Clinical presentation and basic defect of the CFTR genotype p.Phe508del / p.Arg117His in a mother and her monozygous twin daughters.

A non-consanguineous two-generation family of parent and monozygous twins who all three share the same CFTR mutation genotype p.Phe508del / p.Arg117His, was examined in clinical features, sweat test, nasal potential difference and intestinal current measurements. As expected the twins were very much alike in anthropometry and appearance and shared the clinical manifestation of CFTR dysfunction albeit at different intensity but unexpectedly like in comparison to their mother they were discordant in their CFTR-mediated basic defect and the response thereof to CFTR potentiation by ivacaftor. This case report illustrates the strong impact of non-inherited factors on the electrophysiological phenotype of the most common CFTR mutation genotype of variable clinical significance.

Multicentre feasibility of multiple-breath washout in preschool children with cystic fibrosis and other lung diseases.

BACKGROUND: Multiple-breath washout (MBW)-derived lung clearance index (LCI) detects early cystic fibrosis (CF) lung disease. LCI was used as an end-point in single- and multicentre settings at highly experienced MBW centres in preschool children. However, multicentre feasibility of MBW in children aged 2-6 years, including centres naïve to this technique, has not been determined systematically. METHODS: Following central training, 91 standardised nitrogen MBW investigations were performed in 74 awake preschool children (15 controls, 46 with CF, and 13 with other lung diseases), mean age 4.6±0.9 years at investigation, using a commercially available device across five centres in Germany (three experienced, two naïve to the performance in awake preschool children) with central data analysis. Each MBW investigation consisted of several measurements. RESULTS: Overall success rate of MBW investigations was 82.4% ranging from 70.6% to 94.1% across study sites. The number of measurements per investigation was significantly different between sites ranging from 3.7 to 6.2 (p<0.01), while the mean number of successful measurements per investigation was comparable with 2.1 (range, 1.9 to 2.5; p=0.46). In children with CF, the LCI was increased (median 8.2, range, 6.7-15.5) compared to controls (median 7.3, range 6.5-8.3; p<0.01), and comparable to children with other lung diseases (median 7.9, range, 6.6-13.9; p=0.95). CONCLUSION: This study demonstrates that multicentre MBW in awake preschool children is feasible, even in centres previously naïve, with central coordination to assure standardised training, quality control and supervision. Our results support the use of LCI as multicentre end-point in clinical trials in awake preschoolers with CF.

Intestinal current measurement and nasal potential difference to make a diagnosis of cases with inconclusive CFTR genetics and sweat test.

BACKGROUND: Nasal potential difference (NPD) and intestinal current measurements (ICM) are cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers recommended to make a diagnosis in individuals with inconclusive sweat test and CFTR genetics and a clinical suspicion for cystic fibrosis (CF) or CFTR-related disorder (CFTR-RD). METHODS: NPD and ICM were measured according to standard operating procedures of the European Cystic Fibrosis Society Diagnostic Network Working Group. RESULTS: We assessed 219 individuals by NPD or ICM who had been referred to our laboratory due to clinical symptoms suggestive of CF, but inconclusive sweat test and CFTR genetics (median age: 16.3 years, range 0.4 to 76 years). CF or CFTR-related disorder was diagnosed in 22 of 29 patients (76%) with a CFTR genotype of unknown or variable clinical significance and in 51 of 190 carriers (27%) of one (35/42) or no (16/148) identified CFTR mutation. If two CFTR sequence variants had been identified, the outcome of NPD and ICM was consistent with the classification of the CFTR2 database. Moreover, a suspected false-positive diagnosis of CF was confirmed in seven and withdrawn in eight patients. Of 26 individuals assessed by both NPD and ICM, eleven individuals exhibited discordant tracings of ICM and NPD, with one measurement being in the CF range and the other in the normal range. CONCLUSION: The majority of patients whom we diagnosed with CF or CFTR-RD by extended electrophysiology are carriers of the wild-type CFTR coding sequence on at least one of their CF alleles. The disease-causing genetic lesions should reside in the non-coding region of CFTR or elsewhere in the genome, affecting the regulation of CFTR expression in a tissue-depending fashion which may explain the large within-group variability of CFTR activity in the respiratory and intestinal epithelium seen in this group.