Human Reproduction, Vol. 17, No. 9, 2459-2463,
September 2002
© 2002 European Society of Human Reproduction and Embryology
Complete hydatidiform mole and normal live birth: a novel case of confined placental mosaicism: Case report
1 Departments of Obstetrics and Gynaecology and 2 Pathology, Ioannina University Hospital, Ioannina, Greece and 3 Trophoblastic Screening and Treatment Centre, Charing Cross Hospital, London, UK
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Abstract |
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Hydatidiform molar change, characterized by abnormal fetoplacental development and placental villous trophoblast hyperplasia, results from genetically abnormal conception, in which there is an excess of paternally derived genetic material. The majority of pregnancies in which molar change has been reported in association with a live fetus represent dizygotic twin pregnancies in which one fertilization results in a complete hydatidiform mole (CM) and the other a normal co-twin. In such cases, there is usually a clear distinction, both sonographically and pathologically, between the molar and non-molar regions of the placenta. We present a singleton pregnancy, with diffuse placental molar change detected prenatally, which resulted in a chromosomally and phenotypically normal female infant at term. Pathological examination revealed the presence of intermixed populations of morphologically normal chorionic villi and villi with the characteristics of CM. Studies of genetic polymorphisms demonstrated that the CM, normal villi and fetus were all derived from the same sperm; the fetus was diploid and biparental whereas the areas of pathological CM were androgenetic and monospermic. We believe this represents the first well-documented case of apparent confined placental mosaicism involving CM and a coexisting normal fetus, which has presumably arisen following mitotic abnormalities in the early post-fertilization period.
Key words: androgenetic/complete hydatidiform mole/monospermic/live birth/placental mosaicism
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Introduction |
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TopAbstractIntroductionCase ReportResultsDiscussionAcknowledgementsReferences |
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Hydatidiform molar change is the pathological manifestation of genetically abnormal conceptions, in which an excess of paternally derived genetic material results in abnormal fetoplacental development and placental villous trophoblast hyperplasia. Hydatidiform mole may by classified as partial (PM) or complete (CM), on the basis of distinctive histopathological features and genetic abnormalities. The majority of PM are paternally derived triploids (Lawler et al., 1982
), whilst most CM are androgenetic (Kajii and Ohama, 1977). Pregnancies in which molar change has been reported in association with a live fetus generally represent dizygotic twin pregnancies in which one fertilization results in a CM and the other in a normal co-twin (Paradinas, 1997). In such cases, there is usually clear distinction, both sonographically and pathologically, between the molar and non-molar placenta. Singleton PM may occasionally survive into the third trimester and be associated with a live fetus but in such cases the fetus is also usually triploid. We present a case of a singleton pregnancy with prenatally detected diffuse placental molar change, resulting in a phenotypically normal female infant at term, which we believe represents the first well-documented case of apparent confined placental mosaicism for CM with a coexisting normal fetus.
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Case Report |
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Clinical history
A 28 year old Caucasian woman was referred at 15 weeks gestation in her first pregnancy following a small amount of vaginal bleeding. Her booking investigations were unremarkable. Ultrasound examination revealed a singleton pregnancy with no fetal structural abnormalities and fetal biometry consistent with gestation but numerous placental echolucent cysts were present, suggestive of diffuse molar change (Figure 1
). The patient was counselled regarding the possible diagnoses and amniocentesis was carried out which revealed a normal female karyotype, 46,XX. Serial ultrasound examinations performed at 3-weekly intervals demonstrated normal fetal growth and biometry and persistence of the apparent molar changes throughout the placenta. At 36 weeks of gestation she was delivered by Caesarean section because of a reduction in fetal growth velocity and fetal heart rate decelerations on cardiotocograph. A phenotypically normal female infant, 1770 g, was delivered with Apgar scores of 6 at 1 min and 9 at 5 min. The placenta weighed 730 g and on sectioning revealed widespread, diffuse vesicle formation, consistent with molar change (Figure 2).
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Pathology
Pathological examination of the placenta revealed areas of morphologically normal third-trimester chorionic villi with focal chorangiosis-like change, whilst other areas demonstrated features of third trimester CM; there was marked villous hydrops with central cistern formation, moderate focal trophoblast hyperplasia and stromal karyorrhectic debris, with only mild fibrosis of the molar villi. (Figure 3
) (Paradinas, 1994, 1997). The pathological features were those of CM rather than placental mesenchymal dysplasia (Paradinas et al., 2001).
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Molecular genetic investigation
Molecular genetic studies were carried out to determine the genetic origin of the fetus (using tissue from the umbilical cord), and of the normal and CM villi of the placenta. DNA was prepared from peripheral blood samples from the patient and her husband using standard techniques. DNA from the umbilical cord, normal chorionic villi and complete molar villi was prepared from pathological blocks of formalin-fixed, paraffin-embedded tissue. In each case, the appropriate tissue was identified and microdissected from 5 µm unstained sections of tissue with reference to a consecutive section stained with haematoxylin and eosin. DNA was then extracted using a modification of a previously described method (Wright and Manos, 1990
). Briefly, the tissue was extracted with octane, washed with 100% ethanol and dried under vacuum. When dry, the tissue was incubated in 25 µl of digestion buffer [50 mmol/l Tris (pH 8.5), 1 mmol/l EDTA, 0.5% Tween 20] containing 200 µg/ml of proteinase K. After 3 h at 55°C the tube was incubated for 8 min at 95°C to inactivate the proteinase K. One µl of supernatant was then used as template for PCR amplification.
A total of 50 ng of DNA from the patient and her partner and 1 µl DNA from each of the tissue DNA samples was amplified using pairs of fluorescently labelled primers which flank polymorphic microsatellite repeats. One pair of primers was used for each of the 22 pairs of autosomes (Reed et al., 1994). Following amplification, 5 µl of each PCR reaction product underwent electrophoresis in a 1% agarose gel to assess the yield of product. PCR products were diluted as appropriate and subsequently resolved by capillary electrophoresis using an ABI Prism 310 Genetic Analyser (Applied Biosystems Ltd, UK). Analysis and sizing of the microsatellite polymorphisms was performed using ABI Prism GeneScan software (Applied Biosystems Ltd). Where a marker was uninformative with respect to the paternal contribution to the tissue, a further marker for that chromosome was examined.
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Results |
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The allele sizes of microsatellite polymorphisms on different chromosomes are shown in Table I
for the patient, her partner, the umbilical cord, normal placenta and molar villi. Analysis of DNA from the umbilical cord and normal placenta showed that the same alleles were consistently present in both tissues. Where two alleles were present for a microsatellite marker, the sizes of the two alleles were consistent with one being maternal and one paternal in origin. Where the cord and placenta were homozygous, the homozygous allele was found in both parents.
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Examination of the molar tissue showed that it was androgenetic in origin for 16 of the 22 of markers examined, having only paternally derived alleles. For all other markers, the results were compatible with an androgenetic origin. The molar tissue was homozygous for all 22 markers examined and was therefore monospermic in origin (Figure 4
). In cases where four different alleles were present in the maternal and paternal DNA samples, the same paternal allele was identified in the umbilical cord, normal placenta and molar tissue. For markers where the parents shared alleles, the origin of each of the markers could be deduced in the umbilical cord/normal placental tissue. For these markers the paternal contribution to the normal tissue was consistently the same as that in the molar areas. Since the mole was monospermic, it would be female, having only X chromosomes, and a sex chromosome constitution the same as the infant, which was female. Given that the father was heterozygous for every marker examined, the probability that the same allele would have been present in two independent conceptions, one normal and one molar, by chance alone is 1 in 223. The infant, normal placenta and CM must therefore have developed from the same conceptus. The infant is phenotypically normal with normal developmental milestones at 15 months of age and the mother’s serum hCG returned to normal within 4 weeks of delivery and has remained so.
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Discussion |
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We have reported a case of a singleton pregnancy in which the fetus was phenotypically normal at birth but in which diffuse changes of CM were present in the placenta, most likely representing a variant of confined placental mosaicism. Microsatellite analysis of the CM components of the placenta showed the molar tissue to be androgenetic and monospermic in that only one of the two possible paternal alleles was identified in the molar tissue for all 22 autosomal loci examined. Identical alleles were identified in the paternal contribution to the normal, non-molar placenta, showing the same sperm to have been involved in both cell lines. Since both centromeric and distal polymorphic markers were identical in the normal and molar regions of the placenta, the paternal contribution to both is likely to have arisen from a single haploid sperm rather than a diploid sperm that had failed to undergo reduction during meiosis.
Confined placental mosaicism occurs in ~2% of viable pregnancies as a result of mitotic non-disjunction or translocation in the progenitor cells of specific placental cell lineages (Kalousek and Vekemans, 1996). It is difficult to envisage a mechanism that would result in loss of the complete maternal chromosome complement during mitosis of one of the cells of the trophoblast lineage, suggesting that the events giving rise to mosaicism in this case may have occurred as early as the first post-zygotic division. We propose that, following normal fertilization, asynchronous mitosis of the male pronucleus gave rise to a cell containing two identical male, and one female, pronucleus. At cleavage this would result in two blastomeres, one containing a male and female pronucleus and the other a single male pronucleus. The first blastomere would have the potential to develop normally while the second, following a subsequent failure of cytokinesis, or endoreduplication of the nucleus, would result in a second, androgenetic, cell line. Since ploidy studies were not carried out, we cannot formally exclude the possibility of the androgenetic cell line in this case being haploid.
Since the fetus was normal at birth and the child continues to develop normally at 15 months, the androgenetic cell line appears to be confined to the placental tissue. The fetus develops from only a small number of embryonic progenitor cells which may all have originated in the normal cell population in this case. Alternatively, preferential partitioning of the androgenetic cells to the extraembryonic cell lineages (Thomson and Solter, 1988) may have resulted in androgenetic cells being confined to the placenta. However, the presence of androgenetic cells in some tissues in the child cannot be excluded.
The vast majority of pregnancies with an apparently normal fetus in conjunction with molar change in the placenta, and identified by ultrasound examination, represent either triploid partial mole, in which there would be no viable fetus, or dizygotic twin pregnancies in which one conceptus is a CM and the other a normal co-twin (Paradinas, 1997). Pseudomolar changes may also be present in placental mesenchymal dysplasia, a condition usually associated with an apparently normal fetus (although there is an association with Beckwith–Wiedemann syndrome), but with distinctive, non-molar, histopathological features (Paradinas et al., 2001). The association of CM and live fetus in the same pregnancy is well reported but these cases represent dizygotic twin pregnancies with molar change in one conceptus (Fisher et al., 1982; Altaras et al., 1992; Hsu et al., 1993; Miller et al., 1993; Stellar et al., 1994; Hurteau et al., 1997; Fishman et al., 1998; Matsui et al., 2000). Where genetic studies have been carried out in these cases, the normal and molar placentas have been genetically distinct.
Previous publications have reported apparent singleton pregnancies with hydatidiform molar change and co-existent live fetus but these cases either show different pathological findings to the present case and/or have not provided genetic analysis of the molar tissue (Crooij et al., 1985; Feinberg et al., 1988; Pool et al., 1989; Hsieh et al., 1999). In three cases where genetic studies were performed, the placenta was shown to comprise two cell lines, one diploid and one triploid (Sarno et al., 1993; Ikeda et al., 1996; Zhang et al., 2000) consistent with the presence of both a normal and PM cell line. A case of CM was described as mosaic, following growth of both biparental and androgenetic cells from cultured tissue (Ford et al., 1986). However, the biparental cell line could have arisen from the cells of an unrecognized twin pregnancy and, in any event, unlike the present case, involved two different sperm.
The present case demonstrates clear, focal, pathological changes of CM, distinct from either partial molar change or placental mesenchymal dysplasia, and genetic analysis confirms the androgenetic, monospermic DNA content of the molar tissue. To the best of our knowledge, the present case is the first reported with pathological and genetic confirmation, in which both androgenetic CM and normal fetal cell lines are present in the same placenta. The concept that CM never occurs in the presence of a normal fetus, except in dizygotic twin pregnancies, is no longer tenable since in very rare situations, such as the present case, a post-fertilization event may also result in molar change. Since, both pathologically and genetically, the CM tissue appears identical to otherwise classical CM, the implications for the current patient in terms of risk of persistent trophoblastic disease are presumably the same as for any other CM, and appropriate surveillance with serial hCG estimations is being carried out (Newlands, 1997). The pregnancy was uncomplicated by severe obstetric conditions such as pre-eclampsia or antepartum haemorrhage in this case, although an increased prevalence of such complications in twin pregnancies with coexistent CM has been reported (Matsui et al., 2000). Pregnancy management must be determined on an empirical basis in these rare conditions and the possible increased risks of pregnancy complications should be discussed with the patient.
In summary, we have described a unique singleton pregnancy with normal fetus and placental mosaicism for androgenetic, monospermic CHM. This case illustrates a potential new mechanism for the development of diffuse molar change, mimicking PM.
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Acknowledgements |
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Facilities for 310 analysis were provided through funds from the Wellcome Trust and the Trustees of Charing Cross Hospital. This work was supported by grants from the Cancer Treatment and Research Trust.
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Notes |
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4 To whom correspondence should be addressed at: Trophoblastic Screening and Treatment Centre, Faculty of Medicine, Imperial College, Charing Cross Hospital, Fulham Palace Road, London, W6 8RF, UK. E-mail: r.fisher{at}ic.ac.uk
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Submitted on April 11, 2002; accepted on May 14, 2002.
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