of Hemophagocytic Lymphohistiocytosis (HLH) in patients with XIAP deficiency). Testing can also assist in exploring treatments targeting specific underlying immunologic defects, including medications like IL-1 antagonists or interventions such as hematopoietic stem cell transplantation (HSCT).
Documentation of the family history should be more extensive in VEO-IBD, and it is important to recognize that many immune dysregulation conditions do not have the same phenotype in all affected family members. Therefore, inheritance patterns and a wide range of conditions including HLH, arthritis, susceptibility to infections, and malignancy should be noted. Other findings suggestive of underlying primary immunodeficiencies include physical exam findings such as splenomegaly, adenopathy (Canna SW et al. J Allergy Clin Immunol. 2017; Murthy A et al. Immunity. 2012); laboratory abnormalities such as neutropenia or leukocytosis (in leukocyte adhesion deficiency); histologic features such as eosinophilic infiltrates, villous atrophy, apoptosis, and increased intraepithelial lymphocytes (Yang TB et al. Nat Commun. 2017; Ensari A et al Virchows Arch. 2018). A multidisciplinary approach is necessary in the setting of VEO-IBD where understanding the underlying genetic causes of disease may facilitate treatments guided toward the specific defect, outside of FDA-approved biologics for IBD (i.e., IL-1 antagonists or HSCT).