Turner’s syndrome (TS) is characterized by the complete or partial loss of one X chromosome in female individuals, and occurs in 1 : 2500 live births 1. The most important common clinical manifestations are short stature and gonadal insufficiency. A 45,XO karyotype is associated with worse clinical manifestations compared with that in mosaicism. Other common structural abnormalities include prominent ears, retrognathia, narrow palate, cubitus valgus, short fourth metacarpals, renal malformations, strabismus, ptosis, low posterior hairline, webbed neck, and nail dysplasia. Lymphedema of arms and legs is commonly seen because of lymphatic absence or hypoplasia. Less common structural abnormalities include kyphosis, scoliosis, pectus excavatum, single palmar crease, and inverted nipples. Germ cell development is normal in ovaries, but there is accelerated loss of oocytes by 15 weeks of gestation. Thus, only one-third of girls with TS have spontaneous puberty, but menstrual problems are common in this subgroup 2. Two to five percent of patients may achieve spontaneous pregnancy 3.
TS is also associated with an increased incidence of functional/medical problems, most commonly, chronic otitis media, low bone density and fractures, poor feeding in infancy, abnormal liver function tests, sensorineural hearing loss, learning disabilities, and sleep apnea. Hypothyroidism and diabetes mellitus are common endocrinological problems. Common cardiovascular abnormalities include hypertension, coarctation of the aorta (CA), elongated transverse aortic arch, and bicuspid aortic valve (BAV). Less commonly, TS can be associated with aortic dissection and prolonged QT interval.
Diagnosis is often missed in the neonatal period. In a Danish study, the median age at diagnosis was 15.1 years; the standardized mortality ratio was 2.86, with causes including coronary disease, congenital malformations, and endocrine, nutritional, and metabolic disorders 4. Circulatory disorders, including aortic aneurysm, congenital cardiovascular abnormalities, aortic valve disease, and ischemic heart disease, accounted for most deaths 5. Life expectancy can be reduced by more than 10 years 6, and the mortality remains increased even after excluding patients with congenital cardiovascular anomalies 5,7. Indeed, both congenital and acquired cardiovascular problems are major causes of morbidity and mortality in TS patients.
Although most patients with TS have normal intelligence, some patients have been shown to have a number of neuropsychiatric abnormalities including poor visual–spatial skills and other cognitive defects 8,9, psychosocial difficulties 10, depression 11, and poor sexual function 12. Despite these factors and the burden of associated physical abnormalities, women with TS are able to reach a good level of achievement with regard to education and employment, which is at least similar to that of their peers 13,14. Quality of life of patients with timely induction of puberty and growth hormone treatment has been reported to be normal 15.
The focus of this review is structural cardiovascular abnormalities in TS. For a more comprehensive account of the whole spectrum of metabolic and endocrinological anomalies impacting the cardiovascular system in TS, interested readers may refer to another recent review by Mortensen et al. 16.
Congenital heart disease occurs in about 60% of fetuses and 20–30% of live-born girls with TS; the discrepancy between these figures is due to the high mortality among 45,XO fetuses with cardiovascular malformations, most commonly due to CA and hypoplastic left heart 17. Increased nuchal translucency during prenatal ultrasonography is commonly the first sign pointing to the presence of TS. Postnatally, the most common abnormalities are BAV (seen in 12–39% of patients) and CA (2–18.5%) (Table 1). BAV usually manifests as fusion of the right and left coronary cusps (in 95% of patients), and 15% have moderate or severe regurgitation, although severe stenosis is rare 24. However, regardless of aortic valve morphology, the incidence of aortic stenosis and aortic regurgitation of any degree is substantial, estimated at up to 16 and 23%, respectively, in studies of adult patients 28–30. These functional abnormalities are mostly due to, although not exclusively, the presence of bicuspid aortic valves 22,29. It is not clear whether there is an increased incidence of mitral valve prolapse, as suggested by a previous study 31, with more recent figures in TS patients ranging from 2% 19,23,32 to 5% 18 to 9% 20. Mitral regurgitation, including mild regurgitation in all cases, had an incidence of 24% in a recent study 29. Although not specifically shown in TS patients, these valvular abnormalities may theoretically increase the risk for endocarditis, and they occasionally require surgical intervention.
Of the patients, 47–49% have abnormal angulation and elongation of the aortic arch, occasionally accompanied by pseudocoarctation (an indentation or kink on the lesser curvature of the aorta, without overt obstruction to flow) and abnormal origin of the left subclavian artery from the arch posterior to the trachea 28,33. Partial anomalous pulmonary venous drainage (PAPVD; typically affecting left pulmonary veins) is not uncommon, with a prevalence of 13–18% 27,33,34, and it is 322 times more common among TS patients compared with the general population 35. Other structural defects include persistent left-sided superior vena cava (PLSVC), aberrant origin of the right subclavian artery, atrial and ventricular septal defects, and left heart hypoplasia 18,20,23,27,33,35–37.
The underlying karyotype appears to be predictive of the risk for and severity of congenital cardiovascular malformations 22. In a large study of 594 TS patients, the prevalence of congenital heart disease was significantly more frequent among patients with a 45,XO karyotype (30%) than among patients with X-mosaicism (24.3%) and those with structural abnormalities of the X chromosome (11%) 20. The 45,XO karyotype has also been shown to be associated with higher overall mortality compared with that among patients with mosaic patterns, including higher mortality from aortic aneurysm and ischemic heart disease 5.
The presence of a webbed neck, which is thought to be a residual effect of fetal central lymphedema, is associated with a higher prevalence of CA and BAV, independent of the underlying karyotype 24,38. In one study, 36% of TS patients with a webbed neck had BAV, compared with 12% of patients without a webbed neck, resulting in an odds ratio of 4.1 for BAV in patients with a webbed versus nonwebbed neck; a similar odds ratio for CA of 5 was obtained 38. On the basis of the association between venous and left-sided arterial congenital lesions and the presence of a webbed neck 20,24,33,38, it has been suggested that obstruction of fetal lymphatic flow results in mechanical pressure on the developing cardiovascular system, causing malformations such as CA, BAV, PLSVC, and PAPVD 39. Alternatively, haploinsufficiency of a gene on the X chromosome may be responsible for both lymphedema and cardiovascular defects, independent of each other 40. A detailed discussion on the possible genetic mechanisms in TS and their causative role in congenital heart disease can be found in a recent review 16.
Dilatation of the arterial tree has been documented in TS patients, at the aortic root, ascending aorta, aortic arch, descending aorta, and carotid artery levels 24–26,41–43, with the ascending aorta being the most common site of dilatation 25. When normalized for body size, different studies have shown dilatation of the aortic root in 11–20% 21,24,30,44 and of the ascending aorta in 30–37% of TS patients 21,25,30,42. Aortic dilatation is more common among patients with hypertension, BAV, CA, the 45,XO karyotype 26,30,45, and a history of congenital lymphedema 44. The rate of growth at the aortic sinus, sinotubular junction, and ascending aorta, but not at other aortic sites, in TS patients exceeded that in normal controls, as shown by a cardiovascular magnetic resonance (CMR) study with a mean follow-up duration of 2.4 years 30. In longitudinal studies, the rate of growth at these three sites of the proximal aorta exceeded that at other sites of the thoracic aorta 46. Moreover, the presence of BAV was a multivariate predictor for a more rapid increase in aortic sinus diameter over time, compared with the presence of a tricuspid aortic valve 30. To generate TS-specific prediction models for identifying patients with increased growth rates of the aorta, Mortensen et al. 46 incorporated various potential risk factors into a mathematical model derived from 102 TS patients followed up over 4.8±0.5 years, with CMR-derived measurements of aortic dimensions at several positions at three time points during the study period. Importantly, in addition to the presence of BAV, CA, and hypertension, they showed that increasing body surface area (BSA) and age, and administration of antihypertensive medication were also independently associated with higher growth rates of the ascending aorta. In addition, certain risk factors (age, BAV, CA, hypertension) have a different influence on growth rates at different sites of the aorta, whereas BSA affected all aortic sites uniformly. The presence of the 45,XO karyotype, as opposed to other karyotypes, had no independent influence on aortic diameters in this study. A vasculopathic process with conduit artery enlargement, intima thickening, and reduced arterial distensibility, without endothelial dysfunction, has also been observed 47,48. Estrogen deficiency may contribute to the increased intima media thickness 47. Cystic medial necrosis, as in Marfan’s syndrome, has been noted in biopsies of patients operated for aortic dissection or at autopsy 49–51.
The relative risks for coronary artery and cerebrovascular diseases in TS patients are increased by a factor of 2.1 and 2.7, respectively 52, whereas mortality from ischemic heart disease can be increased by up to seven-fold 53. Although the exact mechanisms behind the increased cardiovascular risk are uncertain, the higher incidence of traditional cardiovascular risk factors, including hypertension 43, dyslipidemia and atherogenic lipid profile 54–56, impaired glucose tolerance and diabetes mellitus 52,57, obesity 58,59, and estrogen deficiency, probably plays a major role. Impaired glucose tolerance and diabetes, compounded by the insulin resistance associated with obesity, may be present in about 50% of patients 57. Another factor contributing to elevated cardiovascular risk is hypothyroidism: thyroid autoantibodies and treated hypothyroidism were present in 41 and 16% of patients, respectively, in one series of 145 women with TS 60. Perhaps the major contributing risk factor for cardiovascular events is hypertension, which affects up to 25% of adolescents and 40–60% of adults with TS 36,43,61. A structural renal cause may be involved in some individuals, but essential hypertension is the most common 62. Increased night-time blood pressure (nondippers) and abnormal autonomic function have been observed in TS patients 57,61,63–65. The latter is also reflected by the increased heart rate in TS patients, which may also contribute to increased cardiovascular risk 57,63,64,66.
One of the most feared complications is aortic dissection, which occurs in 36/100 000 TS patients, compared with an incidence of 6/100 000 in the general population 49. In the latter study, the median age at dissection was 35 years, compared with 77 years among female individuals in the general population. Most of these patients have a pure 45,XO karyotype, and dissections predominantly affect the proximal aorta 67. Hypertension and aortic dilatation are important predisposing factors 43, whereas CA and congenital aortic valve abnormalities may also increase the risk for and are likely drivers of aortic dilatation 43,68,69. Of great concern, 10% of TS patients with dissections do not have recognized predisposing features such as BAV, CA, dilated aorta, or hypertension 19,67, suggesting the presence of a generalized vasculopathy. Aortic dissection will probably be low in the clinician’s list of differential diagnoses when presented with a case of a young girl presenting with chest pain; however, the presence of underlying TS should certainly alert one to the possibility 67.
Spontaneous or assisted pregnancy in TS patients is a high-risk situation, mostly because of the risk of hypertensive complications and aortic dissection, requiring special attention (see the Issues surrounding pregnancy section below).
A few studies have raised the possibility of intrinsic conduction defect and myocardial dysfunction in TS patients. A higher incidence of prolonged QT interval, right axis deviation (mostly attributable to the effect of PAPVD), right ventricular hypertrophy, accelerated atrioventricular conduction, and T-wave abnormalities were found among girls with TS 70. In this study, 36% of girls aged between 7 and 17 years with TS had QTc greater than 440 ms, although an increased risk for life-threatening arrhythmias has not been demonstrated in TS. In a study of 88 adult patients with TS (age 42.3±10.4 years), 7–11% had a QTc of 460 ms or higher; in addition, patients with a 45,XO karyotype had a longer QTc interval compared with other karyotypes. Interestingly, of the 40 patients with QTc greater than 432 ms, eight patients had mutations in one or more of five genes related to the long QT syndrome 71. Another study of 86 children with TS, aged 11.0±3.6 years, found a longer QTc interval in patients compared with age-matched children with short stature, with QTc greater than 450 ms being observed in 20.9% of TS patients 72. Although this latter study reports a single case of sudden cardiac death in a 17-year-old girl with TS and prolonged QT, the frequency of sudden arrhythmic death and the contribution of prolonged QTc to the mortality risk in TS patients are not known. Finally, an echocardiographic study revealed reduction of longitudinal systolic strain rates and diastolic abnormalities as compared with those in age-matched healthy female controls 73.
Cardiovascular issues in the treatment of Turner’s syndrome
Growth hormone treatment
The initial goal of medical treatment in TS is to maximize adult height, minimize the negative effects of hormonal deficiencies, and induce timely feminization. Growth retardation starts in utero, and the average girl with TS falls below the fifth percentile for height by 1.5 years of age 74. Growth failure is exacerbated by poor feeding and the lack of pubertal growth spurt. The final adult height in untreated individuals is about 20 cm less than the mean height for healthy adult female individuals 75. Supraphysiological doses of growth hormone (GH) are used to overcome the end-organ resistance to GH and insulin-like growth factor-1 seen in TS patients 76. In a randomized control trial, GH treatment (in combination with sex steroid therapy at the time of puberty) resulted in a 7.2-cm mean gain in height over controls after treatment for a mean of 5.7 years 77. It seems that the maximal developmental benefit from GH treatment is derived when therapy is started early. Studies indicate that GH is safe and effective beginning as early as 9 months of age 78. Besides gain in height, GH treatment has other metabolic benefits, namely, reduction in body fat and increased muscle mass 79, better long-term glucose tolerance (despite the decreased glucose sensitivity associated with GH administration), and a less atherogenic lipid profile 80. The achievement of a normal or near normal height and normal secondary sexual characteristics with GH and sex hormone therapy appears to have other psychosocial benefits on quality of life 15 and these potential benefits should not be underestimated.
Guidelines recommend GH therapy in all TS patients, as soon as growth failure is diagnosed and until the achievement of final adult height 81. Of particular interest to the cardiologist is the effect of GH treatment on the cardiovascular system. Most clinical data are derived from studies on GH administered to patients with GH deficiency (GHD), whereas theoretical cardiovascular risks of long-term GH treatment are based on the known adverse cardiovascular effect of excess GH in acromegaly and the field of sports doping.
GH treatment is beneficial in patients with GHD, with positive effects including improved cardiac contractile and diastolic functions 82,83, physiological increase in left ventricular (LV) mass and cardiac dimensions 82, reduction in arterial wall thickness and stiffness 84, improved exercise capacity 83, reversal of atherosclerosis 85, improved lipid profile and decrease in inflammatory markers, 83,85,86, increased lean body mass 86, and reduced peripheral vascular resistance 87. In contrast, excess GH in acromegaly is known to be associated with LV hypertrophy 88,89, hypertension 90, and increased cardiovascular mortality 91. Administration of supraphysiologic doses of GH to individuals without GH deficiency increases cardiac output and decreases systemic vascular resistance, but also promotes LV hypertrophy 92 and increases aortic size 93. Thus, the main concerns about GH treatment in TS is the hypothetical risk of inducing disproportionate increase in cardiac mass and aortic dimensions, which may result in cardiac dysfunction and an increased risk of aortic dissection, respectively. Some studies on GHD suggest that long-term GH treatment may induce an increase in LV mass that is disproportionate to the concomitant increase in body size 94,95. Data obtained specifically from TS patients, however, are more reassuring. In one study with a mean duration of treatment of 4.7 years and an average age at initiation of treatment of 9.4 years, GH treatment did not seem to affect the size of the ascending and descending aorta beyond the increase in dimensions that is expected with increased body size after treatment 96. Results from the TS subgroup of the National Cooperative Growth Study registry do not suggest an increased risk of aortic dissection with GH treatment, beyond the already raised baseline risk in these patients 97. Further, aortic distensibility appeared to be improved with GH treatment 48. Echocardiographic and CMR studies did not reveal any excessive increase in LV wall thickness and mass, or impairment in ventricular function, in TS patients treated for a mean duration of 9 years 66, 7 years 98, and 4.4 years 99, even at higher doses 66,98. No adverse effect on blood pressure and lipid profile has been noted 80,98,100.
Guidelines recommend initiation of low-dose estradiol therapy at as early as 12 years of age, if follicle stimulating hormone is elevated, which should be continued until the time of normal menopause to maintain feminization and prevent osteoporosis. The aim is to improve development of secondary sexual characteristics, uterine size, reproductive capacity, and bone mineral density 101, and to optimize liver 102 and cardiovascular function, as well as brain development. Timely induction of puberty can lead to better social adjustment, self-esteem, sexual function, and quality of life 15,103. In TS patients, there is evidence that estrogen treatment improves endothelial function, manifested by an improvement in bradykinin-induced vasodilatation 104 and a reduction in the aortic augmentation index 105. Slight reductions in high-density lipoprotein levels have been observed with estrogen treatment 57, whereas others have shown no effect on lipid profile 105. Finally, with reference to the effect on cardiovascular risk, adult TS women treated with estrogen showed increased fat-free mass and physical fitness, and reduced diastolic blood pressure, although glucose tolerance worsened 57,63. The long-term cardiovascular effects of hormone replacement therapy in TS patients are not known, but large studies in the general population have failed to show the benefit of this treatment for primary 106 or secondary prevention 107.
Issues surrounding pregnancy
As only ∼2% of patients are spontaneously fertile, assisted pregnancy is increasingly adopted with reasonably good success rates 108–111. Pregnancy in TS patients also entails a high risk for diabetes and hypertensive complications 109,112,113, as well as fetal complications (intrauterine growth retardation and premature delivery) 109,112,114. There is also an increased need for a Cesarean section because of their relative small size or to avoid the cardiovascular stress of vaginal delivery in the presence of aortopathy 110,111,114. In a French multicentre retrospective study of 93 TS patients achieving pregnancy through oocyte donation, Chevalier et al. 112 reported pregnancy-induced hypertension and pre-eclampsia in 17 and 21% of their patients, respectively, which were associated with low birth weight and premature delivery. They also reported that only 40% of pregnancies were completed without maternofetal complications. In this study, two patients died of aortic dissections after a Cesarean section carried out at 38 weeks.
There is no doubt that aortic dissection occurs in pregnant TS women, in both assisted 112,115,116 and spontaneous pregnancies, 117 and carries a high mortality. In a literature review, Carlson et al. 67 reported that 86% (six of seven patients) of pregnant TS patients with aortic dissection died. However, the magnitude of risk of fatal aortic dissection in pregnant women with TS is not clear. Previous estimates, based on questionnaires and literature surveys, placed the risk of maternal death from aortic rupture or dissection during pregnancy at about 2% 108,118. More realistic outcomes of pregnancies in TS patients can be expected from long-term nationwide studies, such as the series of Nordic studies by Hagman et al.114. There was no maternal mortality in a Swedish registry of 115 pregnant TS women and a Nordic study of 106 women with TS who delivered after oocyte donation 113, and this result remained valid even in a long-term study of 124 Swedish women with TS who gave birth between 1973 and 2010, followed up for a median of 10 years after the first delivery 119. The authors did, however, report two cases of nonfatal aortic dissection, diagnosed during pregnancy 113,114.
Other results of these Nordic studies are worth mentioning. In the Swedish registry of pregnant TS women, the authors were unable to find an increased risk for intrauterine growth retardation or for birth defects in the offspring, but there was a higher rate of preterm delivery compared with that in non-TS pregnant controls 114. In the retrospective Nordic cohort study of TS women who delivered after oocyte donation, potentially life-threatening complications occurred in 3.3% 113. Similar to previous studies, the authors reported a high rate of hypertensive complications in 35% of pregnancies (including severe pre-eclampsia in 4.3%), Cesarean section in 82%, and placental complications in 4.7% 113. Overall, neonatal outcomes were quite favorable compared with previous studies 113,114. Finally, as expected, there was a high burden of cardiovascular and thyroid diseases during pregnancy, compared with control non-TS mothers matched for maternal age, number of children, and year of birth of first child 119.
Patients with TS who are planning for a pregnancy should be carefully screened for cardiovascular abnormalities, ideally by CMR 81. Regrettably, a survey of US donor egg programs showed that only 49% of TS women had undergone preconception screening echocardiography; of the screened patients, 8% had a cardiovascular structural abnormality 108. Worse figures are quoted in the French study, with only 38% of oocyte donation recipients having had undergone prepregnancy echocardiography or CMR 112. Recent studies are more reassuring – 63.5% of oocyte donation patients in the above-mentioned Nordic study had undergone comprehensive cardiovascular examination before pregnancy 113. Women with BAV, aortic dilatation (>2.0 cm/m2), and CA should be advised against pregnancy 120, whereas pregnant women (even those with normal images on screening) should undergo periodic cardiology reviews and echocardiography, with an elective Cesarean section if there is baseline dilatation or progressive dilatation of the aorta 118. Whether pregnant TS women with normal aortic valves and/or normal aortic dimensions on prepregnancy screening have an increased risk for aortic emergencies is not currently known: fatal aortic dissection, preceded by aortic enlargement, has been reported during and after assisted pregnancies in patients with normal findings on preconception cardiovascular examination 113,115,121. When attempting assisted reproduction, in addition to a full cardiovascular assessment, women should be screened for thyroid, hepatic, and renal abnormalities, as well as for diabetes, and multiple pregnancies should be avoided 113,116. Imaging and surveillance in these high-risk pregnancies, and preconception counseling, are best carried out in specialized TS centers. The onset of aortic dissection remains difficult to predict 113.
Other treatment options
There is no evidence base for any medical treatment in TS to reduce the risk for progressive aortic dilatation and dissection, although the use of antihypertensive drugs in patients with confirmed hypertension makes intuitive sense. Experts suggest the use of β-blockers and angiotensin converting enzyme inhibitors 40. β-Blockers may also attenuate sinus tachycardia that is observed in TS patients 63. Whereas β-blockers 122, angiotensin converting enzyme inhibitors 123, and angiotensin II receptor blockers 124 have shown benefit in terms of reducing progression of aortic dilatation in Marfan’s syndrome, there are no clinical studies on any class of antihypertensive drugs, specifically for TS patients.
Besides the surgical treatment of valvular disease, aortic aneurysms, coarctation, and dissections, and the Norwood procedure for hypoplastic left heart syndrome, TS patients may be candidates for various forms of minimally invasive interventions including balloon angioplasty for aortic stenosis and CA (with or without stenting) 125, endovascular stent grafts for aneurysms of the descending aorta, percutaneous valve implantation for aortic stenosis, device closure of atrial septal defects and patent ductus arteriosus, and coil implantation in arteriovenous connections.
Patient monitoring and the role of cardiovascular imaging
Monitoring of patients with TS has two objectives: (a) detection and management of cardiovascular risk factors, and (b) diagnosis, timely reassessment, and treatment of congenital cardiovascular malformations and their functional sequelae. The intensity of treatment and frequency of visits depend on the identification of high-risk subgroups (Table 2). Pregnant TS patients, or patients contemplating pregnancy, require special attention, as discussed above.
The screening for cardiovascular risk factors should include blood pressure measurement, fasting glucose and oral glucose tolerance tests, BMI measurements, fasting lipid profile, and thyroid and liver function tests. Hypertension, being the most common predisposing factor for aortic dilatation and dissection, should be treated aggressively. In normotensive patients, blood pressure readings should be documented at least annually 126; 24-h blood pressure monitors may be useful for detecting nocturnal hypertension. Patients with hypertension should be investigated for CA, renal abnormalities, and target organ damage. Extrapolating from studies on nonsyndromic aortic dilatation, in which smoking can be associated with larger aortic dimensions 127, it may be wise to strongly advise against smoking, which may also contribute to the increased cardiovascular risk in these patients. All TS patients require an ECG at some stage. The presence of right ventricular strain and right axis deviation should alert caregivers to the possibility of PAPVD 70. QT-prolonging drugs should be avoided in TS patients with prolonged QT. Obesity is a common cardiovascular risk factor in TS 58, and related issues like diet and exercise need to be addressed, keeping in mind the presence of underlying cardiovascular structural abnormalities and skeletal problems.
Cardiovascular imaging in Turner’s syndrome
All patients with TS should undergo some form of cardiac imaging at diagnosis, together with further imaging at regular intervals, with a frequency and modality tailored to the individual’s clinical needs. The following discussion will focus on (a) the difficulty in defining ‘high-risk’ aortic dimensions, (b) the choice of imaging modality, and (c) the imaging schedule for the individual patient.
In patients with a normal karyotype and with Marfan’s syndrome, aortic dilatation is a well-recognized risk factor for aortic dissection and can be used to judge the timing of surgical intervention 128. However, the utility of aortic dimensions in predicting the clinical course in TS has not been fully elucidated. It is not known whether aortic dissection in TS is preceded by progressive dilatation of the aorta. In addition to reports of dissection occurring in TS patients without aortic dilatation, the limited longitudinal data suggest that aortic dilatation is a very slow process and proceeds at the same rate regardless of the presence or absence of baseline dilatation 44. Although some TS patients do manifest an increased rate of growth of aortic dimensions compared with normal patients, especially in the proximal aorta, 46 the relation between growth rate and risk of dissection is not known. Worryingly, aortic dissection can occur in the presence of a normal growth rate 69. There is uncertainty with regard to the definition of ‘normal’ aortic diameter in TS patients because of their small body size compared with the general population. To account for different body size, BSA appears to be the best normalization parameter within the TS population 45. With regard to defining a putative ‘high-risk’ aortic diameter, it may not be appropriate to borrow cutoff points commonly used in Marfan’s syndrome, another syndrome in which patients are prone to aortic dilatation and dissection, as these patients tend to have a large body size 129. Another approach is to quantify the ratio of the ascending to the descending aortic diameter 21, which eliminates the need for normalization to body size. However, this index may be rendered insensitive to the presence of true ascending aortic dilatation if the descending aorta is also dilated.
Although determining the presence of aortic dilatation is an important issue, the complete picture requires an understanding of the syndrome-specific risk of dissection associated with a given aortic size, which can only be achieved through large longitudinal studies. The importance of such syndrome-specific cutoff points was illustrated by data from the International Turner Syndrome Aortic Dissection Registry 69. In this paper, TS women with dissection had a mean absolute ascending aorta measurement of 4.1 cm, which is well below the cutoff points for prophylactic surgery (5.0 cm) recommended in patients with Marfan’s syndrome and nonsyndromic BAV. In a cohort of 166 TS patients, Matura et al. 42 reported three cases of aortic dissection over a follow-up of 3 years. All patients had absolute diameters of the ascending aorta of above 3.5 cm, although none had a diameter above the absolute cutoff point of 5.5 cm advocated by guidelines for nonsyndromic patients 130. All patients had normalized aortic diameters of greater than 2.5 cm/m2 (the 99th percentile value for normal controls). In other words, 33% of women with normalized aortic diameters above this cutoff point had dissection. The authors went on to suggest that TS women with ascending aorta dilatation of 2 cm/m2 or higher during screening should be further evaluated (including CMR if the initial screening test was echocardiography). The presence of coexisting BAV, CA, transverse aortic arch, and/or pseudocoarctation should place the patients in a high-risk subgroup. Finally, using the 2.5 cm/m2 cutoff point for recommending prophylactic surgery in these patients is also supported by findings from the International Turner Syndrome Aortic Dissection Registry 69.
Although the growth rate of the aorta appears to be increased in TS, the use of growth rate as a risk stratifier is difficult because of paucity of studies linking this parameter with outcomes 16. The prediction of growth rate of the aorta is complicated by the interplay of the various risk factors for aortic dilatation, their varying influence on different aortic sites, and the probably erroneous assumption of linear growth of the aorta. Using an innovative approach to assess risk of dissection, Mortensen et al.46 developed a mathematical model based on measurements at nine sites in the thoracic aorta at three different time points during follow-up, and generated prediction charts of expected aortic diameters at various sites depending on the patient’s clinical risk profile. The authors were able to generate a robust nomogram for predicting aortic dimensions at various sites in TS patients on the basis of their age, body size, and risk factors. Patients whose measurements deviate considerably from expected values may be considered for prophylactic surgery.
Generally speaking, the cardiologist has a choice between three imaging modalities for diagnosing and monitoring TS patients: echocardiography, CMR, and computed tomography (CT). Transthoracic echocardiography has the obvious advantages of being widely available, transportable, and a relatively cheap technique, which is not hampered by potential claustrophobia issues. For these reasons, it is most suited for repeated frequent examinations with minimal inconvenience to the patient. Echocardiography provides useful information on aortic dimensions, presence and severity of aortic coarctation and aortic valve lesions, and cardiac function. This technique is adequate for assessment and monitoring of aortic root dimensions in TS patients 44, especially in young children. Beyond infancy, echocardiography may miss findings such as PAPVD 37 and PLSVC, although indirect signs may be appreciated (dilated right-sided cardiac chambers and dilated coronary sinus, respectively).
The most significant limitations are the lack of good image quality in patients with poor echocardiographic windows, restriction to a few imaging planes, and the aortic ‘blind spots’ encountered both on transthoracic and transesophageal echocardiography. The former issue is particularly problematic in patients with abnormal or unusual anatomy of the intrathoracic organs. Unusual thoracic cage architecture in patients with fetal lymphedema, that is, the patients at highest risk for abnormalities, may impair adequate echocardiographic visualization of the aortic valve and aorta 40. A diagnosis of BAV may be missed because of poor visualization of the aortic valve 24. Generally speaking, although there is a high degree of agreement in aortic dimensions between echocardiography and CMR, feasibility of aortic dimension measurement by echocardiography decreases beyond the aortic arch 131. False reassurance may be provided by an echocardiographic study, which reveals normal aortic root dimensions but misses dilatation of the rest of the aorta or CA, as shown by studies utilizing both echocardiography and CMR 18,21,26,132.
CMR provides an excellent means for screening and follow-up of cardiovascular abnormalities in patients with TS. A comprehensive CMR examination in TS patients should provide information on ventricular structure and function, cardiac valvular morphology and function, aortic dimensions, architecture of the aortic arch, presence and severity of CA, presence of PAPVD and PLSVC, and other abnormal arterial and venous connections 33. Assessment of the entire extent of the aorta by CMR is rapid and can be carried out with and without contrast 46,132. Excellent visualization of the thoracic vasculature with good blood–tissue contrast can be obtained with balanced steady state free precession and double inversion black blood turbo spin echo sequences (both of which use intrinsic rather than exogenous contrast), complemented by the ability to acquire three-dimensional datasets using both noncontrast techniques and contrast-enhanced angiography. An important CMR study found a high prevalence of aortic abnormalities in TS patients, including elongation of the transverse arch (49%), aortic coarctation (12%), and an aberrant right subclavian artery (8%), in addition to venous anomalies such as PLSVC (13%) and PAPVD (13%) 33. By measuring jet velocities using phase-contrast velocity mapping, quantifying the extent of collateral flow 133 and the degree of lumen narrowing, and assessing blood flow characteristics 134, CMR is able to determine the severity of aortic coarctation and facilitate decision-making with respect to surgical management. Finally, CMR may prove to be indispensable in patients with poor echocardiographic windows due to chest wall deformities. Figures 1–3 illustrate common abnormalities of the aortic valve, aortic root, ascending aorta, aortic arch, and thoracic venous connections in TS patients who have undergone CMR using various pulse sequences.
Although CT provides accurate information on aortic anatomy and abnormalities, the additional hemodynamic and cardiac structural and functional information provided by CMR, together with the risks associated with radiation exposure on repeated CT scanning, make CT a less attractive approach as both a screening and a follow-up monitoring tool for TS patients, especially because this condition often demands a scanning schedule starting from a very young age. However, CT is more widely available, provides complete coverage of the aorta, can help visualize calcification, may be simpler and more rapid than a CMR examination, and is particularly useful in the emergency diagnosis of acute aortic syndromes because of its 24-h availability, fewer constraints in terms of hemodynamic patient monitoring, and its potential to diagnose other causes of acute chest pain. CT also provides superior images, compared with CMR, of the coronary arteries (which may be useful in preoperative planning), and can be used in patients with pacemakers, aortic endovascular stents, and metallic implants. The presence of renal dysfunction complicates the use of both iodinated and gadolinium contrasts in CT and CMR, respectively, albeit for different reasons (i.e. contrast nephropathy and risk of nephrogenic systemic fibrosis, respectively). However, excellent delineation of aortic pathology can be provided by noncontrast pulse sequences with CMR.
The best way to use cardiac imaging in monitoring patients with TS has not been fully elucidated. In general, if the initial screening using echocardiography and CMR is completely normal and the patient is normotensive, routine follow-up at 5–10-year intervals, using echocardiography to monitor aortic dimensions, is advised 81. Yearly echocardiography is advised if the aortic root dimensions exceed 3 cm 126. Patients with ascending aortic diameters greater than 2 cm/m2 should be considered a high-risk group, and a dimension exceeding 2.5 cm/m2 confers an even higher risk 42,69. BAV is frequently asymptomatic in young patients, but the risk of functional deterioration demands a regular imaging schedule. Although echocardiography may be sufficient for screening infants and young girls, Bondy 40 recommends that all young adults with TS be comprehensively assessed with CMR at some point. Reassessment, preferably with CMR, is advised before planning for pregnancy, at transition to adult clinics, and when a new diagnosis of hypertension is made. Patients with hypertension or abnormal findings may need more frequent visits, the frequency of which depends on the presence of underlying high-risk features (BAV, CA, and dilated aorta) and specialist cardiological opinion 81,126. For routine monitoring, CMR is the best imaging modality for patients with these high-risk features and with poor echocardiographic windows.
A large proportion of TS patients are still being diagnosed in adulthood, emphasizing the importance of heightened awareness on behalf of both the adult cardiologists and their pediatric colleagues. Monitoring patients with known abnormalities, especially patients with aortic malformations, remains a challenge for various reasons. Quantification of the risk of aortic dissection is difficult because of the lack of certainty on the natural history of aortic dilatation and on how to define high-risk aortic dimensions. Uncertainty also exists with regard to the mechanism of aortic disease in TS, and whether specific medical treatment may slow the progression of aortic root dilatation, as in Marfan’s syndrome. It must be emphasized that aortic dissection in TS patients can occur at a considerably younger age compared with the general population, and it has also been reported in a minority of patients without predisposing features. Pregnancy in TS women with aortic malformations is a high-risk situation to both the mother and the fetus, requiring vigilance and preconception counseling. It is imperative to perform preconception imaging in all patients contemplating pregnancy. For the purpose of screening and monitoring TS patients in general, the choice of the best imaging modality depends on several considerations, although CMR holds promise as the technique of choice.
Conflicts of interests
There are no conflicts of interest.
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