Hum. Reprod. Advance Access originally published online on December 21, 2006
Human Reproduction 2007 22(4):1114-1122; doi:10.1093/humrep/del462
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Origin and outcome of pregnancies affected by androgenetic/biparental chimerism
1 Department of Medical Genetics 2 Department of Obstetrics and Gynaecology 3 Department of Pathology, University of British Columbia, British Columbia, Canada 4 Reproductive Health Research Program, BC Research Institute for Children's and Women's Health, Vancouver British Columbia, Canada 5 Department of Medical Genetics, Alberta Children's Hospital, University of Calgary, Calgary, Canada
6 To whom correspondence should be addressed at: 950 W. 28th Ave, Rm 3096, Vancouver, British Columbia, Canada V5Z4H4. Email: wprobins{at}interchange.ubc.ca
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Abstract |
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BACKGROUND: Androgenetic diploid cells confined to the placenta have recently been reported in several cases of normally developed fetuses in association with placental mesenchymal dysplasia (PMD).
METHODS AND RESULTS: We investigated two singleton, mildly growth-restricted, female pregnancies ascertained on the basis of PMD. One case had liver hemangiomas and both infants had multiple skin hemangiomas. Post-natal development was normal. Molecular marker analysis confirmed the diagnosis of androgenetic and normal mixed cell populations in the placenta. Both cases derived from a single maternal genome (M1) and two distinct paternal genomes (P1 and P2). In one case, the androgenetic cell population contained both paternal genomes (P1P2), with one shared in common with the biparental (M1P1) population. In the second case, the androgenetic lineage showed complete homozygosity (P2P2) for a paternal genome not common to the biparental cell population.
CONCLUSION: These new PMD cases help to define the range of possible clinical presentations of androgenetic/biparental mosaicism or chimerism. Placentas with androgenetic/biparental chimeric cell populations may derive from a single tri-pronuclear (3PN) zygote in which one or more parental genomes are not equally apportioned to the daughter cells in the first cell division.
Key words: androgenetic/chimera/hemangioma/mosaicism/placental mesenchymal dysplasia
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Introduction |
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The presence of a mixed cell population consisting of normal and androgenetic (complete paternal uniparental disomy) cells has been reported in several instances to be associated with placental mesenchymal dysplasia (PMD) (Kaiser-Rogers et al., 2005
; Surti et al., 2005). Placentas with PMD are typically larger than average and show cystic areas on ultrasound; however, the diagnosis can only be confirmed by the observation of enlarged hydropic villi, abnormal placental blood vessels, and absence of trophoblast hyperplasia on pathological examination (Jauniaux et al., 1997; Ohyama et al., 2000; Paradinas et al., 2001; Matsui et al., 2003; Gibson et al., 2004). The associated fetuses may be completely normal, but are at risk for intrauterine growth restriction (IUGR) and fetal or neonatal death, and may show features associated with Beckwith–Wiedemann syndrome (BWS), including omphalocele, macroglossia, visceromegaly, and infantile hemangiomas (Jauniaux et al., 1997; Ohyama et al., 2000; Paradinas et al., 2001; Matsui et al., 2003; Gibson et al., 2004). Androgenetic mosaicism/chimerism has also been reported in complete hydatidiform moles with no fetal tissue (Ford et al., 1986), presence of amnion only (Weaver et al., 2000), or a live-born fetus (Makrydimas et al., 2002). The latter case was similar to the reported cases of PMD except that trophoblast hyperplasia was present.
As with chromosomal mosaicism, a range of pregnancy outcomes is expected depending on the number of cells present at the time of origin of the two cell populations, selection for or against each cell population at various stages of development, and chance events affecting the allocation of cells into each tissue (Kalousek and Vekemans, 1996; Wolstenholme, 1996; Robinson et al., 1997; Robinson et al., 2002). Because of the critical role of imprinted gene expression in early embryo and placental development (Constancia et al., 2004), selection may be particularly important in determining the distribution of androgenetic cells in a chimeric embryo. In those placentas studied in detail, the androgenetic cells seemed to be predominantly confined to placental vessels, chorion and mesenchyme (Kaiser-Rogers et al., 2005). Nonetheless, androgenetic cells were present in amniotic fluid of one case, suggesting these cells might persist in at least some embryonic tissues (Kaiser-Rogers et al., 2005). Few pregnancies have yet been investigated for the presence of androgenetic cells, as these are karyotypically normal and thus cannot be identified using routine cytogenetic methods. Thus, some issues remain to be resolved including whether all cases of PMD can be attributed to androgenetic chimerism, the range of possible placental and fetal phenotypes associated with this condition and the range of possible mechanisms by which such mixed cell populations may arise and the factors contributing to their occurrence. We therefore present two further cases of androgenetic-biparental chimerism associated with PMD and discuss the mechanisms and possible phenotypes that may be associated with this condition.
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Clinical case 1
Case 1 was ascertained as a result of marked placental changes observed on prenatal ultrasound at 18 weeks gestation. The placenta appeared enlarged, thickened and hydropic. Other prenatal ultrasound findings included symmetrical growth restriction and a cyst in the fetal liver. Amniocentesis showed a normal female karyotype, and a fetal echocardiogram was normal. There was premature rupture of membranes at 28 weeks gestation with subsequent delivery by C-section. The patient was born to a healthy 31 year-old primigravida with a birthweight of 820 g (10th percentile). Pathological examination of the placenta showed extremely dilated, tortuous and congested surface vessels and the presence of numerous fluid filled cysts. On histological examination, numerous edematous stem cell villi with central cistern formation were seen. There was no trophoblast hyperplasia and the appearances were those of PMD.
In the neonatal period, the patient was treated for many complications of prematurity including phototherapy for jaundice, transfusion for mild anemia, patent ductus arteriosus ligation and laser surgery for retinopathy of prematurity. An echocardiogram revealed an atrial septal defect. In addition, the child had chronic lung disease and was on supplemental oxygen for the first year of life. The patient was found to have two large lesions in the liver, biopsy of which showed a hemangioma in the right lobe of the liver and a benign cyst in the left lobe. Abdominal imaging showed numerous additional heterogeneous nodules in the left lobe of the liver. Hemangiomas in the kidneys and lungs were not found.
At two and half years of age, the patient's development was normal. Physical examination showed normal growth parameters. The patient was non-dysmorphic. She was found to have a hemangioma on the left shoulder and a deep venous malformation on her right lower leg. There were no features of BWS, specifically no macrosomia, macroglossia, ear lobe creases, umbilical hernia or limb asymmetry. Regular screening abdominal ultrasounds have been performed which have shown regression of the hemangioma in the right lobe of the liver.
Clinical case 2
A healthy, 27-year-old woman, with one previous pregnancy resulting in a healthy child, was referred at 21 weeks gestation because of an abnormal appearing placenta and mild asymmetrical IUGR. Maternal serum screening at 17 + 5 weeks had shown an elevated maternal serum alpha fetal protein (AFP) at 4.87 MoM (multiples of the median), normal unconjugated estriol (E3) at 1.47 MoM and normal human chorionic gonadotrophin (hCG) at 1.59 MoM. At a 19-week scan, the biometry showed mild asymmetrical IUGR, normal amniotic fluid volume and no other noted abnormalities other than an elevated nuchal index of 12.9 (Lim et al., 2002). The placenta was described as being bulky (thickness of 4 cm) with multiple echo-poor areas. At 22 weeks, biometry was measured in the normal range and there was normal fluid, no fetal anomalies, and a normal nuchal index. Uterine artery doppler showed no notching. Initial investigations included Toxoplasma, Rubella, CMV, HSV (TORCH) serology and chromosomal karyotype, all of which were normal. The pregnancy was followed with biweekly growth scans and weekly amniotic fluid index and Doppler studies. The fetus continued to grow appropriately until 32 weeks, when decreased interval growth of the abdominal circumference was noted. At 34 weeks, biometry showed symmetrical IUGR. Amniotic fluid levels were appropriate at all times, and the umbilical artery dopplers demonstrated end diastolic flow throughout, however, the mean peak systolic to end-diastolic (S/D) umbilical artery ratio was increased above the 90th percentile from 28 weeks onward. The placental appearance on ultrasound changed over time, becoming progressively thicker, bulkier, and the echo-poor areas became more numerous and larger (see Figure 1). A 2235 g (10th percentile) female infant with apgars of 9 and 9 at 1 and 5 min was born after spontaneous labor at 36 + 4 days. Length was at the 10th percentile and head circumference was > 10th percentile.
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The placenta was diagnosed as mesenchymal dysplasia upon pathologic examination. The baby girl was healthy and developing normally at 5 months of age and no concerns for the baby's health were raised. Two capillary hemangiomas were present on the neck.
Molecular studies
Molecular investigations were preformed for case 1 on DNA extracted from a placental sample (chorionic villi) and newborn and parental blood samples. In case 2, a single placental biopsy was taken that was then separated into three parts: a piece of enlarged chorionic vessel was mechanically separated from the surrounding villi, then the villi were subjected to enzymatic digestion to separate trophoblast cells from the remaining mesenchyme. Parental DNA was extracted from a saliva sample using OrageneTMDNA Self-Collection Kit (DNA Genotek, Toronto, Canada). PCR amplification was performed using standard conditions with primer pairs for microsatellite markers located on multiple different chromosomes. Markers were genotyped using fluorescently labelled primers with PCR products quantified on an ABI 310 Prism Genetic Analyzer (ABI, Foster City, CA).
DNA analysis of the placenta was undertaken in an effort to determine the cause of the placental findings. In particular, androgenetic mosaicism was considered a possible explanation and this was investigated by considering inheritance and allelic dosage at a large number of markers, as described previously (Kaiser-Rogers et al., 2005). This study was approved by the Clinical Research Ethics Board of the University of British Columbia.
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Results |
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All typed markers in DNA extracted from patient blood of case 1 and trophoblast from case 2, were consistent with normal biparental inheritance, with no obvious dosage differences between alleles. In contrast, all loci tested in the chorionic villus sample of case 1 and villus mesenchyme and chorionic vessel of case 2 showed an excess dosage of paternal alleles, consistent with the presence of mixed biparental and androgenetic (paternal-derived genome only) cell populations. As two different paternal alleles were observed at multiple loci, at least two distinct haploid paternal contributions were involved.
For case 1, the level of androgenetic cells was estimated as approximately 35% in the placental sample (see Table I). It was possible to distinguish one of two patterns in the placenta for all markers heterozygous (Aa) in the father:
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- Excess dosage of a single paternal allele (e.g. A or a) in the placenta (8 of 13 informative unlinked markers) (Figure 2B): in this case, the androgenetic lineage was inferred to be homozygous and sharing the same paternal allele as the biparental cells (e.g. biparental: MPa and androgenetic: PaPa pattern);
- Presence of two different paternal alleles, but with excess dosage of the paternal allele that was also present in the biparental cell population (inferred from blood) (5 of 13 informative unlinked markers) (Figure 2A): this pattern implies heterozygosity for paternal alleles in the androgenetic cell population (e.g. biparental: MPa and androgenetic: PAPa pattern).
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In no instance for case 1 did the inheritance pattern suggest that the androgenetic population was homozygous for the paternal allele not present in the biparental cells (e.g. MPa and PAPA pattern), the pattern expected for 25% of markers if the androgenetic cells derived from a completely separate dispermic conceptus with subsequent fusion of biparental and androgenetic embryos (i.e. the involvement of three haploid paternal complements rather than two with M1P1 and P2P3 genomic contributions for the biparental and androgenetic lineages). Thus this later model was statistically rejected (P < 0.002) (see Table III). Instead, the inheritance pattern fit most closely to a model whereby the androgenetic cell population shared one haploid paternal genome in common with the biparental line and one haploid paternal genome derived from a separate sperm (M1P1 and P1P2).
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In contrast, the androgenetic population in case 2 appeared to be completely homozygous at all markers, and frequently differed from the paternal contribution to the biparental lineage (e.g. MPa and PAPA pattern). (Table II, Figure 2B). The estimated proportion of androgenetic cells was 72% in the chorionic vessel, 34% in chorionic mesenchyme, and too low to measure (<
5%) in trophoblast. The results were most consistent with a model whereby separate sperm contributed to the androgenetic and biparental populations, with complete homozygosity in the androgenetic lineage (M1P1 and P2P2) (Table III).
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In theory, the presence of two different paternal genomes can derive from a diploid sperm, resulting from a meiosis I or II division failure, rather than from two distinct sperm. The distinction between these types of errors can be made by analysis of multiple centromeric markers as has been preformed in analysis of triploidy (McFadden and Langlois, 2000
; Zaragoza et al., 2000; McFadden et al., 2002). If the two paternal genomes derive from a diploid sperm that has undergone an error in meiosis I, both alleles should be transmitted (one in each genome) at all centromeric markers that are heterozygous in the father; whereas in a meiosis II error, transmission of the same paternal allele is expected in both complements at all centromeric loci (heterozygosity distal to the centromere is observed as a consequence of meiotic recombination). If two distinct haploid sperm are involved, the transmission of paternal centromeric alleles should be transmitted randomly to the two haploid complements (i.e. sharing the same allele on average 50% of the time). In the first case (Table I), two different paternal alleles were transmitted for D2S113, D4S518 and D16S409, while the same paternal allele was transmitted for EGFR, D12S87 and AR, all of which map to <1 cM from the centromere and thus likely reflect the centromeric state. In the second case, two different paternal alleles were transmitted for D9S1788 and D16S409, while the same paternal allele was transmitted for D12S87, D21S120 and AR. Therefore, in each case, the two paternal genomes derived from two distinct sperm, as has been demonstrated to be the case for most or all cases of diandric triploidy (Zaragoza et al., 2000; McFadden et al., 2002). |
Discussion |
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The present two cases are, to our knowledge, the fourth and fifth cases of PMD investigated molecularly and are again consistent with androgenetic mosaicism/chimerism as the cause of the unusual placental findings. In addition, the androgenetic/biparental case of Makrydimas et al. presented a very similar placental phenotype and pregnancy course, although a diagnosis of PMD was rejected due to the presence of trophoblast hyperplasia (Makrydimas et al., 2002
). The difference between this and other cases is likely to be due only to presence/absence of the androgenetic population in the trophoblast (Sebire and Fisher, 2005). Thus it appears that most cases of PMD, as well as some other instances of a ‘partly molar pregnancy that is not a partial mole’(Thaker, 2005), will be due to this mechanism. As rare cases of complete hydatidiform moles have a biparental origin (Fisher and Hodges, 2003; Fisher et al., 2004), it would not be surprising to find other instances of PMD with a uniformly biparental cell make-up, but showing global imprinting defects in a subset of cells. It also appears that abnormalities of 11p15.5 associated with BWS can lead to this placental phenotype (Robinson et al., unpublished).
A review of previously published cases of androgenetic mosaicism/chimerism is presented in Table IV. Growth delay of the fetus in the second half of pregnancy appears to be a consistent feature of the investigated cases and may be due to impaired nutrient transfer by the affected placenta. The presence of liver cysts/hemangiomas in case 1, a previous case that died in utero (Kaiser-Rogers et al., 2005), as well as in other reported cases of PMD (Jauniaux et al., 1997; Laberge et al., 2005), suggest that this is a consistent abnormality that may be due to the presence of androgenetic cells in this organ. Furthermore, all three cases for which we have follow-up information displayed multiple capillary hemangiomas. Vascular hemangiomas (liver and skin) in the neonate have been reported previously in association with PMD (Gibson et al., 2004) as well as in association with chorangioma (placental hemangioma) (Witters et al., 2003; Bakaris et al., 2004), a placental anomaly which has been suggested to have a common embryological origin with PMD (Jauniaux et al., 1997). These infantile hemangiomas have been hypothesized to be of placental origin due to their phenotype and gene expression profiles and appear to derive from cells that have migrated from the placenta rather than being of true embryonic origin (Bree et al., 2001; Barnes et al., 2005). The abnormal vasculature seen in PMD and these associated hemangiomas suggest a role of imprinting in disordered angiogenesis. While the liver cysts and hemangiomas may be of little clinical consequence, their presence may be useful for identifying androgenetic mosaicism/chimerism as a possible diagnosis in other cases. An association with PMD could also help explain why capillary hemangiomas are more commonly found in female, low birthweight and premature infants (Amir et al., 1986; Powell et al., 1987), as these are also findings associated with PMD.
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In addition to the clinical relevance, the present cases serve to illustrate the difficulty in distinguishing an aggregation chimera (derived from two separately fertilized oocytes), from a single-embryo chimera (derived from whole-genome segregation errors in the first cell division). As the two parental genomes do not normally become incorporated into a single nucleus until the two-cell stage, genome replication and segregation errors occurring in the first cell division can lead to a variety of 3N/2N and 2N/1N mixed cell populations. The term mosaicism, while commonly used to refer to such embryos, should perhaps be limited to single chromosome or single gene errors. The usage of the terms, however, varies in the literature (Boklage, 2006
).
In speculating on how whole genome segregation errors may arise, it is important to recognize that the sperm and oocyte are at very different points in their cell cycle at the time of fertilization and the two pronuclei function independently. For example, the maternal genome undergoes the final reduction division of meiosis II (which the paternal genome has completed earlier) only after fertilization; this is followed by extensive epigenetic reprogramming of the paternal, but not the maternal genome; and subsequent to this stage, the genomes undergo replication still within their separate pronuclei (Morgan et al., 2005). As has been demonstrated in mouse, delayed timing in one pronucleus can lead to failed replication/condensation/and nuclear envelope breakdown and then failure of the chromosomes from that haploid genome to migrate to the metaphase plate and segregate; instead the chromosomes from the delayed pronucleus remain in a clump within one daughter cell (Maleszewski et al., 1999). Failed segregation of the maternal genome in a normal bi-pronuclear (2PN) zygote would result in a 2N/N chimeric two-cell embryo. Subsequent endoreduplication of the haploid paternal complement could then occur to form an androgenetic lineage as proposed previously (Kaiser-Rogers et al., 2005).
In the present case 1, although two haploid paternal genomes were present, the same paternal haploid complement in the biparental cells (M1P1) had also contributed to the androgenetic cells (P1P2). The origin of this case can be explained by a very similar model as that proposed previously (Kaiser-Rogers et al., 2005), but by starting with a tri-pronuclear (3PN) zygote (Figure 3). Human fertilized oocytes displaying three pronuclei are observed in 5% of zygotes analysed after IVF and can lead to triploidy in vivo. However, when followed to the early cleavage stage, such embryos displayed a pure triploid complement in only a minority of cases, with a large portion of the resulting embryos being either fully diploid or diploid/haploid mosaics (Ma et al., 1995; Staessen and Van Steirteghem, 1997; Pang et al., 2005). This suggests that 3PN zygotes are particularly susceptible to abnormalities leading to failed replication and segregation of one or more haploid genomes and contribute to the frequent observation of 3N/2N and 2N/1N chimeric 2–8 cell embryos after assisted reproduction (Pieters et al., 1992; Harper et al., 1995; Golubovsky, 2003).
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Fully diploid two-celled embryos arising from a 3PN zygote can occur when only one of the three haploid genomes replicates and segregates at the end of the one-cell stage, with the other two genomes remaining in a clump [i.e. as is observed to occur with pronuclear delay in mouse (Maleszewski et al., 1999
)] with one randomly ending up in each daughter cell (Figure 3). This mechanism can explain the marker pattern observed in case 1. Alternatively, a tripolar spindle could also contribute to such an outcome as discussed by Golubovsky (Golubovsky 2003). In either case, cells that differed in terms of haploid contributions could result from a single fertilized oocyte. In contrast, the present case 2 showed different paternal genomes in the biparental and homozygous androgenetic cell populations, as has been observed in one other case of PMD (Surti et al., 2005) and two cases of complete hydatidiform mole with amnion but no other fetal tissue present (Ford et al., 1986; Weaver et al., 2000). While it has been suggested previously that these cases arise by fusion of embryos derived from separately fertilized oocytes, it is also possible to derive such an embryo from a single 3PN zygote as shown in Figure 3. As the presentations of these latter cases of PMD are similar to other androgenetic/biparental cases, and as both types of two-celled embryos are common observed cleavage outcomes from a 3PN zygote, a common mechanism seems likely. The occurrence of dizygotic twin gestations in three of the eight cases listed in Table III, including both bi-gametic and tetra-gametic cases, suggests that conditions leading to supernumerary ovulation may be related to an increase of pronuclear abnormalities (number and timing) in the oocytes produced (perhaps as a consequence of oocyte immaturity).
It is worth noting that few of the reported cases of ‘human chimeras’, most of which were ascertained through 46,XX/46,XY hemaphrodites, have been investigated extensively with molecular markers. Of those that have, some cases were shown to be mosaics with only sex-chromosome involvement (Wit et al., 1987; Niu et al., 2002), some cases were shown to be tri-gametic, deriving from fertilization of a single oocyte with two sperm (i.e. M1P1/M1P2 pattern) (Giltay et al., 1998; Chen et al., 2005); while some cases were ‘tetra-gametic’, i.e. involved two different maternal and two different paternal haploid complements (Uehara et al., 1995; Yu et al., 2002). It has been suggested that some ‘tetra-gametic’ cases, could have arisen from fertilization of the first or second polar body by a separate sperm (Verp et al., 1992). Alternatively, a binucleate oocyte could be fertilized by two separate sperm. Giant binuclear oocytes have been observed in 0.3% of oocytes harvested for in vitro fertilization (Balakier et al., 2002). Clearly, there are many types of errors that can arise in oocytes and early embryos.
Why does it matter whether a chimera derived from a single oocyte rather than later fusion of embryos derived from two distinct and separately fertilized oocytes? The incidence of twinning, including monochorionic dizygotic twinning, and chimerism have been suggested to be increased among pregnancies conceived by use of assisted reproductive technologies (Strain et al., 1998; Balakier et al., 2002; Miura and Niikawa, 2005; Yoon et al., 2005). Such observations are usually assumed to be a consequence of implantation of multiple embryos, but they could instead be due to defects of oocyte maturation after hormonal stimulation, as has been suggested to influence the frequency of binuclear oocytes (Balakier et al., 2002). Furthermore, the distribution of cells in the resulting embryo, and thereby clinical outcomes, may differ depending on whether the embryo was chimeric at the two-cell stage or instead resulted from later amalgamation of two embryos that had already started to show signs of trophoblast lineage commitment. Thus, detailed investigation of additional cases of chimerism is of both academic and clinical interest.
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Acknowledgements |
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This research was supported by a Canadian Institutes of Health Research Grant (15667) to W.P.R. We thank the families and clinicians involved for their cooperation.
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Submitted on July 20, 2006; resubmitted on November 7, 2006; resubmitted on November 7, 2006; accepted on November 1, 2006.
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