Hydatidiform mole is an aberrant pregnancy with abnormal embryonic development and hydropic placental villi. Common moles are sporadic, not recurrent and affect one in every 1500 pregnancies in Western societies. Approximately, half of common moles are complete and mostly diploid androgenetic, whereas the remaining are partial and mostly triploid diandric. NLRP7 has been found to be responsible for a recurrent form of molar pregnancies. Recently, we showed that patients with NLRP7 mutations have an impaired inflammatory response to various stimuli. To date, molar tissues analyzed from patients with NLRP7 mutations have been found to be diploid and biparental. In this study, we report 10 new non-synonymous variants and one stop codon found in patients and not in controls. We demonstrate the presence of different types of moles, diploid biparental, diploid androgenetic, triploid and tetraploid conceptions, in patients with NLRP7 variants. We document in vitro and in vivo early embryo cleavage abnormalities in three patients. We propose a two-hit mechanism at the origin of androgenetic moles. This mechanism consists of variable degrees of early embryo cleavage abnormalities leading to chaotic mosaic aneuploidies, with haploid, diploid, triploid and tetraploid blastomeres. Surviving embryonic cells that reach implantation are then subject to the maternal immune response. Because of the patients' impaired inflammatory response, androgenetic cells, which are complete allograft, are able to grow and proliferate. In women with normal immune system, chaotic mosaic aneuploidies may also occur during early cleavage, however, androgenetic cells would die after implantation or stay undetected, confined to a small portion of the placenta.
Hydatidiform mole (HM) is a human pregnancy with no embryo but cystic degeneration of chorionic villi. The common form of this condition occurs in 1 in every 1500 pregnancies in western societies and at a higher incidence in some geographic regions and populations. Recurrent moles account for 2% of all molar cases and a few of them occur in more than one family member. By studying a familial form of recurrent moles, a recessive maternal locus responsible for this condition was mapped to 19q13.4 and causative mutations identified. The defective protein, NALP7, is part of the CATERPILLAR protein family with roles in pathogen-induced inflammation and apoptosis. The exact role of NALP7 in the pathophysiology of molar pregnancies is unknown yet. NALP7 could have a role either in oogenesis or in the endometrium during trophoblast invasion and decidualization. In this review, we outlined recent advances in the field of HMs and reviewed the literature in the light of the new data.
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