Related Subjects:
|Autosomal Dominant
|Autosomal Recessive
|X Linked Recessive
๐งฌ Marfan syndrome is a systemic connective tissue disorder caused by mutations in the FBN1 gene, affecting fibrillin-1, a key glycoprotein of microfibrils.
It weakens connective tissue in multiple organ systems (skeletal, cardiovascular, ocular), with the most feared complication being progressive aortic root dilatation โ dissection โ rupture.
Histologically, it is associated with cystic medial necrosis โ fragmentation of elastic fibres with myxoid degeneration in the aortic media.
๐ About
- Inheritance: Autosomal dominant connective tissue disorder.
- Incidence: ~1 in 9,800 individuals worldwide.
- De novo mutations: ~27% of cases occur without family history.
- High morbidity due to aortic dissection and valvular disease ๐.
๐งฌ Genetics
- Gene: Mutation in FBN1 on chromosome 15.
- Fibrillin-1: Provides a scaffold for elastin deposition in connective tissues, especially in the aorta, suspensory ligament of the lens, and periosteum.
- Mutations: >800 identified โ variable expression even within families.
- Pathogenesis also involves excessive TGF-ฮฒ signalling, leading to abnormal connective tissue remodelling.
๐ง Clinical Features
- Skeletal System ๐ฆด:
- Tall stature, dolichostenomelia (long limbs) โ arm span:height ratio >1.05.
- Arachnodactyly ("spider fingers") โ positive Steinberg or Walker-Murdoch sign.
- High-arched palate, crowding of teeth.
- Kyphoscoliosis, chest wall deformities (pectus excavatum or carinatum).
- Joint hypermobility, recurrent dislocations.
- Ocular ๐๏ธ:
- Ectopia lentis (typically upward dislocation โ contrast with homocystinuria, which is downward).
- Severe myopia, risk of retinal detachment.
- Glaucoma and cataracts more common.
- Cardiovascular โค๏ธ:
- Aortic root dilatation โ aneurysm, regurgitation, dissection (esp. type A).
- Mitral valve prolapse (midsystolic click ยฑ late systolic murmur) ยฑ MR.
- Aortic regurgitation โ early diastolic murmur, โ LV dilation and HF.
- Respiratory ๐ฌ๏ธ:
- Spontaneous pneumothorax from apical blebs.
- Restrictive lung disease due to chest wall deformities.
- Other: Dural ectasia (ballooning of lumbosacral meninges), herniae, liver/kidney cysts.
๐ Differentials for Marfanoid Habitus
- Homocystinuria (AR, lens dislocation downward, thromboembolism risk).
- Familial thoracic aortic aneurysm syndromes.
- Lujan-Fryns syndrome (X-linked, intellectual disability).
- Multiple Endocrine Neoplasia type 2B (MEN2B).
- Loeys-Dietz syndrome (TGF-ฮฒ receptor mutations, arterial tortuosity, bifid uvula).
๐งช Investigations
- Ghent Criteria (Revised 2010): Uses a combination of clinical features (aortic root dilatation, ectopia lentis, systemic score) and FBN1 mutation status.
- Genetic Testing: Confirms FBN1 mutation.
- Echocardiography: Annual monitoring of aortic root, ascending aorta, and valves.
- CT/MRI: Baseline and follow-up imaging of the entire aorta for aneurysm/dissection risk.
- Ophthalmology: Slit-lamp for lens dislocation, IOP monitoring for glaucoma.
- Skeletal Imaging: Spine X-rays if scoliosis suspected.
๐ฉบ Management
- Surveillance: Annual echocardiogram; more frequent if aortic root >4.5 cm.
- Medical:
- Beta-blockers (e.g., propranolol) โ reduce aortic wall stress.
- ARBs (e.g., losartan) โ attenuate TGF-ฮฒ signalling, slow aortic dilatation.
- Surgical:
- Prophylactic aortic root replacement when diameter โฅ50 mm (or โฅ45 mm with family history or rapid expansion).
- Valve-sparing aortic root replacement preferred when feasible.
- Repair of severe mitral regurgitation.
- Ophthalmology: Lens replacement if ectopia lentis impairs vision, glaucoma treatment.
- Lifestyle: Avoid contact sports and isometric exercise ๐๏ธ; encourage moderate aerobic activity.
- Genetic Counseling: Family screening essential given autosomal dominant inheritance.
๐ Prognosis
Without treatment, median survival is ~40 years due to aortic rupture.
With modern medical and surgical care, life expectancy can approach normal, especially with early recognition and prophylactic aortic surgery.
Pregnancy carries high risk of aortic dissection โ requires expert cardiology and obstetric input.
๐ References