Article

Prolonged Rate-Corrected QT Interval and Other Electrocardiogram Abnormalities in Girls With Turner Syndrome

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Abstract

We recently reported that electrocardiographic abnormalities are common in adults with monosomy X (Turner syndrome), but this issue has not been investigated in girls with Turner syndrome. We analyzed electrocardiograms in 78 girls with Turner syndrome and 50 age-matched control girls. The girls with Turner syndrome had additional cardiac and metabolic evaluations. Girls with Turner syndrome were more likely to demonstrate > or = 1 electrocardiographic findings including right axis deviation, right ventricular hypertrophy, accelerated atrioventricular conduction, T-wave abnormalities, and a prolonged rate-corrected QT interval. The right-sided findings were associated with partial anomalous pulmonary venous connection, but the etiology of the other findings remains unknown. The rate-corrected QT interval was significantly longer in girls with Turner syndrome (431 +/- 22 vs 407 +/- 21 milliseconds). Twenty-eight girls with Turner syndrome but only 2 controls had a rate-corrected QT interval above the reference range. We found no correlation between body habitus, cardiac dimensions, or metabolic parameters and the rate-corrected QT interval duration in girls with Turner syndrome. Cardiac conduction and repolarization abnormalities seem to affect both young girls and adults with Turner syndrome equally, suggesting that electrophysiologic defects are intrinsic to the syndrome and indicating that electrocardiogram analysis should be included in evaluating and monitoring even the youngest patients with Turner syndrome. Attention to the rate-corrected QT interval is important, because some common medications may further prolong this interval and increase the risk of arrhythmias.

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... Besides cardiovascular malformations, electrocardiogram (ECG) abnormalities, mainly QTc prolongation, have been reported (Atici et al., 2018;Bondy, Ceniceros, et al., 2006;Dalla Pozza et al., 2006;Dalla Pozza et al., 2009;Sozen et al., 2008;Trolle et al., 2013). We recently found no increased prevalence of QTc prolongation using Hodges formula in a large cohort of girls (n = 101) and women (n = 251) with TS, as was confirmed by Harrahill et al. in 112 women with TS (Harrahill et al., 2020;Noordman et al., 2020). ...
... Reports on ECG abnormalities other than QTc prolongation are limited (Bondy, Ceniceros, et al., 2006;, and the clinical consequences of ECG abnormalities remain unclear. ...
... Most studies have suggested that the prevalence of cardiovascular malformations is higher in patients with a monosomy 45,X karyotype, compared with other karyotypes. However, associations between karyotype and specific cardiac function tests such as ECG or GLS, have hardly been described (Bondy, Ceniceros, et al., 2006). ...
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Article
Turner syndrome (TS) is a chromosomal condition which is associated with an increased prevalence of cardiac morbidity and mortality. In this cross‐sectional study, Minnesota‐based electrocardiographic (ECG) abnormalities, aortic dimensions, routine‐ and myocardial strain echocardiographic parameters, and karyotype‐cardiac phenotype associations were assessed in girls with TS. In total, 101 girls with TS (0–18 years) were included. The prevalence of major ECG abnormalities was 2% (T‐wave abnormalities) and 39% had minor ECG abnormalities. Dilatation of the ascending aorta (z‐score > 2) was present in 16%, but the prevalence was much lower when using TS‐specific z‐scores. No left ventricular hypertrophy was detected and the age‐matched global longitudinal strain was reduced in only 6% of the patients. Cardiac abnormalities seemed more common in patients with a non‐mosaic 45,X karyotype compared with other karyotypes, although no statistically significant association was found. Lowering the frequency of echocardiography and ECG screening might be considered in girls with TS without cardiovascular malformations and/or risk factors for aortic dissection. Nevertheless, a large prospective study is needed to confirm our results. The appropriate z‐score for the assessment of aortic dilatation remains an important knowledge gap. The karyotype was not significantly associated with the presence of cardiac abnormalities, therefore cardiac screening should not depend on karyotype alone.
... (2) A number of studies have reported a higher prevalence of abnormal electrocardiogram (ECG) findings in small patient groups, of which prolongation of the corrected QT (QTc) interval was the most frequently suggested abnormality. (3)(4)(5)(6)(7)(8)(9) A resting ECG at the time of diagnosis is therefore recommended.(1) The mechanism behind QTc prolongation in TS is unknown, although there are theories suggesting that it is due to the loss of a sex chromosome or associated with (administration) of sex hormones. ...
... (21,22) The association between karyotype and QTc prolongation was rarely studied, and the outcomes were contradicting. (3,5,8) Our objectives were: (1) to evaluate the prevalence of QTc prolongation with both Bazett's and Hodges' formulas, (2) to compare the mean QTc intervals of girls and women with TS to those of healthy age-matched references derived from the literature, and (3) to evaluate whether QTc prolongation is associated with a monosomy 45,X karyotype in a large population of patients with TS of all ages. ...
... We found a clear difference in the prevalence of QTc prolongation using Bazett's and Hodges' formulas, since only Hodges' formula (linear approach) adequately corrects for the high heart rate in patients with TS. (1,8,15) This current study describes a much lower prevalence of QTc prolongation compared to other recent studies investigating the QTc interval in patients with TS (Bazett: 11-36%, Hodge 7-15%). (3)(4)(5)8) It is important to note the differences between our study and previous studies investigating the QTc interval in patients with TS, which could explain the differences in the results. At first, in our study different cut off values were used for the definition of QTc prolongation (450 ms for girls and 460 ms for women, compared to 440 ms in some other studies). ...
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Article
Context Turner syndrome (TS) is a genetic condition and reported to be associated with a prolonged rate-corrected QT interval (QTc). Objectives To evaluate the prevalence of QTc prolongation in patients with TS, to compare their QTc intervals with healthy controls, and to investigate whether QTc prolongation is associated with a monosomy 45,X karyotype. Methods Girls (n=101) and women (n=251) with TS visiting our expertise center from 2004-2018 were included in this cross-sectional study. QT intervals of 12-leaded electrocardiograms were measured manually, using Bazett’s and Hodges’ formulas to correct for heart rate. A QTc interval of >450 ms for girls and >460 ms for women was considered prolonged. QTc intervals of patients with TS were compared to the QTc intervals of healthy girls and women from the same age-groups derived from the literature. Results In total, 5% of the population with TS had a prolonged QTc interval using Bazett’s formula and 0% using Hodges’ formula. Mean QTc intervals of these patients were not prolonged compared to the QTc interval of healthy individuals from the literature. Girls showed shorter mean QTc intervals compared to women. We found no association between monosomy 45,X and prolongation of the QTc interval. Conclusions This study shows that the QTc interval in girls and women with TS is not prolonged compared to the general population derived from the literature, using both Bazett’s and Hodges’ formulas. Furthermore, girls show shorter QTc intervals compared to women, and a monosomy 45,X karyotype is not associated with QTc prolongation.
... The corrected QT interval (QTc-interval) is prolonged in 33% of children and 20% of adults with Turner syndrome (TS) [1][2][3]. A prolonged QTc-interval is associated with increased risk of sudden death in the general population [4]. ...
... Increased morbidity and mortality are present due to congenital heart disease, ischemic heart disease, hypertension, and diabetes [8][9][10]. A relative sinus tachycardia is a life-long phenomenon [1,2], where conduction of the electrical impulse through the atria and atrioventricular node is accelerated [2], and the risk of atrial tachycardia may be increased [11] whereas bradycardia is rare [12]. Whether a QTcinterval prolongation contributes to the increased excess mortality in women with TS remains to be solved [9]. ...
... Our use of both equations makes comparisons with previous studies feasible and Hodges's formula effectively eliminates any residual correlation with heart rate. We found the prevalence of QTc above 440 ms (bQTc 20% and hQTc 15%) comparable with previous studies (21-36%) [1][2][3]. We suggest future use of Hodges's formula when estimating QTc as to remove the dependence of heart rate. ...
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Article
Objective: QT interval prolongation of unknown aetiology is common in Turner syndrome (TS). This study set out to explore the presence of known pathogenic long QT (LQT) mutations in TS and to examine the corrected QT interval (QTc) over time and relate the findings to the TS phenotype. Methods: Adult females with TS (n=102) were examined thrice with a mean follow-up of 4.7±0.5 years, and 68 age-matched healthy controls were examined once. QTc was measured by one blinded reader (intra-reader variability: 0.7%), and adjusted for influence of heart rate by Bazett’s (bQTc) and Hodges’s formula (hQTc). The prevalence of mutations in genes related to Long QT syndrome (LQTS) was determined in females with TS and a QTc >432.0 ms. Echocardiographic assessment of aortic valve morphology, 24-h blood pressures and blood samples were done. Results: The mean hQTc in females with TS (414.0±25.5 ms) compared to controls (390.4±17.8 ms) was prolonged (P<0.001) and did not change over time (416.9±22.6 vs 415.6±25.5 ms; P=0.4). 45,X karyotype was associated with increased hQTc prolongation compared to other TS karyotypes (418.2±24.8 vs 407.6±25.5 ms; P=0.03). In females with TS and a bQTc >432 ms, seven had mutations in major LQTS-genes (SCN5A and KCNH2) and one in a minor LQTS-gene (KCNE2). Conclusion: The prevalence of mutations in major LQTS genes was strikingly high for females with TS and the longest QTc interval.
... The ECG of TS girls differs from that of normal controls. They show a higher resting heart rate (91±15 bpm vs. 76±11 bpm), shorter PR (127±16 ms vs. 144±26 ms) and a longer QTc interval (431±22 ms vs. 407±21 ms) [12,14,33]. A QTc interval > 440 ms is found in 20 to 36% of TS girls [12,34]. ...
... They show a higher resting heart rate (91±15 bpm vs. 76±11 bpm), shorter PR (127±16 ms vs. 144±26 ms) and a longer QTc interval (431±22 ms vs. 407±21 ms) [12,14,33]. A QTc interval > 440 ms is found in 20 to 36% of TS girls [12,34]. During exercise test and increasing heart rates, the QTc interval normalises [34]. ...
... Only one study describes the prevalence of ECG abnormalities in young TS patients: a QTc interval that exceeds 440 ms was found in 35% [12]. ...
... The corrected QT interval (QTc-interval) is prolonged in 33% of children and 20% of adults with Turner syndrome (TS) [1][2][3]. A prolonged QTc-interval is associated with increased risk of sudden death in the general population [4]. ...
... Increased morbidity and mortality are present due to congenital heart disease, ischemic heart disease, hypertension, and diabetes [8][9][10]. A relative sinus tachycardia is a life-long phenomenon [1,2], where conduction of the electrical impulse through the atria and atrioventricular node is accelerated [2], and the risk of atrial tachycardia may be increased [11] whereas bradycardia is rare [12]. Whether a QTcinterval prolongation contributes to the increased excess mortality in women with TS remains to be solved [9]. ...
... Our use of both equations makes comparisons with previous studies feasible and Hodges's formula effectively eliminates any residual correlation with heart rate. We found the prevalence of QTc above 440 ms (bQTc 20% and hQTc 15%) comparable with previous studies (21-36%) [1][2][3]. We suggest future use of Hodges's formula when estimating QTc as to remove the dependence of heart rate. ...
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Article
Background An unfavorable cardiovascular and metabolic phenotype causes 3-fold excess mortality in Turner syndrome (TS), and perturbed cardiac substrate metabolism is increasingly recognized as a common component of cardiovascular and metabolic diseases. We therefore hypothesized that myocardial glucose uptake (MGU) is reduced in TS and that growth hormone (GH) treatment improves MGU. To this end, this controlled trial elucidates MGU in TS and the impact of 6 months of growth hormone treatment on MGU.Methods and ResultsWomen with TS (n=9) were examined at baseline, sequentially treated with either Norditropin® SimpleXx or placebo and re-examined after 6 months. MGU and myocardial blood flow (MBF) were measured using 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) during a hyperinsulinemic euglycemic clamp (at baseline and 6 months). Blood pressure measurement, blood sampling, echocardiography, and dual energy X-ray absorptiometry scan were also performed. Age-matched female controls (n=9) were examined once. Baseline MGU was reduced in TS (0.24±0.08 vs. 0.36±0.13 μmol/g/min in controls; p=0.036) despite similar insulin sensitivity (whole body glucose uptake (M-value): 9.69±1.86 vs. 9.86±2.58 mg/(min*kg) in controls; p=0.9). Six months of GH carried no impact on MGU (0.25±0.08 vs. 0.26±0.12 μmol/g/min in the placebo group; p=0.8). Plasma glucose, low-density cholesterol, and triglycerides increased, while M-value and exercise capacity decreased during 6 months of GH treatment.ConclusionMGU is reduced in TS despite normal insulin sensitivity. GH treatment does not alter MGU despite decreased whole body insulin sensitivity. A perturbed cardiac glucose uptake appears to be a feature of TS.This article is protected by copyright. All rights reserved.
... The corrected QT interval (QTc-interval) is prolonged in 33% of children and 20% of adults with Turner syndrome (TS)123. A prolonged QTc-interval is associated with increased risk of sudden death in the general population [4]. ...
... Increased morbidity and mortality are present due to congenital heart disease, ischemic heart disease, hypertension, and diabetes8910. A relative sinus tachycardia is a life-long phenomenon [1,2], where conduction of the electrical impulse through the atria and atrioventricular node is accelerated [2], and the risk of atrial tachycardia may be increased [11] whereas bradycardia is rare [12] . Whether a QTcinterval prolongation contributes to the increased excess mortality in women with TS remains to be solved [9]. ...
... Prior studies have explored differences in electrolytes between women with TS and controls as well as groups with TS and prolonged versus normal QTc. However, an actual correlation between the electrolytes and the QTc is a novel finding12331]. A correlation between QTc and calcium within the reference interval has been described in non-TS patients with cirrhosis [32] and with serum sodium [33]. ...
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Article
QT-interval prolongation of unknown aetiology is common in Turner syndrome. This study set out to explore the presence of known long QT mutations in Turner syndrome and to examine the corrected QT-interval (QTc) over time and relate the findings to the Turner syndrome phenotype. Adult women with Turner syndrome (n = 88) were examined thrice and 68 age-matched healthy controls were examined once. QTc was measured by one blinded reader (intra-reader variability: 0.7%), and adjusted for influence of heart rate by Bazett's (bQTc) and Hodges's formula (hQTc). The prevalence of mutations in genes related to Long QT syndrome was determined in women with Turner syndrome and a QTc >432.0 milliseconds (ms). Echocardiographic assessment of aortic valve morphology, 24-hour blood pressures and blood samples were done. The mean hQTc in women with Turner syndrome (414.0±25.5 ms) compared to controls (390.4±17.8 ms) was prolonged (p<0.001) and did not change over time (416.9±22.6 vs. 415.6±25.5 ms; p = 0.4). 45,X karyotype was associated with increased hQTc prolongation compared to other Turner syndrome karyotypes (418.2±24.8 vs. 407.6±25.5 ms; p = 0.055). In women with Turner syndrome and a bQTc >432 ms, 7 had mutations in major Long QT syndrome genes (SCN5A and KCNH2) and one in a minor Long QT syndrome gene (KCNE2). There is a high prevalence of mutations in the major LQTS genes in women with TS and prolonged QTc. It remains to be settled, whether these findings are related to the unexplained excess mortality in Turner women. NCT00624949. https://register.clinicaltrials.gov/prs/app/action/SelectProtocol/sid/S0001FLI/selectaction/View/ts/3/uid/U000099E.
... In a recent cross-sectional study, Atici et al. demonstrated that 38 patients with TS had significantly longer QTc than 35 controls (respectively, QTc 411.9 ± 22.7 vs. 392.1 ± 13.2 ms, p < 0.001), with the major limitation being the lack of data on karyotype or hormonal treatment [60]. This lengthening of the QTc interval had already been highlighted by Bondy et al. as early as 2006 [61]. In their study population, 36% of the TS patients (after puberty and discontinuation of HRT) had a QTc above the reference range in comparison to only 4% of the controls (440 ms; p = 0.0001). ...
... Another possible explanation could be linked to the karyotypic formula of the patients (monosomia or mosaic). Although the association of karyotype with Y chromosomal material and shortening of QTc was recently demonstrated by Harrahill et al. [58], this association has been rarely studied and the outcomes remain contradicting [61,62]. Finally, a high prevalence of mutations in the major LQTS genes in women with TS and prolonged QTc have already been discussed in 2013 [63]. ...
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Article
Significant variations from the normal QT interval range of 350 to 450 milliseconds (ms) in men and 360 to 460 ms in women increase the risk for ventricular arrhythmias. This difference in the QT interval between men and women has led to the understanding of the influence of sex hormones on the role of gender-specific channelopathies and development of ventricular arrhythmias. The QT interval, which represents the duration of ventricular repolarization of the heart, can be affected by androgen levels, resulting in a sex-specific predilection for acquired and inherited channelopathies such as acquired long QT syndrome in women and Brugada syndrome and early repolarization syndrome in men. Manipulation of the homeostasis of these sex hormones as either hormonal therapy for certain cancers, recreational therapy or family planning and in transgender treatment has also been shown to affect QT interval duration and increase the risk for ventricular arrhythmias. In this review, we highlight the effects of endogenous and exogenous sex hormones in the physiological and pathological states on QTc variation and predisposition to gender-specific pro-arrhythmias.
... The clinical relevance of these potential abnormalities may be 2-fold: Right-axis deviation in an individual with TS is correlated with the presence of partial anomalous pulmonary venous connection 76 and should trigger further diagnostic testing in those cases that are not already known, and QTc prolongation is associated with an increased risk for arrhythmias or even sudden cardiac death in the general population. It should be emphasized, however, that there is no published evidence to date for sudden cardiac death related to QTc prolongation in women with TS. ...
... Whether QTc prolongation should be considered an intrinsic feature of TS is unclear; a potential correlation with variants in the long-QT syndrome genes deserves further investigation. 77 Two observations suggest that prolonged QTc does not put girls and women with TS at risk: (1) No significant dysrhythmia has been documented in any girl or women with TS and prolonged QTc, and (2) in 1 TS study, QTc prolongation returned to normal in 40% of ambulatory ECGs 76 and returned to normal during exercise stress testing. Of note, QTc does not normalize during exercise in long-QT syndrome. ...
Article
Girls and women with Turner syndrome face a lifelong struggle with both congenital heart disease and acquired cardiovascular conditions. Bicuspid aortic valve is common, and many have left-sided heart obstructive disease of varying severity, from hypoplastic leftsided heart syndrome to minimal aortic stenosis or coarctation of the aorta. Significant enlargement of the thoracic aorta may progress to catastrophic aortic dissection and rupture. It is becoming increasingly apparent that a variety of other cardiovascular conditions, including early-onset hypertension, ischemic heart disease, and stroke, are the major factors reducing the life span of those with Turner syndrome. The presentations and management of cardiovascular conditions in Turner syndrome differ significantly from the general population. Therefore, an international working group reviewed the available evidence regarding the diagnosis and treatment of cardiovascular diseases in Turner syndrome. It is recognized that the suggestions for clinical practice stated here are only the beginning of a process that must also involve the establishment of quality indicators, structures and processes for implementation, and outcome studies.
... Treatment with QT prolongation is well documented in patients with Turner's syndrome, but the clinical significance is still uncertain [3,4]. New data indicate that there is a connection between human estrogen levels and QT duration, where high levels of estradiol were associated with shorter QTc intervals in healthy women due to effects on KCNH2 receptors in the cell membrane [5]. ...
... New data indicate that there is a connection between human estrogen levels and QT duration, where high levels of estradiol were associated with shorter QTc intervals in healthy women due to effects on KCNH2 receptors in the cell membrane [5]. Conversely, this may explain why some patients with Turner's syndrome and low estrogen levels may have prolonged QT intervals [3,4]. It has also been found that a rather high number of patients with Turner's syndrome carry variants in the long QT genes, including the SCN5A and KCNH2 genes [6]. ...
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Article
Key Clinical Message Low‐dose QT‐prolonging drugs may have detrimental effects on women with Turner's syndrome. Preventive measures would be to use potential QT‐prolonging drugs with precaution and ensure that both before and during treatment, ECGs are evaluated and drug treatment stopped if the QT interval increases.
... Notably, aneuploid hiPSC lines were used to study the early mortality and aberrant development of patients with TS [76]. Interestingly, taking into consideration the overall arrhythmias that patients with TS suffer from [77], TS hiPSCs were able to differentiate into functional cardiomyocyte-like cells, showing QT intervals comparable to control cells [76]. In addition, the expression of CSF2RA, a pseudoautosomal gene encoding the alpha subunit of the receptor for colony-stimulating factor 2, which is important for placenta development, has been found to be reduced in TS hiPSCs compared with the 46,XX hiPSCs [76]. ...
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Article
Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality. Interestingly, male and female patients with CVD exhibit distinct epidemiological and pathophysiological characteristics, implying a potentially important role for primary and secondary sex determination factors in heart development, aging, disease and therapeutic responses. Here, we provide a concise review of the field and discuss current gaps in knowledge as a step towards elucidating the “sex determination–heart axis”. We specifically focus on cardiovascular manifestations of abnormal sex determination in humans, such as in Turner and Klinefelter syndromes, as well as on the differences in cardiac regenerative potential between species with plastic and non-plastic sexual phenotypes. Sex-biased cardiac repair mechanisms are also discussed with a focus on the role of the steroid hormone 17β-estradiol. Understanding the “sex determination–heart axis” may offer new therapeutic possibilities for enhanced cardiac regeneration and/or repair post-injury.
... Tachycardia is more frequent in TS, and prolonged rate-corrected QT interval (QTc) has been described, but its real prevalence is actually unknown [61,62]. ...
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Article
Cardiomyopathy (CMP) is a rare disease in the pediatric population, with a high risk of morbidity and mortality. The genetic etiology of CMPs in children is extremely heterogenous. These two factors play a major role in the difficulties of establishing standard diagnostic and therapeutic protocols. Isolated CMP in children is a frequent finding, mainly caused by sarcomeric gene variants with a detection rate that can reach up to 50% of analyzed cohorts. Complex multisystemic forms of pediatric CMP are even more heterogenous. Few studies in literature take into consideration this topic as the main core since it represents a rarity (systemic CMP) within a rarity (pediatric population CMP). Identifying etiology in this cohort is essential for understanding prognosis, risk stratification, eligibility to heart transplantation and/or mechanical-assisted procedures, preventing multiorgan complications, and relatives’ recurrence risk calculation. The previous points represent a cornerstone in patients’ empowerment and personalized medical care approach. The aim of this work is to propose a new approach for an algorithm in the setting of the diagnostic framework of systemic pediatric CMP. On the other hand, during the literature review, we noticed a relatively common etiologic pattern in some forms of complex/multisystem CMP. In other words, certain syndromes such as Danon, Vici, Alström, Barth, and Myhre syndrome share a common pathway of directly or indirectly defective “autophagy” process, which appears to be a possible initiating/triggering factor for CMPs. This conjoint aspect could be important for possible prognostic/therapeutic implications in this category of patients. However, multicentric studies detailed functional and experimental models are needed prior to deriving conclusions.
... Less common defects in surviving individuals include venous abnormalities, atrial and ventricular septal defects, hypoplastic left heart syndrome, and mitral and pulmonary valve abnormalities [3]. An association with arrythmias including prolonged QT interval has also been noted [13]. Coronary artery abnormalities including absent left main coronary artery are often asymptomatic but affect surgical courses. ...
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Article
Turner syndrome is a rare disorder resulting from complete or partial loss of the second sex chromosome. Common manifestations include delayed growth, premature ovarian failure, congenital heart defects, endocrine disorders, lymphedema, and webbed neck. People with Turner syndrome have significantly increased mortality risk primarily due to cardiovascular abnormalities. The mechanisms that lead to these defects are not completely understood and are obscured by the significant variability of both karyotype and phenotype without consistent correlation between the two. This paper presents a review of the recent literature surrounding the symptoms, mechanisms, diagnosis, and treatment of Turner syndrome with a focus on cardiovascular manifestations. With technological advancements in genetics, the molecular processes of Turner syndrome have begun to be dissected. Certain genes on the X chromosome that typically escape inactivation have been implicated in both specific manifestations and broader risk categories. Recently identified genome-wide epigenetic changes may help explain the variability in presentation. It remains unclear as to how the combination of these factors results in the overall clinical picture, but advances in genomic, genetic, epigenetic, and -omics technology hold promise for providing insights that will improve the medical management of individuals with Turner syndrome.
... Minor electrocardiographic findings, including right axis deviation, T wave abnormalities, bundle branch block, QTc prolongation, and increased heart rate variability are more common among girls (30%) and adults (>50%) with TS, compared with age-matched female controls. 170,171 Most of these findings are of uncertain significance. Specifically for QTc prolongation, there does not appear to be a worsening of this finding with increasing age. ...
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Chapter
Turner syndrome (TS) is a disorder of phenotypic females who have one intact X chromosome and complete or partial absence of their second sex chromosome. This results in a constellation of features that includes—but is not limited to: lymphedema, cardiac anomalies, short stature, primary ovarian failure, and neurocognitive difficulties, as the most important ones. Traditionally, TS implied the presence of physical characteristics, such as a typical facial appearance and neck webbing. However, the clinical manifestations of TS should be viewed more broadly to include other features, such as growth failure, pubertal delay, sensorineural hearing loss, and specific cardiovascular, liver, and renal anomalies, as well as a particular neurodevelopmental profile. Optimizing healthcare delivery is important to enable TS individuals to achieve their full potential. This chapter reviews the current diagnostic, genetic, and management recommendations for individuals with TS, including screening recommendations for other comorbidities, based on recently developed international consensus guidelines.
... A resting electrocardiogram is necessary in the check-up of patients with TS. Tachycardia is more frequent than in the general population [15]. Furthermore, prolonged rate-corrected QT interval (QTc) has been described in patients with TS. ...
Article
Turner syndrome (TS) is a rare disease (ORPHA #881) which affects about 50 in 100 000 newborn girls. Their karyotype shows a complete or partial loss of the second X chromosome. In TS, congenital cardiovascular malformations, such as bicuspid aortic valves and aortic coarctation are frequent, affecting 20-30% and 7-18% of the TS population, respectively. The morbidity and mortality of these patients are high and related to the presence of hypertension and/or aortic dilatation (40%), inducing aortic dissection. European guidelines published in 2017 have indicated how to monitor patients using magnetic resonance imaging (MRI) and/or echography. Different studies have shown that a cardiovascular lifelong follow-up is necessary and therefore education of patients with TS and their families represents a major issue. This review will present recent data concerning the progression of aortic diameters as well as current molecular knowledge of the cardiovascular system in patients with TS.
... Since none of the examined TS patients presented with significant arrythmia, left bundle branch block or advanced heart failure, these results seem to be plausible. However, TS has been described to be associated with heart rhythm disorders (27)(28)(29). Further studies will have to investigate whether TS patients displaying heart rhythm disorders also show abnormalities in global wasted work and hence global myocardial work efficiency. ...
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Article
Background: Turner syndrome (TS), a relatively rare chromosomal disease, is associated with multiple cardiovascular risk factors that possibly lead to increased left ventricular afterload and functional impairment. The aim of this study was to investigate whether alterations in myocardial work and work efficiency can be found in TS patients through left ventricular pressure-strain loop analysis (PSL). Methods: Thirty-eight patients with TS and 19 healthy, age-matched controls were recruited for this study. Global peak systolic strain (GLPS) and PSL of the left ventricle was assessed in study participants. TS patients whose history included coarctation of the aorta or prior cardiac surgery were excluded from GLPS and PSL analyses (n=5). Results: Median age was 16.00 years in the TS group and 16.35 years in the control group (P=0.236). GLPS did not show significant differences between both groups (P=0.524). TS patients demonstrated, compared to controls, a significantly higher global myocardial work index (BSA) (mean ± SD: 1,497±505 vs. 1,214±245 mmHg*%/m2; P=0.027). Heart rate was significantly increased in TS patients, compared to controls (mean ± SD: 90.08±14.79 vs. 73.95±15.05 bpm; P<0.001), and correlated significantly with global myocardial work index [body surface area (BSA)] within the TS cohort (r=0.558, P=0.001). Conclusions: TS patients showed signs of increased myocardial workload that were only detectable through the novel PSL analysis method and not through GLPS. Moreover, elevated resting heart rate was linked with increased myocardial workload in TS patients. Further studies will have to investigate whether TS patients may develop advanced left ventricular systolic dysfunction later in life.
... Cardiac conduction and repolarization abnormalities are supposedly caused by intrinsic defects of conduction system in pwTS. The QTc interval prolongs at varying rates in elderly and young pwTS (6)(7)(8). Recent studies have shown that the genetic defects causing congenital anomalies in the cardiovascular evolution can be associated with conduction defects and extensive myopathical changes in the adult population (9). ...
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Article
Objective: To evaluate ventricular repolarization parameters using the interval from the peak to the end of the T wave (Tp-Te), together with QT and corrected QT (QTc) intervals, QT dispersion (QTd), and Tp-Te/QTc ratio in patients with Turner syndrome (pwTS) and to compare the results with those from healthy controls. Methods: In total, 38 patients previously diagnosed with Turner syndrome (TS) and 35 healthy girls (controls) were included in our cross-sectional study. Twelve-lead electrocardiography (ECG) and echocardiography after a 30-min rest were performed. The QT, QTc, QTd, Tp-Te interval, and Tp-Te/QTc ratio were determined. Results: No differences in age or sex were observed between the groups. QT intervals were similar in both groups [pwTS: 354.76±25.33 ms, controls (C): 353.29±17.51 ms, p=0.775]. pwTS had significantly longer QTc and QTd than controls (411.87±22.66 ms vs. 392.06±13.21 ms, p<0.001 and 40.31±2.02 ms vs. 37.54±1.83 ms, p<0.001, respectively). Similarly, the Tp-Te interval and Tp Te/QTc ratio were significantly longer in pwTS than in controls (71.89±3.39 ms vs. 65.34±2.88 ms, p<0.001 and 0.17±0.01 vs. 0.16±0.01, p=0.01). Conclusion: As pwTS have longer QTc, QTd, Tp-Te interval, and Tp-Te/QTc ratio, an annual follow-up with ECG can provide awareness and even prevent sudden death in them. Also avoiding the use of drugs that makes repolarization anomaly and having knowledge about the side effects of these drugs are essential in pwTS.
... Cardiac conduction and repolarization abnormalities are supposedly caused by intrinsic defects of conduction system in pwTS. The QTc interval prolongs at varying rates in elderly and young pwTS (6)(7)(8). Recent studies have shown that the genetic defects causing congenital anomalies in the cardiovascular evolution can be associated with conduction defects and extensive myopathical changes in the adult population (9). ...
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Objective To evaluate ventricular repolarization parameters using the interval from the peak to the end of the T wave (Tp–Te), together with QT and corrected QT (QTc) intervals, QT dispersion (QTd), and Tp-Te/QTc ratio in patients with Turner syndrome (pwTS) and to compare the results with those from healthy controls. Methods In total, 38 patients previously diagnosed with Turner syndrome (TS) and 35 healthy girls (controls) were included in our cross-sectional study. Twelve-lead electrocardiography (ECG) and echocardiography after a 30-min rest were performed. The QT, QTc, QTd, Tp-Te interval, and Tp-Te/QTc ratio were determined. Results No differences in age or sex were observed between the groups. QT intervals were similar in both groups [pwTS: 354.76±25.33 ms, controls (C): 353.29±17.51 ms, p=0.775]. pwTS had significantly longer QTc and QTd than controls (411.87±22.66 ms vs. 392.06±13.21 ms, p<0.001 and 40.31±2.02 ms vs. 37.54±1.83 ms, p<0.001, respectively). Similarly, the Tp-Te interval and Tp-Te/QTc ratio were significantly longer in pwTS than in controls (71.89±3.39 ms vs. 65.34±2.88 ms, p<0.001 and 0.17±0.01 vs. 0.16±0.01, p=0.01). Conclusion As pwTS have longer QTc, QTd, Tp–Te interval, and Tp-Te/QTc ratio, an annual follow-up with ECG can provide awareness and even prevent sudden death in them. Also avoiding the use of drugs that makes repolarization anomaly and having knowledge about the side effects of these drugs are essential in pwTS.
... Shortening of the PR-interval (due to accelerated atrioventricular conduction) may be a consequence of excessive sympathetic drive. The clinical relevance of these potential abnormalities may be twofold: (1) right-axis deviation in an individual with TS is correlated with the presence of partially abnormal pulmonary venous return (310) and should trigger further diagnostics in those cases that are not already known and (2) QTc prolongation is associated with an increased risk for arrhythmias or even sudden cardiac death in the general population. Yet, it should be emphasized that there is no published evidence so far for sudden cardiac death related to QTc prolongation in women with TS, although case-based QTc prolongation due to a dose of amiodarone followed by cardiac arrest has been seen (311). ...
... Shortening of the PR-interval (due to accelerated atrioventricular conduction) may be a consequence of excessive sympathetic drive. The clinical relevance of these potential abnormalities may be twofold: (1) right-axis deviation in an individual with TS is correlated with the presence of partially abnormal pulmonary venous return (310) and should trigger further diagnostics in those cases that are not already known and (2) QTc prolongation is associated with an increased risk for arrhythmias or even sudden cardiac death in the general population. Yet, it should be emphasized that there is no published evidence so far for sudden cardiac death related to QTc prolongation in women with TS, although case-based QTc prolongation due to a dose of amiodarone followed by cardiac arrest has been seen (311). ...
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Turner syndrome affects 25–50 per 100,000 females and can involve multiple organs through all stages of life, necessitating multidisciplinary approach to care. Previous guidelines have highlighted this, but numerous important advances have been noted recently. These advances cover all specialty fields involved in the care of girls and women with TS. This paper is based on an international effort that started with exploratory meetings in 2014 in both Europe and the USA, and culminated with a Consensus Meeting held in Cincinnati, Ohio, USA in July 2016. Prior to this meeting, five groups each addressed important areas in TS care: 1) diagnostic and genetic issues, 2) growth and development during childhood and adolescence, 3) congenital and acquired cardiovascular disease, 4) transition and adult care, and 5) other comorbidities and neurocognitive issues. These groups produced proposals for the present guidelines. Additionally, four pertinent questions were submitted for formal GRADE (Grading of Recommendations, Assessment, Development and Evaluation) evaluation with a separate systematic review of the literature. These four questions related to the efficacy and most optimal treatment of short stature, infertility, hypertension, and hormonal replacement therapy. The guidelines project was initiated by the European Society for Endocrinology and the Pediatric Endocrine Society, in collaboration with The European Society for Pediatric Endocrinology, The Endocrine Society, European Society of Human Reproduction and Embryology, The American Heart Association, The Society for Endocrinology, and the European Society of Cardiology. The guideline has been formally endorsed by the European Society for Endocrinology, the Pediatric Endocrine Society, the European Society for Pediatric Endocrinology, the European Society of Human Reproduction and Embryology and the Endocrine Society. Advocacy groups appointed representatives who participated in pre-meeting discussions and in the consensus meeting.
... Despite significant autocorrelations between FSH and LH, our multivariable analysis supports a major role of FSH in regulating QTc interval duration. Interestingly, Turner syndrome, a congenital condition associated with an ovarian steroid hormone deficit counterbalanced by high FSH concentrations, is associated with QTcF prolongation (41). In childbearing age women, bilateral oophorectomy followed by FSH increment was associated with the prolongation of T wave duration. ...
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Objectif La duree de l’intervalle QT est plus longue chez les femmes que chez les hommes. L’implication des hormones sexuelles a ete proposee. Nous rapportons ici l’influence combinee des steroides et des gonadotrophines sur l’intervalle QT chez des sujets sains et des patients porteurs d’une hyperplasie congenitale des surrenales (HCS) par deficit en 21-hydroxylase. Patients et methodes Etude cas/controle. Les concentrations de 17-OH-progesterone, la progesterone, la testosterone, l’œstradiol, la FSH et la LH ont ete mesurees en meme temps que l’enregistrement d’un electrocardiogramme numerise. Resultats Quatre-vingt-quatre patients avec HCS (58 femmes) et 84 sujets sains apparies pour le sexe et l’âge ont ete inclus. Le QTcFridericia (QTcF) etait plus court chez les femmes avec HCS que chez les femmes temoins (404 ± 2 msec vs 413 ± 2 msec, p ≤ 0,001). En l’analyse multivariee chez l’ensemble des femmes, le rapport progesterone/estradiol (β = − 0,33) et les taux plasmatiques de FSH (β = 0,34) etaient lies au QTcF (r = 0,5, p < 0,0001). Chez les hommes, le QTcF n’etait pas different entre les patients avec HCS (404,7 ± 3,7 msec) ou sujets sains (396 ± 2,8 msec). Il etait significativement (r = 0,48, p < 0,01) lie aux taux plasmatiques de testosterone (β = −0,29) et de FSH (β = 0,34). Conclusion La repolarisation cardiaque est influencee par des interactions complexes selon le sexe entre les steroides et les gonadotrophines. Nos resultats indiquent que le rapport progesterone/estradiol chez les femmes, la testosterone chez les hommes, et la FSH dans les deux sexes sont des determinants majeurs de la repolarisation ventriculaire avec des effets opposes sur l’intervalle QTc.
... Despite significant autocorrelations between FSH and LH, our multivariable analysis supports a major role of FSH in regulating QTc interval duration. Interestingly, Turner syndrome, a congenital condition associated with an ovarian steroid hormone deficit counterbalanced by high FSH concentrations, is associated with QTcF prolongation (41). In childbearing age women, bilateral oophorectomy followed by FSH increment was associated with the prolongation of T wave duration. ...
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Context: QT interval duration is longer in women than in men. Sex steroid hormones have inconsistently been suggested to explain this difference. The implication of gonadotropins has never been studied. Objective: We report here the combined influence of sex steroid hormones and gonadotropins on QT interval duration in healthy subjects and patients with congenital adrenal hyperplasia (CAH) as a model of T and progesterone overexpression. Design and patients: Eighty-four CAH patients (58 women) and 84 healthy subjects matched and paired for sex and age were prospectively included. Circulating concentrations of 17-OH-progesterone, progesterone, T, estradiol, FSH, and LH were measured concomitantly to the recording of a digitized electrocardiogram. Results: QTcFridericia (QTcF) was shorter in women with CAH than in control women (404 ± 2 vs 413 ± 2.1 milliseconds; P ≤ .001). 17-OH-progesterone, progesterone, the progesterone/estradiol ratio, and total T were higher in women with CAH than in female controls (P < .05), whereas FSH was lower (P ≤ .05). According to multivariable analysis in all women, the progesterone/estradiol ratio (β = -0.33) and FSH levels (β = 0.34) were related to QTcF (r = 0.5; P < .0001), with no influence of CAH or healthy status. QTcF was not different between CAH (404.7 ± 3.7 milliseconds) or healthy men (396 ± 2.8 milliseconds). For men, QTcF (r = 0.48; P < .01) was negatively related to free T (β = -0.29) and positively to FSH levels (β = 0.34). Conclusion: Cardiac repolarization is influenced by complex interactions between sex steroid hormones and gonadotropins, depending on gender. Our results indicate that the progesterone/estradiol ratio in women, T in men, and FSH in both genders are major determinants of ventricular repolarization with opposite effects on QTc interval.
... 157,158 Electrocardiographic abnormalities including prolonged QT interval are frequently encountered, but risk of life-threatening arrhythmia has not been established. 159 Turner syndrome does not appear to increase mortality risk after repair of coarctation of the aorta but has been associated with longer hospitalisation (Table 1 and Supplementary Table S6). 160 By comparison, mortality appears to be significantly increased in patients with hypoplastic left heart syndromefor instance, 9 out of 11 infants with Turner syndrome undergoing Norwood stage 1 operation died by 4 months of age as per the Congenital Heart Surgeons' Society database. ...
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CHD is frequently associated with a genetic syndrome. These syndromes often present specific cardiovascular and non-cardiovascular co-morbidities that confer significant peri-operative risks affecting multiple organ systems. Although surgical outcomes have improved over time, these co-morbidities continue to contribute substantially to poor peri-operative mortality and morbidity outcomes. Peri-operative morbidity may have long-standing ramifications on neurodevelopment and overall health. Recognising the cardiovascular and non-cardiovascular risks associated with specific syndromic diagnoses will facilitate expectant management, early detection of clinical problems, and improved outcomes - for example, the development of syndrome-based protocols for peri-operative evaluation and prophylactic actions may improve outcomes for the more frequently encountered syndromes such as 22q11 deletion syndrome.
... In TS, ECG abnormalities are frequently seen both in girls and adults. Heart rates of TS patients tend to be higher compared to normal controls and QTc prolongation is more frequent (in 20 to 30%)[31][32][33]. Although for all patients in our series heart rate was within the normal limits, 6 patients (3 F, 3 M) showed a frequency at the upper limit. ...
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The phenotype of 45,X/46,XY mosaicism is heterogeneous ranging from females with Turner syndrome (TS) to apparently normal males. Males with 45,X/46,XY frequently show stigmata typically associated with TS. We hypothesised that males with 45,X/46,XY have similar cardiovascular pathology as females with 45,X/46,XY. To investigate cardiovascular abnormalities in 45,X/46,XY males and to compare them with 45,X/46,XY females. Patients with 45,X/46,XY mosaicism were selected from the Belgian Registry for Growth and Puberty problems and via the multidisciplinary clinic for disorders of sexual development. EIGHTEEN PATIENTS WERE INCLUDED: 8 raised as females (F) and 10 as males (M). Complete cardiac examination with blood pressure measurement, ECG, echocardiography and MRI. Cardiac parameters were registered for both groups. In a second phase, clinical features and external masculinisation score (EMS) were retrospectively collected from the medical files. A structural heart defect was diagnosed before inclusion in 1 F with coarctation and 1 M with spontaneously closed VSD. A bicuspid aortic valve was found in 8 (3 F, 5 M). Dilation of the ascending aorta was present in 4 M and was severe in 2 young boys. QTc was prolonged in 3 F and 2 M. Males with 45,X/46,XY mosaicism have similar cardiovascular pathology as 45,X/46,XY females. Dilation of the ascending aorta can be important, also in males. We advise cardiac screening and life-long monitoring in all males with 45,X/46,XY mosaicism according to the existing guidelines for Turner syndrome.
Article
Turner syndrome (TS) is a chromosomal disorder that affects 25–50 per 100,000 live born females. Patients with TS face a heavy burden of cardiovascular disease (congenital and acquired) with an increased risk of mortality and morbidity compared to the general population. Cardiovascular diseases are a major cause of death in females with TS. Approximately 50% of TS patients have a congenital heart abnormality, with a high incidence of bicuspid aortic valve (BAV), coarctation of the aorta (CoA) and generalised arteriopathy. Frequently, females with TS have systemic hypertension, which is also a risk factor for progressive cardiac dysfunction and aortopathy. This paper aims to provide an overview of the cardiovascular assessment, management and follow up strategies in this high-risk population of TS patients.
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Background: While left-sided congenital heart defects have been well described in females with Turner syndrome (45, X), the literature is scarce regarding arrhythmias in this patient population. Case summary: A full-term neonate referred to cardiology was found to have a non-apex forming left ventricle and partial anomalous pulmonary venous return. During the echocardiogram, she developed atrial flutter, followed by orthodromic reentrant supraventricular tachycardia (SVT). She was started on propranolol and eventually switched to sotalol due to breakthrough SVT. A genetics evaluation revealed Turner syndrome with complete monosomy X (45, X). The patient is now 18 months old and has not had any further arrhythmias. Discussion: We present a rare case of atrial flutter followed by supraventricular tachycardia in a neonate with Turner syndrome and left-sided heart defects. This case highlights the importance of early and precise investigation of cardiac abnormalities in neonatal patients, especially among females with Turner syndrome given their relatively higher risk of cardiovascular disease compared to the general population.
Article
Patients with the Turner syndrome (TS) often have longer QT intervals compared with age-matched peers although the significance of this remains unknown. We sought to determine the degree, frequency and impact of QTc prolongation in patients with TS. A chart review of all patients with an electrocardiogram (ECG) and genetically proven TS was performed. Medications at the time of the ECG were reviewed and QTc calculated. Medications were classified according to QTc risk using www.crediblemeds.com. ECG parameters were compared with an age, gender, and cardiac lesion-matched control group. Over the 10-year period of review, 112 TS patients with a mean age of 34 ± 25 years underwent 226 ECGs. At least 1 QTc prolonging medication was prescribed in 81 (74%) patients. Longer QTc interval correlated with absence of y chromosomal material (p = 0.01), older age (p <0.0001), increased number of QTc prolonging and nonprolonging medications (p <0.0001 each). During the 7.0 ± 5.1 years of follow-up, no patient had ventricular arrhythmia or unexplained sudden death. QTc was significantly shorter in matched controls using either Bazett or Hodges formula (424 ± 16 ms vs 448 ± 28 ms, p <0.0001; and 414.8 ± 16 ms vs 424.2 ± 20 ms; p = 0.0002, respectively). However, there was no difference in the frequency of QTc prolongation >460 msec (2.8% vs 2.6%, p = 0.9). In conclusion, despite frequent use of QT-prolonging medications, ventricular arrhythmias are rare in TS.
Article
Short stature, ovarian dysgenesis, infertility, and cardiovascular malformations are classic features in Turner syndrome (TS), but the phenotypical spectrum is wide. Through early diagnosis and appropriate treatment, TS patients have a chance to achieve satisfactory adult height and sexual development. The doses of recombinant growth hormone (rGH) used are usually higher than the substitution dose. The safety aspects of this therapy are very important, especially in terms of the cardiovascular system. The presented study aimed to analyze how the rGH therapy may influence the cardiovascular system in TS based on current literature data. We conducted a systematic search for studies related to TS, cardiovascular system, and rGH therapy. The results show that rGH seems to have a positive effect on lipid parameters, reducing the risk of ischemic disease. It is additionally optimized by estradiol therapy. Although rGH may increase insulin resistance, the metabolic derangement is rare, probably due to lower fat content and an increase in lean body mass. Several studies showed that rGH treatment could cause aorta widening or increase the aorta growth rate. IGF-1 can be independently associated with increased aortic diameters. The studies analyzing the impact of GH on blood pressure show conflicting data. The proper cardiovascular imaging before and during rGH treatment and detecting the known risk factors for aorta dissection in every individual is very important. The long-term effects of growth hormone treatment on the heart and arteries are still not available and clearly estimated and have to be monitored in the future.
Chapter
Sex differences exist in a myriad of human diseases, including disorders of cardiac electrophysiology. These differences are poorly understood and have been traditionally attributed to the role of gonadal sex hormones. Recent work studying the evolution of sex chromosomes has brought to light the potential contribution of sex chromosome complement in sexual dimorphism. Natural sex chromosome complement variants in the form of Turner syndrome (45, XO) and Klinefelter syndrome (47, XXY) display an increased propensity for congenital heart disease and changes in electrophysiological parameters. An example of this includes QTc, which is prolonged in Turner syndrome and shortened in Klinefelter syndrome. We propose that studying phenotypes such as QTc in sex chromosome aneuploidy patients will not only be essential for appropriate clinical management of these patients but will also provide a model to help to elucidate the complex interplay between the contributions of genetics and hormones in euploid male–female differences.
Chapter
Cardiovascular disease is the leading cause of early morbidity and mortality in girls and women with Turner syndrome (TS). Congenital heart abnormalities are common and often include left-sided obstructive lesions of varying severity. Progressive aortic enlargement may lead to aneurysm formation, dissection, and rupture, a potentially fatal complication. Coronary artery disease, myocardial infarction, and stroke are important acquired cardiovascular complications, which may be further aggravated by an increased propensity for additional comorbidities, such as hypertension, dyslipidemia, diabetes, and obesity. Given the broad spectrum of cardiovascular concerns affecting individuals with Turner syndrome, these patients require a continuum of care, counseling, and preventive management into their adult years. It is therefore particularly relevant that the primary care provider has a good understanding of potential risks involved and how to manage them in order to deliver the best care for these patients and assure their best long-term outcomes.
Chapter
Turner syndrome affects approximately 1 in 2500 live female births and is characterised by an abnormal or missing X chromosome. It is associated with increased morbidity and mortality due to the associated phenotypic abnormalities. The commonest presentation is aged 10–16 with short stature and primary amenorrhoea, however the considerable phenotypic variation some of which is associated with a particular/mosaic karyotype may lead to delay/missed diagnosis. Girls and women with TS should be followed up for life with screening for complications, and management of short stature, primary (and more rarely secondary) ovarian failure, cardiovascular complications, and increased autoimmune and metabolic risk. Recent guidelines provide useful guidance for the successful lifelong management of girls and women. A multidisciplinary approach addressing (Fig. 40.6) all aspects of their care including expert cardiological monitoring and intervention when required, access to fertility and obstetric expertise when appropriate, expert genetic counselling if indicated, and discussion of psychosocial, education, employment issues is key to the successful outcome for all women with Turner syndrome.
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An increasing number of children are born with intersex variation (IV; ambiguous genitalia/hermaphrodite, pseudohermaphroditism, etc.). Evidence shows that endocrine-disrupting chemicals (EDCs) in the environment can cause reproductive variation through dysregulation of normal reproductive tissue differentiation, growth, and maturation if the fetus is exposed to EDCs during critical developmental times in utero. Animal studies support fish and reptile embryos exhibited IV and sex reversal when exposed to EDCs. Occupational studies verified higher prevalence of offspring with IV in chemically exposed workers (male and female). Chemicals associated with endocrine-disrupting ability in humans include organochlorine pesticides, poly-chlorinated biphenyls, bisphenol A, phthalates, dioxins, and furans. Intersex individuals may have concurrent physical disorders requiring lifelong medical intervention and experience gender dysphoria. An urgent need exists to determine which chemicals possess the greatest risk for IV and the mechanisms by which these chemicals are capable of interfering with normal physiological development in children.
Chapter
For medical practitioners who care for children with congenital heart disease, it is very evident that chromosomal disorders are commonly associated with heart defects. In fact, chromosomal disorders account for up to 10-12 % of cases presenting with cardiac disease in infants, and overall, genetic syndromes may account for 20 % [Hartman et al. (Pediatr Cardiol 32:1147-1157, 2011), Goldmuntz et al. (Congenit Heart Dis 6:592-602, 2011), Pierpont et al. (Circulation 115:3015-3038, 2007)]. Down syndrome is the most common chromosomal cause of congenital heart disease, followed by Turner syndrome, trisomy 18, and the 22q.11.2 deletion syndromes. This chapter will address the relationship between congenital heart disease (CHD) and chromosomal disorders to familiarize the medical practitioners who care for these patients. We will discuss aspects of the most common chromosomal disorders, including autosomal trisomies, a sex-chromosome anomalies, and microdeletion syndromes. The cardiac practitioner should be able to recognize distinctive features and cardiac lesions associated with these syndromes, appreciate the necessity of a complete medical genetics evaluation, and understand the risk of CHD for a patient with a particular syndrome. The cardiac medical team should be familiar with the outcomes associated with medical, palliative, or corrective treatments, and need for ongoing cardiac surveillance.
Chapter
Si la prise en charge des patientes est bien codifiée au moment de l’enfance et de l’adolescence, sous la responsabilité des endocrinologues pédiatres, le suivi à l’âge adulte (lorsqu’il a lieu !) apparaît beaucoup plus éclaté. La transition des services de pédiatrie vers les services d’adultes ou vers les praticiens spécialisés est délicate et le suivi des pathologies associées devient souvent aléatoire à l’âge adulte. Pour preuve, une enquête française auprès de jeunes femmes Turner révèle que 20% d’entre elles sont suivies exclusivement par un généraliste, les autres étant suivies par un gynécologue, un endocrinologue, voire encore par un endocrinologue pédiatre. La création récente d’un Centre de référence des maladies endocriniennes rares de la croissance (dont le syndrome de Turner) nous a amenés à réfléchir à des propositions spécifiques destinées à améliorer la prise en charge de ces patientes et à rédiger, sous l’égide de l’HAS, des recommandations qui viennent d’être publiées (www.has-sante.fr). Plusieurs revues de la littérature ont fait le point récemment sur les problèmes posés par le syndrome de Turner (ST) à l’âge adulte (1–5).
Chapter
Des anomalies cardiaques congénitales sont décrites chez environ 30% des patientes avec syndrome de Turner (1–3). Elles sont plus fréquentes dans les séries où le bilan cardiologique associe à l’échocardiographie une imagerie par résonance magnétique (IRM) (3,4). L’incidence est plus élevée en cas de monosomies 45X, plus rare (20%) en cas de mosaïque ou d’anomalie structurale du X.
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Sex-chromosome abnormalities are frequent and give rise to two well-defined syndromes, Turner and Klinefelter syndromes, and other less well-defined syndromes such as 47,XXX and 47,XYY syndromes and other conditions with mosaicism, translocations or additional sex chromosomes. The genetic background for these syndromes is incompletely understood, and only one gene on the sex chromosomes, the SHOX gene, has been unequivocally linked with the syndromes. Other genes are expected to play a role in the different phenotypes presented by the syndromes and await discovery. All syndromes are characterized by delay in diagnosis or even nondiagnosis, increased mortality to a host of different causes, increased morbidity, neurocognitive deficits, but either normal or slightly reduced intelligence quotient. Most females with Turner syndrome do well in society while existing data suggest that persons with Klinefelter, 47,XXX and 47,XYY syndromes do less well.
Article
Turner’s syndrome (TS) is a relatively common chromosomal abnormality frequently associated with cardiovascular abnormalities, such as a bicuspid aortic valve and coarctation of the aorta, as well as cardiovascular risk factors such as hypertension, hypothyroidism, and diabetes mellitus. Epidemiological studies have shown that these patients have increased cardiovascular morbidity and mortality. In addition, there is at least the theoretical potential that well-established treatments that are intended to address the short stature and hormonal deficiencies in these patients may negatively influence their cardiovascular risk profile. Further, the congenital structural abnormalities commonly found in TS, and long-term complications associated with them, warrant regular monitoring utilizing various cardiovascular imaging modalities to determine the need for timely surgical intervention. In this review, we summarize the main features of this syndrome, with emphasis on issues that impact the management, diagnostic work up, and monitoring of cardiovascular problems in adult patients with TS.
Article
There is a general lack of awareness of the risk of aortic dissection in Turner syndrome (TS) from both patients with TS and their physicians. Patients often ignore symptoms for up to 24 h before seeking medical advice, significantly increasing their risk of death. A clinical profile of those at risk of dissection is emerging and includes the presence of congenital heart defects, aortic dilatation and hypertension. MRI has revolutionised the visualisation of cardiovascular anatomy in TS but remains underutilised, especially in children and adolescents, and there is currently little guidance on blood pressure (BP) assessment or hypertension management. Children and adolescents with TS at risk of dissection could be easily identified by timely imaging and BP assessment. This would allow medical management or surgical intervention to be put in place to reduce the risk of this major, and often fatal, complication. Since guidance is lacking, we have reviewed the literature on the risk factors for dissection in TS during childhood and adolescence, and make recommendations on the assessment and management of these patients. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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Abstract Aortic dilatation and aortic dissection are increasingly recognised in patients with Turner syndrome (TS). Risk factors for aortic dissection include aortic dilatation, bicuspid aortic valves, coarctation of aorta and pregnancy. The risk of death due to aortic dissection in pregnancy in TS is 2%, which is approximately 100 times higher than the general population, as maternal mortality is extremely low. Ongoing cardiovascular monitoring is recommended, although there remain several unanswered questions in relation to cardiovascular imaging especially the choice of modality for detection of vascular, valvular abnormalities and measurements of aortic dimensions. Due to the relative short stature of patients with TS, aortic dimensions need to be defined by aortic measurements adjusted for body surface area, known as aortic sized index (ASI). The relationship of ASI and other risk factors with aortic dissection is only beginning to be clarified. Clinical management and monitoring of such patients should be delivered by a group of clinicians familiar with the issues unique to TS patients in a multidisciplinary fashion. All clinicians including the non-specialists need to have a low threshold of suspecting aortic dissection in these adolescents and young adults. This up to date review, including a summary of all 122 published cases of TS patients with aortic dissection, aims to provide a summary of recent publications on characteristics of aortic dissection and aortic dilatation in TS to highlight gaps in knowledge and propose possible clinical monitoring pathway of cardiovascular health in children and adults with TS. Cardiovascular assessment and risk counselling is especially crucial during the period of transition of adolescents with TS, although life long monitoring by expert cognizant to the issues specific in TS is essential.
Article
Aim: The aim of this study was to evaluate the morphology and elastic properties of the aorta in children and adolescents with Ullrich-Turner syndrome (UTS) treated with growth hormone, by using magnetic resonance imaging (MRI). Methods: Thirty-seven conscious UTS patients were examined using a 1.5-T whole-body MRI. Contrast-free three-dimensional (3D)-MR angiographies were performed, including 2D cine MRI, to calculate the aortic compliance (C) and cine of the aortic valve. Results: Changes of aortic morphology were evident in 40% of the patients, whereas six had more than one alteration. A bicuspid aortic valve was identified in three patients that were missed by previous echocardiography. The aortic compliances in UTS patients were similar to those in healthy persons. Conclusion: This study shows that aortic morphology and compliance can be assessed by MRI without using contrast agents and without sedation in children and adolescents with UTS.
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Approximately one in 2500 live-born females is affected by Turner syndrome (TS). Short stature and gonadal failure are the most consistent features of this syndrome. However, multiple physiological systems can be affected to varying degrees, especially the cardiovascular system, with congenital cardiovascular disease being the major cause of premature mortality in these patients, although other cardiovascular abnormalities can be present depending on age. Indeed, dissection of the aorta is a life-threatening event that, in recent years, has been reported with relative frequency. This article describes the spectrum of cardiovascular defects in TS with special attention to aortic dilatation/ dissection and their risk factors. The incorporation of new imaging techniques, such as MRI, to evaluate the aortic valve and aortic dilatation/dissection is discussed. In addition, recent guidelines for diagnosis, follow-up and treatment of girls with TS are described.
Article
New treatments for girls and women with Turner syndrome (monosomy X) have dramatically improved their quality of life and health. Young girls are treated with growth hormone to enhance adult height, and with estrogen to induce and maintain feminization, and prevent osteoporosis. Vigilant screening for otitis, thyroid disease, hypertension, dyslipidemia and diabetes allows for early and effective medical treatment of these common problems. Comprehensive cardiovascular evaluation and regular monitoring of aortic diameter are essential to identify individuals at risk for dissection or rupture. Insights derived from the study of metabolic risk factors in women with Turner syndrome may illuminate gender differences in atherosclerotic heart disease.
Aims: We evaluated echocardiography and electrocardiography (ECG) results in children with non-specific mitochondrial disease (MD) in order to study early cardiac involvement, a well-known complication of the disease. Methods: Among non-specific MD children whose isolated mitochondrial respiratory chain complex I defect was confirmed by muscle biopsy and satisfied the criteria of MD, 27 who had no cardiac symptoms were evaluated by echocardiography and ECG. Results: Three (11.1%) out of the 27 non-specific MD patients had left ventricular ejection fraction of less than 55% and two of them (7.4%) had fractional shortening of less than 26%. ECG abnormalities were observed in 16 of the non-specific MD patients (59.3%). Prolongation of heart rate-corrected QT interval was seen in 11 (40.7%) and widening of the QRS interval in eight (29.6%). Left ventricular ejection fraction and fractional shortening of the patients were significantly decreased compared with those in the control group while heart rate-corrected QT interval was prolonged in the former group. QRS interval was more widened in non-specific MD patients, but without statistical significance. Conclusion: The potentially severe cardiac involvement observed in our subjects suggests that early cardiac evaluation after confirming the diagnosis of MD and regular follow-up tests should be strongly recommended in children even in cases without typical cardiac manifestations.
Article
Cardiovascular disease affects >50% of Turner syndrome (TS) patients. With newer imaging modalities, this prevalence increases and the spectrum of recognized anomalies broadens. To determine the prevalence and hemodynamic significance of partial anomalous pulmonary venous return (PAPVR) in adolescents and young adults with TS using transthoracic echocardiogram (TTE) and cardiac magnetic resonance (CMR), and to study the association with phenotype. The records of 39 young TS patients who had received TTE and CMR were reviewed. PAPVR was diagnosed in seven (18%) patients; six were newly diagnosed by CMR after normal TTE. In one subject, PAPVR was associated with right ventricular enlargement and a pulmonic blood flow (Qp) to systemic blood flow (Qs) ratio of 1.9:1.0, necessitating surgical repair. In other subjects with and without PAPVR, Qp:Qs and the right ventricle to left ventricle end-diastolic volume ratio were statistically different. Other clinical features were not predictive of PAPVR. The prevalence of PAPVR is high in TS, and it may be hemodynamically significant. Diagnosis by TTE can be difficult. Appropriate screening and management are indicated.
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Cardiovascular disease is emerging as a cardinal trait of Turner syndrome, being responsible for half of the 3-fold excess mortality. Turner syndrome has been proposed as an independent risk marker for cardiovascular disease that manifests as congenital heart disease, aortic dilation and dissection, valvular heart disease, hypertension, thromboembolism, myocardial infarction, and stroke. Risk stratification is unfortunately not straightforward because risk markers derived from the general population inadequately identify the subset of females with Turner syndrome who will suffer events. A high prevalence of endocrine disorders adds to the complexity, exacerbating cardiovascular prognosis. Mounting knowledge about the prevalence and interplay of cardiovascular and endocrine disease in Turner syndrome is paralleled by improved understanding of the genetics of the X-chromosome in both normal health and disease. At present in Turner syndrome, this is most advanced for the SHOX gene, which partly explains the growth deficit. This review provides an up-to-date condensation of current state-of-the-art knowledge in Turner syndrome, the main focus being cardiovascular morbidity and mortality. The aim is to provide insight into pathogenesis of Turner syndrome with perspectives to advances in the understanding of genetics of the X-chromosome. The review also incorporates important endocrine features, in order to comprehensively explain the cardiovascular phenotype and to highlight how raised attention to endocrinology and genetics is important in the identification and modification of cardiovascular risk.
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Many human diseases share a developmental origin that manifests during childhood or maturity. Aneuploid syndromes are caused by supernumerary or reduced number of chromosomes and represent an extreme example of developmental disease, as they have devastating consequences before and after birth. Investigating how alterations in gene dosage drive these conditions is relevant because it might help treat some clinical aspects. It may also provide explanations as to how quantitative differences in gene expression determine phenotypic diversity and disease susceptibility among natural populations. Here, we aimed to produce induced pluripotent stem cell (iPSC) lines that can be used to improve our understanding of aneuploid syndromes. We have generated iPSCs from monosomy X [Turner syndrome (TS)], trisomy 8 (Warkany syndrome 2), trisomy 13 (Patau syndrome) and partial trisomy 11;22 (Emanuel syndrome), using either skin fibroblasts from affected individuals or amniocytes from antenatal diagnostic tests. These cell lines stably maintain the karyotype of the donors and behave like embryonic stem cells in all tested assays. TS iPSCs were used for further studies including global gene expression analysis and tissue-specific directed differentiation. Multiple clones displayed lower levels of the pseudoautosomal genes ASMTL and PPP2R3B than the controls. Moreover, they could be transformed into neural-like, hepatocyte-like and heart-like cells, but displayed insufficient up-regulation of the pseudoautosomal placental gene CSF2RA during embryoid body formation. These data support that abnormal organogenesis and early lethality in TS are not caused by a tissue-specific differentiation blockade, but rather involves other abnormalities including impaired placentation.
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To describe the first case of established chromosome 22q11 deletion syndrome with late onset presentation of hypocalcemia secondary to hypoparathyroidism. We present the history, clinical and laboratory investigations, and management of a 17-year-old adolescent boy who presented with 3 separate seizures secondary to hypocalcemia. This patient had an established diagnosis of chromosome 22q11 deletion syndrome at the time of the seizure presentations, but had previously normal calcium levels. Hypocalcemia was noted during each seizure, with corrected calcium levels ranging from 6.64 to 7.76 mg/dL (reference range, 8.52 to 10.52 mg/dL). The hypocalcemia was secondary to hypoparathyroidism, with parathyroid hormone levels < 2.75 pg/mL (reference range, 22.9 to 68.75 pg/mL). He was treated with calcitriol, 0.5 μg daily, and calcium carbonate, 2,400 mg daily, leading to normalization of serum calcium and resolution of seizures. Chromosome 22q11 deletion syndrome is a relatively common genetic disorder with a wide variety of phenotypic manifestations including cardiac abnormalities, abnormal facies, thymic dysfunction, cleft palate, and hypocalcemia. This case shows that medical practitioners should be aware that hypocalcemia can present after an established diagnosis, which has implications for the management of this disorder.
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The aim of the study was to establish the prevalence of cardiovascular malformations in females with Turner's syndrome and analyse possible associations with the various karyotypes. One hundred and seventy nine of 393 females who had Turner's syndrome diagnosed in Denmark were examined. Complete chromosome analysis was available in all cases. Clinical examination, electrocardiography, and echocardiography including Doppler were performed. The distribution of the various karyotypes was 45,X, 58%; mosaic monosomy X, 35%; and structural abnormalities of the X chromosome, 7%. In 46 (26%) of the females a total of 69 cardiovascular malformations were found; aortic valve abnormality (18%) and aortic coarctation (10%) being the most common. There was a significant difference in the prevalence of cardiovascular malformations between 45,X and mosaic monosomy X (38% v 11%), primarily due to a significant difference in the prevalence of aortic valve abnormalities and aortic coarctation. Pulmonary valve abnormalities were seen only in females with mosaic monosomy X but the prevalence was low (3%). No patient with structural abnormalities of the X chromosome had cardiovascular malformations.
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Turner syndrome afflicts approximately 50 per 100,000 females and is characterized by retarded growth, gonadal dysgenesis, and infertility. Much attention has been focused on growth and growth promoting therapies, while less is known about the natural course of the syndrome, especially in adulthood. We undertook this study to assess the incidence of diseases relevant in the study of Turner syndrome. The study period was from January 1, 1984 to December 31, 1993, and the study base was all women living in Denmark during the study period. We used data from the Danish Cytogenetic Central Register and the Danish National Registry of Patients to assess morbidity. This study supports several earlier studies reporting increased morbidity and confirms results of a recent study on cancer in Turner syndrome. Women with Turner syndrome seem to have an increased incidence of fractures, osteoporotic fractures in adulthood, and non-osteoporotic fractures in childhood. Furthermore, diabetes mellitus, both NIDDM and IDDM, was found with a markedly increased incidence in Turner syndrome, as well as ischemic heart disease, hypertension, and stroke. The risk of cancer, except cancer of the large bowel, does not seem to be elevated in Turner syndrome. Our data suggest that patients with Turner syndrome are extraordinarily prone to abnormalities constituting the metabolic syndrome (e.g., hypertension, dyslipidaemia, NIDDM, obesity, hyperinsulinemia and hyperuricemia). The present data may help to explain the decreased life span found in patients with Turner syndrome.
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Impaired glucose tolerance and diabetes mellitus have been associated with a prolonged QT interval among select populations. However, these associations remain unclear among the general population. We examined these relationships using data from 5833 adults aged 40-90 years from NHANES III (1988-1994). Univariate differences in cardiovascular disease (CVD) risk factors were examined across tertiles of heart rate corrected QT (QTc). The association between glucose intolerance, CVD risk factors and a prolonged QTc (> or = 0.440 s) was also assessed with logistic regression adjusting for age, race, gender, education, and heart rate. Prolonged QTc was observed among 22.0% of persons with normal glucose tolerance (NGT), 29.9% of those with impaired fasting glucose (IFG), and among 42.2% of persons with diabetes. Hypertension, serum cholesterol, obesity, heart rate, and fasting C-peptide and serum insulin levels were associated with prolonged QTc (all: P < or = 0.05). After multivariate adjustment, persons with IFG were 1.2 times (95% CI=0.7-2.0) as likely and persons with diabetes 1.6 times (95% CI=1.1-2.3) as likely to have a prolonged QTc as persons with NGT. In addition, persons with diabetes and two or more additional CVD risk factors were 2.3 times (95% CI=1.3-4.0) as likely to have a prolonged QTc as persons with NGT and no CVD risk factors after multivariate adjustment. Diabetes was associated with an increased likelihood of prolonged QTc independent of age, race, gender, education, and heart rate. In addition, persons with diabetes and multiple CVD risk factors were more likely to have a prolonged QTc than those with NGT and no additional risk factors, suggesting that these persons may be at increased risk for cardiac arrhythmia and sudden death.
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Objective: There is a high prevalence of congenital heart defects in patients with Turner’s syndrome. Few studies have reported echocardiographic data in unselected patients according to the different chromosomal patterns. The aim of our study was to evaluate a large series of patients with Turner’s syndrome, comparing these data with those of the general population. Methods: Five hundred ninety-four patients with Turner’s syndrome, aged 1 month to 24 years, in the Italian Study Group for Turner Syndrome underwent full cardiologic evaluation. Karyotype distribution was: 45,X (54%), X-mosaicism (13%), and X-structural abnormalities (33%). Results: The prevalence of cardiac malformations was 23%. Bicuspid aortic valve (12.5%), aortic coarctation (6.9%), and aortic valve disease (3.2%) were the most prevalent malformations. In comparison with the general population, partial anomalous pulmonary venous drainage had the highest relative risk. A correlation was found between type of congenital heart defect and karyotype. The patients with 45,X karyotype had the greatest prevalence of partial anomalous pulmonary venous drainage and aortic coarctation, whereas bicuspid aortic valve and aortic valve disease were more common in the patients with X-structural abnormalities. The patients with severe dysmorphic signs showed a significantly higher relative risk of cardiac malformations. Conclusion: X-linked factors may be involved in determining cardiac defects in Turner’s syndrome. (J Pediatr 1998;133:688-92)
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Human mutations in Nkx2-5 lead to progressive cardiomyopathy and conduction defects via unknown mechanisms. To define these pathways, we generated mice with a ventricular-restricted knockout of Nkx2-5, which display no structural defects but have progressive complete heart block, and massive trabecular muscle overgrowth found in some patients with Nkx2-5 mutations. At birth, mutant mice display a hypoplastic atrioventricular (AV) node and then develop selective dropout of these conduction cells. Transcriptional profiling uncovered the aberrant expression of a unique panel of atrial and conduction system-restricted target genes, as well as the ectopic, high level BMP-10 expression in the adult ventricular myocardium. Further, BMP-10 is shown to be necessary and sufficient for a major component of the ventricular muscle defects. Accordingly, loss of ventricular muscle cell lineage specification into trabecular and conduction system myocytes is a new mechanistic pathway for progressive cardiomyopathy and conduction defects in congenital heart disease.
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A 13-year incidence study of sex chromosome abnormalities in Arhus, Denmark of 34,910 newborn children showed that 1 per 448 had a sex chromosome abnormality. The incidences of the most common sex chromosome abnormalities were Klinefelter syndrome, 1 per 576 boys; XYY, 1 per 851 boys; triple X, 1 per 897 girls; Turner syndrome, 1 per 2130 girls. Follow-up of children with autosomal abnormalities is not included in this study. None of the 78 surviving children with sex chromosome abnormalities was mentally retarded. All children above school age attended regular schools. Seventy-seven percent of Klinefelter, triple X, and XYY children aged 15-19 had received remedial teaching, 29% were receiving remedial teaching at the last follow-up, 32% had been in special classes at a regular school due to learning problems, and 24% were still in such classes at the last time of follow-up. There was no increased frequency of criminal activity or behavior disorders, nor was there any increased frequency of mental or physical disorders. The distribution of planned training or occupation for the 25 youths with sex chromosome abnormalities between 15 and 19 years of age was similar to that of their sibs. Testosterone undecanoate treatment has been given to Klinefelter boys from puberty and growth hormone treatment to Turner girls from the age of 7, and very small doses of estrogen were given to these girls from around the age of 12 when FSH was increasing to postmenopausal levels. Prevention or reduction of deviations in mental development from the normal range in children with sex chromosome abnormalities is possible if educational and social resources are available and the parents are well informed and counseled regularly. Information in Denmark has been given in part by publishing four booklets about triple X, XYY, Turner, and Klinefelter syndrome. Information, support, and stimulation to self-help have, to a certain extent, been given through contact groups. Parents having a child with a sex chromosome abnormality need information, counseling, and assistance. The type and magnitude of this assistance depend on the individual child, the specific sex chromosome abnormality, and the parents' own resources, psychologically, socially, and otherwise.
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We have presented recommendations for the optimum acquisition of quantitative two-dimensional data in the current echocardiographic environment. It is likely that advances in imaging may enhance or supplement these approaches. For example, three-dimensional reconstruction methods may greatly augment the accuracy of volume determination if they become more efficient. The development of three-dimensional methods will depend in turn on vastly improved transthoracic resolution similar to that now obtainable by transesophageal echocardiography. Better resolution will also make the use of more direct methods of measuring myocardial mass practical. For example, if the epicardium were well resolved in the long-axis apical views, the myocardial shell volume could be measured directly by the biplane method of discs rather than extrapolating myocardial thickness from a single short-axis view. At present, it is our opinion that current technology justifies the clinical use of the quantitative two-dimensional methods described in this article. When technically feasible, and if resources permit, we recommend the routine reporting of left ventricular ejection fraction, diastolic volume, mass, and wall motion score.
Article
To determine the accuracy of echocardiographic left ventricular (LV) dimension and mass measurements for detection and quantification of LV hypertrophy, results of blindly read antemortem echocardiograms were compared with LV mass measurements made at necropsy in 55 patients. LV mass was calculated using M-mode LV measurements by Penn and American Society of Echocardiography (ASE) conventions and cube function and volume correction formulas in 52 patients. Penn-cube LV mass correlated closely with necropsy LV mass (r = 0.92, p less than 0.001) and overestimated it by only 6%; sensitivity in 18 patients with LV hypertrophy (necropsy LV mass more than 215 g) was 100% (18 of 18 patients) and specificity was 86% (29 of 34 patients). ASE-cube LV mass correlated similarly to necropsy LV mass (r = 0.90, p less than 0.001), but systematically overestimated it (by a mean of 25%); the overestimation could be corrected by the equation: LV mass = 0.80 (ASE-cube LV mass) + 0.6 g. Use of ASE measurements in the volume correction formula systematically underestimated necropsy LV mass (by a mean of 30%). In a subset of 9 patients, 3 of whom had technically inadequate M-mode echocardiograms, 2-dimensional echocardiographic (echo) LV mass by 2 methods was also significantly related to necropsy LV mass (r = 0.68, p less than 0.05 and r = 0.82, p less than 0.01). Among other indexes of LV anatomy, only measurement of myocardial cross-sectional area was acceptably accurate for quantitation of LV mass (r = 0.80, p less than 0.001) or diagnosis of LV hypertrophy (sensitivity = 72%, specificity = 94%).(ABSTRACT TRUNCATED AT 250 WORDS)
Article
There is a high prevalence of congenital heart defects in patients with Turner's syndrome. Few studies have reported echocardiographic data in unselected patients according to the different chromosomal patterns. The aim of our study was to evaluate a large series of patients with Turner's syndrome, comparing these data with those of the general population. Five hundred ninety-four patients with Turner's syndrome, aged 1 month to 24 years, in the Italian Study Group for Turner Syndrome underwent full cardiologic evaluation. Karyotype distribution was: 45,X (54%), X-mosaicism (13%), and X-structural abnormalities (33%). The prevalence of cardiac malformations was 23%. Bicuspid aortic valve (12.5%), aortic coarctation (6.9%), and aortic valve disease (3.2%) were the most prevalent malformations. In comparison with the general population, partial anomalous pulmonary venous drainage had the highest relative risk. A correlation was found between type of congenital heart defect and karyotype. The patients with 45,X karyotype had the greatest prevalence of partial anomalous pulmonary venous drainage and aortic coarctation, whereas bicuspid aortic valve and aortic valve disease were more common in the patients with X-structural abnormalities. The patients with severe dysmorphic signs showed a significantly higher relative risk of cardiac malformations. X-linked factors may be involved in determining cardiac defects in Turner's syndrome.
Article
The preferential association between Turner's syndrome and congenital heart defects (CHD) have been well known since the first description by Morgagni. There are few studies about the different cardiologic problems stemming from different chromosomal patterns of X monosomies. We reviewed a large series of 136 patients with Turner syndrome without cardiologic preselection, 29 of whom had some kind of CHD (21.5%). Partial anomalous pulmonary venous drainage (PAPVD; 2.9%), aortic valve disease (stenosis and/or incompetence) (AoVD; 5. 1%), aortic coarctation (AoCo; 4.4%), and bicuspid aortic valve (BicAo; 14.7%) are much more frequent in Turner's syndrome than in the normal population, with the difference being statistically highly significant. In our cases, only the 45, X subjects showed severe CHD and multiple lesions, whereas the X-ring pattern was associated with an elevated prevalence of BicAo. Patients with X-deletion showed no signs of congenital heart malformations. Eleven patients, all with 45, X pattern, and significant CHD, underwent cardiac surgery at a mean age of 7.7 +/- 5.3 years (range 7 days-18 years) without complications. At follow-up of 3-18 years (8.6 +/- 5. 2), we were unable to observe any type of evolution of the remaining untreated cardiovascular anomalies.
Article
Introduction: Elevated blood pressure (BP) is an important predictor of morbidity and mortality from cardiovascular disease. Patients with Turner syndrome (TS) have a higher morbidity and mortality in middle age than the normal population. As BP in childhood or early adulthood is predictive of BP later in adult life, we assessed manual and 24 h ambulatory BP in patients with TS to determine whether the BP pattern is altered at an early stage in these patients who are known to be at risk of cardiovascular disease. Patients and methods: We studied manual and 24 h ambulatory BP profiles in 75 girls with Turner syndrome, age range 5.4-22.4 years. A monitor with an oscillometric device (SpaceLabs model 90207) and an appropriate sized cuff was used. BP was measured during the day-time (0800-2000 h) and the night-time periods (2200-0800 h). The BP measured were compared with population standards. The effect of different growth promoting agents on BP was also evaluated. Results: Mean manual and 24 h ambulatory BP measurements were 118/77 mmHg (range 95/60-140/102) and 115/70 mmHg (range 93/57-154/99), respectively. There was minimal difference between the two methods with a positive bias of 2.4 mmHg for diastolic BP and a negative bias of 2.1 mmHg for systolic BP. The mean standard deviation scores (SDS) corresponding to the mean BP recordings were 24 h systolic + 0. 81 (range - 1.26 to + 4.45), 24 h diastolic + 0.43 (range - 0.85 to + 3.42), day-time systolic + 1.08 (range - 0.95 to + 4.72), day-time diastolic + 0.70 (range - 0.94 to + 3.71), night-time systolic + 0. 22 (range -2.2 to + 3.64) and night-time diastolic - 0.18 (range -2. 0 to + 2.43). The SDS for both the mean 24 h and day-time systolic and diastolic BP were shifted to the right of the normal distribution. 57% of the girls had less than the normal 10% reduction in nocturnal systolic blood pressure. 17% had diastolic and 21% had systolic blood pressure above the 95th percentile for age and sex. There was no significant difference in the BP SDS between girls on no treatment and those receiving treatment. Conclusion: Over 50% of girls with Turner syndrome have an abnormal BP circadian rhythm, which is similar to adult patients with secondary hypertension. Patients with Turner syndrome have higher blood pressure measurements compared to published population standards, as evidenced by the shift to the right of both the systolic and diastolic BP SDS. These findings suggest that girls with Turner syndrome should be carefully monitored in childhood and adulthood for blood pressure and other cardiovascular risk factors.
Article
Before chromosomal analysis became available, the diagnosis of Turner's syndrome was based on the characteristics independently described by Otto Ullrich and Henry Turner, such as short stature, gonadal dysgenesis, typical, visible dysmorphic stigmata, and abnormalities in organs, which present in individuals with a female phenotype. Today, Turner's syndrome or Ullrich-Turner's syndrome may be defined as the combination of characteristic physical features and complete or part absence of one of the X chromosomes, frequently accompanied by cell-line mosaicism. The increasing interest in Turner's syndrome over the past two decades has been motivated both by the quest for a model by which the multi-faceted features of this disorder can be understood, and the endeavour to provide life-long support to the patient. New developments in research allow patients with Turner's syndrome to have multidisciplinary care.
Article
Turner's syndrome is the most common chromosomal abnormality in females, affecting 1:2,500 live female births. It is a result of absence of an X chromosome or the presence of a structurally abnormal X chromosome. Its most consistent clinical features are short stature and ovarian failure. However, it is becoming increasingly evident that adults with Turner's syndrome are also susceptible to a range of disorders, including osteoporosis, hypothyroidism, and renal and gastrointestinal disease. Women with Turner's syndrome have a reduced life expectancy, and recent evidence suggests that this is due to an increased risk of aortic dissection and ischemic heart disease. Up until recently, women with Turner's syndrome did not have access to focused health care, and thus quality of life was reduced in a significant number of women. All adults with Turner's syndrome should therefore be followed up by a multidisciplinary team to improve life expectancy and reduce morbidity.
Article
Hypoglycaemia alters cardiac repolarization acutely, with increases in rate-corrected QT (QTc) interval and QT dispersion (QTd) on the electrocardiogram (ECG); such changes are related to the counterregulatory sympatho-adrenal response. Adrenaline produces both QTc lengthening and a fall in plasma potassium (K+) when infused into healthy volunteers. Hypokalaemia prolongs cardiac repolarization independently however, and therefore our aim was to determine whether adrenaline-induced repolarization changes are mediated directly or through lowered plasma K+. Ten healthy males were studied on two occasions. At both visits they received similar l-adrenaline infusions but on one occasion potassium was also administered; infusion rates were adjusted to maintain circulating K+ at baseline. The QTc interval, QTd, peripheral physiological responses and plasma adrenaline and potassium concentrations were measured during both visits. The QTc interval and QTd increased both with and without potassium clamping. Without K+ replacement, mean (SE) QTc lengthened from 378 (5) ms to a final maximum value of 433 (10) ms, and QTd increased from 36 (5) ms to 69 (8) ms (both P < 0.001). During K+ replacement, QTc duration at baseline and study end was 385 (7) ms and 423 (11) ms, respectively (P < 0.001), and QTd 38 was (4) ms and 63 (5) ms (P = 0.001). These data suggest that disturbed cardiac repolarization as a result of increases in circulating adrenaline occurs independently of extracellular potassium. A direct effect of adrenaline upon the myocardium appears the most likely mechanism.
Article
The Bremen Diabetes Study is an observation study to characterise type 2 diabetic patients at high risk for death and cardiovascular complications by routine metabolic and cardiovascular tests. The aim of the present analysis was to evaluate the prediction of QTc interval prolongation and/or heart rate for cardiovascular mortality in comparison to traditional cardiovascular risk factors. We followed 475 type 2 diabetic patients (age 55 - 75 years; 304 women, 171 men) from a defined residential area, seen in our clinic primarily for metabolic control. Patients with coexisting micro- or macroangiopathic complications were not excluded. Outcome data were obtained for 423 subjects. QT intervals were measured in a 12 lead ECG and corrected for heart rate with Fridericia's equation [QTc = QT/RR1/3]. During the 5 year observation period 57 patients (13.5 %) died due to cardiovascular causes. In multivariate analysis we found that QTc interval prolongation (p = 0.0008), elevated heart rate (p = 0.0001), serum creatinine (p = 0.0260), smoking (p = 0.0056) and peripheral arterial disease (p = 0.0127) at baseline were independent predictors for cardiovascular death. The odds ratio was 2.7 (95 % CI 1.07 - 4.11) for QTc interval prolongation (> 421 ms) and 3.3 (95 % CI 1.33 - 8.19) for elevated heart rate (> 75/min). Easily established ECG criteria such as prolonged QTc time and elevated heart rate obviously are powerful predictors of cardiovascular death in type 2 diabetic patients and are possibly superior to the traditional cardiovascular risk factors. As heart rate itself is an independent risk indicator, QTc time should be calculated by a formula (e.g. Fridericia's equation) that more accurately corrects QT for heart rate than the widely used Bazett's formula.
Article
A long QT interval is a risk factor for arrhythmic events and sudden death. Whether moderate QT prolongation is associated with clinical events in community-dwelling elderly patients is uncertain. We measured the QT interval in a population-based sample of 5888 men and women at least 65 years of age who were participants in the Cardiovascular Health Study. The association between Bazett's rate-corrected QT (QTc, in ms) and mortality during the subsequent 10 years was evaluated. We stratified participants by the presence or absence of coronary heart disease status at baseline, and adjusted for coronary heart disease risk factors. The rates of all-cause and coronary heart disease mortality were greater in participants with longer QTc intervals. Among participants without known coronary heart disease, those whose QTc interval was >450 ms were at increased risk of all-cause mortality (relative risk [RR] = 1.34; 95% confidence interval [CI]: 1.07 to 1.67) and coronary heart disease mortality (RR = 1.6; 95% CI: 1.0 to 2.5) when compared with participants whose QTc interval was <410 ms. The associations were stronger among those with known coronary heart disease (RR for all-cause mortality = 2.3; 95% CI: 1.6 to 3.3; and RR for coronary heart disease mortality = 2.0; 95% CI: 1.1 to 3.7). The QT interval from the standard electrocardiograms is of value for identification of elderly persons at increased risk of coronary heart disease and total mortality. A QTc interval >450 ms should prompt clinical evaluation and possible interventions to reduce the risk of coronary events.
Article
Unlabelled: Congenital cardiovascular defects, commonly affecting the aortic valve or the aortic arch (50% to 70%), are seen in ca. 17%-44% of patients with Ullrich-Turner syndrome (UTS). However, there are only 36 case reports worldwide on the coincidental finding of partial anomalous pulmonary vein connection (PAPVC) in UTS. In 4 out of 108 patients with UTS seen in our clinic, PAPVC was suspected echocardiographically and confirmed by angiography in three patients. Surgical correction was performed in one patient with right ventricular enlargement. PAPVC can lead to right ventricular volume load and hypertrophy in adolescence. Early diagnosis and when necessary treatment is recommended. Conclusion: cardiological evaluation in patients with Ullrich-Turner syndrome should pay special attention to partial anomalous pulmonary vein connection.
Article
Type 2 diabetes is associated with increased risk of cardiovascular (CV) and all-cause mortality. Although electrocardiographic measures of repolarization abnormality and complexity stratify risk in the general population, their prognostic value in diabetes has not been well characterized. Digital electrocardiogram (ECG) readings were acquired for 994 American Indians with type 2 diabetes. ST segment depression (STD) >/=50 micro V and rate-corrected QT interval (QTc) >460 ms were examined as measures of repolarization abnormality. The principal component analysis (PCA) of the ratio of the second to first eigenvalues of the T-wave vector (PCA ratio) (>32.0% in women and >24.6% in men) was examined as a measure of repolarization complexity on the ECG. After a mean follow-up of 4.7 +/- 1.0 years, there were 56 CV deaths and 155 deaths from all causes. In univariate analyses, STD, QTc, and the PCA ratio predicted CV and all-cause mortality. After multivariate adjustment for age, sex, and other risk factors, STD (hazard ratio 3.68, 95% CI 1.70-7.96) and PCA ratio (2.61, 1.33-5.13) remained predictive of CV mortality and both STD (2.36, 1.38-4.02) and QTc (2.03, 1.32-3.12) predicted all-cause mortality. Computerized ECG measures of repolarization abnormality and complexity predict CV and all-cause mortality in type 2 diabetes, supporting their use to identify high-risk individuals with diabetes.
Article
Human mutations in Nkx2-5 lead to progressive cardiomyopathy and conduction defects via unknown mechanisms. To define these pathways, we generated mice with a ventricular-restricted knockout of Nkx2-5, which display no structural defects but have progressive complete heart block, and massive trabecular muscle overgrowth found in some patients with Nkx2-5 mutations. At birth, mutant mice display a hypoplastic atrioventricular (AV) node and then develop selective dropout of these conduction cells. Transcriptional profiling uncovered the aberrant expression of a unique panel of atrial and conduction system-restricted target genes, as well as the ectopic, high level BMP-10 expression in the adult ventricular myocardium. Further, BMP-10 is shown to be necessary and sufficient for a major component of the ventricular muscle defects. Accordingly, loss of ventricular muscle cell lineage specification into trabecular and conduction system myocytes is a new mechanistic pathway for progressive cardiomyopathy and conduction defects in congenital heart disease.
Article
An increased risk for life-threatening arrhythmias and sudden death has been observed in hypertensive patients, associated with either left ventricular hypertrophy (LVH) or prolonged QT interval. To investigate the influence of autonomic imbalance and LVH on QT interval in hypertensive patients, we compared two different models of LVH: hypertension and endurance physical training. Forty-seven untreated subjects affected by essential hypertension and 35 endurance runners, with a similar degree of LVH, were enrolled into the study. All subjects underwent 24-h ambulatory ECG recording and morning blood sampling for catecholamines. Heart rate variability was evaluated by spectral analysis and a computerized algorithm was used to measure the QT interval; QTc was then computed by the Bazett's formula. Left ventricular mass index (LVMI) was assessed by echocardiogram. No difference in LVMI was found between hypertensive patients and athletes. Athletes showed lower heart rate (64 +/- 1 vs. 75 +/- 1 bpm, p<0.001, mean +/- S.E.M.) and shorter QTc (401 +/- 3 vs. 434 +/- 4 ms, p<0.001) than hypertensive patients throughout the 24-h period. Athletes showed a higher vagal drive compared to hypertensive patients as suggested by bradycardia and higher values of vagal indices, which negatively correlated with QTc. Plasma norepinephrine was significantly lower in athletes than in hypertensive patients (p<0.05) and positively correlated with QTc. Conclusion: Despite similar degrees of LVH, hypertensive patients show QTc lengthening, as compared to athletes. Heart rate variability and plasma norepinephrine levels suggest sympathetic predominance in hypertensive patients, which could contribute to abnormal ventricular repolarization, thus identifying patients with an increased arrhythmic risk.
Article
Turner syndrome (TS) is associated with aortic coarctation and dissection; hence, echocardiographic evaluation of all patients is currently recommended. X-ray angiography in clinically symptomatic patients has suggested a range of other vascular anomalies, but the true prevalence of such lesions in TS is unknown. To better understand the prevalence and pathogenesis of cardiovascular defects in TS, we prospectively evaluated a group of asymptomatic adult volunteers with TS using magnetic resonance (MR) angiography. A total of 85 adults with TS and 27 normal female adult volunteers underwent gadolinium-enhanced 3D MR angiography. A high prevalence of aortic anomalies was seen in women with TS, including elongation of the transverse arch (49%), aortic coarctation (12%), and aberrant right subclavian artery (8%). Venous anomalies were also prominent, including persistent left superior vena cava (13%) and partial anomalous pulmonary venous return (13%). None of these anomalies were found in healthy female controls. The constellation of elongation of the transverse arch, aortic coarctation, and persistent left superior vena cava was significantly associated with women with TS. Neck webbing and increased thoracic anterior-to-posterior dimension diameters were strong predictors for arterial and venous anomalies. Thoracic vascular anomalies are common in TS, occurring in approximately 50% of a group not preselected for cardiovascular disease. The highly significant association between neck webbing, increased chest diameter, and these vascular anomalies suggests that in utero, centrally localized lymphatic obstruction may contribute to these cardiovascular deformities in TS. Improved recognition of these often-undetected vascular lesions may be important for identification of patients in need of closer cardiovascular monitoring.
Article
Until recently, sudden cardiac death in a young person often remained an unexplained tragedy. However, in the last decade there have been dramatic advances in medical knowledge regarding inheritable dysrhythmias that increase the risk of SCD in otherwise healthy young individuals. The primary mechanism in this group of dysrhythmias appears to be an alteration of cardiac repolarization. In some diseases, the specific genes affected and even precise cellular mechanisms have been identified. The information about these diseases is often complex and rapidly evolving, challenging both healthcare providers and the families who must make important decisions based on emerging and incomplete information. The purpose of this article is to describe current understanding of the repolarization-related dysrhythmias and discuss the clinical implications for advanced practice nurses.
Article
We aimed to study the predictive value of heart rate-corrected QT interval (QTc) for incident coronary heart disease (CHD) and cardiovascular disease (CVD) mortality in the black and white general population, and to validate various QT measurements. QTc prolongation is associated with higher risk of mortality in cardiac patients and in the general population. Little is known about the association with incident CHD. No previous studies included black populations. We studied the predictive value of QTc prolongation in a prospective population study of 14,548 black and white men and women, age 45 to 64 year. QT was determined by the NOVACODE program in the digital electrocardiogram recorded at baseline. In quintiles of QTc, cardiovascular risk profile deteriorated with longer QTc, and risk of CHD and CVD mortality increased. The high risk in the upper quintile was mostly explained by the 10% with the longest QTc. The age-, gender-, and race-adjusted hazard ratios for CVD mortality and CHD in subjects with the longest 10% relative to the other 90% of the gender-specific QTc distribution were 5.13 (95% confidence interval 3.80 to 6.94) and 2.14 (95% confidence interval 1.71 to 2.69), respectively. The increased risk was partly, but not completely, attributable to other risk factors or the presence of chronic disease. The association was stronger in black than in white subjects. Manual- and machine-coded QT intervals were highly correlated, and the method of rate correction did not affect the observed associations. Long QTc is associated with increased risk of CHD and CVD mortality in black and white healthy men and women.
Article
This study sought to investigate whether prolongation of the heart rate-corrected QT (QTc) interval is a risk factor for sudden cardiac death in the general population. In developed countries, sudden cardiac death is a major cause of cardiovascular mortality. Prolongation of the QTc interval has been associated with ventricular arrhythmias, but in most population-based studies no consistent association was found between QTc prolongation and total or cardiovascular mortality. Only very few of these studies specifically addressed sudden cardiac death. This study was conducted as part of the Rotterdam Study, a prospective population-based cohort study that comprises 3,105 men and 4,878 women aged 55 years and older. The QTc interval on the electrocardiogram was determined during the baseline visit (1990 to 1993) and the first follow-up examination (1993 to 1995). The association between a prolonged QTc interval and sudden cardiac death was estimated using Cox proportional hazards analysis. During an average follow-up period of 6.7 years (standard deviation, 2.3 years) 125 patients died of sudden cardiac death. An abnormally prolonged QTc interval (>450 ms in men, >470 ms in women) was associated with a three-fold increased risk of sudden cardiac death (hazard ratio, 2.5; 95% confidence interval, 1.3 to 4.7), after adjustment for age, gender, body mass index, hypertension, cholesterol/high-density lipoprotein ratio, diabetes mellitus, myocardial infarction, heart failure, and heart rate. In patients with an age below the median of 68 years, the corresponding relative risk was 8.0 (95% confidence interval 2.1 to 31.3). Abnormal QTc prolongation on the electrocardiogram should be viewed as an independent risk factor for sudden cardiac death.
Article
Anatomic anomalies of the cardiovascular system occur in approximately 50% of individuals with Turner syndrome (TS), with the specific genetic cause(s) for the heart defects still unknown. Because congenital heart disease may be associated with conduction system abnormalities, we compared electrocardiograms (ECGs) in 100 women with TS and 100 age-matched female controls. Women with TS were significantly more likely to demonstrate left posterior fascicular block (p < 0.005), accelerated AV conduction (p < 0.006), and T wave abnormalities (p < 0.006). The PR interval was significantly shorter (137 +/- 17 vs. 158 +/- 18 ms, p < 0.0001) and the rate-corrected QT interval (QTc) significantly longer in women with TS than in controls (423 +/- 19 ms vs. 397 +/- 18 ms; p < 0.0001). Twenty-one women with TS but no controls had a QTc greater than 440 ms. We found no statistically significant relation between body habitus, cardiac dimensions, evidence of congenital heart disease, or metabolic parameters and the incidence of ECG abnormalities or QTc duration in TS. Cardiac conduction and repolarization abnormalities appear to be intrinsic features of TS, suggesting that deletion of the second sex chromosome has more profound effects on the cardiovascular system than previously recognized, and that ECG analysis should be included in evaluating and monitoring patients with Turner syndrome.
Article
Men typically have a more atherogenic lipid profile than women characterized by higher low-density lipoprotein (LDL) cholesterol and triglyceride levels and reduced lipid particle size, contributing to a greater risk for coronary disease. To determine whether X-chromosomal gene dosage affects lipid metabolism independent of sex steroid effects, we compared lipid profiles in age- and body mass-matched young women with ovarian failure, differing only in X-chromosome dosage. Women with premature ovarian failure associated with monosomy X or Turner syndrome (TS, n = 118) were compared with women with 46,XX premature ovarian failure (n = 51) in an in-patient clinical research center unit at the National Institutes of Health. These women were normally on estrogen replacement treatment but discontinued the estrogen 2 wk before study. MAJOR OUTCOMES: Fasting lipid levels and nuclear magnetic resonance lipid particle profiles in the two study groups were the major outcomes. Average age and body mass were similar in the two groups of women, but LDL cholesterol (P = 0.001) and triglyceride levels (P = 0.0005) were higher in the TS group. Also among women with TS, average LDL particle size was reduced (P < 0.0001) and LDL particle concentration increased, with a 2-fold increase in the smallest particle categories (P < 0.0001). Whereas total high-density lipoprotein cholesterol levels were similar, high-density lipoprotein particle size was significantly smaller in women with TS, compared with women with premature ovarian failure (P < 0.0001). Women with 45,X with ovarian failure exhibit a distinctly more atherogenic lipid profile than 46,XX women with ovarian failure, suggesting that the second X-chromosome contributes to a more salutary lipid profile in normal women, independent of sex steroid effects.
An analysis of time relation of electrocardiograms
  • J Bazett
Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings
  • R Devereux
  • D Alonso
  • E Lutas