2024 年 71 巻 7 号 p. 713-719
Cardiovascular disease is one of the most important complications in girls and women with Turner syndrome (TS). Although the latest international guideline provides useful suggestions for the management of cardiovascular diseases in TS, some unknown cardiac conditions warrant physicians’ attention and awareness. Here, we have reported two adult cases wherein significant cardiovascular diseases were detected during the transition period. The first case patient was diagnosed with aortic crank deformity and left subclavian artery aneurysm at 14 years based on the report of cardiac catheterization, computed tomography angiography, and cardiac magnetic resonance imaging, which had remained undetected by annual evaluations using transthoracic echocardiography (TTE). This case emphasizes the importance of cardiac reevaluation during the transition period. The second case patient was diagnosed with moderate mitral valve regurgitation (MR) due to mitral valve prolapse at 18 years through TTE, although the first evaluation at 7 years by TTE detected slight MR without any clinical concerns. The condition however progressed to severe MR at 28 years, requiring mitral valvuloplasty. MR is the most common valve disease worldwide, which makes it challenging to comprehend whether the condition is a complication. However, the condition requiring surgery at this age is extremely rare, which implies the possibility of early progression. Because almost all literature on cardiovascular complications in TS is cross-sectional, further information about longitudinal cardiovascular conditions is vital for optimal care for girls and women with TS. The two cases reported in this article provide significant information for improving lifelong cardiovascular health issues in TS.
Turner syndrome (TS) is a condition in girls and women wherein a karyotype contains a cell line of monosomy lacking at least a distal major portion in the short arm of the X chromosome. TS occurs 1 in 2,000 to 2,500 live female births. In TS, multiple organs are involved throughout all stages of life, which includes short stature, premature ovarian insufficiency, cardiovascular disease, endocrine disorders, and other complications. Therefore, a multidisciplinary approach is deemed vital for undertaking the care of girls and women with TS [1-3]. For this purpose, international clinical practice guidelines have been developed that address comprehensive lifelong care for girls and women with TS [1, 4, 5]. Although these guidelines are essential in clinical practice and widely employed, several areas of uncertainty remain where the accumulation of cases and additional research seem necessary.
Cardiovascular diseases, including both congenital and acquired heart diseases, are one of the most remarkable complications affecting girls and women with TS owing to the high prevalence of mortality and morbidity [6, 7]. Congenital heart disease is reported in approximately 50% of girls with TS, and cardiac evaluation by transthoracic echocardiography (TTE) is considered mandatory at diagnosis [8-10]. The bicuspid aortic valve, coarctation of the aorta, and aortopathy are the most common. In addition to congenital heart disease, acquired heart disease, including systemic hypertension, ischemic heart disease, aortic root dilation, and strokes, are the major factors that reduce the lifespan of women with TS [7]. It is also recommended that cardiac reevaluation should be performed during the transition period. Considering that aortic dissection in women with TS, sometimes fatal, occurs approximately six times more often than in the general population at a median age of 29–35 years [11], medical and operative management of aortic enlargement and aneurysm were addressed in detail in the recent international guidelines [1]. Although the guideline provides useful suggestions for the management of cardiovascular conditions in girls and women with TS, there may be other unknown cardiac conditions seeking physicians’ attention. Therefore, such significant cases should be accumulated to help establish optimal lifelong care measures for girls and women with TS.
Here, we have reported two noteworthy cases of severe cardiovascular conditions that were detected during the transition period. Both patients provided written informed consent for the publication of details of their medical cases and any accompanying images.
The patient was delivered at 40 weeks of gestation with a birth weight of 2,750 g (–0.5 SD) and a body length of 49 cm (0.3 SD). At 8 years of age, she was referred to her previous doctor because of her short stature. She was suspected of having TS based on her symptoms, including her short stature, webbed neck, shield-like chest, and hypoplastic nails. G-banding analysis revealed her karyotype as 45, X, and she was diagnosed with TS. At 9 years of age, she was referred to our hospital for the total care of TS. Her height and weight at that time were 117.6 cm (–2.4 SD) and 24.5 kg (–0.9 SD), respectively. Growth hormone (GH) treatment was administered from 9 to 15 years of age, and sex hormone replacement was started at 12 years of age, followed by Kaufmann therapy at 15 years of age.
TTE was performed at her first visit to our hospital, which identified mild aortic valve stenosis (aortic flow 2 m/s) and mild aortic constriction; therefore, she was followed up by TTE annually thereafter. Myocardial thickening of the ventricular septum was observed after 10 years of age, and an aortic bicuspid valve was detected at 12 years of age. It was thought that myocardial thickening of the ventricular septum appeared due to the left heart load induced by the bicuspid valve and aortic stenosis. At 14 years of age, cardiac catheterization, computed tomography angiography (CTA), and cardiac magnetic resonance scan (CMR) were performed for further investigation, which revealed aortic crank deformity and left subclavian artery aneurysm (Fig. 1). Since then, she has been followed up by cardiologists using TTE and CTA every year. At 34 years of age, her height, weight and body surface area were 153.8 cm, 46.7 kg and 1.41 m2, respectively.
A: Left subclavian artery aneurysm detected in Case #1
B: Aortic crank deformity detected in Case #1
The patient was suspected of TS at 7 years of age because of her short stature, epicanthus, shield-like chest, inverted nipple, and webbed neck. G-banding analysis revealed her karyotype as 45, X. She was diagnosed with TS and referred to our hospital at 7 years of age for total care of TS. Accordingly, the GH treatment was performed from 7 to 16 years of age, and sex hormone replacement was started at 13 years of age, followed by Kaufmann therapy at 15 years of age.
TTE at the first visit indicated slight mitral valve regurgitation (MR) without clinical concerns. Therefore, routine cardiac evaluation was not performed. However, at 18 years of age, a systolic murmur of Levine 2/6 was detected during her regular visit to a pediatric endocrinologist, which required consultation with a cardiologist. TTE identified moderate MR (regurgitant volume: 35 mL, effective regurgitant orifice area (ERO): 0.3 cm2) due to mitral valve prolapse (MVP). Subsequently, she was followed up by a cardiologist every 3–6 months, with normal blood pressure (around 100/70 mmHg) and plasma brain natriuretic peptide (BNP) levels of 10.6–37.2 pg/mL (normal range: <18.4 pg/mL). However, cardiac evaluation at 28 years of age displayed severe MR (regurgitant volume: 77 mL, ERO: 0.40 cm2) with a plasma BNP level of 46 pg/mL, indicating the need for surgery. Mitral valvuloplasty was performed at 28 years of age. At 33 years of age, her height, weight and body surface area were 149.0 cm, 59.4 kg and 1.53 m2, respectively.
To overview our understanding of cardiovascular health issues in girls and women with TS, we conducted a literature review focusing on cardiovascular diseases in the TS population, which were available up to 2023 based on a PubMed search. The search terms were “Turner syndrome” (title or abstract) and (“cardiovascular complications,” “congenital heart disease,” “acquired heart disease,” “cardiac complications,” “heart complications,” or “vascular complications”) as the basis for the search terms, with references to important papers cited by noteworthy articles. We calculated the prevalence of each disease by dividing the case numbers by the total number of cases studied in the literature and multiplying the value by 100. Table 1 summarizes the prevalence and number of cases of each disease [8-10, 12-29]. Ideally, each disease should provide an age range at diagnosis and the data should be divided into children and adults, but this would be unrealistic and innately biased because many studies did not provide these data correctly. Therefore, case and total numbers were counted by adding up all subjects in each reference according to each cardiovascular disease as follows: elongated transverse arch [25, 29-31], coarctation of the aorta [8-10, 12-20, 23-30, 32], bovine arch [29-31], cervical aortic arch [27], ductus diverticulum [27], right arcus aorta [17, 31], bicuspid aortic valve [9, 10, 12, 14-19, 21-28, 30-32], aortic valve stenosis [10, 16-18, 22], aortic valve regurgitation [13, 16-18, 20, 22], MVP [13, 15-18, 21, 26, 27], MR [13, 14, 16, 18, 19], mitral valve stenosis [17], pulmonary valve abnormality [13, 19, 32], tricuspid valve regurgitation [13], atrial septal defect [10, 13, 16, 17, 31, 32], ventricular septal defect [10, 16, 17, 32], patent foramen ovale [14, 16], tetralogy of Fallot [17], endocardial cushion defect [17], partial atrioventricular canal defect [32], aberrant right subclavian artery [25, 29-31], persistent left superior vena cava [13, 27, 29-32], partial anomalous pulmonary venous vein [8-10, 16, 26, 29-31], interrupted inferior vena cava [27, 30], anomalous left vertebral artery origin [29, 31], cardiac dextroposition [27], ventricular septum aneurysm [27], patent ductus arteriosus [32], pericardiac effusion [13], and unroofed coronary sinus [32]. The three most common diseases associated with TS were identified as elongated transverse arch (44.1%), bicuspid aortic arch (14.6%), and coarctation of the aorta (9.6%). Moreover, several cardiovascular conditions were reported, which made it challenging to decipher whether they were complications or comorbidities, especially when there was only a single case reported in the literature. In addition, there may be a possibility that some cardiovascular diseases remain asymptomatic and hence were not diagnosed at the time of evaluation. The proportion of each cardiovascular complication in TS should vary with age, but Table 1 could not provide this information because sufficient information was not available in the literature.
Cardiovascular diseases and their prevalence in females with Turner syndrome
| Cardiovascular diseases | Prevalence (%) (Reported range) |
Case numbers/ Total numbers |
References | |
|---|---|---|---|---|
| Aorta | ||||
| Elongated transverse arch | 44.1% (31.4–49) | 121/274 | [25, 29-31] | |
| Coarctation of the aorta | 9.6% (1.8–15.4) | 312/3,230 | [8-10, 12-20, 23-30, 32] | |
| Bovine arch | 7.4% (5.9–8.6) | 13/175 | [29-31] | |
| Cervical aortic arch | 2.5% | 1/40 | [27] | |
| Ductus diverticulum | 2.5% | 1/40 | [27] | |
| Right arcus aorta | 1.4% (0.9–2.8) | 2/146 | [17, 31] | |
| Aortic valve | ||||
| Bicuspid aortic valve | 14.6% (1.5–39.2) | 513/3,507 | [9, 10, 12, 14-19, 21-28, 30-32] | |
| Aortic valve stenosis | 5.9% (1.8–11) | 62/1,055 | [10, 16-18, 22] | |
| Aortic valve regurgitation | 3.7% (0–21) | 42/1,145 | [13, 16-18, 20, 22] | |
| Other valves | ||||
| Mitral valve prolapse | 2.9% (1.5–26.1) | 37/1,283 | [13, 15-18, 21, 26, 27] | |
| Mitral valve regurgitation | 2.7% (2.3–7.4) | 29/1,055 | [13, 14, 16, 18, 19] | |
| Mitral valve stenosis | 0.93% | 1/107 | [17] | |
| Pulmonary valve abnormality | 0.88% (0.7–1.2) | 5/568 | [13, 19, 32] | |
| Tricuspid valve regurgitation | 0.83% | 1/121 | [13] | |
| Intracardial | ||||
| Atrial septal defect | 2.0% (1.7–2.8) | 28/1,379 | [10, 13, 16, 17, 31, 32] | |
| Ventricular septal defect | 1.2% (0.7–4.3) | 15/1,219 | [10, 16, 17, 32] | |
| Patent Foramen Ovale | 1.0% (0.8–5.9) | 7/731 | [14, 16] | |
| Tetralogy of Fallot | 0.93% | 1/107 | [17] | |
| Endocardial cushion defect | 0.93% | 1/107 | [17] | |
| Partial atrioventricular canal defect | 0.36% | 1/281 | [32] | |
| Vascular | ||||
| Aberrant right subclavian artery | 7.4% (5.7–8.3) | 20/271 | [25, 29-31] | |
| Persistent left superior vena cava | 5.2% (0.8–12.9) | 24/457 | [13, 27, 29-32] | |
| Partial anomalous pulmonary venous vein | 3.5% (0.4–15.7) | 66/1,903 | [8-10, 16, 26, 29-31] | |
| Interrupted inferior vena cava | 2.2% | 2/91 | [27, 30] | |
| Others | ||||
| Anomalous left vertebral artery origin | 3.2% (2.8–4) | 4/124 | [29, 31] | |
| Cardiac dextroposition | 2.5% | 1/40 | [27] | |
| Ventricular septum aneurysm | 2.5% | 1/40 | [27] | |
| Patent ductus arteriosus | 1.8% | 5/281 | [32] | |
| Pericardiac effusion | 0.83% | 1/121 | [13] | |
| Unroofed coronary sinus | 0.36% | 1/281 | [32] |
The cases and total numbers were calculated by adding all subjects in each reference according to each cardiovascular disease, as described in the main text.
Cardiovascular healthcare is a critical issue in lifelong care management for girls and women with TS. The issue has been receiving increasing attention since the international guidelines were published [1], because it is the major factor that determines the lifespan of girls and women with TS [7]. Nevertheless, cardiovascular complications in girls and women with TS, especially in adult life, remain inadequately understood. Thus, we think that the present two cases can provide additional useful information in terms of optimal cardiovascular health care and management for girls and women with TS.
It is thought that CMR offers several benefits over TTE for identifying cardiovascular diseases in girls and women with TS [33]. Although TTE is more accessible than CMR, there are several undiagnosed abnormalities in TS with a high prevalence, such as the elongation of the transverse aortic arch, aortic coarctation, and partial anomalous pulmonary venous return [12, 25, 30, 33]. Indeed, aortic crank deformity and left subclavian artery aneurysm were not detected in our first case when only TTE was used for cardiovascular evaluation. Although echocardiographic follow-up is commonly employed owing to its simplicity, it has been indicated that observation of the dorsal aortic region is challenging and that CMR is superior to TTE in terms of the accuracy of aortic diameter assessment [22, 26]. However, CMR is less readily available than TTE and usually requires general sedation in young children. Therefore, international guidelines recommend that they should be performed at the time of diagnosis in adolescents and adults with TS, and a CMR scan should be performed as soon as it is feasible without the need of general anesthesia. [1]. In addition, appropriate follow-up intervals for cardiac examination have been proposed according to the Z-score of aortic diameters based on the presence or absence of aortic stenosis, bicuspid valve, or hypertension as the underlying pathology. In the absence of a bicuspid aortic valve or other significant diseases at the initial screening, TTE or CMR surveillance studies are recommended every 5 years in children, every 10 years in adults, or prior to anticipated pregnancy to evaluate the aorta [1]. Taken together, our first case indicates the importance of lifelong cardiovascular care in girls and women with TS following international guidelines. We truly recommend that detailed cardiovascular reevaluation should be performed during the transition period in terms of the medical significance and feasibility.
MR is an age-related progressive disease and the most common valve disease occurring worldwide. A lifelong-community-based study reported that the prevalence of moderate or severe MR diagnosed through doppler echocardiography was 0.46% (95% confidence interval: 0.42–0.49) with a median age of 77 years (interquartile range: 66–84) [34], while the prevalence among those aged <45 years was only 0.027% [35]. Considering these findings in the general population, we concluded that our second patient, for whom moderate MR and MVP were detected at 18 years of age and progressed to a severe MR at 28 years of age requiring mitral valvuloplasty, is an extremely rare case. Therefore, we suspect a relationship between our extremely rare experience and TS. There is another report of a 34-year-old woman with TS and severe MR requiring valvuloplasty [36]. In fact, our present review shows that MR and MVP are complicated at the rate of 2.7% (range: 2.3–7.4) and 2.9% (range: 1.5–26.1), respectively, in the TS population [14, 16, 18, 21, 26, 27]. They are estimated at 1.5%–1.9% and 1.1%–2.4%, respectively, in the general population [37, 38], which is smaller than that in the TS population. Moreover, it is uncertain whether MR and MVP are more frequent in TS than in the general population as mild types are relatively common in aged populations [21, 39]. Although we cannot conclude that severe MR occurs as a complication of TS and there are few descriptions of mitral valve abnormality in the recent international guidelines [1], our second case highlights that MR and MVP deserve careful consideration at the time of cardiovascular evaluation in women with TS.
Nevertheless, it is challenging to judge whether cardiovascular diseases frequently detected in the general population present as complications or comorbidities in girls and women with TS. In addition, almost all studies addressing cardiovascular complications in girls and women with TS are not longitudinal, but rather cross-sectional, which implies that the proportion should be different according to the age at which cardiovascular evaluations were performed, except for congenital diseases. Moreover, frequent complications in the TS population, such as the elongation of the transverse aortic arch, aortic coarctation, and partial anomalous pulmonary venous return, can be easily overlooked at the first evaluation using TTE [12, 25, 30, 33]. Therefore, we calculated the prevalence of each cardiovascular disease by combining all reports in our review. Retrospectively, we realize that, in our two cases, aortic crank deformity and left subclavian artery are definitely complications, albeit it remains uncertain whether severe MR and MVP requiring surgery at 28 years of age occurred as complications. We speculated that very early progression should be related to TS because it is an age-related progressive disease in the general population. To uncover our speculation, more information describing longitudinal cardiovascular evaluations in girls and women with TS and remarkable cases should be accumulated.
In conclusion, it is essential to evaluate lifelong cardiovascular health for optimal care in girls and women with TS. Therefore, longitudinal repeated evaluations of cardiovascular diseases are vital. Particularly, a detailed cardiovascular evaluation during the transition period is mandatory. With the accumulation of more remarkable cases, it is hoped that the pathogenesis of adult TS cardiac diseases will be better understood and the management of girls and women with TS will be further improved.
All authors have no financial relationships relevant to this article to disclose.
