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Devil in the detail of newborn screening for cystic fibrosis
  1. Iolo Doull1,2
  1. 1 Department of Paediatric Respiratory Medicine and Paediatric Cystic, Childrens Hospital for Wales, Cardiff, UK
  2. 2 Welsh Health Specialist Services, Caerphilly, UK
  1. Correspondence to Professor Iolo Doull, Department of Paediatric Respiratory Medicine and Paediatric Cystic, Children’s Hospital for Wales, Cardiff, CF14 4XN, UK; doullij{at}cf.ac.uk

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The recognition that the sweat chloride concentration was elevated in people with cystic fibrosis (CF) was fundamental to its diagnosis and treatment.1 A sweat chloride >60 mmol/L was diagnostic of CF, while a sweat chloride of <40 mmol/L was normal, with clear blue water in between. In truth, there was recognition that there were brackish sweat tests, neither salty nor fresh, although their significance was unclear.

The identification of the gene for CF and its product cystic fibrosis transmembrane conductance regulator (CFTR) expanded our understanding of the clinical phenotype but also expanded the diagnostic uncertainty. It became apparent that there was variability of clinical phenotype, with the age of onset and severity of symptoms being dependent on the level of CFTR dysfunction. Some CFTR mutations presenting with a CF phenotype (eg, 3849+10 kb C>T) were associated with a normal sweat chloride concentration, while the clinical consequences of some CFTR mutations were unclear. Nevertheless, the sweat test remains pivotal—the most recent international consensus recommends that ‘diagnoses associated with CFTR mutations in all individuals, from newborn to adult, be established by evaluation of CFTR function with a sweat chloride test’,2 while sweat chloride is increasingly used as an outcome measure for small molecule treatment.3 Alternative assessments of CFTR function include measurement of nasal potential difference or intestinal current, while measurement of sweat sodium or sweat conductivity is not recommended.

Diagnostic uncertainties were brought to the fore with the widespread adoption of newborn screening (NBS) for CF—the majority of people with CF are now diagnosed through NBS. Most CF NBS programmes comprise two stages—an initial raised blood spot immune-reactive trypsin (IRT), with subsequent identification of CFTR mutations. For those with two disease-causing mutations, the diagnosis is straightforward, but for those with one identified mutation screening pathways vary, but most culminate in a diagnostic …

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