Abstract
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.
Highlights
Placental mesenchymal dysplasia (PMD) is a rare clinical condition often misdiagnosed as partial hydatidiform mole (PHM) [1,2,3,4,5]
Both PMD and PHM are characterized by placentomegaly and grapelike cystic structures intermingled with morphologically normal placental tissues on gross appearance [6]
The major difference between PMD and PHM is that PMD affects only the mesenchymal lineage of the placenta and lacks the typical trophoblast hyperplasia shown in molar pregnancies [6]
Summary
Placental mesenchymal dysplasia (PMD) is a rare clinical condition often misdiagnosed as partial hydatidiform mole (PHM) [1,2,3,4,5]. Up to one-third of PMD cases are associated with Beckwith Wiedemann syndrome (BWS), which is identified as an imprinting disorder [13] These findings imply that the deregulation of certain imprinted gene expression may be part of the etiology of the PMD phenotype. Genetic analysis showed that both placental tissues and the living fetus contained a biparental diploid (46, XX) karyotype without detectable androgenetic mosaicism This pregnancy leads to a grossly healthy child except for liver hamartoma, which is a characteristic complication found in PMD-associated babies [20]. We would like to use this reported PMD case with PHM-associated characteristics to test the hypothesis that PMD and molar pregnancy may represent a spectrum of imprinting deregulation that can result in overlapping phenotypes with different levels of severity. Whether PMD and molar pregnancies represent a spectrum of various placental mesenchymal/trophoblast diseases will be discussed
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