The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening.

BACKGROUND: Cystic fibrosis (CF) is caused by compound heterozygosity or homozygosity of CF transmembrane conductance regulator gene (CFTR) mutations. Phenotypic variability associated with certain mutations makes genetic counselling difficult, notably for R117H, whose disease phenotype varies from asymptomatic to classical CF. The high frequency of R117H observed in CF newborn screening has also introduced diagnostic dilemmas. The aim of this study was to evaluate the disease penetrance for R117H in order to improve clinical practice. METHODS: The phenotypes in all individuals identified in France as compound heterozygous for R117H and F508del, the most frequent CF mutation, were described. The allelic prevalences of R117H (p(R117H)), on either intron 8 T5 or T7 background, and F508del (p(F508del)) were determined in the French population, to permit an evaluation of the penetrance of CF for the [R117H]+[F508del] genotype. RESULTS: Clinical details were documented for 184 [R117H]+[F508del] individuals, including 72 newborns. The disease phenotype was predominantly mild; one child had classical CF, and three adults' severe pulmonary symptoms. In 5245 healthy adults, p(F508del) was 1.06%, p(R117H;T7) 0.27% and p(R117H;T5)<0.01%. The theoretical number of [R117H;T7]+[F508del] individuals in the French population was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). The penetrance of classical CF for [R117H;T7]+[F508del] was estimated at 0.03% and that of severe CF in adulthood at 0.06%. CONCLUSIONS: These results suggest that R117H should be withdrawn from CF mutation panels used for screening programmes. The real impact of so-called disease mutations should be assessed before including them in newborn or preconceptional carrier screening programmes.

[Development of an exposure index of air pollution caused by motor vehicles for use in epidemiological studies]. / Elaboration d'un indice d'exposition a la pollution atmospherique d'origine automobile a l'usage des etudes epidemiologiques.

Air pollution due to motor vehicles is a worrying issue, in particular in the urban environment, all the more as a number of pollutants such as benzene and PAH are known to have carcinogenic effects. Epidemiological studies seem to be required, so a cumulated score of exposure must be developed. A correlation with pathology should be investigated. The calculation of an index of exposure to motor vehicle-related pollution requires a good assessment of pollutant emissions and a precise knowledge of pollutant transfer mechanisms by advection and spreading in built-up areas. In this study, it is proposed to use current theoretical and experimental knowledge to develop a calculation algorithm for this index. The following issues will be addressed in the presentation: an analysis of epidemiological requirements and of constraints of data acquisition using questionnaire surveys; a model for assessing, for each residential area, the average annual concentration of gaseous pollutants from motor vehicles. It will consider the environment geometry, traffic emissions and wind distributions. The model CALINE3 is used for open areas near roads and highways and the Danish model OSPM is introduced for street canyon environments.

Prenatal diagnosis of a true fetal tetraploidy in direct and cultured chorionic villi.

Prenatal diagnosis of a true fetal tetraploidy in direct and cultured chorionic villi: Tetraploidy is characterized by four complete sets of chromosomes (4n= 92). Although it has been frequently reported in spontaneous abortions, tetraploidy is extremely rare in term pregnancy. Most of late surviving patients are diploid/tetraploid mosaics and present severe mental and physical impairment. Up to date, only five tetraploidies were ascertained in the prenatal stage in amniocytes and/or fetal blood lymphocytes. No one has been reported in chorionic villi probably because tetraploidy is generally considered in this tissue as a false positive result due to confined placental mosaicism (CPM) or placental culture artefacts. We report here on a case of tetraploidy detected in chorionic villi because of fetal cystic hygroma. We discuss the reliability of this diagnosis and propose guidelines in the follow-up of tetraploidies detected after chorionic villus sampling (CVS). Thus a misdiagnosis of this poor condition will be avoided at best and an appropriate genetic counseling will be given to the parents.

Exposure to traffic pollution: comparison between measurements and a model.

French researchers from the Building Scientific and Technical Center have produced a traffic-exposure index. To achieve this, they used an air pollution dispersion model that enabled them to calculate automobile pollutant concentrations in front of subjects' residences and places of work. Researchers used this model, which was tested at 27 Paris canyon street sites, and compared nitrogen oxides measurements obtained with passive samplers during a 6-wk period and calculations derived from the model. There was a highly significant correlation (r = .83) between the 2 series of values; their mean concentrations were not significantly different. The results suggested that the aforementioned model could be a useful epidemiological tool for the classification of city dwellers by present-or even cumulative exposure to automobile air pollution.

[Determination of proteinuria in children: changes in results according to the methods used (author's transl)]. / Dosage de la protéinurie chez l'enfant. Variabilité des résultats selon la méthode de dosage.

Five methods for determination of proteinuria are compared : gravimetry, colorimetry (bromocresol green, Biuret test, Lowry's test), opacimetry (sulfosalicylic acid). Determinations were performed on normal urine, overloaded with albumin or gammaglobulins or on abnormal urine, after varying several parameters (pH, osmolarity, glucose, fructose, red blood cells, hemoglobin. leukocytes, germs). Some methods give non linear results depending on the concentrations (gravimetry, sulfosalicylic acid, bromocresol green). Some systematically give over-results (Biuret test, Lowry's test). Some almost exclusively determine albumin levels (bromocresol green, sulfosalicylic acid). In some, results are altered by glucose or fructose (Biuret, Lowry) or by red blood cells (Biuret, Lowry, sulfosalicylic acid). None of the tested methods can be used as a reference method. The method using sulfosalicylic acid is suitable for routine determination; however, results should be interpreted according to the parameters mentioned above.

[Medical treatment of neonatal chylous ascites: apropos of a case]. / Le traitement médical de l'ascite chyleuse néo-natale: à propos d'un cas.

We report a case of congenital neonatal chylous ascites successfully managed by diet therapy with medium chain triglycerides. There was a rapid decrease in the lipid content of the ascitic fluid which preceded the clinical response.

[Linkage between the gene responsible for adrenal hyperplasia caused by 21-hydroxylase deficiency and chromosome-6 short-arm markers]. / Liaison entre le gène responsable de l'hyperplasie surrénalienne par déficit en 21 hydroxlase et les marqueurs de bras court du chromosome 6.

In six patients from four different families, the study of the genetic markers of te short arm of chromosome 6 allows to confirm the situation of the gene responsible for congenital adrenal hyperplasia by deficiency of 21 hydroxylase. Thanks to the discovery of a recombination of the maternal haplotype in an affected girl. we consider the situation of the pathological gene with regard to that of the glyoxalase I gene. In the families including at least one patient, these studies permit to tract the heterozygotes and to make a very early or even antenatal diagnosis.

In utero fetal muscle biopsy: a precious aid for the prenatal diagnosis of Duchenne muscular dystrophy.

Prenatal diagnosis for Duchenne muscular dystrophy can usually be performed using DNA analysis. This approach would be impossible when there is only one prior affected male and no identifiable gene deletion. Therefore, in utero fetal thigh muscle biopsy with direct examination of muscle by dystrophin analysis may provide the only means of prenatal diagnosis. We report such a case in which fetal muscle biopsy was able to exclude Duchenne muscular dystrophy. A detailed literature review of the topic is provided.

Direct fetal chromosome studies from chorionic villi.

An easy and reproducible technique for direct fetal chromosome analysis after chorionic biopsy is described. Very high colchicine concentration and rehydratation of the fixed villi are the two original points of this method.

Circulating cell-free fetal DNA in maternal serum appears to originate from cyto- and syncytio-trophoblastic cells. Case report.

Circulating cell-free fetal DNA in maternal serum offers an early and non-invasive method for prenatal diagnosis, but the origin of this DNA is still unknown. We report the absence of the SRY gene in maternal serum of a pregnant woman despite male genitalia at ultrasound. The karyotype was 45,X after direct trophoblast analysis and 45,X/46,Xidic(Yp) after culture and in all fetal tissues studied. Due to the absence of the SRY sequence in maternal blood and in the cytotrophoblast, we presume that free fetal DNA in this case originates from trophoblastic cells. As the case presented here is exceptional, it only has a minor impact on the accuracy of fetal sex determination by maternal serum analysis, but highlights the importance of and the necessity for the complementary ultrasonographic control.

[Determination of fetal karyotype in the first trimester of pregnancy by direct examination of chorionic villi]. / Détermination du caryotype foetal au premier trimestre de la grossesse par examen direct des villosités choriales.

Chorionic biopsy during the first trimester of pregnancy allows fast and precise study of fetal karyotype. Considering the results of our ten prenatal diagnoses, we discuss the advantages and the risks of this method.

[Correlations between pregnancy pathology, study of the placenta, antenatal echography and examination of the product of conception in a series of 175 congenital malformations]. / Corrélations entre la pathologie gravidique, l'étude du placenta, l'échographie anténatale et l'examen du produit de conception dans une série de 175 malformations congénitales.

In order to verify the hypothesis that during pregnancy in a woman without peculiar history, signs could be discovered when the fetus is malformed we have reviewed the files of 175 women who had a malformed child and of 300 controls. All of these women had at least one clinical examination and one ultrasonographic examination during pregnancy. Two clinical symptoms were more often discovered in the mother of the malformed fetus (p less than 0.001): decrease of fetal movements and small for date fetus. The placenta is never abnormal in the mother with normal fetus. Placenta is abnormal in 31% of the mother with malformed fetus but the abnormalities are not specific. Ultrasonographic examinations allowed more often the discovery of a malformation when hydramnios (p less than 0.001) or fetal hypotrophy (p less than 0.01) or an anomaly of the morphology of the fetus is discovered. Accuracy of prenatal diagnostic is considered for the different categories of congenital malformations.