Description
Marfan Syndrome is one of the most common autosomal dominant multisystemic disorders of connective tissue, classically with ocular, cardiovascular, and musculoskeletal abnormalities.
Pathophysiology
Marfan syndrome is an autosomal dominant inherited defect in an extracellular glycoprotein fibrillin-1, encoded by the FBN1 gene located on chromosome 15q21.1. Fibrillin-1 is an essential component of microfibrils, a type of connective tissue that provides strength and elasticity to tissues throughout the body
Fibrillin also exists in another homologous form, fibrillin-2, encoded by the FBN2 gene located on chromosome 5q23.31. Mutations of the FBN2 gene give rise to congenital contractural arachnodactyly, another autosomal dominant disorder of skeletal abnormalities.
Epidemiology
- Estimated incidence of around 1 in 5,000 individuals
- No gender or ethnic group predilection.
- About 75% of cases are inherited from an affected parent
- 25% of cases are due to de novo mutations.
- A classical association of Marfan Syndrome is with cardiovascular complications, particularly annuloaortic ectasia (75% of cases), aortic dissection and mitral valve prolapse.
Clinical Features
Musculoskeletal
Musculoskeletal abnormalities represent the most prominent manifestation of Marfan Syndrome.
- Tall with dolichostenomelia (disproportionately long extremities).
- Arachnodactyly (finger and toes are long and tapering).
- Joint laxity.
- Dolichocephalic (long) head with frontal eminence bossing and prominence of supraorbital ridges.
- Spinal deformities: kyphosis, scoliosis, rotation or slipping of the thoracolumbar vertebrae.
- Chest deformities: pectus excavatum or carinatum (pigeon-breast), can cause restrictive lung disease
Ocular
- Bilateral ectopia lentis (subluxation/dislocation of lens in upward and outward direction).
- Cataract, myopia (common), and retinal detachment.
Cardiovascular
Cardiovascular lesions represent the most life-threatening features of Marfan Syndrome.
- Cardiac abnormalties: mitral valve regurgitation (40 – 50% of cases), aortic valve regurgitation secondary to aortic annulus dilatation (more clinically important but less common), tricuspid valve prolapse, dilated cardiomyopathy (uncommon)
- Children: Mitral regurgitation and heart failure, pulmonary hypertension, death in infancy
- Vascular abnormalities
- Annuloaortic ectasia and aortic aneurysm
- Pulmonary trunk dilatations
Other
- Pulmonary: bullae predisposing to spontaneous pneumothorax
Complications
- Aortic dissection: often type A; ± propagation to descending aorta. Pregnant women are at particular risk of aortic dissection and surveillance imaging should be considered.
- Acute-onset heart failure typically from severe aortic regurgitation
- Involvement of coronary arteries; myocardial infarction or sudden cardiac death
Pathological Features
Morphology and Histopathology
- Loss of connective tissue support makes mitral valve leaflets soft and billowy. Lengthening of the chordae tendineae, frequently giving rise to mitral regurgitation.
- Dilation of the ascending aorta due to cystic medionecrosis or medial degeneration, characterised by fragmentation and loss of elastic fibres, accumulation of ground substance, and pooled mucoid material.
- Loss of medial support results in progressive dilation of the aortic valve ring and the root of the aorta, giving rise to severe aortic incompetence.
- Media weakening also predisposes to an intimal tear, which may initiate an intramural hematoma that cleaves the layers of the media to produce aortic dissection. Intramural haematoma may rupture through the aortic wall.
Genetics
Marfan Syndrome is caused by mutations in the FBN1 gene located on chromosome 15q21.1. This gene codes for fibrillin-1, a major component of the microfibrils that constitute much of the body’s connective tissue. The majority of mutations are missense mutations, but frameshift and splice-site mutations are also seen.
Radiological Features
Radiography
- Ascending aortic aneurysm
- Cardiomegaly
- Pectus deformity, scoliosis, scalloped vertebrae
- Pneumothorax; apical bullae
- Skeletal X-ray: Can show long bone overgrowth and deformities of the chest wall, such as pectus excavatum or pectus carinatum.
CT
- Annuloaortic ectasia – tulip bulb or pear-shaped dilation of the aortic annulus
- Aneurysm
- Aortic rupture: Crescent sign, haematoma
- Dissection: Intimal flap, true/false lumen
Echocardiography
- Aortic root dilatation, mitral valve prolapse, and signs of aortic or mitral regurgitation.
- Performed at diagnosis to assess ascending aorta and 6 months thereafter to determine rate of enlargement
MRI
- Spine: May show dural ectasia, an enlargement of the dural sac, predominantly in the lower lumbar and sacral regions (distinctive feature of Marfan Syndrome).
- Cardiac: Can demonstrate aortic root dilatation, aortic dissection, or mitral valve prolapse. Aortic root diameter measurements are crucial in monitoring patients with Marfan Syndrome due to the risk of aortic dissection.
US
- Ocular Ultrasound: May show lens dislocation, an ocular hallmark of Marfan Syndrome.
Diagnosis & Classification
No specific laboratory test except for molecular genetic testing.
Clinical diagnosis of Marfan syndrome is currently based on the revised Ghent criteria. Major involvement of two of the four organ systems (skeletal, cardiovascular, ocular, and skin) and minor involvement of another organ is required for diagnosis.
| Diagnostic criteria (Revised Ghent Criteria 2010) | ||
| In absence of family history |
| |
| In presence of family history |
| |
| Scoring of systemic features |
Wrist and thumb sign (wrist or thumb sign: 1) | 3 |
|
Pectus carinatum deformity (chest asymmetry: 1) | 2 | |
|
Hindfoot deformity (plain pes planus: 1 point) | 2 | |
|
Protrusio acetabuli | 2 | |
|
Reduced upper segment:lower body segment ratio and increased arm/height and no severe scoliosis | 1 | |
|
Scoliosis or thoracolumbar kyphosis: | 1 | |
|
Reduced elbow extension | 1 | |
|
Facial features (3/5):
| 1 | |
|
Pneumothorax | 2 | |
|
Skin striae | 1 | |
|
Myopia > 3 diopters | 1 | |
|
Mitral valve prolapse (all types) | 1 | |
|
Dural ectasia | 2 | |
| Diagnostic criteria (Revised Ghent Criteria 2010) | |
| In absence of family history | |
| |
| In presence of family history | |
| |
| Scoring of systemic features | |
|
Wrist and thumb sign (wrist or thumb sign: 1) | 3 |
|
Pectus carinatum deformity (chest asymmetry: 1) | 2 |
|
Hindfoot deformity (plain pes planus: 1 point) | 2 |
|
Protrusio acetabuli | 2 |
|
Reduced upper segment:lower body segment ratio and increased arm/height and no severe scoliosis | 1 |
|
Scoliosis or thoracolumbar kyphosis: | 1 |
|
Reduced elbow extension | 1 |
|
Facial features (3/5):
| 1 |
|
Pneumothorax | 2 |
|
Skin striae | 1 |
|
Myopia > 3 diopters | 1 |
|
Mitral valve prolapse (all types) | 1 |
|
Dural ectasia | 2 |
Differential Diagnosis
Other hereditary disorders of connective tissue:
- Ehlers-Danlos Syndrome: Characterised by skin hyperextensibility, joint hypermobility, and tissue fragility.
- Loeys-Dietz Syndrome: Presents with features similar to Marfan Syndrome but may also include widely spaced eyes, cleft palate, and arterial tortuosity.
- Homocystinuria: Can mimic the skeletal abnormalities of Marfan Syndrome but also presents with intellectual disability and a risk of thromboembolic events.
Management
- Incurable
- Surgical repair: Diameter > 4.5 cm (pregnant women if > 4 cm), rapid rate of growth (> 1 cm/year), new significant aortic regurgitation
- Medical therapy: beta-blockers and afterload-reducing agents to reduce stress on the aortic valve, mitral valve, and aortic root
Prognosis
Decreased life expectancy occurs primarily due to aortic complications including aortic root dilatation and dissection.