Prenatal diagnosis of the Wiskott-Aldrich syndrome by PCR-based methods.
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Chorionic Villi Sampling↗
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Results of chromosomal analysis in fetuses with cardiac anomalies as diagnosed by first- and early second-trimester echocardiography.
Chromosomal analyses were performed in 36 fetuses with cardiac anomalies diagnosed by echocardiography at 11 + 1 to 15 + 6 weeks of gestation. Karyotyping was successful in 35 cases and 17 (48.6%) had anomalies, including five with Turner's syndrome, seven with trisomy 18, four with trisomy 21 and one with triploidy. The commonest cardiac anomaly observed in trisomy 21 was a complete atrioventricular canal; in trisomy 18 was ventricular septal defect; in Turner's syndrome was a hypoplastic aortic arch in combination with hypoplasia of the left ventricle and left ventricular outflow tract; and in the case of triploidy was a ventricular septal defect. These findings confirm the opinion that, in fetuses with chromosomal anomalies, there is a high incidence of cardiac defects. Furthermore, there is a distinct pattern of cardiac defects associated with each chromosomal anomaly.
Amniocentesis↗
Early detection of reversed diastolic umbilical flow: should we offer karyotyping?
In normal pregnancy, end-diastolic flow appears in the umbilical artery around the 13th week of gestation, with a velocity which increases progressively with advancing gestation. The detection of reversed flow in the umbilical artery, the highest expression of an increase in placental vascular resistance, is extremely uncommon in the first half of gestation and, in three of the four cases reported in the literature, there were chromosomal abnormalities. We report a new case of reversed end-diastolic flow in the umbilical artery in a 13-week fetus with increased nuchal translucency thickness, megacystis and tachycardia. Cytogenetic analysis of chorionic villi and amniocytes revealed trisomy 13. The findings provide further evidence for a possible association between reversed end-diastolic flow in the umbilical artery and chromosomal abnormalities. However, the effectiveness of this potential marker in an unselected population requires further evaluation.
Adult↗
Neural tube defects in chromosomally normal and abnormal human embryos.
Neural tube defects (NTDs) were recognized in eight out of 91 intact embryos from spontaneous abortions and in one case of an induced abortion following prenatal diagnosis of a chromosomal disorder. Five of the nine cases showed chromosomal abnormalities. Trisomy 18 and triploidy were associated with spina bifida in three cases, trisomy 7 with parieto-occipital encephalocele and monosomy X with spina bifida and iniencephaly in one case. A sixth anencephalic embryo in which chromosomal analysis was not performed showed a malformation pattern highly suggestive for trisomy 18. Discussion focuses on the high rate and the type of chromosomal abnormalities among spontaneously aborted NTD embryos, on the contrasting phenotype of 45,X conceptions and on the morphogenesis of the different neural tube defects in early development. In view of future early endovaginal ultrasound diagnosis, the changing morphological pattern is exemplified, and ranges from apparently hyperplastic to degenerative alterations of the exposed neural tissue.
Chorionic Villi Sampling↗
Body stalk anomaly at 10-14 weeks of gestation.
In a multicenter project of screening for chromosomal defects by fetal nuchal translucency thickness and maternal age at 10-14 weeks, 14 of 106,727 fetuses examined had body stalk anomaly. The ultrasonographic features were a major abdominal wall defect, severe kyphoscoliosis and a short umbilical cord. In all cases, the upper part of the fetal body was in the amniotic cavity, whereas the lower part was in the celomic cavity. The nuchal translucency thickness was above the 95th centile in ten (71.4%) of the cases, but the fetal karyotype was normal in all 12 fetuses evaluated. The findings suggest that early amnion rupture before obliteration of the celomic cavity is a possible cause of the syndrome.
Abdominal Muscles↗
Prenatal diagnosis of body stalk anomaly in the first trimester of pregnancy.
Ultrasound examination in a 10-week fetus demonstrated a marked deformity of the lower half of the fetus that was in the celomic cavity, and the upper half of the body was in the amniotic sac. There was abdominal wall defect with herniation of the liver and bowel, the lower limbs were deformed and the umbilical cord was short and thin. These abnormalities were suggestive of body stalk anomaly. The diagnosis was confirmed by pathological examination after termination of the pregnancy at 18 weeks.
Abdominal Muscles↗
Short-term safety of celocentesis for the mother and the fetus.
OBJECTIVE: Celocentesis offers the potential for prenatal diagnosis from as early as 6 weeks of gestation. The aim of this study was to examine the short-term safety of celocentesis. METHODS: Eligible for the study were pregnant women with single live fetuses at 6-10 weeks of gestation, requesting pregnancy termination for social indications. At presentation, the patients were asked if they were willing to undergo celocentesis and in those women who agreed the procedure was performed at the time of the initial scan. A second scan was carried out just before termination to measure fetal crown-rump length and heart rate. RESULTS: Four hundred and forty-seven women requested termination of pregnancy and 108 of these agreed to have celocentesis. There were no significant differences between the groups in maternal age, prevalence of primigravidas, cigarette smokers, existence of uterine fibroids, the median fetal crown-rump length or the interval between the initial scan (or celocentesis) at presentation and the pregnancy termination. At the time of termination, ultrasound examination demonstrated fetal death in five (4.7%) of the celocentesis group and nine (2.7%) of the controls (odds ratio, 1.804; 95% confidence interval, 0.5912-5.504). In all other cases, there was normal fetal growth and there were no significant differences between the groups in fetal crown-rump length. CONCLUSIONS: The procedure related fetal loss associated with celocentesis may be approximately 2%.
Adolescent↗
Teaching ultrasound-guided invasive procedures in fetal medicine: learning curves with and without an electronic guidance system.
OBJECTIVE: To compare the learning curves of inexperienced junior obstetrics/gynecology registrars for ultrasound-guided invasive procedures on a training model, with and without an electronic guidance system. STUDY DESIGN: Four junior registrars performed their first 100 procedures on a training model with a new electronic guidance system, and four other junior registrars performed their first 100 procedures on the same training model without using the guidance system. All procedures were performed using a free-hand technique. We evaluated the quality of the procedure, which we defined as the time spent with the entire needle clearly visualized on the screen over the total duration of the procedure. We constructed learning curves for the eight junior registrars for comparative analysis. RESULTS: Quality of the procedure increased over time for all trainees. The learning curves were significantly steeper for trainees using the electronic guidance system. Trainees using the electronic guidance system performed better in the middle of their learning curve (procedures 25-75). All trainees reached the same level of quality by the end of their 100 procedures. CONCLUSIONS: The automated electronic guidance system helps faster learning but, after 100 procedures on a training model, both groups reached the same level of quality.
Amniocentesis↗
Why study human limb malformations?
Congenital limb malformations occur in 1 in 500 to 1 in 1000 human live births and include both gross reduction defects and more subtle alterations in the number, length and anatomy of the digits. The major causes of limb malformations are abnormal genetic programming and intra-uterine disruption to development. The identification of causative gene mutations is important for genetic counselling and also provides insights into the mechanisms controlling limb development. This article illustrates some of the lessons learnt from the study of human limb malformation, organized into seven categories. These are: (1) identification of novel genes, (2) allelic mutation series, (3) pleiotropy, (4) qualitative or (5) quantitative differences between mouse and human development, (6) physical and teratogenic disruption, and (7) unusual biological phenomena.
Animals↗
Prenatal exclusion of Ehlers-Danlos syndrome type VI by mutational analysis.
We have performed the first prenatal assessment of clinical phenotype in a family affected by Ehlers-Danlos syndrome type VI (EDS VI), an inherited collagen disorder, by screening the fetal DNA for mutations in the lysyl hydroxylase (LH) gene. We have previously reported that the affected child in this family is compound heterozygous for mutations in the LH gene. One allele has a paternally inherited C1557 to G change that codes for a premature stop codon (Y511X) in exon 14 and the other allele has a deletion of exon 5 that results from a maternally inherited mutation in the consensus donor splice site of intron 5. To perform the prenatal diagnosis, we sequenced genomic DNA isolated from cultured chorionic villus cells at 10 weeks of gestation. One allele had the maternally inherited gt --> at splice-site mutation in exon 5, and the other paternally inherited allele was normal. As EDS VI is a recessive disorder, we predicted that although a carrier, the baby should be unaffected. This conclusion, which was supported by a normal level of LH activity in the chorionic villus cells, was confirmed by the birth of a healthy unaffected baby.
Alleles↗
Specific substrate for CLN2 protease/tripeptidyl-peptidase I assay.
The classic late infantile neuronal ceroid lipofuscinosis (LINCL, CLN2) is a fatal neurodegenerative disorder that results from mutations in a gene encoding a lysosomal proteinase, known as CLN2 protease (CLN2p) or tripeptidyl peptidase I (TPP-I). Three different substrates, fluorescein isothiocyanate-labelled haemoglobin, A-F-F-7-amino-4-methylcoumarin (AAF-AMC) and G-F-F-L-7-amino-4-trifluoromethylcoumarin (GFFL-AFC) have been used for the CLN2p/TPP-I assay with varying degrees of residual activities in patients with LINCL. Further, conclusive identification of carriers are not possible with the first two substrates. An assay for the CLN2p/TPP-I based on the cleavage of amino terminal tripeptide from G-F-F-L-AFC was applied to prenatal and postnatal diagnosis of LINCL patients and heterozygote carriers. In leukocytes, the CLN2p/TPP-I activities in controls and heterozygote carriers were 1995 +/- 154 (n = 15) and 918 +/- 253 (n = 15) nmol/h/mg protein respectively. No CLN2p/TPP-I activity was detectable in all but two patients. These two patients had less than 2% residual activity, and had delayed clinical symptoms for LINCL. This shows that the G-F-F-L-AFC is a highly specific substrate for the CLN2p/TPP-I assay. The fact that with this substrate the enzyme cleaves a peptide bond between the two amino acids may be the reason for the high level of specificity.
Aminopeptidases↗
Pre- and postnatal enzyme analysis for infantile, late infantile and adult neuronal ceroid lipofuscinosis (CLN1 and CLN2).
The recent development of simple, fluorogenic enzyme assays for infantile and late infantile neuronal ceroid lipofuscinosis (INCL and LINCL; CLN1 and CLN2) has greatly facilitated the diagnostic process for these diseases. In leucocytes and fibroblasts from INCL (n = 38) patients we found profound deficiencies of palmitoyl-protein thioesterase I (PPT1), the residual activity was < 5% of mean control activity. In fibroblasts from LINCL patients we found a similar deficiency of tripeptidyl-peptidase I activity (TPP-I), with < 2% activity in 16 patients. The residual TPP-I activity in leucocytes from LINCL patients seemed substantially higher. We also showed the feasibility of reliable prenatal enzyme analysis. In five first-trimester and two second-trimester prenatal analyses for INCL, four affected foetuses were detected (PPT activity 3-6%). Two first trimester pregnancies at risk for LINCL were analysed and a clear TPP-I deficiency was detected in both cases (TPP-I activity 3-4%). The first patient with adult neuronal ceroid lipofuscinosis (ANCL) due to a deficiency of PPT is presented; her present age is 53 years and the onset of the disease was at 38 years with psychiatric symptoms.
Adult↗
Pre- and postnatal diagnosis of patients with CLN1 and CLN2 by assay of palmitoyl-protein thioesterase and tripeptidyl-peptidase I activities.
Palmitoyl-protein thioesterase (PPT) and tripeptidyl-peptidase I (TPP-I) activities were measured in leucocytes and fibroblasts. Fourteen patients were confirmed as having late infantile neuronal ceroid lipofuscinosis due to a deficiency of TPP-I activity. This included one patient with a milder and more protracted form of the disease. In addition this enzyme deficiency was found in a clinically normal younger sibling of a patient. Of particular importance was the finding of normal TPP-I activity in two patients who had been diagnosed as having classical late infantile neuronal ceroid lipofuscinosis. A deficiency of PPT was confirmed retrospectively in stored fibroblasts from two patients who had already died having been diagnosed with infantile neuronal ceroid lipofuscinosis. Palmitoyl-protein thioesterase or TPP-I activities were measured in chorionic villi and cultured chorionic villi cells in three pregnancies. The enzyme results were confirmed by mutational analysis if the mutations were known, or, in the case of the pregnancy at risk for infantile neuronal ceroid lipofuscinosis by electron microscopy of the chorionic villi. Our results show that assay of PPT and TPP-I is reliable in the diagnosis of patients with mutations in the CLN1 and CLN2 genes. It is imperative to assay these enzymes in all patients to confirm the diagnosis and ensure accurate genetic counselling of other family members. Once an enzyme deficiency has been confirmed reliable prenatal diagnosis is available even if both mutations have not been detected.
Adult↗
Evaluation of Down syndrome screening strategies.
Women contemplating pregnancy today have many different Down syndrome screening protocols from which to choose. Sensitive and specific first and second trimester screening protocols are now widely available, and strategies that combine first and second trimester markers are moving from investigational use into the clinical arena. Modeling indicates that a high detection rate (85%) associated with a very low screen positive rate (1.3%) can be achieved with contingent screening, in which all women undergo first trimester screening and only a portion (25%) go on to second trimester screening.
Adult↗
Prenatal diagnosis and multiple pregnancy.
The incidence of twins, triplets, and high-order multiples has increased dramatically in the last two decades secondary to greater reliance on fertility treatments and to delayed childbearing. Offspring of a multiple gestation are at increased risk for both chromosomal and structural abnormalities. Prenatal diagnosis in these patients is challenging. Options for screening tests are limited. Invasive diagnostic procedures are complex. Likewise, physicians and patients may be faced with the dilemma of deciding how to manage discordant results. The following paper will review the unique concerns associated with prenatal diagnosis in a multiple pregnancy and the current methods of prenatal screening in these patients. Invasive prenatal diagnosis will also be explored.
Adult↗
Oestradiol stimulates morphological and functional differentiation of human villous cytotrophoblast.
Trophoblast differentiation is a complex process involving interactions of cytotrophoblastic cells with their evolutive milieu. During pregnancy, the feto-placental unit produces large amounts of steroids. Progesterone and oestradiol are increasingly produced when the syncytiotrophoblast is highly differentiated. Furthermore, receptors to these hormones are expressed by the trophoblast. This led us to test the hypothesis that steroid production could affect the morphological and functional differentiation of the trophoblast during gestation. The fusion of cytotrophoblastic cells into syncytiotrophoblast was assessed using fluorescence recovery after photobleaching for gap junctional communication analysis (gap-FRAP), desmoplakin immunostaining and connexin 43 expression. In parallel, functional differentiation was assessed by beta-human chorionic gonadotrophin (betahCG) production and human chorionic somatomammotropin (hCS) expression analysis. The presence of oestradiol, 1 microm, increased the percentage of coupled cells (3. 8-fold), connexin 43 expression and stimulated the syncytium formation. In parallel, oestradiol (1, 3 and 5 microm) induced a significant increase in the daily hCG production. The steroid action was specific, as the stimulatory effects were inhibited by tamoxifen. Oestradiol also stimulated hCS expression (51 per cent compared to control after 3 days). As trophoblastic differentiation is specifically stimulated by hCG, oestradiol could act via the stimulation of hCG production or via a direct action. In the presence of an efficient concentration of hCG antibody, oestradiol still stimulated hCS expression, suggesting a self-sufficient effect of the steroid. Physiological concentrations of progesterone were ineffective in modulating trophoblast differentiation. In conclusion, oestradiol could be implicated in the maturation and aging of the trophoblast.
Cell Differentiation↗
Studies of mesenchymal cells from 1st trimester human placenta: expression of cytokeratin outside the trophoblast lineage.
A fibroblast cell strain that expressed cytokeratins 8 and 18 was isolated from explanted first trimester placenta. Its properties were consistent with an origin in the villous fibroblast-myofibroblast lineage, including expression of vimentin, smooth muscle alpha-actin and fibroblast surface protein. The cells grew rapidly in vitro, and exhibited tightly aligned bipolar morphology at confluence, absence of multi-nucleated cells, lack of secreted chorionic gonadotrophin, and absence of HLA G, placental alkaline phosphatase and pregnancy-specific beta-1 glycoprotein (SP1). On these criteria it was concluded they were not trophoblasts. On the basis of their morphology, cytokeratin expression and absence of CD34 and endoglin it was concluded they were not endothelial cells. They lacked desmin and smooth muscle myosin and so were not vascular smooth muscle cells. Further mesenchymal cell isolates were studied to determine the generality of these findings. Phenotypic heterogeneity was a consistent characteristic, but cytokeratin-positive cells were always present both in first trimester and term strains. Desmin was absent from almost all the cells isolated using the protocols employed, despite its occurrence in a significant subpopulation of cells in the villous stroma. Cytokeratins 8 and 18 can be observed in the stromal compartment of both first trimester and term placental villi. Cytokeratin has hitherto been regarded as a highly reliable marker for cells of the trophoblast lineage in vitro. These observations suggest that care should be taken in characterization of placental cell isolates; trophoblasts should be identified by the presence of cytokeratin 7 in preference to cytokeratin 8/18. The functional significance of cytokeratin expression in placental mesenchymal cells remains to be established.
Biomarkers↗