Optimizing the Care for Children with Marfan Syndrome and Aortic Disease: Insights from a Joint Statement

Marfan syndrome (MFS), a genetic disorder affecting connective tissue, poses significant risks to cardiovascular health, particularly due to aortic root dilatation, which can lead to life-threatening dissection if untreated. This paper, authored by a collaboration between the European Reference Network of Vascular Diseases and the Association for European Paediatric and Congenital Cardiology, provides critical guidelines for managing aortic disease in children with pathogenic variants in the fibrillin-1 (FBN1) gene [1]. 

Children with MFS require precise and regular imaging of the aorta, which begins with echocardiography as the first-line tool. The preferred method for measuring aortic diameter is the inner-to-inner edge method during systole, as recommended by pediatric guidelines. Normalization of measurements for body size using Z-score calculation is standard practice but significant differences exist when using various available dataset and careful assessment and consistency of method used are warranted to ensure diagnosis and management are appropriately planned.  The Lopez z-score dataset is the most widely used, as it is based on a larger patient cohort compared to the oldest ones. Some data suggest that the Lopez equation may tend to overestimate values, but the key factor is maintaining consistency by using the same z-score system over time to accurately track growth trends [1,2]. 

Magnetic resonance imaging (MRI) is recommended for detailed assessments, accepting long acquisition time, particularly to minimize radiation exposure from repeated computed tomography (CT) scans in the long term. However, CT may be preferred even in childhood in specific circumstances. Both diagnostic modalities use the Kaiser z-score to grade the dilatation. Although vascular disease distal to the ascending aorta is less common in Marfan syndrome (MFS) than in other connective tissue disorders, adolescents and young adults may develop it and need surveillance [3-5]. Neck vessel tortuosity is a well-recognized feature and an established predictor of outcomes in children with MFS, making a neck-to-pelvis angiographic evaluation a reasonable adjunct. Early diagnosis of aortic and vascular disease is crucial for timely intervention and preventing complications [1]. 

The goal of medical management is to slow the progression of aortic dilatation. While studies have demonstrated medications can effectively slow the rate of growth, they have not shown a reduction in adverse events. The paper recommends the use of beta-blockers (BBs), particularly atenolol at doses of 0.5-4 mg/kg/d secondly propranolol 0.75-3 mg/kg/d, or angiotensin receptor blockers (ARBs), such as losartan at 0.7-1.4 mg/kg, and more recently irbesartan at 1-2 mg/kg and valsartan 1-4mg/kg/d. Combination therapy is suggested for patients with more advanced disease. Medical therapy is typically initiated when the aortic z-score reaches 2 or higher, with treatment tailored to the patient's clinical presentation. These medications reduce stress on the aorta by reducing heart rate and blood pressure. Studies in animal models have also shown that ARB may have a potential mechanism in blocking the TGF-β1 pathway, preventing the breakdown of fibrillin in the aortic wall reducing the extracellular degeneration [6-10]. 

Although medical treatment can slow the rate of aortic dilatation and delay the need for surgery, aortic root intervention remains the only definitive way to prevent dissection. Prophylactic surgery, performed before a dissection occurs, has a low mortality rate compared to emergency surgery in acute settings, making it the standard of care. For children with significant aortic dilatation, surgical intervention is required to prevent dissection, typically when the aortic root diameter reaches 50 mm, similar to the threshold in adults. However, surgery may be considered earlier in high-risk patients, such as those with a strong family history of dissection or rapid dilatation at a younger age. Aortic valve-sparing techniques are preferred to avoid the long-term complications of valve replacement, such as the need for lifelong anticoagulation [11-13]. 

In individuals with MFS, strenuous exercise can exacerbate aortic dilatation and increase the risk of aortic dissection. Historically, this concern led to the recommendation to avoid intense physical activity. The impact of exercise on the aortic wall depends on the type and intensity of the activity. Isotonic exercises, which increase cardiac output, generally have a moderate effect on blood pressure, while isometric activities cause significant increases in both diastolic and systolic blood pressure. Since most sports involve a combination of isotonic and isometric components, they are now categorized into skill, power, mixed, and endurance sports. Frequency and intensity of activity are also critical and can be classified as elite, competitive, or recreational, depending on the level of training and exertion. 

A key aspect of managing children with MFS involves providing individualized recommendations on physical activity. While high-intensity, competitive sports are generally discouraged, low-intensity recreational activities are allowed. The guidelines advocate for a personalized approach, allowing safe participation in sports based on factors like aortic size and individual risk, while promoting physical activity to support children's overall health and social development [14]. 

New challenges are emerging in the management of children with MFS, particularly with the increasing diagnosis of neurodivergent conditions such as ADHD. The use of stimulant medications has sparked interest in this group as they can elevate heart rate and blood pressure,  potentially posing a risk. While there is no absolute contraindication for starting these medications, monitoring for the development of hypertension or acceleration of aortic/vascular disease is strongly recommended as per current guidance so that treatment can be interrupted if necessary. 

Additionally, the role of puberty and hormonal changes in paediatric MFS and more generally in aortic growth rate in connective tissue diseases remains unclear. Further research is needed to understand their impact and this is particularly relevant for children undergoing hormonal therapy, such as treatments for gender dysphoria, where the effects on aortic growth are not yet fully understood. 

The management of aortic disease in children with Marfan syndrome (MFS) requires a collaborative, multidisciplinary approach to ensure the best possible outcomes. Given the systemic nature of MFS, there is a growing need to establish comprehensive multidisciplinary assessments and networks of care for these patients. Expanding such networks will be invaluable in providing coordinated care, addressing the various aspects of the disease, and improving long-term outcomes.  

This paper represents a key effort to raise awareness in the paediatric field about the importance of considering MFS and not underestimating the risk of aortic dissection in affected patients, those with a family history, or additional risks presenting to the emergency department with chest pain. A crucial support in this diagnostic process would be the implementation of a hub-and-spoke system, connecting peripheral healthcare providers with specialized central centres to offer expert guidance and management, especially in complex cases. This approach could significantly enhance early detection and intervention for at-risk patients [1].