Overview
Definition:
Marfan syndrome is an autosomal dominant genetic disorder affecting the connective tissues throughout the body
It is caused by mutations in the FBN1 gene, which encodes fibrillin-1, a protein essential for the structure and elasticity of connective tissues.
Epidemiology:
The prevalence is estimated to be between 1 in 3,000 to 1 in 5,000 live births worldwide
It affects both sexes and all ethnic groups equally
Approximately 75% of cases are inherited, while 25% arise from spontaneous new mutations.
Clinical Significance:
Marfan syndrome has significant implications for pediatric health, primarily due to its potential to cause life-threatening cardiovascular complications, particularly aortic root dilation and dissection
It also affects skeletal, ocular, pulmonary, and dural systems, requiring multidisciplinary management and surveillance.
Clinical Presentation
Symptoms:
Tall stature
Arachnodactyly (long, slender fingers and toes)
Pectus excavatum or pectus carinatum
Scoliosis or kyphosis
Lens dislocation (ectopia lentis)
Mitral valve prolapse
Aortic root dilation
Shortness of breath
Chest pain.
Signs:
Positive wrist sign (thumb and fifth finger overlap when encircling the contralateral wrist)
Positive thumb sign (thumb protrudes beyond the ulnar border of the palm)
High-arched palate with crowded teeth
Joint hypermobility
Striae (stretch marks) not associated with weight changes.
Diagnostic Criteria:
Diagnosis is typically made using the revised Ghent nosology criteria, which integrate family history, clinical manifestations, and genetic testing
Key criteria include aortic root dilation (Z-score >= 2), ectopia lentis, and systemic score based on various phenotypic features.
Diagnostic Approach
History Taking:
Detailed family history of cardiovascular events (e.g., aortic dissection, aneurysm), sudden death, or known connective tissue disorders
Personal history of scoliosis, joint hypermobility, visual problems, or pneumothorax
Inquiry about rapid growth spurts or skeletal pain.
Physical Examination:
Systematic assessment of skeletal features (height, arm span, wrist/thumb signs, joint laxity, spinal curvature)
Cardiovascular examination focusing on murmurs (mitral regurgitation, aortic regurgitation) and peripheral pulses
Ocular examination for lens position
Palpation for striae and assessment of lung sounds.
Investigations:
Echocardiography: serial measurements of aortic root diameter (Z-score is crucial for monitoring)
Electrocardiogram (ECG) and Holter monitoring: to detect arrhythmias or conduction abnormalities
MRI or CT angiography: for detailed evaluation of the aorta, especially if echocardiography is limited or suggests significant dilation
Genetic testing for FBN1 mutations: confirms diagnosis and aids in family screening
Skeletal survey: to assess scoliosis and other skeletal abnormalities
Slit-lamp examination: for ectopia lentis.
Differential Diagnosis:
Loeys-Dietz syndrome, Ehlers-Danlos syndrome (vascular type), familial thoracic aortic aneurysm and dissection (FTAAD), mass effect syndromes, simple marfanoid habitus
Distinguishing features include specific gene mutations, pattern of organ involvement, and characteristic physical findings.
Management
Initial Management:
Multidisciplinary team approach involving pediatric cardiologists, geneticists, ophthalmologists, orthopedic surgeons, and pulmonologists
Regular surveillance and early intervention are key.
Medical Management:
Beta-blockers (e.g., propranolol, atenolol): to reduce heart rate and contractility, decreasing shear stress on the aortic wall
Angiotensin II receptor blockers (ARBs, e.g., losartan): shown to be effective in reducing aortic root growth in some studies, often used in conjunction with or as an alternative to beta-blockers
Regular BP monitoring and control are essential.
Surgical Management:
Aortic root replacement surgery: indicated for severe aortic root dilation (typically Z-score >= 3, or rapid progression), aortic dissection, or significant aortic regurgitation
Valve-sparing root replacement is preferred when feasible to preserve aortic valve function
Prophylactic surgery may be considered in select cases based on imaging and risk factors.
Supportive Care:
Ophthalmologic care: regular monitoring for ectopia lentis, glaucoma, and retinal detachment
Orthopedic management: bracing or surgery for scoliosis, management of joint pain
Pulmonary care: monitoring for pneumothorax, appropriate management of asthma or other respiratory issues
Psychological support for patients and families.
Aortic Root Monitoring
Monitoring Frequency:
Annual echocardiograms are recommended for all patients with Marfan syndrome
More frequent monitoring (e.g., every 6 months) may be necessary for children with known significant aortic dilation, rapid growth, or those on less effective medical therapy.
Echocardiographic Parameters:
Measurement of the aortic root at the sinuses of Valsalva, sinotubular junction, and ascending aorta
Calculation of Z-scores based on age and body surface area is critical
Assessment of aortic regurgitation severity and LV dimensions/function.
Indications For Intervention:
Surgical intervention is typically considered when the aortic root diameter reaches 5.0-5.5 cm in adults, or for children with a Z-score of 2.0 or greater with a rapidly progressive dilation, or when aortic dissection occurs
Individualized decision-making is paramount.
Genetic Screening:
First-degree relatives of individuals with Marfan syndrome should undergo evaluation, including cardiovascular screening
Genetic testing can confirm diagnosis and aid in risk stratification for family members.
Sports Participation
Risk Assessment:
Athletic participation in children with Marfan syndrome requires careful risk assessment, particularly regarding cardiovascular status
The primary concern is the risk of aortic dissection or rupture during strenuous physical activity.
Guidelines:
Current guidelines, such as those from the American Heart Association (AHA) and the American College of Cardiology (ACC), generally recommend restricting participation in competitive, high-intensity, or contact sports for individuals with significant aortic root dilation (e.g., Z-score > 2.0) or other cardiovascular abnormalities.
Recommended Activities:
Low-intensity, non-competitive activities are generally considered safe
These may include recreational swimming, walking, golf, doubles tennis (with modified exertion), and light strength training
Avoidance of activities involving sudden bursts of maximal exertion, heavy lifting, and rapid changes in direction is advised.
Individualized Approach:
Decision-making should be individualized and based on a thorough cardiovascular evaluation, the severity of aortic dilation, family history, and the specific demands of the sport
Close collaboration between the patient, family, and medical team is essential
Regular reassessment of cardiovascular status is necessary.
Prognosis
Factors Affecting Prognosis:
The prognosis is largely determined by the presence and severity of cardiovascular complications, especially aortic root dilation and dissection
Early diagnosis, consistent medical management, and timely surgical intervention significantly improve outcomes.
Outcomes:
With modern management strategies, life expectancy for individuals with Marfan syndrome has significantly improved, approaching that of the general population in well-managed cases
However, cardiovascular complications remain the leading cause of morbidity and mortality.
Follow Up:
Lifelong follow-up is essential, with regular cardiovascular imaging (echocardiography), ophthalmologic evaluations, and orthopedic assessments
Monitoring for new or worsening symptoms and adherence to medical therapy are crucial for long-term well-being.
Key Points
Exam Focus:
Ghent nosology criteria for diagnosis
Key echocardiographic parameters for aortic root monitoring (Z-score)
Indications for beta-blockers and ARBs
Surgical indications for aortic root repair
Cardiovascular risks associated with sports participation in Marfan syndrome.
Clinical Pearls:
Always measure the aortic root Z-score, not just absolute diameter
Consider ARBs alongside or instead of beta-blockers for aortic root dilation
Educate families about the importance of annual cardiac screening and safe sports participation
Remember the multisystemic nature of Marfan syndrome.
Common Mistakes:
Underestimating the risk of aortic dissection in asymptomatic individuals
Inconsistent follow-up of aortic root diameter
Inappropriate recommendations regarding sports participation without thorough cardiac evaluation
Over-reliance on family history alone for diagnosis in de novo mutations.