turner syndrome 2008 2009

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Fax +41 61 306 12 34E-Mail [email protected]

Pediatric Meet the Professors 1

Horm Res 2009;71(suppl 1):5256

DOI: 10.1159/000178039

Turner Syndrome 2008

Carolyn A. Bondy

Developmental Endocrinology Branch, National Institute of Child Health and Human Development,

National Institutes of Health, Bethesda, Md., USA

Introduction

The diagnosis of Turner syndrome (TS) is applied tophenotypic females missing all or part of one sex chro-mosome, and it affects approximately 1/2,500 live fe-male births [1]. The two most common features, whichaffect over 90% of recognized patients, are short statureand premature ovarian failure. Early surveys based onclinically obvious cases emphasized physical traits, suchas webbed neck, low-set or malrotated ears, ptosis andskeletal abnormalities (e.g., Madelung anomaly), butthese features are now reported for fewer than half ofaffected girls. The great majority of girls and womenwith TS are of normal intelligence, though a significantnumber have a nonverbal learning disorder that may beassociated with a disparity in verbal versus performanceIQ [2]. Congenital cardiovascular defects are found inapproximately 50% of affected girls, placing them at in-creased risk for aortic dissection, which is the most life-threatening medical problem facing patients with TS

[35].

Prenatal Diagnosis

Sex chromosome anomalies are a frequent result (ap-proximately 30% of cases) of amniocentesis and chori-onic villous cytogenetic testing. Hence, many prospectiveparents need to know the significance of a prenatal diag-

Key Words

Turner syndrome Sex chromosome anomaly Pubertal

induction Short stature Congenital heart disease

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 manage-

ment, 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 sur-

vival rate and may have no or only mild features of TS. Cur-

rent Guidelines: At present, appropriate treatment for girls

with TS may include growth-promoting therapy and puber-

tal induction with the dual aims of optimizing adult height

and facilitating psychosocial adjustment. Current recom-

mendations 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 recog-nize there is an unacceptably high rate of premature mortal-

ity in adults with TS, mainly because of complications from

congenital heart disease. Cardiac magnetic resonance imag-

ing is recommended to screen for individuals at high risk for

serious complications. Copyright 2009 S. Karger AG, Basel

Published online: January 21, 2009HORMONERESEARCH

Carolyn A. BondyNational Institute of Chi ld Health and Human DevelopmentNational Institutes of Health CRC 1-333010 Center Dr, Bethesda, MD 20892-1862 (USA)Tel. +1 301 496 4686, Fax +1 301 402 0574, E-Mail [email protected]

2009 S. Karger AG, Basel03010163/09/07170052$26.00/0

Accessible online at:www.karger.com/hre


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Turner Syndrome 2008 Horm Res 2009;71(suppl 1):5256 53

nosis of a 45,X cell line karyotype. There are few studiesof the natural outcome of such pregnancies. When fetalultrasound detects cystic hygroma or fetal hydrops, andcytogenetic testing reveals a karyotype of 45,X, the prog-nosis for survival is poor. In most cases the fetus dies dueto 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. Ac-cording to a review of the Danish cytogenetic registry, TSwas diagnosed in as many as 1/250 fetuses using chori-onic villous sampling and 1/500 using amniocentesis.However, approximately 83% of these pregnancies thatwere allowed to come to term resulted in live births, and30% of the infants appeared normal and had normalkaryotypes on repeat postnatal testing. These results sug-gest that such testing has a high rate of false positives anda rather poor predictive value [6]. For example, a cytoge-netic laboratory in the United States recently reviewed

nine cases in which the fetal karyotype was determinedto be nonmosaic 45,X with normal results on ultrasound[7]. Of these nine, one pregnancy was electively termi-nated and another was lost to follow-up, but seven fetus-es were born live: four girls, one of whom had signs of TS,and 3 apparently normal boys. Hence, available data sug-gest that prenatal cytogenetic diagnosis of X chromo-some monosomy without clinical correlation (i.e., abnor-mal fetal ultrasound) is a poor predictor of clinical out-come.

Typically, prenatal screening is not prompted by con-cern about possible sex chromosome anomalies. Conse-quently, there is usually little discussion with parents re-garding the possibility of TS or other sex chromosomeabnormalities before testing. This common reality poseschallenges for counseling parents about what the diagno-sis might mean for their child, as such anomalies are of-ten not anticipated. The expertise of the counselor andthe nature of any negative information imparted to theparents may have a major impact on the decision ofwhether to terminate the pregnancy [8]. Notably, whenthe term severe phenotype is used in regard to TS, it re-fers to neck webbing, infertility and a high probability of

cardiovascular defects, such as bicuspid aortic valve.However, these are treatable conditions and are compat-ible with a fully independent and indeed successful adult-hood and good quality of life. The incidental prenataldiagnosis of TS is associated with a milder phenotypecompared with those diagnosed on traditional clinicalgrounds after birth [9, 10].

Treatment of Short Stature

Short stature in TS is due to haploinsufficiency for thepseudoautosomal gene known as SHOX. This gene en-codes a transcription factor that is expressed in the devel-oping skeleton and implicated in various skeletal anoma-

lies seen in TS. It is also associated with reduced long-bone growth. Girls with TS are not usually deficient ingrowth hormone (GH), but when treated for short staturewith GH most demonstrate significant augmentation ofgrowth rate. According to a randomized, controlled Ca-nadian study of GH use in girls with TS, final adult heightincreased by approximately 7 cm when GH treatment wasstarted by age 89 and continued for approximately 5years, with puberty initiated at age 12 [11]. In a commen-tary on this important study, Carel noted that the expect-ed benefits in terms of improved quality of life and self-esteem from the GH-induced increased height have not

yet been demonstrated [12]. To date, however, GH use bygirls with TS seems relatively safe, though short-termrisks, such as intracranial hypertension, slipped capitalepiphysis and scoliosis, are slightly more common in girlswith TS compared with other GH-treated children [13].

Girls with TS respond well to GH treatment adminis-tered as early as 9 months of age [14]. This finding raisesthe question of how early and for how long these girlsshould be treated. Currently, known risks of GH treat-ment in girls with TS derive from cohorts that typicallystarted treatment after age 6 and were treated for an aver-age of 35 years. Consequently, new issues may emergeassociated with GH treatment of very young children andfor treatment periods of 10 years or more. The long-termrisks of GH treatment in TS are not known, and it is im-portant to discuss these issues with parents. Current dos-age recommendations and issues relating to the use ofoxandrolone in addition to GH to promote growth ingirls are summarized elsewhere.

Puberty

Gonadal dysgenesis is often used in reference to TSand to completely unrelated disorders affecting both girlsand boys. This anachronistic term is neither accurate norinformative and should be discarded in favor of terminol-ogy referring to specific, genetically defined disorders[15]. In the absence of a Y chromosome or SRYgene, in-different gonads develop as ovaries, as in TS. In the ab-sence of a second X chromosome, the ovaries form nor-mally but undergo premature and accelerated follicular


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atresia, possibly due to meiotic difficulties in aneuploidoocytes and/or haploinsufficiency for X-linked genes re-quired for oocyte survival. These ovaries may degenerateduring fetal life, in childhood or in early adulthood.Overall, 1030% of girls with TS have spontaneous initialpubertal development, and a few may have natural preg-

nancies.Potential pubertal development in girls with TS ismonitored by physical examination and assessment offollicle-stimulating hormone levels beginning about age10. The preferred regimen for pubertal induction in girlswithout spontaneous puberty is low-dose, transdermalestrogen treatment (i.e., 1014 g of 17--estradiol/d not ethinylestradiol) beginning by age 12, with gradualdose increases over approximately 23 years until femi-nization is adequate. At that time, cyclic progesteronetreatment is added [16].

A critical part of healthy pubertal development for

girls with TS is psychosocially adapting to prematureovarian failure and its implications. As soon as a girl canunderstand the concepts, sex education should begin,with emphasis on her ability to develop with medicaltreatment as a fully fledged female. Continuing educa-tion should be provided as age and maturity allow. Themedical team should address sexual activity when appro-priate and discuss the possibility of infertility, emphasiz-ing self-esteem and the diverse possibilities for familybuilding in the future. It is crucial that the girl and herfamily be educated about the importance of continuedestrogen use during adulthood to prevent osteoporosis(fig. 1) [17].

Preventing Premature Mortality

Adults with TS have a 4- to 5-fold increased rate ofpremature mortality, which is attributed mainly to com-plications of congenital heart disease (CHD) and prema-ture coronary artery disease [reviewed by Stochholm etal., 1]. Clinically severe CHD is obvious in approximately10% of newborns with TS. Many of these infants suc-

cumb to hypoplasia of the left ventricle or aorta; aorticvalve stenosis or aortic coarctation is usually surgicallyremediable. Up to 50% of infants with TS will have clini-cally silent defects mainly bicuspid aortic valve, but alsoascending aortic dilation, partial anomalous pulmonary venous connections and other anomalies [4, 18]. Thesedefects may only become apparent later in life, sometimespresenting as catastrophic aortic dissection. The cause ofCHD in TS is unknown. However, there is a highly sig-

nificant statistical correlation between evidence of fetallymphedema and bicuspid aortic valve and/or coarcta-tion [18, 19], suggesting that haploinsufficiency for an X-linked (likely pseudoautosomal) gene causes both de-fects.

The National Institutes of Health (NIH) provided the

first prospective measure of the incidence of aortic dis-section in TS, which then served as a basis for proposingnew guidelines to identify high-risk patients [3]. Thestudy used cardiac magnetic resonance (CMR) imagingto prospectively screen for cardiovascular defects in morethan 300 unselected girls and women with TS [3, 4, 18].CMR imaging has many advantages over echocardiogra-phy. It permits visualization of the entire aortic arch,greatly facilitating the detection of proximal aortic dila-tion relative to transverse and descending aortic diame-ters. In addition, CMR shows all the great vessels includ-ing the pulmonary veins, and any anomalies detected in-

dicate involvement of the cardiovascular system. Prior tothe NIH study, there was no information on specific aor-tic diameters associated with increased risk of dissection.Women with TS are typically!147 cm in height, so the56 cm threshold currently used to identify at-risk adultsappeared too high. The NIH study also evaluated the aor-tic diameters of asymptomatic, unselected women withTS who were followed for an average of 3 years and ana-lyzed outcomes with respect to premorbid aortic mea-sures. Of 158 patients evaluated, three had aortic dissec-tion. These women had aortic diameters ranging from 3.7to 4.8 cm and were under the care of cardiologists, butbecause their diameters were !5 cm they were not con-sidered candidates for prophylactic intervention. Ap-proximately 33% of the women with an absolute ascend-ing aortic diameter63.5 cm and 27% of those with aorticdiameter 62.5 cm/m2 after adjusting for body surfacearea (BSA) experienced aortic dissection within 3 years[3]. Hence, waiting for aortic diameter to reach 5 cm isnot appropriate for patients with TS, and women with aBSA-adjusted diameter62.5 cm/m2 need evaluation forprophylactic intervention.

Figure 2 is a f lowchart for screening and following in-

dividuals with TS for CHD. At the time of diagnosis, re-gardless of age, a ll patients need a comprehensive cardio-vascular evaluation by a cardiologist specializing in CHD.Evaluation should include imaging with good visualiza-tion of the aortic valve, since structural abnormalities areso common and their presence serves to identify indi-viduals at risk for complications, examination of the en-tire aortic arch and measurement of its diameters andassessment of aortic coarctation and partial anomalous


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a b

Fig. 1. Estrogen replacement is essential tomaintain vertebral bone mineralization inadults with TS. These plain radiographs ofthe lateral spine were taken from 30-year-old women with 45,X TS. Both began es-trogen treatment at age 12, but one womandiscontinued estrogen use while away atcollege (a), while the other woman contin-ued estrogen replacement therapy to thepresent (b). As shown by the arrowheads,the 12th thoracic vertebra collapsed in pa-tient A, who has lost height and has marked

kyphosis (dowagers hump). (Modifiedfrom 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 andtreatment as

needed

Transition to Adult

CHD Clinic

Avoid isometric

exercise and hard

contact sports

Repeat evaluation

of cardiovascular

system at transition

to adult care and

before pregnancy

Fig. 2. Flowchart for screening and follow-ing individuals with TS for CHD.


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pulmonary venous return. In the young girl, transtho-racic echocardiogram is sufficient if it permits the car-diac anatomy to be clearly seen. If not, or if otherwiseindicated, CMR, with sedation if necessary, may be ad- vised. In addition to echocardiogram, CMR is recom-mended as a screening test for older girls who can coop-

erate without sedation and for all adults. TS patients withcongenital anomalies indicating involvement of the car-diovascular system should be followed by a cardiologyspecialist. Ideally, adults with TS and CHD should receivefollow-up on a regular basis at an adult CHD clinic.

Acknowledgment

This work was supported by the intramural research programof the National Institute of Child Health and Development, Na-tional Institutes of Health.

Disclosure Statement

C.B. declares no conflict of interest.

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