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Sweat Chloride Testing

Educational Objective
Based on this clinical scenario and the accompanying image, understand how to arrive at a correct diagnosis.
1 Credit CME

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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Article Information

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.

References
1.
Farrell  PM, White  TB, Ren  CL,  et al.  Diagnosis of cystic fibrosis: consensus guidelines from the Cystic Fibrosis Foundation.  J Pediatr. 2017;181S:s4-s15.e1. doi:10.1016/j.jpeds.2016.09.064PubMedGoogle Scholar
2.
Riordan  JR, Rommens  JM, Kerem  B,  et al.  Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.  Science. 1989;245(4922):1066-1073. doi:10.1126/science.2475911PubMedGoogle ScholarCrossref
3.
Kerem  B, Rommens  JM, Buchanan  JA,  et al.  Identification of the cystic fibrosis gene: genetic analysis.  Science. 1989;245(4922):1073-1080. doi:10.1126/science.2570460PubMedGoogle ScholarCrossref
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Castellani  C, Duff  AJA, Bell  SC,  et al.  ECFS best practice guidelines: the 2018 revision.  J Cyst Fibros. 2018;17(2):153-178. doi:10.1016/j.jcf.2018.02.006PubMedGoogle ScholarCrossref
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Massie  J, Greaves  R, Metz  M,  et al.  Australasian guideline (2nd edition): an annex to the CLSI and UK guidelines for the performance of the sweat test for the diagnosis of cystic fibrosis.  Clin Biochem Rev. 2017;38(3):115-130.PubMedGoogle Scholar
6.
Cole  DE, Boucher  MJ.  Use of a new sample-collection device (Macroduct) in anion analysis of human sweat.  Clin Chem. 1986;32(7):1375-1378.PubMedGoogle Scholar
7.
LeGrys  V, Applequist  R, Briscoe  D,  et al.  Sweat Testing: Sample Collection and Quantitative Chloride Analysis; Approved Guideline-Third Edition. Wayne, PA: Clinical Laboratory Standards Institute; 2009. https://clsi.org/media/1362/c34a3_sample.pdf.
8.
Rock  MJ, Makholm  L, Eickhoff  J.  A new method of sweat testing: the CF Quantum sweat test.  J Cyst Fibros. 2014;13(5):520-527. doi:10.1016/j.jcf.2014.05.001PubMedGoogle ScholarCrossref
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Höfmann  T, Bohmer  O, Hüls  G,  et al.  Conventional and modified nasal potential-difference measurement in cystic fibrosis.  Am J Respir Crit Care Med. 1997;155(6):1908-1913. doi:10.1164/ajrccm.155.6.9196094PubMedGoogle ScholarCrossref
10.
Derichs  N, Sanz  J, Von Kanel  T,  et al.  Intestinal current measurement for diagnostic classification of patients with questionable cystic fibrosis: validation and reference data.  Thorax. 2010;65(7):594-599. doi:10.1136/thx.2009.125088PubMedGoogle ScholarCrossref
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