P-199 Pathogenic CFTR Mutation in Crohnʼs Disease in the Absence of Other CFTR-Related Manifestations

Abstract

Background: The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein is an important ion channel expressed by pulmonary and intestinal epithelial cells. Variants in CFTR lead to cystic fibrosis (CF), a chronic progressive inflammatory condition of the lungs. Although individuals with CF have a 17-fold greater risk of developing Crohn's disease, a molecular genetic mechanism linking the 2 conditions has yet to be established. Evidence from the pulmonary model suggests that variants in CFTR lead to exaggerated activation of NF-kB, a key player in the inflammatory cascade common to many chronic inflammatory disorders (e.g., CF, psoriasis, IBD). In vitro, incubation of human mutant CFTR (DF508/W1282X) epithelial cells with TNF-alpha demonstrates a marked upregulation of NF-kB, and subsequent overproduction of pro-inflammatory cytokines (e.g., IL-8), compared to wild-type and CFTRcorrected bronchial epithelial cells. In this case report, we describe a compoundheterozygous pathogenic variant in CFTR in twin girls with Crohn's disease, but without CF or any other typical CFTR-related manifestations. Methods: The Probands are Caucasian monozygotic twin females (enrolled in the IRB-approved Genome Center Repository at the Children's Mercy Hospital) who presented with chronic diarrhea, fever and weight loss at age 10 and 12 years, respectively. Both were diagnosed with granulomatous ileocolonic Crohn's disease, based on clinical, laboratory, histopathologic and imaging findings, and achieved disease remission within 4 months of starting anti-TNF-alpha therapy. Given the similarities in disease phenotype, exome sequencing was performed on the probands and their parents to look for a potential concordant genetic basis of disease. Results: Sequence analysis in the twins revealed compound heterozygosity for 2 likely pathogenic missense variants in CFTR: c.2249C.T (p.Pro750Leu), inherited paternally, and c.2506G.T (p.Asp836Tyr), inherited maternally. Both variants were confirmed clinically by Sanger sequencing. A thorough medical history and review of systems verified that both probands were otherwise healthy, without history/ evidence of chronic lung disease or pancreatic insufficiency. Pulmonary function tests, sweat chloride tests, and fecal elastase levels were performed and were within normal limits. Conclusions: Our observations suggest that variants in CFTR may have a pathogenic role in the development and/or expression of ileocolonic Crohn's disease, perhaps via exaggerated NF-kB overexpression in response to TNF-alpha stimulation, as suggested by the CF disease model. To our knowledge, this is the first case report of a CFTR-related-disease that is limited to a Crohn's-only phenotype. Further investigation of whether CFTR may play a role in the pathogenesis of Crohn's disease, and/ or treatment responsiveness to anti-TNF-alpha agents, may be warranted.