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, Michael Silberbach, MDf
aCongenital Heart Institute, Miami Children’s Hospital, Miami, Florida; Departments ofbEpidemiology and Public Health anddPediatrics, University of Miami, Miami,
Florida;cDepartment of Cardiology, Children’s Hospital Boston, Boston, Massachusetts;eGenetics Unit, Massachusetts General Hospital for Children, Boston,
Massachusetts;fDivision of Pediatric Cardiology, Doernbecher Children’s Hospital, Oregon Health and Science University, Portland, Oregon
The authors have indicated they have no financial relationships relevant to this article to disclose.
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 compre-hensive statistical analysis of the determinants of aortic size in young individuals with Turner syndrome.
ABSTRACT
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 com-pleted a questionnaire regarding their medical history. Echocardiographic measure-ments of their aorta were converted tozscores 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 zscores 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 atⱖ1 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 inde-pendent risk factor for aortic dilation.Pediatrics2008;121:e1622–e1627
A
ORTIC DILATION OCCURSwith Turner syndrome,1–6potentially increasing the riskof aortic dissection.7–9 Risk factors for aortic dilation and dissection in the general population include
hyper-tension, bicuspid aortic valve (BAV), and coarctation,10,11all of which are common with Turner syndrome12,13and
probably contribute to aortic dilation in affected individuals with Turner syndrome.14Like Marfan syndrome, Turner
syndrome may involve a generalized aortopathy, which can increase the risk of aortic dissection associated with these factors.15Because it is a rare disorder (occurring in 1 in 2130 females),16the 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 echocardi-ography 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.
www.pediatrics.org/cgi/doi/10.1542/ peds.2007-2807
doi:10.1542/peds.2007-2807
Dr Lopez’s current affiliation is the Division of Pediatric Cardiology, Children’s Hospital at Montefiore, Bronx, New York.
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
Accepted for publication 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@ llmd.net
PATIENTS AND METHODS
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. Al-though 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 Chil-dren’s Hospital from 1987 to 2005, and analysis of car-diac measurements obtained between 1987 and 1998 has been published previously.17 Exclusion criteria
in-cluded structural or functional heart disease, acute or chronic systemic disorder, hypertension, family history of hypertrophic or dilated cardiomyopathy, and abnor-mal height or weight percentiles.
Questionnaire
Each subject with Turner syndrome or a parent com-pleted a questionnaire regarding karyotype (45,X versus non-45,X), heart disease, cardiac surgery, catheteriza-tion, 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 Med-ical Systems, Bothell, WA) or Siemens Cypress (Siemens Medical Solutions, Mountain View, CA) ultrasound sys-tem. Height, weight, and blood pressure (BP) were mea-sured, and body surface area (BSA) was calculated by using the Haycock formula18: BSA ⫽ (0.024265) ⫻
(height0.3964)⫻(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.
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 de-scribe the effect of Turner syndrome on AR size in the absence of a BAV. In addition, all of the aortic measure-ments 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 meanzscore of the control group. Inde-pendentttests or 1-way analyses of variance were used to determine whether the presence or absence of a Turner syndrome characteristic was predictive of differ-ences in aorticzscores. Because of possible interactions among the characteristics, a multivariable analysis was performed to identify the significant independent pre-dictors of the z scores in the group of patients with Turner syndrome. The .05 level was used to define sig-nificance. SAS (SAS Institute, Inc, Cary, NC) was used for all of the analyses.
RESULTS
A total of 285 individuals with Turner syndrome were evaluated by echocardiography. Among these, 165 stud-FIGURE 1
ies 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 coarcta-tion (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.
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.23Although only 4% reported a history of
hyper-tension on the questionnaire, 56 subjects with Turner syndrome (40%) were classified as hypertensive, 16 (12%) as prehypertensive, and 55 (40%) as
normoten-sive using the guidelines. The BP category was not avail-able for 11 subjects (8%).
Among the subjects with Turner syndrome, thyroid disorders, renal or urologic defects, and hearing prob-lems 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, ventricu-lar septal defect, atrioventricuventricu-lar canal defect, and pro-longed QT interval.
In the absence of a BAV, the best-fit regression anal-ysis of AR diameter and BSA revealed that a logarithmic transformation of both variables provided the best pre-dictive power (R2⫽0.81) with the equation: log normal
(AR)⫽[0.435⫻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 syn-drome without a BAV, as well as the control population (P⫽.016).
Because thezscores for all of the measurements were based on the control population, the mean zscores for control subjects were, by definition, 0. In contrast, the meanzscores for subjects with Turner syndrome were significantly⬎0 for proximal aortic diameters and⬍0 for aortic arch diameters (Table 2). The maximum zscore 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). Azscore 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 scoresⱖ2, 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 rel-ative risks of 4.8 to 12.0 times those of the control
TABLE 1 Frequency of Clinical Features Among All 138 of the Subjects With Turner Syndrome
Clinical Feature Yes,n(%) No,n(%) Not Known,n(%)
45,X karyotype 68 (49) 59 (43) 11 (8)
BAV 36 (26) 81 (59) 21 (15)
Aortic coarctation 23 (17) 115 (83) 0 (0)
GH 109 (79) 29 (21) 0 (0)
Hypertension 5 (4) 133 (96) 0 (0)
Thyroid disorders 23 (16) 0 (0) 115 (84)
Renal or urologic defects 19 (14) 0 (0) 119 (86)
Hearing problems 22 (16) 0 (0) 116 (84)
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⫽
population, wherezscoresⱖ2, by definition, occurred in only 2.5%.
Bivariable analyses comparing the presence or ab-sence of a specific characteristic among the subjects with Turner syndrome involved the following candidate vari-ables: BAV, history of coarctation, history of cardiac surgery, hypertension (based on the BP category guide-lines 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 com-pared 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 thezscores 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 ther-apy; in other words, Turner syndrome alone indepen-dently 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.
DISCUSSION
Aortic dissection occurs in ⬃1.4% of individuals with Turner syndrome,9generally presenting at a younger age
compared with the general female population (30 vs 67 years old).14,24Approximately 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 vascu-lopathy characterized by arterial dilation, vessel wall thick-ening, and abnormal pulse wave propagation,15although
the molecular or genetic basis for this observation is un-known. 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 ves-sel size and somatic growth in all young individuals.17
Furthermore, whether aortic dilation in Turner syndrome begins during childhood has not been investigated previ-ously.
This study represents the largest echocardiographic cross-sectional analysis of young individuals with Turner syndrome. In the young participants with Turner syn-drome 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 impor-tant predictor of this dilation.26–29 Importantly, young
individuals with Turner syndrome without a BAV also have a significantly larger proximal aorta when com-pared 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 sug-gested that the aortopathy in Marfan and Loeys-Dietz syndromes involves abnormalities in a common molec-ular-genetic pathway, whereby abnormal signal trans-duction in the cytokine transforming growth factor- pathway causes a simultaneous thickening and weaken-ing of the aortic wall.30,31The role of this pathway in the
aortic dilation associated with a BAV or Turner syn-drome is unknown.
Hypertension has also been associated with increased aortic size in Turner syndrome.32The prevalence of
self-reported hypertension in this study is markedly lower than the reported prevalence of Turner syndrome–associated hypertension,12possibly because hypertension is
underdi-agnosed in the pediatric population. When actual BP mea-surements are used to categorize the participants using standard guidelines,23the prevalence of hypertension
cor-responds with published reports, although assigning this diagnosis based on a single BP measurement is not
stan-TABLE 3 Multivariable Analysis of Predictors of Aortic Size in Subjects With Turner Syndrome
Variable n Predictor Value Pa Pb R2
ANN 115 BAV Yes ⬍.001 .001 0.15
No .131 NA NA
GH Yes ⬍.001 .008 NA
No .319 NA NA
AR 107 BAV Yes ⬍.001 ⬍.001 0.22
No ⬍.001 NA NA
STJ 114 BAV Yes ⬍.001 ⬍.001 0.20
No .006 NA NA
AAO 113 Age NA .057 0.18
BAV Yes ⬍.001 .001 NA
No ⬍.001 NA NA
GH Yes ⬍.001 .065 NA
No .008 NA NA
DTA 133 Age NA .03 0.04
IST 131 None NA NA NA
NA indicates not applicable.
aData show thePvalue for a 1-samplettest of difference from zero (from control population). bData show thePvalue for the regression coefficient.
TABLE 2 Mean AorticzScores for 135 Subjects With Turner Syndrome With Available BSA Data
Variable n Mean⫾SDa
ANN 135 0.63⫾1.16
AR 135 0.99⫾1.16
STJ 134 0.73⫾1.27
AAO 132 1.26⫾1.55
DTA 133 ⫺1.18⫾1.24
IST 131 ⫺0.30⫾1.05
dard 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 be-tween 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.33,34In
fact, 1 study suggests that Turner syndrome may have a beneficial effect on blood vessel compliance.35Although
the 45,X karyotype generally has a more severe cardio-vascular phenotype than non-45,X karyotypes,3,19it does
not have a significant independent effect on aortic size in the multivariable analysis, possibly because there is in-sufficient power in this study to demonstrate an effect. In addition, the subjects with the non-45,X karyotype represent a genetically heterogeneous group with mo-saic 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 azscore is ⱖ2, the associated mea-surement 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 compo-nents of Turner aortopathy need to be characterized, be-cause 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 infor-mal 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
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 popu-lation, 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 sur-veillance and treatment.
ACKNOWLEDGMENTS
This work is supported in part by grants from the Ge-nentech 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 Trans-lation 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.
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DOI: 10.1542/peds.2007-2807 originally published online May 26, 2008;
2008;121;e1622
Pediatrics
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Lopez-Mitnik, Angela E. Lin, Mark D. Reller, Roque Ventura and Michael
Leo Lopez, Kristopher L. Arheart, Steven D. Colan, Nancy S. Stein, Gabriela
Young
Turner Syndrome Is an Independent Risk Factor for Aortic Dilation in the
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