Abstract
Background
Congenital aortic valve fusion is associated with aortic dilation, aneurysm and rupture in girls and women with Turner syndrome (TS). Our objective was to characterize aortic valve structure in subjects with TS, and determine the prevalence of aortic dilation and valve dysfunction associated with different types of aortic valves.
Methods and Results
The aortic valve and thoracic aorta were characterized by cardiovascular magnetic resonance imaging in 208 subjects with TS in an IRB-approved natural history study. Echocardiography was used to measure peak velocities across the aortic valve, and the degree of aortic regurgitation. Four distinct valve morphologies were identified: tricuspid aortic valve (TAV) 64%(n=133), partially fused aortic valve (PF) 12%(n=25), bicuspid aortic valve (BAV) 23%(n=47), and unicuspid aortic valve (UAV) 1%(n=3). Age and body surface area (BSA) were similar in the 4 valve morphology groups. There was a significant trend, independent of age, towards larger BSA-indexed ascending aortic diameters (AADi) with increasing valve fusion. AADi were (mean +/− SD) 16.9 +/− 3.3 mm/m2, 18.3 +/− 3.3 mm/m2, and 19.8 +/− 3.9 mm/m2 (p<0.0001) for TAV, PF and BAV+UAV respectively. PF, BAV, and UAV were significantly associated with mild aortic regurgitation and elevated peak velocities across the aortic valve.
Conclusions
Aortic valve abnormalities in TS occur with a spectrum of severity, and are associated with aortic root dilation across age groups. Partial fusion of the aortic valve, traditionally regarded as an acquired valve problem, had an equal age distribution and was associated with an increased AADi.
Keywords: aorta, defects, echocardiography, imaging, magnetic resonance imaging
Turner syndrome (TS) or Monosomy X is a relatively common genetic disorder characterized by the loss of all or part of one of the sex chromosomes in a phenotypic female patient. It affects approximately 1 in every 2500 live born females1 and presents with a relatively variable phenotype, with short stature, premature ovarian failure and physical traits including webbed neck, low-set or malrotated ears, ptosis, and skeletal abnormalities2,3. The most serious clinical aspect of TS is the presence of congenital heart disease, particularly aortic valve disease, coarctation of aorta, and partial anomalous pulmonary venous return4–6. There is a higher rate of prenatal diagnosis of TS as well as a higher rate of major cardiac malformations, such as hypoplastic left heart syndrome, which may account for the high rate of observed fetal demise (80%) amongst all fetuses with TS between 10 weeks and term5, 7–9. Thus, the most common cardiac defects seen in fetuses are not the most common cardiac defects seen in viable infants, children, and women.
The reported incidence of congenital heart disease in children and women with TS varies from 45% to 76%5, 6, 10, 11 with the most common defects being aortic valve disease and coarctation of the aorta. Aortic valve disease is associated with valve dysfunction, aortic dilation and even aortic dissection and aortic rupture in 1–2% of these women5, 12–15 which underlies the importance of early identification of these defects in asymptomatic women. Previously, Sachdev et al reported the incidence of bicuspid aortic valve (BAV) amongst asymptomatic, unselected female subjects with TS as 30%, and a significant proportion of these patients had aortic dilatation, elevated peak flow across the aortic valve, and aortic regurgitation16. However, in this study, a BAV was defined as partial or complete fusion of 2 aortic cusps leading to the loss of a functional commissure between the fused leaflets. Partial fusion of the aortic valve is not a clearly defined entity, and generally refers to the calcific changes of the aortic valve that are commonly acquired with age. Waller et al have described various forms of this abnormality, emphasizing the differentiation between a ‘classical congenital BAV’ and acquired cusp fusion17. Various pathology reports, autopsy series, and imaging studies have postulated an association of the nonsyndromic bicuspid aortic valve with aortic dilatation, calcific aortic stenosis and/or aortic regurgitation18–22. Although patients with partial fusion were included, these reports did not specifically focus on partial fusion of the aortic valve and did not report its prevalence in the general population. In many cases, the morphological structure of partial commissural fusion in these studies could not be determined with certainty, usually due to extensive valve destruction and heavy calcific deposits which prevented differentiation between a congenitally bicuspid and acquired valvular fusion. As such, no published description of this lesion and its prognosis in living patients exists in the literature.
The purpose of this study is to classify aortic valve abnormalities in a large group of girls and women with TS and determine the prevalence of valve dysfunction and degree of aortic dilation associated with different types of aortic valve abnormalities.
Methods
Study subjects
Between January 2007 and December 2010, 208 female patients, aged between 7 to 67 years (mean age 32.9 ± 15.5 years), with genetically proven Turner syndrome participated in an ongoing National Institute of Child Health and Human Development IRB approved Turner syndrome genotype- phenotype protocol at the National Institutes of Health. This study was approved by an institutional review committee and that the subjects gave informed consent. Inclusion criteria for the study was phenotypic females with age ≥ 7 years who on a 50 cell peripheral karyotype had ≥ 70% cells demonstrating complete or partial loss of the second sex chromosome. The karyotype based on analysis of 50 metaphase spreads for this study group was 45,X in 66%, 46,X,delXp or 46,X,iXq in 9%, mosaic for 45,X and a 2nd abnormal cell line in 18% (commonly 45,X/46,XiXq) and mosaic for 45,X and a normal cell line in 7%.
No patients were referred by a cardiologist, thus minimizing bias for patients with congenital heart disease. All subjects underwent cardiovascular magnetic resonance (CMR) imaging to define aortic valve anatomy, ascending aorta and the aortic root, as well as transthoracic echocardiography to evaluate valve function. All adult subjects gave written informed consent, and all minors gave informed assent. Body surface area (BSA) was calculated using the DuBois and DuBois formula.
CMR Imaging
CMR imaging techniques, including cine magnetic resonance imaging, black blood imaging, three-dimensional magnetic resonance angiography (MRA) with and without contrast (for subjects 18 and older or in the presence of known pathology in subjects < 18 years), and velocity-encoded cine phase contrast pulse sequences were utilized in dedicated study of the aortic valve, aortic root and thoracic aorta with a Siemens 1.5T Avanto or Espree (Siemens, Erlangen, Germany). Cross-sectional measurements of the aortic valve annulus, sinuses of Valsalva, and sinotubular junction were performed on 3D non-contrast MRA data sets. Measurements of the ascending and descending thoracic aorta were performed on axial black blood images at the level of the pulmonary artery bifurcation. Contrast-enhanced MRA data sets were used to examine the anatomy of the thoracic aorta, arrangement of the head and neck vessels and presence of aortic dilation or coarctation in adults. Finally, velocity-encoded cine phase contrast imaging was used to examine the aortic valve, classify valve defects, and detect aortic stenosis and/or regurgitation, if present. Images were interpreted by two readers. Both readers were blinded to prior clinical history and other diagnostic images.
Tricuspid aortic valves (TAV) were noted to have three cusps, three commissures which opened completely and a triangular shape on phase contrast imaging. Partially fused aortic valves (PF) valves had three cusps, two commissures which opened freely, and one commissure which was partially fused, and a “puckered” orifice appearance on phase contrast imaging. BAV were noted to have three cusps, a completely fused commissure between two cusps and an oval-shaped orifice on phase contrast imaging. Finally, a unicuspid aortic valve (UAV) was noted to have three cusps and fusion of 2 or more commissures; typically one completely fused commissure and one partially fused commissure. The shape of the orifice on phase contrast imaging was irregular and eccentrically located within the valve area. To differentiate between BAV and PF, a BAV was defined as complete fusion of two aortic valve leaflets with or without a central raphe such that a functional commissure between the fused leaflets was absent, while a PF was defined as fusion to a lesser extent (Figure 1-B). While there are no accepted imaging-based criteria for partial fusion of the aortic valve, autopsy data from the 1980’s defined a partially fused aortic valve in an adult patient as fusion of two cusps less than 5 mm extending from the wall of the aorta along the commissure19.
Figure 1.
Aortic valve structure shown on cardiac magnetic resonance imaging.
Gradient echo (left panels) and phase contrast (right panels) images of A) Tricuspid aortic valve (TAV), B) Partially fused aortic valve (PF), C) Bicuspid aortic valve (BAV), and D) Unicuspid aortic valve (UAV). A PF valve was defined by three main criteria: the degree of fusion (subjectively assessed by how much of the commissure was still visible at peak systole), the shape of the phase contrast at peak systole and the “centeredness” of the orifice in the valve.
Echocardiography
Transthoracic 2-dimensional and Doppler echocardiography using commercially available echocardiography machines was obtained. Standard parasternal, apical, and subcostal views were obtained with the subject in a left lateral recumbent position. Images were stored digitally and on VHS videotape which were subsequently analyzed. Echocardiography was used as a secondary modality to ascertain aortic valve function by the presence and degree of aortic regurgitation and stenosis only. Degree of aortic regurgitation was graded as trivial, mild, moderate and severe based on the size of the regurgitant jet determined by color Doppler and the downward slope of the continuous-wave Doppler. Peak flow velocity across the aortic valve was assessed by continuous-wave Doppler. The classification of both valvar stenosis and regurgitation were made according to the American Society of Echocardiography Guidelines respectively. Limited echocardiographic data from a subset of our cohort was reported in an earlier study on the prevalence of aortic valve disease in TS16.
Valve classification
The anatomic features of the aortic valve were examined and valves were classified according to the appearance of the cusps/commissures on cine CMR imaging and the shape of the valve orifice on phase contrast imaging. Four distinct valve morphologies were noted; TAV, PF, BAV, and UAV. Figure 1 illustrates the four types of aortic valves observed in the cohort. Aortic valve classification was based on CMR imaging and was completed by two independent reviewers, kappa=0.82
Statistical analysis
Continuous data are presented as means with standard deviation; nominal data are given as number and percent. Because there were just 3 subjects in the UAV group, these subjects were combined with the BAV group.
Analysis of variance was used to compare age across valve-structure groups, and analysis of covariance adjusting for age was used to compare body size, blood pressure and aortic diameters across these groups. Continuous variables were log transformed prior to analysis to approximate normal distribution for all groups. Nominal variables were compared by χ2. The risk of having a dilated ascending aorta was assessed in a multiple logistic regression model that included type of aortic valve, aortic valve function, and age as independent variables. These independent variables were selected by stepwise regression analysis. Variables that did not meet statistical significance for inclusion were: presence or absence of coarctation, systolic and diastolic blood pressure. Statistical significance was set at a p value ≤0.05. JMP 8.0 statistical software (SAS Institute, Cary, North Carolina) was used.
Results
The 208 study participants ranged in age 7 to 67 years (mean age 32.9± 15.5 years), including 46 pediatric subjects < 19 years of age. Table 1 lists baseline characteristics of the groups.
Table 1.
Baseline characteristics of the four groups. There were no significant differences in mean age, BSA, height, weight or blood pressure between groups.
| TAV N=134 |
PF N=25 |
BAV N=46 |
UAV N=3 |
P | |
|---|---|---|---|---|---|
| Age years (SD) | 33.6 (16.5) | 33.9(12.9) | 30.8(13.3) | 28.0 (15.7) | 0.763 |
| Pediatric age n(%) | 28 (20.9%) | 2 (8%) | 10 (21.7%) | 1 (33.3%) | 0.666 |
| Height cm (SD) | 146.1 (9.6) | 147.5 (8.2) | 148.6(7.8) | 145.7 (8.1) | 0.426 |
| Weight kg (SD) | 60.3 (19.4) | 56.4 (12.2) | 58.8(17.3) | 51.1 (3.4) | 0.648 |
| BSA m2 (SD) | 1.50 (0.25) | 1.47 (0.16) | 1.51(0.22) | 1.4 (0.09) | 0.899 |
| Mean SBP mmHg (SD) | 116 (11) | 116 (10) | 118 (13) | 106 (11) | 0.441 |
| Mean DBP mmHg (SD) | 71 (8) | 71 (8) | 72 (7) | 70 (5) | 0.859 |
Aortic valve anatomy
The prevalence of the different valve configurations within the total cohort is as follows: TAV 64% (n=134), PF 12% (n=25), BAV 23 %( n=46) and UAV 1% (n=3). Right-left (RL) coronary cusp (92%) fusion predominated over right-non (RN) coronary cusp (8%) fusion within both the BAV and PF groups, which is consistent with previously reported studies 16,18,23. No significant differences in age, height, weight or BSA were found among the four groups.
Echocardiography/CMR Comparison
All 208 participants underwent transthoracic echocardiography, including anatomic assessment of the aortic valve. Of these, 28 echo studies (13%) could not establish aortic valve anatomy due to inadequate views. An additional 20 (10%) echo studies described aortic valve anatomy which was discrepant with CMR findings. The majority of discrepancies involved valves determined to be partially fused by CMR. The 48 inadequate and misclassified echoes included 11 PF and 4 BAV. Of the 20 misclassified echo studies, 9 aortic valves were misclassified as normal and were found to have pathology by CMR. The remainder of the discrepancies involved severity of the aortic valve lesion. Table 2 illustrates comparison of echo and CMR aortic valve diagnoses. The frequency of inadequate and discrepant echo studies amongst the pediatric subjects (11% (n=5) and 9% (n=4), respectively) was comparable to the adult subjects (14% (n=23) and 10% (n=16), respectively).
Table 2.
Comparison grid of valve morphology as determined by echocardiography and cardiac magnetic resonance imaging.
| Echo | |||||
|---|---|---|---|---|---|
| TAV | PF | BAV | UAV | ||
| TAV | 113 | 3 | 0 | 0 | |
| MRI | PF | 8 | 7 | 3 | 0 |
| BAV | 1 | 2 | 40 | 0 | |
| UAV | 0 | 0 | 3 | 0 |
Aortic valve function
Aortic valve stenosis and regurgitation were assessed using standard techniques based on transthoracic echocardiography. Valve dysfunction was classified as trivial, mild, moderate, or severe according to established guidelines. Subjects were placed into one of three cohorts; those with trivial or less, mild, and moderate or greater valvular dysfunction. Table 3 depicts results of valvular function by type of valve.
Table 3.
Echo evidence of aortic valve dysfunction by valve type. Aortic stenosis and insufficiency were graded as absent, trivial, mild, moderate or severe, and these groups were cohorted into three groups: None/Trivial, Mild, and Moderate/Severe.
| Aortic Valve Dysfunction | TAV N=134 |
PF N=25 |
BAV/UAV N=49 |
P |
|---|---|---|---|---|
| Insufficiency | ||||
| None/trivial | 127 (97.8%) | 20 (80%) | 25 (51%) | P<0.0001 |
| Mild | 6 (4.5%) | 5 (20%) | 20 (40.1%) | |
| Moderate/severe | 1 (0.7%) | 0 | 4 (8.2%) | |
| All with Insufficiency | 7 (5.2%) | 5 (20%) | 24 (49%) | |
| Stenosis | ||||
| None | 134 (100%) | 23 (92%) | 42 (85.7%) | P<0.0001 |
| Mild | 0 | 1 (4%) | 4 (8.2%) | |
| Moderate/severe | 0 | 1 (4%) | 3 (6.1%) | |
| All with Stenosis | 0 | 2 (8%) | 7 (14.3%) |
Overall, there was a low incidence of clinically significant valve dysfunction within the cohort. Only 8 of 208 subjects had greater than mild stenosis or insufficiency or both, demonstrated in Table 3. Any degree of valve fusion, including PF, BAV and UAV, was significantly associated with mild aortic regurgitation and stenosis.
Thoracic aorta dimensions
Aortic dimensions increased with degree of valve fusion at all levels of the arch, and this was significant from the level of the aortic valve to the ascending aorta (Figure 2). No significant differences in aortic size were observed distal to the ascending aorta in the groups. There was a significant trend towards larger BSA-indexed ascending aorta diameters (AADi) from TAV to BAV/UAV after adjusting for age using ANCOVA (Figure 3). The mean age-adjusted AADi for TAV, PF, BAV+UAV were (mean +/− SD) 16.6 ± 3.3 mm/m2, 17.85 ± 3.3 mm/m2 and 19.70 ± 3.9 mm/m2 (p<0.0001). A post-hoc analysis evaluating the AADi while excluding the 8 subjects with more than mild valve dysfunction revealed an identical relationship between AADi and valve type.
Figure 2.
Valve morphology and aortic diameters Aortic diameters in mm/m2 observed in each of the valve groups with standard deviation in parentheses. Significant differences in size were seen at all levels of the ascending aorta including aortic valve annulus, sinuses of Valsalva, sinotubular junction, and ascending aorta. BSA body surface area, TAV tricuspid aortic valve, PF partially fused, BAV bicuspid aortic valve, UAV unicuspid aortic valve
Figure 3.
Progressive increase in AADi corresponding to aortic valve morphology. The graph depicts a progressive, step-wise increase for body surface area-indexed ascending aortic diameter (AADi) with increasing fusion of the aortic valve, controlled for age by ANCOVA analysis, p<0.001. Error bars indicated one standard deviation in the positive direction.
Forty subjects had aortic dilation with an aortic size index (ASI)>2.012; 15 with TAV, 6 with PF, 16 with BAV and 2 with UAV. In terms of valve function, 25 of these 40 had trivial or no AI, 12 had mild AI and 3 had greater than mild AI. Thirty-four had no AS, four had mild AS and 2 had more than mild AS. In terms of the aortic isthmus geometry, 30 subjects had no coarctation of the aorta, past or present, while 4 had a history of coarctation repair, 4 had evidence of a pseudocoarctation of the aorta, and 2 had evidence of a trivial coarctation.
There were no significant differences in ascending aorta size between RL and RN fused valves, with any degree of fusion (PF or BAV).
The probability of having a dilated ascending aorta was analyzed by using backward stepwise regression analysis with the following independent variables: type of aortic valve, presence or absence of aortic valve dysfunction, presence or absence of coarctation, age, average systolic and diastolic blood pressure. The probability of a dilated ascending aorta was significantly associated with abnormal aortic valve leaflets (OR 2.61, 95%CI 1.66; 4.23; p<0.0001), aortic valve dysfunction (OR: 2.45, 95%CI: 1.02; 5.99; p=0.045), and age (OR 1.08, 95%CI: 1.05; 1.11; p<0.0001).
Discussion
The present study of asymptomatic, unselected female subjects diagnosed with TS confirms congenital aortic valve disease in TS is common, and suggests that it occurs along a spectrum of severity, as opposed to the traditional binary classification of TAV or BAV. This is particularly notable, as partial fusion of the aortic valve has previously been described as an acquired valve disorder, the incidence of which increases with age. Prior studies have reported the incidence of BAV in TS ranging from 12.5% to 30% in their patients5, 16, 24–26. In most cases, echocardiography was used to image the valve, and the criterion for diagnosis of a BAV was either not defined or no distinction between partial and complete fusion of the aortic valve leaflets was made. It is likely that echocardiograms in the earlier studies may not have captured partial fusion of the aortic valve, reporting them as normal valves, or BAV and PF valves were combined into one category. Echocardiography is widely available and is an excellent tool for evaluation of valve dysfunction. However, in certain cases, direct visualization of the aortic valve morphology in women with TS by ultrasound may be limited by chest wall anomalies associated with fetal lymphedema, the “barrel-shaped chest”, and obesity. Our study shows that up to 23% of transthoracic echocardiograms were inaccurate or inadequate in their anatomic description of the aortic valve, while no CMR studies were deemed inadequate. Given these limitations, cardiac MRI is a reliable alternative, with reliable direct visualization of the aortic leaflets at high resolution in both adults and older children27. By using cardiac MRI to classify valve structure, we have eliminated any potential bias from inadequately imaged, abnormal valves.
A correlation between aortic valve defect and aortic dissection in women with TS has been reported in recent studies13, 14, 28. Aortic dissection is often preceded by aortic dilatation, which in turn is influenced by established risk factors like BAV, coarctation of aorta, and uncontrolled hypertension12, 16, 29. Lanzarini et al have reported a slow, clinically irrelevant progression of aortic dilatation in women with TS over a median follow up of 37 months. Presence of baseline dilatation, hypertension and congenital cardiovascular disease, including coarctation of the aorta, was not found to influence increase in aortic diameters over the follow up period30. Similarly, a slow progression of aortic dilatation has been reported in adult subjects with BAV22.
Partially fused aortic valves are associated with aortic root remodeling, albeit less severe than a BAV which can progress to significant aortic dilatation in some cases. Aortic root dilation can potentially progress to an aortic dissection. As such, the diagnosis of PF in TS is clinically relevant, and may follow a course similar to a BAV. The diagnosis of PF should warrant a baseline evaluation by a cardiologist including two-dimensional echocardiography, ECG, and close follow up similar to a diagnosed BAV 31. Theoretically, they may also be subject to different age-related aortic valve calcification when compared to normal TAV.
At present, the pathogenesis of BAV in TS and the etiology behind its association with aortic dilatation and proximal aortic anomalies is still not known. Most recent studies have postulated an intrinsic abnormality of this entire region involving the aortic valve and aorta simultaneously, a so-called aortopathy. In 1999, Bonderman et al have suggested premature apoptosis of the smooth muscle cells of the medial muscular layer of the aorta, prior to aortic dilatation, as a part of a genetic program that causes progression to aneurysms and dissections in patients with abnormal aortic valve morphology32. This is in agreement with the histological observation of cystic medial necrosis that has been reported in a majority of cases of aortic dissection in patients with a BAV5, 15, 33. Abnormal elastic properties of the aorta, and altered collagen resistance in the aortic wall has also been suggested5, 34. Recently, Ostberg et al reported enlargement of the extra aortic conduit arteries and increased carotid thickening in women with TS, likely due to estrogen deficiency predisposing to intimal hyperplasia in TS35. These findings are in support of the hypothesis that abnormal aortic valve morphology and proximal aortic pathology i.e., dilatation, aneurysms and dissections occur along a spectrum of severity in TS. It is likely that PF and BAV represent variable phenotypic expression of these genes such that PF represents a less severe, but clinically significant pathology in this region.
Whether type of valve fusion correlates with valve dysfunction and aortic dilatation in TS as it does in the general population is contentious. A recent review of BAV in a general pediatric population confirms that right-left leaflet fusion is more common, and usually associated with coarctation of the aorta. Right-non leaflet fusion was associated with more significant valve pathology and dilation of the aorta18. Recently, a phenotypic classification for BAV that includes aortic root shape and leaflet morphology has also been proposed. A significantly different pattern of dilatation has been reported based on the leaflets involved in fusion such that possible differences in development, hemodynamics, and possibly tissue composition between the different valve types may be inferred23. In our study of unselected, asymptomatic women with TS, we found no differences in the distribution of valve dysfunction or aortic dimensions based on this classification; however, the young mean age and asymptomatic clinical status are likely factors that would bias our group towards having less valvular dysfunction.
Limitations of this study include lack of an age-matched group of 46, XX women to determine and compare the incidence and prognosis of PF of the aortic valve in the general population. Despite the lack of an age-matched control group, we believe that the described spectrum of aortic valvulopathy in TS is informative. Confirmation of effects of PF on valve function and aortic dimensions in the general population would have to come from longitudinal studies in young children and adolescents since the relationship may be confounded by acquired valve fusion in the aging, calcified valves.
Conclusions
Aortic valve abnormalities occur in over one-third of TS patients, occur with a spectrum of severity, and are associated with aortic root dilation across age groups. Partial fusion of the aortic valve, traditionally regarded as an acquired valve problem, had an equal distribution across age groups and had an increased ascending aortic diameter in subjects with TS. Patients with TS require a clear, focused visualization of the aortic root and aortic valve, and if traditional echocardiography is inadequate, CMR should be considered.
Supplementary Material
Acknowledgements
We would like to thank all of the girls and women who were a part of this study.
Sources of Funding
This work was supported by the NIH Division of Intramural Research at the National Heart, Lung, and Blood Institute as well as the Division of Intramural Research at the National Institute of Child Health and Human Development.
Footnotes
Disclosures
None.
References
- 1.Nielsen J, Wohlert M. Sex chromosome abnormalities found among 34,910 newborn children: Results from a 13-year incidence study in arhus, denmark. Birth Defects Orig Artic Ser. 1990;26:209–223. [PubMed] [Google Scholar]
- 2.Lippe B. Turner syndrome. Endocrinol Metab Clin North Am. 1991;20:121–152. [PubMed] [Google Scholar]
- 3.Gravholt CH. Turner syndrome in adulthood. Horm Res. 2005;64(Suppl 2):86–93. doi: 10.1159/000087763. [DOI] [PubMed] [Google Scholar]
- 4.Bondy CA. Congenital cardiovascular disease in turner syndrome. Congenit Heart Dis. 2008;3:2–15. doi: 10.1111/j.1747-0803.2007.00163.x. [DOI] [PubMed] [Google Scholar]
- 5.Sybert VP. Cardiovascular malformations and complications in turner syndrome. Pediatrics. 1998;101:E11. doi: 10.1542/peds.101.1.e11. [DOI] [PubMed] [Google Scholar]
- 6.Ho VB, Bakalov VK, Cooley M, Van PL, Hood MN, Burklow TR, Bondy CA. Major vascular anomalies in turner syndrome: Prevalence and magnetic resonance angiographic features. Circulation. 2004;110:1694–1700. doi: 10.1161/01.CIR.0000142290.35842.B0. [DOI] [PubMed] [Google Scholar]
- 7.Surerus E, Huggon IC, Allan LD. Turner's syndrome in fetal life. Ultrasound Obstet Gynecol. 2003;22:264–267. doi: 10.1002/uog.151. [DOI] [PubMed] [Google Scholar]
- 8.Gravholt CH, Juul S, Naeraa RW, Hansen J. Prenatal and postnatal prevalence of turner's syndrome: A registry study. BMJ. 1996;312:16–21. doi: 10.1136/bmj.312.7022.16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.van Egmond H, Orye E, Praet M, Coppens M, Devloo-Blancquaert A. Hypoplastic left heart syndrome and 45x karyotype. Br Heart J. 1988;60:69–71. doi: 10.1136/hrt.60.1.69. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Ostberg JE, Brookes JA, McCarthy C, Halcox J, Conway GS. A comparison of echocardiography and magnetic resonance imaging in cardiovascular screening of adults with Turner syndrome. J Clin Endocrinol Metab. 2004;89:5966–5971. doi: 10.1210/jc.2004-1090. [DOI] [PubMed] [Google Scholar]
- 11.Dawson-Falk KL, Wright AM, Bakker B, Pitlick PT, Wilson DM, Rosenfeld RG. Cardiovascular evaluation in Turner syndrome: Utility of MR imaging. Australas Radiol. 1992;36:204–209. doi: 10.1111/j.1440-1673.1992.tb03152.x. [DOI] [PubMed] [Google Scholar]
- 12.Matura LA, Ho VB, Rosing DR, Bondy CA. Aortic dilatation and dissection in Turner syndrome. Circulation. 2007;116:1663–1670. doi: 10.1161/CIRCULATIONAHA.106.685487. [DOI] [PubMed] [Google Scholar]
- 13.Gravholt CH, Landin-Wilhelmsen K, Stochholm K, Hjerrild BE, Ledet T, Djurhuus CB, Sylven L, Baandrup U, Kristensen BO, Christiansen JS. Clinical and epidemiological description of aortic dissection in Turner's syndrome. Cardiol Young. 2006;16:430–436. doi: 10.1017/S1047951106000928. [DOI] [PubMed] [Google Scholar]
- 14.Carlson M, Silberbach M. Dissection of the aorta in Turner syndrome: Two cases and review of 85 cases in the literature. J Med Genet. 2007;44:745–749. doi: 10.1136/jmg.2007.052019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Lin AE, Lippe B, Rosenfeld RG. Further delineation of aortic dilation, dissection, and rupture in patients with Turner syndrome. Pediatrics. 1998;102:e12. doi: 10.1542/peds.102.1.e12. [DOI] [PubMed] [Google Scholar]
- 16.Sachdev V, Matura LA, Sidenko S, Ho VB, Arai AE, Rosing DR, Bondy CA. Aortic valve disease in Turner syndrome. J Am Coll Cardiol. 2008;51:1904–1909. doi: 10.1016/j.jacc.2008.02.035. [DOI] [PubMed] [Google Scholar]
- 17.Waller BF, Carter JB, Williams HJ, Jr, Wang K, Edwards JE. Bicuspid aortic valve. Comparison of congenital and acquired types. Circulation. 1973;48:1140–1150. doi: 10.1161/01.cir.48.5.1140. [DOI] [PubMed] [Google Scholar]
- 18.Fernandes SM, Sanders SP, Khairy P, Jenkins KJ, Gauvreau K, Lang P, Simonds H, Colan SD. Morphology of bicuspid aortic valve in children and adolescents. J Am Coll Cardiol. 2004;44:1648–1651. doi: 10.1016/j.jacc.2004.05.063. [DOI] [PubMed] [Google Scholar]
- 19.Nitta M, Ihenacho D, Hultgren HN. Prevalence and characteristics of the aortic ejection sound in adults. The American Journal of Cardiology. 1988;61:142–145. doi: 10.1016/0002-9149(88)91320-3. [DOI] [PubMed] [Google Scholar]
- 20.Roberts WC. The congenitally bicuspid aortic valve. A study of 85 autopsy cases. Am J Cardiol. 1970;26:72–83. doi: 10.1016/0002-9149(70)90761-7. [DOI] [PubMed] [Google Scholar]
- 21.Roberts WC, Ko JM. Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation. Circulation. 2005;111:920–925. doi: 10.1161/01.CIR.0000155623.48408.C5. [DOI] [PubMed] [Google Scholar]
- 22.Thanassoulis G, Yip JW, Filion K, Jamorski M, Webb G, Siu SC, Therrien J. Retrospective study to identify predictors of the presence and rapid progression of aortic dilatation in patients with bicuspid aortic valves. Nat Clin Pract Cardiovasc Med. 2008;5:821–828. doi: 10.1038/ncpcardio1369. [DOI] [PubMed] [Google Scholar]
- 23.Schaefer BM, Lewin MB, Stout KK, Gill E, Prueitt A, Byers PH, Otto CM. The bicuspid aortic valve: An integrated phenotypic classification of leaflet morphology and aortic root shape. Heart. 2008;94:1634–1638. doi: 10.1136/hrt.2007.132092. [DOI] [PubMed] [Google Scholar]
- 24.Mazzanti L, Cacciari E. Congenital heart disease in patients with Turner's syndrome. Italian study group for turner syndrome (isgts) J Pediatr. 1998;133:688–692. doi: 10.1016/s0022-3476(98)70119-2. [DOI] [PubMed] [Google Scholar]
- 25.Gotzsche CO, Krag-Olsen B, Nielsen J, Sorensen KE, Kristensen BO. Prevalence of cardiovascular malformations and association with karyotypes in Turner's syndrome. Arch Dis Child. 1994;71:433–436. doi: 10.1136/adc.71.5.433. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Volkl TM, Degenhardt K, Koch A, Simm D, Dorr HG, Singer H. Cardiovascular anomalies in children and young adults with Ullrich-Turner syndrome - the erlangen experience. Clin Cardiol. 2005;28:88–92. doi: 10.1002/clc.4960280209. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Arai AE, Epstein FH, Bove KE, Wolff SD. Visualization of aortic valve leaflets using black blood MRI. J Magn Reson Imaging. 1999;10:771–777. doi: 10.1002/(sici)1522-2586(199911)10:5<771::aid-jmri22>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
- 28.Bondy CA. Aortic dissection in Turner syndrome. Curr Opin Cardiol. 2008;23:519–526. doi: 10.1097/hco.0b013e3283129b89. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Elsheikh M, Casadei B, Conway GS, Wass JA. Hypertension is a major risk factor for aortic root dilatation in women with Turner's syndrome. Clin Endocrinol (Oxf) 2001;54:69–73. doi: 10.1046/j.1365-2265.2001.01154.x. [DOI] [PubMed] [Google Scholar]
- 30.Lanzarini L, Larizza D, Prete G, Calcaterra V, Klersy C. Prospective evaluation of aortic dimensions in Turner syndrome: A 2-dimensional echocardiographic study. J Am Soc Echocardiogr. 2007;20:307–313. doi: 10.1016/j.echo.2006.08.028. [DOI] [PubMed] [Google Scholar]
- 31.Bondy CA. Care of girls and women with Turner syndrome: A guideline of the Turner syndrome study group. J Clin Endocrinol Metab. 2007;92:10–25. doi: 10.1210/jc.2006-1374. [DOI] [PubMed] [Google Scholar]
- 32.Bonderman D, Gharehbaghi-Schnell E, Wollenek G, Maurer G, Baumgartner H, Lang IM. Mechanisms underlying aortic dilatation in congenital aortic valve malformation. Circulation. 1999;99:2138–2143. doi: 10.1161/01.cir.99.16.2138. [DOI] [PubMed] [Google Scholar]
- 33.Bordeleau L, Cwinn A, Turek M, Barron-Klauninger K, Victor G. Aortic dissection and Turner's syndrome: Case report and review of the literature. J Emerg Med. 1998;16:593–596. doi: 10.1016/s0736-4679(98)00041-9. [DOI] [PubMed] [Google Scholar]
- 34.Nistri S, Sorbo MD, Basso C, Thiene G. Bicuspid aortic valve: Abnormal aortic elastic properties. J Heart Valve Dis. 2002;11:369–373. discussion 373-364. [PubMed] [Google Scholar]
- 35.Ostberg JE, Donald AE, Halcox JP, Storry C, McCarthy C, Conway GS. Vasculopathy in Turner syndrome: Arterial dilatation and intimal thickening without endothelial dysfunction. J Clin Endocrinol Metab. 2005;90:5161–5166. doi: 10.1210/jc.2005-0677. [DOI] [PubMed] [Google Scholar]
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