Prenatal diagnosis and management of monozygotic twins discordant for severe fetal abnormalities

ObjectiveWe present prenatal diagnosis and management of monozygotic (MZ) twins discordant for severe fetal abnormalities.Case reportA 36-year-old woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age, and hydrops fetalis, a giant cystic hygroma of 5 × 3.5 cm and left hydronephrosis in a co-twin. The other co-twin was structurally normal. Amniocentesis revealed a karyotype of 46,XY in both co-twins. Simultaneous polymorphic DNA marker analysis using the DNAs extracted from maternal blood and uncultured amniocytes confirmed MZ twinning. The woman underwent a successful selective fetal reduction by radiofrequency ablation at 22 weeks of gestation. At 28 weeks of gestation, premature rupture of membranes occurred, and a 1280-g normal male baby and a 275-g dead malformed co-twin were delivered. The normal co-twin was phenotypically normal and was doing well at age seven weeks.ConclusionsPrenatal diagnosis of MZ twins discordant for structural abnormalities should include a differential diagnosis of MZ twinning, and a zygosity test is necessary under such a circumstance.     

Application of QF-PCR for the prenatal assessment of discordant monozygotic twins for fetal sex

OBJECTIVE: To establish the utility of quantitative fluorescent polymerase chain reaction (QF-PCR) in order to determine the zygosity of multiple pregnancies, as well as to define the origin of the most frequent aneuploidies in amniotic fluid samples. METHODS: We describe the case of a monochorionic (MC) diamniotic (DA) pregnancy with phenotypically discordant twins (nuchal cystic hygroma and non-immune hydrops in twin A and no anomalies in twin B). QF-PCR was performed for rapid prenatal diagnosis in uncultured amniocytes and subsequently in cultured cells. Polymorphic markers for chromosomes X, Y, 13, 18 and 21 were used for determination of zygosity as well as sex chromosome aneuploidy. RESULTS: Twin A showed a Turner Syndrome (TS) mosaicism pattern by QF-PCR in uncultured amniocytes. The monozygotic origin of the pregnancy was determined. Interphase fluorescence in situ hybridization (I-FISH) in this sample showed a mosaicism X0/XY (83/17%). Cytogenetic analysis revealed a 45,X0 karyotype in twin A and a 46,XY karyotype in twin B. CONCLUSIONS: QF-PCR is a reliable tool for the determination of the zygosity independently of the chorionicity and the fetal sex in case of twin pregnancy. Testing both direct and cultured cells can provide useful results for genetic counselling in chromosomal mosaicisms.     

Prenatal diagnosis of the fragile-X in male monozygotic twins: discordant expression of the fragile site in amniocytes

A prenatal diagnosis of the fragile-X syndrome in monozygotic male twins is reported. The expression of the fragile site was discordant in amniotic cells. Fetal blood and, after therapeutic abortion, skin fibroblasts were positive in both fetuses. Our data suggest that great care should be taken when using amniocytes for prenatal diagnosis of the fragile-X syndrome.     

Prenatal diagnosis of heterokaryotypic mosaic twins discordant for fetal sex

The presence of a monozygotic twin gestation with discordant sex of the twins is a very rare constellation, which is referred to as heterokaryotypic monozygotic pregnancy. This constellation can develop either due to a chromosomal aberration after twinning or is - as in the following case - due to a mitotic error before twinning and an unequal distribution of mosaicism in both embryos. So far the diagnosis of heterokaryotypic monozygotic pregnancy has always been made postnatally, with only one exception (Gonsoulin et al., 1990). In this case we suspected the presence of monozygotic twins ultrasonically because of the chorionic and amniotic membrane characteristics. Surprisingly the sex of the fetuses was discrepant. As one of them had hydrops and a structural heart defect, we carried out an amniocentesis, which revealed mosaicism [45,X/46,X,i(Y)(p10)] of both fetuses. The female fetus with a predominant 45,X set of chromosomes and the typical intrauterine signs of the Ullrich-Turner syndrome (massive hygroma colli, hydrops fetalis and multiple cardiac defects) died during the 25th week of gestation due to cardiac decompensation. The other fetus appeared to be male with a predominance of a 46,X,i(Y)(p10) set of chromosomes and was born a few days after the intrauterine death of the hydropic fetus. In conclusion, our observation shows that ultrasonic evidence of discordant fetal sex in twins does not necessarily exclude monozygosity.     

Prenatal diagnosis in monozygotic twins with Down syndrome who had different phenotypes

We report the case of monozygotic (MZ) male twin fetuses with different Down syndrome (DS) phenotypes. Prenatal fetal sonography showed a bichorial biamniotic pregnancy with increased nuchal translucency in twin A and a cervical cystic hygroma and heart defect in twin B. Cytogenetic analysis performed after double amniocentesis showed free and homogeneous trisomy 21 in both twins. Monozygosity was confirmed by molecular analysis. The pregnancy was terminated at 17 weeks of gestation (WG). Postmortem analysis confirmed the phenotypic discordance. To our knowledge, this is the first reported prenatal diagnosis of MZ male twins with different Down syndrome phenotypes but identical karyotypes. We discuss the mechanisms involved in phenotypic discordance of monozygotic twins and particularly the role of environmental factors.     

Cystic hygroma: prenatal diagnosis and genetic counselling

Six cases of cystic hygromas detected during second trimester ultrasound examination are reported: 4 fetuses (67 per cent) had a 45, X karyotype, 1 fetus had trisomy 18, 1 fetus had a normal karyotype (46,XX) and at autopsy multiple anomalies were observed. In the latter case the family history suggested an autosomal recessive pattern of inheritance. In order to reach a definite diagnosis and give proper genetic counselling when a fetus is found to have cystic hygroma, a fetal karyotype as well as a family and reproductive history should be obtained.     

Prenatal diagnosis of DMD in a female foetus affected by Turner syndrome

OBJECTIVES: We report on a prenatal diagnosis of DMD complicated by a 45,X karyotype that was revealed only in the chorionic villus long-term culture. METHODS: Cytogenetic investigations were performed on both short-term (STC) and long-term cultures (LTC) of the chorionic villus sample. Familial segregation was performed using a panel of intragenic polymorphic markers, and multiplex PCR was used to characterize exonic deletion. RESULTS: Investigations performed for sex determination after STC of the chorionic villus sample showed a normal karyotype 46,XX, while the karyotype performed after LTC revealed a homogeneous monosomy X. Cytogenetic analysis performed on amniotic fluid cells showed 45,X/46,XX mosaicism. Familial segregation analysis for DMD showed loss of heterozygosity for the STR49 marker in the DNA of the proband, her mother and the foetus. Dystrophin gene analysis on the 45,X cells led to the identification of a deletion of exon 50. CONCLUSIONS: The report described a rare situation of monosomy X associated with a DMD genotype. The data confirmed the DMD carrier status of the proband and her mother and indicated that the foetus had a high risk to combine a Turner phenotype and DMD. This study illustrated the potential risk of using short-term culture of villi as the only source of biological material for prenatal diagnosis.     

Pericentric inversion of chromosome 19: prenatal diagnosis and genetic counselling

During prenatal diagnosis for advanced maternal age, a pericentric inversion of a chromosome 19 was detected in a male fetus. The inversion was familial, transmitted to the fetus by the phenotypically normal mother. The pregnancy resulted in a term birth of a phenotypically normal male infant. Inversion 19 appears to be a rare abnormality with only seven families reported thus far including ours. Infants with duplication deficiencies for chromosome 19 have not been reported in these families. This may suggest an apparent suppression of crossing over and recombination within the inverted segment of chromosome 19 during meiosis.     

Prenatal diagnosis of apparently isolated unilateral multicystic kidney: implications for counselling and management

Cases where initial prenatal diagnosis was made of isolated unilateral multicystic kidney (UMCK) were reviewed to determine appropriate counselling and management strategies. For the 73 cases, chromosome abnormalities, pregnancy complications and family histories were reviewed. In addition, subsequently diagnosed birth defects, and pediatric medical and surgical outcomes were available for 54 cases. Of those with outcome information available renal/genital-urinary tract abnormalities were diagnosed subsequently in 33% and non-renal abnormalities in 16% of cases. Of the non-renal abnormalities, congenital heart defects were most frequent (7%). One chromosome abnormality, a trisomy 21, was present among 32 cases where karyotypes were known (3%). Amniotic fluid volume abnormalities were present in 11 cases but not predictive of associated anomalies, with the exception of one case where polyhydramnios accompanied multiple malformations consistent with VATER association. A family history of structural renal anomalies was reported in 11 cases (20%). There were 14 cases of partial or complete involution (25%), including two cases of complete prenatal involution of the cystic kidneys. No long-term associated morbidity such as hypertension or malignancy was present in our cohort. Based on our study and corroborating literature, amniocentesis should be offered to women when a seemingly isolated UMCK is detected on routine prenatal ultrasound. Furthermore, a detailed ultrasound with careful assessment of the fetal heart and contralateral kidney is indicated at diagnosis and during the third trimester to assess for further evidence of structural abnormalities, as well as amniotic fluid volume abnormalities. Careful assessment of the newborn is indicated with appropriate speciality referral as required.     

Prenatal diagnosis and genetic screening--integration into prenatal care

In the last 3 decades, perinatal medicine has made tremendous advances in scientific knowledge and in the successful application of this knowledge toward understanding the fetal aspects of pregnancy. Evaluation of the health of the fetus and screening for birth defects has become an important part of prenatal care. This article provides an overview of birth defects and the various screening methods for diagnosing birth defects before birth. It also discusses the role of preconception genetic screening.     

Pregnancy outcome after genetic counselling for prenatal diagnosis of unexpected chromosomal anomaly

OBJECTIVES: Couples undergoing invasive prenatal diagnosis (PD) are informed and concerned mainly about autosomal trisomies. However, unexpected chromosomal abnormalities (UCA) are a frequent finding at PD. We have analysed the psychological and practical consequences in the couples counselled in our centre because of the identification of foetal UCA at PD. METHODS: The study was carried out on a sample of 52 couples referred for genetic counselling in the period 1997-2000. The couples underwent a structured interview and two self-report instruments to measure anxiety and psychological characteristics. RESULTS: The couples have been divided into three groups: (1) low risk - without or with negligible risk, (2) mild risk - with mild risk or mild clinical phenotype and (3) sex chromosome anomaly. All couples received the diagnosis of chromosomal anomaly from the obstetrician without any other comments and were referred to our service for genetic counselling. Most couples felt fear (11/17 in the LR group, 5/7 in the MR group and 12/21 in the SCA group), while sadness was lower frequently felt by those parents-to-be in the LR group. CONCLUSIONS: Our study suggests that a specific counselling that mentions the possibility of UCA is mandatory before PD, and the cost-benefit estimate of PD should take into account the psychological implications of UCA detection.     

Clinical and counselling implications of preimplantation genetic diagnosis for Huntington's disease in the UK

Huntington's disease is an autosomal dominant neurodegenerative disorder that usually occurs in adult life. Individuals at risk can have a gene test before the onset of symptoms, and prenatal diagnosis is available. Preimplantation genetic diagnosis (PGD) for Huntington's disease is now available for couples in whom one partner has the gene for Huntington's disease. A licence to practise PGD is required from the Human Fertilisation and Embryology Authority, and there are several complex issues relating to PGD for Huntington's disease that require consideration. The partner of the Huntington's disease gene carrier should have a presymptomatic test to ensure accuracy in a PGD cycle. There should be a delay between blood sampling and testing for Huntington's disease to allow time for reflection and withdrawal from testing. All PGD treatment has an associated risk of misdiagnosis. If confirmatory prenatal testing is not undertaken after a successful PGD cycle, no confirmation of diagnosis will be obtained at birth. Guidelines indicate that individuals who are at risk cannot be tested before 18 years. There is concern over the ability of a child or adolescent to make an informed choice about testing before this age. Confirmatory testing at birth after PGD would be in direct contravention of these guidelines. In the UK, the law requires consideration of the welfare of children born after assisted conception treatment. Presenting symptoms of Huntington's disease may affect the parenting abilities of an affected individual. There is a need for an assessment of a patient's current Huntington's disease status and their planned provision of care of children if Huntington's disease affects parenting. It has been necessary to create a detailed working protocol for the management of PGD for Huntington's disease to address these issues.     

Prenatal diagnosis of a large centromeric heteromorphism of chromosome 12: implications for genetic counseling

Chromosomal centromeric variants can be found in the course of a prenatal diagnosis. When following the discovery of fetal abnormalities at ultrasound examination, such variants may lead to some difficulties in genetic counseling. Here we describe a new heteromorphism implicating chromosome 12, found in a fetus with a suspicion of microcephaly, and we discuss its prognostic value.     

Prenatal diagnosis of an extremely rare type of conjoined twins: cranio-rachi-pygopagus twins

Prenatal diagnosis of conjoined twins is rare. An accurate diagnosis is important to provide the parents the best information about the prognosis of the twins. We report a first-trimester diagnosis of an extremely rare type of conjoined twins using two-dimensional transvaginal ultrasound.