Klotz communications 2021: Heart and Hormones
Heart and Turner syndromeCœur et syndrome de Turner

https://doi.org/10.1016/j.ando.2020.12.004Get rights and content

Abstract

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.

Résumé

Le syndrome de Turner (TS) est une maladie rare (ORPHA # 881) qui touche environ 50 nouveau-nés sur 100 000. Leur caryotype montre une perte complète ou partielle du deuxième chromosome X. Dans le TS, les malformations cardiovasculaires congénitales, telles que les valves aortiques bicuspides et la coarctation aortique sont fréquentes, affectant respectivement 20-30 % et 7-18 % de la population TS. La morbidité et la mortalité de ces patients sont élevées et liées à la présence d’hypertension et/ou de dilatation aortique (40 %), induisant une dissection aortique. Les directives européennes publiées en 2017 ont indiqué comment surveiller les patients par imagerie par résonance magnétique (IRM) et/ou échographie. Différentes études ont montré qu’un suivi cardiovasculaire tout au long de la vie est nécessaire et que l’éducation des patients TS et de leurs familles représente donc un enjeu majeur. Cette revue présentera des données récentes concernant la progression des diamètres aortiques ainsi que les connaissances moléculaires actuelles du système cardiovasculaire chez les patients atteints de TS.

Introduction

Turner syndrome (TS) is a rare disease (ORPHA #881) which affects about 50 in 100 000 newborn girls. The chromosomal disorder observed in TS, is a complete or partial loss of the second X chromosome in phenotypic females who have one intact X chromosome. The most frequent abnormalities are growth failure (> 95% of cases), primary ovarian insufficiency (POI) (95%), elevated liver enzymes (50-80%), autoimmune diseases (58%) and hypertension (50%). Congenital or acquired cardiovascular diseases are present in about half of patients with TS [1], [2]. Mortality of patients with TS is increased by a factor of 3 compared to the general population (SMR = 3.0 [95%CI= 2.7-3.4]) [3]. It is due to cardiovascular diseases, including aortic dissection.

Section snippets

Epidemiology and Karyotyping

The prevalence of TS diagnosis is 50/100 000 in female newborns. It is lower when incidentally found at the adult age, as shown by the UK Biobank study including 244 848 women [4]. In a recent French study, including 1501 patients with TS, the median age at diagnosis was 9.4 years [5] In Europe, the Danish cytogenetic register identified all cases (n = 781) of TS alive in Denmark, during the period from 1970 to 2001. Their median age at diagnosis was 15.1 years.

The diagnosis of TS relies on the

Congenital malformations

The most prevalent congenital cardiovascular malformation is bicuspid aortic (BAV), which is present in 20% to 30% of TS patients [1], [11], [12]. Its prevalence is however difficult to report, since asymptomatic vascular abnormalities can remain undiagnosed until adulthood. In our reference center of rare diseases (CMERCD), the median age at diagnosis of BAV was 20 (P25-P75th: 15-30) [12]. This delayed diagnosis is probably related to the fact that cardiac echography may be difficult to

Heart rhythm disturbances

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. Its prevalence is unknown. When resting QTc > 460 ms, exercise testing and 24 h Holter monitoring should confirm the diagnosis. In such patients, drugs prolonging the QTc should be avoided. However, a recent study reports that the QTc interval in girls and women

Aortic dilatation and aortic dissection

There are two main imaging techniques for aortic evaluation: transthoracic cardiac echocardiography (TTE) and aortic magnetic resonance imaging (MRI). The aortic root should be measured at least at the four following levels: aortic annulus, Valsalva sinuses, sino-tubular junction and tubular ascending aorta (Fig. 1). Aortic diameters can also be measured at the aortic cross and the descending aorta. The cost and availability are in favor of TTE. However, clinicians trained in congenital heart

Mechanisms of cardiovascular disease

Haplo-insufficiency for gene(s) located on the short arm of the X chromosome (Xp) have been implicated in the cardiovascular phenotype [41]. As BAV are much more frequent in TS than in the general population, this suggests that the second X chromosome is a protecting factor against BAV. In a whole genome study from the GenTAC registry [42], 188 TS patients were included. BAV, aortic dimension z-scores have been used as covariates of aortopathy. This analysis revealed that one gene, named TIMP3,

Prevention and treatment

In order to slow down aortic root dilatation in patients with BAV, beta-blockers or inhibitors of angiotensin II receptor (Losartan) are advised if AD  20 mm/m2 [46]. Those treatments are recommended in patients with Marfan syndrome. However, there is no scientific proof, so far, of a benefit of such treatments on aortic progression in patients with TS.

The best prevention of aortic dissection is to educate patients and perform their counselling. Transition between pediatric and adult hospital

Conclusion

Cardiovascular outcomes remain a major issue in patients with TS. Clinicians taking care of such patients have to face a lifelong challenge in order to avoid aortic dilatation, aortic dissection and premature death. A multidisciplinary approach is needed, involving rare disease centers. Patients and their family should be aware of the risks of cardiovascular diseases, such as BAV, CoA, hypertension and pregnancy. However, data are still lacking concerning the natural history of aortic disease

Disclosure of interest

The authors declare that they have no competing interest.

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