European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations (ECARUCA); an online database for rare chromosome abnormalities.

During recent years a considerable improvement in diagnostic techniques has enabled cytogeneticists to find more and smaller chromosomal aberrations. However, accurate clinical knowledge about rare chromosome disorders is frequently lacking, mostly due to a significant decline in publishable cases. On the other hand, there is an increasing demand from parents and physicians for reliable information. In order to improve the quality and the quantity of data available, we designed a new database named the European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations (ECARUCA) at http://www.ecaruca.net. This Internet-database contains cytogenetic and clinical data of patients with rare chromosome abnormalities, including microscopically visible aberrations, as well as microdeletions and -duplications. Cases with certain breakpoints collected in the Zurich Cytogenetic Database were transferred to ECARUCA. The advantages of ECARUCA compared to existing sources are that ECARUCA is interactive, dynamic and has long-term possibilities to store cytogenetic, molecular and clinical data. Professionals can login to submit new cases and perform searches in the database through the Internet. Currently the database contains 1500 unique chromosomal aberrations from almost 4000 patients. A frequent submission of new data ensures the up-to-date quality of the collection. Individual parent accounts allow parents to inform the ECARUCA team about the follow-up of their child. The ECARUCA database provides health care workers with accurate information on clinical aspects of rare chromosome disorders. Additionally, detailed correlations between chromosome aberrations and their phenotypes are of invaluable help in localising genes for mental retardation and congenital anomalies.

Identification of susceptibility loci for nonsyndromic cleft lip with or without cleft palate in a two stage genome scan of affected sib-pairs.

Nonsyndromic cleft lip with or without cleft palate (CL/P) is a complex disorder of multigenic origin involving between two and ten loci. Linkage and association studies of CL/P have implicated a number of candidate genes and regions but have often proved difficult to replicate. Here, we report the findings from a two-stage genome-wide scan of 92 affected sib-pairs to identify susceptibility loci to CL/P. An initial set of 400 microsatellite markers was used, with an average spacing of 10 cM throughout the genome. Eleven regions on eight chromosomes were found to have a P-value smaller than 0.05. These eight chromosomes were then further mapped with a second set of markers to increase the average map density to 5 cM. In seven out of eleven areas densely mapped, significance was markedly increased by decreasing the marker interval. Excessive allele sharing was found at 1p (NPL=2.35, P=0.009, MLS=1.51), 2p (NPL=1.77, P= 0.04, MLS=0.66), 6p (NPL=2.35, P=0.009, MLS=1.34), 8q (NPL=2.15, P=0.015, MLS= 1.51) 11 cen (NPL=2.70, P=0.003, MLS=2.10), 12q (NPL=2.08, P=0.02, MLS= 1.5), 16p (NPL=2.1, P=0.018, MLS=0.97) and Xcen-q (NPL=2.40, P=0.008, MLS=2.68). Although none reached the level required for significant susceptibility loci, two of these areas have previously been implicated in CL/P, viz. 2p13, an area harbouring the TGFA gene, and 6p23-24. We also demonstrate highly suggestive linkage to a susceptibility locus for nonsyndromic clefting on the X chromosome. Further studies are currently underway to replicate these findings in a larger cohort of affected sib-pairs.

Popliteal pterygium syndrome: a clinical study of three families and report of linkage to the Van der Woude syndrome locus on 1q32.

Popliteal pterygium syndrome (PPS) is a rare autosomal dominant disorder, thought to occur with an incidence of approximately 1 in 300 000 live births. The main clinical manifestations are popliteal webbing, cleft lip, cleft palate, lower lip pits, syndactyly, and genital and nail anomalies. This report describes the clinical features in two families with PPS and one isolated case, showing the range of anomalies found both within and between the families. PPS has some features in common with Van der Woude syndrome (VWS), also inherited as an autosomal dominant condition, with cleft lip/palate and, more distinctively, lower lip pits. Although the gene for VWS has not yet been identified, it has been localised to within 1.6 cM in the region 1q32-41. To determine whether PPS and VWS represent allelic forms of the same gene, three families were genotyped for markers flanking and within the critical region. A multipoint lod score of 2.7 was obtained, with no evidence of recombination, supporting the hypothesis that these two disorders are allelic.

Frontonasal dysplasia with optic disc anomalies and other midline craniofacial defects: a report of six cases.

The association of optic disc abnormalities with basal encephaloceles, specifically of the sphenoethmoidal type, and midline facial clefts has rarely been reported, although the association of midline facial clefts with encephaloceles is well described. We now report six cases of children, three males and three females, presenting with a sphenoethmoidal encephalocele, optic disc anomalies, midline facial clefting, hypertelorism, complete or partial agenesis of the corpus callosum, and endocrinological disturbances, including diabetes insipidus and pituitary dysfunction. This report underlines the importance of careful ophthalmic and endocrinological investigation of children with midline clefts associated with basal encephaloceles. These cases may represent a distinct entity within the spectrum of frontonasal dysplasia.

The predictability of subnormal penetrating capacity of sperm in cases of unexplained infertility.

Multivariate discriminant analysis has been used to determine the predictability of sub-normal penetrating capacity in cases of unexplained infertility. The product of this analysis was the identification of 7 discriminating variables, all of which described various aspects of the post-capacitation movement characteristics exhibited by the spermatozoa, omitting all reference to the conventional parameters of semen quality. On the basis of these discriminating variables, 90.9% of samples exhibiting penetration rates within the normal range were correctly predicted to be functionally competent. The same variables correctly identified only 60% of samples with impaired penetrating capacity, indicating that in the remaining 40%, defects are present in the spermatozoa which are not reflected in their motility patterns.

An analysis of semen quality and sperm function in cases of oligozoospermia.

This study is based upon an analysis of 27 severely oligozoospermic men, in whom defects in sperm motility and morphologic defects were also evident, and 35 control subjects of proven fertility. Semen samples recovered from these men were assessed by conventional criteria, time-exposure photomicrography, and the zona-free hamster egg penetration test. Evidence of severely defective sperm function was obtained for the oligozoospermic group, which gave a mean +/- standard error (SE) fertilization rate of 2.8% +/- 1.5, compared with 44.0% +/- 3.4 for the normal fertile control subjects. Multivariate discriminant analysis was used for selection of those parameters of semen quality that could most accurately identify the 70% of oligozoospermic samples that failed to exhibit any fertilizing potential in the hamster egg assay. This analysis correctly identified 89% of such samples, on the basis of seven discriminating variables, of which the most significant were percentage of motile sperm, the log of sperm density, and a log transformation of the concentration of progressive spermatozoa.

Relation between the luteinizing hormone peak, the nadir of the basal body temperature and the cervical mucus score.

The results of a cervical mucus scoring system and of basal body temperature (BBT) chart interpretation were compared with those of a short-incubation radioimmunoassay for luteinizing hormone (LH) in 198 ovulatory menstrual cycles. The timing of the maximal cervical mucus score was similar to that of the LH peak in all but 7% of assessable cycles. In contrast, the timing of the nadir of the BBT differed widely from that of the LH peak in 45% of cycles with interpretable charts. These findings suggest that cervical mucus scoring might be useful for identifying the time of ovulation where LH assays are unavailable or where speed and economy are at a premium.

An analysis of sperm function in cases of unexplained infertility: conventional criteria, movement characteristics, and fertilizing capacity.

A detailed analysis of semen quality was carried out in 85 couples with unexplained infertility by the use of conventional criteria of semen analysis, time-exposure photomicrography, and the zona-free hamster egg penetration test. According to the latter, 34.1% of the male partners exhibited evidence of defective sperm function, although only 4% of these patients were devoid of any demonstrable fertilizing capacity. Of the conventional parameters of semen analysis examined, the most revealing was the morphologic character of the sperm, which was significantly poorer (P less than 0.001) in the group with unexplained infertility than in the normal fertile control group and also showed a significant relationship (P less than 0.001) with the presence of subnormal fertilizing capacity in the hamster egg assay. A majority of movement characteristics measured by time-exposure photomicrography were significantly depressed in the group with unexplained infertility, compared with the normal fertile control group. In addition, certain of the movement characteristics investigated were significantly related to the fertilizing capacity of the spermatozoa; and, in this respect, a progressive swimming speed (greater than 25 micrometers/sec), a straight swimming mode of progression, and a small amplitude of lateral head displacement (Ah) all appeared to be important qualities.

The correlates of fertilizing capacity in normal fertile men.

An investigation has been carried out in normal fertile men on the correlates of fertilizing capacity as defined by the zona-free hamster egg penetration test. The results demonstrate that the apparent fertility of these men is compatible with a wide range of intrinsic sperm quality as reflected by penetration rates ranging from 14% to 90% and differences in the minimum concentration of motile spermatozoa required to initiate penetration. These differences in sperm function could not be correlated with any of the conventional parameters of semen analysis or any of a large number of sperm movement characteristics analyzed by time-exposure photomicrography, with two exceptions: (1) the percentage of progressively (greater than 25 micron/sec) motile spermatozoa exhibiting an amplitude of lateral head displacement (Ah) of less than 10 micron, which was positively correlated with penetrating capacity (P less than 0.01), and (2) the percentage of progressively (less than 25 micron/sec) motile spermatozoa exhibiting an Ah of greater than 10 micron, which was negatively correlated with penetration rate (P less than 0.05). The information obtained in this study should provide a useful basis against which to compare the properties of spermatozoa in cases of suspected infertility.

Central circulatory responses in normotensive and hypertensive pregnancy.

Haemodynamic responses in normotensive pregnancy in the antenatal phase show that cardiac output is elevated by the end of the first trimester, and remains elevated throughout pregnancy, although it may fall very slightly at the end of the third trimester of pregnancy. Heart rate remains virtually static throughout pregnancy, although it may fall very slightly at the end of the third trimester of pregnancy. Arterial blood pressure remains virtually unaltered. During labour in patients with traditional anaesthesia, cardiac output is elevated by 40% overall at the end of the labour, and this rise may be as much as 60% in the immediate post-partum period. Patients with epidural analgesia show no overall rise in cardiac output throughout labour. Following Caesarean section there may be massive rises in cardiac output. In patients who become hypertensive as a result of pregnancy, there are marked individual patterns. These different groups show patients with elevated levels of cardiac output, patients with a pure elevation of systemic vascular resistance, and a third group in which there is elevation of both resistance and output. It seems certain that different syndromes are occurring, the theoretical explanations for which are discussed.

Effects of posture on limb blood flow in late pregnancy.

Arm and leg blood flow was measured in 40 patients in late pregnancy in the supine and left lateral positions, and the changes were contrasted with changes found in 15 patients investigated in the early puerperium. A significant reduction in leg flow occurred in the pregnant subjects when the supine position was assumed. A further 30 patients in late pregnancy had leg flow measured in the following positions: left lateral, supine, right lateral, and the two mid-positions. Leg flow significantly increased on moving from the supine to all other positions except the right intermediate position, indicating that a leftward tilt is more effective in preventing caval compression.