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BACKGROUND: Multiple breath inert gas washout (MBW) has been suggested as a tool for detecting early cystic fibrosis (CF) lung disease. A study was undertaken to compare the relative sensitivity of MBW and spirometry for detecting abnormal lung function in school age children with CF and to compare MBW results obtained from healthy children in the UK with those recently reported from Sweden. METHODS: Forced expiratory volume in 1 second (FEV1) and maximal expiratory flow when 25% of forced vital capacity remains to be expired (MEF25) were compared with the lung clearance index (LCI) derived from sulphur hexafluoride MBW in 22 children with CF aged 6-16 years and in 33 healthy controls. RESULTS: LCI was higher in children with CF than in healthy controls (mean difference 5.1 (95% CI of difference 4.1 to 6.1) and FEV1 and MEF25 z-scores were lower (mean difference -2.3 (95% CI -2.9 to -1.7) and -1.8 (95% CI -2.4 to -1.3), respectively; p<0.001 for all). There was a significant negative correlation between LCI and FEV1 (r2 = 0.62) and MEF25 (r2 = 0.46). However, while normal (> or =-1.96 z-scores) FEV1 and MEF25 results were seen in 11 (50%) and 12 (53%) children with CF, respectively, all but one of these children had an abnormally increased LCI. LCI was repeatable in both groups (within subject CV for three measurements 6% for CF and 5% for healthy children). In healthy subjects LCI was independent of age and virtually identical in the British and Swedish children (mean difference 0.1 (95% CI -0.1 to 0.4), p = 0.38) CONCLUSIONS: MBW is reproducible between laboratories, generates normal ranges which are constant over childhood, and is more frequently abnormal than spirometry in children with CF.

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BACKGROUND: Recombinant human deoxyribonuclease (rhDNase) is currently used to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis. OBJECTIVES: To determine whether the use of rhDNase in cystic fibrosis is associated with improved mortality and morbidity compared to placebo or other mucolytics and to identify any adverse events associated with its use. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group trials register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and abstracts from conferences. Date of the most recent search of the Group's register: January 2003. SELECTION CRITERIA: All randomized and quasi-randomized controlled trials where rhDNase was compared to either placebo, standard therapy or another mucolytic. DATA COLLECTION AND ANALYSIS: Trials were independently assessed for inclusion criteria and the lead reviewer and a colleague carried out analysis of methodological quality and data extraction. MAIN RESULTS: The searches identified 38 trials, of which 12 trials met our inclusion criteria, including a total of 2294 participants. Three additional studies examined the health care cost from one of the clinical trials. Ten studies compared rhDNase to placebo; one compared daily rhDNase with hypertonic saline and alternate day rhDNase; and one compared daily rhDNase to hypertonic saline. Study duration varied from six days to two years. The number of deaths was not significant between treatment groups. Lung function improved in the treated groups, with significant differences at one month, three months, six months and two years. The mean percentage change in FEV1in the two largest trials were 5.80 (95% CI 3.99 to 7.61) and 3.24 (95% CI 1.03 to 5.45). There was no excess of adverse effects except voice alteration (and rash, which were reported more frequently in one trial in the treated groups. Insufficient data were available to analyse differences in antibiotic treatment, inpatient stay and quality of life. REVIEWER'S CONCLUSIONS: There is evidence to show that therapy with rhDNase over a one month period is associated with an improvement in lung function in CF, results from a trial lasting six months also showed the same effect. Therapy over a two year period (based on one trial) significantly improved FEV1 in children and there was a non-significant reduction in the risk of infective exacerbations. Voice alteration and rash appear to be the only adverse events reported with increased frequency in randomised controlled trials.

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BACKGROUND: Recombinant human deoxyribonuclease is currently used to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis. OBJECTIVES: To determine whether the use of recombinant human deoxyribonuclease in cystic fibrosis is associated with improved mortality and morbidity as compared to placebo and to identify any adverse events associated with its use. To compare the efficacy of recombinant human deoxyribonuclease with other mucolytics. SEARCH STRATEGY: The Cochrane Cystic Fibrosis and Genetic Disorders Group specialist trials register which comprises references identified from comprehensive electronic database searches, hand searching relevant journals and abstracts from conferences. The company producing recombinant human deoxyribonuclease was also contacted. Date of the most recent search of the Group's specialised register: November 1999. SELECTION CRITERIA: All randomised and quasi-randomised trials where recombinant human deoxyribonuclease was compared to either placebo, standard therapy or another mucolytic for any duration, dose regimen and age of patient with cystic fibrosis of any disease severity. DATA COLLECTION AND ANALYSIS: Trials were independently assessed for inclusion criteria, methodological quality and data extraction by the two reviewers. Comparisons were between recombinant human deoxyribonuclease and placebo and recombinant human deoxyribonuclease and other mucolytics. The following outcomes were recorded: Mean % change from baseline in forced vital capacity (FVC), forced expiratory voloume at one second (FEV1) and weight, mean number of respiratory tract exacerbations, days intravenous and oral antibiotics used, mean number of days as inpatient, number of deaths, adverse events and the cost of therapy. MAIN RESULTS: Seven primary clinical trials were identified, totalling 1710 patients. Two further studies examined the health care cost of patients from one of the clinical trials. No eligible studies compared recombinant human deoxyribonuclease to another mucolytic. Five trials presented outcomes at up to one month, one at three months and one at six months. No reduction in mortality for treated patients was identified (Relative Risk (RR) at six month 1.01, 95%Confidence Interval (CI) 0.09, 11.11). Lung function improved to a greater extent in the treated groups (at six months Weighted Mean Difference (WMD) FEV1 5.7, 95%CI 4.18, 7.23, at three months 7.3, 95%CI 4.04, 10.65). Pooled data from the five trials of up to one month gave WMD 9.2 95%CI 0.93, 17. 6 although there was significant heterogeneity). Recombinant human deoxyribonuclease was well tolerated with no excess of serious adverse events (RR haemoptysis 0.89, 95%CI 0.54, 1.45, pneumothorax 0.97 95%CI 0.19, 4.96). Voice alteration was, however, reported more frequently in the treated groups (RR 2.33 95%CI 1.38, 3.93). No study analysed our pre-defined outcome measure for respiratory exacerbations and insufficient data was available to analyse differences in antibiotic treatment, inpatient stay and quality of life. REVIEWER'S CONCLUSIONS: Studies are of insufficient duration to identify a reduction in mortality or number of respiratory exacerbations. Further trials are required to answer these important questions. Recombinant human deoxyribonuclease therapy is associated with an improvement in lung function after six months treatment, but it is not possible to assess whether this effect on lung function is sustained in the long-term. No studies were identified that compared recombinant human deoxyribonuclease to another mucolytic.

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We describe two children with diagnostic features of Jeune syndrome who also had Hirschsprung disease. An association between the two conditions has not previously been described and has implications both for clinical management and for further study.

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A brother and sister from the island of Rodrigues had mental retardation, blindness owing to severe ocular malformations, short stature, dysmorphic facial features, hypotrichosis, and dental abnormalities. It is likely that they have a hitherto unrecognised autosomal recessive ectodermal dysplasia syndrome.

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A Chinese girl with oculocutaneous albinism has the Prader-Willi syndrome and a normal karyotype. This association emphasises the importance of further molecular study of the 15(q12) region of the genome in the search for the locus of an albinism gene.

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Nine markers from the pericentromeric region of chromosome 17 were typed in 16 British and five South African families with neurofibromatosis type 1 (NF1). The markers--p17H8, pHHH202, and EW204--were linked to NF1 at recombination fractions less than 1%. No evidence of locus heterogeneity was detected. Inspection of recombinant events in families informative for several markers suggests that the NF1 gene is located between the markers EW301 (cen-p11.2) and EW206 (cen-q12) and possibly distal to pHHH202 (q11.2-q12).

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Five members of a four-generation Mauritian family with ectrodactyly (split-hand/split-foot deformity) and ectodermal dysplasia but without clefting of the lip or palate have been investigated. The ectrodactyly ranged from virtual normality to severe tetramelic deficiencies. The ectodermal dysplasia manifested as hypotrichosis and abnormal dentition. Distinction is drawn between this autosomal dominant condition and the classical EEC syndrome; independent syndromic status is proposed.

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An autosomal dominant (AD) antecubital pterygium syndrome has been documented on the Indian Ocean Island of Rodrigues, and 11 affected family members in five generations have been studied over four decades. The consistent features include a fleshy web extending across the anterior aspect of the cubital fossa, absence of the long head of the triceps, limitation of full elbow extension and missing skin creases over the terminal inter-phalangeal joints of the fingers. On the basis of our observations, we consider that this condition warrants acceptance as an autonomous AD entity.

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Autosomal dominant microcornea with a cataract, previously described in four families, was documented in a seven-generation family. Eighteen family members had microcornea and a cataract, and an additional six had sclerocornea or Peters' anomaly. Most individuals with microcornea had a corneal diameter of less than 11 mm in both meridians, with moderately steep corneal curvatures. The inherited cataract progressed to form a total cataract after visual maturity had been achieved. In the four affected children who had not undergone cataract extraction, the common abnormality was a posterior polar lens opacity. The variability of expressivity of the dominant gene would suggest that the embryological origins of microcornea and sclerocornea are similar.

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Relationships among genetic markers in the region of the neurofibromatosis type 1 (NF1) gene on chromosome 17 were investigated by linkage studies in a large sample set of affected families and in a panel of 58 normal families. A new marker, pHHH202 (D17S33), was included along with two markers known to be closely linked to NF. The maximum likelihood estimate of the recombination rate between the pHHH202 and NF1 loci was found to be O. Multilocus analysis suggested the following marker order: pA10-41-(p3-6, pHHH202); the NF1 gene fell with equal likelihood between either pA10-41-p3-6 or p3-6-pHHH202. The odds against NF1 being outside this cluster of tightly linked markers were greater than 15:1.

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Ninety-five members of three South African Indian families were examined for neurofibromatosis (NF) and 45 were deemed to be affected in terms of accepted diagnostic criteria. Analysis of the pedigrees revealed autosomal dominant inheritance with full penetrance. The absence of macromelanosomes in skin biopsies of café-au-lait macules and the failure to detect Lisch nodules (hamartomas of the iris) in this population group raises further evidence that NF might be a heterogeneous condition. The potential importance of heterogeneity in molecular linkage studies is emphasised.

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