Genetic Disorders and the Fetus. Группа авторов
changes on ultrasound. Usually not grossly or histologically cystic. May show irregularities of trophoblast epithelium. Fetal growth restriction is common. Fetal anomalies may occur in a subset of cases
Complete hydatidiform mole
CHMs are generally the result of androgenetic (paternal only) development and are observed in about 1/800 human pregnancies.127 Diagnosis is characterized by cystic, edematous chorionic villi (fluid accumulation within the placental villi), trophoblastic hyperplasia (overgrowth of the outer layer of the villi), and, generally, absent amnion, chorion, and fetal development (Figure 4.1a, b). Pathological diagnosis is aided by absence of p57KIP2 staining, a protein expressed only from the maternal allele of the CDKN1C gene and, consequently, negative in CHMs. Most CHMs are diandric diploid with genomic contribution from either one or two sperm.128 The abnormal development of embryos lacking a maternal genome can be explained by loss of expression of developmentally important paternally imprinted (maternally expressed) genes.129, 130 A small portion of CHMs are biparental in origin and these are more likely to be recurrent and familial. Maternal homozygous and compound mutations in NLRP7 have been detected in the majority of women experiencing recurrent biparental hydatidiform moles.131, 132 Mutations in c6orf221 have also been reported.133 Biparental moles generally exhibit abnormal maternal imprints, although the extent of this and loci involved are variable.134–136
Figure 4.1 (a) Complete hydatidiform mole (CHM) gross – cystic villi; (b) CHM microscopic – cystic villi with cisterns, circumferential trophoblastic hyperplasia, stromal karyorrhexis; (c) partial hydatidiform mole (PHM) gross – cystic villi; (d) PHM microscopic – normal and cystic villi, focal trophoblastic hyperplasia, fetal vessels, and blood cells present; (e) placental mesenchymal dysplasia (PMD) gross – abnormal extension of vessels and Wharton's jelly into placenta parenchyma; (f) PMD micro – large, myxomatous stem villi with abnormal and dilated vessels.
Partial hydatidiform mole
PHM is the result of triploidy, but is present in only a subset of diandric triploid pregnancies.137 PHMs show some phenotypic overlap with CHMs on ultrasound assessment, but pathologically, exhibit a range of villi from normal to cystic villi with focal trophoblastic hyperplasia (Figure 4.1c, d).138 Staining for p57 is preserved (normal). Although triploidy most commonly ends in miscarriage in the first trimester, PHM may be detected in a second‐trimester ultrasound where it presents as cystic placenta in association with an abnormally developed fetus, and may be associated with abnormal serum analytes (high hCG and α‐fetoprotein)139, 140 and PE.141 Diagnosis may be confirmed with chromosome testing by CVS or amniocentesis.
Placental mesenchymal dysplasia
A rarer, but important, placental phenotype recognizable prenatally, is that of PMD (Figure 4.1e, f). This can be misdiagnosed on ultrasound as a PHM and has been referred to as a “pseudo partial mole.”142–146 Placentas with PMD may appear on ultrasound as unusually large and thick with multiple echo‐poor regions representing edematous stem villi and possibly enlarged blood vessels. Remarkably, PMD can often coexist with a completely normal fetus; however, there is increased risk of FGR and fetal or neonatal death. PMD can be distinguished from a partial or complete mole on pathology examination as there is no trophoblast hyperplasia. PMD shows abnormal vessels in enlarged and myxomatous appearing stem villi. There may be some edematous chorionic villi but this is not usually a prominent feature. Whereas partial moles are triploid, PMD generally have a normal diploid karyotype, but molecularly can be shown to have a chimeric mix of androgenetic and biparental cells.147–149 In some cases, a CHM can grow closely adjacent to a twin placenta that is normal diploid and mimic the appearance of PMD on ultrasound.
Diagnosis of PMD has been associated with fetuses exhibiting features of BWS, including omphalocele, macroglossia, and visceromegaly.143, 145, 146 PMD associated with BWS generally results from mosaicism for maternal deletion, paternal duplication, or paternal UPD of chromosome 11p15.5, but appears to be a relatively rare finding among BWS cases as a whole.150 Additionally, androgenetic chimerism (often reported as mosaic “complete paternal uniparental disomy”) has been associated with BWS.151, 152 In such cases, phenotype can be variable and there may be features of multiple imprinting disorders.153
A frequent feature in the fetus from pregnancies affected by PMD, even in the absence of other fetal involvement, is the presence of hemangiomas. These may be benign skin hemangiomas, but in some cases hepatic hemangiomas are identified, as are hepatic mesenchymal hamartomas. These have been observed to be present in utero and may grow to an extent as to be life‐threatening to the fetus.148, 154, 155 Androgenetic chimerism can be found in some cases of liver hemangioma or hepatic mesenchymal hamartoma even in the absence of overt signs of PMD.156 Other cases of PMD have been reported to involve rearrangements of chromosome 19, which contains the C19MC imprinted, placenta‐specific microRNA cluster.157 Infantile hemangiomas may derive from placental mesenchymal cells that have invaded the fetus through the vascular system.158–160
DNA methylation studies in the placenta and their clinical application
Epigenetic studies, such as analysis of genome‐wide DNA methylation, have aided our understanding of placental development and its unique nature.161, 162 Relative to somatic cells, the placenta exhibits global hypo‐methylation, although this is not distributed randomly but mainly in distinct blocks along the chromosomes referred to as “partially methylated domains.”161 There is striking hypo‐methylation of some repetitive elements and the inactive X chromosome promoters in females, whereas average methylation at autosomal gene promoters does not differ.163, 164 The distinct methylation of placental cells from somatic cells, such as blood, provides a means of distinguishing placental (fetal) from maternal cell‐free DNA in maternal blood for NIPT.
DNA methylation profiling can be used to characterize placental pathologies. For example, placentas associated with early‐onset PE exhibit widespread changes in DNA methylation.98, 165–169 A subset of these changes overlap sites altered in syncytial trophoblast differentiation and hypoxia exposure;165 however, the relationship of the DNA methylation changes to the observed pathology is likely complex. Systematic changes in DNA methylation throughout gestation allow for methylation to be used as a gestational age “clock”.170 While this clock is largely robust to placental pathology, placentas associated with PE show evidence of acceleration