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CFTR Mutation Carriers State Presenting with CFTR Related Diseases
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A6722 - CFTR Mutation Carriers State Presenting with CFTR Related Diseases
Author Block: P. Ramirez1, A. J. Hayek2, V. E. Brito3; 1Internal Medicine, Baylor Scott and White Health, Temple, TX, United States, 2Pulmonary Critical Care Fellowship, Baylor Scott and White, Temple, TX, United States, 3Baylor Scott and White, Temple, TX, United States.
INTRODUCTION. Cystic fibrosis is an autosomal recessive disorder due to a defective chloride-conducting transmembrane regulator, known as cystic fibrosis transmembrane conductance regulator (CFTR). Correlations between those with carrier mutations and CFTR related disease have been documented. Lack of evidence for treating patients with one allele mutations provides a unique challenge.
CASE PRESENTATION.
Case 1:A 43 year old male presents with recurrent upper respiratory infection symptoms refractory to antibiotics. He has normal PFTs, methocholine challenge and a bronochoscopy showing mucus plugging. HRCT shows atypical infiltrate patterns and bronchiectasis. Aspergillous-specific IgE is elevated. The patient was diagnosed with allergic bronchopulmonary aspergillosis (ABPA) and treated with itraconazole and prednisone. Due to lack of clinical improvement, a CFTR genetic analysis was performed which was positive for (TG)11-5T carrier state, a “disease-modifying” splicing mutation. Sweat chloride testing was negative (29 mmol/L).
Case 2: A 71 year old female with a long history of idiopathic chronic pancreatitis, recurrent sinusitis and upper respiratory infections. Chest and abdomen CT reveal bronchiectasis with numerous nodular opacities and pancreatic stranding with fibrosis, respectively. Bronchoalveolar washings reveal chronic colonization of S. aureus and P. aeruginosa. This patient was also diagnosed with ABPA. She is a c3528delC Class I mutation carrier. Her sweat chloride was intermediate (59 mmol/L).
DISCUSSION. Patients who have a known CF carrier mutation have been documented to present with CFTR related disease. One study revealed idiopathic chronic pancreatitis risk is increased in CF carriers who have one documented normal CFTR allele (1). Another study of 55 patients with bronchiectasis of unknown etiology showed 14 patients (25%) had one allele CFTR mutations (2). The poor correlation between CFTR genotype and severity of lung disease raise questions regarding diagnostic criteria and, therefore, treatment (2). The question raised is “what is the role for novel, small molecule therapies in this patient population.” While novel gene-based therapies, like Ivacaftor, increase ion-function of activated cell-surface CFTR, how could these therapies be expected to respond in mutations that cause only modest dysfunction of the CFTR?
Reference
1. Cohn JA et al. Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers. Hum Mutat. 2005 Oct;26(4):303-7.
2. Casals T et al. Bronchiectasis in adult patients: an expression of heterozygosity for CFTR gene mutations? Clin Genet. 2004 Jun;65(6):490-5.
2. Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration 2000;67:117-133
Author Block: P. Ramirez1, A. J. Hayek2, V. E. Brito3; 1Internal Medicine, Baylor Scott and White Health, Temple, TX, United States, 2Pulmonary Critical Care Fellowship, Baylor Scott and White, Temple, TX, United States, 3Baylor Scott and White, Temple, TX, United States.
INTRODUCTION. Cystic fibrosis is an autosomal recessive disorder due to a defective chloride-conducting transmembrane regulator, known as cystic fibrosis transmembrane conductance regulator (CFTR). Correlations between those with carrier mutations and CFTR related disease have been documented. Lack of evidence for treating patients with one allele mutations provides a unique challenge.
CASE PRESENTATION.
Case 1:A 43 year old male presents with recurrent upper respiratory infection symptoms refractory to antibiotics. He has normal PFTs, methocholine challenge and a bronochoscopy showing mucus plugging. HRCT shows atypical infiltrate patterns and bronchiectasis. Aspergillous-specific IgE is elevated. The patient was diagnosed with allergic bronchopulmonary aspergillosis (ABPA) and treated with itraconazole and prednisone. Due to lack of clinical improvement, a CFTR genetic analysis was performed which was positive for (TG)11-5T carrier state, a “disease-modifying” splicing mutation. Sweat chloride testing was negative (29 mmol/L).
Case 2: A 71 year old female with a long history of idiopathic chronic pancreatitis, recurrent sinusitis and upper respiratory infections. Chest and abdomen CT reveal bronchiectasis with numerous nodular opacities and pancreatic stranding with fibrosis, respectively. Bronchoalveolar washings reveal chronic colonization of S. aureus and P. aeruginosa. This patient was also diagnosed with ABPA. She is a c3528delC Class I mutation carrier. Her sweat chloride was intermediate (59 mmol/L).
DISCUSSION. Patients who have a known CF carrier mutation have been documented to present with CFTR related disease. One study revealed idiopathic chronic pancreatitis risk is increased in CF carriers who have one documented normal CFTR allele (1). Another study of 55 patients with bronchiectasis of unknown etiology showed 14 patients (25%) had one allele CFTR mutations (2). The poor correlation between CFTR genotype and severity of lung disease raise questions regarding diagnostic criteria and, therefore, treatment (2). The question raised is “what is the role for novel, small molecule therapies in this patient population.” While novel gene-based therapies, like Ivacaftor, increase ion-function of activated cell-surface CFTR, how could these therapies be expected to respond in mutations that cause only modest dysfunction of the CFTR?
Reference
1. Cohn JA et al. Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers. Hum Mutat. 2005 Oct;26(4):303-7.
2. Casals T et al. Bronchiectasis in adult patients: an expression of heterozygosity for CFTR gene mutations? Clin Genet. 2004 Jun;65(6):490-5.
2. Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration 2000;67:117-133
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