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Consequences of Identifying XIAP Deficiency in an Adult Patient With Inflammatory Bowel Disease

2018; Elsevier BV; Volume: 155; Issue: 1 Linguagem: Inglês

10.1053/j.gastro.2018.03.069

1528-0012

Maria Quaranta, Rachel Wilson, Eva Serra, Sumeet Pandey, Tobias Schwerd, Kimberly Gilmour, Paul Klenerman, Fiona Powrie, Satish Keshav, Simon Travis, Carl A. Anderson, Holm H. Uhlig,

Helicobacter pylori-related gastroenterology studies

In some patients with extreme phenotypes of inflammatory bowel disease (IBD; in particular in those with infantile or very early onset IBD with <6 years of onset, nonresponsiveness to therapy, or extraintestinal manifestations), Mendelian forms of IBD have been described.1Uhlig H.H. et al.Gastroenterology. 2014; 147: 990-1007 e3Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar To identify patients with Mendelian disease-associated IBD in a cohort with age at diagnosis between 7 and 40 years of age, we screened for 59 Mendelian forms of IBD by exome sequencing across 503 patients with IBD with severe disease, as indicated by need for intestinal surgery and/or therapy progression to biologics (Supplementary Material). This enriched the group of patients toward those with a diagnosis of Crohn's disease: 73% Crohn's disease and 26% ulcerative colitis, 1% IBD unclassified. Owing to the selection criteria, rates of surgery and exposure to biological anti-tumor necrosis factor therapy (in particular adalimumab and infliximab) were higher compared with the overall Oxford IBD cohort (67% vs 26% and 74% vs 27%, respectively; P < .05), reflecting an enrichment of patients with acute severe ulcerative colitis (30% of patients with ulcerative colitis) or Crohn's-associated fistulizing disease, abscesses, or strictures. We identified 1 patient with XIAP deficiency. The patient originally presented at 11 years of age with diarrhea, abdominal pain, weight loss, and perianal disease. Inflammatory and penetrating disease necessitated multiple resections of the colon and small bowel over the following 30 years. During the clinical course he required multiple hospital admissions totaling >1000 days in hospital for the treatment of recurrent inflammation, fistulation, and perianal disease, needing multiple operations (Figure 1A, B). Response to immunomodulator and biologic anti-tumor necrosis factor therapies was insufficient to control the disease. The outcome was a high jejunostomy with T (NM_001167.3) results in a stop codon p.R49* leading to a truncated protein, which completely abrogates XIAP protein expression and NOD2 signaling (Figure 1C-E). The genetic diagnosis of XIAP deficiency meant that small bowel transplantation was deferred until after hematopoietic allogeneic stem cell transplantation, which is currently under discussion. XIAP deficiency is a recognized Mendelian disorder causing IBD, with many patients presenting with Crohn's disease-like granulomatous intestinal inflammation.2Rigaud S. Fondaneche M.C. et al.Nature. 2006; 444: 110-114Crossref PubMed Scopus (558) Google Scholar, 3Worthey E.A. Mayer A.N. et al.Genetics Med. 2011; 13: 255-262Abstract Full Text Full Text PDF PubMed Scopus (574) Google Scholar, 4Speckmann C. et al.Clin Immunol. 2013; 149: 133-141Crossref PubMed Scopus (124) Google Scholar, 5Zeissig Y. Petersen B.S. et al.Gut. 2014; 64: 66-76Crossref PubMed Scopus (113) Google Scholar Most recently, Amininejad et al6Amininejad L. Charloteaux B. et al.Gastroenterology. 2018; 154: 2165-2177Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar have described an increased burden of rare coding XIAP variants in patients with IBD without an immunodeficiency phenotype. Several variants described previously do not cause a complete loss of the XIAP protein function. The XIAP-deficient patient identified herein illustrates the exceptional clinical impact that a genetic diagnosis provides. It illustrates the magnitude of health care use by patients with Mendelian disorders, the potential to seek curative approaches such as allogeneic hematopoietic stem cell transplantation, and the opportunity to prevent suffering or unnecessary procedures that collectively have major implications for health care. In the case of the XIAP-deficient patient alone, over the 4-year period between 2013 and 2017, hospital-related costs were >£400,000, excluding the costs associated with home parental nutrition at £70,000 per year and a potential small bowel transplant, which would have been likely fatal in the setting of XIAP deficiency (UK cost of £250,000). Our study has several implications. Clearly, the number of patients needed to screen to identify 1 patient with a Mendelian disorder is high. The diagnostic yield of Mendelian disorders in this older population was low compared with patients with infantile IBD. However, the clinical consequences and opportunities of finding such diagnoses for the individual patient are enormous, even if established at an adult age with decades of delay. In the case of XIAP deficiency, where a proportion of patients present with a dominant IBD phenotype rather than an immunodeficiency phenotype, genomic screening with subsequent functional validation7Ammann S. et al.Clin Exp Immunol. 2014; 176: 394-400Crossref PubMed Scopus (66) Google Scholar is the diagnostic approach of choice. The costs of genomic-screening (either via targeted panel sequencing or via exome/genome sequencing and initial virtual panel analysis) in patients with a severe IBD phenotype represent only a fraction of the health care costs of those patients and is, therefore, justified. Because an early, precise genetic diagnosis may avoid decades of disease progression, failing therapies, and debilitation, early screening of patients for known disease-causing highly penetrant variants might be rational and even cost effective but—as in many other disorders8Schwarze K. et al.Genet Med. 2018 Feb 15; ([Epub ahead of print])PubMed Google Scholar—there is need for a formal analysis of health care use, including cost–benefit analyses in different disease stages. The authors thank all patients and blood donors for participation in this study. The authors acknowledge the contribution of the BRC Gastrointestinal Illness Biobank, which is supported by the NIHR Oxford Biomedical Research Centre (11/YH/0020, 16/YH/0247). The authors thank Jochen Schmitz and Jon Sedgwick for discussions, Sema Berktas, James Chivenga, and Jennifer Hollis for patient recruitment or clinical data curation. We acknowledge the contribution of the Oxford IBD Cohort Investigators: Carolina Arancibia-Cárcamo, Adam Bailey, Ellie Barnes, Beth Bird-Lieberman, Oliver Brain, Barbara Braden, Jane Collier, James East, Alessandra Geremia, Lucy Howarth, Simon Leedham, Rebecca Palmer, Astor Rodrigues, Alison Simmons, and Peter Sullivan. Download .docx (.02 MB) Help with docx files Supplementary Material