Pediatric Meet the Professors 1

HORMONE RESEARCH

Horm Res 2009;71(suppl 1):5256 DOI: 10.1159/000178039

Published online: January 21, 2009

Turner Syndrome 2008

Carolyn A. Bondy
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md., USA

Key Words Turner syndrome Sex chromosome anomaly Pubertal induction Short stature Congenital heart disease

Introduction

Abstract Background: Fetuses with prenatal diagnoses of 45,X Turner syndrome (TS) and abnormal fetal ultrasounds have poor prognoses for survival, but with modern medical management, those that do survive to birth may have good clinical outcomes. Fetuses with incidental diagnoses of mosaicism for 45,X associated with normal ultrasounds have a high survival rate and may have no or only mild features of TS. Current Guidelines: At present, appropriate treatment for girls with TS may include growth-promoting therapy and pubertal induction with the dual aims of optimizing adult height and facilitating psychosocial adjustment. Current recommendations advocate mimicking normal physiology as much as possible, with use of microdose estradiol to initiate puberty. Healthcare providers should play a role in helping girls psychosocially adapt to ovarian failure. We now recognize there is an unacceptably high rate of premature mortality in adults with TS, mainly because of complications from congenital heart disease. Cardiac magnetic resonance imaging is recommended to screen for individuals at high risk for serious complications. Copyright 2009 S. Karger AG, Basel

The diagnosis of Turner syndrome (TS) is applied to phenotypic females missing all or part of one sex chromosome, and it affects approximately 1/2,500 live female births [1]. The two most common features, which affect over 90% of recognized patients, are short stature and premature ovarian failure. Early surveys based on clinically obvious cases emphasized physical traits, such as webbed neck, low-set or malrotated ears, ptosis and skeletal abnormalities (e.g., Madelung anomaly), but these features are now reported for fewer than half of affected girls. The great majority of girls and women with TS are of normal intelligence, though a significant number have a nonverbal learning disorder that may be associated with a disparity in verbal versus performance IQ [2]. Congenital cardiovascular defects are found in approximately 50% of affected girls, placing them at increased risk for aortic dissection, which is the most lifethreatening medical problem facing patients with TS [35].

Prenatal Diagnosis

Sex chromosome anomalies are a frequent result (approximately 30% of cases) of amniocentesis and chorionic villous cytogenetic testing. Hence, many prospective parents need to know the significance of a prenatal diagCarolyn A. Bondy National Institute of Child Health and Human Development National Institutes of Health CRC 1-3330 10 Center Dr, Bethesda, MD 20892-1862 (USA) Tel. +1 301 496 4686, Fax +1 301 402 0574, E-Mail bondyc@mail.nih.gov

2009 S. Karger AG, Basel 03010163/09/07170052$26.00/0 Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Accessible online at: www.karger.com/hre

nosis of a 45,X cell line karyotype. There are few studies of the natural outcome of such pregnancies. When fetal ultrasound detects cystic hygroma or fetal hydrops, and cytogenetic testing reveals a karyotype of 45,X, the prognosis for survival is poor. In most cases the fetus dies due to circulatory failure. By contrast, if the fetal karyotype is mosaic for 45,X with an additional normal cell line (46,XX or 46,XY), the outlook for survival is better. According to a review of the Danish cytogenetic registry, TS was diagnosed in as many as 1/250 fetuses using chorionic villous sampling and 1/500 using amniocentesis. However, approximately 83% of these pregnancies that were allowed to come to term resulted in live births, and 30% of the infants appeared normal and had normal karyotypes on repeat postnatal testing. These results suggest that such testing has a high rate of false positives and a rather poor predictive value [6]. For example, a cytogenetic laboratory in the United States recently reviewed nine cases in which the fetal karyotype was determined to be nonmosaic 45,X with normal results on ultrasound [7]. Of these nine, one pregnancy was electively terminated and another was lost to follow-up, but seven fetuses were born live: four girls, one of whom had signs of TS, and 3 apparently normal boys. Hence, available data suggest that prenatal cytogenetic diagnosis of X chromosome monosomy without clinical correlation (i.e., abnormal fetal ultrasound) is a poor predictor of clinical outcome. Typically, prenatal screening is not prompted by concern about possible sex chromosome anomalies. Consequently, there is usually little discussion with parents regarding the possibility of TS or other sex chromosome abnormalities before testing. This common reality poses challenges for counseling parents about what the diagnosis might mean for their child, as such anomalies are often not anticipated. The expertise of the counselor and the nature of any negative information imparted to the parents may have a major impact on the decision of whether to terminate the pregnancy [8]. Notably, when the term severe phenotype is used in regard to TS, it refers to neck webbing, infertility and a high probability of cardiovascular defects, such as bicuspid aortic valve. However, these are treatable conditions and are compatible with a fully independent and indeed successful adulthood and good quality of life. The incidental prenatal diagnosis of TS is associated with a milder phenotype compared with those diagnosed on traditional clinical grounds after birth [9, 10].

Treatment of Short Stature

Short stature in TS is due to haploinsufficiency for the pseudoautosomal gene known as SHOX. This gene encodes a transcription factor that is expressed in the developing skeleton and implicated in various skeletal anomalies seen in TS. It is also associated with reduced longbone growth. Girls with TS are not usually deficient in growth hormone (GH), but when treated for short stature with GH most demonstrate significant augmentation of growth rate. According to a randomized, controlled Canadian study of GH use in girls with TS, final adult height increased by approximately 7 cm when GH treatment was started by age 89 and continued for approximately 5 years, with puberty initiated at age 12 [11]. In a commentary on this important study, Carel noted that the expected benefits in terms of improved quality of life and selfesteem from the GH-induced increased height have not yet been demonstrated [12]. To date, however, GH use by girls with TS seems relatively safe, though short-term risks, such as intracranial hypertension, slipped capital epiphysis and scoliosis, are slightly more common in girls with TS compared with other GH-treated children [13]. Girls with TS respond well to GH treatment administered as early as 9 months of age [14]. This finding raises the question of how early and for how long these girls should be treated. Currently, known risks of GH treatment in girls with TS derive from cohorts that typically started treatment after age 6 and were treated for an average of 35 years. Consequently, new issues may emerge associated with GH treatment of very young children and for treatment periods of 10 years or more. The long-term risks of GH treatment in TS are not known, and it is important to discuss these issues with parents. Current dosage recommendations and issues relating to the use of oxandrolone in addition to GH to promote growth in girls are summarized elsewhere.

Puberty

Gonadal dysgenesis is often used in reference to TS and to completely unrelated disorders affecting both girls and boys. This anachronistic term is neither accurate nor informative and should be discarded in favor of terminology referring to specific, genetically defined disorders [15]. In the absence of a Y chromosome or SRY gene, indifferent gonads develop as ovaries, as in TS. In the absence of a second X chromosome, the ovaries form normally but undergo premature and accelerated follicular
Horm Res 2009;71(suppl 1):5256

Turner Syndrome 2008

53

atresia, possibly due to meiotic difficulties in aneuploid oocytes and/or haploinsufficiency for X-linked genes required for oocyte survival. These ovaries may degenerate during fetal life, in childhood or in early adulthood. Overall, 1030% of girls with TS have spontaneous initial pubertal development, and a few may have natural pregnancies. Potential pubertal development in girls with TS is monitored by physical examination and assessment of follicle-stimulating hormone levels beginning about age 10. The preferred regimen for pubertal induction in girls without spontaneous puberty is low-dose, transdermal estrogen treatment (i.e., 1014 g of 17- -estradiol/d not ethinyl estradiol) beginning by age 12, with gradual dose increases over approximately 23 years until feminization is adequate. At that time, cyclic progesterone treatment is added [16]. A critical part of healthy pubertal development for girls with TS is psychosocially adapting to premature ovarian failure and its implications. As soon as a girl can understand the concepts, sex education should begin, with emphasis on her ability to develop with medical treatment as a fully fledged female. Continuing education should be provided as age and maturity allow. The medical team should address sexual activity when appropriate and discuss the possibility of infertility, emphasizing self-esteem and the diverse possibilities for family building in the future. It is crucial that the girl and her family be educated about the importance of continued estrogen use during adulthood to prevent osteoporosis (fig. 1) [17].

Preventing Premature Mortality

Adults with TS have a 4- to 5-fold increased rate of premature mortality, which is attributed mainly to complications of congenital heart disease (CHD) and premature coronary artery disease [reviewed by Stochholm et al., 1]. Clinically severe CHD is obvious in approximately 10% of newborns with TS. Many of these infants succumb to hypoplasia of the left ventricle or aorta; aortic valve stenosis or aortic coarctation is usually surgically remediable. Up to 50% of infants with TS will have clinically silent defects mainly bicuspid aortic valve, but also ascending aortic dilation, partial anomalous pulmonary venous connections and other anomalies [4, 18]. These defects may only become apparent later in life, sometimes presenting as catastrophic aortic dissection. The cause of CHD in TS is unknown. However, there is a highly sig54
Horm Res 2009;71(suppl 1):5256

nificant statistical correlation between evidence of fetal lymphedema and bicuspid aortic valve and/or coarctation [18, 19], suggesting that haploinsufficiency for an Xlinked (likely pseudoautosomal) gene causes both defects. The National Institutes of Health (NIH) provided the first prospective measure of the incidence of aortic dissection in TS, which then served as a basis for proposing new guidelines to identify high-risk patients [3]. The study used cardiac magnetic resonance (CMR) imaging to prospectively screen for cardiovascular defects in more than 300 unselected girls and women with TS [3, 4, 18]. CMR imaging has many advantages over echocardiography. It permits visualization of the entire aortic arch, greatly facilitating the detection of proximal aortic dilation relative to transverse and descending aortic diameters. In addition, CMR shows all the great vessels including the pulmonary veins, and any anomalies detected indicate involvement of the cardiovascular system. Prior to the NIH study, there was no information on specific aortic diameters associated with increased risk of dissection. Women with TS are typically !147 cm in height, so the 56 cm threshold currently used to identify at-risk adults appeared too high. The NIH study also evaluated the aortic diameters of asymptomatic, unselected women with TS who were followed for an average of 3 years and analyzed outcomes with respect to premorbid aortic measures. Of 158 patients evaluated, three had aortic dissection. These women had aortic diameters ranging from 3.7 to 4.8 cm and were under the care of cardiologists, but because their diameters were !5 cm they were not considered candidates for prophylactic intervention. Approximately 33% of the women with an absolute ascending aortic diameter 63.5 cm and 27% of those with aortic diameter 62.5 cm/m2 after adjusting for body surface area (BSA) experienced aortic dissection within 3 years [3]. Hence, waiting for aortic diameter to reach 5 cm is not appropriate for patients with TS, and women with a BSA-adjusted diameter 62.5 cm/m2 need evaluation for prophylactic intervention. Figure 2 is a flowchart for screening and following individuals with TS for CHD. At the time of diagnosis, regardless of age, all patients need a comprehensive cardiovascular evaluation by a cardiologist specializing in CHD. Evaluation should include imaging with good visualization of the aortic valve, since structural abnormalities are so common and their presence serves to identify individuals at risk for complications, examination of the entire aortic arch and measurement of its diameters and assessment of aortic coarctation and partial anomalous
Bondy

Fig. 1. Estrogen replacement is essential to maintain vertebral bone mineralization in adults with TS. These plain radiographs of the lateral spine were taken from 30-yearold women with 45,X TS. Both began estrogen treatment at age 12, but one woman discontinued estrogen use while away at college (a), while the other woman continued estrogen replacement therapy to the present (b). As shown by the arrowheads, the 12th thoracic vertebra collapsed in patient A, who has lost height and has marked kyphosis (dowagers hump). (Modified from Hanton et al. [17].)

Initial evaluation by CHD specialist: must view aortic valve and aortic arch and measure aortic diameter adjusted for body surface area

CHD

Normal

Continue cardiac monitoring and treatment as needed Transition to Adult CHD Clinic Fig. 2. Flowchart for screening and following individuals with TS for CHD.

Avoid isometric exercise and hard contact sports

Repeat evaluation of cardiovascular system at transition to adult care and before pregnancy

Turner Syndrome 2008

Horm Res 2009;71(suppl 1):5256

55

pulmonary venous return. In the young girl, transthoracic echocardiogram is sufficient if it permits the cardiac anatomy to be clearly seen. If not, or if otherwise indicated, CMR, with sedation if necessary, may be advised. In addition to echocardiogram, CMR is recommended as a screening test for older girls who can cooperate without sedation and for all adults. TS patients with congenital anomalies indicating involvement of the cardiovascular system should be followed by a cardiology specialist. Ideally, adults with TS and CHD should receive follow-up on a regular basis at an adult CHD clinic.

Acknowledgment
This work was supported by the intramural research program of the National Institute of Child Health and Development, National Institutes of Health.

Disclosure Statement
C.B. declares no conflict of interest.

References
1 Stochholm K, Juul S, Juel K, Naeraa RW, Hojbjerg Gravholt C: Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab 2006;91: 38973902. 2 Ross J, Roeltgen D, Zinn A: Cognition and the sex chromosomes: studies in Turner syndrome. Horm Res 2006;65: 4756. 3 Matura LA, Ho VB, Rosing DR, Bondy CA: Aortic dilatation and dissection in Turner syndrome. Circulation 2007;116:16631670. 4 Ho VB, Bakalov VK, Cooley M, Van PL, Hood MN, Burklow TR, Bondy CA: Major vascular anomalies in Turner syndrome: prevalence and magnetic resonance angiographic features. Circulation 2004; 110: 16941700. 5 Gravholt CH, Landin-Wilhelmsen K, Stochholm K, Hjerrild BE, Ledet T, Djurhuus CB, Sylven L, Baandrup U, Kristensen BO, Christiansen JS: Clinical and epidemiological description of aortic dissection in Turners syndrome. Cardiol Young 2006; 16:430436. 6 Gravholt CH, Juul S, Naeraa RW, Hansen J: Prenatal and postnatal prevalence of Turners syndrome: a registry study. BMJ 1996; 312:1621. 7 Huang B, Thangavelu M, Bhatt S, Sandlin CJ, Wang S: Prenatal diagnosis of 45,X and 45,X mosaicism: the need for thorough cytogenetic and clinical evaluations. Prenat Diagn 2002;22:105110. 8 Robinson A, Bender B, Linden M: Decisions following the intrauterine diagnosis of sex chromosome aneuploidy. Am J Med Genet 1989;34:552554. 9 Koeberl DD, McGillivray B, Sybert VP: Prenatal diagnosis of 45,X/46,XX mosaicism and 45,X: implications for postnatal outcome. Am J Hum Genet 1995;57:661666. 10 Gunther DF, Eugster E, Zagar AJ, Bryant CG, Davenport ML, Quigley CA: Ascertainment bias in Turner syndrome: new insights from girls who were diagnosed incidentally in prenatal life. Pediatrics 2004;114:640644. 11 The Canadian Growth Hormone Advisory Committee. Impact of growth hormone supplementation on adult height in Turner syndrome: results of the Canadian randomized controlled trial. J Clin Endocrinol Metab 2005;90:33603366. 12 Carel J-C: Growth hormone in Turner syndrome: twenty years after, what can we tell our patients? J Clin Endocrinol Metab 2005; 90:37933794. 13 Bolar K, Hoffman AR, Maneatis T, Lippe B: Long-term safety of recombinant human growth hormone in Turner syndrome. J Clin Endocrinol Metab 2008;93:344351. 14 Davenport ML, Crowe BJ, Travers SH, Rubin K, Ross JL, Fechner PY, Gunther DF, Liu C, Geffner ME, Thrailkill K, Huseman C, Zagar AJ, Quigley CA: Growth hormone treatment of early growth failure in toddlers with Turner syndrome: a randomized, controlled, multicenter trial. J Clin Endocrinol Metab 2007;92:34063416. 15 Opitz JM, Pallister PD: Brief historical note: the concept of gonadal dysgenesis. Am J Med Genet 1979;4:333343. 16 Bondy CA: Care of girls and women with Turner syndrome: a guideline of the Turner syndrome study group. J Clin Endocrinol Metab 2007;92:1025. 17 Hanton L, Axelrod L, Bakalov V, Bondy CA: The importance of estrogen replacement in young women with Turner syndrome. J Womens Health (Larchmt) 2003;12:971977. 18 Sachdev V, Matura LA, Sidenko S, Ho VB, Arai AE, Rosing DR, Bondy CA: Aortic valve disease in Turner syndrome. J Am Coll Cardiol 2008;51:19041909. 19 Loscalzo ML, Van PL, Ho VB, Bakalov VK, Rosing DR, Malone CA, Dietz HC, Bondy CA: Association between fetal lymphedema and congenital cardiovascular defects in Turner syndrome. Pediatrics 2005; 115: 732 735.

56

Horm Res 2009;71(suppl 1):5256

Bondy