Retinoic acid (RA) is a potent teratogen in all vertebrates when tight homeostatic controls on its endogenous dose, location, or timing are perturbed during early embryogenesis.
STRA6 encodes an ...integral cell-membrane protein that favors RA uptake from soluble retinol-binding protein; its transcription is directly regulated by RA levels. Molecular analysis of
STRA6 was undertaken in two human fetuses from consanguineous families we previously described with Matthew-Wood syndrome in a context of severe microphthalmia, pulmonary agenesis, bilateral diaphragmatic eventration, duodenal stenosis, pancreatic malformations, and intrauterine growth retardation. The fetuses had either a homozygous insertion/deletion in exon 2 or a homozygous insertion in exon 7 predicting a premature stop codon in
STRA6 transcripts. Five other fetuses presenting at least one of the two major signs of clinical anophthalmia or pulmonary hypoplasia with at least one of the two associated signs of diaphragmatic closure defect or cardiopathy had no
STRA6 mutations. These findings suggest a molecular basis for the prenatal manifestations of Matthew-Wood syndrome and suggest that phenotypic overlap with other associations may be due to genetic heterogeneity of elements common to the RA- and fibroblast growth factor–signaling cascades.
Après la Révolution de 1789, le théâtre s'engage dans un processus qui propose à la société française de se réconcilier, non seulement avec son histoire immédiate, mais aussi avec tous ses ...représentants. Afin d'atteindre une véritable unité sociale dans le respect des droits humains, certains dramaturges de l'époque révolutionnaire (1789—1799) explorent des solutions éthiques aux troubles politiques. En présentant deux comédies de Picard et un opéra de Lebrun Tossa, cet article montre comment l'usage des allusions révèle l'intentionnalité des auteurs dramatiques d'instiller de nouveau parmi leur public les valeurs humanitaires des Lumières.
Cobblestone lissencephaly represents a peculiar brain malformation with characteristic radiological anomalies, defined as cortical dysplasia combined with dysmyelination, dysplastic cerebellum with ...cysts and brainstem hypoplasia. Cortical dysplasia results from neuroglial overmigration into the arachnoid space, forming an extracortical layer, responsible for agyria and/or 'cobblestone' brain surface and ventricular enlargement. The underlying mechanism is a disruption of the glia limitans, the outermost layer of the brain. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal recessive diseases with cerebral, ocular and muscular deficits, Walker-Warburg syndrome, muscle-eye-brain and Fukuyama muscular dystrophy. Mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN and FKRP genes attributed these diseases to α-dystroglycanopathies. However, studies have not been able to identify causal mutations in the majority of patients and to establish a clear phenotype/genotype correlation. Therefore, we decided to perform a detailed neuropathological survey and molecular screenings in 65 foetal cases selected on the basis of histopathological criteria. After sequencing the six genes of α-dystroglycanopathies, a causal mutation was observed in 66% of cases. On the basis of a ratio of severity, three subtypes clearly emerged. The most severe, which we called cobblestone lissencephaly A, was linked to mutations in POMT1 (34%), POMT2 (8%) and FKRP (1.5%). The least severe, cobblestone lissencephaly C, was linked to POMGNT1 mutations (18%). An intermediary type, cobblestone lissencephaly B, was linked to LARGE mutations (4.5%) identified for the first time in foetuses. We conclude that cobblestone lissencephaly encompasses three distinct subtypes of cortical malformations with different degrees of neuroglial ectopia into the arachnoid space and cortical plate disorganization regardless of gestational age. In the cerebellum, histopathological changes support the novel hypothesis that abnormal lamination arises from a deficiency in granule cells. Our studies demonstrate the positive impact of histoneuropathology on the identification of α-dystroglycanopathies found in 66% of cases, while with neuroimaging criteria and biological values, mutations are found in 32-50% of patients. Interestingly, our morphological classification was central in the orientation of genetic screening of POMT1, POMT2, POMGNT1, LARGE and FKRP. Despite intensive research, one-third of our cases remained unexplained; suggesting that other genes and/or pathways may be involved. This material offers a rich resource for studies on the affected neurodevelopmental processes of cobblestone lissencephaly and on the identification of other responsible gene(s)/pathway(s).
Abstract Objectives Fetal rhesus D ( RhD ) status determination using circulating cell-free fetal DNA from maternal plasma or serum is now recognized in Europe as a reliable and useful tool. A few ...countries are presently using this test in their management policy of rhesus D negative patients. The objective of this study is to evaluate the impact of this test on the costs of managing RhD-negative pregnant women, whether or not they are allo-immunized. Study design A prospective follow-up of rhesus D negative women during their pregnancy was performed in three French obstetric departments. Non-invasive fetal RhD genotyping was performed in the first trimester and pregnancies were followed The costs of all procedures (biological tests and medication) associated with patient management in relation to their RhD-negative status were calculated according to different management options. Results A comprehensive follow-up, including medical and biological monitoring, was obtained for 99 of the 101 patients included in the study. Patients were separated into two groups: the “Adverse Event” group (AE, n = 23) for which a potentially sensitizing event occurred and the “No Adverse Event” group (NAE, n = 76). Fetal RhD status was accurately determined in all cases. The mean cost per patient was estimated at 237€ (range: 115–644) with differences observed depending on the group, notably 331€ (range: 236–644) for the AE group and 208€ (range: 115–366) for the NAE group. Various cost simulations were performed according to various policies of allo-immunization antenatal prophylaxis. Variations ranged from +36.2% to +105.3%. Conclusion This study demonstrates that fetal RhD genotyping early during pregnancy is not an effective cost-reduction strategy whether or not antenatal prophylaxis is given. The economic issues could, however, be overcome by the fact that there is a major clinical benefit to offering the test systematically to all RhD-negative pregnant women while avoiding unnecessary testing and immunoglobulin injections.
Abstract The Smith–Lemli–Opitz syndrome (SLOS) is an autosomal recessive multiple congenital malformation syndrome caused by dehydrocholesterol reductase deficiency. The diagnosis is confirmed by ...high 7- and secondarily 8-dehydrocholesterol levels in plasma and tissues and/or by detection of biallelic mutations in the DHCR7 gene. The phenotypic spectrum of SLOS is broad, ranging from a mild phenotype combining subtle physical anomalies with behavioral and learning problems, to a perinatally lethal multiple malformations syndrome. The fetal phenotype of SLOS has been poorly described in the literature. We report a series of 10 fetuses with molecularly proven SLOS. Even in young fetuses, the facial dysmorphism appears characteristic. Genital abnormalities are rare in 46,XX subjects. Gonadal differentiation appears histologically normal and in agreement with the chromosomal sex, contrary to what has been previously stated. We observed some previously unreported anomalies: ulnar hypoplasia, vertebral segmentation anomalies, congenital pulmonary adenomatoid malformation, fused lungs, gastroschisis, holomyelia and hypothalamic hamartoma. This latter malformation proves that SLOS phenotypically overlaps with Pallister-Hall syndrome which remains clinically a major differential diagnosis of SLOS.