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A6720 - Fifty Shades of Cystic Fibrosis
Author Block: N. Pakzad1, E. Langfelder-Schwind2, L. DePalo3, M. M. O'Sullivan1, P. A. Walker2; 1Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Mount Sinai - St. Lukes/West/Beth Israel, New York, NY, United States, 2Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Mount Sinai Beth Israel, New York, NY, United States, 3Division of Medicine, Mount Sinai-National Jewish Health Respiratory Institute, Mount Sinai Hospital, New York, NY, United States.
Introduction: A subset of patients diagnosed with idiopathic bronchiectasis have been reported to possess cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations1,2. As cystic fibrosis (CF) has become increasingly recognized as a spectrum of disease, clinicians should maintain a high suspicion for CFTR mutations in patients with bronchiectasis, even when lacking the classic CF phenotype. Case: A 30 year old female with cough productive of brown sputum and a history of partially treated Mycobacterium Avium Complex (MAC) infection, presented to our pulmonary clinic after recurrence of symptoms. A recent CT chest had showed new mild central and upper lobe predominant bronchiectasis. The patient had no significant personal or family history of lung disease. She emigrated from Ecuador in 2005, had no known exposures, and never smoked. She reported two normal pregnancies with no miscarriages, periodic sinus and ear infections, and occasional irritable bowel. Physical examination was unremarkable. Labwork revealed normal immunoglobulins, and negative testing for HIV, quantiferon, and rheumatologic disease. Acid-fast bacilli sputum cultures were sent at that time, resulting in 6/6 samples positive for Mycobacterium Abscessus. Sweat chloride testing (SCT) showed intermediate values (44meq/L and 41meq/L); CFTR gene panel testing for over 170 variants, well beyond that recommended by the American College of Medical Genetics, was negative. However due to high suspicion, further CFTR sequencing recommended by CF specialists was performed demonstrating two rare variants, 5T-TG13 and H609R. Familial testing confirmed these variants were in trans. Discussion: CFTR mutations can cause sufficient mucosal transport disturbance to result in clinically detectable CF3. These low-frequency, protein-affecting variants predispose patients to nontuberculous mycobacteria infections3,8. The H609R variant is relatively common among Ecuadorian CF patients4,5, whereas the 5T-TG13 CFTR variant is a complex allele of varying clinical consequence. The 5T allele is modified by an adjacent TG repeat sequence of 11, 12, or 13 repeats, with higher number of repeats correlating to greater likelihood of pathogenicity6,7. Compound heterozygosity for these variants provides important insight into the etiology of our patient’s symptoms, and warrants ongoing monitoring for additional CF symptoms. Additionally, our case highlights the importance of SCT in symptomatic individuals. Had the genetic testing panel been interpreted in absence of SCT, the results would have been false-negative. The elevated SCT values prompted further CFTR sequencing, revealing the two abnormal variants. This case supports physicians maintaining low thresholds to refer patients with idiopathic bronchiectasis for CF evaluation, including sweat chloride testing and genetic counseling.