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.     

Prenatal diagnosis of female monozygotic twins discordant for Turner syndrome: implications for prenatal genetic counselling

We describe a set of monozygotic (MZ) female twins, one of whom presented with a typical Turner syndrome (TS) phenotype and the other a normal female phenotype. Prenatal fetal ultrasonographic examination showed a monochorial diamniotic pregnancy with a hygroma colli and growth delay in Twin A and no anomalies in Twin B. Karyotypic analysis performed on fetal blood samples demonstrated a 46,XX/45,X (23/2) mosaicism in Twin A and a normal 46,XX chromosome constitution in Twin B. At birth, Twin A presented with a typical TS and Twin B had a normal female phenotype. Postnatal cytogenetic investigation of blood lymphocytes showed the same 46,XX/45,X mosaicism in both twins: 46,XX/45,X (40/7) in Twin A and 46,XX/45,X (40/5) in Twin B. Further investigations at the age of 10 months showed in Twin A a 46,XX/45,X (98/2) mosaicism in lymphocytes and 100% of 45,X (50 analysed cells) in fibroblasts, and in Twin B a normal 46,XX (100 analysed cells) chromosome constitution in lymphocytes but a mild 46,XX/45,X (78/2) mosaicism in fibroblasts. Monozygosity was confirmed by molecular analysis. To our knowledge, this is the first report of prenatal diagnosis of MZ female twins discordant for TS. Review of reported sets of MZ female twins (eight cases) or triplets (one case) discordant for TS shows, as in the present case, that the phenotype correlates better with the chromosomal distribution of mosaicism in fibroblasts than in lymphocytes. In the blood of MZ twins chimerism may modify the initial allocation of the mosaicism. These results suggest that, in cases of prenatal diagnosis of MZ female twins discordant for TS, the phenotype of each twin would be better predicted from karyotype analysis of cells from amniotic fluid than from fetal blood.     

单绒毛膜双羊膜囊双胎之一胎先天性心脏病的产前诊断

目的探讨单合子之单绒毛膜双羊膜囊(monochorionic diamniotic，MCDA)双胎之一胎先天性心脏病(简称"先心病")产前诊断。 方法2013年1月至2017年6月在中山大学附属第一医院妇产科就诊的MCDA双胎之一胎先心病共79对，每对胎儿分别行羊膜腔穿刺，羊水标本送检染色体核型分析和染色体微阵列分析(chromosomal microarray analysis，CMA)，并对其产前诊断的结果进行临床分析。 结果79对中75对共150个胎儿进行了CMA，71对共142个胎儿进行染色体核型分析。染色体核型异常检出率为7.7%(11/142)；除外良性拷贝数变异(copy number variant, CNV)，CMA对CNV和非整倍体的检出率为21.3%(32/150)，高于核型分析(χ²＝8.025，P ＝0.005)；核型正常胎儿异常CNV检出率为16.0%(21/131)。5对单合子双胎两个胎儿间存在不一致的染色体核型或CNV，发生率为7.0%(5/71)，其中4对先心病胎儿检出异常核型或CNV，而心脏发育正常胎未检出异常。 结论对于先心病的产前诊断，CMA较传统的核型分析具有更高的检出率。单绒双胎尤其单合子双胎可存在遗传异质性，当MCDA双胎出现先心病，尤其两胎表型不一致时，有必要对双胎同时进行侵入性产前诊断。     

Discordance in Mayer-von Rokitansky-Küster-Hauser Syndrome Noted in Monozygotic Twins

BackgroundWe report a case of monochorionic, monoamniotic female twins with discordant congenital reproductive tract anomalies.CaseWe present the case of a 17-year-old monochorionic-monoamniotic female twin with Mayer-von Rokitansky-Küster-Hauser Syndrome (MRKH) and her twin sister, who had with normal female reproductive system. Monozygosity is investigated by the complete history, physical, and imaging data, antenatal and birth reports of both the patient and her monozygotic twin sister. Examination of these documents proves monozygosity of the sisters, and imaging studies demonstrate MRKH in one twin and normal female genitalia in the other.Summary and ConclusionThis case is presented as proof of MRKH discordance in monozygotic twins.     

Birth of twin males with normal karyotype after intracytoplasmic sperm injection with use of testicular spermatozoa from a nonmosaic patient with Klinefelter’s syndrome

Objective: To report the birth of healthy twin males after the use of testicular spermatozoa from a nonmosaic patient with Klinefelter’s syndrome.

Design: Case report.

Setting: Private reproduction center with university affiliation.

Patient(s): A couple undergoing intracytoplasmic sperm injection (ICSI) combined with testicular sperm extraction because of the husband’s secretory azoospermia and a nonmosaic 47,XXY peripheral blood karyotype. The wife, a healthy female, presented with a history of oligomenorrhea.

Intervention(s): ICSI was performed using testicular spermatozoa; 3 mM pentoxifylline solution was used to induce sperm motility because the spermatozoa recovered were all immotile.

Main Outcome Measure(s): Normal fertilization, embryo cleavage, pregnancy outcome, and peripheral blood karyotype of the newborns.

Result(s): Thirteen metaphase II oocytes were injected. Seven of them fertilized normally and six did not fertilize. Three good-quality embryos (4-cell stage class III) were transferred, and four were cryopreserved at the two-cell and four-cell stages using a slow freezing protocol. Twelve days after ET, a β-hCG determination was positive. Ultrasonographic examination revealed three intrauterine fetal sacs, but one of them showed a fetal pole without cardiac activity and vanished in subsequent ultrasonographic examinations. The patient delivered twins with normal male peripheral blood karyotypes.

Conclusion(s): Normal outcome after the use of testicular sperm extraction and ICSI in a nonmosaic patient with Klinefelter’s syndrome reaffirms the notion of low transmission risk of this gonosomal aneuploidy.     

Monochorionic-diamniotic twins discordant in gender from a naturally conceived pregnancy through postzygotic sex chromosome loss in a 47,XXY zygote

OBJECTIVE: It is generally believed that monochorionic-diamniotic twin pregnancies result from one fertilized oocyte with both siblings having the same genotype and phenotype. In rare instances, due to somatic mutations or chromosome aberrations, the karyotypes and phenotypes of the two twins can differ. METHOD: We report cytogenetic, molecular genetic and clinical examinations in monochorionic-diamniotic twins discordant in gender. RESULTS: The monochorionic-diamniotic status of the twins was diagnosed by ultrasound and histologic examination of the placenta. Prenatal chromosome examination performed on amniocytes revealed a normal female karyotype in one and a 46,XX(26)/46,XY(3) karyotype in the other twin. Molecular examinations confirmed monozygosity despite discordant sex. Based on the cytogenetic and molecular results of lymphocytes and placental cells, the only explanation for gender discordance was that the conceptus originally had a 47,XXY chromosome complement. CONCLUSION: A 47,XXY zygote appears to have undergone a twinning process. A postzygotic loss of the X chromosome in some cells and the Y chromosome in other cells, either before or after twinning, resulted in 46,XX/46,XY mosaicism in both monozygotic (MZ) twins. The sex discordance of the MZ twins can be explained by different proportions of the 46,XX and 46,XY cell lines in the gonads and other tissues.     

Discordance of fetal genotype or phenotype in monozygotic twins: a report of 2 cases

BACKGROUND: Discordance of fetal genotype or phenotype in a monozygotic twin pregnancy is rare. CASE: In case 1, a 28-year-old woman at 15 weeks' gestation was found to have a dichorionic twin pregnancy with 1 fetus affected with hydrop fetalis. The result of chromosomal study showed that the structurally normal fetus was 46,XY and that the hydropic fetus was 45,X. One week after selective termination of the hydropic fetus at 19 weeks' gestation, the cotwin died in utero. In case 2, a 30-year-old woman at 20 weeks' gestation, was found to have a monochorionic twin pregnancy with 1 fetus presenting with omphalocele. The result of chromosomal study showed that both fetuses were 46,XX. The fetus with omphalocele died in utero at 29 weeks' gestation, and the normal cotwin was delivered later due to fetal distress. Analysis by short tandem repeat markers in both cases indicated that they were monozygotic twins. CONCLUSION: These cases emphasize the importance of zygosity/chorionicity identification in twin pregnancy even though discordance of fetal genotype or phenotype was found. In monozygotic monochorionic twins, the normal cotwin is at risk for an adverse fetal outcome after 1 spontaneous intrauterine fetal death or selective termination. In monozygotic dichorionic twins, the risk of intrauterine fetal demise of the cotwin after selective termination still exists.     

性畸形四例遗传学分析

在细胞遗传学核型分析的基础上，利用Ｙ染色性体决定区基因（ｓｅｘ－ｄｅｔｅｒｍｉｎｉｇｒｅｇｉｏｎｏｆｔｈｅＹｃｈｒｏｍｏｓｏｍｅ，ＳＲＹ）探针，对４例性畸形病例进行了Ｓｏｕｔｈｅｒｎ杂交分析。同时运用ＳＲＹ编码区的特异性引物，对其基因组ＤＮＡ进行了聚合酶链式反应（ＰＣＲ）扩增检测。结果显示：１例４６，ＸＹ女性伴性腺发育不良症；１例４５，ＸＯ／４６，ＸＹ女性表现为Ｔｕｒｎｅｒ综合征，未检出ＳＲＹ特异     

Successful monozygotic twin pregnancy fathered by a male 46,XY true hermaphrodite

This report presents an unusual case of absolute non-obstructive azoospermia revealed to be a male 46,XY true hermaphrodite who was successfully treated to father healthy monozygotic twins. A 27-year-old infertile male with non-obstructive azoospermia previously underwent an unsuccessful testicular sperm extraction procedure and refused donor sperm insemination.Revising the patient’s old records revealed that he was born with ambiguous genitalia. He had a 46,XY karyotype and was raised as a male. During childhood he underwent ambiguous genitalia reconstruction, right orchiopexy and left salpingo-oophorectomy that revealed a gonadoblastoma. A new treatment was employed performing testicular fine needle aspiration leading successfully to a monozygotic twin pregnancy. As far as is known, this is the first reported case of healthy twins fathered by a male 46,XY true hermaphrodite.     

A cytogenetic and endocrinologic study of a set of monozygotic isokaryotic 45,X/46,XY twins discordant for phenotypic sex: mosaicism versus chimerism

Newborn monozygotic twins with phenotypic sexual discordance were diagnosed with 45,X/46,XY gonadal dysgenesis. Cytogenetic studies of peripheral blood (serial), skin, and gonad were performed. Serial comparative gonadotropin data and luteinizing hormone-releasing hormone stimulation tests were obtained. A phenotypically normal male twin was found to have a significant number of 45,X cells only in lymphocytes and was considered endocrinologically intact. The sexually ambiguous twin sister demonstrated a significant number of 45,X cell lines in all tissues and was considered endocrinologically agonadal. These data demonstrate the role of the 45,X karyotype on abnormal gonadal formation and function and make possible different etiologies for the 45,X cell line in both twins. While mosaicism is likely for both, chimerism is possible for the normal male.     

Evaluation of the clinical usefulness of isolation of fetal DNA from the maternal circulation

OBJECTIVE: To assess the reliability of isolating free fetal DNA from maternal usefulness. DESIGN: Fetal DNA was isolated from plasma or serum that was either collected prospectively or from archived samples collected for the purposes of second trimester screening. METHODS: Prospective samples were collected from patients undergoing prenatal diagnostic procedures (n = 24). A second group of samples from Rhesus negative women (n = 28) were assayed in which blood had originally been collected for maternal triple serum screening. DNA was extracted from all samples and assayed for the presence of the beta-globin gene, sex-determing region Y (SRY) gene and Rh gene. All DNA sample handling and extraction was carried out by a single operator, and polymerase chain reaction (PCR) was carried out using previously published PCR primers and appropriate controls. The accuracy of results was assessed relative to the karyotype in the case of the SRY gene or cord blood phenotype in the case of the Rh gene. RESULTS: The SRY PCR results were compared to fetal cell karyotypes obtained from invasive diagnostic testing, 21 out of the 24 samples were correctly 'sexed'. The RhD PCR results were compared to fetal cord blood samples at the time of delivery, and showed both false positive and false negative results. Two RhD negative babies were genotyped as RhD positive, despite repeat analysis. CONCLUSION: It is possible to isolate fetal DNA from maternal serum. It is a potentially clinically useful technique in our laboratory and can be used to detect male fetuses, and Rh negative fetuses. To be useful in clinical practice, it is necessary to safeguard against contamination at the time of sample handling, and to use the optimal range of primers available to cover the polymorphisms present within the RhD gene. Although not robust enough yet to be used with diagnostic certainty in our hands, immense improvements in technique, probes and real-time PCR equipment make this type of diagnosis a reality in the near future.     

Monozygotic twins discordant for low-level mosaic trisomy 17 at amniocentesis in a pregnancy with a favorable outcome and a literature review of heterokaryotypic monozygotic twins at amniocentesis

ObjectiveWe present a set of twins discordant for low-level mosaic trisomy 17 at amniocentesis, and we review the literature of heterokaryotypic monozygotic twins at amniocentesis.Materials and methodsWe describe a monozygotic twin pregnancy with discordant karyotypes and structural abnormalities. A 22-year-old, primigravid woman underwent amniocentesis at 21 weeks of gestation because of an abnormal maternal serum screening result for Down syndrome. Prenatal ultrasound revealed twin-twin transfusion syndrome but no detectable fetal structural abnormalities. Conventional cytogenetic analysis was applied on cultured amniocytes and parental bloods. Polymorphic DNA marker analysis by quantitative fluorescent polymerase chain reaction (QF-PCR) testing was performed on the DNAs extracted from cultured amniocytes, parental bloods and peripheral bloods of the twins after birth. Interphase fluorescence in situ hybridization (FISH) analysis was performed on buccal mucosal epithelial cells.ResultsAmniocentesis revealed a karyotype of 47,XX,+17 [3]/46,XX [23] in twin A and a karyotype of 46,XX in twin B. The parental karyotypes were normal. QF-PCR confirmed monozygotic twinning and excluded uniparental disomy (UPD) 17. At 35 weeks of gestation, a 1778-g twin A and a 2396-g twin B were delivered smoothly. Both infants had the karyotype of 46,XX in the peripheral bloods and were phenotypically normal except that twin A had preaxial polydactyly on the right hand. Postnatal QF-PCR testing confirmed monozygotic twinning. The infants were doing well at age 2 years and 7 months at follow-ups with normal physical and psychomotor development. FISH analysis on buccal mucosal epithelial cells showed trisomy 17 signals in 4.16% (4/96) cells, compared with 5% (5/101 cells) in normal control.ConclusionsMonozygotic twins discordant for low-level mosaic trisomy 17 at amniocentesis without ultrasound abnormalities can have a favorable outcome. Prenatal diagnosis of twins discordant for structural abnormalities and/or chromosomal aberrations should alert the possibility of monozygotic twinning, and QF-PCR testing is useful for rapid determination of zygosity and exclusion of UPD under such a circumstance.     

Does chorionicity or zygosity predict adverse perinatal outcomes in twins?

OBJECTIVE: The purpose of this study was to evaluate chorionicity and zygosity as risk factors for adverse perinatal outcomes in twins. STUDY DESIGN: A population-based, retrospective cohort study was conducted of all twin deliveries in Nova Scotia, Canada, from 1988 to 1997. Chorionicity was established by histologic examination. Zygosity was determined by chorionicity, sex, and infant blood group. Three groups were established: monochorionic/monozygotic twins, dichorionic/dizygotic twins, and dichorionic/majority monozygotic twins. RESULTS: Outcomes from 1008 twin pregnancies were analyzed. Monochorionic/monozygotic twins had lower mean birth weights compared with dichorionic/dizygotic twins. Rates of perinatal mortality of at least 1 twin were significantly higher among monochorionic/monozygotic twins relative to dichorionic/dizygotic twins (relative risk, 2.5; 95% CI, 1.1-2.5). Dichorionic/majority monozygotic twins had similar perinatal outcomes compared with dichorionic/dizygotic twins. CONCLUSION: Monochorionicity increases the risk of adverse perinatal outcome, whereas the effect of zygosity is less clear. Because chorionicity can be determined by prenatal ultrasound scanning, this information should be considered in the prenatal care of twin pregnancies.     

An Australian twin study of the genetic basis of preeclampsia and eclampsia

OBJECTIVE: We investigated maternal versus fetal genetic causes of preeclampsia and eclampsia by assessing concordance between monozygotic and dizygotic female co-twins, between female partners of male monozygotic and dizygotic twin pairs, and between female twins and partners of their male co-twins in dizygotic opposite-sex pairs. STUDY DESIGN: Two large birth cohorts of volunteer Australian female twin pairs (N = 1504 pairs and N = 858 pairs) were screened and interviewed, and available medical and hospital records were obtained and reviewed where indicated, with diagnoses assigned according to predetermined criteria. RESULTS: With strict diagnostic criteria used for preeclampsia and eclampsia, no concordant female twin pairs were found. Collapsing diagnoses of definite, probable, or possible preeclampsia or eclampsia resulted in very low genetic recurrence risk estimates. CONCLUSION: Results from these two cohorts of female twin pairs do not support clear, solely maternal genetic influences on preeclampsia and eclampsia. Numbers of parous female partners of male twins were too low for conclusions to be drawn regarding paternal transmission.     

Novel mutation in OTC gene causes neonatal death in twin brothers.

Ornithine transcarbamylase (OTC) deficiency is the most common inborn error of the urea cycle. OTC locus is located in the short arm of X-chromosome. Authors report a case of a woman who gave birth to monozygotic male twins who later died because of severe neonatal-onset hyperammonaemic encephalopathy caused by a novel mutation of OTC gene. Post-mortem liver biopsy was taken from the second twin; afterwards, blood was drawn from the mother for examination. DNA sequence data showed that the mother was a carrier of the same novel mutation that was previously detected in the case of her son. In OTC deficiency, detection of female carriers is important for genetic counselling and eventual prenatal diagnosis.     

Transmission of de novo mutations of the deleted in azoospermia genes from a severely oligozoospermic male to a son via intracytoplasmic sperm injection

Objective: To investigate the transmission of microdeletions in the deleted in azoospermia (DAZ) genes to a male offspring via intracytoplasmic sperm injection (ICSI).

Design: Case report.

Setting: Reproductive unit of a university teaching hospital.

Patient(s): A 29-year-old, severely oligozoospermic male with microdeletions of the DAZ genes in Yq interval 6 and his son, who was conceived via ICSI.

Intervention(s): DNA screening for the microdeletions in Yq interval 6 with 24 sequence tagged sites with the use of polymerase chain reaction amplification for the patient, the patient’s father, and the patient’s son. Paternity identification was performed using nine hypervariable short tandem repeats.

Main Outcome Measure(s): Deletion mapping of Yq interval 6 from sequence tagged sites and electropherogram of short tandem repeats for DNA fingerprinting.

Result(s): The son had the same microdeletions of the DAZ genes as the patient, and the patient’s father had normal DAZ genes. The paternity of the patient, the patient’s father, and the patient’s son was verified.

Conclusion(s): De novo DAZ microdeletions in an infertile male can be transmitted to a male offspring via ICSI. DNA screening tests for DAZ genes before ICSI may help in the genetic counseling of patients with idiopathic azoospermia or severe oligozoospermia.     

Fetal blood sampling demonstrating chimerism in monozygotic twins discordant for sex and tissue karyotype (46,XY and 45,X)

Fetal blood sampling has been used in the genetic work-up of twin gestations for rapid karyotyping. We present a case of twins which on ultrasound evaluation revealed hydrops fetalis in one twin and a normal second twin. Fetal blood sampling revealed the presence of mosaicism for 46,XY/45,X in both twins. HLA antigen testing showed the twins to be identical. The patient elected pregnancy termination. Blood chromosomal analysis after delivery revealed both twins to have 46,XY/45,X mosaicism, but the twin with signs of hydrops fetalis had tissue chromosomes of 45,X and the normal twin had tissue chromosomes of 46,XY. Amniotic fluid chromosomal analysis revealed 46,XY in twin A and 45,X in twin B. This represents a case of identical (monozygotic) twins with sex discordance. In this case, there was the probable occurrence of post-zygotic chromosomal non-disjunction leading to the discordancy of the sex in this set of twins. With the presence of vascular communication in monozygotic twins, there is the possibility of exchange of blood in monozygotic twins and the result of blood chimerism in twins.     

Carcinoma in situ cervicis uteri and inheritance--a Danish twin study

OBJECTIVE: To determine the relative environmental and genetic influence in the development of carcinoma in situ (CIS) cervicis uteri. METHODS: Retrospective follow-up study with record linkage between The Danish Twin Register and The Danish Cancer Register. The study base comprises 27,004 female twins from 13,502 same-sex twin pairs. 5,258 were monozygotic and 8,244 dizygotic twin pairs. The statistic measurements are the coincidence ratio and the probandwise concordance rate in the two groups of twins with different zygosity. RESULTS: 750 twins were diagnosed with CIS cervicis uteri. 291 monozygotic twins came from 275 pairs and 459 dizygotic twins came from 435 pairs. There were 16 concordant monozygotic twin pairs and 24 concordant dizygotic pairs. The probandwise concordance rate was 0.11 (0.06-0.16) in monozygotic twins and 0.10 (0.06-0.14) in dizygotic twins. CONCLUSION: A family clustering of CIS was demonstrated in both groups of zygosity. The probandwise concordance rate was equal in the monozygotic and the dizygotic groups, which means that genetic factors are not important in the development of the disease. However, a shared environment among twins plays a role in the development of CIS cervicis uteri.     

A 46,XX SRY-negative man with complete virilization and infertility as the main anomaly

OBJECTIVE: To report a case of a 46,XX SRY-negative man with a male phenotype and azoospermia. DESIGN: Case report. SETTING: Molecular and Cytogenetic Unit in a University Hospital. PATIENT(S): A 35-year-old man with complete masculinization who referred to our institution because of a history of several years of infertility. INTERVENTION(S): Lymphocytic karyotype and genetic counseling. MAIN OUTCOME MEASURE(S): Peripheral blood metaphases were analyzed by standard G-banding and Q-banding. Fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR) analyses were performed. RESULT(S): Semen analysis showed azoospermia. Chromosome analysis revealed a 46,XX karyotype; molecular and cytogenetic analyses excluded the presence of SRY (the sex-determining region of the Y chromosome) gene. CONCLUSION(S): This case is one of the rare patients reported in the literature in whom testicular differentiation and a complete virilization in a 46,XX chromosomal constitution does not account for a translocation of the SRY gene to the X chromosome or to the autosomes. This finding suggests that other genes downstream from SRY, not yet identified, play an important role in sex determination.