Diandric Triploidy Research Articles

The Contribution of QF-PCR and Pathology Studies in the Diagnosis of Diandric Triploidy/Partial Mole.

Objective: the aim of our study was to assess the contribution of quantitative fluorescent polymerase chain reaction (QF-PCR) and pathology studies in the diagnosis of diandric triploidies/partial hydatidiform moles. Methods: this study included all fet al triploidies diagnosed by QF-PCR in chorionic villi or amniotic fluid in the 2 centers of BCNatal in which a maternal saliva sample was used to establish its parental origin. Pathology studies were performed in products of conception and concordance between a partial hydatidiform mole diagnosis and the finding of a diandric triploidy was assessed. Results: among 46 fetal triploidies, found in 13 ongoing pregnancies and in 33 miscarriages, there were 26 (56%) diandric triploidies. Concordant molecular (diandric triploidy) and pathology results (partial mole) were achieved in 14 cases (54%), while in 6 cases (23%) pathology studies were normal, and in the remaining 6 cases (23%) pathology studies could not be performed because miscarriage was managed medically. Conclusions: diandric triploidy is associated with partial hydatidiform mole and its diagnosis is crucial to prevent the development of persistent trophoblastic disease. QF-PCR analysis in chorionic villi or amniotic fluid provides a more accurate diagnosis of the parental origin of triploidy than the classical pathology studies.

Triploid pregnancy-Clinical implications.

Triploidy is a life-limiting genetic aberration resulting from an extra haploid set of chromosomes of paternal (diandric triploidy) or maternal origin (digynic triploidy). Triploidy affects around 1%-2% of all conceptions. The majority of cases is miscarried at early developmental stages. In consequence of genomic imprinting, parental origin affects the phenotype of triploid pregnancies as well as the prevalence and spectrum of related maternal complications. Distinctive ultrasound features of both triploid phenotypes as well as characteristic patterns of biochemical markers may be useful in diagnosis. Molecular confirmation of the parental origin allows to predict the risk of complications, such as gestational trophoblastic neoplasia, hyperthyroidism, hypertension, or preeclampsia associated with the paternal origin of triploidy. Diagnosis of partial hydatidiform mole associated with diandric triploidy is challenging especially in the first trimester pregnancy loss due to the limitations of both histopathology and ultrasound. We present important clinical aspects of triploid pregnancies and indicate unresolved issues demanding further studies.

Distribution of diandric and digynic triploidy depending on gestational age

PurposeTo establish the distribution of diandric and digynic triploidy depending on gestational age.Methods107 triploid samples tested prospectively in a single genetic department during a four-year period were analyzed for parental origin of triploidy by Quantitative Fluorescent Polymerase Chain Reaction (QF-PCR) (n=95) with the use of matching parental samples or by MS-MLPA (n=12), when parental samples were unavailable. Tested pregnancies were divided into three subgroups with regard to the gestational age at spontaneous pregnancy loss: <11 gestational weeks, 11–14 gestational weeks, and >14 gestational weeks.ResultsDiandric triploidy constituted overall 44.9% (46.5% in samples miscarried <11 gestational weeks, 64.3% in samples miscarried between 11 and 14 gestational weeks, and 27.8% in pregnancies which survived >14 gestational weeks).ConclusionsThe distribution of diandric and digynic triploidy depends on gestational age. The majority of diandric triploid pregnancies is lost in the first trimester of pregnancy. In the second trimester, diandric cases are at least twice less frequent than digynic ones.

Variants in Maternal Effect Genes and Relaxed Imprinting Control in a Special Placental Mesenchymal Dysplasia Case with Mild Trophoblast Hyperplasia.

Placental mesenchymal dysplasia (PMD) and partial hydatidiform mole (PHM) placentas share similar characteristics, such as placental overgrowth and grape-like placental tissues. Distinguishing PMD from PHM is critical because the former can result in normal birth, while the latter diagnosis will lead to artificial abortion. Aneuploidy and altered dosage of imprinted gene expression are implicated in the pathogenesis of PHM and also some of the PMD cases. Diandric triploidy is the main cause of PHM, whereas mosaic diploid androgenetic cells in the placental tissue have been associated with the formation of PMD. Here, we report a very special PMD case also presenting with trophoblast hyperplasia phenotype, which is a hallmark of PHM. This PMD placenta has a normal biparental diploid karyotype and is functionally sufficient to support normal fetal growth. We took advantage of this unique case to further dissected the potential common etiology between these two diseases. We show that the differentially methylated region (DMR) at NESP55, a secondary DMR residing in the GNAS locus, is significantly hypermethylated in the PMD placenta. Furthermore, we found heterozygous mutations in NLRP2 and homozygous variants in NLRP7 in the mother’s genome. NLRP2 and NLRP7 are known maternal effect genes, and their mutation in pregnant females affects fetal development. The variants/mutations in both genes have been associated with imprinting defects in mole formation and potentially contributed to the mild abnormal imprinting observed in this case. Finally, we identified heterozygous mutations in the X-linked ATRX gene, a known maternal–zygotic imprinting regulator in the patient. Overall, our study demonstrates that PMD and PHM may share overlapping etiologies with the defective/relaxed dosage control of imprinted genes, representing two extreme ends of a spectrum.

Cost Analysis and Diagnostic Yield of Histopathology Versus Genetic Testing for Evaluation of Pregnancy Loss [10O

INTRODUCTION: Miscarriage evaluations, including histopathology studies and genetic testing, are performed to determine the cause of the loss and provide maternal medical management guidance. This study examined the cost and diagnostic effectiveness of histopathology and single nucleotide polymorphism (SNP) array-based genetic testing to identify molar pregnancies, defined as conceptions with excess paternal genetic contribution, or another cause of the loss. METHODS: Products of conception cases from a single institution (Recurrent Pregnancy Loss Center, Fertility Associates of Memphis, Memphis, TN), are routinely sent for histopathological examination and genetic testing. Retrospective analysis of the results and cost of both evaluations were compared. (IRB E&amp;I 15148-03). RESULTS: Fifty-nine cases were examined. SNP array-based testing showed 27 normal (46%) and 32 abnormal cases (54%), including 3 molar (diandric triploidy). Histopathology identified three molar cases; only one was confirmed by SNP microarray. In this cohort, the self-pay cost for histopathology was $241 and for SNP array was $349. The rate of correctly identifying molar pregnancy by histopathology was 1/59 or $14,219/case identified, and by SNP array was 3/59 or $6,864/case identified. Similarly, the rate of identifying a cause of the loss by histopathology was 1/59 or $14,219/case identified and by SNP array was 32/59 or $643/case identified. CONCLUSION: Comparison of the cost of SNP array analysis with histopathology evaluation results in a similar expense to the patient. SNP array is an alternative to identifying patients with a molar pregnancy and provides additional clinical information to providers at a significantly lower cost per case for cause of loss identified.

Maternal complications in molecularly confirmed diandric and digynic triploid pregnancies: single institution experience and literature review

ObjectivesAssessment of the maternal complications in molecularly confirmed diandric and digynic triploid pregnancies.MethodsSonographic features, biochemical results, and clinical presentation were analyzed. Beta-hCG level was controlled after diandric triploidy.ResultsThe study included nine diandric and twelve digynic triploid pregnancies at the mean gestational age at diagnosis of 14.9 and 18.0 weeks, respectively (p = 0.0391). Mean value of total-hCG was 979 703.6 U/ml in diandric cases and 5 455.4 U/ml in digynic ones (p < 0.000). Maternal complications occurred in 88.9% of diandric triploid pregnancies, including: thecalutein cysts (44.4%), hyperemesis gravidarum (44.4%), symptomatic hyperthyreosis (33.3%), early onset gestational hypertension (22.2%) and vaginal bleeding (11.1%). No case of proteinuria, preeclampsia or HELLP syndrome was observed. Only maternal complication observed in digynic triploidy was vaginal bleeding (50.0%). The mean time of beta-hCG normalization after diandric triploid pregnancies was 84 days (range 11–142 days). No case of gestational trophoblastic neoplasia (GTN) was observed.ConclusionsMaternal complications (except for vaginal bleeding) are associated with diandric triploidy. The relatively low incidence of hypertensive maternal complications and their less severe course in our cohort may be attributed to the earlier prenatal diagnosis. The frequency of GTN after diandric triploidy may be lower than previously reported.

Prevalence of Partial Hydatidiform Mole in Products of Conception From Gestations With Fetal Triploidy Merits Reflex Genotype Testing Independent of the Morphologic Appearance of the Chorionic Villi.

Diagnosis of first-trimester partial mole is challenging as the key morphologic features may not be well-developed and may overlap with those of a nonmolar gestation harboring a cytogenetic disorder or degenerative changes. Genotype testing has emerged as the reference tool to distinguish partial mole (diandric triploid genotype) from its nonmolar mimics. However, observer variation in defining the minimum threshold of how much morphologic alteration is required to trigger genotype testing may result in a subset of partial moles that go undetected. We hypothesized that the results of fetal aneuploidy testing performed for prenatal screening or evaluation of miscarriage may assist with triggering molecular testing in the evaluation of products of conception, specifically if fetal triploidy is detected. Gestations with fetal triploidy are either a partial mole (diandric triploidy) or are nonmolar (digynic triploidy). The aims of this study were to define the prevalence of partial mole in 20 products of conception specimens with known fetal triploidy by performing genotype testing and then to determine how well established morphologic criteria for partial mole correlate with the genotype results in this setting. Genotype testing demonstrated that 65% (13/20) were a partial mole and the remainder were nonmolar digynic triploid gestations. Most partial moles were under 9 weeks gestational age and, as expected, lacked classic well-developed morphologic features. Nearly a third (4/13) of the partial moles were originally interpreted as normal or nonmolar gestations with minimal abnormalities that did not merit molecular testing to exclude a partial mole. Even with the retrospective systematic morphologic review, only 23% (3/13) exhibited the combination of chorionic villous enlargement of ≥2.5 mm and cisterns, which has been previously established as the morphologic criteria with the highest predictive value for a molecularly defined partial mole. The other 77% exhibited focal, limited, variable degrees and extent of villous morphologic alterations. We conclude that, given the high prevalence of partial mole among products of conception with known fetal triploidy and the low prevalence of diagnostic morphologic findings in such specimens, reflex genotype testing should be performed in all such cases, regardless of whether or not the morphologic features are suspicious for a partial mole. This reflex testing strategy mitigates against the subjectivity of determining whether subtle villous abnormalities are significant enough to merit pursuing genotype testing. The success of this strategy depends on the clinician documenting the fetal triploidy result at the time of submitting the products of conception specimen and therefore clinician education is needed. Finally, it remains to be determined whether the risk for postmolar gestational trophoblastic disease is the same in diandric triploid gestations that exhibit classic morphologic features as in those that exhibit minimal or negligible villous morphologic abnormalities.

Diandric triploidy in a liveborn infant with 3-4 syndactyly and a neural tube defect

Triploidy is a chromosomal abnormality caused by an additional haploid set of chromosomes. It is a common cause for early first trimester miscarriages. Only very rarely are babies with triploidy born alive and even more rarely do they survive beyond the first few days of life. We present here a case of a term baby with confirmed paternal (diandric) triploidy and some unusual features, who survived for 50 days and review the literature on those who survived.

EP15.11: Partial hydatiform mole: a case report

Partial hydatidiform mole is a histopathologic entity characterised by focal trophoblastic hyperplasia with villous hydrops together with identifiable fetal tissue. 90% of partial moles are due to diandric triploidy. In Type I placenta is modified; in type II placenta is normal. We report a case of PHM type I with increased fetal NT and other fetal anomalies (Dandy-Walker complex and tetralogy of Fallot). A 32 year old woman (gravida 2, para 0 with a miscarriage) was referred to Fetal Medicine AOUI Verona Centre for an increased fetal NT (4.6 mm) and vacuole formations in the placenta diagnosed at I trimester US scan. An expert US scan which reported nuchal edema (5.2 mm), vacuole formations in the placenta and heart anomalies was performed at 15+2 weeks. Amniocentesis showed a 69 XXY fetal karyotype. US scan at 18 weeks showed a IUGR, Dandy-Walker Complex, Tetralogy of Fallot, molar changes of placenta and ovaries enlarged with multiple bilateral theca lutein cysts. The patient had no clinical symptoms of molar pregnancy. BHCG was 1.255.660 UI/L. Pregnancy was terminated at 19+4 weeks by induction of labour with intravaginal Gemeprost. A fetus with molar placenta was delivered; suction and curettage were performed. Histopathologic analysis and immunohistochemistry confirmed the diagnosis of partial hydatiform mole. Cytogenetic analysis showed a triploid kariotype. Fetal autopsy wasn't done under request of the patient. Chest-X- ray was negative. BHCG levels were checked every 2 weeks until the values were within the normal range. A closed follow up is still being performed. Definitive diagnosis of partial mole by ultrasound is often difficult especially in the early scan. It might be confused with missed abortions or blighted ovum. Triploidy is usually incompatible with life. In this case the fetus survived up to the second trimester with IUGR and a major anomaly of the heart. Molar pregnancies generally have severe outcomes. Serial follow up of HCG levels after termination of pregnancy is necessary. Cytogenetic pattern has to be correlated with histopathological diagnosis.

Triploidy - variability of sonographic phenotypes.

To analyze sonographic abnormalities in triploid pregnancies and assess the usefulness of the classification proposed by McFadden and Kalousek for prenatal sonographic assessment of triploid fetuses. We conducted a retrospective analysis of the sonographic features in a series of 67 triploid fetuses evaluated between 11 and 30weeks of gestation in a single referral center between 1997 and 2015. Non-specific structural fetal defects were visualized in the majority of fetuses (61.2%) regardless of the parental origin of the triploidy. A 'diandric phenotype' was identified in eight relatively well-grown fetuses (11.9%) that presented with cystic placentas. A 'digynic phenotype' was identified in 47 asymmetrically growth-restricted fetuses with non-cystic placentas (70.2%). In 12 cases (17.9%), features of both phenotypes were present. Nearly 40% of triploid fetuses do not have any apparent structural abnormalities, and only careful assessment of fetal growth and placenta may lead to the suspicion of the diagnosis. As diandric triploidy carry a high risk for maternal complications, identification of these cases is vital for prenatal counseling. In nearly 20% of triploid pregnancies, parental origin cannot be established based on sonographic assessment. © 2017 John Wiley & Sons, Ltd.

Maternal GRB10 microdeletion is a novel cause of cystic placenta: Spectrum of genomic changes in the etiology of enlarged cystic placenta

IntroductionThe genetics and pathology of diploid complete and triploid partial hydatidiform moles have been well established. Enlarged cystic placenta often indicates an underlying etiology and is frequently associated with adverse pregnancy outcome. Several imprinted genes are strongly expressed in placental tissues and essential for normal placental growth and development. Disruption of these imprinted genes can lead to abnormal placental pathology and placental stunting or overgrowth. We present the genetic etiologies of five unusual mosaic cases of enlarged cystic placentas and report a novel etiology, mosaicism for deletion of the maternal GRB10 gene. MethodsFive mosaic placental mesenchymal dysplasia cases with discrete populations of “cystic” and “normal” villi and/or atypical p57KIP2 immunostaining were evaluated by genetic analysis; including G-banded karyotyping, fluorescence in situ hybridization (FISH), whole genome CGH + SNP microarray, conventional Sanger sequencing, and STR microsatellite analysis. ResultsGenetic etiologies ranged from genome-wide changes, including mosaic androgenetic isodisomy and mosaic diandric triploidy, to a novel microdeletion of the maternally-expressed GRB10 gene. An abnormal mosaic population of cells was also detected in the fetus in two cases. DiscussionFour cases were mosaic for either diandric triploidy or an androgenetic cell population, and the enlarged cystic placentas were likely due to an excess of paternally-expressed growth promoting genes and also the absence of maternally-expressed growth restricting genes. Also we identified mosaicism for a novel microdeletion of the maternal GRB10 allele, a potent growth inhibitor, which resulted in placental overgrowth in the cystic area of one placenta. We advocate the use of ancillary techniques to investigate complex mosaic cases of enlarged cystic placentas to discover atypical genetic etiologies and to increase our understanding of the placental genome.

DNA Genotyping of Suspected Partial Hydatidiform Moles Detects Clinically Significant Aneuploidy.

The diagnosis of partial hydatidiform mole (PM) is especially difficult early in gestation as the morphology of nonmolar abortus (NMA) may mimic PM. Molecular genotyping analysis can definitively identify diandric triploidy, the genetic basis for PM, whereas NMA cases show a biparental inheritance. This 4-year retrospective study sought to determine what proportion of NMA cases which were initially suspected as being PM was aneuploid, and whether this knowledge of aneuploidy status is clinically useful. Cases with atypical villous morphology on histopathology suggestive of PM were subjected to molecular genotyping. The genotyping testing panel contained 19 highly polymorphic short-tandem repeat markers on chromosomes 13, 18, 21, X, and Y and 2 nonpolymorphic markers for sex determination. Informative molecular genotyping analysis was available in 127 cases (56 PMs and 71 NMAs). Aneuploidy was detected in 15/71 of NMAs (21.1%): 7 cases of trisomy 18, 3 of trisomy 13, 1 of trisomy 21, and 4 of monosomy X. It is concluded that most cases of aneuploid NMAs (11/15) detected by molecular genotyping analysis of atypical villous morphology cases are sporadic in type with a low or age-related recurrence risk. Nevertheless, this information may be useful in subsequent counseling and in women undergoing in vitro fertilization by directing preimplantation genetic diagnosis in subsequent cycles. In about a quarter of aneuploid NMAs (4/15) specific aneuploidy types which may be caused by unbalanced familial chromosome rearrangement are identified and are clinically important to patient management. Detection of clinically relevant aneuploidy in NMAs represents an important secondary benefit to the adoption of molecular genotyping analysis in suspected PM.

Molecular and histological characteristics of early triploid and partial molar pregnancies

Molar pregnancy has the highest incidence of all gestational trophoblastic diseases. This is a heterogeneous group of diseases, composed of precancerous lesions and gestational trophoblastic tumours. The hydatidiform mole is characterised by varying degrees of proliferation of syncytiotrophoblastic and cytotrophoblastic cells and stromal oedema. Based on established morphological and cytogenetic criteria, molar pregnancy is divided into partial and complete. The risk of persistent trophoblastic disease is higher in complete moles compared with partial moles. The aim of this study was to assess the importance of additional molecular methods as a conjunction to the standard histopathological analysis to accurately determine the type and origin of triploidy and to detect partial molar pregnancy. This study examined a total of 24 cases of triploidy. Apart from the detailed histomorphological analysis, a molecular analysis of the placental tissue and maternal DNA was also performed. Digynic triploidy was found in 15 cases, whereas diandric triploidy was found in nine of the cases. The results showed that due to the histomorphological overlap between partial molar pregnancy and hydropic abortions, concomitant histopathological analysis of the placental tissue and molecular analysis of the placental and maternal DNA can lead to correct diagnosis.

Non-Invasive Prenatal Testing Using Cell Free DNA in Maternal Plasma: Recent Developments and Future Prospects.

Recent advances in molecular genetic technologies have facilitated non-invasive prenatal testing (NIPT) through the analysis of cell-free fetal DNA in maternal plasma. NIPT can be used to identify monogenic disorders including the identification of autosomal recessive disorders where the maternally inherited mutation needs to be identified in the presence of an excess of maternal DNA that contains the same mutation. In the future, simultaneous screening for multiple monogenic disorders is anticipated. Several NIPT methods have been developed to screen for trisomy. These have been shown to be effective for fetal trisomy 21, 18 and 13. Although the testing has been extended to sex chromosome aneuploidy, robust estimates of the efficacy are not yet available and maternal mosaicism for gain or loss of an X-chromosome needs to be considered. Using methods based on the analysis of single nucleotide polymorphisms, diandric triploidy can be identified. NIPT is being developed to identify a number of microdeletion syndromes including α-globin gene deletion. NIPT is a profoundly important development in prenatal care that is substantially advancing the individual patient and public health benefits achieved through conventional prenatal screening and diagnosis.

Prenatal Detection of Fetal Triploidy from Cell-Free DNA Testing in Maternal Blood

Objective: To investigate potential performance of cell-free DNA (cfDNA) testing in maternal blood in detecting fetal triploidy. Methods: Plasma and buffy coat samples obtained at 11-13 weeks' gestation from singleton pregnancies with diandric triploidy (n = 4), digynic triploidy (n = 4), euploid fetuses (n = 48) were sent to Natera, Inc. (San Carlos, Calif., USA) for cfDNA testing. Multiplex polymerase chain reaction amplification of cfDNA followed by sequencing of single nucleotide polymorphic loci covering chromosomes 13, 18, 21, X, and Y was performed. Sequencing data were analyzed using the NATUS algorithm which identifies copy number for each of the five chromosomes. Results: cfDNA testing provided a result in 44 (91.7%) of the 48 euploid cases and correctly predicted the fetal sex and the presence of two copies each of chromosome 21, 18 and 13. In diandric triploidy, cfDNA testing identified multiple paternal haplotypes (indicating fetal trisomy 21, trisomy 18 and trisomy 13) suggesting the presence of either triploidy or dizygotic twins. In digynic triploidy the fetal fraction corrected for maternal weight and gestational age was below the 0.5th percentile. Conclusions: cfDNA testing by targeted sequencing and allelic ratio analysis of single nucleotide polymorphisms covering chromosomes 21, 18, 13, X, and Y can detect diandric triploidy and raise the suspicion of digynic triploidy.

Diagnostic Reproducibility of Hydatidiform Moles

Distinction of hydatidiform moles from nonmolar specimens (NMs) and subclassification of hydatidiform moles as complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM) are important for clinical practice and investigational studies; however, diagnosis based solely on morphology is affected by interobserver variability. Molecular genotyping can distinguish these entities by discerning androgenetic diploidy, diandric triploidy, and biparental diploidy to diagnose CHMs, PHMs, and NMs, respectively. Eighty genotyped cases (27 CHMs, 27 PHMs, 26 NMs) were selected from a series of 200 potentially molar specimens previously diagnosed using p57 immunohistochemistry and genotyping. Cases were classified by 6 pathologists (3 faculty level gynecologic pathologists and 3 fellows) on the basis of morphology, masked to p57 immunostaining and genotyping results, into 1 of 3 categories (CHM, PHM, or NM) during 2 diagnostic rounds; a third round incorporating p57 immunostaining results was also conducted. Consensus diagnoses (those rendered by 2 of 3 pathologists in each group) were also determined. Performance of experienced gynecologic pathologists versus fellow pathologists was compared, using genotyping results as the gold standard. Correct classification of CHMs ranged from 59% to 100%; there were no statistically significant differences in performance of faculty versus fellows in any round (P-values of 0.13, 0.67, and 0.54 for rounds 1 to 3, respectively). Correct classification of PHMs ranged from 26% to 93%, with statistically significantly better performance of faculty versus fellows in each round (P-values of 0.04, <0.01, and <0.01 for rounds 1 to 3, respectively). Correct classification of NMs ranged from 31% to 92%, with statistically significantly better performance of faculty only in round 2 (P-values of 1.0, <0.01, and 0.61 for rounds 1 to 3, respectively). Correct classification of all cases combined ranged from 51% to 75% by morphology and 70% to 80% with p57, with statistically significantly better performance of faculty only in round 2 (P-values of 0.69, <0.01, and 0.15 for rounds 1 to 3, respectively). p57 immunostaining significantly improved recognition of CHMs (P<0.01) and had high reproducibility (κ=0.93 to 0.96) but had no impact on distinction of PHMs and NMs. Genotyping provides a definitive diagnosis for the ∼25% to 50% of cases that are misclassified by morphology, especially those that are also unresolved by p57 immunostaining.

Diagnostic Reproducibility of Hydatidiform Moles

Distinction of hydatidiform moles (HMs) from nonmolar specimens (NMs) and subclassification of HMs as complete hydatidiform moles (CHMs) and partial hydatidiform moles (PHMs) are important for clinical practice and investigational studies; yet, diagnosis based solely on morphology is affected by interobserver variability. Molecular genotyping can distinguish these entities by discerning androgenetic diploidy, diandric triploidy, and biparental diploidy to diagnose CHMs, PHMs, and NMs, respectively. Eighty genotyped cases (27 CHMs, 27 PHMs, and 26 NMs) were selected from a series of 200 potentially molar specimens previously diagnosed using p57 immunostaining and genotyping. Cases were classified by 3 gynecologic pathologists on the basis of H&E slides (masked to p57 immunostaining and genotyping results) into 1 of 3 categories (CHM, PHM, or NM) during 2 diagnostic rounds; a third round incorporating p57 immunostaining results was also conducted. Consensus diagnoses (those rendered by 2 of 3 pathologists) were determined. Genotyping results were used as the gold standard for assessing diagnostic performance. Sensitivity of a diagnosis of CHM ranged from 59% to 100% for individual pathologists and from 70% to 81% by consensus; specificity ranged from 91% to 96% for individuals and from 94% to 98% by consensus. Sensitivity of a diagnosis of PHM ranged from 56% to 93% for individual pathologists and from 70% to 78% by consensus; specificity ranged from 58% to 92% for individuals and from 74% to 85% by consensus. The percentage of correct classification of all cases by morphology ranged from 55% to 75% for individual pathologists and from 70% to 75% by consensus. The κ values for interobserver agreement ranged from 0.59 to 0.73 (moderate to good) for a diagnosis of CHM, from 0.15 to 0.43 (poor to moderate) for PHM, and from 0.13 to 0.42 (poor to moderate) for NM. The κ values for intraobserver agreement ranged from 0.44 to 0.67 (moderate to good). Addition of the p57 immunostain improved sensitivity of a diagnosis of CHM to a range of 93% to 96% for individual pathologists and 96% by consensus; specificity was improved from a range of 96% to 98% for individual pathologists and 96% by consensus; there was no substantial impact on diagnosis of PHMs and NMs. Interobserver agreement for interpretation of the p57 immunostain was 0.96 (almost perfect). Even with morphologic assessment by gynecologic pathologists and p57 immunohistochemistry, 20% to 30% of cases will be misclassified, and, in particular, distinction of PHMs and NMs will remain problematic.

Oocyte Defects Leading to Triploid Miscarriages After Donor Oocyte IVF

The most common form of aneuploidy observed in first trimester miscarriages is trisomy, followed by polyploidy. Whereas, the risk of meiotic non-disjunction leading to trisomy increases with maternal age, the risk factors for triploid conceptions are poorly understood. Diandric triploidy is commonly thought to be due to polyspermia, but the etiology of and risk factors for digynic triploidy are unknown.

Diandric Triploid Hydatidiform Mole With Loss of Maternal Chromosome 11

Distinction of hydatidiform moles (HM) from nonmolar specimens and their subclassification as complete (CHM) versus partial hydatidiform mole (PHM) are important for clinical practice and investigational studies to refine ascertainment of risk of persistent gestational trophoblastic disease (GTD), which differs among these entities. Immunohistochemical analysis of p57 expression, a paternally imprinted maternally expressed gene on 11p15.5, and molecular genotyping are useful for improving diagnosis. CHMs are characterized by androgenetic diploidy, with loss of p57 expression due to lack of maternal DNA. Loss of p57 expression distinguishes CHMs from both PHMs (diandric triploidy) and nonmolar specimens (biparental diploidy), which retain expression. We report a unique HM characterized by morphologic features suggesting an early CHM, including lack of p57 expression by immunohistochemistry, but with genetic features more in keeping with a PHM. Specifically, molecular genotyping by short tandem repeat markers provided evidence to support interpretation as a PHM by demonstrating allele patterns and ratios most consistent with diandric triploidy, with evidence of loss of the maternal copy of chromosome 11 to explain the lack of p57 expression. This case illustrates the value of combined traditional pathologic and ancillary molecular techniques for refined diagnosis of molar specimens. It also raises questions regarding which modalities should be used to ultimately define the subtypes of HMs and whether chromosomal losses or gains, particularly involving imprinted genes such as p57, might play a role in modifying risk of persistent GTD.

Diagnosis of Hydatidiform Moles by Polymorphic Deletion Probe Fluorescence in Situ Hybridization

Because products of conception often contain maternal and villous tissues, the determination of maternal and villous genotypes based on genetic polymorphisms can help discern maternal and paternal chromosomal contribution and aid in the diagnosis of hydatidiform moles. Polymorphic deletion probe (PDP) fluorescence in situ hybridization (FISH) probes based on copy number variants are highly polymorphic and allow in situ determination of genetic identity. By using three informative PDPs on chromosomes 2p, 4q, and 8p, we compared maternal with villous genotypes and determined the ploidy of villous tissue. PDP FISH was performed on 13 complete moles, 13 partial moles, 13 nonmolar abortions, and an equivocal hydropic abortion. PDP FISH permitted definitive diagnosis of complete moles in five of 13 cases for which maternal and villous genotypes were mutually exclusive. A complete mole was highly suspected when all three PDP loci showed homozygous villous genotypes. The diagnosis of a complete mole by PDP FISH yielded a theoretical test sensitivity of 87.5%, specificity of 91.8%, an observed test sensitivity of 100%, and specificity of 92.3%. Triploidy was observed in all partial moles, in which diandric triploidy was confirmed in six cases. In the equivocal hydropic abortion, PDP FISH combined with p57 immunofluorescence revealed placental androgenetic/biparental mosaicism. PDP FISH can be used in clinical practice and research studies to subclassify hydatidiform moles and evaluate unusual products of conception.