Genetic counseling for cystic fibrosis: A basic model with new challenges.

While the goals of genetic counseling for cystic fibrosis - delivering relevant information on the risk of recurrence and nondirectional support of couples at risk in their reproductive choices - have not changed fundamentally, the practice has evolved considerably in the last decade, growing more complex to face new challenges but also proving more effective. Many factors have contributed to this evolution: technical progress in the exploration of the genome (new generation sequencing) and in reproductive medicine, but also societal developments promoting access to genetic information and the professionalization of genetic counselors in France. The prospect of expanded pre-conception screening of at-risk couples makes genetic counselors major actors not only in medical care centers, but also in modern society by contributing to genetic education among citizens. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

Guidelines for the clinical management and follow-up of infants with inconclusive cystic fibrosis diagnosis through newborn screening.

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 59mmol/L or (2) two CFTR mutations with at least one of unknown pathogenic potential and a sweat chloride concentration below 60mmol/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.

[Management of infants whose diagnosis is inconclusive at neonatal screening for cystic fibrosis]. / Recommandations pour la prise en charge et le suivi des nourrissons pour lesquels un diagnostic de mucoviscidose n'a pu être conclu après dépistage néonatal.

Neonatal screening for cystic fibrosis (CF) may detect infants with elevated immunoreactive trypsinogen (IRT) levels but with inconclusive sweat tests and/or DNA results. This includes cases associating (1) either the presence of at most one CF-causing mutation and sweat chloride values between 30 and 59mmol/L or (2) two CFTR mutations with at least one of unknown pathogenicity and a sweat chloride below 60mmol/L. This encompasses different clinical situations whose progression cannot be predicted. These cases require redoing the sweat test at 12 months and if possible at 6 and 24 months of life. This must be associated with extended genotyping. CFTR functional explorations can also help by investigating CFTR dysfunction. These infants must be initially evaluated in dedicated CF centers including bacteriological sputum analysis, chest radiology and fecal elastase dosage. A home practitioner must be informed of the specificity of follow-up. These infants will be reviewed in the CF center at 3, 6 and 12 months and every year. Any CF-related symptom requires reevaluation of the diagnosis. These guidelines were established by the "neonatal screening and difficult diagnoses" working group of the French CF Society. They aim to standardize management of infants with unclear diagnosis in French CF centers.

[Comparison of palliative care representations between pediatrician residents and oncologist residents: A qualitative study]. / Comparaison des représentations des soins palliatifs des internes de pédiatrie à celles des internes d'onco-hématologie - étude qualitative.

BACKGROUND: Pediatrics residents treat patients who are particularly vulnerable and they care for many patients in palliative situations. The purpose of this study was to build a typology detailing the representations of pediatrics and oncology residents on palliative care and how these transfer to their practice, and to determine their knowledge of euthanasia and end-of-life legislation. METHODS: To draw up this typology, we used a semidirective interview method. The topics treated were their definition of palliative care, end of life, the emotions involved in these situations, and their daily practice. Then we asked them to speak about their opinions and knowledge of euthanasia and end-of-life legislation. RESULTS: Thirteen residents were interviewed: eight pediatrics residents, two oncologists, and three hemato-oncologists. Interviews lasted around 45min. Pediatrics and oncology residents had common representations based on "care giving." Nevertheless, pediatrics residents remained within the technical aspects to protect themselves from their negative emotions and stayed away from their patients. Oncology residents set their emotions aside to be able to carry on taking care of their patients. CONCLUSION: It seems necessary to disseminate a palliative culture, particularly in pediatrics, to improve management of children in palliative situations and to improve resident's feelings.

[National French guidelines for management of infants with cystic fibrosis]. / Recommandations nationales pour la prise en charge du nourrisson dépisté atteint de mucoviscidose. Consensus de la fédération des centres de ressources et de compétences de la mucoviscidose.

These guidelines aim to standardize the care of infants diagnosed with a typical form of cystic fibrosis (CF) at neonatal screening. They have been implemented by the National Working Group for Neonatal Screening of the French Federation for CF and have been validated using the Delphi methodology by a large group of clinicians involved in the care of CF infants. These guidelines encompass management and organization of care at diagnosis and describe nutritional, digestive, and respiratory monitoring and treatment during the first 2 years of life.

Characteristics of endobronchial primitive tumors in children.

Primary endobronchial tumors are rare in children and they include a broad spectrum of lesions. The aim of this study was to determine the characteristic features, treatments and outcomes of these tumors. We report a retrospective analysis of all patients treated for endobronchial tumor in nine French hospitals between 1990 and 2010 and a comparison of the results with those reported in the medical literature. Twelve tumors were reported: five low grade muco epidermoid carcinomas, two inflammatory myofibroblastic tumors, two hemangiomas, one anaplastic large cell lymphoma, one carcinoid tumor, and one juvenile xanthogranuloma. The mean age of the patients was 7.5 ± 3.5 years. The most common sign revealing the disease was persistent atelectasis or recurrent pneumonia (eight cases). The other revealing signs were a persistent bronchospasm (three cases) and hemoptysis (one case). The clinical presentation, biology, serum tumor markers, and chest X-ray abnormalities were not specific to a particular histological diagnosis. Chest CT scan revealed the presence of an endobronchial tumor in 11 cases. Nine tumors could be diagnosed from a biopsy obtained by video endoscopy. Complete surgical resection was performed in seven patients. Bronchoscopic removal was performed in five cases and was successful in three. There were no deaths. Endobronchial tumors are rare in childhood and their histology is diverse. Chest CT scan and per-endoscopic endobronchial biopsies are required for diagnosis, when possible. Surgical or endoscopic treatment should be discussed by a multidisciplinary team. Despite the multiple etiologies, the prognosis of these tumors is good if diagnosis is early and if resection is complete. Long-term recurrences have been described, so long-term follow-up of these children is recommended.

[Two uncommon extrapulmonary forms of Mycoplasma pneumoniae infection]. / Infections extrapulmonaires àMycoplasma pneumoniae : atteintes neurologique et rénale.

Mycoplasma pneumonia is the second most frequent bacterium in pneumonia and the leading intracellular type. M. pneumoniae pulmonary infection is characterized by a slower onset profile and a lower biological inflammatory picture than pneumococcal infection. Both upper and lower respiratory tracts are often affected and sometimes a Kawasaki-like syndrome can be associated, with conjunctivitis or cheilitis. Extrapulmonary forms of the disease can occur, whether or not it is associated with pulmonary infection. We report two cases: in the first case, a renal form of M. pneumoniae disease developed in a 6-year-old girl, with membranous proliferative glomerulonephritis expressed as a picture of impure nephritic syndrome with decreased serum complement concentration, following an upper respiratory infection. Diagnosis was obtained by means of a kidney biopsy. The second case occurred in an 8-year-old girl who expressed, after a respiratory tract infection, neurological symptoms such as ocular flutter, perception disorder, and ataxia. This onset is typical of post-infectious rhombencephalitis. Biological investigations and imaging were normal. In both cases, M. pneumoniae infection was diagnosed on the basis of immunoglobulin M-positive serology. Direct exploration of the bacterium was negative, due to its fragility and delayed diagnostic hypothesis. Several forms of M. pneumoniae infection are either the direct effect of the bacterium or are secondary to a cross-immunological reaction. As its frequency is increasing, M. pneumoniae infection should be raised as a cause of atypical, less well-known extrapulmonary forms of the disease.

[Human metapneumovirus]. / Métapneumovirus humain.

The human metapneumovirus (hMPV) is a new Pneumovirinae related to the avian metapneumovirus type C. hMPV genome differs from human respiratory syncytial virus (RSV) genome by the gene order and the lack of nonstructural genes. Two genetic sub-groups and four sub-types of hMPV are identified. hMPV infections evolve as regular winter outbreaks which have roughly the same size and overlaping RSV epidemics. Among hospitalized children in Caen, hMPV is detected in 9.7% of the cases after RSV (37%), rhinovirus (18%), influenza virus (14.5%), adenovirus (9%), and parainfluenza virus (5%). Most of hMPV infections are observed in children suffering from bronchiolitis, but the localization to lower respiratory tract and the severity of the disease are less frequent in comparison with RSV infections. hMPV is very difficult to isolate using cell culture. Up to now, the only way for hMPV diagnosis was the TS-CRP assays. But the recent apparition of direct antigenic tests allows us to get a fair, rapid, and economic diagnostic tool.

[Virology: the contribution of molecular biology in the microbiologic diagnosis of pediatric respiratory diseases]. / Virologie : l'apport de la biologie moléculaire dans le diagnostic microbiologique en pneumopédiatrie.

The conventionnal tools used for virological diagnosis include direct antigen detection by immunofluorescence (IFA) or an immunoenzymatic test (EIA), and viral isolation technique (VIT). In most cases, IFA and EIA have a slightly lower sensitivity than VIT but are also able to detect some VIT-negative samples. Results of several teams using RT-PCR technologies show that the molecular methods detect more positive cases than the conventional tools. Work is under way to expand the number of viruses detected by multiplex RT-PCR and to determine wether newly discovered viruses, such as human metapneumovirus, contribute to burden of paediatric lower respiratory infections. In conclusion, according to requirements of speed, low cost of the methods, and to achieve the highest rate of detection of respiratory viruses, the combined use of IFA and multiplex RT-PCR is today likely to be the best way to improve diagnosis of respiratory illnesses in children.

[Modifier genes and cystic fibrosis]. / Les gènes modificateurs dans la mucoviscidose.

Cystic fibrosis is the most common lethal autosomal recessive disease among the Caucasian population. It is caused by defects in the CFTR gene (Cystic Fibrosis Transmembrane Conductance Regulator). Although over 1600 disease-causing mutations in the CFTR gene have been described, the highly variable disease phenotype in cystic fibrosis cannot be explained on the basis of this gene alone. Both the environment and other non-CFTR genes are likely to be important. The increased understanding of pathophysiological processes in the cystic fibrosis lung has led to several studies on genes in these pathways. One of the major aims of such studies is to produce targets for novel drug developments.

[Pseudomonas aeruginosa and cystic fibrosis: first colonization to chronic infection]. / Pseudomonas aeruginosa et mucoviscidose: "de la primocolonisation a l'infection chronique".

Pseudomonas aeruginosa (Pa) is the most common virulent respiratory pathogen in cystic fibrosis and is characterized by an important capacity of adaptation, adherence and communication. The factors of virulence of Pa play a major part in adherence with the respiratory epithelial cells and in occurrence of infectious episodes. The factors responsible for the transition of first Pa acquisition to the chronic infection are not elucidated yet. The system of secretion of type III and the quorum sensing (QS) play an important role. The QS would intervene in the maturation of the biofilm of Pa, responsible for the "mucoid" phenotype of Pa, associated to a degradation of the respiratory function. We made a retrospective study on the period 1984-2005 within the Center of Cystic fibrosis of Caen allow to determine the percentage of firstly-colonized and chronic infected patients with Pa according to age. At 6 months of life, 11% of the infants were colonized with Pa reaching 48% to 7 years and 85% at the 18 years age. The percentage of chronic children carrying Pa was 0% at 1 year, 11% at 4 years, 44% at 12 years and 74% at 18 years according to the method of Kaplan-Meier. Comparing the period 1984-1994 with that of 1995-2005, the firstly-colonization and the chronic carrying of Pa occurred earlier and significantly during the second period. The current objective, beside the respiratory care, comprises the maintenance of an optimal nutritional statute and, waiting for an effective vaccine, the development of new therapeutic targets in order to attenuate the virulence of the stocks of Pa and as much as possible to delay the age of firstly-colonization and the age of chronic colonization with mucoid Pa.

[Acute respiratory tract infections due to a human metapneumovirus in children: descriptive study and comparison with respiratory syncytial virus infections]. / Infections respiratoires aiguës à métapneumovirus humain chez l'enfant: études descriptive et comparative avec le virus respiratoire syncytial.

BACKGROUND: A new paramyxovirus, the human metapneumovirus was recently isolated. We report the first French cases collected between 2000 and 2002. MATERIAL AND METHODS: Samples were obtained from nasopharyngeal aspirates from children hospitalised for acute respiratory tract infection in hospitals of Caen and Flers in Basse-Normandie. Human metapneumovirus was studied by polymerase chain reaction on negative samples for respiratory syncytial virus, influenza A and B virus, parainfluenza (1, 2 and 3) virus, adenovirus, coronavirus and rhinovirus. Comparison between metapneumovirus virus and respiratory syncytial virus infections was done after matching sex, age and infection month. RESULTS: Twenty-six human metapneumovirus infections were identified. A comparative study of a matched group of children infected by respiratory syncytial virus found no significative difference for hospitalisation motive, clinical criteria and treatment. CONCLUSION: The human metapneumovirus is responsible for typical acute bronchiolitis in children.

Comparison of the quick view influenza test (Quidel) to an immunofluorescence assay for the detection of influenza virus infections.

The performancs of a membrane-based EIA, the Quick Vue Influenza test, (Quidel,USA) were compared to those of an immunofluorescence assay (IFA) for the detection of influenza virus A antigens in respiratory samples from children hospitalized during the 2002-2003 winter season. A prospective study was carried out on 2 nasal swabs drawn in parallel from 33 children: 13 samples were positive and 18 negative on both the Quick Vue test and IFA. Using an in-house reverse transcription (RT)- PCR assay as a gold standard, the two discordant results were identified as a false-positive reaction of the IFA and a false-negative one of the Quick Vue test . The sensitivity, specificity, positive and negative predictive values of the Quick Vue test were 87.5%, 100%, 100% and 89.5%, respectively. In the retrospective study of frozen samples, 57 of the 70 positive samples were detected by the Quick Vue test and 5 of 50 negative samples. Using the RT-PCR as a gold standard, there were 4 false-negative and 3 false-positive results on IFA and 10 false-negative results on the Quick Vue test. Our study suggests that performances of the Quick Vue are good if the test is carried out directly on nasal secretions, but that they can be decreased when nasal aspirates are collected in transport medium and frozen.

[Adenoviral respiratory diseases in healthy children: a study of 116 hospital cases]. / Prise en charge des pathologies respiratoires à adénovirus chez l'enfant immunocompétent: À propos d'une étude rétrospective de 116 enfants hospitalisés.

Adenoviruses most commonly cause respiratory illness; however, depending on the infecting serotype, they may also cause various other diseases. Diagnosis may be difficult to achieve.The clinical findings for 116 children hospitalised with adenoviral infection were studied retrospectively. In 71 children, the diagnosis was based on detection of adenovirus antigen in the nasopharyngeal specimens and in 71 children on viral culture. The clinical picture of adenoviral infection was characterised by high-grade (mean 39°1C) and prolonged fever (mean duration 4,3 days). Upper respiratory and lower respiratory symptoms were the most common infections. Twelve had been admitted to the hospital due to febrile convulsions, 6 had meningitis. Laboratory findings varied from normal values to values seen in bacterial infections. Thus it was difficult to distinguish adenoviral disease from a bacterial disease. Fifty-nine children were referred to the hospital due to infection unresponsive to antimicrobial therapy.Symptoms of respiratory infection caused by adenovirus may range from the common cold syndrome to pneumonia, croup and bronchiolitis. Adenoviruses can be responsible for severe consequences, even in previously healthy children. Studies of the molecular mechanisms of viral infections of the airways could provide important insights into the nature of the inflammatory process involved in asthma and chronic obstructive pulmonary disease. Most infections are mild and require no therapy or only symptomatic treatment. There are at present time no recognised antiviral agents that are effective in treating serious adenovirus disease. The rapid detection of adenovirus antigen in nasopharygeal specimens proved to have a great clinical value in the diagnosis.

[Rhinovirus and acute respiratory infections in hospitalized children. Retrospective study 1998-2000]. / Rhinovirus et infections respiratoires aiguës de l'enfant hospitalisé. Etude rétrospective de 1998 à 2000.

OBJECTIVES: Rhinoviruses are the most common aetiological agents of colds, but the frequency and the severity of other locations of the infection are not well known. This study describes the clinical aspects and the severity of rhinovirus infections in hospitalised children. METHODS: Isolation in culture and a RT-PCR were performed for the detection of rhinovirus in nasal aspirates from hospitalised children from September 1998 to October 2000. A group of 211 children found to be positive for rhinovirus was studied. RESULTS: Rhinovirus-infected children suffered from the following clinical syndromes: 60 (28.4%) upper airway infections, 81 (38.4%) bronchiolitis, 25 (11.9%) pneumonias and 12 (4.7%) acute attacks of asthma. Clinical symptoms were wheezing (32%), ronchi (37%) and 29% of children presented with acute distress respiratory syndrome; 40% of the available chest X-Ray were abnormal. Eight children were hospitalised in the intensive care unit and two children died. Twenty-five children (10.9%) had a nosocomial infection; a dual infection was observed in 19 cases (9%) with the following viruses: RSV (3), influenza (2) parainfluenza (8), adenovirus (2), enterovirus (4); 19 (9%) children had a secondary bacterial infection. Rhinoviruses were detected in nasal aspirates in 112 cases (53%) according to the culture and in the rhinovirus culture-negative samples in 99 cases (47%) according to the RT-PCR assay. CONCLUSION: After eliminating cases of bacterial or viral dual infections, the clinical aspects of rhinovirus infections in children are the following: upper respiratory tract infections (25.6%), bronchiolitis ou bronchitis (25.6%), pneumonia (6.2%), acute attack of asthma (5.7%). The virological diagnosis according to culture is mainly improved by molecular techniques.

[Evaluation of diagnosis and follow-up in screened children with cystic fibrosis in Normandy]. / Evaluation du diagnostic et du suivi de la cohorte normande d'enfants dépistés atteints de mucoviscidose.

The neonatal screening programme in Normandy (France) allowed the formation of a homogenous cystic fibrosis (CF) cohort of 150 children diagnosed between 1980 and 1997. At the time of this retrospective study, 11 were deceased, out of which nine had meconium ileus (eight deaths after surgery, one at 5 years of age). Sixty children born between 1980 and 1993 in the Basse-Normandie region were followed up during a mean 80 months following similar protocols. The mean age at diagnosis was 41 days (SD = 27 d) for infants without meconium ileus. The occurrence of Pseudomonas aeruginosa (P. aeruginosa) infection and chronic colonization was studied using a monovariate followed by a multivariate analysis including the following variables: sex; meconium ileus; anthropometric data at birth and at diagnosis; pancreatic insufficiency; radiological data (Brasfield score); microbiology data at diagnosis; and genetic data. P. aeruginosa infection appeared earlier in children with pancreatic insufficiency (OR = 2.2; p < 0.05) or with radiological abnormalities (Brasfield score < 21) at diagnosis (OR = 3.9; p < 0.05). Meconium ileus (OR = 5.3; p < 0.01), pancreatic insufficiency (OR = 3.8; p < 0.01) and Brasfield score < 21 at diagnosis (OR = 5.6; p < 0.001) were prognosis factors for early chronic P. aeruginosa colonization. In CF children without meconium ileus, the major risk factor found through multivariate analysis for earlier infection and for earlier chronic colonization by P. aeruginosa was a diagnosis delay > 40 days (respectively OR = 4.6; p < 0.001 and OR = 10.4; p < 0.005). These results must be compared with the lower Brasfield score at diagnosis in infants diagnosed after 40 days of life (p < 0.01).

[Obstructive sleep apnea syndrome and hypertrophic tonsils in infants]. / Le syndrome d'apnées obstructives du sommeil et hypertrophie amygdalienne chez le nourrisson.

BACKGROUND: Even if failure to thrive in infants suffering from obstructive sleep apnea syndrome (OSAS) due to hypertrophic tonsils is well documented in the literature, the surgical act is often delayed due to the lack of diagnostic evidence. CASE REPORTS: We report three cases which share the common characteristic of age of onset, tonsillar hypertrophy, growth retardation and growth catch-up after tonsillectomy. Authors emphasize the importance of clinical diagnosis as a sufficient tool in making the decision of surgery, thus avoiding unnecessary and expensive investigations. CONCLUSION: The diagnosis of OSAS in infants and children is essentially clinical, depending mainly on a history provided by the parents, laying stress on nocturnal symptoms and clinical examination. Growth retardation is frequent in this syndrome and should be systematically sought. Tonsillectomy, which is effective in relieving respiratory manifestations, also allows growth recovery.

[Viral co-infections in immunocompetent infants with bronchiolitis: prospective epidemiologic study]. / Co-infections virales lors des bronchiolites du nourrisson immunocompétent: étude prospective épidémiologique.

The nature of viral infection was prospectively investigated in 202 immunocompetent infants with bronchiolitis. Nasal aspirates were evaluated by immunofluorescence assay, viral isolation technique and polymerase-chain-reaction-hybridization assay. In 55 infants (27%) more than one respiratory virus were detected. A Rotavirus was found in 40 infants (20%), without any relationship with the respiratory viral status, respiratory syncytial virus being the main virus (46/55), and the association of respiratory syncytial virus and adenovirus being the most frequent (21/55). No difference was found between monoviral infections on the one hand and simultaneous viral infections on the other hand according to age, weight, neonatal disease, past history of personal or familial atopy, central temperature, Silverman's index, oxygen dependency, length of hospitalization, microbiology data. There was no indication that simultaneous virus infections were associated with an increased severity of the bronchiolitis in immunocompetent infants.