Measurement of nasal potential difference in young children with an equivocal sweat test following newborn screening for cystic fibrosis

Abstract

Background A challenging problem arising from cystic fibrosis (CF) newborn screening is the significant number of infants with hypertrypsinaemia (HIRT) with sweat chloride levels in the intermediate range and only one or no identified CF-causing mutations. Objectives To investigate the diagnostic value for CF of assessing CF transmembrane conductance regulator (CFTR) protein function by measuring nasal potential difference in children with HIRT. Methods A specially designed protocol was used to assess nasal potential difference (NPD) in 23 young children with HIRT (3 monthse4 years) with inconclusive neonatal screening. Results were analysed with a composite score including CFTR-dependent sodium and chloride secretion. Results were correlated with genotype after extensive genetic screening and with clinical phenotype at follow-up 3 years later.

Outcomes of Infants With Indeterminate Diagnosis Detected by Cystic Fibrosis Newborn Screening

“…18,19 A common genotype identified in our study was F508del/ R117H, a finding that also has been reported in other studies of CRMS. 8,9 Among those with poly T data available, similar to previous studies, we found that 7T was the most common polymorphism identified in infants with CRMS. Although R117H with 7T is considered unlikely to act as a disease-causing mutation, in some cases it can be associated with clinical symptoms of CF.…”

“…6 Data on the prevalence, clinical features, and clinical outcomes of infants with CRMS have been limited to small retrospective single-center studies. [7][8][9] The US CFF Patient Registry (CFFPR) added CRMS as a diagnostic category in 2010. In this report, we describe the clinical features and short-term outcomes of infants with CRMS and the accuracy of diagnostic classification of CF and CRMS in the CFFPR.…”

CFTR biomarkers: time for promotion to surrogate end-point

“…25 studies consistently show a statistically significant difference in chloride and sodium conductance between patients with cystic fibrosis and healthy controls. In patients with ''questionable'' cystic fibrosis, NPD composite scores provided a highly sensitive tool to diagnose patients as ''CF-likely'' and ''CF-unlikely'', with both cohorts having significantly different disease presentation [39,[77][78][79]. Data from studies with ataluren, ivacaftor, the CFTR corrector VX-809 and gene therapy confirm that NPD is a responsive endpoint.…”

“…However, NPD can be problematic in young children. NPD in infants can be done for diagnostic purposes in single centres with extensive experience in this age group [77,89]. As such, use of NPD as an outcome measure in clinical trials in infants and preschool children has a limited role.…”

Cystic fibrosis, primary ciliary dyskinesia and non-cystic fibrosis bronchiectasis: update 2008–11

“…Sermet-Gaudelus et al used nasal potential difference (NPD) measurement to investigate a group of 23 children with positive newborn screening tests but indeterminate sweat tests 14. All had fewer than two CFTR mutations identified by genetic analysis.…”