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A Genetic Review of Complete and Partial Hydatidiform Moles and Nonmolar Triploidy

1992; Elsevier BV; Volume: 67; Issue: 8 Linguagem: Inglês

10.1016/s0025-6196(12)60805-2

1942-5546

Noralane M. Lindor, Judith A. Ney, Thomas A. Gaffey, Robert B. Jenkins, Stephen N. Thibodeau, Gordon W. Dewald,

Genetic Syndromes and Imprinting

Complete and partial hydatidiform moles are genetically aberrant conceptuses. Usually, complete moles have 46 chromosomes (diploidy), all of paternal origin. Most partial moles have 69 chromosomes (triploidy), including 23 of maternal origin and 46 of paternal origin. Triploidy that involves 23 paternal chromosomes and 46 maternal chromosomes is not associated with molar placental changes and, rarely, can result in a live-born infant with multiple birth defects. Herein we review the mechanisms of fertilization that may produce these unbalanced sets of parental chromosomes and the role of genomic imprinting as a possible explanation for these clinical conditions. Complete and partial hydatidiform moles are genetically aberrant conceptuses. Usually, complete moles have 46 chromosomes (diploidy), all of paternal origin. Most partial moles have 69 chromosomes (triploidy), including 23 of maternal origin and 46 of paternal origin. Triploidy that involves 23 paternal chromosomes and 46 maternal chromosomes is not associated with molar placental changes and, rarely, can result in a live-born infant with multiple birth defects. Herein we review the mechanisms of fertilization that may produce these unbalanced sets of parental chromosomes and the role of genomic imprinting as a possible explanation for these clinical conditions. Complete and partial hydatidiform moles are aberrant conceptuses that are classified as gestational trophoblastic neoplasms and are distinguishable from each other on the basis of histologic characteristics, cytogenetic origin, and clinical features. The distinction between complete and partial moles is important because they have different potentials for clinical persistence, malignant transformation, recurrence, and presence of a fetus. Triploid fetuses and newborns that are not associated with molar placentas arise by cytogenetic mechanisms similar to those that produce triploid partial molar pregnancies. Genetic imprinting may account for the different phenotype noted between triploid partial hydatidiform moles and triploid nonmolar conceptuses. In this report, we review the genetics of hydatidiform moles and triploid fetuses. Molar pregnancies are characterized by fluid-filled cysts that range from 1 to 3 cm in diameter and are derived from chorionic villi of the placenta. The trophoblastic tissue of molar pregnancies may "burrow" into the uterus—hence the name, hydatidiform mole. Molar pregnancies are classified as either partial or complete. Partial molar pregnancies have a normal to slightly larger placental volume than do normal pregnancies and have a mixture of normal-appearing villi and hydropic villi. Microscopically, wide distention of the core of many villi creates a central "cistern." The presence of cisterns may help distinguish partial moles from hydropic degeneration of normal placental villi. Trophoblastic hyperplasia is often present around many of the fluid-filled villi, and the villi often appear to have "scalloped" borders. In partial molar pregnancies, a fetus is always present in the early embryonic stages, but this fetal tissue may or may not survive up to the time of diagnosis. Complete molar pregnancies are characterized by a large placental volume and diffuse hydrops that involves almost all the villi and causes the placenta to resemble a cluster of grapes. Cisterns form in the villi. Trophoblastic proliferation is increased and disorganized. A fetus is not associated with complete moles at any stage of pregnancy.1Rosai J Seventh edition. Ackerman's Surgical Pathology. Vol 2. CV Mosby Company, St. Louis1989: 1179-1185Google Scholar Even experienced pathologists have difficulty distinguishing some partial moles from complete moles because the degree of trophoblastic proliferation and the proportion of hydropic villi vary in both conditions. Furthermore, because hydropic degeneration occurs in 15 to 40% of nonmolar spontaneous abortions,2Abaci F Aterman K Changes of the placenta and embryo in early spontaneous abortion.Am J Obstet Gynecol. 1968; 102: 252-263PubMed Scopus (14) Google Scholar some of these conceptuses can be confused with partial hydatidiform moles. Concordance among pathologists for the diagnosis of molar types ranges from 55 to 75%.3Javey H Borazjani G Behmard S Langley FA Discrepancies in the histological diagnosis of hydatidiform mole.Br J Obstet Gynaecol. 1979; 86: 480-483Crossref PubMed Scopus (45) Google Scholar, 4Conran RM Hitchcock CL Griffin JL Popek EJ Hydatidiform moles: a clinicopathologic study (abstract).Am J Clin Pathol. 1991; 96: 408Google Scholar, 5Messerli ML Parmley T Woodruff JD Lilienfeld AM Bevilacqua L Rosenshein NB Inter- and intra-pathologist variability in the diagnosis of gestational trophoblastic neoplasia.Obstet Gynecol. 1987; 69: 622-626PubMed Google Scholar We are unaware of any reliable method for accurately distinguishing complete from partial hydatidiform moles on the basis of morphologic characteristics. The results of genetic studies of the origin of complete and partial moles may eliminate this diagnostic dilemma. An early molar pregnancy may be clinically indistinguishable from a normal pregnancy. The hydatidiform mole produces β-hurhan chorionic gonadotropin, a hormone that causes positive results of a pregnancy test and symptoms that are common in early normal pregnancies. In molar pregnancies, the β-human chorionic gonadotropin level continues to increase after the 14th week of gestation and can become extraordinarily high. The outcome may be related to the severe nausea and vomiting that are sometimes experienced by patients with molar pregnancies. The high β-human chorionic gonadotropin value and abnormal placentation in molar pregnancies may explain why a molar pregnancy is virtually the only medical situation in which preeclampsia occurs before 20 weeks of gestation. The most common initial manifestation of molar pregnancy is vaginal bleeding. The extent of bleeding varies among patients and ranges from scant to profuse. Because vaginal bleeding is a nonspecific abnormality in early pregnancy, the diagnosis of hydatidiform mole is not always suspected. The results of one study of women dismissed from a hospital after partial mole had been diagnosed indicated that the diagnosis on admission was spontaneous abortion in 49% of cases, missed abortion in another 43%, and partial mole in only 8%.6Berkowitz RS Goldstein DP Bernstein MR Natural history of partial molar pregnancy.Obstet Gynecol. 1985; 66: 677-681PubMed Google Scholar On admission, these study patients were correctly diagnosed as carrying a complete mole in only 48% of the cases. Routine use of ultrasonography for patients with first-trimester bleeding may improve the early diagnosis of many hydatidiform moles. Ultrasonography of complete moles usually discloses a "snowstorm" pattern of echoes arising from the fluid-filled cysts and the absence of a fetus. For partial moles, ultrasonography may identify only about 32% of the cases.6Berkowitz RS Goldstein DP Bernstein MR Natural history of partial molar pregnancy.Obstet Gynecol. 1985; 66: 677-681PubMed Google Scholar By using a combination of β-human chorionic gonadotropin levels and ultrasonography, diagnostic sensitivity for gestational trophoblastic disease may be improved.7Romero R Horgan JG Kohom EI Kadar N Taylor KJW Hobbins JC New criteria for the diagnosis of gestational trophoblastic disease.Obstet Gynecol. 1985; 66: 553-558PubMed Google Scholar Specific criteria for ultrasonographic diagnosis of partial moles have recently been proposed.8Fine C Bundy AL Berkowitz RS Boswell SB Berezin AF Doubilet PM Sonographic diagnosis of partial hydatidiform mole.Obstet Gynecol. 1989; 73: 414-418PubMed Google Scholar Unfortunately, the diagnosis of partial moles is often not considered until curettage specimens have been examined histologically. Patients with either complete or partial hydatidiform moles generally undergo vacuum curettage and clinical follow-up by serial monitoring of the β-human chorionic gonadotropin levels. These levels should return to normal 2 to 3 months after the procedure. Hydatidiform moles regressed spontaneously in 81% of 738 patients after primary uterine evacuation.9Lurain JR Brewer JI Torok EE Halpern B Natural history of hydatidiform mole after primary evacuation.Am J Obstet Gynecol. 1983; 145: 591-595PubMed Scopus (140) Google Scholar Nevertheless, 5 to 10% of patients with partial moles6Berkowitz RS Goldstein DP Bernstein MR Natural history of partial molar pregnancy.Obstet Gynecol. 1985; 66: 677-681PubMed Google Scholar, 10Rice LW Berkowitz RS Lage JM Goldstein DP Bernstein MR Persistent gestational trophoblastic tumor after partial hydatidiform mole.Gynecol Oncol. 1990; 36: 358-362Crossref PubMed Scopus (82) Google Scholar and 15 to 25% of patients with complete moles9Lurain JR Brewer JI Torok EE Halpern B Natural history of hydatidiform mole after primary evacuation.Am J Obstet Gynecol. 1983; 145: 591-595PubMed Scopus (140) Google Scholar had persistently increased P-human chorionic gonadotropin values because of residual trophoblastic tissue in pelvic or extrapelvic sites. Molar tissue can invade uterine blood vessels and be transported hematogenously to distant sites, such as the brain, lung, liver, and kidneys. For persistent hydatidiform moles, a combination of chemotherapy and surgical intervention will usually yield excellent results. Gestational choriocarcinoma (trophoblastic malignant disease) is preceded by a complete hydatidiform mole in about 50% of cases. In the other cases, choriocarcinoma is preceded by normal gestations, abortions, or ectopic pregnancies. Investigators have reported that 15 to 20% of complete moles undergo malignant degeneration to choriocarcinoma.11Soper JT Hammond CB Gestational trophoblastic neoplasms.in: Scott JR DiSaia PJ Hammond CB Spellacy WN Danforth's Obstetrics and Gynecology. Sixth edition. JB Lippincott Company, Philadelphia1990: 1141-1155Google Scholar A recent study of 153 women treated for complete hydatidiform mole suggested that those percentages may be too high, inasmuch as no histologically proven choriocarcinoma developed in this group.12Genest DR Laborde O Berkowitz RS Goldstein DP Bernstein MR Lage J A clinicopathologic study of 153 cases of complete hydatidiform mole (1980–1990): histologic grade lacks prognostic significance.Obstet Gynecol. 1991; 78: 402-409PubMed Google Scholar Although some controversy still exists about whether partial moles may develop choriocarcinoma, a recent study reported rare instances of such development.13Bagshawe KD Lawler SD Paradinas FJ Dent J Brown P Boxer GM Gestational trophoblastic tumours following initial diagnosis of partial hydatidiform mole.Lancet. 1990; 335: 1074-1076Abstract PubMed Scopus (131) Google Scholar Aggressive chemotherapy and surgical treatment resulted in a 5-year survival rate of almost 100% for patients with gestational choriocarcinoma.11Soper JT Hammond CB Gestational trophoblastic neoplasms.in: Scott JR DiSaia PJ Hammond CB Spellacy WN Danforth's Obstetrics and Gynecology. Sixth edition. JB Lippincott Company, Philadelphia1990: 1141-1155Google Scholar Complete or partial hydatidiform moles occur in 1 in every 1,500 pregnancies in the United States. Partial moles may constitute up to 50% of these cases.14Czernobilsky B Barash A Lancet M Partial moles: a clinicopathologic study of 25 cases.Obstet Gynecol. 1982; 59: 75-77PubMed Google Scholar, 15Lage JM Mark SD Roberts DJ Goldstein DP Bernstein MR Berkowitz RS A flow cytometric study of 137 fresh hydropic placentas: correlation between types of hydatidiform moles and nuclear DNA ploidy.Obstet Gynecol. 1992; 79: 403-410Crossref PubMed Scopus (125) Google Scholar For unknown reasons, complete hydatidiform moles are more frequent in older than in younger pregnant patients. Between 35 and 39 years of age, the relative risk is 2.5%; after age 40 years, the relative risk is 9.8%.16Graham IH Fajardo AM Richards RL Epidemiological study of complete and partial hydatidiform mole in Abu Dhabi: influence of maternal age and ethnic group.J Clin Pathol. 1990; 43: 661-664Crossref PubMed Scopus (16) Google Scholar No apparent age-related risk has been reported for partial moles.16Graham IH Fajardo AM Richards RL Epidemiological study of complete and partial hydatidiform mole in Abu Dhabi: influence of maternal age and ethnic group.J Clin Pathol. 1990; 43: 661-664Crossref PubMed Scopus (16) Google Scholar The possible effect of paternal age or a history of normal pregnancy has not yet been established.17Bracken MB Incidence and aetiology of hydatidiform mole: an epidemiological review.Br J Obstet Gynaecol. 1987; 94: 1123-1135Crossref PubMed Scopus (102) Google Scholar In comparison with the United States, the incidence of hydatidiform moles is 5 to 15 times higher in eastern Asia, Japan, Indonesia, and Iran.18Ishizuka N Studies on trophoblastic neoplasia.GANN Monogr Cancer Res. 1976; 18: 203-216Google Scholar In the continental United States, the Rocky Mountain states have a twofold to sixfold incidence of moles in comparison with regions on the eastern seaboard and lower Mississippi valley.19Hayashi K Bracken MB Freeman Jr, DH Hellenbrand K Hydatidiform mole in the United States (1970–1977): a statistical and theoretical analysis.Am J Epidemiol. 1982; 115: 67-77Crossref PubMed Scopus (72) Google Scholar The reason for these geographic differences is unknown, but they could be due to variations in genetics, race, diet, or exposure to harmful environmental agents. Complete moles have a diploid karyotype, whereas partial moles have a polyploid karyotype. Among complete moles, 85% are 46,XX and 15% are 46,XY. Studies of cytogenetic and molecular polymorphisms show that complete moles lack a maternal genetic contribution in at least 80% of cases.20Kovacs BW Shahbahrami B Tast DE Curtin JP Molecular genetic analysis of complete hydatidiform moles.Cancer Genet Cytogenet. 1991; 54: 143-152Abstract Full Text PDF PubMed Scopus (70) Google Scholar Thus, in most complete moles, all chromosomes are of paternal origin, a condition known as diandric diploidy (Fig. 1). Most partial moles have a triploid karyotype: 69,XXX; 69,XXY; or 69,XYY (Fig. 2). Tetraploidy among partial moles has been described occasionally.21Surti U Szulman AE Wagner K Leppert M O'Brien SJ Tetraploid partial hydatidiform moles: two cases with a triple paternal contribution and a 92,XXXY karyotype.Hum Genet. 1986; 72: 15-21Crossref PubMed Scopus (69) Google Scholar, 22Lage JM Weinberg DS Yavner DL Bieber FR The biology of tetraploid hydatidiform moles: histopathology, cytogenetics, and flow cytometry.Hum Pathol. 1989; 20: 419-425Abstract Full Text PDF PubMed Scopus (51) Google Scholar Studies of genetic polymorphisms indicate that about 85% of triploid partial moles contain one haploid maternal set of chromosomes and two haploid paternal sets of chromosomes.23Szulman AE Surti U The clinicopathologic profile of the partial hydatidiform mole.Obstet Gynecol. 1982; 59: 597-602PubMed Google Scholar This condition is known as diandric triploidy (paternally derived triploidy). Among triploid abortuses, 15% have two haploid maternal complements and one haploid paternal complement. This condition is referred to as digynic triploidy (maternally derived triploidy). Unlike diandric triploidy, no molar changes are associated with the placenta in digynic triploidy. Triploidy occurs in 1.2% of clinically recognizable pregnancies and in approximately 6% of first-trimester spontaneous abortions. After monosomy X (45,X), triploidy is the second most common specific chromosomal aberration in first-trimester spontaneous abortions.24Jacobs PA Szulman AE Funkhouser J Matsuura JS Wilson CC Human triploidy: relationship between parental origin of the additional haploid complement and development of partial hydatidiform mole.Ann Hum Genet. 1982; 46: 223-231Crossref PubMed Scopus (299) Google Scholar, 25Kajii T Ohama K Androgenetic origin of hydatidiform mole.Nature. 1977; 268: 633-634Crossref PubMed Scopus (592) Google Scholar, 26Schinzel A Catalogue of Unbalanced Chromosome Aberrations in Man. Walter de Gruyter & Company, Berlin1983: 747-751Google Scholar, 27Kelly TE Clinical Genetics and Genetic Counseling. Second edition. Year Book Medical Publishers, Chicago1986: 81-84Google Scholar Triploidy can arise by at least three mechanisms. (1) A haploid egg may be fertilized by two haploid sperm and result in diandric triploidy (69,XXX; 69,XXY; or 69,XYY). (2) A haploid egg may be fertilized by a diploid sperm to result in diandric triploidy (69,XXX or 69,XYY). (3) The fusion of a haploid egg, a haploid polar body, and a haploid sperm can result in digynic triploidy (69,XXX or 69,XXY). The estimated ratio of sex chromosome complements among triploid conceptions is 60% for 69,XXY; 37% for 69,XXX; and 3% for 69,XYY.24Jacobs PA Szulman AE Funkhouser J Matsuura JS Wilson CC Human triploidy: relationship between parental origin of the additional haploid complement and development of partial hydatidiform mole.Ann Hum Genet. 1982; 46: 223-231Crossref PubMed Scopus (299) Google Scholar In complete hydatidiform moles, diandric diploidy arises by cytogenetic mechanisms that are analogous to the origin of triploidy with one important difference—no chromosomes are contributed by the woman in whom the mole implants. Diandric diploidy can originate by at least two mechanisms. 1.An anuclear (empty) egg can be fertilized by a haploid sperm, after which endoreduplication of the male pronucleus occurs in the zygote. Endoreduplication is a process of DNA replication that occurs without cell division and doubles the number of chromosomes. Studies of chromosome polymorphisms indicate that approximately 75% of complete moles arise by this mechanism.28Fisher RA Povey S Jeffreys AJ Martin CA Patel I Lawler SD Frequency of heterozygous complete hydatidiform moles, estimated by locus-specific minisatellite and Y chromosome-specific probes.Hum Genet. 1989; 82: 259-263Crossref PubMed Scopus (61) Google Scholar Hydatidiform moles that arise in this manner are termed "homozygous" complete moles. Evidence suggests that only 46,XX conceptuses survive, perhaps because 46,YY is a nonviable karyotype.2.An anuclear egg fertilized by two haploid sperm can result in diandric diploidy—either 46,XX or 46,XY. This dispermic mechanism, which is estimated to occur in 25% of complete moles, produces a condition termed "heterozygous" complete moles. When physicians suspect a molar pregnancy, cytogenetic studies can be particularly useful in distinguishing diploid complete moles from triploid pregnancies. Furthermore, the results of one study suggest that a greater malignant potential may be associated with heterozygous complete moles than with homozygous complete moles.29Wake N Seki T Fujita H Okubo H Sakai K Okuyama K Hayashi H Shiina Y Sato H Kuroda M Ichinoe K Malignant potential of homozygous and heterozygous complete moles.Cancer Res. 1984; 44: 1226-1230PubMed Google Scholar This observation, however, was not confirmed in a recent study by Lawler and associates.30Lawler SD Fisher RA Dent J A prospective genetic study of complete and partial hydatidiform moles.Am J Obstet Gynecol. 1991; 164: 1270-1277Abstract Full Text PDF PubMed Scopus (153) Google Scholar When cytogenetic studies are done on diploid molar pregnancies, clinicians could request that chromosome polymorphisms be analyzed. If the polymorphisms of homologues are identical, the evidence is strong that the conception is a homozygous complete mole (Fig. 1). If the polymorphisms differ, the conception is most likely a heterozygous complete mole. Molecular DNA "fingerprinting" techniques can also be used to establish the parental origin of chromosomes and to determine whether the mole is homozygous or heterozygous (Fig. 3). A haploid egg can undergo endoreduplication or retain an extra haploid set of chromosomes and thus produce a digynic diploid conceptus. This mechanism results in parthenogenesis and has been proposed for the origin of some cases of benign ovarian teratomas.31Linder D McCaw BK Hecht F Parthenogenic origin of benign ovarian teratomas.N Engl J Med. 1975; 292: 63-66Crossref PubMed Scopus (300) Google Scholar, 32Deka R Chakravarti A Surti U Hauselman E Reefer J Majumder PP Ferrell RE Genetics and biology of human ovarian teratomas. II. Molecular analysis of origin of nondisjunction and gene-centromere mapping of chromosome 1 markers.Am J Hum Genet. 1990; 47: 644-655PubMed Google Scholar Digynic diploidy does not seem to have a role in the formation of hydatidiform moles. A few sporadic cases of complete hydatidiform moles with both a maternal and a paternal set of chromosomes have been described. Two recent studies in which molecular techniques were used indicated that up to 20% of complete moles may contain both maternal and paternal DNA.20Kovacs BW Shahbahrami B Tast DE Curtin JP Molecular genetic analysis of complete hydatidiform moles.Cancer Genet Cytogenet. 1991; 54: 143-152Abstract Full Text PDF PubMed Scopus (70) Google Scholar, 33Ko T-M Hsieh C-Y Ho H-N Hsieh F-J Lee T-Y Restriction fragment length polymorphism analysis to study the genetic origin of complete hydatidiform mole.Am J Obstet Gynecol. 1991; 164: 901-906Abstract Full Text PDF PubMed Scopus (23) Google Scholar Several theories have been proposed to explain these exceptional cases of complete moles. Some such cases may involve only certain paternal chromosomes. Other cases may involve erroneous results because of interference from unsuspected contamination of the specimen by maternal cells. Because of an erroneous diagnosis, some cases may not be moles. Other hypotheses involve novel mechanisms that cause molar placental changes and twin gestations. The histologic characteristics of partial and complete moles may seem to be a continuum in a disease process; however, these two types of moles are genetically dissimilar. Furthermore, triploid or tetraploid partial moles do not evolve into diploid complete moles. The determination of the ploidy status of a mole has both diagnostic and prognostic value. Occasionally, diploid complete moles progress to choriocarcinoma. Triploid partial moles rarely progress to a malignant lesion;13Bagshawe KD Lawler SD Paradinas FJ Dent J Brown P Boxer GM Gestational trophoblastic tumours following initial diagnosis of partial hydatidiform mole.Lancet. 1990; 335: 1074-1076Abstract PubMed Scopus (131) Google Scholar however, 5 to 10% become persistent,6Berkowitz RS Goldstein DP Bernstein MR Natural history of partial molar pregnancy.Obstet Gynecol. 1985; 66: 677-681PubMed Google Scholar, 10Rice LW Berkowitz RS Lage JM Goldstein DP Bernstein MR Persistent gestational trophoblastic tumor after partial hydatidiform mole.Gynecol Oncol. 1990; 36: 358-362Crossref PubMed Scopus (82) Google Scholar and chemotherapy is necessary. The prognosis for patients with tetraploid moles is unknown. The risk of recurrence of hydatidiform moles is reportedly 4 to 5 times greater in patients who have a history of diploid complete hydatidiform mole than in those without such a history. The risk of recurrence of triploid partial hydatidiform moles is unknown. Flow cytometry can be used to assess the ploidy status of placentas and other tissues by determining the DNA content of cells.34Lage JM Berkowitz RS Rice LW Goldstein DP Bernstein MR Weinberg DS Flow cytometric analysis of DNA content in partial hydatidiform moles with persistent gestational trophoblastic tumor.Obstet Gynecol. 1991; 77: 111-115PubMed Google Scholar This method can be used in retrospective investigations because it can be performed on paraffin-embedded specimens. Flow cytometry may also help pathologists distinguish triploid partial moles from those nonmolar placentas that have hydropic degeneration of chorionic villi. Traditionally, cytogenetic studies have been used for determining the ploidy level in molar pregnancies. For these studies, cell cultures are usually necessary to produce mitotic cells for chromosome analysis. Chromosome polymorphisms can also be analyzed by routine cytogenetic studies, and the resultant information can be used to determine whether a complete mole has a homozygous or heterozygous origin. Additionally, cytogenetic studies can identify the occasional conceptus that has a familial structural abnormality or other chromosome abnormality. Fluorescent in situ hybridization with use of chromosome-specific DNA probes is a new cytogenetic technique that can establish the ploidy status in suspected molar pregnancies (Fig. 4). This rapid and inexpensive method can determine the chromosome number of cells, even in nondividing interphase cells; however, it is not yet available in many cytogenetic laboratories. Retrospective diagnosis based on paraffin-embedded specimens is also possible with this technology. Diandric (paternally derived) and digynic (maternally derived) triploidy are associated with different clinical features (Table 1). The mean duration of trophoblastic viability is 122 days in diandric triploidy in comparison with 74 days in digynic triploidy.24Jacobs PA Szulman AE Funkhouser J Matsuura JS Wilson CC Human triploidy: relationship between parental origin of the additional haploid complement and development of partial hydatidiform mole.Ann Hum Genet. 1982; 46: 223-231Crossref PubMed Scopus (299) Google Scholar The placenta is larger in diandric triploidy than in digynic triploidy. A fetus may be present in triploid conceptions of either diandric or digynic origin, but no diandric triploid fetus has been reported to survive to term. Although the placenta in digynic triploidy is small, some triploid live-born fetuses also have small placentas. Studies in mice suggest that paternally derived DNA may be particularly essential for extraembryonic growth, whereas certain maternal genes may be more directed at embryonic growth.35Surani MAH Barton SC Norris ML Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis.Nature. 1984; 308: 548-550Crossref PubMed Scopus (1035) Google Scholar If these factors are also true for humans, some of the phenotypic differences among human triploid conceptions may be explained (Table 1).Table 1Comparison of Major Features of Diandric (Paternally Derived) and Digynic (Maternally Derived) TriploidyFeatureDiandric triploidyDigynic triploidySex chromosomesXXY, XXX, or XYYXXY or XXXPartial moleAlmost always*Two tetraploid moles with three paternal sets of chromosomes have been reported,21 as well as two other tetraploid partial moles.22Almost neverComplete moleNoNoMean trophoblastic viability122 days74 daysFetus presentSometimesSometimesFetal viabilityNever to termOccasionally to termDegenerates to choriocarcinomaAlmost neverNoOrigin of triploid conception85%15%* Two tetraploid moles with three paternal sets of chromosomes have been reported,21Surti U Szulman AE Wagner K Leppert M O'Brien SJ Tetraploid partial hydatidiform moles: two cases with a triple paternal contribution and a 92,XXXY karyotype.Hum Genet. 1986; 72: 15-21Crossref PubMed Scopus (69) Google Scholar as well as two other tetraploid partial moles.22Lage JM Weinberg DS Yavner DL Bieber FR The biology of tetraploid hydatidiform moles: histopathology, cytogenetics, and flow cytometry.Hum Pathol. 1989; 20: 419-425Abstract Full Text PDF PubMed Scopus (51) Google Scholar Open table in a new tab Triploidy of both diandric and digynic derivation may produce a fetus. In some cases, at the time of diagnosis or miscarriage, only fetal remnants or blood cells may be evident. Digynic triploidy (69,XXX or 69,XXY) may result in a fetus with a large head and growth retardation. Diandric triploid fetuses (69,XXY; 69,XXX; or 69,XYY) are usually retarded in growth and do not have macrocephaly.36McFadden DE Kalousek DK Two different phenotypes of fetuses with chromosomal triploidy: correlation with parental origin of the extra haploid set.Am J Med Genet. 1991; 38: 535-538Crossref PubMed Scopus (143) Google Scholar Some features common to both diandric and digynic triploid infants include syndactyly (especially of the third and fourth fingers), incomplete ossification of the skull, dysplastic kidneys, and hypoplastic adrenal glands (Fig. 5). In triploid infants, structural defects of the central nervous system, including hydrocephalus, holoprosencephaly, and neural tube defects, are common. Facial clefts, cardiac malformations, ambiguous genitalia, eye anomalies, and hypoplasia of the thyroid gland, thymus, and pancreas have also been described. In fact, a complete listing of reported anomalies would include virtually every organ of the body.25Kajii T Ohama K Androgenetic origin of hydatidiform mole.Nature. 1977; 268: 633-634Crossref PubMed Scopus (592) Google Scholar Only digynic triploid fetuses have survived to term, and these infants have been profoundly mentally retarded. The longest known duration of survival of a triploid fetus is only 2 months.37Fryns JP van de Kerckhove A Goddeeris P van den Berghe H Unusually long survival in a case of full triploidy of maternal origin.Hum Genet. 1977; 38: 147-155Crossref PubMed Scopus (40) Google Scholar In our studies of amniotic fluid for prenatal diagnosis, we have encountered at least three triploid pregnancies. Thus, distinguishing diandric from digynic triploidy in prenatal cytogenetic studies might be important. For such a determination, cytogenetic or molecular genetic polymorphisms of the fetus would have to be compared with tissue specimens from the parents.38Dewald G Haymond MW Spurbeck JL Moore SB Origin of chi46,XX/46,XY chimerism in a human true hermaphrodite.Science. 1980; 207: 321-323Crossref PubMed Scopus (31) Google Scholar Some investigators wonder why triploidy with 23 extra chromosomes is sufficiently compatible with life to be observed among abortuses, whereas a single extra chromosome in trisomic conceptuses is generally lethal. For trisomies, the biologic consequences are believed to result from an imbalance of those genes on the specific chromosomes involved in the aneuploidy. In comparison, triploidy produces an overall balance of genes, albeit three copies of each gene instead of the usual two copies. Perhaps the imbalance of maternal to paternal chromosomes or an inappropriate ratio of autosomes to X chromosomes is the answer. In normal males, the ratio of autosomes to X chromosomes is 2:1. In normal females, one of the X chromosomes becomes inactivated; thus, the ratio of autosomes to active X chromosomes is also 2:1. In triploidy, the number of X chromosomes that inactivate varies among conceptuses.39Weaver DD Gartler SM Boué A Boué JG Evidence for two active X chromosomes in a human XXY triploid.Humangenetik. 1975; 28: 39-42PubMed Google Scholar, 40Junien C Rubinson H Dreyfus JC Meienhofer MC Ravise N Boué J Boué A Gene dosage effect in human triploid fibroblasts.Hum Genet. 1976; 33: 61-66Crossref PubMed Scopus (15) Google Scholar Nevertheless, in a triploid fetus, the same 2:1 ratio of X chromosomes to autosomes that occurs in normal conceptions cannot be achieved (Table 2).Table 2Ratio of Autosomes to Active X Chromosomes in Triploid FetusesX chromosomes inactivatedTriploid karyotypeNone1269,XXX3:33:23:169,XXY3:23:1…69,XYY3:1…… Open table in a new tab At least one nonmosaic tetraploid infant with multiple anomalies has been reported to survive to 15 months.41Shiono H Azumi J Fujiwara M Yamazaki H Kikuchi K Tetraploidy in a 15-month-old girl.Am J Med Genet. 1988; 29: 543-547Crossref PubMed Scopus (25) Google Scholar Thus, in comparison with triploid infants, tetraploid infants may have a longer duration of survival, perhaps because of a balanced ratio of maternal to paternal chromosomes and a more normal ratio of active X chromosomes to autosomes. Why complete moles with a normal 46,XX or 46,XY karyotype do not develop normally is unknown. In addition, why diandric triploidy has an increased placental viability but a decreased fetal development in comparison with digynic triploidy is unknown. Some investigators attribute the nonviability of diploid complete moles and the phenotypic differences between molar and nonmolar triploid conceptuses to genetic imprinting.42Hall JG Genomic imprinting: review and relevance to human diseases.Am J Hum Genet. 1990; 46: 857-873PubMed Google Scholar The concept of genetic imprinting originated from studies of Sciara (gnat)43Crouse HV The controlling element in sex chromosome behavior in Sciara.Genetics. 1960; 45: 1429-1443PubMed Google Scholar and mice35Surani MAH Barton SC Norris ML Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis.Nature. 1984; 308: 548-550Crossref PubMed Scopus (1035) Google Scholar, 44Lyon MF Rastan S Parental source of chromosome imprinting and its relevance for X chromosome inactivation.Differentiation. 1984; 26: 63-67Crossref PubMed Scopus (62) Google Scholar, 45Cattanach BM Kirk M Differential activity of maternally and paternally derived chromosome regions in mice.Nature. 1985; 315: 496-498Crossref PubMed Scopus (515) Google Scholar and provides compelling evidence that genes on homologous chromosomes may function differently on the basis of the parental origin. For example, the same gene mutation may have different phenotypic effects depending on whether the gene was inherited from the mother or the father. The precise genes and the specific mechanisms of gene imprinting associated with molar pregnancies are unknown. Some evidence suggests that genetic imprinting in mammals occurs by selective methylation of DNA during gametogenesis and embryogenesis.46Chaillet JR Vogt TF Beier DR Leder P Parental-specific methylation of an imprinted transgene is established during gametogenesis and progressively changes during embryogenesis.Cell. 1991; 66: 77-83Abstract Full Text PDF PubMed Scopus (191) Google Scholar Thus, the imprinting process does not alter the nucleotide sequence of genes but rather controls the time and degree of gene expression during embryogenesis. The imprinting process seems to be erasable sometime during development in order to permit individuals to imprint their own eggs or sperm on the basis of their own sex and, in turn, affect the next generation. Thus, the imprinting process is not related to the sex of the offspring but rather to the sex of the parent. Apparently, genetic imprinting is necessary for normal gene function, and alteration of this process is associated with several human disorders including the Prader-Willi syndrome, the fragile X syndrome, and congenital myotonic dystrophy.42Hall JG Genomic imprinting: review and relevance to human diseases.Am J Hum Genet. 1990; 46: 857-873PubMed Google Scholar, 44Lyon MF Rastan S Parental source of chromosome imprinting and its relevance for X chromosome inactivation.Differentiation. 1984; 26: 63-67Crossref PubMed Scopus (62) Google Scholar, 46Chaillet JR Vogt TF Beier DR Leder P Parental-specific methylation of an imprinted transgene is established during gametogenesis and progressively changes during embryogenesis.Cell. 1991; 66: 77-83Abstract Full Text PDF PubMed Scopus (191) Google Scholar The evolution of mammalian imprinting may have resulted in the requirement of a genetic contribution from both mother and father to produce phenotypically normal offspring. Imprinting may have a role in modulating the growth of mammalian placental tissue and may prevent the potentially deleterious effects of parthenogenesis, such as homozygosity for lethal genes. Modulation of gene dosage and control of gene dominance may also result from genetic imprinting. The complete and partial hydatidiform moles may provide important genetic models for comparing the effect of maternally and paternally derived chromosomes. Conversely, as more is learned about the process of genetic imprinting in humans, the medical community will be more likely to comprehend the phenomena of molar pregnancies and nonmolar triploidy.