To determine the prevalence and the timing of pregnancy termination relative to the type of central nervous system (CNS) malformations. Design Retrospective cohort study.
Multidisciplinary centre for ...prenatal diagnosis in the Languedoc-Roussillon region, France.
A cohort of 481 pregnancy terminations performed between 2005 and 2009.
Detailed post-termination fetal and neuropathological analyses were carried out to identify the CNS malformations. Then, the prevalence and timing of pregnancy termination were assessed relative to the identified malformations.
About one-third of pregnancy terminations (143/481) were performed for severe CNS malformations. Up to 24 weeks of gestation (WG), pregnancy terminations (56.6%) were carried out mainly for defects occurring during the two major first steps of CNS development (neurulation and differentiation of cerebral vesicles). After 24 WG, pregnancy terminations (43.3%) were mainly performed for corpus callosum agenesis (16/17), vermian agenesis (10/12) and gyral anomalies (13/15). For hindbrain malformations and gyral anomalies, there was a significant relationship between the timing of pregnancy termination and the presence of a severe ventriculomegaly at prenatal diagnosis (p=0.002 and p=0.02, respectively).
By classifying CNS malformations according to the neuropathological analysis, the authors show that the timing and prevalence of pregnancy termination are distributed in a manner that is consistent with what is currently known on the development of brain. They are also influenced by the French prenatal screening policy and the variable expressivity of the brain malformations and associated lesions.
The understanding of the pathogenesis of cytomegalovirus (CMV)-induced fetal brain lesions is limited. We aimed to quantify adaptive and innate immune cells and CMV-infected cells in fetal brains ...with various degrees of brain damage.
In total, 26 archived embedded fetal brains were studied, of which 21 were CMV-infected and classified in severely affected (
= 13) and moderately affected (
= 8), and 5 were uninfected controls. The respective magnitude of infected cells, immune cells (CD8
, B cells, plasma cells, NK cells, and macrophages), and expression of immune checkpoint receptors (PD-1/PD-L1 and LAG-3) were measured by immunochemistry and quantified by quantitative imaging analysis.
Quantities of CD8
, plasma cells, NK cells, macrophages, and HCMV
cells and expression of PD-1/PD-L1 and LAG-3 were significantly higher in severely affected than in moderately affected brains (all
values < 0.05). A strong link between higher number of stained cells for HCMV/CD8 and PD-1 and severity of brain lesions was found by component analysis.
The higher expression of CD8, PD-1, and LAG-3 in severely affected brains could reflect immune exhaustion of cerebral T cells. These exhausted T cells could be ineffective in controlling viral multiplication itself, leading to more severe brain lesions. The study of the functionality of brain leucocytes ex vivo is needed to confirm this hypothesis.
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.
Bardet-Biedl syndrome (BBS) is a multisystemic disorder characterized by postaxial polydactyly, progressive retinal dystrophy, obesity, hypogonadism, renal dysfunction, and learning difficulty. Other ...manifestations include diabetes mellitus, heart disease, hepatic fibrosis, and neurological features. The condition is genetically heterogeneous, and eight genes (
BBS1–BBS8) have been identified to date. A mutation of the
BBS1 gene on chromosome 11q13 is observed in 30%–40% of BBS cases. In addition, a complex triallelic inheritance has been established in this disorder—that is, in some families, three mutations at two
BBS loci are necessary for the disease to be expressed. The clinical features of BBS that can be observed at birth are polydactyly, kidney anomaly, hepatic fibrosis, and genital and heart malformations. Interestingly, polydactyly, cystic kidneys, and liver anomalies (hepatic fibrosis with bile-duct proliferation) are also observed in Meckel syndrome, along with occipital encephalocele. Therefore, we decided to sequence the eight
BBS genes in a series of 13 antenatal cases presenting with cystic kidneys and polydactyly and/or hepatic fibrosis but no encephalocele. These fetuses were mostly diagnosed as having Meckel or “Meckel-like” syndrome. In six cases, we identified a recessive mutation in a
BBS gene (three in
BBS2, two in
BBS4, and one in
BBS6). We found a heterozygous
BBS6 mutation in three additional cases. No
BBS1, BBS3, BBS5, BBS7, or
BBS8 mutations were identified in our series. These results suggest that the antenatal presentation of BBS may mimic Meckel syndrome.
Meckel syndrome (MKS) is a rare autosomal recessive lethal condition characterized by central nervous system malformations (typically occipital meningoencephalocele), postaxial polydactyly, ...multicystic kidney dysplasia, and ductal proliferation in the portal area of the liver. MKS is genetically heterogeneous and three loci have been mapped respectively on 17q23 (MKS1), 11q13 (MKS2), and 8q24 (MKS3). Very recently, two genes have been identified: MKS1/FLJ20345 on 17q in Finnish kindreds, carrying the same intronic deletion, c.1408-35_c.1408-7del29, and MKS3/TMEM67 on 8q in families from Pakistan and Oman. Here we report the genotyping of the MKS1 and MKS3 genes in a large, multiethnic cohort of 120 independent cases of MKS. Our first results indicate that the MKS1 and MKS3 genes are each responsible for about 7% of MKS cases with various mutations in different populations. A strong phenotype-genotype correlation, depending on the mutated gene, was observed regarding the type of central nervous system malformation, the frequency of polydactyly, bone dysplasia, and situs inversus. The MKS1 c.1408-35_1408-7del29 intronic mutation was identified in three cases from French or English origin and dated back to 162 generations (approx. 4050 years) ago. We also identified a common MKS3 splice-site mutation, c.1575+1G>A, in five Pakistani sibships of three unrelated families of Mirpuri origin, with an estimated age-of-mutation of 5 generations (125 years).
Background
Increasing number of mutations responsible for vascular lesions, leading to ischemic or hemorrhagic stroke in young adults, has been identified in the recent years. It has been ...demonstrated in both mice and humans, that mutations in COL4A1 gene promote cerebral hemorrhages. In humans, both adults and children may be affected, and the spectrum has been broadened recently to neonates and fetuses.
Methods
We present a cohort of eight COL4A1 mutated fetuses in which cerebral hemorrhages were detected by ultrasound leading to elective terminations of pregnancy.
Results
Our neuropathological studies demonstrated a strikingly similar pathological pattern, dominated by supra- and infratentorial multifocal hemorrhagic lesions of various abundance and age in the vicinity of enlarged small vessels having a discontinuous wall. This was constantly associated with a spectrum of supratentorial post-ischemic damages of the grey and white matters. Morphometric studies of brain vessels confirmed vascular dilation and hypervascularization in both grey and white matters and severe attenuation of the smooth-muscle actin staining in the white matter.
Conclusion
These observations add to the rare human neuropathological phenotype of COL4A1 mutations. Its recognition is mandatory to enhance the number of tested patients in the future, as well as the genetic counseling of parents.
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