Explain Marfan syndrome, including its genetic basis, clinical manifestations, and management.

Marfan Syndrome Overview

Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in the FBN1 gene encoding fibrillin-1, characterized by progressive aortic root dilation leading to life-threatening dissection, ectopia lentis, and skeletal overgrowth; immediate beta-blocker therapy and lifelong aortic surveillance are mandatory upon diagnosis. 1, 2

Genetic Basis and Inheritance

Molecular Pathophysiology:

• Pathogenic variants in the FBN1 gene on chromosome 15q21 disrupt fibrillin-1, a glycoprotein essential for extracellular matrix microfibrils in the aorta, periochondrium, and ocular structures. 1, 3
• Fibrillin-1 deficiency weakens connective tissues and dysregulates transforming growth factor-beta (TGF-β) signaling, driving progressive aortic dilation. 1, 2
• Over 1,000 unique FBN1 mutations have been identified, with only 12% recurring in unrelated families. 1
• Molecular testing detects pathogenic variants in approximately 90-95% of clinically definite cases; 10% of patients meeting Ghent criteria have no detectable FBN1 mutation. 1, 2, 4

Inheritance Pattern:

• Autosomal dominant transmission with 50% recurrence risk for each offspring. 2
• De novo mutations account for 25-30% of cases, with no prior family history. 1, 3
• Phenotypic variability is marked even within families carrying identical mutations. 1

Clinical Manifestations by System

Cardiovascular (Life-Threatening)

Aortic Disease:

• Progressive aortic root dilation at the sinuses of Valsalva occurs in 60-80% of patients and is virtually universal over a lifetime. 1
• Aortic dissection or rupture is the leading cause of death, with risk increasing proportionally to aortic diameter. 1
• Dissection can occur at diameters below 5.0 cm in approximately 15% of cases. 2
• Dilation extending into the aortic arch carries worse prognosis than isolated sinus involvement. 1, 2

Valvular Abnormalities:

• Mitral valve prolapse with or without regurgitation is very common. 1, 5
• Aortic regurgitation develops secondary to cusp distortion by the dilated root. 1, 5
• Tricuspid valve prolapse may also occur. 5

Ocular System

• Ectopia lentis (lens dislocation) is the most specific ocular finding and, together with aortic dilation, confirms the diagnosis even without other features. 1, 5
• Detected by slit-lamp examination and present in a substantial proportion of patients. 5
• Myopia exceeding 3 diopters contributes 1 point to the systemic score. 2, 5
• Corneal flattening and elongated globes are characteristic. 5

Skeletal System (Revised Ghent Scoring)

Major Features (point values for systemic score ≥7):

• Wrist sign OR thumb sign: 1 point each; both together: 3 points. 2, 5
• Pectus carinatum: 2 points; pectus excavatum: 1 point. 2, 5
• Hindfoot deformity: 2 points; pes planus: 1 point. 2, 5
• Protrusio acetabuli: 2 points. 2, 5
• Scoliosis >20° or spondylolisthesis: 1 point. 2, 5
• Arachnodactyly (long, slender fingers) and dolichostenomelia (arm span exceeds height). 1, 5
• Dolichocephaly and high-arched palate. 5
• Reduced elbow extension (<170°). 5

Pulmonary Manifestations

• Spontaneous pneumothorax: 2 points. 2, 5
• Apical pulmonary bullae are frequently observed. 5

Dermatologic Features

• Striae atrophicae (stretch marks without weight change): 1 point. 2, 5
• Recurrent or incisional hernias are common. 5

Neurologic Involvement

• Dural ectasia (lumbar dural sac dilation): 2 points; may cause back pain or neurologic symptoms. 2, 5
• Identified by lumbar MRI when symptomatic. 2, 5

Additional Systemic Features

• Facial features (≥3 of 5 characteristic findings): 1 point. 2
• Mitral valve prolapse: 1 point. 2

Diagnostic Criteria (Revised Ghent Nosology)

For patients WITHOUT a family history, diagnosis requires ONE of the following combinations: 1, 2

1. Aortic root dilation (Z-score ≥2) AND ectopia lentis
2. Aortic root dilation AND a pathogenic FBN1 mutation
3. Aortic root dilation AND systemic score ≥7 points
4. Ectopia lentis AND an FBN1 mutation previously associated with aortic disease

For patients WITH an affected first-degree relative: 1

• Ectopia lentis alone OR
• Systemic score ≥7 points alone OR
• Aortic root dilation (Z-score ≥2 above age 20, ≥3 below age 20)

Critical Diagnostic Pitfall:

• Marfan syndrome remains primarily a clinical diagnosis; genetic testing supports but cannot replace clinical assessment using Ghent criteria. 1, 2

Immediate Diagnostic Work-Up

Upon Suspected Diagnosis:

1. Transthoracic echocardiography (TTE) without delay to measure aortic root at annulus, sinuses of Valsalva (most critical), sinotubular junction, and ascending aorta. 1, 2
2. Complete aortic imaging (MRI or CT) from root through descending thoracoabdominal aorta for baseline evaluation. 1, 2
3. Slit-lamp ophthalmologic examination to detect ectopia lentis. 2, 5
4. Skeletal assessment documenting systemic score features. 2
5. Three-generation family pedigree focusing on aortic dissection, sudden death, ectopia lentis. 6
6. FBN1 genetic testing when clinical criteria are insufficient or to enable family cascade screening. 2, 6

Medical Management

Beta-Blocker Therapy (Gold Standard):

• Initiate immediately in all confirmed Marfan patients regardless of aortic size. 1, 2
• Slows aortic root growth, reduces cardiovascular endpoints (dissection, surgery, death), and improves survival. 1, 2
• Target systolic blood pressure <120 mmHg (or <110 mmHg if prior dissection). 2

Angiotensin Receptor Blockers (ARBs):

• Reasonable alternative or adjunct therapy to reduce aortic dilation rate via TGF-β antagonism. 2
• Combined beta-blocker and ARB therapy at maximally tolerated doses should be considered. 2

Surveillance Protocol

Imaging Frequency Based on Aortic Dimensions: 1, 2

Aortic Root Diameter	Growth Rate	Imaging Interval
<4.5 cm	<0.5 cm/year	Annual TTE
≥4.5 cm OR >2 SD in adults	≥0.5 cm/year	TTE every 6 months
Stable disease (no surgery)	—	Full aortic MRI/CT every 3-5 years

• Repeat TTE 6 months after initial diagnosis to determine aortic growth rate. 1, 2
• Internal diameter (echocardiography) is 0.2-0.4 cm smaller than external diameter (CT/MRI); use external diameter for surgical thresholds. 1
• Index measurements to body surface area using Z-scores, especially in children. 1

Surgical Indications (Prophylactic Aortic Root Replacement)

Refer for surgery when: 1, 2

• Aortic root diameter >4.5 cm in adults
• Growth rate >1 cm/year
• Progressive aortic regurgitation
• Lower thresholds (4.0-4.5 cm) apply for:
  • Rapid growth
  • Family history of early dissection
  • Women desiring pregnancy

Critical Caveat:

• Dissection can occur at smaller diameters (<5.0 cm) in Marfan patients compared to the general population. 2

Differential Diagnosis

Distinguish Marfan syndrome from overlapping conditions: 1, 5

• Loeys-Dietz syndrome: Arterial tortuosity, bifid uvula, craniosynostosis, dissection at smaller aortic diameters; absence of ectopia lentis is key differentiator. 1, 5
• Ehlers-Danlos syndrome: Articular hypermobility, skin hyperextensibility, tissue fragility. 1
• MASS phenotype: Mitral valve prolapse, aortic enlargement, skin/skeletal findings without ectopia lentis. 1, 5
• Familial thoracic aortic aneurysm: Isolated aortic disease without systemic features. 1

Lifestyle and Activity Recommendations

Physical Activity:

• Avoid heavy isometric exercises and competitive contact sports due to sudden blood pressure spikes increasing dissection risk. 1, 2
• Regular moderate aerobic exercise is encouraged, individualized to aortic size and family history. 2
• Patients with arterial hypertension, residual obstruction, or aortic diameter >4.5 cm should avoid extensive static sports. 1

Pregnancy Considerations

High-Risk Scenario:

• Pregnancy markedly increases risk of aortic rupture, dissection, and cerebral aneurysm rupture, especially with unrepaired disease, hypertension, or aortic diameter >4.0 cm. 1, 5
• Pre-conception evaluation is mandatory: Complete aortic imaging (MRI/CT), genetic counseling, and risk stratification. 2
• Prophylactic aortic root surgery is recommended if diameter >45 mm; may be considered at 40-45 mm before pregnancy. 2
• Continue beta-blockers during pregnancy; follow-up frequency determined by aortic diameter and growth. 2
• Excess miscarriages and hypertensive disorders are reported. 1

Family Cascade Testing

• Offer FBN1 genetic testing to all first-degree relatives to identify asymptomatic carriers. 2
• Early identification enables preventive management before aortic complications develop. 2
• Examine siblings and parents clinically, as many features are silent. 6

Prognosis

Untreated Disease:

• Mean survival is approximately 40 years, with aortic dissection or rupture as the primary cause of death. 1, 5

With Aggressive Management:

• Life expectancy approaches 60-70 years with beta-blocker therapy, systematic imaging surveillance, and timely prophylactic surgery. 2, 5
• The primary goal is preventing aortic dissection through early detection and intervention. 2

Common Pitfalls to Avoid

• Do not delay echocardiography based on normal physical examination; aortic disease is often asymptomatic until catastrophic dissection. 2
• Do not rely solely on genetic testing for diagnosis; 10% of clinically definite cases have no detectable FBN1 mutation. 1, 2
• Do not use a single imaging modality; TTE monitors the root, but MRI/CT is required for complete aortic assessment. 1, 2
• Do not assume safety at aortic diameters <5.0 cm; 15% of dissections occur below this threshold in Marfan patients. 2
• Do not overlook ectopia lentis; its presence with aortic dilation confirms diagnosis even without systemic features. 1, 5