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Purpose. – Arterial or venous thromboses are frequent in patients with homocystinuria. Because severe homocystinuria is rare, prevalence of thombosis, especially in France, is still unknown.Methods. – Review of the clinical outcome of 37 patients with homocystinuria due to cystathionine-cystathionine beta-synthase deficiency (34) and 5,10-methylenetetrahydrofolate reductase (three) lead us to describe vascular complications occurring in 12 (32%) of them.Results. – Venous thromboembolism is the earlier and the most frequent one and is mainly found in untreated late-diagnosed cases. Under specific treatment of homocystinuria, thromboses are rare and always a complication of surgery associated with high thromboembolic risk. Association with factor V Leiden increased the risk of venous thrombosis. [ABSTRACT FROM AUTHOR]

Objectives: To assess: (1) lower limb primary lymphedema or post-thrombotic syndrome patient's pathway in terms of health care professional use and (2) if aetiology of edema has an impact on this pathway., Methods: Ancillary survey of the transversal prospective CHROEDEM pilot study. Forty patients with either lower limb primary lymphedema or post-thrombotic syndrome were invited to participate., Results: Seventy-five percent of primary lymphedema patients and 50% of post-thrombotic patients benefited from a multidisciplinary management (P=0.10) including the general practitioner, the vascular medicine physician and either a physiotherapist (particularly in case of primary lymphedema), a registered nurse (particularly in case of post-thrombotic syndrome). Main ambulatory health care professionals' correspondent of hospital-based vascular medicine physicians were general practitioners (80%) in post-thrombotic patients, and general practitioners (60%) and physiotherapists (45%) in primary lymphedema patients. Pharmacists were also involved in patient education., Conclusion: Management of primary lymphedema and post-thrombotic related chronic edema is usually multidisciplinary. General practitioners and vascular medicine physicians are the cornerstones of this management, that also involves the physiotherapist in case of primary lymphedema and in a lesser extent the registered nurse and the pharmacist. This suggests that these five healthcare professional should play a key role in case of development of standardized patient pathways for primary lymphedema and post-thrombotic syndrome., (Copyright © 2020. Published by Elsevier Masson SAS.)

Background: In routine clinical practice, in most countries, patients with pulmonary embolism (PE) are hospitalized for clinical surveillance and to start anticoagulant treatment. Clinical trials and guidelines suggest that patients with stable PE can be safely treated as outpatients. This shift in management may increase general practitioners' (GP) role in PE early management. However, GP opinion regarding PE home treatment has never been assessed., Methods: Survey conducted in France among a random sample of 360 GP (564 contacted to reach targeted sample size) working in regions representative of national access to French healthcare system. Main objectives were to assess i) GP' acceptability to PE home treatment ii) GP' preferred outpatient pathway., Results: 87% of GP were favorable to home treatment of stable PE if the medical report is immediately available when the patient is discharged from ER (100%), in the absence of social and medical facility isolation of the patient (99%) and if the patient (99%) and GP (76%) consented. Outpatient pathways should be collaborative, between GP and a thrombosis specialist, and should include specialized follow-up visits at one week (80%), 3-6 months (80%) and when anticoagulant treatment is stopped (97%). 61% of GP felt that direct oral anticoagulants (DOAC) should facilitate PE home treatment, which should improve patient's quality of life., Conclusion: The vast majority of interviewed GP are favorable to home treatment of stable PE if a formal outpatient pathway is established. DOAC are perceived as another key for the success of the development of PE home treatment., Competing Interests: Declaration of competing interest JP Galanaud received a research grant from Bayer to conduct the study. Other authors state that they have no conflicts to disclose in relation with this work., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Cutaneous microcystic lymphatic malformations (CMLMs) are rare conditions in children and adults. They present as clusters of vesicles full of lymph and blood to various extents, inducing maceration, esthetic impairment, pain, and impaired quality of life. The treatment is challenging. Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR) involved in angio-lymphangiogenesis. Topical sirolimus has recently been reported as effective in a few reports of patients with CMLMs. The objective is to compare the efficacy and safety of a 12-week application of 0.1% topical sirolimus versus topical vehicle in CMLMs in children and adults., Methods: This French blinded multicenter within-person randomized controlled phase 2 trial aims to include 55 patients aged ≥ 6 years who have a primary CMLM. The CMLM will be divided into two equal areas that will be randomly allocated to 0.1% topical sirolimus or topical vehicle applied for 12 weeks. At the end of the 12-week period, the patient/parent will treat the whole area of CMLM with 0.1% topical sirolimus on remaining lesions, for eight more weeks. Patients will be seen at week 20 (treatment will be stopped) and at month 12 to evaluate long-term efficacy. The primary outcome will be improvement of the CMLM in the area treated with topical sirolimus compared to the area treated with topical vehicle by the investigator physician (blinded to the treatment) with the Physician Global Assessment score at week 12. Secondary outcomes will include: assessment of efficacy by independent experts on the basis of standardized photographs; impact on quality of life; efficacy for oozing, bleeding, erythema, and thickness evaluated by the investigators; and global efficacy as well as efficacy for functional and aesthetic impairment evaluated by the patient. Systemic passage of sirolimus will be measured at weeks 6, 12, and 20, and at week 16 for CMLMs ≥ 900 cm 2 ., Discussion: For patients with CMLMs, topical sirolimus could be a non-invasive and well-tolerated therapeutic option. If the trial demonstrates efficacy and safety of this treatment, this result will lead to a real change in the management of this condition, and 0.1% sirolimus cream would become the first-line treatment., Trial Registration: ClinicalTrials.gov, NCT03972592. Registered on 3 June 2019. EU Clinical Trials Register EudraCT, 2018-001359-11.

Introduction: Venous thromboembolism (pulmonary embolism and deep-vein thrombosis) is a frequent, serious but also chronic disease. Studies reported that both general practitioners (GPs) and vascular medicine physicians (VMPs) report participating in patient education concerning venous thromboembolic disease., Objective: To assess the role of GPs and VMPs in venous thromboembolic disease patient education, examining the patient's perspective., Method: Phone survey of the French patients recruited in the CACTUS trial assessing anticoagulant treatment in case of first distal deep-vein thrombosis., Results: Among the 103 participating patients, 92% (n=95) reported being satisfied by information provided by the GP and VMP. Information was considered as necessary in 96% of cases (n=99). Eighty-five percent of patients (n=88) felt they did not need complementary information. The VMP would have spent more time on education as compared with the GP (an entire consultation in 93.2% vs. 38.8% of cases respectively) the information provided by the VMP being also clearer and more complete. More than 75% of patients reported that no physician warned them about risks of anticoagulants, long-term complications of venous thromboembolic disease or its prevention., Conclusion: In CACTUS, patients reported being satisfied by information provided by their managing physicians and information provided by the VMP was clearer and more complete. Important education messages may not have been delivered suggesting the need for a standardization of venous thromboembolic disease patient's education., (Copyright © 2019. Published by Elsevier Masson SAS.)

Out-of-pocket payments might threaten the vertical equity of financing and generate unmet medical needs. The main objective was to assess the vertical equity of outpatient out-of-pocket payments for lymphedema patients in France. Twenty-seven centres, among which 11 secondary care hospitals and 16 primary care practices participated in this prospective national multicenter study. We measured the lymphedema-specific outpatient out-of-pocket payments over 6 months. The vertical equity of out-of-pocket payments was examined using concentration curves, the Gini coefficient for income, the Kakwani index, and the Reynolds-Smolensky index. We included 231 lymphedema patients aged 7 years or more, living in metropolitan France, and being able to use Internet and email. After voluntary health insurance reimbursement, the mean out-of-pocket payment was equal to 101.4 Euros per month, mainly due to transport (32%) and medical devices (26%). Concentration curves indicated regressivity of out-of-pocket payments. Total out-of-pocket payments represented 10.1% of the income by consumption unit for the poorest quintile and 3.5% for the wealthiest (p<0.05). The Kakwani index for out-of-pocket payments was equal to -0.18. Regarding outpatient health care, French lymphedema patients face significant and regressive out-of-pocket payments, associated with an increased risk of unmet medical needs. Such results shed light on significant socioeconomic inequalities and bring into question the current financing arrangements of outpatient health care in France. Trial registration: ClinicalTrials.gov ID: NCT02988479., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Distal deep-vein thromboses (iDDVT) are infra-popliteal DVTs. They are as frequent but less serious than proximal DVT. Their management is debated., Methods: Clinical practice survey among a random selection of 111 general practitioners (GP) and 56 vascular medicine physicians (VMP) working in Languedoc-Roussillon (France) to assess and compare iDDVTs management by GP and VMP., Results: In case of DVT, GP manage their patients alone in 35% of cases. In case of collaborative management, VMP initiate and stop anticoagulants (>74% of cases) whereas GP monitor anticoagulation (>76% of cases). With iDDVT, there was no difference between GP and VMP in terms of use (94% vs. 92%) and intensity of anticoagulation (full dose: 99%vs.100%). Duration of anticoagulation differed: GP modulated less frequently duration of anticoagulation in presence of a transient risk factor (58% vs. 90%, p<0.05) or according to the deep-calf or muscular location of iDDVT (6% vs. 36%, p<0.05) and treated more frequently iDDVT as long as proximal DVT (49% vs. 13%, p<0.05). When comparing GP, there was no significant difference in terms of therapeutic management between those who used to manage DVT alone and those who used to manage in collaboration with a thrombosis expert., Conclusion: Treatment of iDDVT differed between GP and VMP. Half of GP don't modulate treatment according to anatomical location or to the provoked/unprovoked character of DVT. Given the low frequency of exposure to DVT in general practice, systematic referral to a thrombosis expert rather than continuous medical formation program seems appropriate to improve management., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: In France, initial management of pulmonary embolism (PE) is performed in the hospital setting. The latest international guidelines suggest that PE at low risk of mortality can be treated in the ambulatory care setting. This means that ambulatory care pathways and general practitioner (GP) opinions concerning such a change in practice need to be determined., Objectives: To determine: (1) rate of patients eligible for an ambulatory management of their PE and reasons for hospitalization of PE at low risk of mortality; (2) acceptability for GPs of PE home care and patient's desired care pathway., Methods: Two-part prospective observational study conducted in Montpellier University Hospital from May 2012 to August 2013: (1) in-hospital study including all consecutive patients with non-hospital acquired PE; (2) telephonic survey on PE patient's ambulatory care pathway conducted among GPs., Results: In-hospital study: 99.1% (n=211) of included patients were hospitalized and only 14.1% (n=30) had all criteria for home care. Patient's pathway survey: 68.3% (n=112) of GPs, particularly those aged 40-54 years and those who had already managed patients alone after hospital discharge, were in favour of home care for PE. One hundred and thirty-nine (84.8%) GPs wanted a collaborative management with an expert thrombosis physician and an outpatient follow-up visit at one week., Conclusion: Few patients managed at Montpellier University Hospital are eligible for ambulatory management of their PE. GPs have a favorable opinion of home care for PE if it is conducted in collaboration with an expert thrombosis physician., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

The incidence of thrombosis in the purely obstetric form of antiphospholipid syndrome is uncertain. We performed a 10-year observational study of 1592 nonthrombotic women who had experienced 3 consecutive spontaneous abortions before the 10th week of gestation or 1 fetal death at or beyond the 10th week of gestation. We compared the frequencies of thrombotic events among women positive for antiphospholipid Abs (n = 517), women carrying the F5 6025 or F2 rs1799963 polymorphism (n = 279), and women with negative thrombophilia screening results (n = 796). The annual rates of deep vein thrombosis (1.46%; range, 1.15%-1.82%), pulmonary embolism (0.43%; range, 0.26%-0.66%), superficial vein thrombosis (0.44%; range, 0.28%-0.68%), and cerebrovascular events (0.32%; range, 0.18%-0.53%) were significantly higher in aPLAbs women than in the other groups despite low-dose aspirin primary prophylaxis. Women carrying 1 of the 2 polymorphisms did not experience more thrombotic events than women who screened negative for thrombophilia. Lupus anticoagulant was a risk factor for unprovoked proximal and distal deep and superficial vein thrombosis and women in the upper quartile of lupus anticoagulant activity had the highest risk. Despite data suggesting that aPLAbs may induce pregnancy loss through nonthrombotic mechanisms, women with purely obstetric antiphospholipid syndrome are at risk for thrombotic complications.

Aims: To describe the clinical presentation and 3-month mortality in recognized forms of venous thromboembolism (VTE)., Methods: All 8256 patients referred to 359 vascular physicians for clinical suspicion of VTE were included over a 15-month period in France. Subjects without a confirmed diagnosis of VTE served as controls. Risk factors, clinical presentation and estimated 3-month survival for each form of VTE were evaluated., Results: Of 5889 patients, 426 had pulmonary embolism (PE) with deep vein thrombosis (DVT), 148 had PE without DVT, and 5315 had no VTE. 2350 patients with other VTE events (DVT and superficial vein thrombosis) and 17 other patients were excluded of the analysis. PE without DVT patients presented differently for risk factors in the univariate analysis. Three-month mortality was 4.0% for controls, 12.9% for PE with DVT, and 4.6% for PE without DVT. Compared with controls, only PE with DVT patients (adjusted hazard ratio: 2.6 95% CI [1.4-4.7]) were at increased risk of mortality., Conclusions: PE without DVT is not associated with a higher 3-month mortality compared to controls, in contrast to PE with DVT. When diagnosing PE in patients, the clinical significance of an associated DVT is important., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)

Venous thromboembolism (VTE) is a major therapeutic issue in cancer patients. Advances in this field and heterogeneities in clinical practices prompted us to establish guidelines in the management of VTE in cancer patients according to the SOR (Standards, Options and Recommendations) methodology. A literature review of the studies published on this topic between 1999 and 2007 was performed. The guidelines were developed from the analysis of 38 out of 418 publications selected. They were peer-reviewed by 65 independent experts. The treatment of VTE in patients with cancer, including those with intracranial malignancies, should be based on low-molecular-weight heparins administered at therapeutic doses for at least 3 months. In the event of recurrent VTE, pulmonary embolism with hemodynamic failure or contra-indication to anticoagulant treatment, the indications and usages of vena cava filters and thrombolytic drugs should be the same as in non-cancer patients.

Rapid advances has been made in the diagnosis and treatment of venous thromboembolic disease, but many questions or controversies remain. In this review, we present a progress report on various concepts still open to discussion. New epidemiologic data from the French epidemiology study, Optimev, are presented. Widespread use of multidetector CT scan for the diagnostic work-up of pulmonary embolism has had considerable impact on clinical practices. We discuss indications and use of the various imaging methods. The review ends with a report on constitutional or acquired thrombophilia, particularly cancer-associated venous thromboembolic disease, which remains a daily preoccupation with various approaches still under debate. This review was the topic of the French vascular medicine teaching seminary in November2007.

The "Standards, Options: Recommendations" (SOR) project has been undertaken by the French National Federation of Cancer Centers (FNCLCC) and is now part of the French National Cancer Institute. The project involves the development and updating of evidence-based Clinical Practice Guidelines (CPG) in oncology. In order to answer questions related to venous thromboembolic events (VTE) treatment and to central venous catheter thrombosis (CVCT) management in cancer patients, the SOR elaborated national guidelines, here presented in a short report. It results of a collaborative work with members from three learned societies (<< Société nationale française de médecine interne >> : SNFMI, << Société française de médecine vasculaire >> : SFMV and << Société française d'anesthésie-réanimation >> : SFAR).

The <> (SOR) project has been undertaken by the French National Federation of Cancer Centers (FNCLCC) is now part of the French National Cancer Institute. The project involves the development and updating of evidence-based Clinical Practice Guidelines (CPG) in oncology. In order to answer questions related to venous thromboembolic events (VTE) treatment and to central venous catheter thrombosis (CVCT) management in cancer patients, the SOR elaborated national guidelines, here presented in a short report. It results of a collaborative work with members from three learned societies ("société nationale française de médicine interne": SNFMI, "société française de médicine vasculaire": SFMV and "société française d'anesthésie-réanimation": SFAR).

It was the objective of this study to design a clinical prediction score for the diagnosis of upper extremity deep venous thrombosis (UEDVT). A score was built by multivariate logistic regression in a sample of patients hospitalized for suspicion of UEDVT (derivation sample). It was validated in a second sample in the same university hospital, then in a sample from the multicenter OPTIMEV study that included both outpatients and inpatients. In these three samples, UEDVT diagnosis was objectively confirmed by ultrasound. The derivation sample included 140 patients among whom 50 had confirmed UEDVT, the validation sample included 103 patients among whom 46 had UEDVT, and the OPTIMEV sample included 214 patients among whom 65 had UEDVT. The clinical score identified a combination of four items (venous material, localized pain, unilateral pitting edema and other diagnosis as plausible). One point was attributed to each item (positive for the first 3 and negative for the other diagnosis). A score of -1 or 0 characterized low probability patients, a score of 1 identified intermediate probability patients, and a score of 2 or 3 identified patients with high probability. Low probability score identified a prevalence of UEDVT of 12, 9 and 13%, respectively, in the derivation, validation and OPTIMEV samples. High probability score identified a prevalence of UEDVT of 70, 64 and 69% respectively. In conclusion we propose a simple score to calculate clinical probability of UEDVT. This score might be a useful test in clinical trials as well as in clinical practice.

Calf vein thrombosis corresponds to infrapopliteal deep vein thrombosis which accounts for roughly 50% of all cases of deep vein thrombosis and shares the same risk factors as proximal deep vein thrombosis. The complication rate and proper management remain debated. Recent studies suggest that the risk of proximal extension of calf vein thrombosis is 1 to 5% and that the risk of postthrombotic syndrome is 3%. In France, calf vein thrombosis is usually treated with compression stockings associated with a six week to three month regimen of anticoagulation therapy in patients presenting a transient triggering factor or longer otherwise. However, the benefit of such treatment, in terms of the hemorragic risk incurred, remains uncertain. The randomized double blind trial CACTUS (compression stocking + placebo versus compression stocking + heparin, for six weeks) that will start in September 2007, should provide answers the following question: should calf vein thrombosis be treated with anticoagulants?

Within the framework of a patient education training programme, a group of health sector professionals comprised of hospital doctors, general practitioners, nurses, physiotherapists and dieticians created a programme intended for people with peripheral vascular disease (intermittent claudication). A study was carried out simultaneously utilising a questionnaire and a series of four interviews which permitted professionals to collect data on the patients' expectations regarding such a programme and their points of view at each specific stage of its development. This article analyses the contribution of the patients to the therapeutic patient education programme design, namely with respect to their influence on the programme's content, on the educational process and approach as well as on the professionals' perspectives on disease, various treatments and people with this particular illness. The discussion highlights the range of goals and objectives that can potentially be met through dialogue and exchange between people suffering from the same disease.

Unlabelled: Venous thromboembolism (VTE) is a frequent disease and remains a major cause of mortality and morbidity among our patients. During the 20 past years, clinical description, diagnostic tools, and treatment have changed dramatically. Most published data describing risk factors for VTE no longer apply to the patients seen in daily practice. We present here the rationale, aims, and methodology of the OPTIMEV Study (OPTimisation de l'Interrogatoire pour la Maladie thromboEmbolique Veineuse)., Rationale: Risk factors for VTE are numerous, complex and interactions between them and their clinical importance is difficult to measure (table I). For example, odds ratios for VTE recurrence vary greatly across longitudinal studies. We searched the National Library of Medecine (PubMed) and the Amedeo website using the following keywords: "venous thromboembolism", "pulmonary embolism", "deep vein thrombosis", "risk factors". We selected 84 relevant articles published between 1972 and 2005. Based on this literature analysis, we identified the following major risk factors: VTE recurrence, surgery, cancer, immobilization, age, biological factors. For these factors, data are lacking and some questions are proposed., Objectives: The broad objective of the study is to better evaluate clinical risk factors that fit today's practice against VTE. Specific aims are: 1) to determine whether risk factors are different between proximal and distal deep vein thrombosis (DVT); 2) to develop and prospectively validate a new prediction rule for outpatients. The primary hypothesis is that careful assessment of VTE recurrence, adequate surgical thromboprophylaxis, cancer staging, and varicose vein stratification according to the CEAP classification, is mandatory for accurate evaluation of thromboembolic disease risk., Methods: We conducted a multicenter, prospective, cohort study of 10000 patients. Enrollees are inpatients and outpatients presenting with a clinical suspicion of VTE in Emergency Departments and outpatient clinics in France. 4173 patients have been enrolled at this time (Figure 2). All eligible patients are enrolled during a selected period of time through different seasons. Data are collected by physicians in charge of the patients using an electronic case recording form. Collected data include baseline characteristics, risk factors, results of diagnostic investigations. Outcome measures obtained through telephone interview at 3 and 12 months include cancer diagnosis, VTE recurrence, haemorrhagic events, treatments, death. Univariate and multivariate analysis will be performed using multilevel logistic regression. The study organization is performed by the Centre d'Investigation Clinique de Grenoble and is sponsored by the French Society of Vascular Medicine. First results, to be published in 2006, will allow development of new prediction rules for VTE diagnosis.

In the last 5 years, mutations in three genes, the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the cationic trypsinogen (PRSS1) gene, and the pancreatic secretory trypsin inhibitor (PSTI) gene, have been found to be associated with chronic pancreatitis (CP). In this study, using established mutation screening methods, we systematically analysed the entire coding sequences and all exon/intron junctions of the three genes in 39 patients with idiopathic CP (ICP), with a view to evaluating the relative contribution of each gene to the aetiology of the disease. Our results demonstrate that, firstly, 'gain-of-function' mutations in the PRSS1 gene may occasionally be found in an obvious ICP subject. Secondly, presumably 'loss-of-function' mutations in the PSTI gene appear to be frequent, with a detection rate of at least 10% in ICP and, finally, abnormal CFTR alleles are common: at least 20% of patients carried one of the most common CFTR mutations, and about 10% of patients were compound heterozygotes, having at least one 'mild' allele. Thus, in total, about 30% of ICP patients carried at least one abnormal allele in one of the three genes, and this is the most conservative estimate. Moreover, a trans-heterozygous state with sequence variations in the PSTI/CFTR genes was found in three patients. However, an association between the 5T allele in intron 8 of the CFTR gene and ICP remains unproven.

Nowadays, most of the neonatal screening programs for cystic fibrosis (CF) combine the assay of immunoreactive trypsinogen (IRT) with the analysis of the most common mutations of the CFTR gene. The efficiency of this strategy is now well established, but the identification of heterozygotes among neonates with increased IRT is perceived as a drawback. We proposed to assess the heterozygosity frequency among the children with hypertrypsinaemia detected through the CF screening program implemented in Brittany (France) 10 years ago, to describe the CFTR mutations detected in them and to determine the frequency of the IVS8-5T variant. The molecular analysis relies, in our protocol, on the systematic analysis of three exons of the gene (7-10-11). A total of 160,019 babies were screened for CF in western Brittany between 1992 and 1998. Of the 1964 newborns with increased IRT (1.2%), 60 were CF and 213 were carriers. Heterozygosity frequency was 12.8%), i.e. 3 times greater than in the general population (3.9%; p < 10(-6)), Variability of mutations detected in carriers was greater than in CF children (21 mutations versus 10) and a high proportion of mild mutations or variants (A349V, R297Q, R347H, V317A, G544S, R553G, etc) was observed in carriers. The allelic frequency of the 5T (5.6%) was not significantly increased in this cohort. This study is consistent with previous ones in finding a significantly higher rate of heterozygotes than expected among neonates with hypertrypsinaemia. The strategy of screening used here allows to highlight the variability of mutations detected in heterozygotes and to show that severe mutations, as well as mild mutations, have been observed in neonates with hypertrypsinaemia. If there is no doubt that neonatal hypertrypsinaemia is associated with an elevated frequency of carriers, the underlying mechanisms remain obscure.

Background: Neonatal screening for cystic fibrosis has been a subject of debate over the past few years. This study assesses 10 years of neonatal screening in Brittany, France, and examines its impact on prenatal screening of subsequent pregnancies in couples with an affected child., Methods: The study included all the neonates screened for cystic fibrosis in Brittany from Jan 1, 1989, to Dec 31, 1998. The screening consisted of an immunoreactive trypsinogen assay from dried blood spots, plus, from 1993, mutation analysis. Data were collected on incidence of cystic fibrosis, and genotypic and biochemical characteristics. The use of prenatal screening of subsequent pregnancies in affected families was also investigated., Findings: Of the 343,756 neonates screened, 118 children with cystic fibrosis were identified, giving an incidence of one in 2913. All mutated alleles were characterised: 34 different mutations resulting in 36 genotypes were detected. The introduction of DNA analysis into the protocol greatly reduced the recall rate and increased the sensitivity of the test. The mean cost of the screening programme was US$2.32 per screened child. 39 (34%) of the families identified by neonatal screening opted for subsequent prenatal diagnosis at least once. 12 couples would have benefited from this procedure while their first child was still symptom-free. 42 healthy children were born, and 18 pregnancies were terminated (therapeutic abortion rate of 100%)., Interpretation: We have shown the feasibility of neonatal screening for cystic fibrosis in Brittany. Through the detection of a large range of mutations, neonatal screening provides the opportunity for more reliable prenatal diagnosis and cascade screening. The neonatal screening programme described here could provide a good model for other countries intending to initiate such a scheme.

Apart from the high frequency of the delta F508 mutation (81.81%) in Breton cystic fibrosis chromosomes, one mutation, 1078 del T, is also observed frequently (4.96%) in this group, in comparison with the rest of the French where it occurs with a frequency of 0.57%. These two mutations account for more than 86.5% of the total CF mutations identified on Breton chromosomes. We have conducted an unblinded retrospective analysis of 25 patients with the 1078 del T mutation and compared their phenotypes with those of a group of 70 delta F508 homozygous patients. Both groups of patients had the same ethnic origin and were regularly attending the same CF centre in Brittany, which makes this sample highly homogeneous despite the small size. The 1078 del T mutation appeared to be associated with severe presentation of the disease with, however, a trend to reduced mortality and less Pseudomonas aeruginosa colonisation.

To assess the relationship between the genotype and phenotype of adult CF patients we have selected from a group of 512 CF patients attending centres in France, all these of greater than 35 years. We have analysed the entire coding sequence of their CFTR genes. The complete genotype was determined in 7 of the 8 patients and clinical data regarding pancreatic, respiratory and reproductive function were carefully evaluated. All these patients are compound heterozygote, seven carrying the delta F508 and one the G542X on one allele. The other allele carried is: (i) a missense mutation located in exons coding for transmembrane region in five patients [R334W (1); I336K (2); R117H (1); H1054D (1)]; (ii) a splice mutation in two patients [2789 + 5G-->A], (iii) an uncharacterised mutations in one patient. These results strongly suggest less severe CF phenotype to be associated with these mutations and strengthen the hypothesis that less severe phenotype are genetically determined.

The cystic fibrosis transmembrane regulator gene, one of the most commonly mutated in the European population, was cloned in 1989 and since then has been extensively analysed in patients of various ethnic backgrounds. We have screened the entire coding sequences of the cystic fibrosis transmembrane regulator gene and identified many mutations and polymorphisms. In this paper we propose a general strategy to improve prenatal diagnosis and genetic counselling of cystic fibrosis (CF). As this approach based on denaturing gradient gel electrophoresis is adaptable to different populations, it greatly increases the sensibility and specificity of CF prenatal diagnosis.