Mutations inNLRP7 andKHDC3LConfer a Complete Hydatidiform Mole Phenotype on Digynic Triploid Conceptions

Abstract

Digynic triploidy is classically associated with a severely growth restricted fetus and a small nonmolar placenta. However, in genotyping hydatidiform moles as part of clinical practice, we identified two digynic triploid conceptions presenting with histopathological features of classical complete hydatidiform mole (CHM). Both cases occurred in women with a history of previous molar pregnancies and no normal pregnancies. Pathological review and genotyping of other molar pregnancies in these cases showed them to be typical CHM with negative p57(KIP2) immunostaining of the cytotrophoblast cells and villous stroma and to be diploid but biparental, confirming a diagnosis of familial recurrent hydatidiform mole (FRHM). Mutation screening of NLRP7 had identified a homozygous duplication, leading to a truncated protein, in case 1 whereas mutation screening of KHDC3L (C6orf221) in case 2 showed both the proband and her sister to be compound heterozygotes for mutations in KHDC3L. The observation of a single digynic, triploid conception presenting as a CHM in women with FRHM, where other pregnancies are diploid and biparental, supports the hypothesis that the role of both NLRP7 and KHDC3L in pregnancy is in setting and/or maintaining the maternal imprint. Clinically, a diagnosis of FRHM should be considered in women with genetically unusual conceptions that are phenotypically CHM.

Comprehensive genotype–phenotype correlations betweenNLRP7mutations and the balance between embryonic tissue differentiation and trophoblastic proliferation

“…NLRP7 is a major gene for recurrent HMs and is mutated in 48%–80% of patients, depending on patients’ ascertainment criteria and populations 20–23 . KHDC3L is a minor gene for recurrent HMs and is mutated in only 10%–14% of patients with no NLRP7 mutations 19 23 24. To date, approximately 47 different mutations have been reported in patients with two NLRP7 -defective alleles (http://fmf.igh.cnrs.fr/ISSAID/infevers/).…”

“…At the genotypic level, the parental contribution to approximately 80 HMs from patients with two NLRP7 -defective alleles has been analysed so far and were found all diploid biparental21–23 29–39 with the exception of two moles that were found to be triploid digynic23 and triploid diandric 38. Despite their diploid biparental genome, HMs from patients with NLRP7 or KHDC3L mutations lack maternal methylation marks on several imprinted, paternally expressed genes and display gain of methylation marks on some imprinted, maternally expressed genes 21 40–42.…”

Characteristics of hydatidiform moles: analysis of a prospective series with p57 immunohistochemistry and molecular genotyping

“…Some non-molar specimens are digynic triploid conceptions (two maternal and one paternal chromosome complements) but do not exhibit molar features, 39 with the exception of rare examples having the morphology and immunophenotype (p57-negative) of complete hydatidiform moles occurring in patients with familial recurrent hydatidiform mole associated with mutations in NLRP7 (NALP7) or KHDC3L (C6orf221). 40 In addition, some non-molar specimens with cytogenetic abnormalities such as trisomy can simulate partial hydatidiform moles, causing problems in diagnostic reproducibility. 41,42 In 2007, we began a prospective analysis of all potentially molar products of conception specimens encountered on the Gynecologic Pathology Service of The Johns Hopkins Hospital, Baltimore, MD using immunohistochemical analysis of p57 expression and molecular genotyping with short tandem repeat markers.…”

Clinical utility of selective molecular genotyping for diagnosis of partial hydatidiform mole; a retrospective study from a regional trophoblastic disease unit

“…However, triploidy may be missed if most tissue in a section is maternal, tetraploid PHM can be misdiagnosed as CHM, and mosaics, comprising two diploid cell lines, would not be recognised. Neither technique is able to distinguish between diandric and maternally derived triploidy 17. Molecular genotyping is based on DNA polymorphisms and can therefore determine parental contributions to placental tissue even in FFPE material.…”