First-trimester molecular diagnosis of complete hydatidiform mole associated with dizygotic twin pregnancy conceived by intrauterine insemination

ObjectiveTo present first-trimester molecular diagnosis of complete hydatidiform mole (CHM) associated with dizygotic twin pregnancy conceived by intrauterine insemination.Materials and methodsA 32-year-old woman presented to the hospital with a huge complex cystic mass measuring about 8.5 cm × 4.1 cm in the uterine cavity and a living co-existing fetus with fetal biometry equivalent to 9 weeks. She underwent chorionic villus sampling at 13 weeks of gestation, and microsatellite genotyping for molar pregnancy test was applied. A molar pregnancy test was performed by a short tandem repeat (STR) identifier polymerase chain reaction (PCR) polymorphic marker analysis. The pregnancy was terminated at 14 weeks of gestation. Postnatal polymorphic DNA marker analysis of the placenta by quantitative fluorescent PCR (QF-PCR) was performed. Analysis of maternal blood total β-human chorionic gonadotropin revealed a high level of 551,600 mIU/mL at 10 weeks of gestation and a level of 1.0 mIU/mL at 15 weeks postpartum. The woman was doing well at 4 months after delivery.ResultsThe results of STR identifier PCR polymorphic marker analysis showed androgenic conception in the complex cystic mass and biparental conception in the living fetus. Pathological analysis of the cystic mass confirmed the diagnosis of CHM. The results of QF-PCR showed biparental inheritance in the normal fetus and complete paternal homozygosity in the CHM of the abnormal fetus in all STRs, indicating dizygotic twinning and CHM of monospermy.ConclusionPrenatal sonographic diagnosis of placentomegaly with many grape-like vesicles should include a differential diagnosis of CHM, partial hydatidiform mole (PHM), placental mesenchymal dysplasia (PMD), and recurrent hydatidiform mole. Microsatellite genotyping for molar pregnancy testing and zygosity testing is useful in cases of prenatal diagnosis of placentomegaly associated with many grape-like vesicles and a twin pregnancy with a living fetus in the first trimester.     

Molecular analysis of a gestation consisting of a complete hydatidiform mole and normal dizygotic twin.

OBJECTIVE: To identify a twin pregnancy consisting of a complete mole and coexistent fetus by means of molecular cytogenetics and DNA polymorphisms. STUDY DESIGN: Seven highly polymorphic DNA markers were used to establish the androgenetic origin of a complete hydatidiform mole that coexisted with a normal 46,XY fetus. Cytogenetic analysis of mole nuclei was performed with centromeric probes, demonstrating a 46,XX constitution. RESULTS: Molar tissue was diploid with two X chromosomes, possibly due to chromosome doubling after monospermic fertilization of an ovum with inactivated or absent nucleus. CONCLUSION: Although contamination with maternal tissue may be difficult to avoid, molecular markers provide the possibility of distinguishing between a complete hydatidiform mole and coexisting normal fetus versus a partial mole, with methods that can be performed antenatally. This distinction is important since in the first case up to 24% of fetuses described in the literature have been viable, and the risk of subsequent development of persistent trophoblastic tumor in patients with a complete mole and a coexisting fetus is considerably higher than in patients with a single, complete hydatidiform mole.     

Hydatidiform mole and fetus with normal karyotype: support of a separate entity

Repetitive hydatidiform mole was observed in four pregnancies. The pregnancies presented with heavy bleeding and vomiting, but the post-evacuation courses were uncomplicated, with rapid regression of serum hCG levels. Cytogenetic investigations, analyses of restriction fragment length polymorphisms, and flow cytometry in three pregnancies were consistent with diploid, biparental conception as the origin of fetal tissue and molar and nonmolar villi. In one pregnancy, the analyses of cytogenetic markers suggested the coexistence of two different cell lines of dizygotic, biparental origin, whereas DNA analysis was consistent with a single conception. With incomplete genetic information, a hydatidiform mole with coexistent normal fetus is generally considered to result from dizygous twinning comprising an androgenetic complete mole and a normal conception. In the present gestations, the results based on several techniques applied on numerous samples from different tissues render this possibility unlikely. Some of the contradictions between histologic and cytogenetic classifications of hydatidiform mole may be explained by diploid, biparental partial mole, which seems to constitute a separate subgroup within hydatidiform mole. Following chorionic villus sampling or amniocentesis, continued pregnancy may be considered, depending on prenatal diagnosis including genetic marker analysis.     

Triplet pregnancy with hydatidiform mole

Abstract. Amr MF, Fisher RA, Foskett MA, Pardinas FJ. Triplet pregnancy with hydatidiform mole.
Multiple pregnancies with hydatidiform mole are rare. We describe here a patient who delivered a male fetus and a female fetus together with molar tissue following treatment for infertility. comparing microsatellite polymorphisms in the DNA from the patient, her partner, the two normal placentas and the molar tissue, we were able to show that this was a triplet pregnancy with two normal conceptions and a complete hydatidiform mole of monospermic origin.     

Hydatidiform mole with coexistent fetus. Cytogenetic features, diagnosis, and management

Hydatidiform mole with coexistent fetus is an unusual entity caused by two distinct types of pregnancy: the first one is a partial hydatidiform mole, while the second is a twin pregnancy in which a mole coexists with a normal fetus. In these two separate genetic entities, the counseling and the mother-fetus prognosis are different. Two cases of mole with coexistent fetus are reported: a partial hydatidiform mole typically tripliod and a partial mole with unusual diploid karyotype. Prenatal diagnosis is remarkable for the evaluation of fetus development related with his karyotype. Triplody excludes all hope of a non-malformed surviving child and termination of pregnancy is desirable, while normal karyotype the possibility of a continuation of pregnancy may be considered.     

Differential diagnosis between complete and partial mole using a TSSC3 antibody: correlation with DNA polymorphic marker analysis

OBJECTIVE: To investigate the use of maternally expressed, imprinted genes for the differential diagnosis of complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM). STUDY DESIGN: Expression patterns of imprinted genes in CHM were validat ed by microarray analysis. Twenty CHMs and 10 PHMs were then subjected to Western blot analysis and immunostaining with appropriate antibodies. RESULTS: TSSC3 (also known as PHLDA2, IPL), SLC22A1L, KCNQ1 and decorin were shown to be down-regulated, with the suppression of TSSC3 most marked. In all 20 CHM cases for which the diagnosis had been confirmed by DNA polymorphic markers, the expression of TSSC3 was completely lost on Western blots. In contrast, in 10 PHMs that had also been diagnosed by DNA analysis, TSSC3 was expressed normally. Immunohistochemistry showed an identical result. CONCLUSION: Complete silencing of TSSC3 expression in CHM offers a convenient and novel diagnostic strategy for diagnosing molar lesions.     

Complete mole coexistent with a twin fetus

We report two cases of a complete hydatidiform mole coexistent with a live fetus diagnosed by DNA polymorphism analysis. A 27-year-old woman revealed symptoms of pre-eclampsia and ultrasound showed multicystic tumor and placenta coexistent with a live fetus at 16 weeks' gestation. The placenta with partly hydropic change and the fetus without anomaly were consequently evacuated. Another 30-year-old woman had a multicystic mass attached to a normal placenta with a 20-week live fetus on ultrasound examination. A hysterotomy was carried out because of persistent bleeding due to placenta previa. In both cases, DNA was extracted from the placental tissue and the tumor, as well as from maternal and paternal blood. Genetic analysis demonstrated that the placental tumor consisted of only paternal origin, which is consistent with the diagnosis of complete hydatidiform mole.     

Epidemiologic and clinicopathologic studies of partial hydatidiform mole

To determine the epidemiological and clinicopathological characteristics of partial hydatidiform mole (PHM), a comparative study of PHM and complete hydatidiform mole (CHM) was performed in molar patients who were entered in the regional registry of Niigata Prefecture and/or who were admitted for treatment at Niigata University Hospital. The results obtained are as follows. 1. From 1971 to 1988, 2,290 hydatidiform moles (HMs) were documented in the registry. The incidence of HM was annually decreasing with an almost constant ratio to the total number of pregnancies. Since 1986, the number of PHM was rising with an inverse decrease in CHM. One hundred fifty one of 1,923 CHM (7.9%) had persistent trophoblastic disease (PTD), but on the other hand only 6 of 367 cases PHM (1.6%) had. 2. In 275 patients treated in our hospital from 1971 to 1990, 134 of 240 with CHM (55.8%) and 6 of 35 with PHM (17.1%) experienced PTD. Of 6 PTD patients following PHM, 3 had invasive mole, 1 metastatic mole and 2 post molar persistent hCG, but no choriocarcinoma. 3. The recent study of DNA analysis in molar tissue revealed that one case, which had been diagnosed as PHM, coexisted with CHM and non-molar pregnancy.     

葡萄胎的分子遗传学分类与大体病理类型的关系

目的探讨葡萄胎的遗传学类型与病理形态学的关系。方法采用ＤＮＡ限制性片段长度多态性分析的方法研究３２例葡萄胎标本。结果ＤＮＡ完全来自父源性的葡萄胎有２１例,其中大体病理形态呈完全性葡萄胎者１６例,占７６％（１６／２１）,部分性葡萄胎者５例,占２４％（５／２１）;ＤＮＡ来自双亲的葡萄胎１１例,其中大体病理形态呈完全性葡萄胎者５例,占４５％（５／１１）,部分性葡萄胎者６例,占５５％（６／１１）;χ２检验结果表明葡萄胎的病理学类型与遗传学类型无明显的平行关系（Ｐ＞０．１０）。结论本研究结果不支持葡萄胎的遗传学类型与大体病理类型间有平行关系的论点     

双胎之一完全性葡萄胎的产前诊断及处理

目的 探讨双胎之一完全性葡萄胎(a twin pregnancy consisting of acomplete mole and coexisting fetus,CMCF)的产前诊断及处理。方法 回顾性分析2例CMCF的临床资料。结果 第1例患者在孕10周时,B超发现胎儿与葡萄胎胎盘共存,患者要求终止妊娠,刮宫物间期细胞荧光原位杂交(fluorescent in situ hybridization,FISH)和核型分析提示,胎儿与葡萄胎均为二倍体,证实为CMCF。第2例患者在孕21周时,B超发现胎儿与葡萄胎胎盘共存,B超引导下经腹壁绒毛活组织检查(活检)和羊膜腔穿刺,葡萄胎和羊水的间期细胞FISH和核型分析提示,胎儿与葡萄胎均为二倍体,证实为CMCF双胎之一完全性葡萄胎,患者继续妊娠,在孕28周时胎膜早破,因继发感染而行剖宫产终止妊娠,胎儿存活,胎盘、新生儿外周血的核型分析结果与产前诊断相符。结论 产前一旦发现胎儿与葡萄胎胎盘共存,应立即进行CMCF和部分性葡萄胎(partial hydatidiform mole,PHM)的鉴别,如果绒毛和羊水行间期细胞FISH和核型分析为二倍体,则为CMCF,是否继续妊娠,需采取个体化原则;如果为三倍体,则为部分性葡萄胎,应及时终止妊娠。     

Prenatal diagnosis and management of twin pregnancies complicated by a co-existing molar pregnancy

Recent advances in ultrasound and molecular genetics have increased our understanding and hence enhanced the perinatal management of complete and partial hydatidiform mole. By contrast, the management of a twin pregnancy combining a normal pregnancy with a normal fetus and a complete hydatidiform mole (CHM) remains complex and controversial due to conflicting data from different parts of the world. The aim of this review is to analyse the international literature on twin pregnancies that include a mole, present the complications and outcome of pregnancy and to discuss the perinatal management. Management is complicated and women should be counselled about the maternal and fetal complications, and the pregnancy monitored carefully by a perinatal team with experience in high-risk obstetrics and access to neonatal care. The data reviewed here suggest that a woman who decides to continue with the pregnancy including a CHM must be aware that, overall, she only has a one in four chance of live birth and in around 35% of cases she will develop persistent trophoblastic disease (PTD) after delivery. In ongoing pregnancies, there will be, in at least 20% of the cases, an early onset of pre-eclampsia (PET) and a 29% risk of fetal loss due to late miscarriage, intrauterine death and neonatal death. Maternal serum human chorionic gonadotrophin (MShCG) could be useful in predicting outcome in twin pregnancy combining normal pregnancy and CHM, but this needs to be investigated prospectively.     

DNA Flow Cytometric Quantification and DNA Polymorphism Analysis in the Case of a Complete Mole with a Coexisting Fetus

Purpose: Our purpose was to investigate whether DNA flow cytometric quantification and DNA polymorphism analysis are useful for cytogenetic diagnosis in the case of a complete hydatidiform mole that coexists with a living fetus. Methods: Flow cytometric analysis of the nuclear DNA content and polymerase chain reaction (PCR) amplification of the minisatellite locus with the MCT118 probe were performed on the tissues (fetus, placenta and mole) obtained at the initial evacuation. Results: DNA histograms of placental, fetal, and molar tissues showed diploid peaks. PCR products demonstrated that the allele of the mole was homozygous and inherited solely from the husband and that the mole differed genetically from the fetus and the placenta. Conclusions: These results suggested that DNA flow cytometry and DNA polymorphism analysis may be useful for the cytogenetic diagnosis of a complete hydatidiform mole and a coexisting fetus.     

Genetic studies in hydatidiform mole with clinical correlations

In an elective study of 163 hydatidiform moles 38 were classified as partial mole (PHM) and 125 as complete mole (CHM) on the basis of pathology. Genetic studies showed the PHM to be triploid with one maternal and two paternal chromosome sets. In all cases of PHM the molar pregnancy resolved spontaneously after evacuation. On the basis of genetic studies CHM which were diploid could be subdivided into two entities: homozygous androgenetic CHMs that were 46,XX, and heterozygous CHMs which were androgenetic and usually 46,XY. In informative cases in this series the frequency of heterozygous CHM was 10 per cent. Twenty-two (17.6 per cent) of all the patients with CHM required subsequent chemotherapy for post-mole trophoblastic tumour. Where patients with CHM could be classified as having homozygous or heterozygous CHM the requirement for treatment (17.8 per cent and 25 per cent, respectively) was not found to be significantly different in the two groups.     

Complete hydatidiform mole coexisting with a viable pregnancy as twins after intracytoplasmic sperm injection: a case report

BACKGROUND: Twin pregnancies with 1 healthy fetus and 1 hydatidiform mole are extremely rare events, occurring in 1:20,000-100,000 twin pregnancies. CASE: A 32-year-old, nulliparous woman underwent assisted reproduction due to male factor infertility. At 15 weeks' gestation a complete hydatidiform mole coexisting with a viable pregnancy was diagnosed. The couple decided to maintain the pregnancy following detailed counseling regarding the risks and benefits. At 26 weeks' gestation the patient prematurely delivered a 720-g fetus who did not survive due to extreme prematurity. The patient also delivered the products of the molar pregnancy. CONCLUSION: In the event ofa twin pregnancy with 1 viable fetus and 1 molar, continuing the pregnancy may be considered as far as the mother is fully informed, not only regarding the complications that may arise but also regarding the chances of delivering a healthy infant.     

Complete hydatidiform mole and a coexistent fetus following ovulation induction in a patient with Sheehan’s syndrome: a first case report and review of literature

Pregnancy in Sheehan’s syndrome (SS) is extremely rare. We present the first reported case of twin pregnancy with complete hydatiform mole (CHM) and a coexistent fetus (CHCF) in a patient with SS. A 29-year-old Chinese patient with SS became pregnant following one cycle of ovulation induction with human menopausal gonadotropin after secondary infertility. A normal live fetus and a low echogenic mass suspected hydatidiform mole (HM) were detected by ultrasound examinations at gestational week 8. The couple highly desired to continue the pregnancy because it is very hard to get pregnant for the patients with SS. However, the pregnancy was terminated for the size of the HM component increased rapidly at gestational week 15. Histological examinations confirmed CHCF. Genetic studies showed that the CHM genome was derived from paternal diploidy, and the normal fetus was from biparental genomes. Furthermore, a literature review on these topics is included. This case highlighted that even in a patient with SS, twin pregnancy with CHCF can still occur after ovulation induction.     

Androgenetic complete mole coexistent with a twin live fetus.

OBJECTIVE: The aim of this study was to evaluate the clinical course and the management policy of complete mole coexistent with a twin live fetus confirmed with DNA polymorphism in a single hospital. METHODS: From 1981 to 1995, six patients with androgenetic complete hydatidiform mole coexistent with a twin live fetus were diagnosed by DNA polymorphism analysis. The clinical course of these six patients was analyzed. RESULTS: Two patients chose to terminate pregnancies and four patients desired to continue the pregnancy. However, the pregnancy had to be interrupted in two patients because of severe preeclampsia and sudden intrauterine fetal death. In two patients, fetuses were growing unremarkably and normal babies were delivered at term. The development of persistent trophoblastic tumor (PTT) in these rare pregnancies was higher (50.0%: 3/6) than that of single complete mole. In three patients, serum hCG titers during pregnancy were monitored. Although serum hCG levels progressively decreased during pregnancy in one patient without PTT, hCG levels initially decreased, but subsequently increased or showed a plateau with advancing gestational age in two patients with PTT. CONCLUSIONS: In patients with complete mole coexistent with a live fetus, the pregnancy may be allowed to continue when the fetal karyotype and development are normal and serum hCG titers are constantly falling with advancing gestational age.     

p57~（K1P2）和PHLDA2蛋白表达对葡萄胎的诊断意义

目的研究母源表达的印记基因p57K1P2和PHLDA2（IPL/TSSC3）蛋白表达对葡萄胎的辅助诊断意义。方法收集北京协和医院刮宫组织存档的石蜡包埋标本,其中病理组织学诊断完全性葡萄胎（completehydatidiformmole,CHM）13例,部分性葡萄胎（partialhydatidiformmole,PHM）16例。全部病例行流式细胞术DNA倍体分析,采用免疫组化二步法检测p57K1P2及PHLDA2在病理组织中表达。结果29例病例DNA倍体分析：二倍体15例,三倍体13例,四倍体1例,诊断为CHM15例,PHM14例,病理诊断的符合率为86.2%。部分性葡萄胎p57K1P2和PHLDA2绒毛滋养细胞层免疫组织化学全部阳性（100%,14/14）。PHLDA2染色阳性位于胞质和胞膜,表达为强阳性。p57K1P2染色阳性位于胞核,表达为强阳性。所有完全型葡萄胎绒毛滋养细胞层p57K1P2和PHLDA2免疫组织化学均阴性（100%,15/15）。结论p57K1P2和PHLDA2可能是鉴别CHM和非CHM的标志物,两者免疫组化学阴性可能是CHM的可靠标志物,但有待扩大样本验证。     

Serum alpha-fetoprotein in hydatidiform mole, choriocarcinoma, and twin pregnancy.

Serum alpha-fetoprotein (AFP) levels in patients with hydatidiform mole, choriocarcinoma, and twin pregnancy were studied by radioimmunoassay. Serum AFP was absent in seven of seven patients (100 per cent) with choriocarcinoma and 10 of 13 (76.9 per cent) with hydatidiform mole. However, low concentrations (below 8 ng. per milliliter) of AFP were detected in two patients (15.4 per cent) and 105 ng. per milliliter in one (7.7 per cent) with hydatidiform mole. In 10 of 14 patients (71.4 per cent) with twin pregnancy serum AFP levels were significantly above the normal range for single pregnancy and approximately twice as high as the average value in pregnancy. It was concluded from these findings that abnormal levels of serum AFP during pregnancy suggest the presence of various complications such as hydatidiform mole, choriocarcinoma, or twin pregnancy and that the determination of serum AFP is valuable for prenatal diagnosis. The origin and significance of elevated AFP in patients with hydatidiform mole are now being investigated.     

Identification of a hydatidiform mole in twin pregnancy following assisted reproduction

The aim of this study was to identify a co-existing hydatidiform mole (HM) in twin pregnancy from the abnormal mixed-genomic products of conception (POC) after assisted reproduction by histopathological review, evaluation of p57kip2 immunostaining and short tandem repeat genotyping. Thirty-seven patients were collected with suspicion for HM by pathological morphology. They had two embryos individually transferred to their uterus after in vitro fertilization and presented two gestational sacs with undeveloped embryos or one sac with an abnormal area by ultrasonography. Thirty patients were diagnosed as singleton pregnancy, including twenty-two non-molar gestations, six trisomy gestations, one homozygous complete mole and one heterozygous partial mole. Although six patients had ultrasonic imaging of two gestational sacs, the embryonic components in the vacant sac might fade away after transferring. Other seven patients were considered as twin pregnancy by the allelic genotype from two individual conceptions. For the patients with uniform p57kip2 positivity, excessive paternal alleles indicated the potential partial HM in the twin pregnancy. For the patients demonstrated divergent and/or discordant p57kip2 immunostaining, twin pregnancy with co-existing complete HM or mosaic conception were confirmed by genotyping of different villi population respectively. These patients were monitored by serum β-HCG, while one twin pregnancy with complete mole suffered invasive mole and received chemotherapy. A strategy composed of selective clinicopathological screening, immunohistochemical interpretation and accurate genotyping is recommended for diagnostically challenging mixed-genomic POC of potential twin pregnancy with HM, especially to differentiate a non-molar mosaic conception from a partial mole.