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A6715 - An Extremely Rare Case of c.418C>T Cystic Fibrosis Transmembrane Regulator Gene Mutation Causing Recurrent Sinopulmonary Infections and Bronchiectasis
Author Block: T. Ashby1, A. Babbar1, P. Staiano2, J. Cury1; 1Pulmonary and Critical Care, UF Health-Jacksonville, Jacksonville, FL, United States, 2Internal Medicine, UF Health-Jacksonville, Jacksonville, FL, United States.
Introduction: Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. Although diagnosis of CF is clinical, patients that don't meet criteria for classic CF are classified as CFTR-related disease (CFTR-RD). These patients have genetic variations in the CFTR gene and partial phenotypic expression. We present a case of a rare CFTR mutation causing CFTR-related disease.
Case presentation: A 62 year old Caucasian female with a previous medical history of asthma, chronic sinusitis, and former smoking presented to our clinic for recurrent sinopulmonary infections. Despite compliance with appropriate treatment for asthma, she reported recurrent infections requiring antibiotic courses and hospitalization during her adult life. Pertinent positives from prior workup included elevated immunoglobulin E, positive allergy testing, heterozygosity for alpha-1 antitrypsin mutation, and specific antibody deficiency. Additionally, chest imaging had multiple areas of patchy tree-in-bud and ground glass opacities and mild diffuse bronchiectasis. Bronchoscopy showed copious purulent secretions, neutrophil-predominant fluid, and culture positive for mixed flora. Subsequent evaluation with CF gene mutation analysis demonstrated heterozygosity for c.418C>T (p.Pro140Ser) mutation on exon 4, which is a reported variant of unknown significance.
Discussion: Cystic Fibrosis is an autosomal recessive disease which can present with varying phenotypes. Our patient presented later in life with mild respiratory illness which is common for CFTR-related disease. There is only one other documented case of c.418C>T CFTR gene mutation in a database of African American patients. Like our patient, this patient had disseminated bronchiectasis. Our initial workup for common causes of diffuse bronchiectasis was unrevealing. However, when CFTR genetic analysis is obtained in patients with bronchiectasis, 10-50% have been reported to have CFTR variations. Fortunately, we obtained complete CF genetic mutation analysis which led to the diagnosis. There are currently over 1700 CFTR gene mutations identified, but only a small proportion have been documented to be disease causing. As genetic analysis becomes more conventional, recognizing the connection between gene dysfunction and phenotypic expression is essential. Analysis of this mutation through bioinformatics testing using silico prediction tools suggested it may be damaging to both the structure and function of the protein. Combining the prior case report, biochemical testing, and phenotype of our patient identifies c.418C>T as a mutation that should be recognized for the potential to cause CFTR-related disease.