Pregnancy after oocyte donation in a patient with NLRP7 gene mutations and recurrent molar hydatidiform pregnancies

Abstract

Molar pregnancies are benign trophoblastic diseases associated with a risk of malignant transformation. If aetiology remains mostly unknown, the risk of recurrent molar pregnancy is around 1.5% after one molar pregnancy and around 25% after 2 molar pregnancies. In the later situation, genetic mutations have been described, increasing hugely this risk. In case of mutations, probability to obtain a normal pregnancy is estimated around 1.8%. We report the case of a Caucasian 30-year-old woman whose previous five spontaneous pregnancies had a negative outcome: a spontaneous miscarriage and then 4 complete hydatidiform moles. Genetic testing revealed that the patient carried two heterozygous mutations in the NLRP7 gene (c.2982-2A > G and Y318CfsX7). According to this, counselling was conducted to advocate for oocyte donation in order to obtain a normal pregnancy. This technique enabled a complication-free, singleton pregnancy that resulted in a healthy term live birth of a 2900 g female. Few months after delivery, the patient presented a new complete hydatidiform mole. Women presented with mutations in the NLRP7, KHDC3L or PADI6 genes are unlikely to obtain normal pregnancies, with a major risk of reproductive failure. In such a context, oocyte donation may be the best option. Only 4 normal pregnancies and deliveries have been published in this situation through this technique to our knowledge.

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References

  1. 1.

    Gestational trophoblastic diseases. Report of a WHO Scientific Group. World Health Organ Tech Rep Ser. 1983;692:7–81.

  2. 2.

    Lurain JR. Gestational trophoblastic disease I: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole. Am J Obstet Gynecol. 2010;203:531–9.

    Article  Google Scholar 

  3. 3.

    Bolze P-A, Attia J, Massardier J, Seckl MJ, Massuger L, van Trommel N, et al. Formalised consensus of the European Organisation for Treatment of Trophoblastic Diseases on management of gestational trophoblastic diseases. Eur J Cancer. 2015;51(13):1725–31.

    Article  Google Scholar 

  4. 4.

    Allias F, Bolze P-A, Gaillot-Durand L, Devouassoux-Shisheboran M. Gestational trophoblastic disease. Ann Pathol. 2014;34(6):434–47.

    Article  Google Scholar 

  5. 5.

    Lawler SD, Fisher RA, Dent J. A prospective genetic study of complete and partial hydatidiform moles. Am J Obstet Gynecol. 1991;164(5 Pt 1):1270–7.

    CAS  Article  Google Scholar 

  6. 6.

    Fisher RA, Newlands ES. Gestational trophoblastic disease. Molecular and genetic studies. J Reprod Med. 1998;43(1):87–97.

    CAS  PubMed  Google Scholar 

  7. 7.

    Seckl MJ, Sebire NJ, Berkowitz RS. Gestational trophoblastic disease. Lancet. 2010;376(9742):717–29.

    Article  Google Scholar 

  8. 8.

    Hui P, Buza N, Murphy KM, Ronnett BM. Hydatidiform moles: genetic basis and precision diagnosis. Annu Rev Pathol. 2017;12:449–85.

    CAS  Article  Google Scholar 

  9. 9.

    Williams D, Hodgetts V, Gupta J. Recurrent hydatidiform moles. Eur J Obstet Gynecol Reprod Biol. 2010;150(1):3–7.

    Article  Google Scholar 

  10. 10.

    Murdoch S, Djuric U, Mazhar B, Seoud M, Khan R, Kuick R, et al. Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans. Nat Genet. 2006;38(3):300–2.

    CAS  Article  Google Scholar 

  11. 11.

    Wang CM, Dixon PH, Decordova S, Hodges MD, Sebire NJ, Ozalp S, et al. Identification of 13 novel NLRP7 mutations in 20 families with recurrent hydatidiform mole; missense mutations cluster in the leucine-rich region. J Med Genet. 2009;46(8):569–75.

    CAS  Article  Google Scholar 

  12. 12.

    Muhlstein J, Golfier F, Rittore C, Hajri T, Philibert L, Abel F, et al. The spectrum of NLRP7 mutations in French patients with recurrent hydatidiform mole. Eur J Obstet Gynecol Reprod Biol. 2011;157(2):197–9.

    CAS  Article  Google Scholar 

  13. 13.

    Parry DA, Logan CV, Hayward BE, Shires M, Landolsi H, Diggle C, et al. Mutations causing familial biparental hydatidiform mole implicate c6orf221 as a possible regulator of genomic imprinting in the human oocyte. Am J Hum Genet. 2011;89(3):451–8.

    CAS  Article  Google Scholar 

  14. 14.

    Qian J, Nguyen NMP, Rezaei M, Huang B, Tao Y, Zhang X, et al. Biallelic PADI6 variants linking infertility, miscarriages, and hydatidiform moles. Eur J Hum Genet. 2018;26(7):1007–13.

    CAS  Article  Google Scholar 

  15. 15.

    Akoury E, Zhang L, Ao A, Slim R. NLRP7 and KHDC3L, the two maternal-effect proteins responsible for recurrent hydatidiform moles, co-localize to the oocyte cytoskeleton. Hum Reprod. 2015;30(1):159–69.

    CAS  Article  Google Scholar 

  16. 16.

    Slim R, Wallace EP. NLRP7 and the genetics of hydatidiform moles: recent advances and new challenges. Front Immunol. 2013;4:242.

    Article  Google Scholar 

  17. 17.

    Kinoshita T, Wang Y, Hasegawa M, Imamura R, Suda T. PYPAF3, a PYRIN-containing APAF-1-like protein, is a feedback regulator of caspase-1-dependent interleukin-1beta secretion. J Biol Chem. 2005;280(23):21720–5.

    CAS  Article  Google Scholar 

  18. 18.

    Messaed C, Akoury E, Djuric U, Zeng J, Saleh M, Gilbert L, et al. NLRP7, a nucleotide oligomerization domain-like receptor protein, is required for normal cytokine secretion and co-localizes with Golgi and the microtubule-organizing center. J Biol Chem. 2011;286(50):43313–23.

    CAS  Article  Google Scholar 

  19. 19.

    Judson H, Hayward BE, Sheridan E, Bonthron DT. A global disorder of imprinting in the human female germ line. Nature. 2002;416(6880):539–42.

    CAS  Article  Google Scholar 

  20. 20.

    Van den Veyver IB, Al-Hussaini TK. Biparental hydatidiform moles: a maternal effect mutation affecting imprinting in the offspring. Hum Reprod Update. 2006;12(3):233–42.

    Article  Google Scholar 

  21. 21.

    Slim R, Mehio A. The genetics of hydatidiform moles: new lights on an ancient disease. Clin Genet. 2007;71(1):25–34.

    CAS  Article  Google Scholar 

  22. 22.

    Sebire NJ, Savage PM, Seckl MJ, Fisher RA. Histopathological features of biparental complete hydatidiform moles in women with NLRP7 mutations. Placenta. 2013;34(1):50–6.

    CAS  Article  Google Scholar 

  23. 23.

    Qian J, Deveault C, Bagga R, Xie X, Slim R. Women heterozygous for NALP7/NLRP7 mutations are at risk for reproductive wastage: report of two novel mutations. Hum Mutat. 2007;28(7):741.

    Article  Google Scholar 

  24. 24.

    Soellner L, Begemann M, Degenhardt F, Geipel A, Eggermann T, Mangold E. Maternal heterozygous NLRP7 variant results in recurrent reproductive failure and imprinting disturbances in the offspring. Eur J Hum Genet. 2017;25(8):924–9.

    CAS  Article  Google Scholar 

  25. 25.

    Fisher RA, Lavery SA, Carby A, Abu-Hayyeh S, Swingler R, Sebire NJ, et al. What a difference an egg makes. Lancet. 2011;378(9807):1974.

    Article  Google Scholar 

  26. 26.

    Akoury E, Gupta N, Bagga R, Brown S, Déry C, Kabra M, et al. Live births in women with recurrent hydatidiform mole and two NLRP7 mutations. Reprod BioMed Online. 2015;31(1):120–4.

    CAS  Article  Google Scholar 

  27. 27.

    Sills ES, Obregon-Tito AJ, Gao H, McWilliams TK, Gordon AT, Adams CA, et al. Pathogenic variant in NLRP7 (19q13.42) associated with recurrent gestational trophoblastic disease: data from early embryo development observed during in vitro fertilization. Clin Exp Reprod Med. 2017;44(1):40–6.

    Article  Google Scholar 

  28. 28.

    Fallahi J, Razban V, Momtahan M, Akbarzadeh-Jahromi M, Namavar-Jahromi B, Anvar Z, et al. A novel mutation in NLRP7 related to recurrent hydatidiform mole and reproductive failure. Int J Fertil Steril. 2019;13(2):135–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Kalogiannidis I, Kalinderi K, Kalinderis M, Miliaras D, Tarlatzis B, Athanasiadis A. Recurrent complete hydatidiform mole: where we are, is there a safe gestational horizon? Opinion and mini-review. J Assist Reprod Genet. 2018;35(6):967–73.

    Article  Google Scholar 

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Correspondence to Claire Cozette.

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Cozette, C., Scheffler, F., Lombart, M. et al. Pregnancy after oocyte donation in a patient with NLRP7 gene mutations and recurrent molar hydatidiform pregnancies. J Assist Reprod Genet (2020). https://doi.org/10.1007/s10815-020-01861-z

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Keywords

  • Trophoblastic disease
  • Recurrent hydatidiform mole
  • Oocyte donation
  • NLRP7 gene mutation