Diminished Ovarian Reserve in Girls and Adolescents with Trisomy X Syndrome

Abstract

An extra X chromosome occurs in ~ 1 in 1000 females, resulting in a karyotype 47,XXX also known as trisomy X syndrome (TXS). Women with TXS appear to be at increased risk for premature ovarian insufficiency; however, very little research on this relationship has been conducted. The objective of this case-control study is to compare ovarian function, as measured by anti-mullerian hormone (AMH) levels, between girls with TXS and controls. Serum AMH concentrations were compared between 15 females with TXS (median age 13.4 years) and 26 controls (median age 15.1 years). Females with TXS had significantly lower serum AMH compared to controls (0.7 ng/mL (IQR 0.2–1.7) vs 2.7 (IQR 1.3–4.8), p < 0.001). Additionally, girls with TXS were much more likely to have an AMH below the 2.5th percentile for age with 67% of them meeting these criteria (OR 11, 95% CI 2.3–42). Lower AMH concentrations in females with TXS may represent an increased risk for primary ovarian insufficiency in these patients and potentially a narrow window of opportunity to pursue fertility preservation options. Additional research is needed to understand the natural history of low AMH concentrations and future risk of premature ovarian insufficiency in girls with TXS.

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References

  1. 1.

    Jacobs P, Baikie A, Brown W, Macgregor T, Maclean N, Harnden D. Evidence for the existence of the human "superfemale". Lancet. 1959;274:423–5.

    Article  Google Scholar 

  2. 2.

    Jacobs P. The incidence and etiology of sex chromosome abnormalities in man. Birth Defects Orig Artic Ser. 1979;15:3–14.

    CAS  PubMed  Google Scholar 

  3. 3.

    Nielsen J, Wohlert M. Sex chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Birth Defects Orig Artic Ser. 1990;26(4):209–23.

    CAS  PubMed  Google Scholar 

  4. 4.

    Berglund A, Viuff MH, Skakkebaek A, Chang S, Stochholm K, Gravholt CH. Changes in the cohort composition of turner syndrome and severe non-diagnosis of Klinefelter, 47,XXX and 47,XYY syndrome: a nationwide cohort study. Orphanet J Rare Dis. 2019;14(1):16. https://doi.org/10.1186/s13023-018-0976-2.

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Tartaglia NR, Howell S, Sutherland A, Wilson R, Wilson L. A review of trisomy X (47,XXX). Orphanet J Rare Dis. 2010;5:8.

    Article  Google Scholar 

  6. 6.

    Tartaglia N. Medical problems and follow-up in trisomy X syndrome. KS&A Scientific Advisory Committee Conference; Los Angeles. 2009.

  7. 7.

    Tartaglia NR, Ayari N, Hutaff-Lee C, Boada R. Attention-deficit hyperactivity disorder symptoms in children and adolescents with sex chromosome aneuploidy: XXY, XXX, XYY, and XXYY. J Dev Behav Pediatr. 2012;33(4):309–18.

    Article  Google Scholar 

  8. 8.

    Linden MG, Bender BG. Fifty-one prenatally diagnosed children and adolescents with sex chromosome abnormalities. Am J Med Genet. 2002;110(1):11–8. https://doi.org/10.1002/ajmg.10394.

    Article  PubMed  Google Scholar 

  9. 9.

    Otter M, Schrander-Stumpel CT, Didden R, Curfs LM. The psychiatric phenotype in triple X syndrome: new hypotheses illustrated in two cases. Dev Neurorehabil. 2012;15(3):233–8. https://doi.org/10.3109/17518423.2012.655799.

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Sugawara N, Maeda M, Manome T, Nagai R, Araki Y. Patients with 47, XXX karyotype who experienced premature ovarian failure (POF): two case reports. Reprod Med Biol. 2013;12(4):193–5. https://doi.org/10.1007/s12522-013-0158-9.

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Skalba P, Cygal A, Gierzynska Z. A case of premature ovarian failure (POF) in a 31-year-old woman with a 47,XXX karyotype. Endokrynol Pol. 2010;61(2):217–9.

    PubMed  Google Scholar 

  12. 12.

    Itu M, Neelam T, Ammini AC, Kucheria K. Primary amenorrhoea in a triple X female. Aust N Z J Obstet Gynaecol. 1990;30(4):386–8. https://doi.org/10.1111/j.1479-828x.1990.tb02039.x.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Menon V, Edwards RL, Butt WR, Bluck M, Lynch SS. Review of 59 patients with hypergonadotrophic amenorrhoea. Br J Obstet Gynaecol. 1984;91(1):63–6. https://doi.org/10.1111/j.1471-0528.1984.tb05280.x.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Smith HC, Seale JP, Posen S. Premature ovarian failure in a triple X female. J Obstet Gynaecol Br Commonw. 1974;81(5):405–9. https://doi.org/10.1111/j.1471-0528.1974.tb00488.x.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Holland CM. 47,XXX in an adolescent with premature ovarian failure and autoimmune disease. J Pediatr Adolesc Gynecol. 2001;14(2):77–80. https://doi.org/10.1016/s1083-3188(01)00075-4.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Michalak DP, Zacur HA, Rock JA, Woodruff JD. Autoimmunity in a patient with 47,XXX karyotype. Obstet Gynecol. 1983;62(5):667–9.

    CAS  PubMed  Google Scholar 

  17. 17.

    Goswami R, Goswami D, Kabra M, Gupta N, Dubey S, Dadhwal V. Prevalence of the triple X syndrome in phenotypically normal women with premature ovarian failure and its association with autoimmune thyroid disorders. Fertil Steril. 2003;80(4):1052–4. https://doi.org/10.1016/s0015-0282(03)01121-x.

    Article  PubMed  Google Scholar 

  18. 18.

    Tungphaisal S, Jinorose U. True 47,XXX in a patient with premature ovarian failure: the first reported case in Thailand. J Med Assoc Thail. 1992;75(11):661–5.

    CAS  Google Scholar 

  19. 19.

    Villanueva AL, Rebar RW. Triple-X syndrome and premature ovarian failure. Obstet Gynecol. 1983;62(3 Suppl):70s–3s.

    CAS  PubMed  Google Scholar 

  20. 20.

    Kodandapani S, Pai MV, Nambiar J, Moka R. Premature ovarian aging in primary infertility: triple X syndrome. J Hum Reprod Sci. 2011;4(3):153–4. https://doi.org/10.4103/0974-1208.92292.

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Visser JA, Schipper I, Laven JS, Themmen AP. Anti-Mullerian hormone: an ovarian reserve marker in primary ovarian insufficiency. Nat Rev Endocrinol. 2012;8(6):331–41. https://doi.org/10.1038/nrendo.2011.224.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med. 2009;360(6):606–14. https://doi.org/10.1056/NEJMcp0808697.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Ratcliffe S, Butler G, Jones M. Edinburgh study of growth and development of children with sex chromosome abnormalities. Birth Defects Orig Artic Ser. 1990;26(4):1–44.

    CAS  PubMed  Google Scholar 

  24. 24.

    Stagi S, di Tommaso M, Scalini P, Lapi E, Losi S, Bencini E, et al. Triple X syndrome and puberty: focus on the hypothalamus-hypophysis-gonad axis. Fertil Steril. 2016;105(6):1547–53. https://doi.org/10.1016/j.fertnstert.2016.02.019.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Hansen KR, Hodnett GM, Knowlton N, Craig LB. Correlation of ovarian reserve tests with histologically determined primordial follicle number. Fertil Steril. 2011;95(1):170–5. https://doi.org/10.1016/j.fertnstert.2010.04.006.

    Article  PubMed  Google Scholar 

  26. 26.

    Hagen CP, Aksglaede L, Sorensen K, Main KM, Boas M, Cleemann L, et al. Serum levels of anti-Mullerian hormone as a marker of ovarian function in 926 healthy females from birth to adulthood and in 172 turner syndrome patients. J Clin Endocrinol Metab. 2010;95(11):5003–10. https://doi.org/10.1210/jc.2010-0930.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Hamza RT, Mira MF, Hamed AI, Ezzat T, Sallam MT. Anti-mullerian hormone levels in patients with turner syndrome: relation to karyotype, spontaneous puberty, and replacement therapy. Am J Med Genet A. 2018;176(9):1929–34. https://doi.org/10.1002/ajmg.a.40473.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Lunding SA, Aksglaede L, Anderson RA, Main KM, Juul A, Hagen CP, et al. AMH as predictor of premature ovarian insufficiency: a longitudinal study of 120 turner syndrome patients. J Clin Endocrinol Metab. 2015;100(7):E1030–8. https://doi.org/10.1210/jc.2015-1621.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Tartaglia N, Howell S, Wilson R, Janusz J, Boada R, Martin S, et al. The eXtraordinarY kids clinic: an interdisciplinary model of care for children and adolescents with sex chromosome aneuploidy. J Multidiscip Healthc. 2015;8:323–34.

    Article  Google Scholar 

  30. 30.

    Pigny P, Merlen E, Robert Y, Cortet-Rudelli C, Decanter C, Jonard S, et al. Elevated serum level of anti-mullerian hormone in patients with polycystic ovary syndrome: relationship to the ovarian follicle excess and to the follicular arrest. J Clin Endocrinol Metab. 2003;88(12):5957–62. https://doi.org/10.1210/jc.2003-030727.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Broer SL, Eijkemans MJ, Scheffer GJ, van Rooij IA, de Vet A, Themmen AP, et al. Anti-mullerian hormone predicts menopause: a long-term follow-up study in normoovulatory women. J Clin Endocrinol Metab. 2011;96(8):2532–9. https://doi.org/10.1210/jc.2010-2776.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Castillo S, Lopez F, Tobella L, Salazar S, Daher V. The cytogenetics of premature ovarian failure. Rev Chil Obstet Ginecol. 1992;57(5):341–5.

    CAS  PubMed  Google Scholar 

  33. 33.

    Otter M, Schrander-Stumpel CT, Curfs LM. Triple X syndrome: a review of the literature. Eur J Hum Genet. 2009.

  34. 34.

    Collen RJ, Falk RE, Lippe BM, Kaplan SA. A 48,XXXX female with absence of ovaries. Am J Med Genet. 1980;6(4):275–8. https://doi.org/10.1002/ajmg.1320060404.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Prueitt RL, Ross JL, Zinn AR. Physical mapping of nine Xq translocation breakpoints and identification of XPNPEP2 as a premature ovarian failure candidate gene. Cytogenet Cell Genet. 2000;89(1–2):44–50. https://doi.org/10.1159/000015560.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Bione S, Rizzolio F, Sala C, Ricotti R, Goegan M, Manzini MC, et al. Mutation analysis of two candidate genes for premature ovarian failure, DACH2 and POF1B. Hum Reprod. 2004;19(12):2759–66. https://doi.org/10.1093/humrep/deh502.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Quilter CR, Karcanias AC, Bagga MR, Duncan S, Murray A, Conway GS, et al. Analysis of X chromosome genomic DNA sequence copy number variation associated with premature ovarian failure (POF). Hum Reprod. 2010;25(8):2139–50. https://doi.org/10.1093/humrep/deq158.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Saito M, Novak U, Piovan E, Basso K, Sumazin P, Schneider C, et al. BCL6 suppression of BCL2 via Miz1 and its disruption in diffuse large B cell lymphoma. Proc Natl Acad Sci U S A. 2009;106(27):11294–9. https://doi.org/10.1073/pnas.0903854106.

    Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Erhart LM, Lankat-Buttgereit B, Schmidt H, Wenzel U, Daniel H, Goke R. Flavone initiates a hierarchical activation of the caspase-cascade in colon cancer cells. Apoptosis. 2005;10(3):611–7. https://doi.org/10.1007/s10495-005-1895-y.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Johnson EK, Finlayson C, Rowell EE, Gosiengfiao Y, Pavone ME, Lockart B, et al. Fertility preservation for pediatric patients: current state and future possibilities. J Urol. 2017;198(1):186–94. https://doi.org/10.1016/j.juro.2016.09.159.

    Article  PubMed  Google Scholar 

  41. 41.

    Committee opinion no. 605: primary ovarian insufficiency in adolescents and young women. Obstet Gynecol. 2014;124(1):193–7. https://doi.org/10.1097/01.AOG.0000451757.51964.98.

  42. 42.

    Nahata L, Quinn GP, Tishelman AC, Section OE. Counseling in pediatric populations at risk for infertility and/or sexual function concerns. Pediatrics. 2018;142(2). https://doi.org/10.1542/peds.2018-1435.

  43. 43.

    Dennis A, Howell S, Cordeiro L, Tartaglia N. “How should I tell my child?” disclosing the diagnosis of sex chromosome aneuploidies. J Genet Couns. 2015;24(1):88–103. https://doi.org/10.1007/s10897-014-9741-4.

    Article  PubMed  Google Scholar 

  44. 44.

    Lefebvre T, Dumont A, Pigny P, Dewailly D. Effect of obesity and its related metabolic factors on serum anti-mullerian hormone concentrations in women with and without polycystic ovaries. Reprod BioMed Online. 2017;35(3):325–30. https://doi.org/10.1016/j.rbmo.2017.05.013.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Simoes-Pereira J, Nunes J, Aguiar A, Sousa S, Rodrigues C, Sampaio Matias J, et al. Influence of body mass index in anti-mullerian hormone levels in 951 non-polycystic ovarian syndrome women followed at a reproductive medicine unit. Endocrine. 2018;61(1):144–8. https://doi.org/10.1007/s12020-018-1555-y.

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Dong YZ, Zhou FJ, Sun YP. Psychological stress is related to a decrease of serum anti-mullerian hormone level in infertile women. Reprod Biol Endocrinol. 2017;15(1):51. https://doi.org/10.1186/s12958-017-0271-4.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Henes M, Froeschlin J, Taran FA, Brucker S, Rall KK, Xenitidis T, et al. Ovarian reserve alterations in premenopausal women with chronic inflammatory rheumatic diseases: impact of rheumatoid arthritis, Behcet's disease and spondyloarthritis on anti-mullerian hormone levels. Rheumatology (Oxford). 2015;54(9):1709–12. https://doi.org/10.1093/rheumatology/kev124.

    CAS  Article  Google Scholar 

  48. 48.

    Szydlowska I, Marciniak A, Brodowska A, Lisak M, Przysiecka S, Rozanski J. Assessment of ovarian reserve as an indicator of fertility and health consequences in patients with chronic kidney disease stages 3-4. Gynecol Endocrinol. 2018;34(11):944–8. https://doi.org/10.1080/09513590.2018.1473364.

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors wish to thank the study participants in the eXtraordinarY Kids Clinic and their families. We also acknowledge Esoterix Laboratories, in particular Walt Chandler, PhD, Kelly Chun, PhD, and Steve Phagoo, PhD. Additionally, we acknowledge funding from the National Center for Advancing Translational Sciences (NIH/NCATS) Colorado CTSA (UL1TR002535), the National Institute of Child Health and Human Development (NIH/NICHD) (K23HD092588), the American Heart Association (13CRP14120015), the National Institute of Digestion, Diabetes, and Kidney Disease (NIH/NIDDK) (K23DK107871), the University of Colorado Departments of Obstetrics and Gynecology and Pediatrics.

Funding

This work was financially supported by the following: National Institute of Child Health and Human Development (NIH/NICHD) (K23HD092588), National Institute of Digestion, Diabetes, and Kidney Disease (NIH/NIDDK) (K23DK107871), National Center for Advancing Translational Sciences (NIH/NCATS) Colorado CTSA (UL1TR002535), American Heart Association (13CRP14120015), University of Colorado Department of Obstetrics and Gynecology Research Funds, and University of Colorado Department of Pediatrics. Availability of Data and Material

All data generated or analyzed during this study are included in this published article.

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Correspondence to Shanlee M. Davis.

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Conflict of Interest

NT and SD serve as medical advisors and SH on the board of directors for the advocacy group AXYS (Association for X&Y syndromes).

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The local institutional review board (COMIRB #08-0512 and #10-1288) approved these protocols and all parents provided written informed consent and girls provided assent as age appropriate. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.

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Davis, S.M., Soares, K., Howell, S. et al. Diminished Ovarian Reserve in Girls and Adolescents with Trisomy X Syndrome. Reprod. Sci. (2020). https://doi.org/10.1007/s43032-020-00216-4

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Keywords

  • Trisomy X syndrome (TXS)
  • Primary ovarian insufficiency (POI)
  • Anti-mullerian hormone (AMH)
  • Sex chromosome aneuploidy
  • Fertility