Mutations in NLRP7 and KHDC3L Confer a Complete Hydatidiform Mole Phenotype on Digynic Triploid Conceptions

Authors

  • Masoumeh Fallahian,

    1. Department of Obstetrics and Gynecology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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  • Neil J. Sebire,

    1. Trophboblastic Tumour Screening and Treatment Centre, Department of Oncology, Imperial College London, Charing Cross Campus, London, United Kingdom
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  • Philip M. Savage,

    1. Trophboblastic Tumour Screening and Treatment Centre, Department of Oncology, Imperial College London, Charing Cross Campus, London, United Kingdom
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  • Michael J. Seckl,

    1. Trophboblastic Tumour Screening and Treatment Centre, Department of Oncology, Imperial College London, Charing Cross Campus, London, United Kingdom
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  • Rosemary A. Fisher

    Corresponding author
    1. Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, London, United Kingdom
    • Trophboblastic Tumour Screening and Treatment Centre, Department of Oncology, Imperial College London, Charing Cross Campus, London, United Kingdom
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  • Contract grant sponsors: Hammersmith Hospitals Trustees’ Research Committee (60312); Cancer Treatment and Research Trust (p11407).

  • Communicated by Graham R. Taylor

Correspondence to: Rosemary A Fisher, FRCPath, Room 3009, Institute of Reproductive and Developmental Biology, Hammersmith Campus, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom. E-mail: r.fisher@imperial.ac.uk

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 p57KIP2 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.

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