Customize your JAMA Network experience by selecting one or more topics from the list below.
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).
Additional genetic testing
Alternative CFTR functional testing
Repeat sweat chloride analysis
No further testing; the patient does not have CF
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.
In sweat glands, CFTR protein facilitates chloride resorption from the ductal lumen into the epithelium. CFTR protein dysfunction results in defective resorption of chloride and elevated sweat chloride concentrations. Sweat chloride testing should be performed by experienced personnel adhering to international guidelines.4,5 The standard approach uses topical pilocarpine, a muscarinic agonist, and a small electric current to stimulate sweat production for 5 minutes, followed by sweat collection on gauze or with a capillary tube for up to 30 minutes.6 Depending on the method, 75 mg or 15 μL of sweat is required to determine chloride concentration.7
The upper limit of normal sweat chloride concentration is 30 mmol/L,1,4 and a concentration greater than 60 mmol/L in a person with clinical features of CF indicates the presence of CF. The test has nearly 100% sensitivity and 96% specificity, and is the criterion standard diagnostic test for CF.1,7,8 Sweat chloride concentrations between 30 mmol/L and 60 mmol/L are considered indeterminate and require additional diagnostic evaluation.4 Federal reimbursement for sweat chloride testing is $82.90.
This patient had sweat chloride concentration values consistently in the indeterminate range. In the absence of factors that may falsely elevate sweat chloride concentration (eg, dehydration; malnutrition; ectodermal dysplasia; endocrine disorders, including hypothyroidism, hypoparathyroidism, or cortisol deficiency7), additional diagnostic testing is necessary. Genetic CFTR testing revealed a single CF-causing mutation, which is insufficient to diagnose CF. Additional physiologic CFTR testing is the next diagnostic step. This diagnostic challenge is increasingly frequent, particularly in adults with relatively mild symptoms. Patients who do not meet the diagnostic criteria for CF following extensive workup may be classified as having CFTR-related metabolic syndrome (newborn screen positive for at least 1 known CF-causing CFTR mutation) or CFTR-related disorder (disease limited to 1 organ [eg, pancreatitis]).1
Indeterminate sweat chloride concentration results should prompt further testing, starting with genetic CFTR analysis. If the CFTR genotype is undefined, further CFTR functional tests should be performed. Nasal potential difference measurement uses electrodes and sequential perfusion of compounds that affect sodium and chloride transport into the nasal cavity to measure CFTR-dependent voltage across the nasal epithelium. This process quantifies CFTR function in vivo and is highly sensitive and specific for diagnosing CF.9 Intestinal current measurement can be a useful alternative. In this test, epithelium from rectal biopsy samples is stimulated by exposure to compounds affecting sodium and chloride transport, and CFTR-dependent ion transport is quantified as electrical current.10
Nasal potential difference testing was attempted but not completed because of poor patient cooperation. Intestinal current measurement demonstrated minimal CFTR function (<5% of normal function; CF diagnostic threshold, <25% of normal function10), and the diagnosis of CF was made. Based on symptoms, including greasy, bulky stools, she was empirically prescribed pancreatic enzyme replacement therapy (PERT). One month after diagnosis, her constipation was improved. PERT and gastrostomy feeding tube improved her BMI to the 70th percentile (eFigureA in the Supplement). Six years after diagnosis she has developed chronic productive cough, sinusitis, mild bronchiectasis (eFigureB in the Supplement), lung function decline, and positive respiratory cultures for classic microorganisms of CF (eFigureC in the Supplement).
CF is a multisystem disease with mild forms increasingly recognized in children and adults.
Sweat chloride testing remains the diagnostic standard for CF. Sweat chloride testing should be the initial test performed in any patient with clinical suspicion of CF.
Genetic testing can help clarify an indeterminate diagnosis, provide prognostic information, and guide disease- and CFTR mutation– specific therapy.
Nasal potential difference/intestinal current measurement may be useful to diagnose CF in a patient with indeterminate sweat chloride concentration values and less than 2 well-characterized disease-causing mutations.
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.
Figure. Clinical Characteristics and Follow-up
McCarthy C, Clancy JP, Brewington J. Sweat Chloride Testing. JAMA. Published online January 30, 2019. doi:10.1001/jama.2018.21998
Create a personal account or sign in to: