The diagnostic approach to monogenic very early onset inflammatory bowel disease

Abstract

Patients with a diverse spectrum of rare genetic disorders can present with inflammatory bowel disease (monogenic IBD). Patients with these disorders often develop symptoms during infancy or early childhood, along with endoscopic or histological features of Crohn's disease, ulcerative colitis, or IBD unclassified. Defects in interleukin-10 signaling have a Mendelian inheritance pattern with complete penetrance of intestinal inflammation. Several genetic defects that disturb intestinal epithelial barrier function or affect innate and adaptive immune function have incomplete penetrance of the IBD-like phenotype. Several of these monogenic conditions do not respond to conventional therapy and are associated with high morbidity and mortality. Due to the broad spectrum of these extremely rare diseases, a correct diagnosis is frequently a challenge and often delayed. In many cases, these diseases cannot be categorized based on standard histological and immunologic features of IBD. Genetic analysis is required to identify the cause of the disorder and offer the patient appropriate treatment options, which include medical therapy, surgery, or allogeneic hematopoietic stem cell transplantation. In addition, diagnosis based on genetic analysis can lead to genetic counseling for family members of patients. We describe key intestinal, extraintestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation. In addition, we provide approaches for identifying patients likely to have these disorders. We also discuss classic approaches to identify these variants in patients, starting with phenotypic and functional assessments that lead to analysis of candidate genes. As a complementary approach, we discuss parallel genetic screening using next-generation sequencing followed by functional confirmation of genetic defects.

Keywords: Crohn’s Disease; Genetics; IBD Unclassified; Immunodeficiency; Indeterminate Colitis; Inflammatory Bowel Disease; Next-Generation Sequencing; Pediatrics; Ulcerative Colitis; Unclassified Colitis; Whole Exome Sequencing.

Figure 1. Age of Onset of IBD-like Symptoms in Patients with Monogenic Diseases

Multiple genetic defects are summarised in the group of atypical SCID, Hoyeraal Hreidarsson Syndrome, chronic granulomatous disease, and Hermansky Pudlak syndrome. By comparison, an unselected IBD population is presented (Oxford IBD cohort study; pediatric and adult referral based IBD cohort, n=1605 patients comprising CD, UC and IBDU). Symbols represent individual patients. Bar represent the age range of case series when individual data are not available. Age range of infantile IBD, VEOIBD, EOIBD and Montreal/Paris classification A1a, A1b, A2 and A3 are shown for reference. Age of onset data refer to references provided in table 2. Additional references for disease subgroups are provided in supplemental information to Figure 1.

Figure 2. Diagnosis of VEOIBD

Patient and family history, physical examination, endoscopic investigations, imaging as well as limited biochemistry and microbiology/virology tests are required to establish the diagnosis of IBD, assess disease localization and behavior, and determine inflammatory activity. If there is doubt, those tests can contribute to exclude the much more frequent gastrointestinal infections and non-IBD immune responses towards dietary antigens. Cow’s milk protein allergy can present with enteropathy and colitis and coeliac disease can mimic autoimmune enteropathies. Fecal calprotectin can be helpful but may be increased even in healthy infants. The current diagnostic strategy to investigate a monogenic cause of IBD-like intestinal inflammation is largely based on restricted functional screening followed by genetic confirmation. A restricted set of laboratory tests are needed to propose candidate genes of the most common genetic defects for subsequent limited sequencing. As a complementary approach, genetic screening for IBD-causative rare variants using next generation sequencing might be followed by limited functional confirmatory studies. The complexity of problems in these children requires an interdisciplinary support including pediatric gastroenterologists, immunologists, geneticists and infectious disease specialists. CBC complete blood count, CRP C-reactive protein, ESR erythrocyte sedimentation rate, CMPA cows milk protein allergy.