Published online May 26, 2008
PEDIATRICS Vol. 121 No. 6 June 2008, pp. e1622-e1627 (doi:10.1542/10.1542/peds.2007-2807)
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ARTICLE

Turner Syndrome Is an Independent Risk Factor for Aortic Dilation in the Young

Leo Lopez, MDa, Kristopher L. Arheart, EdDb, Steven D. Colan, MDc, Nancy S. Stein, PhD, MPHd, Gabriela Lopez-Mitnik, MSd, Angela E. Lin, MDe, Mark D. Reller, MDf, Roque Ventura, RCSa and Michael Silberbach, MDf

a Congenital Heart Institute, Miami Children's Hospital, Miami, Florida
b Departments of Epidemiology and Public Health
d Pediatrics, University of Miami, Miami, Florida
c Department of Cardiology, Children's Hospital Boston, Boston, Massachusetts
e Genetics Unit, Massachusetts General Hospital for Children, Boston, Massachusetts
f Division of Pediatric Cardiology, Doernbecher Children's Hospital, Oregon Health and Science University, Portland, Oregon


   ABSTRACT
TOP
 ABSTRACT
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Because aortic dilation increases the risk for dissection in the general adult population, and dissection occurs with greater frequency at a young age with Turner syndrome, we studied the prevalence, magnitude, and determinants of aortic dilation in a large group of girls and young women with Turner syndrome.

PATIENTS AND METHODS. Participants at annual Turner syndrome society meetings completed a questionnaire regarding their medical history. Echocardiographic measurements of their aorta were converted to z scores by using data from a larger group of normal control female subjects. Bivariable and multivariable analyses evaluated the effects of Turner syndrome features, such as a bicuspid aortic valve, coarctation, growth-hormone therapy, blood pressure, and karyotype, on aortic size.

RESULTS. Among 138 individuals with Turner syndrome <18 years old, 49% had the 45,X karyotype, 26% had bicuspid aortic valve, 17% had a history of coarctation, 78% had a history of growth-hormone therapy, and 40% had hypertension. Aortic z scores were calculated by using data from 407 control subjects. Bivariable analyses revealed that a bicuspid aortic valve, growth hormone, and 45,X karyotype predicted a larger proximal aorta at ≥1 level. Multivariable analysis predicted a larger proximal aorta at all of the levels only for bicuspid aortic valve individuals and at the annular level for those who received growth hormone. Importantly, all of the analyses revealed that Turner syndrome predicted a larger proximal aorta independent of these characteristics.

CONCLUSIONS. Among young individuals with Turner syndrome, a bicuspid aortic valve predicts a larger proximal aorta, and growth-hormone use may predict a larger aortic annulus. Compared with a control population, Turner syndrome alone is an independent risk factor for aortic dilation.

Key Words: Turner syndrome • aortic dilation • aortic dissection • aortic z scores • bicuspid aortic valve

Abbreviations: BAV—bicuspid aortic valve • GH—growth hormone • BP—blood pressure • BSA—body surface area • ANN—aortic annulus • AR—aortic root • STJ—sinotubular junction • AAO—ascending aorta • DTA—distal transverse aortic arch • IST—aortic isthmus

Aortic dilation occurs with Turner syndrome,1–6 potentially increasing the risk of aortic dissection.7–9 Risk factors for aortic dilation and dissection in the general population include hypertension, bicuspid aortic valve (BAV), and coarctation,10,11 all of which are common with Turner syndrome12,13 and probably contribute to aortic dilation in affected individuals with Turner syndrome.14 Like Marfan syndrome, Turner syndrome may involve a generalized aortopathy, which can increase the risk of aortic dissection associated with these factors.15 Because it is a rare disorder (occurring in 1 in 2130 females),16 the determinants of aortic size in Turner syndrome have not been well studied. This is further complicated in the pediatric Turner syndrome population, in which aortic size is also affected by somatic growth.17 To evaluate the known predictors of aortic size in Turner syndrome and to determine whether Turner syndrome alone is an independent risk factor for aortic dilation in young individuals, affected members of the Turner Syndrome Society of the United States were evaluated by echocardiography at their annual meetings. Aortic measurements from these evaluations were compared with corresponding data from a large population of young female subjects without known medical problems.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Population
The protocol was approved by the Western Institutional Review Board at Miami Children's Hospital. All of the participants with Turner syndrome were recruited from and studied at annual meetings of the Turner Syndrome Society of the United States from 2003 to 2005. Although all of the interested participants were evaluated by echocardiography, only those <18 years of age were included in this study. No one had a genetic abnormality other than Turner syndrome. A written consent was obtained from all of the parents or guardians; a written assent was obtained from children able to read the form. Normal control female subjects were studied at Children's Hospital from 1987 to 2005, and analysis of cardiac measurements obtained between 1987 and 1998 has been published previously.17 Exclusion criteria included structural or functional heart disease, acute or chronic systemic disorder, hypertension, family history of hypertrophic or dilated cardiomyopathy, and abnormal height or weight percentiles.

Questionnaire
Each subject with Turner syndrome or a parent completed a questionnaire regarding karyotype (45,X versus non-45,X), heart disease, cardiac surgery, catheterization, hypertension, history of growth hormone (GH) therapy, other medications, and other medical problems.

Echocardiography
Echocardiograms for the subjects with Turner syndrome were performed with a Philips Sonos 5500 (Philips Medical Systems, Bothell, WA) or Siemens Cypress (Siemens Medical Solutions, Mountain View, CA) ultrasound system. Height, weight, and blood pressure (BP) were measured, and body surface area (BSA) was calculated by using the Haycock formula18: BSA = (0.024265) x (height0.3964) x (weight0.5378).

The limited studies used standard echocardiographic views: (1) parasternal long axis to measure the diameters along the proximal aorta of the aortic annulus (ANN), aortic root (AR) at the sinuses of Valsalva, sinotubular junction (STJ), and ascending aorta (AAO) (Fig 1A); (2) parasternal short axis to assess aortic valve morphology; (3) suprasternal long axis to exclude coarctation and measure the diameters along the aortic arch of the distal transverse arch (DTA) and aortic isthmus (IST) (Fig 1B); and (4) subcostal short axis to assess the abdominal aortic Doppler pattern. If turbulence was seen along the annulus or arch, Doppler interrogation was performed from apical or suprasternal views.


Figure 1
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  		FIGURE 1 Shown are echocardiographic measurements along the proximal aorta in the parasternal long-axis view (A) and along the aortic arch in the suprasternal notch long-axis view (B). LCCA indicates left common carotid artery; LSCA, left subclavian artery.

 
Statistical Analysis
Because of the nonlinear relationship between AR size and BSA,17 various transformations of the 2 variables were undertaken to find the "best-fit" equation to describe the effect of Turner syndrome on AR size in the absence of a BAV. In addition, all of the aortic measurements were converted to z scores by using data from Children's Hospital as described by Sluysmans et al.17 Each z score represented the number of SDs from the mean of the control group at the corresponding BSA. One-sample t tests were used to compare the mean z scores for the group of patients with Turner syndrome against 0, the mean z score of the control group. Independent t tests or 1-way analyses of variance were used to determine whether the presence or absence of a Turner syndrome characteristic was predictive of differences in aortic z scores. Because of possible interactions among the characteristics, a multivariable analysis was performed to identify the significant independent predictors of the z scores in the group of patients with Turner syndrome. The .05 level was used to define significance. SAS (SAS Institute, Inc, Cary, NC) was used for all of the analyses.


   RESULTS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
A total of 285 individuals with Turner syndrome were evaluated by echocardiography. Among these, 165 studies were performed on 138 subjects <18 years old (mean age: 10.2 years; mean BSA: 1.12 m2). The 27 repeat examinations were excluded from the analysis. Three individuals with absent height and/or weight values were also excluded. Similar echocardiographic data were obtained from 407 control subjects <18 years old (mean age: 6.4 years; mean BSA: 0.86 m2).

Among the subjects with Turner syndrome, no one had significant aortic stenosis or coarctation (Doppler-derived velocity: >2 m/second). None had more than mild aortic regurgitation. The prevalences of the 45,X (49%) versus the non-45,X (43%) karyotype, BAV (26%), and coarctation (17%) were similar to those reported previously3,13,19–22 (Table 1). Eleven subjects did not know their karyotype, and aortic valve imaging was inadequate in 21. Seventy-nine percent had a history of GH therapy.


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  		TABLE 1 Frequency of Clinical Features Among All 138 of the Subjects With Turner Syndrome

 
Using the BP measured during the evaluation, each subject with Turner syndrome was placed into a BP category using guidelines from the National High Blood Pressure Education Program based on gender, age, and height.23 Although only 4% reported a history of hypertension on the questionnaire, 56 subjects with Turner syndrome (40%) were classified as hypertensive, 16 (12%) as prehypertensive, and 55 (40%) as normotensive using the guidelines. The BP category was not available for 11 subjects (8%).

Among the subjects with Turner syndrome, thyroid disorders, renal or urologic defects, and hearing problems were the most commonly reported "other medical problems" (Table 1). Several individuals reported other heart diseases, including partially anomalous pulmonary venous connection, mitral valve abnormality, ventricular septal defect, atrioventricular canal defect, and prolonged QT interval.

In the absence of a BAV, the best-fit regression analysis of AR diameter and BSA revealed that a logarithmic transformation of both variables provided the best predictive power (R2 = 0.81) with the equation: log normal (AR) = [0.435 x log normal (BSA)] + 0.768. The units are centimeters for AR and meters squared for BSA. Figure 2 depicts the relationship between the logarithm of AR and BSA for all of the subjects with Turner syndrome without a BAV, as well as the control population (P = .016).


Figure 2
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  		FIGURE 2 Best-fit regression analyses involving logarithmic transformation of AR size and BSA for all patients with Turner syndrome without a BAV (solid line) and for the control population (dotted line) (P = .016).

 
Because the z scores for all of the measurements were based on the control population, the mean z scores for control subjects were, by definition, 0. In contrast, the mean z scores for subjects with Turner syndrome were significantly >0 for proximal aortic diameters and <0 for aortic arch diameters (Table 2). The maximum z score value among all of the measurements was 6.38 (at the AAO level); the absolute maximum diameter for all of the measurements along the aorta was 3.1 cm (at the AR level). A z score of 2 represents the 97.5th percentile at the corresponding BSA, a threshold often used to define a clinically abnormal value. Among the subjects with Turner syndrome, the prevalences of subjects with z scores ≥2, representing dilation, were 12% for the ANN, 20% for the AR, 18% for the STJ, and 30% for the AAO. These prevalence rates corresponded with increased relative risks of 4.8 to 12.0 times those of the control population, where z scores ≥2, by definition, occurred in only 2.5%.


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  		TABLE 2 Mean Aortic z Scores for 135 Subjects With Turner Syndrome With Available BSA Data

 
Bivariable analyses comparing the presence or absence of a specific characteristic among the subjects with Turner syndrome involved the following candidate variables: BAV, history of coarctation, history of cardiac surgery, hypertension (based on the BP category guidelines discussed previously), history of GH therapy, 45,X versus non-45,X karyotype, thyroid disorders, renal or urologic defects, and hearing problems. The analyses revealed several notable findings: BAV predicted a larger proximal aorta at all 4 of the levels; GH predicted a larger ANN; and 45,X karyotype predicted a larger AR compared with subjects with Turner syndrome with non-45,X karyotype. When the group of subjects with Turner syndrome was compared with the control population, subjects with and without the candidate variables had larger proximal aortas in almost all of the cases.

Multivariable regression analysis of the z scores using the same candidate variables plus age revealed that, within the group of subjects with Turner syndrome, a BAV was a significant independent predictor of a larger proximal aorta at all 4 of the levels, and GH was an independent predictor of a larger ANN (Table 3). When comparing the subjects with Turner syndrome with the control subjects, the aorta was larger at the AR, STJ, and AAO levels even without a BAV or history of GH therapy; in other words, Turner syndrome alone independently predicted a larger aorta along these levels. The effect of a BAV added incrementally to this independent effect of Turner syndrome on proximal aortic size. In this analysis, coarctation, karyotype, and BP had no effect on aortic size.


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  		TABLE 3 Multivariable Analysis of Predictors of Aortic Size in Subjects With Turner Syndrome

 

   DISCUSSION
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Aortic dissection occurs in ~1.4% of individuals with Turner syndrome,9 generally presenting at a younger age compared with the general female population (30 vs 67 years old).14,24 Approximately 80% to 90% of those who develop aortic dissection have a BAV or hypertension,1–3,14 factors known to contribute to aortic dilation in general.10,11 Furthermore, evidence is now accumulating that the Turner syndrome phenotype includes a generalized vasculopathy characterized by arterial dilation, vessel wall thickening, and abnormal pulse wave propagation,15 although the molecular or genetic basis for this observation is unknown. Aortic dilation is a major risk factor for aortic dissection in the general population,7,8 and aortic size guidelines for aggressive monitoring or intervention have been proposed in adults.25 The difficulty in assessing the determinants of aortic size in young individuals with Turner syndrome stems from the interaction between vessel size and somatic growth in all young individuals.17 Furthermore, whether aortic dilation in Turner syndrome begins during childhood has not been investigated previously.

This study represents the largest echocardiographic cross-sectional analysis of young individuals with Turner syndrome. In the young participants with Turner syndrome in this study, the prevalence of aortic dilation is higher than in control subjects, and, as seen in the general population, a nonobstructive BAV is an important predictor of this dilation.26–29 Importantly, young individuals with Turner syndrome without a BAV also have a significantly larger proximal aorta when compared with control individuals. Thus, Turner syndrome seems to be an independent risk factor for aortic dilation, and Turner syndrome may indeed include a primary aortopathy among its features. Recent studies have suggested that the aortopathy in Marfan and Loeys-Dietz syndromes involves abnormalities in a common molecular-genetic pathway, whereby abnormal signal transduction in the cytokine transforming growth factor-β pathway causes a simultaneous thickening and weakening of the aortic wall.30,31 The role of this pathway in the aortic dilation associated with a BAV or Turner syndrome is unknown.

Hypertension has also been associated with increased aortic size in Turner syndrome.32 The prevalence of self-reported hypertension in this study is markedly lower than the reported prevalence of Turner syndrome–associated hypertension,12 possibly because hypertension is underdiagnosed in the pediatric population. When actual BP measurements are used to categorize the participants using standard guidelines,23 the prevalence of hypertension corresponds with published reports, although assigning this diagnosis based on a single BP measurement is not standard clinical practice. In this study, BP does not have a significant effect on aortic size, and a larger sample size may be needed to demonstrate the reported association between hypertension and aortic dilation in the population of people with Turner syndrome.

In the multivariable analysis, GH is an independent predictor of a larger ANN. The significance of this finding is unclear. Recent reports suggest that GH treatment in Turner syndrome has no effect on aortic or ventricular size when the data are adjusted for height or BSA.33,34 In fact, 1 study suggests that Turner syndrome may have a beneficial effect on blood vessel compliance.35 Although the 45,X karyotype generally has a more severe cardiovascular phenotype than non-45,X karyotypes,3,19 it does not have a significant independent effect on aortic size in the multivariable analysis, possibly because there is insufficient power in this study to demonstrate an effect. In addition, the subjects with the non-45,X karyotype represent a genetically heterogeneous group with mosaic and deletion forms of Turner syndrome, and their specific karyotypes are not evaluated in this study.

z scores based on BSA are used to account for the nonconstant variance associated with somatic growth.17 Furthermore, when a z score is ≥2, the associated measurement is considered an abnormal value and frequently warrants close monitoring and/or therapy. However, there are no data regarding the degree of aortic dilation which places an individual with Turner syndrome at significant risk for dissection. The biochemical and structural components of Turner aortopathy need to be characterized, because aortic disease in other connective tissue disorders seems to have a different natural history. For example, aortic dissection or rupture occurs at smaller aortic sizes in Loeys-Dietz syndrome than in Marfan syndrome or Ehlers-Danlos syndrome.31 Among the 285 individuals with Turner syndrome evaluated in this study (age: 2 months to 66 years), subsequent aortic dissection occurred by informal follow-up in 2 of the adults, ages 24 and 44 years old (neither was included in the analysis for this study); their AR diameters were 3.8 and 2.9 cm, respectively, degrees of dilation that are not usually considered at high risk for dissection. Therefore, the threshold in Turner syndrome for initiating medical or surgical therapy requires additional study.


   CONCLUSIONS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
The proximal aorta is larger in young individuals with Turner syndrome when compared with control subjects, and the cause is multifactorial. As in the general population, a BAV independently predicts a larger proximal aorta in Turner syndrome. A history of GH therapy may predict a larger ANN, but a similar effect is not seen along the other levels of the aorta. The most important finding, however, is the fact that Turner syndrome by itself seems to be an independent predictor of a larger proximal aorta. The relationship between aortic dilation and the risk for aortic dissection in Turner syndrome needs to be defined to provide guidelines regarding surveillance and treatment.


   ACKNOWLEDGMENTS
 
This work is supported in part by grants from the Genentech Center for Clinical Research (San Francisco, CA), the Eli Lilly Company (Indianapolis, IN), and the Armand Anzalone Research Fund (Boston, MA).

We thank Philips Medical Systems for the Sonos 5500 Systems; Dawn Peters of the Oregon Clinical and Translation Research Institute (grant 1 UL1 RR024140-01) for additional statistical analysis; and Heather Curtiss, Dr Konstantinos Boukas, Martha Rivera, Dr Mary Minette, Lori Lampman, Christina Gomez, Alain Gomez, Dr Misty Carlson, Juan Carlos Alvarez, Lisa Gilbert, Irwin Seltzer, and Krista Gaeta for technical assistance.


   FOOTNOTES
 
Accepted Nov 19, 2007.

Address correspondence to Leo Lopez, MD, Children's Hospital at Montefiore, Division of Pediatric Cardiology, 3415 Bainbridge Ave, Rosenthal 3, Bronx, NY 10467. E-mail: llmd{at}llmd.net

The authors have indicated they have no financial relationships relevant to this article to disclose.

Dr Lopez's current affiliation is the Division of Pediatric Cardiology, Children's Hospital at Montefiore, Bronx, New York.


What's Known on This Subject

Aortic dilation, which increases the risk of dissection, occurs with Turner syndrome, partly secondary to the increased prevalence of hypertension, BAV, and coarctation in Turner syndrome. The Turner syndrome phenotype may also include a primary aortopathy.

 

What This Study Adds

This study presents pediatric data regarding aortic dilation with Turner syndrome that have not been published previously. We used a large control population in a comprehensive statistical analysis of the determinants of aortic size in young individuals with Turner syndrome.

 


   REFERENCES
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

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