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A 5-year-old girl was referred to a pediatric gastroenterology clinic for chronic constipation and poor weight gain. During her first week of life, she developed diarrhea and vomiting. With initiation of solid food, she developed laxative-dependent constipation. She underwent newborn genetic screening before routine cystic fibrosis (CF) screening. Results were normal. At the time of presentation to the gastroenterology clinic, she had no respiratory symptoms. Results of anorectal manometry, spinal magnetic resonance imaging, and thyroid studies were normal. Family history included constipation in a sister and a great aunt with CF. Her body mass index (BMI) was below the third percentile (eFigureA in the Supplement). Physical examination findings were unremarkable, including normal respiratory examination. Fecal elastase level was within reference range (>500 μg/g); abdominal computed tomographic image revealed a dilated, tortuous sigmoid colon; and full-thickness rectal biopsy was negative for Hirschsprung disease. She was referred for sweat chloride testing to assess for CF. Results of 3 separate sweat chloride tests were indeterminate (Table), prompting pulmonology referral. A 97-mutation CF transmembrane conductance regulator (CFTR) analysis panel was negative. Whole-genome sequence analysis revealed 1 CF-causing mutation (c.2249C>T) and 2 likely benign variants (c.1408A>G and c.2562T>G).
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B. Alternative CFTR functional testing
Cystic fibrosis is caused by mutations in the CFTR gene on chromosome 7.2,3 The CFTR protein is an anion channel that transports chloride and bicarbonate across the epithelium in many organs. CFTR mutations can cause reduced CFTR protein expression, which subsequently results in a reduction of the number of CFTR anion channels present on the epithelial membrane. CFTR mutations may also result in abnormal channel function, causing impaired ion and fluid homeostasis, hyperviscous secretions, and multisystem disease. CF-related lung disease includes mucus plugging, chronic infection, airway remodeling, and progressive decline in lung function. Gastrointestinal CFTR dysfunction results in chronic constipation and malnutrition due to viscous secretions in the intestinal tract and pancreatic ducts. Additional manifestations of CF include diabetes mellitus, azoospermia, and low bone mineral density. The diagnosis of CF is based on clinical presentation, family history, or a positive newborn screening test in addition to evidence of an abnormal CFTR protein or gene.1 Most patients are now identified through newborn screening; however, there is an increasing number of later diagnoses, especially in adulthood, representing up to 7% of CF cases.
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Corresponding Authors: Cormac McCarthy, MD, PhD, Department of Medicine, University College Dublin, St Vincent’s University Hospital, Dublin 4, Ireland (Cormac.McCarthy@ucd.ie).
Published Online: January 30, 2019. doi:10.1001/jama.2018.21998
Conflict of Interest Disclosures: Dr Brewington reported receiving grants from the Cystic Fibrosis Foundation. No other disclosures were reported.
Additional Contributions: We thank the patient’s parent for providing permission to share her information.
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