Turner Syndrome and the Heart

Turner Syndrome and the HeartCardiovascular Complications and Treatment Strategies

Claus Højbjerg GravholtMedical Department M (Endocrinology and Diabetes) and Medical Research Laboratories, Aarhus Kommunehospital,Aarhus University Hospital, Aarhus, Denmark

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4011. History and Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4012. Congenital Malformations of the Heart and the Great Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4033. Hypertension and Ischemic Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4064. Aortic Dissection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4075. Growth Hormone Treatment and the Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4076. Hormone Replacement Therapy and the Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4087. Cardiovascular Management in Turner Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409

Abstract Turner syndrome is a condition usually associated with reduced final height, gonadal dysgenesis, and thusinsufficient circulating levels of female sex steroids, and infertility. A number of other signs and symptoms areseen more frequently with the syndrome. With respect to cardiac function, congenital malformations of the heartand the great vessels, hypertension and ischemic heart disease, and increased risk of aortic dissection are allconditions that the pediatrician or the physician caring for females with Turner syndrome should keep in mind.Many girls and adolescents with Turner syndrome receive growth hormone (GH) treatment, which has so farbeen an effective and well-tolerated therapy. Nevertheless, because of the experience from acromegaly, thephysician should monitor blood pressure and perform echocardiography, together with clinical examinationsby a cardiologist at regular intervals. During adulthood most women with Turner syndrome are faced withpremature menopause and the need for female hormone replacement therapy (HRT). During clinical evaluationof girls and women with Turner syndrome, these conditions and complications should be kept under surveillance.

Here the cardiovascular complications of Turner syndrome are reviewed. The risk of congenital heart defectssuch as bicuspid aortic valves, aortic coarctation, other valve abnormalities, and septal defect is increased.Likewise, the risk of aortic dissection at a young age is increased, as is the risk of hypertension, ischemic heartdisease, and stroke. GH therapy does not seem to adversely affect the heart, although longer-term follow-upstudies are needed. In short-term studies, HRT lowers blood pressure, while any effect on the risk of ischemicheart disease has not been evaluated. Treatment with GH and HRT are discussed in relation to the heart andgreat vessels. Presently, the pathophysiology of the congenital cardiovascular malformation in Turner syndromeis unexplained, although different theories exist. Recommendations for clinical practice are given, includinglife-long surveillance of cardiac function, aortic diameter and blood pressure.

REVIEW ARTICLE Am J Cardiovasc Drugs 2002; 2 (6): 401-4131175-3277/02/0006-0401/$25.00/0

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1. History and Introduction

Turner syndrome derives its name from the American physi-cian Henry H. Turner of Oklahoma City, Oklahoma.[1] In a reportin Endocrinology in 1938 he described seven patients with sev-eral characteristic features of the syndrome, such as infantilism,cubitus valgus and congenital webbing of the neck. Since the

initial report a number of abnormalities have been recognized inassociation with the syndrome. The cardinal stigmata are growthretardation with reduced final height, gonadal insufficiency andinfertility. Further congenital malformations and conditions aregiven in table I, with tentative frequencies, based on a number ofreferences.

Turner syndrome is caused by an absent or structurally ab-normal X chromosome. The typical karyotype in Turner syn-drome is 45,X; i.e. one X chromosome is missing. Most womenwith Turner syndrome, however, are not carrying the ‘typical’karyotype of 45,X, but have several different variants all causingthe clinical signs of Turner syndrome. The most frequently oc-curring karyotypes are 45,X, karyotypes with an isochromosomeof X [i(Xq) or i(Xp)], the mosaic karyotype of 45,X/46,XX, andkaryotypes containing an entire Y chromosome or parts thereof.The 45,X karyotype was found in only 48% of all live-born fe-males with Turner syndrome during the period 1970–1995.[5] Theprevalence has never been firmly established, but a number ofcytogenetic studies have given estimates ranging from 25–210per 100 000 females,[7-10] and most seem to agree on a hypothet-ical proportion of about 50 per 100 000 girls in Caucasian popu-lations (figure 1). In the future, it is possible that the number ofgirls being born with Turner syndrome will decrease because ofincreased use of prenatal diagnostic measures (amniocentesis,chorionic villus sampling [CVS], ultrasonography, triple-blood-sample testing, etc.). However, treatment and prevention meas-ures are hampered by a considerable delay in diagnosis;[11] inDenmark the median age at diagnosis is 15 years when consider-ing all girls and women diagnosed between 1920 and 2000 (figure2). This means that many girls and women are treated rather latein life, and some are never diagnosed.

Turner syndrome is often complicated by congenital cardio-vascular malformations, hypertension, ischemic heart disease,

Table I. Abnormalities associated with Turner syndrome with tentativefrequencies[2-6]

Feature Frequency (%)

1. Retarded growth and reduced final height 95-100

2. Gonadal dysgenesis no pubertal development 85

infertility 98

chronic estrogen deficiency 95-98

androgen insufficiency ?

3. Endocrine disturbances glucose intolerance 15-50

type 2 diabetes mellitus 10

type 1 diabetes mellitus 2-3

thyroiditis 15

elevated hepatic enzymes 50-80

hypertension 30-50

android body composition ?

4. Physical abnormalitiesa) Eyes

epicanthus 20

nearsightedness 20

strabismus 15

ptosis 10

b) Ears

infection of middle ear 60

hearing defects 30

deformity of external ear 15

c) Mouth

micrognathia (small mandibular bone) 60

high arched palate 35

abnormal dental development ?

d) Neck

low posterior hairline 40

broad short-appearing neck 40

pterygium colli (webbed neck) 25

excess loose skin in the back of the neck of neonates

25

e) Thorax

broad chest (shield chest) with apparently wide-spaced nipples

30

inverted nipples 5

f) Skin, nails and hair

increased skin ridge count 30

lymphedema of hands and feet at birth (or later) 25

multiple pigmented nevi 25

nail hypoplasia 10

vitiligo 5

alopecia 5

g) Skeleton

bone age retardation 85

decreased bone mineral content 80

cubitus valgus 50

short fourth metacarpal 35

genu valgum 35

congenital hip (sub)luxation 20

scoliosis 10

Madelungs deformity 5

h) Heart

bicuspid aortic valves 13-34

coarctation of the aorta 4-14

aortic dilation/aneurysm 2 ?

other cardiac malformations 1-6

i) Kidneys

horseshoe kidney 10

abnormal positioning or duplication of renal pelvis, ureters or vessels

15

renal aplasia 3

5. Psychosocial problems emotional immaturation 40-85

specific learning problems 40

mental problems 25

6. Other failure to thrive during first year of life 50

402 Gravholt

© Adis International Limited. All rights reserved. Am J Cardiovasc Drugs 2002; 2 (6)

and aortic dilation with or without aortic aneurysm. These asso-ciated features are responsible for considerable morbidity, andpremature death in a number of patients.

Today, most girls and adolescents with Turner syndrome aretreated with growth hormone (GH) to increase final height[12] andestrogens to induce puberty, and after the advent of menarche,progestogens are added 10–12 days every month to simulate thecyclic events of the normal menstrual cycle.

Since GH and hormone replacement therapy (HRT) may ex-ert significant cardiovascular effects, complications relating tothe heart and effects on the heart of this treatment given to womenand girls with Turner syndrome are reviewed.

2. Congenital Malformations of the Heartand the Great Vessels

An association between Turner syndrome and congenitalcardiovascular malformations has been known from early on. Inthe early series focusing on heart defects, emphasis was primarilyon coarctation of the aorta;[13-15] pulmonary stenosis was also

noted (possibly due to ‘contamination’ of study groups by pa-tients likely to have Noonan syndrome),[15,16] as well as less se-vere congenital malformations of the heart,[4,17,18] especially withthe 45,X karyotype.[4,19-21] In addition, many case reports havedescribed specific, uncommon malformations linked to the syn-drome. Although the congenital malformations of the heart havebeen recognized for many years, a number of studies during re-cent years have meticulously documented these malformationsin relatively unselected populations, and approximate frequen-cies are available[4,18,22-24] (table II).

Congenital cardiovascular malformations occur more fre-quently in unselected populations of individuals with Turner syn-drome than in the background population. The malformationsnormally involve only the vessels of the left side of the heart andshow a very characteristic pattern when compared with that ofthe general population.[23,24] A recent Italian study found congen-ital cardiac malformations in 136 of 594 (22.9%) patients withTurner syndrome.[24] This figure corroborates previous findingsin unselected groups of patients, in whom congenital cardiac le-

Year

0

10

1920 1930 1940

20

30

40

50

60

70

80

Pre

vale

nce

of T

urne

r S

yndr

ome

per

100

000

liveb

orn

girls

1950 1960 1970 1980 1990 2000

Fig. 1. Recorded prevalence of Turner syndrome per 100 000 live-born girls by year of birth from 1910 to 2000 in Denmark. The broken line indicates the hypothetical prevalence

of 50 per 100 000 live-born girls (data from the Danish Cytogenetic Central Register).

Turner Syndrome and the Heart 403


sions were found in 20–40% of.[4,23,25,26] Notably, a number ofpatients have more than one structural malformation. In a recentlarge study, it was shown that cardiac malformations were moreprevalent among the subgroup of patients with 45,X (39%) thanamong those with karyotypes that include an isochromosome(Xq) [11–12%] (mosaic or not).[23] In the large Italian study itwas also found that cardiac malformations were more prevalentamong patients with 45,X (30%) than among patients with Xmosaicism (24%) and X chromosome structural abnormalities(iXq, r[X], del[X], etc.) [11%].[24] The study group was suffi-ciently large to permit formal statistical evaluation of the risk ofcongenital malformations between these three major groups ofkaryotypes, with more malformations occurring among patientswith 45,X than among the group of patients with X chromosomestructural abnormalities (relative risk [RR] 2.7; 95% confidenceinterval [CI] 1.8–4.2), but with a comparable number of malfor-mations among patients with 45,X and X mosaicism (RR 1.2;95% CI 0.8–1.9).[24] Thus it seems that karyotypes involvingstructural abnormalities of the X chromosome confer some pro-tection towards cardiac malformations.

Likewise, in a registry study of all Danish patients withTurner syndrome, the 45,X karyotype was most frequently asso-ciated with congenital malformations, including cardiac malfor-mations.[5] In the same study, cardiovascular morbidity not re-lated to congenital malformations of the heart (such as acute

myocardial infarction, hypertension and arteriosclerosis) weremore frequently associated with karyotypes other than 45,X. Thesame pattern was seen for endocrine diseases, primarily hypothy-roidism and type 1 and 2 diabetes mellitus, indicating that themany different karyotypes involved in Turner syndrome maylead to different disease patterns, congenital as well as ac-quired.[5] It may be speculated that the increased morbidity dueespecially to endocrine disease is part of the explanation for theincreased morbidity due to cardiovascular diseases. Concerningother karyotypes (i.e. karyotypes with rings and markers or Ychromosomal material) known to result in clinical Turner syn-drome, current numbers are too small to allow formal statisticalcomparison with the 45,X karyotype.

A bicuspid aortic valve is the most common finding and isseen in 13–34% of patients, with Turner syndrome comparedwith only 1–2% in the general population[27] (figure 3). Althoughsome individuals present with a systolic murmur or an ejectionclick on clinical examination, many (perhaps the majority) arenot identified clinically, but only echocardiographically.[22,23]

Bicuspid aortic valves are seen with most karyotypes, but pre-dominantly with the 45,X karyotype.[23,24]

Coarctation of the aorta is present in 4−14% of all patientswith Turner syndrome (figure 3), and predominates in patientswith the ‘classical’ karyotype of 45,X. Most patients with aorticcoarctation are diagnosed early, because of the relative severityof the condition. Coarctation occurs more than 350-fold morefrequently in patients with Turner syndrome than in the generalpopulation.[5] Today, patients with clinically significant coarcta-tion are operated on early, either with resection and end-to-endanastomosis, or subclavian flap operation, while some undergoprimary percutaneous balloon dilatation with or without stenting.Other malformations affecting the valves have also been re-ported, such as aortic valve stenosis, aortic valve regurgitation,mitral valve prolapse, mitral valve stenosis and cleft mitral valve.Furthermore, atrial septal defect, ventricular septal defect andpersistent ductus arteriosus are seen in 1–6% of patients.[4,23,24]

Surgery, or coronary catheterization if possible, should be under-taken wherever required. Clinical follow-up is necessary in mostor all patients. In any case, all patients with either bicuspid valves,septal defects or other valvular diseases should be informed ofthe risk of infectious endocarditis in relation to minor surgery,including dental work, and be issued with proper antibiotic pro-phylaxis when necessary. Rarely, hypoplastic left heart syndromehas also been described,[23,28] which leads to early death if un-treated.[23]

The incidence of any given malformation differs from studyto study (table II). These differences are probably not important,since it is clear that any figure given in the literature is grossly

Age at diagnosis (years)

120

100

80

60

40

20

0

Median = 15 yearsRange = 0−86 yearsn = 746

80706050403020100

Num

ber

Fig. 2. Delay in diagnosis of Turner syndrome. The x-axis illustrates the number of

patients with Turner syndrome at the chronological age of diagnosis. Bars illustrate

2.5-year periods. Data are from the Danish Cytogenetic Central Register from 1910–

2000. Data include all diagnosed females with a karyotype that can be associated with

Turner syndrome.

404 Gravholt


elevated in comparison with the background population. Thus,any individual with Turner syndrome should always be seen bya cardiologist and at least have echocardiography performed. De-pending on the findings on echocardiography, some patientsshould also be examined by magnetic resonance imaging (MRI)scan, and rarely invasive examination, such as right- and/or left-sided cardiac catheterization, might be necessary.

The cause of congenital heart defects in Turner syndromeremains unknown. Various investigators have presented differentviews on the subject depending on whether they see congenitalmalformation of the heart in Turner syndrome as a true malfor-mation, linked to the expression of a specific gene or cluster ofgenes, possibly being X-linked (a gene or genes escaping X in-activation), or the result of disruption of normal embryonic de-velopmental events, and thus not caused by the karyotype itself.Since patients with 45,X karyotype are predominantly affectedby congenital cardiovascular malformations, as well as bylymphedema (and thus webbed neck), deficient development oflymphatics has been proposed as a causative factor. In utero,developing lymph channels distend secondary to failed emptyingof jugular lymph sacs into central veins. It is suggested that thesedistended lymph channels encroach on the heart and great ves-sels, in this way mechanically inducing congenital heart de-fects.[20,21,29] The development of coarctation of the aorta may bedue to a combination of maldevelopment of lymphatics and de-

creased left-sided blood flow in utero (through the aorta), leadingto increased flow through the pulmonary artery and the ductusarteriosus, which may induce development of a shelf or flange,leading to later coarctation.[20] Recent intriguing observationsshow that cardiac hypoplasia, along with lung hypoplasia, iswidespread among Turner syndrome fetuses recognized becauseof massive hydrops or large nuchal hygromas.[30] The authorsexamined 117 Turner syndrome fetuses (32% definitely verifiedby karyotyping, the rest due to typical stigmata), ad found morethan 90% of the fetuses to have heart weights below the 2.5 cen-tile, and suggested that myocardial hypoplasia is a primary defectin Turner syndrome leading cardiac pump inadequacy impedingvenous return and thereby elevating venous pressure, and that theresulting venous hypertension could lead to diminished lym-phatic outflow, and, eventually to hydrops formation. The phe-notype would thus result in intra-uterine death or, if only mini-mally restricted heart growth was seen, the fetus could survive tobirth.[30] The study leaves several questions unanswered: is car-diac and lung hypoplasia present in live-born Turner syndrome;is the hypoplasia linked to other congenital malformations of theheart; is the hypoplasia actually leading to lymphedema, or is itvice-versa, etc. Other researchers have speculated whether oneor more genes on the missing X chromosome are causative. It issupposed that such a gene (or genes) would be one of the manygenes on the X chromosome known to normally escape X inac-

Table II. Incidence of congenital malformations in patients with Turner syndrome. Data have been compiled from five trials with apparent unbiased inclusionof patients and presented as number of patients affected/total number examined (%)

Congenital malformation Incidence in clinical trials

Miller et al.[22]

(n = 35)aDawson-Falk et al.[18]

(n = 40)bGotzsche et al.[4]

(n = 179)aSybert[25]

(n = 244)aMazzanti & Cacciari[24]

(n = 594)c

Aortic coarctation 5/40 (12.5) 18/179 (10) 34/244 (14) 41/594 (6.9)

Dilated ascending aorta 2/35 (6) 5/40 (12.5) 17/594 (2.9)

Hypoplastic aortic arch 1/40 (2.5)

Bicuspid aortic valve 12/35 (34) 7/40 (17.5) 25/179 (14) 33/244 (14) 74/594 (12.5)

Mitral valve prolapse or regurgitation 2/35 (6) 2/40 (5) 1/179 (0.6) 6/244 (2) 53/594 (8.9)

Interrupted inferior vena cava with azygoscontinuation

1/40 (2.5)

Cardiac dextroposition 1/40 (2.5) 1/179 (0.6)

Aortic valve disease (stenosis and/orincompetence)

19/179 (11) 14/244 (6) 19/594 (3.2)

Partial anomalous pulmonary venous drainage 1/179 (0.6) 1/244 (0.5) 17/594 (2.9)

Ventricular septal defect 3/594 (0.5)

Atrioventricular septal defect 12/244 (5) 1/594 (0.2)

Pulmonary valve abnormality (stenosis,regurgitation)

2/179 (1)

Persistent ductus arteriosus 2/179 (1) 1/244 (0.5)

a Patients were examined only with clinical examination and echocardiography.

b Patients were examined by magnetic resonance imaging scan and echocardiography.

c Patients were examined with clinical examination, ECG, chest x-ray and transthoracic echocardiography.



tivation,[31] a situation leading to haploinsufficiency of the gene(or genes) and the gene product.

The recently reported cloning of the SHOX gene (short sta-ture homeobox-containing gene or PHOG [pseudoautosomalhomeobox-containing osteogenic gene]) from the pseudoautoso-mal region (PAR1) on the X and Y chromosome,[32,33] responsi-ble for part of the reduced growth seen in Turner syndrome andin the Leri-Weil syndrome, and perhaps especially the dispropor-tionate growth, has spurred enthusiasm, and work is in progressto identify genes responsible for other parts of the Turner pheno-type. A gene on chromosome 16 responsible for the lymphedemain the lymphedema-distichiasis syndrome has been described.[34]

Very recent work has suggested that at least one lymphogenicgene is present on the short arm of the X chromosome (Xp) distalto Xp11 between the genes of Duchenne muscular dystrophy andmonoamine oxidase A.[35] The concept of chromosomal imbal-ance, and thus disturbed pairing during mitosis, has also beenimplicated.[35]

3. Hypertension and Ischemic Heart Disease

Thirty percent of girls with Turner syndrome have mild hy-pertension on 24-hour ambulatory blood pressure monitoring,and as many as 50% have an abnormal diurnal blood pressureprofile.[36] Hypertension is also prominent in women with Turnersyndrome, who have significantly elevated blood pressure com-

pared with an age-matched control group,[37] and as many as 50%have clinical hypertension.[6,37] The nocturnal fall in diastolicblood pressure is blunted in many compared with controls, andan increase is seen with HRT, as well as in systolic night/dayratio. The significance of this is unknown. It seems that womenwith Turner syndrome are ‘non-dippers’, i.e. have a diminishedreduction of blood pressure during the night.[37] A blunted noc-turnal fall in blood pressure in hypertensive women has beenshown to predict future major cardiovascular events.[38] Inwomen with essential hypertension, non-dippers have an in-creased left ventricular mass which is considered to be an inde-pendent marker of cardiovascular morbidity and mortality.[39,40]

In Turner syndrome, compared with controls, 24-hour, day, andnight heart rate is significantly elevated,[37] which could be sug-gestive of the presence of parasympathetic neuropathy. At pres-ent there are no longitudinal studies of blood pressure and hyper-tension in patients with Turner syndrome. There is a definite needfor such studies. Furthermore, it is essential to establish the effectof treatment and to determine which drugs to choose as first- andsecond-line treatment.

Previously, the incidence of ischemic heart disease was notfound to be increased in patients with Turner syndrome, despitereports of increased plasma levels of cholesterol,[41] increasedblood pressure, and congenital cardiac malformations. Recently,in the Turner syndrome population in Denmark (n = 594), how-ever, ischemic heart disease (acute myocardial infarction and ar-teriosclerosis) was found more frequently in an epidemiologicalregister study of morbidity.[5] The RR of disease was increasedto 2.1 (95% CI 1.2–3.4), while hypertension occurred with an RRof 2.9 (95% CI 1.2–6.0), and cerebrovascular diseases of 2.7(95% CI 1.04–5.3). In a clinical study, we could not detect anydifference in measures of lipid status between a group of un-treated women with Turner syndrome before treatment and a con-trol group.[42]

Compensated hypothyroidism is associated with coronaryartery disease and elevated plasma levels of low-density lipopro-tein-cholesterol and apolipoprotein B.[43,44] This may help ex-plain part of the increased risk of cardiovascular disease in Turnersyndrome,[5] since hypothyroidism and thyroid antibody forma-tion are common in Turner syndrome, especially in a subgroupwith an isochromosome of the long arm of the X chromosome[i(Xq)].[45-57] In a recent cross-sectional study of 145 women withTurner syndrome, 14% had hypothyroidism; in a subgroup ofwomen with an isochromosome (iXq), an impressive 37.5% hadhypothyroidism, emphasizing the grossly elevated risk of thecondition linked to this karyotype.[58]

Aorticdissection

Aorticcoarctation

Fig. 3. Typical congenital malformations seen in Turner syndrome, i.e. coarctation of

the aorta and bicuspid aortic valves. The figure also illustrates the occurrence of aortic

dilation and dissection. It is noteworthy that the presence of congenital malformations

and/or systemic hypertension is not a prerequisite for the development of dilation and

dissection of the aorta.

406 Gravholt


4. Aortic Dissection

The association of aortic dissection and Turner syndrome hasbeen acknowledged for many years.[23] More than 60 case reportsof aortic dilation or dissection, some of which were fatal, havebeen described.[26,59-85] In most cases, risk factors were present.In the general population, risk factors for aortic dissection includethe following: systemic hypertension, which is present in up to90% of cases;[86,87] Marfan and Ehlers-Danloss syndrome, wheremutations in the fibrillin and the collagen type III gene are pres-ent, respectively, (which are also conditions with increased riskof dilation, aneurysm and rupture); congenital bicuspid or uni-commissural aortic valves (especially for type I and II dissec-tions);[27,86] and coarctation of the aorta.[86,87] In addition, preg-nancy, trauma and iatrogenic trauma (cannulation or incisiontrauma during cardiopulmonary bypass procedures) are risk fac-tors.[86,87] Other, rarer, risk factors include temporal arteritis, con-nective tissue disease, cystic medial necrosis of the aorta, syphi-litic aortitis, and fibromuscular dysplasia.[87] Usually, but notalways, these risk factors (other than Turner syndrome) areknown to be present in the reported cases of aortic dissection inTurner syndrome.[26,68]

At the same time, the prevalence and the nature of cardio-vascular malformations have been described in several studies(see section 2).[4,18,23,24,88] Aortic root dilation, which is a riskfactor for later rupture, is often seen and seems to be associatedwith elevated systolic blood pressure.[6] Undoubtedly, Turnersyndrome should be included in this list of risk factors for aorticdissection. At present, no abnormalities of the aortic wall havebeen identified in Turner syndrome. Cystic medial necrosis, sim-ilar to the changes found in Marfan syndrome, has been describedin some (for review see Lin et al.[26]), but not in all cases. Nobiochemical or genetic abnormalities have been described inTurner syndrome thus far.

Pregnancy is a rare event in patients with Turner syn-drome.[89,90] Owing to an increasing number of egg donation pro-grams, more patients can be expected to go through pregnancy inthe future.[91] Because of the pregnancy-associated changes inblood pressure, cardiac work load, etc., the risk of aortic dissec-tion is likely to be increased. Uneventful cases of pregnancy havebeen reported;[89,92,93] however, fatal and nonfatal cases due toaortic dissection have also been described.[94-97]

Prospective studies are needed to establish the exact risk ofaortic dissection, to identify patients at an elevated risk, and, ifpossible, to introduce procedures and/or medicine to lower therisk, both during pregnancy and during normal life.

5. Growth Hormone Treatment and the Heart

Short stature is a key feature of Turner syndrome. Growthretardation can be identified prenatally[98-100] and growth remainssubnormal not only during the first years of life[99,100] butthroughout childhood. The normal pubertal growth spurt is ab-sent in Turner syndrome,[101] even in the 15% of girls with spon-taneous puberty.[102] The rationale for starting GH treatment isnot a lack of GH secretion, but rather reduced final height. Al-though the results of different studies are equivocal and the spon-taneous and stimulated GH secretion has been found by some tobe diminished,[103,104] others have found normal GH secre-tion.[105-107] Treatment with GH has generally been found to bewell tolerated in most patients. However, in Turner syndromesupraphysiological (or pharmacological) GH doses are used, re-sulting in circulating insulin-like growth factor (IGF)-1 valuesoften in the acromegalic range, in comparison with conditionssuch as hypopituitarism (including the GH axis), chronic kidneyfailure, and other conditions. The reason for high-dose GH treat-ment is to overcome the apparent GH or IGF resistance presentin Turner syndrome,[108] and thus increase height appropri-ately.[12]

Safety of treatment clearly remains important. This has to beseen in the light of the increased cardiovascular morbidity andmortality in acromegaly,[109] a pathological condition with chron-ically elevated GH and IGF-I levels, where cardiac function isimproved with restoration of normal GH values.[110] Differentaspects of the safety of GH administration have been studied.Studies have shown that insulin resistance is induced by GH treat-ment in Turner syndrome[12,111,112] and reversed when GH treat-ment is stopped.[12] The induction of insulin resistance is of con-siderable concern, since the prevalence of type 2 diabetesmellitus is increased in Turner syndrome,[5] and a prolonged pe-riod of hyperinsulinemia could potentially lead to overt diabetesmellitus. So far, no long-term (more than 5 years) studies haveaddressed the issue of late effects of GH-induced hyperinsuline-mia. Total and regional body composition is altered in Turnersyndrome, with more body fat and less muscle mass,[113] and ismodified during GH treatment, with a reduction in truncal fat andan increase in muscle mass, presumably favorable changes nor-mally associated with a reduction in cardiovascular risk. How-ever, it is doubtful whether these changes persist after cessationof GH treatment.

Few studies have addressed the effect of GH treatment onthe heart. This is of special interest because of the increasedoccurrence of cardiovascular malformations, aortic dilation andcoronary heart disease later in life in Turner syn-drome.[4,5,18,23,26,37,114] In a recent study very high doses of GHwere used in a subgroup of patients for, on average, 7 years.[12]



No signs of left ventricular hypertrophy or evidence of worseningof hypertension were found in these girls. However, two girlswith pre-existing left-sided obstruction (congenital abnormalaortic and mitral valve, respectively) developed significant valvestenosis, and thus possibly left ventricular hypertrophy, and wereexcluded from further statistical analysis. This could suggest thatpre-existing valve abnormalities might be a risk factor for devel-oping left ventricular hypertrophy. At inclusion, many girls withTurner syndrome had relatively increased systolic and diastolicblood pressure in comparison with normal reference values, butat the end of the study there was a slight decrease in the age-adjusted diastolic blood pressure. In a recent cross-sectionalstudy of girls with Turner syndrome receiving either no treatment(mostly young girls), GH or GH in combination with estradioland a progestogen, 17% had elevated blood pressure in compar-ison with age-matched reference data.[115] Furthermore, by 24-hour blood pressure evaluation, it was shown that 57% of allgirls had a blunted nocturnal fall in blood pressure (‘non-dip-pers’).[31,116] This is a situation often encountered in hypertensionand diabetes mellitus, and thought to be indicative of autonomousneuropathy, and in adult women with hypertension (withoutTurner syndrome) it is considered an independent risk factor forlater development of cardiovascular events.[31] It remains to beseen if there are any long-term effects of GH treatment on thecardiovascular system. It is recommended that long-term follow-up is continued in previous and ongoing GH treatment trials forincreasing final height.

6. Hormone Replacement Therapy and the Heart

The chronic estrogen deficiency known to affect many adultwomen with Turner syndrome is likely to be associated with car-diovascular morbidity. It is generally assumed that treatment withestrogens not only confers cardioprotection through a loweringof harmful circulating lipids, but also through direct antioxidanteffects,[117] a change in the vascular reactivity[118] and its inter-action with vascular smooth muscle.[119,120] Part of the increasedcardiovascular morbidity and mortality in Turner syndromecould therefore be explained by non-use of estrogens.

At present, no long-term studies have assessed the effect ofHRT on the heart and on the increased mortality seen in Turnersyndrome. It might be speculated that HRT would have positiveeffects on aortic ‘stiffness’ in the long term,[121] but any directeffect on the aortic wall has not been described. Far from allpatients receive HRT during adulthood, and many adolescentsare introduced to estrogens rather late, in order to achieve thehighest final height. Recently, there has been speculation that thestandard HRT dose given to women with Turner syndrome

(estradiol 2mg or equivalent) is too low. This speculation hasbeen based on the fact that when trying to establish a ripe endo-metrium for egg donation, patients need estradiol 4mg, or more,for a prolonged period.[90]

Hypertension is frequent among patients with Turner syn-drome (see section 3), and treatment with female HRT causes asmall but significant reduction in the 24-hour diastolic pressureand the diastolic day pressure and a near significant fall in sys-tolic day pressure.[37] In postmenopausal women with hyperten-sion, treatment with estrogen, with or without gestagen, has beenshown to decrease 24-hour ambulatory blood pressure in short-term studies.[122] Although lipid abnormalities have been foundin a few, but not in most studies (see section 3), changes havebeen found during HRT in one study, with a significant, albeitsmall, fall in high-density lipoprotein-cholesterol, while otherlipid variables were unchanged;[42,123] another study found lipidsto be unaffected by HRT.[121] There are no long-term studies ofthe effect of HRT on cardiovascular morbidity and mortality inTurner syndrome. In healthy, postmenopausal women (aged 50–75years) without prior cardiovascular disease the results from therecent Women’s Health Initiative randomized trial show thatHRT should not be initiated for primary intervention of cardio-vascular disease.[124] In addition to an increased risk of cardio-vascular disease in the treated group, the results showed increasesin the risk of breast cancer, stroke, and pulmonary embolism, anda decreased risk of fractured and colorectal cancer amongst ac-tively treated women.[124] In postmenopausal women with a pre-vious cardiovascular event (secondary intervention), HRT hasproved to have no effect on cardiovascular mortality and morbid-ity.[125] In postmenopausal women with a previous stroke, has

Sur

viva

l

Median survival: Turner syndrome 70 years Background population 78 years

Age (years)

0 20 40 60 80

Fig. 4. Kaplan-Meier survival plot of females with Turner syndrome versus the back-

ground population.[125]

408 Gravholt


HRT has been unsuccessful, albeit not deleterious, as secondaryintervention.[126]

Previous research has documented that adult women withTurner syndrome are characterized by several features: glucoseintolerance, deficient insulin secretion, thyroid and hepatic ab-normalities, android body composition, decreased physical fit-ness and elevated blood pressure, with a specific increase in thenight/day ratio. Thus, several features of the metabolic syndrome(syndrome X)[127] are present in Turner syndrome, and a compar-ison with the hormonal and metabolic profile of relatives of pa-tients with type 2 diabetes mellitus is warranted. It should also bepointed out that women with Turner syndrome have a decreasedlife expectancy (figure 4), especially those with the 45,X karyo-type (figure 5).[128-130] The RR of death has been found to be high(4.16; 95% CI 3.22–5.39), especially from causes such as aorticdissection, ischemic heart disease, congenital malformations ofthe heart, epilepsy and pneumonia,[130] while the rate of malig-nancy has been found to be low in three studies.[5,128,130] Diabetes

mellitus has in many cases been found to be an accompanyingcause of death.[128] Thus, increased mortality may be due to anumber of reasons: congenital malformations leading to prema-ture death (e.g. coarctation of the aorta); osteoporosis, becauseof lack of replacement therapy; hormonal or metabolic disease,especially type 2 diabetes mellitus; ischemic heart disease;chronic estrogen deficiency, due to insufficient HRT.

At present, there is a lack of longitudinal, observational andinterventional studies in adults with Turner syndrome. It is notknown how long-term HRT affects cardiovascular morbidity andmortality. Likewise, the question of when to stop HRT, if ever,is unresolved.

7. Cardiovascular Managementin Turner Syndrome

In the clinical practice careful monitoring of glucose meta-bolism, weight, thyroid function, bones, hepatic function andblood pressure should be performed in patients with Turner syn-drome. A cardiovascular risk profile should be determined at di-agnosis, and the patient should be informed about risks and ben-efits from GH and HRT. Patients should be seen by a cardiologistand have echocardiography performed, together with clinical ex-amination (table III). When pubertal induction is taking place, itmay be prudent to perform a new cardiovascular assessment, andlikewise in adulthood.[131] If any congenital cardiac malforma-tion is present, this should be dealt with appropriately (see section2), relevant examinations and tests performed, and the patientshould be followed up at regular intervals. Endocarditis prophy-laxis should be given in case of bicuspid aortic valves, and in caseof any surgical procedures having to be performed. The potentialconsequences of GH treatment on the heart and great vesselsshould be discussed, as well as consequences of HRT, and per-haps especially the consequences of not taking HRT. Based onthe available literature, HRT is highly recommended duringadulthood. The unsolved problem of who will eventually developdilation of the aorta, and thus be at great risk of later aortic dis-

Median survival: 45,X 66 years Other karyotypes 72 years p < 0.02

0 20 40 60 80 100

Sur

viva

l

Age (years)

Fig. 5. Kaplan-Meier survival plot of females with Turner syndrome with the 45,X

karyotype versus females with Turner syndrome with any other karyotype.[125]

Table III. Cardiovascular management of patients with Turner syndrome

Echocardiography at diagnosis should be performed in all patients

If congenital cardiac malformations are diagnosed, these should be dealt with appropriately, including: surgery, if deemed clinically necessary; regularclinical examinations (echocardiography, MRI scan, blood tests, BP, etc.); prophylaxis for infectious endocarditis (visits at the dentist, minor surgery, etc.)

The potential consequences of growth hormone treatment should be evaluated

The benefits and drawbacks of HRT should be discussed with the patient at a relevant age; at present, HRT is recommended

Evaluation of the aorta, with emphasis on aortic dilation, and the subsequent risk of aortic dissection

Cardiac monitoring prior to assisted reproductive therapy or spontaneous pregnancy, and during pregnancy

Risk of ischemic heart disease

BP at every visit at the physician

BP = blood pressure; HRT = hormone replacement therapy; MRI = magnetic resonance imaging.



section, leaves the patient and her physician in a situation whererepeat echocardiography, at present, is the only solution. Cur-rently, it is not known how frequently echocardiography (and/orMRI) should be performed.

In adulthood, a new cardiovascular risk assessment shouldbe performed, and at every visit blood pressure should be moni-tored. It is recommended that special precautionary steps be takenbefore and during pregnancy, whether spontaneous or assisted,with cardiac monitoring (heart auscultation, blood pressure,echocardiography and/or MRI [only on vital indication duringpregnancy]) at regular intervals. Since general physicians onlyinfrequently encounter patients with Turner syndrome, it is rec-ommended that the care and treatment of Turner syndrome iscentralized in outpatient clinics devoted to the care of these girlsand women.

Acknowledgements

Claus Højbjerg Gravholt is supported by a research fellowship by theUniversity of Aarhus, by a grant from the Danish Diabetes Association, andthe Danish Health Research Council, grant number 9600822 (Aarhus Univer-sity – Novo Nordisk Center for Research in Growth and Regeneration).

Lone Svendsen, Karen Mathiasen, Joan Hansen, Lone Korsgaard, IbenChristensen, Kirsten Nyborg, Inga Bisgaard, and Merete Møller are thankedfor expert technical help. Line Gether and Solveig Skærlund are thanked forexpert secretarial help.

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Correspondence and offprints: Dr Claus Højbjerg Gravholt, Medical Depart-ment M (Endocrinology and Diabetes), Aarhus Kommunehospital, DK-8000Aarhus C, Denmark. E-mail: [email protected]



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Turner Syndrome and the Heart