Cardiovascular Health in Turner Syndrome - No Small Task

Commentary Highlights

1. Aortic diameter is larger than expected in TS girls under the age of 15 years
2. Aortic measurements in TS individuals should be calculated relative to body surface area
3. Left sided cardiac defects and bicuspid aortic valve are substantially more common in females with TS
4. Pregnancy poses a large cardiac burden but may be achieved safely with intensive monitoring
5. Turner Syndrome is a complex, heterogeneous genetic disorder that will benefit from collaborative research conducted by stakeholders that includes researchers, clinicians, patients and their families, and advocacy groups
6. Awareness of risks should be disseminated to clinicians, researchers, patients, families, the TS community
7. Further genetic studies examining contribution of epigenetic modifications may yield more information

Aortopathy is a significant cause of early morbidity and mortality in women with Turner Syndrome (TS). In the AHA Scientific Statement on Cardiovascular Health in Turner Syndrome published in this issue of Circulation: Genomics and Precision Medicine, Silberbach and colleagues compile relevant scientific studies and propose guidelines for cardiovascular management in TS. The authors note that, like all rigorous scientific investigations, much of what has been identified in TS has generated more questions. Some of the recommendations are based on expert opinion which serve as important framework for future studies to address the burden of morbidity and mortality in the TS population as well as update the paradigm of care.

TS occurs in 50 per 100,000 females born and caused by absence of all or part of the second sex chromosome.¹ The two major manifestations of this condition are cardiovascular disease (CVD) and infertility. The presence of both congenital and acquired heart disease confer a significantly elevated risk of CVD compared to the general population.^2-5 Importantly, the TS population is at high risk for aortic dissection (AoD), a frequent cause of mortality that may occur at a young (mean) age of 35 years as compared to 77 years in the general female population.⁶ As you will read, the dogma of CVD in females with TS differs from that of the general female population, which is intriguing relative to cardiovascular genetics. This disparity hopefully underscores the need to elucidate biological and molecular origins that can be applied to both TS and the general population.

The classic phenotype of TS includes cardiac abnormalities, ovarian insufficiency, and short stature. Over time, we have come to appreciate the heterogeneity of the monosomy X population (and its variations): renal malformations, autoimmune conditions, learning differences, lymphedema, anxiety, diabetes, etc. Clearly the loss of sex chromosome material in this group imparts a wide range of effects. Despite advancing molecular genetic techniques in the last two decades, we still cannot explain the complex relationships between chromosomal loss and developmental disruption in TS. Understanding the impact of endogenous and exogenous hormones on the cardiovascular system, growth, and organ development is of tremendous interest in the TS research community. One victory has been the identification of haploinsufficiency of the SHOX gene on the terminal end of the X chromosome, as a (partial) cause of decreased statural growth in TS.^{7, 8} SHOX haploinsufficiency impairs statural growth in other populations as well, and investigations have shown that growth hormone (GH) therapy increases height in these individuals, thus contributing to positive clinical outcomes. Unfortunately, the extent that SHOX impacts development and growth remains poorly understood. Additionally, although some have wondered if GH impacts cardiac anatomy and CV health, no association has been substantiated to date.

In fact, the value of understanding short stature in TS cannot be understated. Many women report that the modest height gained with GH improved their quality of life. From a clinical standpoint, short stature in TS is directly related to interpretation of systemic evaluations, including cardiovascular assessment. Short stature impacts interpretation of cardiac measurements, risk stratification of blood pressure, interpretation of bone density as well as self-esteem. The last two points are beyond the scope of this discussion

With regards to short stature and cardiovascular assessment, the authors extensively discuss assessment of aortic size and vascular characterization. Aortic measurements in children and adolescents may be catalogued by size, one method is to measure the diameter of the ascending aorta and divide by the individual’s body surface area (BSA), which “corrects” for body size. This is called the aortic size index (ASI) and is the primary parameter used to gauge risk for AoD in TS. Note that this calculation is uniquely developed for TS, aortic measurements in the general pediatric population utilize the square root of the BSA.(9) In this context, the expert panel states that “an ASI >2.5cm/m2 has been used to predict risk of AoD for girls and women over the age of 15 years…but this remains to be proven.” It is critical to recognize that girls aged 2-15 years often have an ASI >2.5 cm/m2.¹⁰ Therefore, this cutoff should not be included as a risk factor for AoD in children under the age of 15 years. To aid in interpreting aortic diameters, the TS Healthy Heart Project has developed normative z-scores for aortic dimension data specific for this population. This calculator can be accessed via the internet and is simple to use.¹¹

The small body size of girls with TS also impacts evaluation of hypertension. Interpretation of blood pressure measurements is based on linear growth percentiles and absolute height measurement.¹² The upper limit of the threshold for hypertension is lower in individuals with short stature, especially relevant in the TS girl whose height may be below the fifth percentile for age on a standard CDC growth curve. In addition, many women and girls with TS have anxiety which may erroneously attribute hypertension to benign “white coat” hypertension, thus further delaying diagnosis of hypertension. It is increasingly evident that hypertension begins in childhood/adolescence and is a contributor to CVD. This AHA statement supports aggressive management of blood pressure, even in the pediatric population.

Uncontrolled hypertension leads to aortic enlargement, which may increase likelihood of aortic dissection and rupture. Gravholt and colleagues calculated that AoD occurred in 36 per 100,000-person years in the TS group compared to 6 per 100,000 years in the general population, stated otherwise, this is a rate of about 1.4 per 100 females with TS. 6 Many were found to have bicuspid aortic valve (BAV), but not all. Evidence suggests that frequent imaging and monitoring is critical for early identification. Echocardiography or cardiac magnetic resonance imaging is recommended every 5 years in childhood and every 10 years in adulthood in the absence of cardiac abnormalities/risk factors, and more frequently otherwise. Pediatric and adult cardiologists should be equally aware of these recommendations, as it is not infrequent that a child or adolescent newly diagnosed with TS has a normal echocardiogram and is erroneously discharged from cardiology follow-up.

Individuals with TS are at much greater risk for congenital heart disease, left sided cardiac defects, and bicuspid aortic valve (BAV). In fact, BAV is 30-60 times more likely to occur in TS than in 46, XX females. (32) ^13,14 The occurrence of congenital heart abnormalities is so common in TS that this working group, in agreement with the 2017 international guidelines, formally recommends that any female with a left sided congenital cardiac defect or bicuspid aortic valve should be tested for TS.¹⁵

Awareness of conditions associated with TS at diagnosis and across the paradigm of care will influence optimal clinical outcomes. Identifying clinicians with expertise in this relatively rare condition may be challenging for patients and families. Discussion of awareness and education are perhaps beyond the scope of this AHA statement but necessary. Proper dissemination of information to clinicians, researchers, and the TS community may contribute to reduced morbidity and mortality. By increasing awareness of risks, complications, and exacerbating factors, we also empower patients to advocate for themselves. For example, aortic dissection, as discussed above, occurs several decades younger than in the general population. A young woman presenting to a medical facility with complaints of chest pain is unlikely to elicit an evaluation for aortic dissection most of the time. A medical alert identification system is not discussed in this statement but may reduce morbidity and mortality. Just as time is of the essence in treatment of anaphylaxis or adrenal insufficiency, so is the case in aortic dissection. Although some may consider this a stigma, it may also save a life.

Another example relates to electrocardiographic abnormalities. Up to one third of individuals with TS have a prolonged corrected QT interval (QTc-interval).^{16, 17} While this has been reported to resolve with exercise, recognition is critical. Although there are no known reports of sudden cardiac death potentially due to this, some frequently prescribed medications may cause prolongation of the QTc-interval. Young girls with TS may be treated with antibiotics for frequent ear or urinary tract infections, whereas older patients may need therapy for anxiety, depression, or mood disorders. While we expect clinicians will be judicious when choosing medications, the reality is that patients may rely on multiple specialists, some of whom may not be familiar with the lesser known manifestations of TS. When we responsibly educate the TS community, we also encourage them to advocate for themselves as needed.

Lastly, pregnancy is also addressed in this statement. Historically women with TS have been counseled that pregnancy, though rare in this condition, is unsafe due to vastly increased cardiac burden. In fact, the American Society of Reproductive Medicine (ASRM) states that TS is a relative contraindication to pregnancy, and any cardiac abnormality converts this to an absolute contraindication to pregnancy.¹⁸ Silberbach and colleagues propose, perhaps controversially, that pregnancy and assisted reproduction can be safely undertaken. Appropriate counseling regarding risks of pre-eclampsia, diabetes, and aortic dissection, as well as fetal risk for anomalies and miscarriage is necessary, but this information is based on expert opinion extrapolated from international health registries, case reports and anecdotal experiences.^19-22 In an effort to cultivate an evidence-based practice guideline for systematically counseling these high-risk patients, some have supported the creation of a pregnancy registry that would collect reliable maternal and fetal health data.²³

The authors conclude with a thoughtful summary of cardiovascular research priorities in TS. Clearly, as stated earlier, our knowledge of TS has advanced in recent years, but there is still much work to be done.

The diverse and heterogeneous clinical manifestations of TS appear to transcend the monogenic and Mendelian modes of inheritance often associated with genetic disorders. Advances in genomics and precision medicine have led to an accumulating body of evidence that is being applied to a variety of medical conditions, including TS. Recent investigations have explored more complex interactions via epigenetic modifications mediated first by loss of (all or part of) a sex chromosome that then secondarily disrupts some combination of autosomal gene expression, altered transcription factors, immunologic dysregulation, methylation changes, post-translational modifications, and others.^23-27

The challenge that lies before us is the relative rarity of this heterogeneous condition. The number of patients at a single institution or even one national health care system is insufficient to truly elucidate the biology of this condition. In fact, this was the premise of the 2017 International TS Consensus group: global experts in TS came together to present evidence from research studies and then created and revised guiding principles to optimize care of individuals with TS.¹⁵ We must continue to leverage data collected globally across institutions. In addition to collaborations between researchers, this will require partnerships with advocacy groups as well. Active engagement with advocacy groups has been shown to provide contributions to study design, patient recruitment, data collection, and even financial support. Inclusion of advocacy groups in research endeavors are the wave of the future. This will expand investigative endeavors, strengthen trust and build relationships between patients, clinicians, and researchers, which in return contributes to stronger foundations and optimal motivation from both parties.²⁸

Ultimately, collaborative efforts among global researchers, clinicians, advocacy groups and the TS community will enhance knowledge that will reduce morbidity and mortality, improve quality of life, and perhaps even identify therapeutic targets that could eliminate or neutralize the clinical manifestations of Turner Syndrome.