Normal Liveborn Research Articles

Long-term follow-up of females with unbalanced X;Y translocations-reproductive and nonreproductive consequences.

BackgroundFemales with Xp;Yq translocations manifest short stature and normal fertility, but rarely have follow-up. The study purpose was to define the phenotype of a family with t(X;Y)(p22.3;q11.2), determine long-term reproductive function, and compare to all reported female cases.MethodsComprehensive clinical and molecular analyses were performed on the female proband, who had regular menses, normal endocrine function, and three pregnancies spanning seven years--a normal liveborn male and two with unbalanced translocations (liveborn female and stillborn male).ResultsThe translocation truncated KAL1 and deleted 44 genes on der(X). Our report constitutes the longest follow-up of an X;Y translocation female. She had no evidence of Kallmann syndrome, gonadoblastoma, or cardiovascular disease. Detailed analysis of 50 published female cases indicated a uniform lack of follow-up and significant morbidity—intellectual disability (10%), facial dysmorphism (28%), eye abnormalities (14%), and skeletal defects (28%).ConclusionsOur findings indicate normal ovarian function to date in a woman with an t(X;Y)(p22.3;q11.2). However, additional published studies in the literature suggest careful follow-up is necessary and contradict the generalization that females with Xp;Yq translocations are usually normal except for short stature.Electronic supplementary materialThe online version of this article (doi:10.1186/s13039-015-0112-0) contains supplementary material, which is available to authorized users.

Diagnosis and management of heterokaryotypic monochorionic twins

The diagnosis, management, and outcome of six consecutive heterokaryotypic monochorionic twins were evaluated. All suspected cases, based on discordant ultrasound findings, underwent amniocentesis of both sacs. Two cases also had chorionic villous sampling (CVS). Dual amniocentesis was superior to CVS in diagnosing heterokaryotypic monochorionic twins. In four cases, the X-chromosome was involved and autosomal aneuploidy was noted in the others. In five cases, the anomalous twin was selectively reduced by cord coagulation. All pregnancies ended with a phenotypically normal liveborn and all children are developing normally at 1-7 years of age.

Significance of a prenatally diagnosed del(10)(q23)

Structural chromosome mosaicism is rare. We report a case of prenatal mosaicism for a deletion of chromosome 10(q23). To our knowledge, there are only three reports of prenatally diagnosed cases of del(10)(q23). Two of these cases were due to an inherited fragile site. In the present case amniocentesis revealed 46,XY,del(10)(q23)[9]/46,XY[45]. Follow-up chromosome analysis of peripheral blood and placental tissue from a phenotypically normal liveborn male revealed the del(10)(q23) in only 3/100 blood cells grown in low-folate medium. It appears that prenatally diagnosed deleted (10q) mosaicism represents culture artifact and is not clinically significant.

Common trisomy mosaicism diagnosed in amniocytes involving chromosomes 13, 18, 20 and 21: karyotype-phenotype correlations

Karyotype-phenotype correlations of common trisomy mosaicism prenatally diagnosed via amniocentesis was reviewed in 305 new cases from a collaboration of North American cytogenetic laboratories. Abnormal outcome was noted in 10/25 (40%) cases of 47,+13/46, 17/31 (54%) cases of 47,+18/46, 10/152 (6.5%) cases of 47,+20/46, and in 49/97 (50%) cases of 47,+21/46 mosaicism. Risk of abnormal outcome in pregnancies with less than 50% trisomic cells and greater than 50% trisomic cells were: 26% (4/15) versus 60% (6/10) for 47,+13/46, 52% (11/21) versus 75% (6/8) for 47,+18/46, 4.5% (6/132) versus 20% (4/20) 47,+20/46, and 45% (27/60) versus 59% (22/37) for 47,+21/46. Phenotypically normal liveborns were observed with mean trisomic cell lines of 9.3% for 47,+13/46, 8.6% for 47,+18/46, 27% for 47, +20/46, and 17% for 47,+21/46. Cytogenetic confirmation rates were 46% (6/13 cases) for 47,+13/46 mosaicism, 66% (8/12 cases) for 47, +18/46, 10% (10/97 cases) for 47,+20/46, and 44% (24/54 cases) for 47,+21/46. There were higher confirmation rates in pregnancies with abnormal versus normal outcome: 50% versus 44% for 47,+13/46 mosaicism, 100% versus 33% for 47,+18/46, 66% versus 7% for 47, +20/46, and 55% versus 40% for 47,+21/46. Repeat amniocentesis is not helpful in predicting clinical outcome. It may be considered when there is insufficient number of cells or cultures to establish a diagnosis. Fetal blood sampling may have a role in mosaic trisomy 13, 18, and 21 as the risk for abnormal outcome increases with positive confirmation: 1/5 (20%) normal cases versus 5/8 (62%) abnormal cases. High resolution ultrasound examination(s) is recommended for clinical correlation and to facilitate genetic counselling.

Prenatal diagnosis of trisomy 4 mosaicism

Trisomy 4 mosaicism is rare. To our knowledge only two cases of prenatally diagnosed trisomy 4 mosaicism have been reported. One case resulted in a normal liveborn male, the other resulted in an abnormal liveborn female. The karyotype of our case at the time of amniocentesis was 47,XY,+4[3]/ 46,XY[33] and resulted in a normal liveborn male. FISH analysis using an alpha satellite chromosome 4 probe was performed to confirm the cytogenetic findings. Follow-up chromosome analysis of cord blood, peripheral blood, foreskin, and umbilical cord fibroblasts showed a normal 46,XY male karyotype in all cells. FISH analysis of cord blood, umbilical cord fibroblasts, and amniotic fluid cells demonstrated two signals in 246 nuclei (i.e., 46,XY) and three signals in six nuclei (i.e., 47,XY,+4). Here we describe the present case of trisomy 4 mosaicism, the literature is reviewed, and the significance of this finding is discussed.

Unintended pregnancies in women delivering at 18 South American hospitals. NFP-ECLAMC Group. Latin American Collaborative Study of Congenital Malformations.

Unintended pregnancies are accepted as associated with social, maternal and perinatal risks, but few data exist in South America. In a selected network of hospitals participating in the ECLAMC (Spanish acronym for Latin American Collaborative Study of Congenital Malformations), the frequency of unintended pregnancies was 49.8% in 5155 mothers of normal liveborns, as interviewed in the post-partum period (1992-1994). Compared with the intended pregnancy group, these mothers were more frequently multiparous, conceived easily, had a surprisingly higher mean maternal age, lower educational level, and Black ancestors. The frequency of mistimed pregnancies was the highest among primiparae. No adverse perinatal outcome could be found with regard to low birthweight (< 2500 g), prematurity (< 37 weeks), and early neonatal death. The rates of Caesarean delivery, twinning and sex ratio were similar in intended and unintended groups. Logistic regression analysis showed that maternal education could be a confounding factor associated with other maternal variables. The rate of unintended pregnancies in the present study is significantly higher than that described for other regions. Knowledge of the characteristics of women experiencing unintended pregnancies would allow proper public health strategies.

Clinical significance of isolated enlargement of the cisterna magna (> 10 mm) on prenatal sonography.

Enlargement of the cisterna magna has been reported to be associated with aneuploidy. In prior studies of cisterna magna enlargement, however, those fetuses with abnormal chromosomes have had other sonographic abnormalities in addition to a large cisterna magna. Our goal was to assess the clinical significance of the isolated finding of a cisterna magna measuring more than 10 mm in anteroposterior dimension on a prenatal sonogram. We retrieved all prenatal sonograms performed at our institution between 1989 and 1996 in which an enlarged cisterna magna was the only sonographic abnormality. Cases were included in our study if the cisterna magna measured more than 10 mm in the appropriate plane and the fetal survey was otherwise normal, including normal cerebellar size and morphology. Pregnancy outcome and postnatal follow-up were obtained in each case. Fifteen cases comprised our study population. In all 15 fetuses, the enlarged cisterna magna was first seen in the third trimester (gestational age range, 26 to 37 weeks). The cisterna magna ranged from 11 to 19 mm in size (mean, 12.9 mm). All 15 pregnancies resulted in phenotypically normal liveborn infants. All the mother and infants had short hospital stays (1 to 4 days), and the infants were normal at discharge. Longer follow-up was available in eight cases (range, 2 to 69 months), and all eight of these infants were normal. Our results suggest that isolated enlargement of the cisterna magna to more than 10 mm is associated with normal pregnancy and neonatal outcome.

Prospective study showing that antisperm antibodies are not associated with pregnancy losses

To obtain prospective data on the relationship between presence of antisperm antibodies in maternal sera and first trimester pregnancy losses. First trimester sera obtained from diabetic and nondiabetic women recruited within 21 days of conception were analyzed using the indirect immunobead test for immunoglobulin (Ig)G, IgA, and IgM antisperm antibodies. Regional binding also was considered: sperm head, midpiece, and sperm tail. Results were correlated with pregnancy outcome. Five university centers. One hundred eleven women who experienced pregnancy loss (55 diabetic; 56 nondiabetic) were matched 2:1 with 104 diabetic and 116 nondiabetic women (controls) who subsequently had a normal liveborn infant. None. Pregnancy outcome (spontaneous abortion, liveborn) correlated with presence or absence of antisperm antibodies. Analyzing samples without knowledge of clinical status, no differences were observed with respect to IgG, IgA, and IgM binding when a positive test was defined as 50% of sperm showing antibody binding. Likewise, no association was found for IgG and IgM antisperm antibodies at 20% binding. The only positive finding was observed for IgA antisperm antibodies at 20% binding (Fisher's Exact test). This one positive finding merely could reflect multiple comparisons. No significant differences between groups were observed when analysis was stratified according to location of antibody binding (head, midpiece, tail tip, entire sperm). When the sample was stratified into those having and not having a prior loss, a relationship between antisperm antibodies and pregnancy loss still was not evident. Further work is necessary to determine whether IgA antisperm antibodies truly are associated with pregnancy loss or whether antisperm antibodies play any role in repetitive aborters. Findings in this study suggest that antisperm antibodies do not play a major role in pregnancy loss.

Incidence and significance of chromosome mosaicism involving an autosomal structural abnormality diagnosed prenatally through amniocentesis: a collaborative study.

Among 179,663 prenatal diagnosis cases collected from ten institutions and two publications, 555 (0.3 per cent) were diagnosed as having chromosome mosaicism. Of these, 57 (10.3 per cent) were mosaic for an autosomal structural abnormality, 28 (5 per cent) for a sex chromosome structural abnormality, and 85 (15.3 per cent) were mosaic for a marker chromosome. Ninety-five cases of prenatally diagnosed mosaicism with a structural abnormality in an autosome and a normal cell line, and with a known phenotypic outcome, were collected for karyotype-phenotype correlations through our collaboration (40 cases), a prior survey (26 cases), and published reports (29 cases). They included 13 balanced reciprocal translocations, one unbalanced reciprocal translocation, four balanced Robertsonian translocations, four unbalanced Robertsonian translocations, four inversions, 17 deletions, three ring chromosomes, 19 i(20q), seven +i(12p), six other isochromosomes, and 17 partial trisomies resulting from a duplication or other rearrangement. All cases mosaic for a balanced structural rearrangement resulted in a normal phenotype. All cases of 46/46,i(20q) resulted in normal liveborns. Five of seven cases with 46/47,+i(12p) had an abnormal phenotype compatible with Killian-Pallister syndrome. The overall risk for an abnormal outcome for a mosaic case with an unbalanced structural abnormality, excluding 46/46,i(20q) and 46/47,+i(12p), is 40.4 per cent. In the same category, the study also suggested a correlation between the percentage of abnormal cells and an abnormal phenotype. For mosaicism involving a terminal deletion, the possibility of a familial fragile site should be considered.

Mosaicism for trisomy 12: Four cases with varying outcomes

Trisomy 12 observed in chorionic villus sampling (CVS) may reflect generalized mosaicism or indicate mosaicism confined to only the placenta. In this report, four cases of trisomy 12 observed in CVS or cultured placental biopsies with varying outcomes are presented. Seven dinucleotide repeat polymorphisms for chromosome 12 were used to determine the chromosome 12 origins in the fetus or child and to delineate the mechanism(s) that gave rise to the trisomy. In two cases (cases A and C), the mosaicism was confined to the placenta, resulting in normal liveborns. Although, in one case, the molecular results suggested an apparent duplication of one paternal chromosome 12 in the placenta, normal biparental inheritance was found in the diploid fetal cell line in both cases. In two other cases (cases B and D), trisomy 12 was observed in both extraembryonic and fetal tissues. In one of these pregnancies, a child was born by Caesarean section at 37 weeks because of intrauterine growth retardation and oligohydramnios, and resulted in neonatal death. Molecular markers and fluorescence in situ hybridization (FISH) revealed low-level trisomy 12 mosaicism in the spleen. In the fourth case, fetal abnormalities were detected on ultrasound and low-level trisomy 12 mosaicism was observed in amniotic fluid cells using conventional cytogenetics and FISH. Molecular markers revealed a maternal meiosis I non-disjunction of chromosome 12 in DNA from a cultured placental biopsy. Although predicting the outcomes of pregnancies involving confined placental mosaicism remains difficult, molecular techniques are valuable tools for distinguishing uniparental from biparental disomy and mechanisms of mosaicism.

Reasons for women's non‐uptake of amniocentesis

More than 10 years after a chromosomal anomaly screening programme was set up in France for pregnant women of advanced age, amniocentesis is still a controversial issue. The reasons why eligible women did not utilize the test and whether or not the existence of social welfare coverage determined women's access to prenatal diagnosis were studied. A group of 291 women aged > or = 35 years who recently gave birth to normal liveborns was interviewed by telephone. Among those aged 38 years and over, who automatically qualified for social security coverage, 75 per cent had undergone amniocentesis as opposed to 23 per cent in the 35 to 37-year-old non-covered age group who did not qualify for social security coverage. In both groups, access to amniocentesis was found to depend on the physicians', women's and male partners' attitudes towards prenatal diagnosis and abortion. Among the younger group, the uptake depended mainly on socio-economic factors. Institutional policies should ensure greater equality of access while allowing for individual preferences.

Recurrent pregnancy loss as an indicator for increased risk of birth defects: a population-based case-control study.

Stillbirths and spontaneous abortuses have higher rates of birth defects than liveborn infants. The relationship between a woman's previous pregnancy loss and the risk of birth defects in the offspring has not been adequately examined, however. Using data from a population-based case-control study, we assessed whether one or more previous pregnancy loss was associated with increased birth defect risks. Case subjects were 4918 infants with serious births defects diagnosed in the first year of life and ascertained by the Metropolitan Atlanta Congenital Defects Program from 1968 to 1980. Control subjects were 3028 normal liveborn infants frequency-matched to case infants by race, hospital and period of birth. Among case and control infants whose mothers had already had at least one previous pregnancy, reported pregnancy losses (stillbirths and miscarriages) were associated with elevated risks of birth defects (odds ratios for one pregnancy loss of 1.24, two pregnancy losses of 1.49, and three or more pregnancy losses of 1.62, P < 0.0001 for trend). This association held after considering several potential confounders using logistic regression analysis. When specific defects were examined, many exhibited this association, notably hydrocephalus, and some cardiovascular, genital and limb defects. We estimate that the risk of serious birth defects increases from 2.5% for infants of women with no prior pregnancy loss to 4.2% for infants of women with three or more pregnancy losses. This finding has both clinical implications for pregnancy counselling and pathogenetic implications related to birth defect aetiology.

Intrauterine Growth and Spastic Cerebral Palsy II. The Association With Morphology at Birth

Abstract This study tests the hypothesis that children with spastic cerebral palsy had different birth morphologies, defined in terms of their weight, length, head circumference, ponderal index and length to head circumference ratio, from that of the normal liveborn population. An earlier study showed a highly significant association of spastic cerebral palsy with low birthweight for gestational age in infants over 34 weeks gestation at delivery. This analysis defines morphological measurements as “abnormal’ if not within the 10th-90th percentile ranges of appropriate total liveborn populations. The proportions with combinations of such measurements in 104 cases of spastic cerebral palsy from a population register of cerebral palsy are compared with those in a total liveborn population. Categories of ‘abnormal’ measurements associated with increased risk contained 44.4% of cases in excess of the proportion observed in the total population. More than half these excess cases were short for their gestation (suggesting size deficits originating before the 3rd trimester) and tended to have more severe forms of cerebral palsy. A further excess of 7.4% of cases had a head circumference above their 90th percentile: these generally developed mild cerebral palsy.

Intrauterine growth and spastic cerebral palsy II. The association with morphology at birth

This study tests the hypothesis that children with spastic cerebral palsy had different birth morphologies, defined in terms of their weight, length, head circumference, ponderal index and length to head circumference ratio, from that of the normal liveborn population. An earlier study showed a highly significant association of spastic cerebral palsy with low birthweight for gestational age in infants over 34 weeks gestation at delivery. This analysis defines morphological measurements as “abnormal’ if not within the 10th-90th percentile ranges of appropriate total liveborn populations. The proportions with combinations of such measurements in 104 cases of spastic cerebral palsy from a population register of cerebral palsy are compared with those in a total liveborn population. Categories of ‘abnormal’ measurements associated with increased risk contained 44.4% of cases in excess of the proportion observed in the total population. More than half these excess cases were short for their gestation (suggesting size deficits originating before the 3rd trimester) and tended to have more severe forms of cerebral palsy. A further excess of 7.4% of cases had a head circumference above their 90th percentile: these generally developed mild cerebral palsy.

Effect of treatment with gonadotropin-releasing hormone analogues on pregnancy outcome in the baboon

The effect of a gonadotropin-releasing hormone (GnRH) agonist, Zoladex (Imperial Chemical Industries, PLC, London, England), and an antagonist, Organon 30276 (Organon, Oss, Holland), on the outcome of pregnancies when administered just after implantation was examined. The antagonist, Organon 30276, was administered continuously from days 14 through 21, and the agonist, Zoladex, was injected as long-acting pellets on day 14 after conception to pregnant baboons. Maternal baboon chorionic gonadotropin and progesterone levels and sonographic measurement were made before, during, and after treatment and throughout pregnancy of control and treated animals. Two pregnant animals were treated with 3.6 mg of Zoladex; one aborted and one had a stillbirth. Another four pregnant baboons were treated with 7.2 mg of Zoladex; two aborted, one had a premature with a low-birthweight infant, and one had a normal liveborn. Organon 30276, at 50 mg, was administered to three pregnant baboons and resulted in one stillbirth, one neonatal death, and one normal liveborn. The two pregnant baboons treated with 100 mg Organon 30276 both aborted. Therefore, treatment with these GnRH analogues in very early baboon pregnancy could adversely affect the outcome of pregnancy. Thus attention should be paid to the possible presence of early pregnancy at the time of GnRH analogue therapy, which might adversely affect the outcome of the pregnancy.

Detection of balanced chromosome rearrangements in 445 couples with repeated abortion and cytogenetic prenatal testing in carriers

Cytogenetic studies were performed in 445 couples presenting because of repetitive abortion. The authors detected a balanced translocation in 19 (4.2%) of the couples, pericentric inversions in 8 (1.8%), and polymorphisms in 52 (11.4%). The results were compared with those obtained in a series of 600 consecutive normal liveborns. Significantly higher frequencies for translocations and polymorphisms were present in couples with repetitive abortion. No sex predominance in translocation carriers was observed, and reciprocal translocations were more common (16 of 19) than the robertsonian type (3 of 19). Contrary to other reports, all of the translocations and inversions were detected among couples without previous abnormal offspring. Cytogenetic prenatal testing in 17 pregnancies from a carrier parent showed that none of the fetuses had the unbalanced karyotype, 13 carried the balanced rearrangement, and 4 had a normal karyotype. Although a risk profile can be obtained for these couples, prenatal testing must be offered to avoid anxiety and unjustified pregnancy interruptions.

Chromosome studies in 2136 couples with spontaneous abortions

Two thousand one hundred and thirty six couples with one or more spontaneous abortions (SAB) before 13 weeks of gestation and with or without one normal liveborn child (NLC) were karyotyped. In 4.31% of the couples one partner was a carrier of a major chromosomal abnormality. Couples with SAB only have 2-fold more chromosomal aberrations than couples with SAB and NLC. A correlation between the frequency of chromosomal abnormalities and the number of SAB was observed. Finally, the various types of chromosome aberrations were analysed.

825 REPRODUCTIVE OUTCOME IN COUPLES WITH PREVIOUS PREGNANCY WASTAGE

A follow up study was carried out of the reproductive experience of 62 couples who had been evaluated earlier at our Genetic Center because of a history of pregnancy wastage (i.e. 2 or more spontaneous abortions (SA)) and no liveborn children. Of 57 couples who had normal peripheral blood chromosome findings, 45 (79%) had subsequent normal liveborn m-fants, although 14 also had one or more additional SA. In a comparison of couples with 2 (n=29) or 3 or more (n=28) previous SA, the latter had a less favorable outlook for a liveborn infant (93.1% vs 64.3% p < 0.02) and also a greater likelihood of no further pregnancies(6.9% vs 25.0% p=n.s.). Among 5 couples with an abnormal karyotype in one member of the pair, only 1 had a normal liveborn child, 1 had an additional SA, and 2 had no recognizable pregnancies despite attempts at conception. Thus, there is a high expectation of favorable pregnancy outcome after 2 SA and a less favorable pregnancy outlook with 3 or more SA among couples with normal karyotype and no previous live births. The reproductive outlook appears to be poor in couples with a structural chromosome rearrangement.

Chromosomal findings in 164 couples with repeated spontaneous abortions: with special consideration to prior reproductive history.

The cytogenetic evaluation of 164 couples who experienced repeated spontaneous abortions revealed 11 chromosomal abnormalities (10 translocations and 1 sex chromosome mosaic, 6.70%). An apparent positive relationship between the frequency of chromosome anomalies and the number of spontaneous abortions was observed. Couples with at least one normal liveborn child, in addition to the spontaneous abortions, had a significant increase in chromosomal abnormalities (17.85%) when compared with those with no liveborn offspring (4.41%) (P less than 0.005). Similarly, couples whose fetal wastage consisted of only first trimester spontaneous abortions had a greater increase in the frequency of chromosomal abnormalities (8.03% vs 0.00%).

Nucleolar organizing regions of human chromosomes.

Silver-stained cells from 49 parents with a history of several abortions were compared with cells from 35 parents with normal liveborn children. The modal and mean number of silver-stained NORs (Ag-NORs) observed on D- or G-group chromosomes was similar in both groups and between males and females. Ag-NORs were randomly distributed on all five acrocentric pairs. The distribution and size of Ag-NORs within an individual was not random and was fairly consistent from cell to cell. The mean number of associations per cell was similar in both males and females of the abortion group and was less than the number of associations in controls. The probability of D- or G-group chromosomes being associated was near the expected probability of 0.6 for D-association and 0.4 for G-association. The frequency of association of any chromosome combination did not differ statistically from the expected values, though the number of associations, 15/22, was higher than expected.