Interstitial deletions of the distal part of chromosome 2p seem to be rarely identified or reported: to date, only nine distinct patients have been published. The last three patients were diagnosed with the use of more recent molecular karyotyping technology (SNP array). We report on the natural history of an 8-year-old boy with dysmorphic features, postnatal overgrowth, microcephaly, generalized hypotonia, and global developmental delay. The diagnosis was accomplished by SNP array investigation that led to the identification of a de novo 7.4 Mb deletion of 2p23.2-p24.1. The present patient also developed a nonsyndromic auditory neuropathy. Since the deletion encompassed the OTOF gene, this haploinsufficiency suggests second allele sequencing as a possible cause (DFNB9). We describe the phenotype of the patient and review reports in patients with del 2p23 subsequent to the advent of the genomic era. At the time of identification of "new" micro- deletion and -duplication syndromes, the present report adds to the description of phenotype in patients with del(2)p(23.2;24.1) and the 2p23.2 region in particular.

A recent study by Leonard, Lebecque, Dingemanse, and Leal [[1]Leonard A. Lebecque P. Dingemanse J. Leal T. A randomized placebo-controlled trial of miglustat in cystic fibrosis based on nasal potential difference.J Cyst Fibros. 2012; 11: 231-236Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar] tested the effect of Miglustat, an alpha inhibitor on the cystic fibrosis conductance regulator gene using total chloride secretion in the nasal epithelium as the key variable estimated from basal nasal potential differences. The conclusion was drawn that “There was no evidence of a treatment effect on any nasal potential difference variable.” This conclusion may not be correct because of a slight misinterpretation of their statistical results. There also is a question of whether longer exposure periods than 8 days would have produced a more pronounced effect. The p and n values in Table 2 of the above study were converted to standardized effect sizes (r) by the methods described in Trikalinos et al. [[2]Trikalinos T.A. Salanti G. Zintzaras E. Ioannidis J.P. Meta-analysis methods.Adv Genet. 2008; 60: 311-334Crossref PubMed Scopus (105) Google Scholar]. The primary clinical endpoint of total chloride secretion had an effect size of 19% (r=0 .191). This is not a large effect size, but it is far from zero. That is, it would need closer to zero before one could conclude that no evidence of a treatment effect was found. The fact that this effect was not statistically significant does not mean that there was absence of evidence of an effect, which was the conclusion of the above study. If this pilot study had more than 11 participants, it is possible that this effect would have been statistically significant, and consequently, some effectiveness cannot be ruled out. Another possibility that confounds the conclusion concerns the duration of exposure to Miglustat. The duration of exposure was 8 days, and this was justified by the finding that plasma concentrations of Miglustat reached a steady-state within four days. However, this duration could have been too short to see long term outcomes from a chronic disease such as cystic fibrosis. A classic example of the dissociation between plasma levels and clinical effects is the lack of correlation between the time to steady the state of plasma levels for amitriptyline and the antidepressant effects [[3]Baumann P. Jonzier-Perey M. Koeb L. Lê P.K. Tinguely D. Schöpf J. Amitriptyline pharmacokinetics and clinical response: I. Free and total plasma amitriptyline and nortriptyline.Int Clin Psychopharmacol. 1986; 1: 89-101Crossref PubMed Scopus (21) Google Scholar]. The above study had many strengths, including the criteria for selecting the participant, the disclosure of the study limitations, the flow and logic of the article, well-founded hypothesis, and many more strengths. However, due to the evidence of some effectiveness of Miglustat on total chloride secretion, the conclusion that no treatment effect was found is probably not justified, which argues in favor of continued consideration of Miglustat in plans for future studies. The authors have no financial or other form of conflict of interest that would influence the objectivity of the information or opinions in this study.

BACKGROUND:Preclinical data suggest that miglustat could restore the function of the cystic fibrosis transmembrane conductance regulator gene in cystic fibrosis cells. METHODS:Single-center, randomized, double-blind, placebo-controlled, crossover Phase II study in 11 patients (mean±SD age, 26.3±7.7 years) homozygous for the F508del mutation received oral miglustat 200 mgt.i.d. or placebo for two 8-day cycles separated by a 14-day washout period. The primary endpoint was the change in total chloride secretion (TCS) assessed by nasal potential difference. RESULTS:No statistically significant changes in TCS, sweat chloride values or FEV(1) were detected. Pharmacokinetic and safety were similar to those observed in patients with other diseases exposed to miglustat. CONCLUSIONS:There was no evidence of a treatment effect on any nasal potential difference variable. Further studies with miglustat need to adequately address criteria for assessment of nasal potential difference.

Nasal potential difference (NPD) quantifies abnormal ion transport in cystic fibrosis. It has gained acceptance as an outcome measure for the investigation of new therapies.To quantify the effect of solution temperature on NPD, we first examined the effect of switching from room temperature (20–25°C) to warmed (32–37°C) solutions andvice versaduring each perfusion step. Secondly, standard protocols were repeated at both temperatures in the same subjects.Changing solution temperature did not alter NPD during perfusion with Ringer’s solution (<1 mV) (p>0.1). During perfusion with zero chloride solution, changing from room temperature to warmed solutions tended to decrease absolute NPD (i.e.it became less negative) by 0.9 mV (p>0.1); changing from warmed to room temperature increased NPD by 2.1 mV (p<0.05). During isoprenaline perfusion, changing from room temperature to warmed solutions increased NPD by 1.5 mV (p<0.01) and from warmed to room temperature decreased NPD by 1.4 mV (p<0.05).For full protocols at room temperature or warmed in the same subjects, mean values were similar (n = 24). During warmed perfusion, group results for total chloride response had a larger standard deviation. As this increased variability will probably decrease the power of trials, this study suggests that solutions at room temperature should be recommended for the measurement of NPD.

BACKGROUND:VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro.METHODS:A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo.RESULTS:The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens.CONCLUSIONS:In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit.CLINICAL TRIAL NUMBER:NCT00865904.

Le recours aux manœuvres de désencombrement des voies aériennes fait partie intégrante de la prise en charge de la mucoviscidose. De nombreuses techniques sont décrites sans qu’une unanimité existe. Les techniques sont regroupées en techniques manuelles et instrumentales. Les techniques instrumentales de désencombrement reposent sur l’application de vibrations ou d’une pression positive lors de la phase expiratoire. Cette pression positive est soit continue, soit oscillante. Plusieurs études ont tenté d’expliquer leurs effets au moyen de données physiologiques et se sont intéressées à leurs répercussions pour les patients avec des résultats non univoques. Bien qu’encore peu utilisées dans de nombreux pays, ces techniques reposent pourtant sur des données physiologiques qui méritent de leur accorder une place dans l’arsenal du kinésithérapeute. Une meilleure connaissance des techniques instrumentales devrait permettre de les intégrer au mieux dans la prise en charge des patients atteints de mucoviscidose. Chest physiotherapy is an essential part of the life-long therapeutic routine in patients with cystic fibrosis. Various manoeuvres are available but there is no consensus supporting one specific technique over others. These techniques can be classified as “manual” or “instrumental”. Instrumental airway clearance techniques are based on physiological principles and consist in the application of vibrations or positive expiratory pressure during expiratory phase to enhance sputum clearance. Positive expiratory pressure can be delivered continuously or in an oscillating pattern. The effects of these devices have been investigated in many studies. Results suggest a potential place for these techniques in the management of cystic fibrosis, but they remain poorly used. A better knowledge of these approaches could enable them to integrate more widely into the physiotherapy management of patients with cystic fibrosis.

A 5′FR/G-260C (NCBI reference: 010393.16:g.15983174C>G) functional polymorphism of Multidrug Resistance-associated Protein 1 (ABCC1) promoter has been reported which influences ABCC1 expression including inflammatory related events.We aimed at investigating the impact of this polymorphism on the severity of CF disease.In this multicentric study, key clinical features of 203 CF patients homozygous for the F508del mutation were recorded. Kaplan–Meier analysis showed that patients with the rare CC genotype were chronically colonized by PA around 6 years earlier (mean±SD: 11.2 year±7.8, 95% CI for the mean: 5.7–16.8) than those with the GG or the CG alleles (p<=0.01) and a FEV1 <60% predicted was first observed earlier in this group (p<0.05). Concordant trends to better nutritional status and FEV1 were observed in the slightly older GG subgroup.The potential role of ABCC1 promoter as a modifier gene deserves further study.

The objective of this prospective study was to assess the prevalence of Exophiala dermatitidis in respiratory secretions of patients with cystic fibrosis (CF) and to identify risk factors for its presence. The results of all cultures performed over a 2-year period in non lung-transplant patients in our CF clinic were included in the study. Samples consisted of sputum (whenever possible) or deep pharyngeal aspirate after a session of physiotherapy. Specimens were inoculated onto Sabouraud gentamicin-chloramphenicol agar (SGCA) medium (Becton-Dickinson) and incubated at 35°C for 2 days and then at ambient temperature (15-25°C) for 3 weeks. The whole study group included 154 patients (mean age ± SD: 18.5 y ± 11.69). E. dermatitidis was isolated from 58 specimens (2.8%) of nine patients (5.8%) out of total of 2065 cultures prepared during the study period. All E. dermatitidis culture-positive patients were pancreatic insufficient and ≥12 y of age. Almost all (8/9) were homozygous for the F508 del mutation. Aspergillus fumigatus colonization and genotype seemed to be predisposing factors. No other significant characteristic was identified in this group, either in terms of predominant bacterial pathogen or treatment. A distinct comparative study performed over 3 months in our laboratory revealed that the use of SGCA yielded identical isolation rates of E. dermatitidis as erythritol-chloramphenicol agar (ECA).

Hepatic involvement is frequent in patients with cystic fibrosis (CF), with focal biliary cirrhosis being the pathognomonic hepatic manifestation. In around one-quarter of CF patients, it results in CF-associated liver disease (CFLD). This occurs as a relatively early complication with the majority of patients presenting in childhood or their early teens. However, a normal US does not preclude significant liver fibrosis and liver biopsy is an invasive procedure that is hampered by potential sampling errors. Transient elastography (TE) (Fibroscan) is a non-invasive, user-friendly and quick technique that provides an objective and reproducible measure of liver stiffness. This is accomplished with a device using an US probe mounted in the axis of a vibrator. Vibrations are transmitted by the transducer, inducing an electronic shear wave that propagates through the underlying tissue.

Pediatric Pulmonology 2009;44(5):516/DOI 10.1002/ppul.21002 2009 Wiley-Liss, Inc.In this Letter to the Editor, IgE values should have been expressed in IU/ml. Inaddition,inthesixthparagraph,baselineIgEvalueofthefirstpatienthadbeenprintedas 261 UI/L erroneously. The correct value should be 4261 IU/ml. Please see the nextpage for the corrected article.The publisher regrets any inconvenience this has caused.

RATIONALEN-butyldeoxynojyrimicin (NB-DNJ, miglustat [Zavesca]) an approved drug for treating Gaucher disease, was reported to be able to correct the defective trafficking of the F508del-CFTR protein.OBJECTIVESTo evaluate the efficacy of in vivo airway delivery of miglustat for restoring ion transport in cystic fibrosis (CF).METHODSWe used nasal transepithelial potential difference (PD) as a measure of sodium and chloride transport. The effect of nasal instillation of a single dose of miglustat was investigated in F508del, cftr knockout and normal homozygous mice. The galactose iminosugar analog N-butyldeoxygalactonojirimycin (NB-DGJ) was used as a placebo.MEASUREMENTS AND MAIN RESULTSIn F508del mice, sodium conductance (evaluated by basal hyperpolarization) and chloride conductance (evaluated by perfusing the nasal mucosa with chloride-free solution in the presence of amiloride and forskolin) were normalized 1 hour after an intranasal dose of 50 picomoles of miglustat. Chloride conductance in the presence of 200 microM 4-4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS), an inhibitor of alternative chloride channels, was much higher after miglustat than after placebo. In cftr knockout mice, a normalizing effect was observed on sodium but not on chloride conductance.CONCLUSIONSOur results provide clear evidence that nasal delivery of miglustat, at picomolar doses, normalizes sodium and Cftr-dependent chloride transport in F508del transgenic mice; they highlight the potential of topical miglustat as a therapy for CF.