Turner Syndrome: Contemporary Thoughts and Reproductive Issues

ABSTRACT

Turner syndrome is a common genetic disorder that has been classically associated with a 45,X karyotype. Several X-chromosomal abnormalities have been identified in these patients, many of which involve mosaicism. These patients have variable but predictable phenotypic findings and are at risk for development of endocrine, autoimmune, and structural abnormalities. As many as 1.5% of the population with Turner syndrome may develop dissection and rupture of the ascending aorta; the presence of abnormalities of the cardiac tree and hypertension increase this risk, but their absence does not preclude it. Rupture has occurred at aortic diameters smaller than previously reported for other patient populations. Five percent or more of women with Turner syndrome may have abbreviated menstrual function before developing amenorrhea and hypergonadotropic hypogonadism. An estimated 1 to 2% of all patients may become pregnant. Only three patients with Turner syndrome (and two of them with streak ovaries) have ever been reported to become pregnant after developing amenorrhea and elevated gonadotropin levels. Pregnancy, either spontaneous or more commonly from donor oocyte, increases maternal mortality rate for these women by an estimated ≥100 fold. It appears that all Turner women are at risk of rupture; neither prior spontaneous menses nor age >30 years provides protection. In addition, the literature suggests that the physiological changes of pregnancy may increase the risk of rupture in future years after delivery for those Turner women who seemingly made it safely through pregnancy. The use of the term primary ovarian insufficiency (POI) for Turner syndrome gives me some discomfort. For women with 46,XX hypergonadotropic hypogonadism, POI accurately provides the suggestion that follicular depletion is often not complete (although remissions are usually self-limiting and the vast majority of patients will not spontaneously become pregnant). I clearly understand the need to prevent any stigmatization to patients unfortunately diagnosed with premature oocyte depletion, and I believe that the use of the diagnosis POI leaves the door open for the occurrence of reproductive function and for the 5 to 10% of 46,XX patients who may spontaneously become pregnant. However, the world literature reports only two women with Turner syndrome, hypergonadotropic amenorrhea, and streak ovaries who have ever become pregnant spontaneously after their diagnosis. It would be unfair to such women with Turner syndrome to give them the same hope for pregnancy as we do for women with 46,XX POI. Amenorrheic women with Turner syndrome truly have ovarian failure. Although I have adopted the term POI in this article for women with Turner syndrome, semantics are no substitute for honest, thorough, and compassionate counseling.

KEYWORDS

Turner syndrome - gonadal dysgenesis - aortic dissection - 45,X

REFERENCES

• 1 Turner H H. A syndrome of infantilism, congenital webbed neck, and cubitus valgus.  Endocrinology. 1938;  23 566-574
• 2 Reindollar R H, Byrd J R, McDonough P G. Delayed sexual development: a study of 252 patients.  Am J Obstet Gynecol. 1981;  140 (4) 371-380
• 3 Clement-Jones M, Schiller S, Rao E et al. The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome.  Hum Mol Genet. 2000;  9 (5) 695-702
• 4 Kosho T, Muroya K, Nagai T et al. Skeletal features and growth patterns in 14 patients with haploinsufficiency of SHOX: implications for the development of Turner syndrome.  J Clin Endocrinol Metab. 1999;  84 (12) 4613-4621
• 5 Bondy C A. Turner Syndrome Study Group . Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group.  J Clin Endocrinol Metab. 2007;  92 (1) 10-25
• 6 Berdahl L D, Wenstrom K D, Hanson J W. Web neck anomaly and its association with congenital heart disease.  Am J Med Genet. 1995;  56 (3) 304-307
• 7 Loscalzo M L, Van P L, Ho V B et al. Association between fetal lymphedema and congenital cardiovascular defects in Turner syndrome.  Pediatrics. 2005;  115 (3) 732-735
• 8 Reindollar R H, Novak M, Tho S P, McDonough P G. Adult-onset amenorrhea: a study of 262 patients.  Am J Obstet Gynecol. 1986;  155 (3) 531-543
• 9 Gunther D F, Eugster E, Zagar A J, Bryant C G, Davenport M L, Quigley C A. Ascertainment bias in Turner syndrome: new insights from girls who were diagnosed incidentally in prenatal life.  Pediatrics. 2004;  114 (3) 640-644
• 10 Sagi L, Zuckerman-Levin N, Gawlik A et al. Clinical significance of the parental origin of the X chromosome in Turner syndrome.  J Clin Endocrinol Metab. 2007;  92 (3) 846-852
• 11 Nef S, Vassalli J D. Complementary pathways in mammalian female sex determination.  J Biol. 2009;  8 (8) 74
• 12 Singh R P, Carr D H. The anatomy and histology of XO human embryos and fetuses.  Anat Rec. 1966;  155 (3) 369-383
• 13 Carr D H, Haggar R A, Hart A G. Germ cells in the ovaries of XO female infants.  Am J Clin Pathol. 1968;  49 (4) 521-526
• 14 Simpson J L. Disorders of Sexual Differentiation: Etiology and Clinical Delineation. New York, NY: Academic Press; 1976
• 15 Reynaud K, Cortvrindt R, Verlinde F, De Schepper J, Bourgain C, Smitz J. Number of ovarian follicles in human fetuses with the 45,X karyotype.  Fertil Steril. 2004;  81 (4) 1112-1119
• 16 Birkebaek N H, Crüger D, Hansen J, Nielsen J, Bruun-Petersen G. Fertility and pregnancy outcome in Danish women with Turner syndrome.  Clin Genet. 2002;  61 (1) 35-39
• 17 Moore A K, Lynch K, Arny M J, Grow D R. Turner mosaicism (45,X/46,XX) diagnosed in a young woman subsequent to low oocyte maturity and failed ICSI.  Fertil Steril. 2008;  90 (5) 2012 e13-e15
• 18 Zinn A R, Ross J L. Molecular analysis of genes on Xp controlling Turner syndrome and premature ovarian failure (POF).  Semin Reprod Med. 2001;  19 (2) 141-146
• 19 Davison R M, Fox M, Conway G S. Mapping of the POF1 locus and identification of putative genes for premature ovarian failure.  Mol Hum Reprod. 2000;  6 (4) 314-318
• 20 Sala C, Arrigo G, Torri G et al. Eleven X chromosome breakpoints associated with premature ovarian failure (POF) map to a 15-Mb YAC contig spanning Xq21.  Genomics. 1997;  40 (1) 123-131
• 21 Bione S, Sala C, Manzini C et al. A human homologue of the Drosophila melanogaster diaphanous gene is disrupted in a patient with premature ovarian failure: evidence for conserved function in oogenesis and implications for human sterility.  Am J Hum Genet. 1998;  62 (3) 533-541
• 22 Sullivan A K, Marcus M, Epstein M P et al. Association of FMR1 repeat size with ovarian dysfunction.  Hum Reprod. 2005;  20 (2) 402-412
• 23 Dube J L, Wang P, Elvin J, Lyons K M, Celeste A J, Matzuk M M. The bone morphogenetic protein 15 gene is X-linked and expressed in oocytes.  Mol Endocrinol. 1998;  12 (12) 1809-1817
• 24 Di Pasquale E, Beck-Peccoz P, Persani L. Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene.  Am J Hum Genet. 2004;  75 (1) 106-111
• 25 Zhang P, Shi Y H, Wang L C, Chen Z J. Sequence variants in exons of the BMP-15 gene in Chinese patients with premature ovarian failure.  Acta Obstet Gynecol Scand. 2007;  86 (5) 585-589
• 26 Chand A L, Ponnampalam A P, Harris S E, Winship I M, Shelling A N. Mutational analysis of BMP15 and GDF9 as candidate genes for premature ovarian failure.  Fertil Steril. 2006;  86 (4) 1009-1012
• 27 Mortensen K H, Rohde M D, Uldbjerg N, Gravholt C H. Repeated spontaneous pregnancies in 45,X Turner syndrome.  Obstet Gynecol. 2010;  115 (2 Pt 2) 446-449
• 28 Landin-Wilhelmsen K, Bryman I, Hanson C, Hanson L. Spontaneous pregnancies in a Turner syndrome woman with Y-chromosome mosaicism.  J Assist Reprod Genet. 2004;  21 (6) 229-230
• 29 Tarani L, Lampariello S, Raguso G et al. Pregnancy in patients with Turner syndrome: six new cases and review of literature.  Gynecol Endocrinol. 1998;  12 (2) 83-87
• 30 Bondy C A. Aortic dissection in Turner syndrome.  Curr Opin Cardiol. 2008;  23 (6) 519-526
• 31 Mimasaka S, Ohtsu Y, Tsunenari S et al. Sudden death of a young woman due to aortic dissection caused by Turner syndrome.  Pathol Int. 2007;  57 (4) 219-223
• 32 Dewhurst J. Fertility in 47,XXX and 45,X patients.  J Med Genet. 1978;  15 (2) 132-135
• 33 Ditkoff E C, Vidali A, Sauer M V. Pregnancy in a woman with Turner mosaicism following ovarian stimulation and in vitro fertilization.  J Assist Reprod Genet. 1996;  13 (5) 447-448
• 34 Kavoussi S K, Fisseha S, Smith Y R, Smith G D, Christman G M, Gago L A. Oocyte cryopreservation in a woman with mosaic Turner syndrome: a case report.  J Reprod Med. 2008;  53 (3) 223-226
• 35 Huang J Y, Tulandi T, Holzer H et al. Cryopreservation of ovarian tissue and in vitro matured oocytes in a female with mosaic Turner syndrome: Case Report.  Hum Reprod. 2008;  23 (2) 336-339
• 36 Eblen A C, Nakajima S T. Spontaneous pregnancy in a woman with 45,X/47,XXX mosaicism in both serum and germ cell lines. A case report.  J Reprod Med. 2003;  48 (2) 121-123
• 37 Devroey P, Wisanto A, Camus M et al. Oocyte donation in patients without ovarian function.  Hum Reprod. 1988;  3 (6) 699-704
• 38 Pados G, Camus M, Van Waesberghe L, Liebaers I, Van Steirteghem A, Devroey P. Oocyte and embryo donation: evaluation of 412 consecutive trials.  Hum Reprod. 1992;  7 (8) 1111-1117
• 39 Salat-Baroux J, Cornet D, Alvarez S et al. Pregnancies after replacement of frozen-thawed embryos in a donation program.  Fertil Steril. 1988;  49 (5) 817-821
• 40 Khastgir G, Abdalla H, Thomas A, Korea L, Latarche L, Studd J. Oocyte donation in Turner syndrome: an analysis of the factors affecting the outcome.  Hum Reprod. 1997;  12 (2) 279-285
• 41 Karnis M F, Zimon A E, Lalwani S I, Timmreck L S, Klipstein S, Reindollar R H. Risk of death in pregnancy achieved through oocyte donation in patients with Turner syndrome: a national survey.  Fertil Steril. 2003;  80 (3) 498-501
• 42 Lin A E, Lippe B M, Geffner M E et al. Aortic dilation, dissection, and rupture in patients with Turner syndrome.  J Pediatr. 1986;  109 (5) 820-826
• 43 Lin A E, Lippe B, Rosenfeld R G. Further delineation of aortic dilation, dissection, and rupture in patients with Turner syndrome.  Pediatrics. 1998;  102 (1) e12
• 44 Rubin K. Aortic dissection and rupture in Turner syndrome.  J Pediatr. 1993;  122 (4) 670
• 45 Ho V B, Bakalov V K, Cooley M et al. Major vascular anomalies in Turner syndrome: prevalence and magnetic resonance angiographic features.  Circulation. 2004;  110 (12) 1694-1700
• 46 Matura L A, Ho V B, Rosing D R, Bondy C A. Aortic dilatation and dissection in Turner syndrome.  Circulation. 2007;  116 (15) 1663-1670
• 47 Loeys B L, Schwarze U, Holm T et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor.  N Engl J Med. 2006;  355 (8) 788-798
• 48 Carlson M, Silberbach M. Dissection of the aorta in Turner syndrome: two cases and review of 85 cases in the literature.  J Med Genet. 2007;  44 (12) 745-749
• 49 Gravholt C H, Landin-Wilhelmsen K, Stochholm K et al. Clinical and epidemiological description of aortic dissection in Turner syndrome.  Cardiol Young. 2006;  16 (5) 430-436
• 50 Gravholt C H. Epidemiology of Turner syndrome.  Lancet Oncol. 2008;  9 (3) 193-195
• 51 Birdsall M, Kennedy S. The risk of aortic dissection in women with Turner syndrome.  Hum Reprod. 1996;  11 (7) 1587
• 52 Nagel T C, Tesch L G. ART and high risk patients!.  Fertil Steril. 1997;  68 (4) 748-749
• 53 Garvey P, Elovitz M, Landsberger E J. Aortic dissection and myocardial infarction in a pregnant patient with Turner syndrome.  Obstet Gynecol. 1998;  91 (5 Pt 2) 864
• 54 Beauchesne L M, Connolly H M, Ammash N M, Warnes C A. Coarctation of the aorta: outcome of pregnancy.  J Am Coll Cardiol. 2001;  38 (6) 1728-1733
• 55 Weytjens C, Bové T, Van Der Niepen P. Aortic dissection and Turner syndrome.  J Cardiovasc Surg (Torino). 2000;  41 (2) 295-297
• 56 Boissonnas C C, Davy C, Bornes M et al. Careful cardiovascular screening and follow-up of women with Turner syndrome before and during pregnancy is necessary to prevent maternal mortality.  Fertil Steril. 2009;  91 (3) 929 e5-e7
• 57 Bondy C, Rosing D, Reindollar R. Cardiovascular risks of pregnancy in women with Turner syndrome.  Fertil Steril. 2009;  91 (5) e31-e32 author reply e34