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Background and aims On 5 March 2007, the law concerning the child protection system was reformed. Since then, child protection services have been responsible for the management of child abuse and neglect. Reporting and asking for child protection is now easier for every physician by submitting a “preoccupying information” form. A study conducted in 2014 in the general practitioners (GP) in the Ille-et-Vilaine department showed that they were quite unfamiliar with the child protection updates and that they needed special training. We wished to study the knowledge and practices of the pediatricians in Brittany and compare these results to the previous study. Methods An anonymous postal investigation was conducted between May and July 2014. The questionnaire was referred to the previous study so the results would be comparable. Results A total of 134 pediatricians (including 99 women) of the 316 pediatricians of Brittany answered our questionnaire regarding their activity and their knowledge about child abuse and neglect. These results were analyzed and compared to the data of GPs in Ille-et-Vilaine. Only 4.4 % of the pediatricians obtained more than 80 % correct answers and 12 % of the pediatricians obtained fewer than 50 % correct answers. Among the pediatricians, 41 % of them had not reported a single time since 2007. The pediatricians who obtained better results (P Conclusion Child protection is a neglected subject, including by pediatricians. To fight against professional denial and isolation, a substantial effort is still needed concerning caregivers’ training as well as pediatric care organization.

Introduction Congenital hypothyroidism (CH) is a condition of thyroid hormone deficiency present at birth. Untreated CH results in severe mental impairment. An increased incidence of CH has been reported in France and worldwide that could be explained by an increase in transient forms of CH (TCH). We aimed to estimate the proportion of transient eutopic gland based on the characteristics of children at birth. Methods A probabilistic matching data from French CH neonatal screening program and French national health data system (SNDS) of children born between 2006 and 2012 (1, 763 with CH) allowed to linking 484 (68.8%) among 703 children with eutopic gland. Infants with six months or greater discontinuation of levothyroxine (LT4) treatment before the 31th December 2017 were classified transient CH. We used the Cox model to examine the predictors of TCH. Results Among infants with eutopic gland, 52.9% were female, 14.9% were preterm and 14, 1 % had low birth weight, 11.8 % had a first degree family history of thyroid diseases, 48.1% of mild CH (TSH Conclusions Prematurity and TSH level were predictors of transient CH. Additional analyses are ongoing to determine whether the occurrence of transient forms of TCH is increasing over the study period. Key messages Transient congenital hypothyroidism represent a significant part of HC at 10 years of follow-up. This finding has important implication on medical practices and should trigger research on the etiology of these transient forms.

Purpose Severe combined immunodeficiency (SCID) refers to a group of genetic disorders characterized by greatly compromised cellular and humoral immunity. Children with SCID are asymptomatic at birth, but they die from infections within the first months of life if not treated. Quantification of T-cell receptor excision circles is an extremely sensitive screening method for detecting newborns who may have SCID.The goal of the DEPISTREC study was to evaluate the feasibility of nationwide newborn screening for severe T-cell lymphopenia in France as well as its economic and clinical utility. Methods The test universally used for neonatal screening for SCID was the quantification of TRECs on Guthrie cards. We compared a group of 190,517 babies from 48 maternities across the country who underwent newborn SCID screening with a control group of 1.4 million babies out of whom 28 were diagnosed with SCID without such screening during the course of the study. Results Within the screening group, 62 babies were found to be lymphopenic, including three with SCID. The cost of screening ranged from 4.7€ to €8.15 per newborn. The average 18-month cost was €257,574 vs €204,697 in the control group. Conclusions In this large-scale study, we demonstrate that routine SCID screening is feasible and effective. This screening offers the additional benefit of aiding in the diagnosis of non-SCID lymphopenia. Economic evaluation allowed us to calculate the cost per test. Newborn screening may also prevent death by SCID before any curative treatment can be administered. The difference in cost between screened and control children could not be ascertained because of the very low numbers and death of one of the children tested.

Resume But La loi du 5 mars 2007 a reforme la protection de l’enfance (PE). A compter de cette date, la saisine des services administratifs en charge de la PE est realisee par l’envoi d’une information preoccupante (IP). Objectif Evaluer l’etat des connaissances et des pratiques des medecins generalistes (MG) concernant la realisation et la transmission d’une IP. Methodes Une enquete epidemiologique descriptive a ete realisee aupres de l’ensemble des MG liberaux d’Ille-et-Vilaine en charge du suivi de la majorite de la population pediatrique dans ce departement. Le but de ce travail a consiste a evaluer leur connaissance sur les dispositions de la loi mars 2007. Resultats Deux cent quatre-vingt-dix-huit medecins (33,15 %) ont repondu au questionnaire, dont 113 femmes (37,9 %). Le profil de l’echantillon etudie et de la population des MG dans ce departement etait comparable. Seuls 25,5 % des MG avaient entendu parler de la loi du 5 mars 2007. Le terme d’IP etait inconnu de 70,1 % des MG et son destinataire de 77,2 % d’entre eux. La difference entre signalement et IP etait ignoree par 79,5 % des MG. De fait, seul 5 % des MG disaient avoir ete formes sur l’IP. L’obstacle majeur quant a la redaction d’un ecrit dans une suspicion d’enfant en danger etait le manque de formation. Parmi les MG, 91,9 % en etaient demandeurs. Conclusion L’IP et la nouvelle loi de PE sont tres mal connues des MG du departement d’Ille-et-Vilaine. Notre etude souligne l’importance et la qualite d’une formation medicale initiale et continue.

Summary Neonatal screening for cystic fibrosis (CF) can detect infants with elevated immunoreactive trypsinogen (IRT) levels and inconclusive sweat tests and/or CFTR DNA results. These cases of uncertain diagnosis are defined by (1) either the presence of at most one CF-associated cystic fibrosis transmembrane conductance regulator (CFTR) mutation with sweat chloride values between 30 and 59 mmol/L or (2) two CFTR mutations with at least one of unknown pathogenic potential and a sweat chloride concentration below 60 mmol/L. This encompasses various clinical situations whose progression cannot be predicted. In these cases, a sweat chloride test has to be repeated at 12 months, and if possible at 6 and 24 months of life along with extended CFTR sequencing to detect rare mutations. When the diagnosis is not definite, CFTR functional explorations may provide a better understanding of CFTR dysfunction. The initial evaluation of these infants must be conducted in dedicated CF reference centers and should include bacteriological sputum analysis, chest radiology, and fecal elastase assay. The primary care physicians in charge of these patients should be familiar with the current management of CF and should work in collaboration with CF centers. A follow-up should be performed in a CF reference center at 3, 6, and 12 months of life and every year thereafter. Any symptom indicative of CF requires immediate reevaluation of the diagnosis. These guidelines were established by the “neonatal screening and difficult diagnoses” working group of the French CF society. Their objective is to standardize the management of infants with unclear diagnosis.

Objectives To evaluate the French cystic fibrosis newborn screening algorithm, based on data tracked by a centralized monitoring process, from 2002 to 2014. The programme aimed to attain European Standards in terms of positive predictive value, sensitivity, the ratio of screen positive patients diagnosed with cystic fibrosis to infants who screen positive but with inconclusive diagnosis (CFSPID), and time to diagnosis. Methods Retrospective analysis of programme performance, compliance with the algorithm, and changes in screening strategy. Results Modifications in the flow chart protocol improved the positive predictive value to 0.31 while maintaining the sensitivity at 0.95. Among infants diagnosed with cystic fibrosis, or identified as CFSPID, sweat test results were obtained for 94%, and two mutations were identified after exhaustive screening for the gene, when applicable, in 99.6%. The rate of pending diagnosis was very low (0.5%). The ratio of infants with cystic fibrosis:CFSPID was 6.3:1. Age at initial visit at the CF centre was ≤ 35 days, respectively, in 53%/26%. Conclusion Performances were in agreement with European standards, but timeliness of initial visit needed improvement. Our data complement an accumulating body of evidence demonstrating that attention must be paid to such ethical considerations as limiting carrier detection and inconclusive diagnosis. Newborn screening programmes should have a rigorous centralized monitoring process to warrant adjustments for improving performance to attain consensus guidelines.

Resume Ces recommandations sont destinees a harmoniser les procedures concernant la prise en charge des nourrissons de moins de 2 ans atteints de formes typiques de mucoviscidose et diagnostiques par depistage neonatal. Elles ont ete elaborees par le Groupe de travail « depistage neonatal de la mucoviscidose » de la Federation des centres de ressources et de competences de la mucoviscidose (CRCM) et validees selon la methodologie Delphi par des pediatres impliques dans le suivi au quotidien de ces nourrissons. Elles concernent la prise en charge au moment du diagnostic a la fois sur le plan de l’organisation des soins que du bilan initial et definissent le cadre du suivi du nourrisson depiste au plan nutritionnel, digestif et respiratoire pendant les 2 premieres annees de vie.

Resume Contexte Le syndrome du « bebe secoue » (SBS) associe classiquement des hemorragies intracrâniennes et retiniennes chez un enfant de moins de 2 ans. Les sequelles neurologiques etant frequentes, l’enfant peut pretendre a une indemnisation de son dommage. Notre etude trouve sa justification dans l’absence de litterature consacree au traitement judiciaire des SBS. Population et methode Il s’git d’une etude retrospective sur 10 ans des SBS signales aux tribunaux de grande instance (TGI) de Rennes et Saint-Malo. Les dossiers ont ete recenses a partir des archives du departement d’information medicale, de la cellule d’accueil specialise de l’enfance en danger et du service de medecine legale du centre hospitalier universitaire (CHU) de Rennes. Les dossiers judiciaires ont ete consultes apres accord des procureurs de la Republique. Resultats Sur 34 dossiers inclus, 12 n’ont pu etre consultes, 16 avaient abouti a un classement sans suite ou une ordonnance de non-lieu. Six dossiers ont abouti a une condamnation penale. L’auteur etait le pere (n = 5) ou l’assistante maternelle (n = 1). Il existait 3 jugements sur interets civils dont le montant moyen etait de 3333 euros (ecart-type 2082). Seulement 2 enfants ont ete indemnises par une Commission d’indemnisation des victimes d’infraction (CIVI). Conclusion La majorite des dossiers aboutit a une absence de condamnation et d’indemnisation. Le diagnostic medical de « secousses » et donc la potentielle intervention d’un tiers ne se traduisent pas necessairement par une condamnation penale. La designation systematique d’un administrateur ad hoc pourrait permettre une saisine plus frequente de la CIVI.

Resume Le depistage neonatal de l’hyperplasie congenitale des surrenales est generalise en France depuis 1995. Une evaluation recente a remis en question son interet chez le premature du fait d’un tres grand nombre de faux-positifs et d’une valeur predictive positive tres faible du dosage de la 17-hydroxyprogesterone. Un groupe de travail issu de l’Association francaise de depistage et de prevention des handicaps de l’enfant a collige l’ensemble des donnees epidemiologiques, cliniques et biologiques des enfants prematures porteurs de la maladie issus de la cohorte nationale. Les resultats des dosages ont ete compares a ceux des prematures sains. L’ensemble de ces donnees permet de conclure a l’absence de pertinence du depistage chez les prematures nes avant 32 semaines d’amenorrhee et a son efficience apres ce terme. Une etude pilote est en cours afin d’evaluer en population la possibilite d’interrompre le depistage chez ces grands prematures.

International audience; PURPOSE: Recent studies have shown an increased incidence of congenital hypothyroidism over the past 2 or 3 decades. The etiology of this change is unknown, but it has been related by several authors to lowering of cutoffs. We sought to determine whether the incidence of congenital hypothyroidism (CH) in France has changed. METHODS: We analyzed data from the nationwide neonatal screening program for CH during the period 1982-2012. We included all children having thyroid-stimulating hormone values above the threshold and for whom diagnosis of CH confirmed by the pediatrician. We estimated multicentric temporal trends in the annual incidence rates adjusted for screening methods for thyroid dysgenesis and eutopic gland. RESULTS: We found 6622 cases of CH (28.0 per 100,000 newborns); 1895 had a eutopic gland, and 4727 had thyroid dysgenesis. The incidence of eutopic glands showed a significant annual average increase of (5.1%; 95% confidence interval: 4.3-5.9) regardless of the screening method or screening center. This increase was confirmed in severe cases (thyroid-stimulating hormone \textgreater/=50: 2.1%; 95% confidence interval, 1.4-2.9). The incidence of dysgenesis remained constant. CONCLUSIONS: The incidence of eutopic glands increased in France, not only in mild forms but also in severe cases.

Aim: To evaluate formative evaluation, a pedagogic method that sensitizes mothers to sudden infant death syndrome (SIDS), as a new way to improve prevention of SIDS. Methods: Prospective and randomized study. Mothers in a test group (n = 148) received an educative questionnaire about SIDS during maternity stay. Three months later, we evaluated, by a telephonic interview, their scores of knowledge and observance of the recommendations in comparison with a control group (n = 144). Results: Mothers’ scores at the educative questionnaire was 5.12 (1.52) [mean(standard deviation)]. The scores performed 3 months later were better in test group for knowledge [7.64 (1.56) vs. 7.16 (1.61), p

Screening programs resulting in the early treatment of patients with congenital hypothyroidism (CH) have successfully improved neurodevelopmental outcome, but little is known about long-term health.The aim of the study was to assess health status, and socioeconomic attainment, for a population-based registry of young adult patients.All 1748 eligible patients diagnosed during the first decade after the introduction of neonatal screening in France were invited to participate in this study at a median age of 23.4 yr. Completed questionnaires were obtained from 1202 of the selected patients. The comparison group included 5817 subjects from the last French Decennial Health Survey.Health indicators including medical conditions, hearing and visual status, sociodemographic characteristics, and quality of life were measured.Patients with CH were significantly more likely than their peers to report associated chronic diseases (5.7 vs. 2.9%), hearing impairment (9.5 vs. 2.5%), visual problems (55.4 vs. 47.9%), and being overweight with a body mass index of at least 25 kg/m(2) (22.8 vs. 15.7%) (P0.0001). Furthermore, fewer patients attained the highest socioeconomic category (14.6 vs. 23.1%) and were in full-time employment (39.9 vs. 44.8%) (P0.0001). They were more likely to still be living with their parents and had a lower health-related quality of life than their healthy peers, particularly for mental dimensions, with a mean difference for the mental summary component of 0.35 SD score (P0.0001). CH severity at diagnosis, treatment adequacy, and the presence of other chronic health conditions were the main determinants of educational achievement and health-related quality of life scores.These findings highlight the need for careful monitoring of neurosensory functioning, weight, and long-term treatment adequacy throughout childhood and adulthood.

The diagnosis of cystic fibrosis (CF) is based on a characteristic clinical picture in association with a sweat chloride (Cl(-)) concentration greater than 60 mmol/L or the identification of two CF-causing mutations. A challenging problem is the significant number of children for whom no definitive diagnosis is possible because they present with symptoms suggestive of CF, a sweat chloride level in the intermediate range between 30 and 60 mmol/L, and only one or no identified CF-causing mutation.To investigate the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein in the airways of children with intermediate sweat tests and inconclusive genetic findings in correlation with clinical phenotype and genotype.We developed a composite nasal potential difference (NPD) diagnostic score to discriminate patients with CF from non-CF patients. We tested NPD in 50 children (age, 6 mo to 18 yr) with equivocal diagnoses and correlated the NPD diagnostic score with clinical phenotypes and genotypes.Fifteen of the 50 children had NPD scores in the CF range. Eight of the 15 carried two CFTR mutations compared with only 5 of the 35 children with normal NPD scores (P = 0.01). They were significantly younger at evaluation and had recurrent lower respiratory tract infections, chronic productive coughs, and chronic Staphylococcus aureus colonization significantly more often than the 35 children with normal NPD results.Evaluation of CFTR function in the nasal epithelium of children with inconclusive CF diagnoses can be a useful diagnostic tool and help clinicians to individualize therapeutic strategy.

Resume Ces recommandations sont destinees a harmoniser les procedures concernant le test de la sueur dans le cadre du depistage neonatal de la mucoviscidose en France. Elles ont ete elaborees par le groupe de travail « depistage neonatal de la mucoviscidose » de la federation des Centres de ressources et de competences de la mucoviscidose (CRCM). Le test de la sueur est pratique chez le nouveau-ne lorsqu’il a atteint le poids de 3 kg et qu’il est âge de plus de 3 semaines d’âge reel. La stimulation de la production de sueur est realisee par administration transdermique de la pilocarpine par iontophorese. Le recueil de sueur s’effectue de facon preferentielle en collecteur capillaire. Seul le dosage specifique de l’ion chlorure est retenu comme methode diagnostique. Un dosage de chlorure sudoral inferieur a 30 mmol/l elimine a priori une mucoviscidose. Un dosage de chlorure sudoral superieur ou egal a 60 mmol/l confirme une mucoviscidose. Le test est dit intermediaire entre ces 2 valeurs.

Sudden infant death syndrome (SIDS) is a huge hardship for parents, but also for health professionals. In 2007, 210 cases occurred in France, corresponding to a crude rate of 31.8 for 100,000 births. Between 1994 and 2007, 140 children of less than 2 years old were examined in the reference centre for SIDS in Rennes, France. We included in our study the children who were aged more than 28 days at death date, did not have a known lethal disease and were autopsied. A total of 80 children fulfilled those criteria. Post-mortem investigation included an autopsy, clinical and paraclinical exams (blood test, radiography, CT-scan...), and investigation of the circumstances of the death. Most of the cases were boys and were 2- to 5-month old. Ventral decubitus and gastrointestinal symptoms were often present. Autopsy gave elements about the causes of death in 23 cases and the other exams performed frequently showed an infectious viral context. Thanks to prevention and information campaigns about childcare done in the 1990s, SIDS incidence has largely decreased in France, but it is still too frequent. In our opinion, advice needs to be given again and again, especially concerning safe sleep practices, in order to increase adherence to these recommendations. Moreover, research should be continued to better understand this unexplained syndrome.

Infections by Nocardia species are uncommon and generally affect immunocompromised patients. This bacteria has rarely been isolated from cystic fibrosis patients (CF), especially those who are not taking oral corticosteroids. We report a case of a patient with CF harbouring Nocardia farcinica. An 18-year-old male diagnosed with CF at the age of eight (F508 del/G85E) had been treated for allergic bronchopulmonary aspergillosis in 1998 with itraconazole, and a first colonization with Pseudomonas aeruginosa was eradicated in 2003. From May 2006, he presented with recurrent left- and right-sided pneumothorax. In June 2006, he presented with dyspnoea, fever, and nodular eruption on his ankles. Chest X-ray and CT scan revealed a right pneumothorax, severe bronchiectasis and bilateral alveolar consolidation. N. farcinica was idolated from his sputum without any other pathogens. Treatment with intravenous cotrimoxazole associated with imipenem and amikacin was initiated for three weeks followed by oral cotrimoxazole for a further nine months. The patient's symptoms and alveolar consolidation on CT scan improved. During 2007, his respiratory condition worsened and his FEV(1) declined from 50 to 26 % predicted. His pneumothorax recurred. He had chronic colonization with P. aeruginosa and was on the list for lung transplantation. Nocardia, a Gram positive bacillus, causes mainly pulmonary infection, usually in the context of immune suppression. The most frequent species is N. asteroides. In CF, very few cases have been reported; almost always N. asteroides, but exceptionally N. farcinica. In CF patients with worsening pulmonary condition, Nocardia should be considered, as well as other unusual pathogens.

BackgroundA comparison of the longitudinal progression of lung disease in cystic fibrosis patients identified through newborn screening (NBS) in cohorts located in two different countries has never been performed and was the primary objective of this study.MethodsThe study included 56 patients in Brittany diagnosed through NBS between 1989 and 1994 and 69 similar patients in Wisconsin between 1985 and 1994. The onset and progression of lung disease was radiographically quantified using the Wisconsin Chest X-ray (WCXR) scoring system. A single pediatric pulmonologist blinded to all identifiers scored the films.ResultsGeneralized estimating equation analyses adjusted for age, genotype, sex, pancreatic insufficiency, and meconium ileus showed worse WCXR scores in Brittany patients compared to Wisconsin patients (average score difference=4.48; p

Summary Objectives The focus of this report is hearing screening of newborns transferred from the regular nursery to a specialized area. The purpose of the study undertaken was: (1) to determine whether screening coverage in this population was achieved; (2) to establish whether the linkage between neonatal screening and the diagnostic follow-up was carried out correctly; (3) to better determine the incidence of permanent childhood hearing impairment (PCHI) in this at-risk population. Methods Six population centres averaging 12,000 births annually participated (Bordeaux, Lille, Paris, Marseille, Toulouse and Lyon). Automated auditory brainstem response (AABR) (Natus ALGO 3i ® ) screening was performed in two stages: i.e. infants with initial “positive” results were screened a second time using the same technique. Of the 117,103 babies born during the study period, 4972 neonates were “transferred” and comprised the population for this report (4.2% of the total births). Results and discussion Screening results for 4972 “transferred” neonates were compared with those of non-transferred neonates ( N = 112,131). Screening coverage of eligible infants was significantly lower (75.4%) in “transferred” neonates (3750 infants screened) compared to 97.5% coverage of non-transferred neonates (109,349 infants screened). The rate of positive results after the first stage AABR was higher in the “transferred” population (11.1%) than in the non-transferred population (6.5%). Of the 415 “transferred” newborns with initial positive screens, 91.3% were rechecked as stipulated in the project protocol. The second pre-discharge AABR ascertained that in half of the cases auditory function had normalized in the day. Of the 183 “transferred” infants whose result remained suspect at the conclusion of both stages of the neonatal screen (4.9% of the tested population), only 70.5% returned to the audiology centre for diagnostic follow-up. The incidence of bilateral PCHI was markedly higher (4/1000) in “transferred” infants than in the non-transferred population (1.08/1000). Conclusions The difficulty of obtaining universal screening coverage in “transferred” infants was, unfortunately, verified in this prospective, multicentre study. Further, the diversity of our “transferred” population was not much greater than that revealed by careful analysis of published hearing screening studies in neonatal intensive care unit (NICU) infants. The influence of risk factors and their more or less complex combinations is apparent.

Resume La mucoviscidose est la maladie genetique letale la plus frequente chez les Caucasiens, due a une lesion d'un gene codant pour la proteine CFTR. L'atteinte de l'appareil respiratoire est la principale cause de morbidite et de mortalite. Une colonisation devenant permanente des voles aeriennes par Haemophilus influenzae, Staphylococcus aureus puis Pseudomonas aeruginosa conduit a une succession de poussees d'inflammation et d'infection aboutissant a l'insuffisance respiratoire. Les patients atteints de mucoviscidose sont egalement predisposes a des complications bronchopulmonaires telles que les infections fongiques et l'aspergillose bronchopulmonaire allergique, l'infection a Burkholderia cepacia, les hemoptysies et les pneumothorax. Un suivi standardise dans un centre de soins specialise et le traitement precoce des symptomes et des complications permettent de retarder l'evolution de la pathologie respiratoire.

Resume Objectifs L'etude avait pour but d'analyser l'evolution de la fonction pulmonaire d'enfants atteints de mucoviscidose ayant beneficie d'un depistage neonatal, en fonction de leur statut infectieux chronique a Pseudomonas aeruginosa (PA), de l'etat nutritionnel, du sexe, de l'âge, de la presence ou non d'une homozygotie ΔF508. Population et methodes Un suivi longitudinal des epreuves fonctionnelles respiratoires (EFR) et bacteriologique a ete effectue au cours de consultations systematiques 3 fois par an. Quarante enfants et 744 EFR ont ete etudies, dont 38 enfants avaient au moins 4 ans de suivi. Resultats L'etude a montre un declin des EFR en rapport avec le statut infectieux chronique a PA et la presence d'une homozygotie ΔF508, independamment des autres facteurs. Les EFR etaient liees aux facteurs nutritionnels de facon independante. Les EFR ont montre un declin graduel qui n'etait pas different apres colonisation recente, mais les EFR des enfants colonises anciennement etaient tres alterees, en faveur d'une deterioration importante probablement avec l'acquisition de souches de PA multiresistantes. Conclusion Notre etude souligne l'interet de la surveillance de la fonction respiratoire avant 5 ans chez ces enfants colonises precocement. Il nous semble important d'affiner notre analyse bacteriologique pour determiner si l'acquisition de PA mucoides est a l'origine de l'importante degradation des EFR, constatee chez ces enfants anciennement colonises.

Objectives To compare the cost effectiveness of adding a pancreatitis-associated protein (PAP) assay to common immunoreactive trypsinogen (IRT) and DNA cystic fibrosis (CF) newborn screening strategies. Methods Using data collected on 553,167 newborns, PAP cut-offs were calculated based on non-inferiority of the detection rates of classical forms of CF. Cost effectiveness was considered from the third-party payer's perspective using only direct medical costs, and the unit costs of PAP assays were assessed based on a micro-costing study. Robustness of the cost-effectiveness estimates was assessed, taking the secondary outcomes of screening (ie. detecting mild forms and CF carriers) into account. Results IRT/DNA, IRT/PAP, and IRT/PAP/DNA strategies had similar detection rates for classical forms of CF, but the strategies involving PAP assays detected smaller numbers of mild forms of CF. The IRT/PAP strategy was cost-effective in comparison with either IRT/DNA or IRT/PAP/DNA. IRT/PAP/DNA screening was cost-effective in comparison with IRT/DNA if relatively low value was assumed to be attached to the identification of CF carriers. Conclusions IRT/PAP strategies could be strictly cost-effective, but dropping DNA would mean the test could not detect CF carriers. IRT/PAP/DNA strategies could be a viable option as they are significantly less costly than IRT/DNA, but still allow CF carrier detection.

Objective Oxidative stress, excess production of reactive oxygen species (ROS) and intense colonization of the respiratory tract by microorganisms are described in CF patients, leading to an influx in macrophages. This results in activation of NADPH oxidase that yields ROS, initiating the oxidative burst responsible for pathogen destruction. We showed that phagocytosis was altered in CF macrophages, yet oxidative status in this cell was not defined. The objective of this study is to draw a link between oxidative stress and plasma membrane integrity in CF macrophages, since lipid peroxidation is known to alter cell membrane. Methods Peripheral blood monocytes-derived macrophages were obtained from CF patients and healthy subjects. Plasma membrane fluidity was assessed with di4-ANEPPDHQ and oxidative status was measured with ROS indicating probes. Results In CF macrophages, membrane fluidity was increased whereas lipid peroxidation was diminished. Surprisingly, general oxidative status remained similar to the one observed in non-CF macrophages. Also, CF macrophages did not abolish chemically induced-oxidative stress. In non-CF macrophages, treatment with cholesterol slightly increased membrane fluidity whereas LPS treatment had no effect. Conclusion CF macrophages displayed an increased membrane fluidity associated with a decreased lipid peroxidation. This raises the hypothesis that membrane alteration in CF macrophages may be due to other mechanism than oxidative stress. Nevertheless, since the killing capacity of CF macrophage is defective, a deregulation of O •− 2 production is very likely, suggesting alteration of NADPH oxidase or mitochondrial dysfunction.

The sources of exposure during diseases due to Aspergillus fungi in cystic fibrosis patients are still poorly explored. We assessed home fungal exposure in patients suffering from cystic fibrosis and analysed its impact on the presence of Aspergillus biological markers, the colonisation of airways, as well as the sensitization and Aspergillus serology. Between March 2012 and August 2012, 34 patients benefited from a visit performed by a home environment medical adviser including sampling for mycological analysis. The number of colonies of Aspergillus was not significantly different in the various sampling sites (P=0.251), but the number of non-Aspergillus colonies was much higher in the kitchen (P=0.0045). Subsequently, home fungal exposure was compared between the groups "absence of Aspergillus-related markers" and "presence of Aspergillus-related markers". Home exposure to Aspergillus (P=0.453) and non-Aspergillus (P=0.972) flora was not significant between the 2 groups. Within this series of 34 patients that should be expanded, we note an absence of clear relationship between home exposure and the Aspergillus-linked markers in patients suffering from cystic fibrosis. This result should be taken into account regarding too restrictive hygiene advices provided to families, given the fact that fungal exposure can also results from activities performed away from home.

Resume Objectifs. – Apprecier l'interet de la mesure de la T LCO chez les patients atteints de mucoviscidose et evaluer son caractere predictif d'une desaturation arterielle a l'exercice. Methodes. – Quarante-quatre patients, âges de 9 a 30 ans, suivis pour mucoviscidose, ont beneficie d'une exploration fonctionnelle respiratoire avec mesure de la T LCO et d'un test d'effort maximal sur bicyclette ergometrique. Le degre de gravite de leur maladie etait variable : score de Shwachman moyen : 77,8 (40–100), VEMS moyen : 72,8 % des valeurs de reference (17–131 %). Les resultats de T LCO ont ete confrontes au score de Shwachman, aux parametres ventilatoires et aux resultats du test d'effort. Resultats. – La T LCO s'est averee longtemps conservee chez les patients atteints de mucoviscidose : 82 % avaient une T LCO normale (moyenne : 91,3 % de la valeur theorique). Elle etait correlee de facon significative au score de Shwachman, au VEMS, au volume residuel, a la puissance maximale developpee, a la consommation maximale d'oxygene. La survenue d'une desaturation arterielle lors de l'exercice etait peu frequente (observee seulement chez 5 patients) et n'etait pas correlee significativement a la T LCO . Conclusions. – La T LCO est un bon critere de gravite de la maladie mais ne permet pas de definir des valeurs seuils au-dessus desquelles l'activite physique peut etre proposee sans risque de desaturation arterielle. Des tests d'effort devraient etre realises plus systematiquement chez ces patients pour apprecier leur adaptation a l'exercice et definir precisement leur facteur limitant.

Resume Le depistage neonatal (DNN) de la mucoviscidose permet le reperage pre-symptomatique des malades. L'enjeu pour l'equipe multidisciplinaire des Centres de Ressources et de Competences pour la Mucoviscidose est la mise en place d'un suivi medical permettant la prevention des complications nutritionnelles et respiratoires et leur prise en charge afin de maintenir ce bon etat de sante. Le DNN repere par ailleurs une cohorte de nouveau-nes suspects de mucoviscidose ne repondant pas aux criteres de la maladie : il s'agit de formes atypiques pour lesquelles le diagnostic, le pronostic et la prise en charge ne sont pas clairement etablis. Les recommandations publiees sont des avis d'experts sur les modalites de suivi et de traitement qui permettent d'aider les familles et les medecins traitants, d'harmoniser les pratiques au sein des equipes specialisees medicales et paramedicales. Un autre enjeu majeur de la prise en charge de ces tres jeunes malades est mise en route d'etudes cliniques randomisees a visee nutritionnelle ou pulmonaire ; ces dernieres sont limitees par l'absence de criteres d'evaluation respiratoire sensibles, standardises et reproductibles. Le reseau europeen des essais cliniques a initie une demarche tres active pour stimuler la recherche clinique chez les tres jeunes enfants.

Cystic fibrosis (CF) is the most common severe inherited disorder that affects children in Caucasian populations. The aim of this study was to define the spatial and temporal distribution of CF and its mutations in Brittany (western France) where the frequency of the disease is high. We retrospectively registered all CF patients born in Brittany since 1960 by cross-checking various data sources (e.g. medical care centres, genetics laboratories, hospital archives). Councils were contacted so that the place of residence of patients at birth could be determined. Moreover, the spectrum of CF transmembrane conductance regulator (CFTR) mutations and their spatial distribution across Brittany were determined. A total of 520 patients was registered in this study. The incidence of CF was assessed according to administrative (department, district) and diocesan divisions of Brittany and its evolution analysed over four decades. The incidence of CF was 1/2630, with a west/east gradient that was confirmed over time (Finistère: 1/2071 vs Ille-et-Vilaine: 1/3286). At present, the incidence of CF is decreasing, mainly as a result of prenatal diagnosis. An excellent mutation detection rate of 99.7% was obtained. Western Brittany presented a specific spectrum of mutations: 1078delT (9.4% of mutated alleles in the diocese of Cornouaille), G551D (7.7% in the diocese of Léon), 4005+1G--A (2.9% in Cornouaille) and W846X (1.5% in western Brittany). On the other hand, the eastern region showed a spectrum more similar to the overall picture in France as a whole. This study enabled a precise measurement of the incidence of CF in Brittany to be obtained. The high frequency of the CFTR mutated alleles may result from founder effects and genetic drifts. Moreover, the study brings together the regional specificities of the CFTR gene and highlights disparities that exist in this part of France, both in incidence and in mutation distribution. These are attributable to different degrees of isolation and of population movements between the eastern and western parts of the region. Given that this is the first time that such a detailed study of the CFTR gene has been performed on a large population, this heightened knowledge of the epidemiology of CF in Brittany should provide a basis for the improvement of diagnostic strategies and refinement of genetic counselling.

Newborn screening (NBS) for cystic fibrosis (CF) was implemented throughout France in 2002. It involves a four-tiered procedure: immunoreactive trypsin (IRT)/DNA/IRT/sweat test was implemented throughout France in 2002. The aim of this study was to assess the performance of molecular CFTR gene analysis from the French NBS cohort, to evaluate CF incidence, mutation detection rate, and allelic heterogeneity. During the 8-year period, 5,947,148 newborns were screened for cystic fibrosis. The data were collected by the Association Francaise pour le Depistage et la Prevention des Handicaps de l’Enfant. The mutations identified were classified into four groups based on their potential for causing disease, and a diagnostic algorithm was proposed. Combining the genetic and sweat test results, 1,160 neonates were diagnosed as having cystic fibrosis. The corresponding incidence, including both the meconium ileus (MI) and false-negative cases, was calculated at 1 in 4,726 live births. The CF30 kit, completed with a comprehensive CFTR gene analysis, provides an excellent detection rate of 99.77% for the mutated alleles, enabling the identification of a complete genotype in 99.55% of affected neonates. With more than 200 different mutations characterized, we confirmed the French allelic heterogeneity. The very good sensitivity, specificity, and positive predictive value obtained suggest that the four-tiered IRT/DNA/IRT/sweat test procedure may provide an effective strategy for newborn screening for cystic fibrosis. Genet Med 17 2, 108–116.

Resume Objectifs. – L’interet de generaliser le depistage neonatal de la mucoviscidose en France fait maintenant l’objet d’un large consensus. La strategie actuellement disponible fait appel au dosage sanguin de trypsin(ogen)e immunoreactive suivi, en cas de trypsine immunoreactive elevee (environ 1 % de la population), d’une recherche de mutations du gene CFTR . Le recours a l’analyse genetique pose cependant de nombreux problemes (diversite des mutations a rechercher selon les regions, prise en charge des heterozygotes, contraintes imposees par les lois sur la bioethique). Une etude anterieure a montre l’interet de la pancreatitis-associated protein , proteine de stress pancreatique, comme test de depistage, et suggere qu’une strategie en deux etapes, dosage de la pancreatitis-associated protein puis de la trypsine immunoreactive pour selectionner les enfants devant subir un test de la sueur, pourrait avoir des performances compatibles avec un depistage de masse, tout en evitant le recours a l’analyse genetique. Le but de cette etude etait d’evaluer cette strategie sur un grand nombre de naissances. Methodes et resultats. – Une etude prospective a ete menee sur 47 213 nouveau-nes de la region Provence-Alpes-Cote-d’Azur. Parmi les enfants ayant une pancreatitis-associated protein superieure a 7,5 ng/mL (1,28 %) (methode ELISA), 176 avaient egalement une trypsine immunoreactive elevee (superieure a 700 ng/mL). Dans cette population restreinte (0,37 % du total), le test de la sueur a permis de detecter cinq enfants atteints. Un sixieme cas, jumeau d’un enfant depiste, n’a pas ete repere, probablement a cause d’une erreur de procedure. L’analyse genetique realisee en parallele a confirme les diagnostics et detecte un nouveau-ne porteur de deux mutations mais de phenotype toujours normal a l’âge de 20 mois. L’incidence observee, correspondant a l’incidence precedemment etablie, et le fait qu’aucun autre cas n’a ete rapporte depuis la cloture de l’etude (deux ans), suggerent que la sensibilite du depistage est satisfaisante. La specificite obtenue etait suffisamment bonne pour qu’un diagnostic par le test de la sueur soit directement realisable sur l’ensemble des enfants depistes, sans selection prealable par l’analyse genetique. Conclusion. – Le depistage neonatal de la mucoviscidose par la strategie associant les tests pancreatitis-associated protein –trypsinogene immunoreactive semble avoir des performances compatibles avec les exigences d’un depistage de masse, sans les inconvenients de la strategie trypsinogene immunoreactive–genetique.

Resume Le vegetalisme peut engendrer chez l’adolescent des lesions osteoarticulaires par rachitisme et osteomalacie et une anemie megaloblastique par carence en vitamine B12. Observation. – Un adolescent de 15 ans a ete hospitalise pour une boiterie et une pâleur intense. Il avait une epiphysiolyse femorale bilaterale avec une demineralisation diffuse par rachitisme et osteomalacie due a une carence en vitamine D. Il existait une anemie megaloblastique par carence en vitamine B12. Apres une supplementation prolongee en calcium, vitamines D et B12, associee a un traitement orthopedique, l’evolution des lesions osseuses a ete stabilisee et l’anemie corrigee. L’adolescent et son frere cadet ont ete victimes d’une carence d’apport par regime vegetalien. En raison d’un refus de soins, des poursuites penales ont abouti a l’incarceration des parents et au placement des enfants. Commentaires. – Le vegetalisme expose a des carences en calcium, vitamines D et B12. L’observation revele egalement le probleme social et juridique d’un regime inadapte impose par des parents adeptes d’une eglise integriste. Au-dela de la prise en charge des enfants des sectes, il revient aux professionnels de la sante de prevenir, depister et supplementer les regimes carences.

Resume Le depistage neonatal systematique de la mucoviscidose est pratique en Bretagne depuis 1989, mais pas dans le departement voisin de Loire-Atlantique. Cette etude compare le devenir des enfants des deux populations neuf ans apres le debut du depistage. Ces enfants sont suivis dans des centres de soins differents, mais selon des protocoles similaires. Population et methodes. – Tous les enfants atteints de mucoviscidose nes entre le 1er janvier 1989 et le 31 decembre 1997 en Bretagne et en Loire-Atlantique, a l’exclusion de ceux revele par un ileus meconial, ont ete compares pour leurs caracteristiques intrinseques initiales et pour leur devenir sur les neuf ans de l’etude. Resultats. – Les deux populations ne differaient pas significativement pour le sex-ratio, l’âge gestationnel, la biometrie de naissance, la proportion d’homozygotes ΔF508, l’âge moyen des enfants. L’âge au moment du diagnostic etait plus faible en Bretagne (37 contre 372 jours, p Conclusion. – Le caractere homogene des deux populations et de leur prise en charge permet, malgre les faibles effectifs et la nature retrospective de l’etude, de degager des tendances benefiques du depistage, deja retrouvees dans d’autres pays le pratiquant partiellement. Cela nous incite a recommander sa generalisation dans nos populations, qui devra s’accompagner d’un suivi des enfants depistes dans des centres de soins de reference, afin d’en tirer les meilleurs benefices.

International audience; BACKGROUND:The high frequency of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene mutation p.Arg117His in patients with congenital bilateral absence of the vas deferens (CBAVD) and in newborns screened for CF has created a dilemma.METHODS:Phenotypic and genotypic data were retrospectively collected in 179 non-newborn French individuals carrying p.Arg117His and a second CFTR mutation referred for symptoms or family history, by all French molecular genetics laboratories, referring physicians, CF care centres and infertility clinics.RESULTS:97% of the patients had the intronic T7 normal variant in cis with p.Arg117His. 89% patients were male, with CBAVD being the reason for referral in 76%. In 166/179 patients with available detailed clinical features, final diagnoses were: four late-onset marked pulmonary disease, 83 isolated CBAVD, 67 other CFTR-related phenotypes, including 44 CBAVD with pulmonary and/or pancreatic symptoms and 12 asymptomatic cases. Respiratory symptoms were observed in 30% of the patients, but the overall phenotype was mild. No correlation was observed between sweat chloride concentrations and disease severity. Five couples at risk of CF offspring were identified and four benefited from prenatal or preimplantation genetic diagnoses (PND or PGD). Eight children were born, including four who were compound heterozygous for p.Arg117His and one with a severe CF mutation.CONCLUSIONS:Patients with CBAVD carrying p.Arg117His and a severe CF mutation should benefit from a clinical evaluation and follow-up. Depending on the CBAVD patients' genotype, a CFTR analysis should be considered in their partners in order to identify CF carrier couples and offer PND or PGD

Resume L'atteinte renale, quoique rare, figure parmi les localisations extradigestives des maladies inflammatoires du tube digestif. Observation. — Un diagnostic de maladie de Crohn a ete porte chez une jeune fille de 12 ans (diarrhee chronique, douleurs abdominales et retard staturoponderal). Une resection de stenose ileocaecale a ete pratiquee 6 mois plus tard, apres correction de la denutrition, suivie de complications locales avec fistule cutanee. Apres 1 an de recul, lors d'une poussee avec ecoulement purulent par la fistule cutanee, apparait une glomerulonephrite, avec hematurie macroscopique et insuffisance renale a diurese conservee. La biopsie renale conclut a une nephropathie glomerulaire a depots mesangiaux d'IgA avec lesions tubulaires aigues. L'evolution est favorable avec le traitement de la fistule par nutrition parenterale et chirurgie: l'insuffisance renale et la proteinurie regressent, l'enfant garde une hematurie microscopique. L'insuffisance renale et la proteinurie ne rechuteront pas, meme lors d'une nouvelle poussee de la maladie de Crohn. Conclusion. — Des glomerulonephrites a IgA secondaires ont ete decrites dans l'evolution des maladies inflammatoires intestinales. Le mecanisme etiopathogenique qui pourrait unir les deux affections n'est pas elucide. On evoque la production d'IgA a partir de la muqueuse digestive, l'augmentation du taux serique d'IgA et/ou la formation de complexes immuns circulants a IgA.

International audience; OBJECTIVE: To assess the efficiency of the French national screening program for 21-hydroxylase deficiency (21-OHD). Neonatal screening for congenital adrenal hyperplasia due to 21-OHD is mainly intended to prevent death due to salt wasting but remains controversial because of the number of false-positive results and the ease with which most female cases can be identified by virilized genitalia at birth. DESIGN: Population-based study. SETTING: National neonatal screening program, pediatric endocrinologists nationwide, and reference center for genotyping. PARTICIPANTS: All neonates screened for 21-OHD in mainland France between January 1, 1996, and December 31, 2003. OUTCOME MEASURES: Screening efficiency indicators, disease severity, contribution of screening to early diagnosis, and disease-specific mortality before and during the study period. RESULTS: A total of 6 012 798 neonates were screened; results in 15 407 were considered positive for 21-OHD. Three hundred eighty-three cases were identified, giving a prevalence of 1 for every 15 699 births. The positive predictive value of screening was 2.3% (95% CI, 2.1%-2.6%), with a sensitivity of 93.5% (90.9%-95.9%) and a specificity of 99.7% (99.7%-99.7%). The false-positive rate was particularly high in preterm infants, for which the positive predictive value was 0.4% (95% CI, 0.2%-0.5%). Screening allowed clinical diagnosis in 162 of 383 cases (42.3%), with the others being detected clinically or through family history. There was a trend toward declining neonatal mortality due to 21-OHD. CONCLUSIONS: In this large population-based study, the efficiency of routine 21-OHD screening was moderate in neonates born at term and very low in preterm neonates. We recommend the discontinuation of screening, as currently performed in France, in preterm neonates.

Background Cystic fibrosis (CF) is an autosomal recessive disorder whose incidence has long been estimated as 1/2500 live births in Caucasians. Expanding implementation of newborn screening (NBS) programs now allows a better monitoring of the disease incidence, what is essential to make reliable predictions for disease management. This study assessed time trends in the birth incidence of CF over a long period (35 years: 1975-2009) in an area where CF is frequent (Brittany, France) and where NBS has been implemented for more than 20 years. Methods This study enrolled CF patients born in Brittany between January 1st 1975 and December 31st 2009 (n = 483). Time trends in incidence were examined using Poisson regression and mainly expressed using the average percent change (APC). Results The average number of patients born each year declined from 18.6 in the late 1970's (period 1975-79) to 11.6 nowadays (period 2005-09). The corresponding incidence rates dropped from 1/1983 to 1/3268, which represented a decline close to 40% between these two periods (APC = -39.3%, 95% CI = -55.8% to -16.7%, p = 0.0020). A clear breakpoint in incidence rate was observed at the end of the 1980's (p < 0.0001). However, the incidence rate has remained quite stable since that time (annual APC = -1.0%, 95% CI = -3.0% to 1.1%, p = 0.3516). Conclusions This study provides an accurate picture of the evolution of the incidence of a genetic disease over a long period and highlights how it is influenced by the health policies implemented. We observed a 40% drop in incidence in our area which seems consecutive to the availability of prenatal diagnosis.

International audience; AIM: To evaluate formative evaluation, a pedagogic method that sensitizes mothers to sudden infant death syndrome (SIDS), as a new way to improve prevention of SIDS. METHODS: Prospective and randomized study. Mothers in a test group (n = 148) received an educative questionnaire about SIDS during maternity stay. Three months later, we evaluated, by a telephonic interview, their scores of knowledge and observance of the recommendations in comparison with a control group (n = 144). RESULTS: Mothers' scores at the educative questionnaire was 5.12 (1.52) [mean(standard deviation)]. The scores performed 3 months later were better in test group for knowledge [7.64 (1.56) vs. 7.16 (1.61), p < 0.01] and for observance [8.28 (1.51) vs. 7.62 (1.72), p < 0.001]. Logistic regression analysis confirmed the benefits in test group regarding knowledge of SIDS risk factors [ORa = 1.69 (1.02-2.77), p < 0.05], of the advice to avoid overheating infants [ORa = 2.50 (1.43-4.38), p < 0.01] and of the risks of bed sharing [ORa = 2.7 (1.6-4.5), p < 0.001]. There was a significant association between non-compliance with the sleeping position recommendation and unemployment (p < 0.01) and absence of postsecondary school education (p < 0.01). CONCLUSION: Formative evaluation using an educative questionnaire could improve maternal awareness on SIDS risk factors and their compliance with recommendations about SIDS prevention.