Crowley E.*1, Elkadri A.2, Warner N.3, Zhang S.4, Horowitz J.4, Staples J.4, Overton J.4, Dewey F.4, Gonzaga-Jauregui C.4, Griffiths A.1, Muise A.3,5
1Hospital for Sick Children, Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, Toronto, Canada 2Medical College of Wisconsin, Department of Gastroenterology, Hepatology & Nutrition, Milwaukee, United States 3Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Inflammatory Bowel Disease Center and Cell Biology Program, Toronto, Canada 4Regeneron Pharmaceuticals Inc, Regeneron Genetics Center, New York, United States 5University of Toronto, Institute of Medical Science, and Department of Biochemistry, Toronto, Canada
Inflammatory bowel disease (IBD) has a multifactorial aetiology, with complex interactions between genetic and environmental factors. Recent studies have suggested an increasing spectrum of human monogenic diseases that can present with IBD-like intestinal inflammation. Mutations in X-linked inhibitor of apoptosis protein (XIAP) result in an X-linked recessive disorder whose phenotype is highly heterogeneous with respect to age at presentation and severity of disease and is poorly understood. Due to X chromosome inactivation heterozygous female carriers can also be symptomatic. Although a severe phenotype with infantile onset disease and predisposition to hemophagocytic lymphohistiocytosis (HLH) or X-linked lymphoproliferative syndrome (XLP) is recognized, one recent study has reported XIAP variants in 4% of male pediatric IBD patients.
1250 individual Hospital for Sick Children pediatric IBD patients have undergone whole exome sequencing in collaboration with the Regeneron Genetics Center. Within the cohort, 39 variants were called across the XIAP gene – 29 of which were high quality, rare (maf <0.01), protein coding variants predicted to be deleterious. 13 of these variants were present in 15 affected patients all of which have been Sanger validated. Case notes were retrospectively reviewed to ascertain phenotypic features of IBD in these 15 pediatric patients.
Of the 15 patients (80% males), 14 (93%) were diagnosed with IBD. 13 (92%) of these with Crohn's disease and 1 (7%) with ulcerative colitis. At the time of diagnosis, CD involved small bowel and colon (L3) in 50% children, colon (L2) in 14% and ileum (L1) in 28%. 21% of the children had perianal disease, with a further 21% having extra intestinal manifestations of IBD (erythema nodosum, fevers, large joint arthritis). A further infant was diagnosed with primary HLH and received a bone marrow transplant. This infant did have some gastrointestinal involvement with diffuse damage noted in the colonic mucosa and frequent apoptotic cells. 14% of these children had a first degree relative with IBD. 21% underwent ileocaecal resection with 57% progressing to biologic therapy. Patient samples, monocytes, are now undergoing a functional test to determine tumour necrosis factor (TNF) production of monocytes in response to NOD2 stimulation by muramyl dipeptides (L18-MDP) for the functional diagnosis of XIAP deficiency.
Analysis of this large pediatric cohort confirms the highly varied phenotypic spectrum of IBD associated with XIAP mutations. Functional studies may more completely explain the observed variation.