Marfan and Ehlers-Danlos Syndromes
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Direct answer
Marfan and Ehlers-Danlos syndromes are inherited disorders of connective tissue, Marfan caused by fibrillin-1 (FBN1) defects and Ehlers-Danlos by collagen defects. The point most often tested is that Marfan syndrome causes aortic root dilatation and dissection in a tall patient with ectopia lentis, while vascular Ehlers-Danlos risks arterial and bowel rupture. Most forms are autosomal dominant, and diagnosis rests on clinical scoring rather than a single test.
What you must remember
- Marfan gene: FBN1 on chromosome 15 encodes fibrillin-1, an extracellular matrix protein that sequesters TGF-beta, so its loss leads to excess TGF-beta signalling.
- Eye clue: Ectopia lentis, usually displaced upwards and outwards, is the ocular sign that points towards Marfan syndrome.
- Skeletal signs: Arachnodactyly, Walker-Murdoch and Steinberg signs, pectus deformity, scoliosis and a high-arched palate.
- Aortic risk: Root dilatation, dissection and mitral valve prolapse; surgery is generally considered when the root reaches about 5 cm, or sooner with rapid growth.
- Vascular EDS: COL3A1 defect in type III collagen, with thin translucent skin, easy bruising and spontaneous arterial, uterine or bowel rupture.
- Hypermobile EDS: The commonest type, diagnosed clinically with no confirmed gene, causing recurrent dislocation and chronic musculoskeletal pain.
- Drug safety: Beta-blockers or losartan protect the aortic root, and fluoroquinolones are avoided because they are linked to aortic aneurysm and dissection.
A diagnostic pathway for a tall young man with a dilated aortic root
A 22-year-old tall, thin man with an aortic root of 4.8 cm and superotemporal lens displacement shows how the diagnosis is built.
- Score with Ghent: The diagnosis rests on the Ghent nosology, which weights skeletal, ocular, cardiovascular, skin and family features.
- Weigh the eye and aorta: Aortic root dilatation (Z-score 2 or more) together with ectopia lentis is sufficient for the diagnosis once Loeys-Dietz and vascular EDS are excluded, and a confirmed FBN1 mutation supports the diagnosis when the score is borderline.
- Re-measure the root: Once confirmed, the root is re-measured at intervals and a beta-blocker or losartan is started.
- Limit strain: Heavy isometric exercise and contact sports are avoided.
- Screen relatives: First-degree relatives are screened, since the condition is autosomal dominant.
Now take a 28-year-old woman with easy bruising, soft translucent skin and a bowel perforation during a routine procedure. Vascular EDS is suspected, and COL3A1 genetic testing confirms the diagnosis. Management focuses on avoiding elective invasive procedures and on beta-blockade to reduce the risk of arterial rupture.
Where the exam tries to catch you
Marfan syndrome and homocystinuria both cause lens dislocation and tall stature, which makes them the most common confusion.
- Trap: Choosing homocystinuria for any tall patient with lens dislocation. Correct: Marfan lens displacement is upward and outward with normal intelligence, whereas homocystinuria dislocates the lens downward and inward and causes learning difficulty and thrombosis.
- Trap: Assuming any aortic aneurysm in a tall patient must be Marfan. Correct: Loeys-Dietz syndrome, with TGF-beta pathway mutations, causes aortic aneurysm and arterial tortuosity without typical ectopia lentis.
- Trap: Diagnosing EDS from joint laxity alone. Correct: Generalised joint laxity alone does not make a diagnosis, since it is common in healthy people.
In pregnancy, the dissection risk is highest in the third trimester and early postpartum period, so aortic assessment before conception is advised.
Frequently asked questions
Which eye finding points towards Marfan syndrome rather than homocystinuria?
Ectopia lentis in Marfan syndrome usually displaces the lens upwards and outwards, whereas homocystinuria dislocates it downwards and inwards. Examiners often pair this with cognition, since Marfan patients have normal intelligence while untreated homocystinuria causes learning difficulty and thromboembolism.
Which gene and protein are defective in Marfan syndrome?
Marfan syndrome results from mutations in the FBN1 gene on chromosome 15, which encodes fibrillin-1, a structural protein of elastic microfibrils. Loss of normal fibrillin-1 allows excess TGF-beta signalling, which is the rationale for using losartan to slow aortic root growth.
Which form of Ehlers-Danlos syndrome is most dangerous and how is it confirmed?
Vascular Ehlers-Danlos syndrome, caused by COL3A1 defects in type III collagen, is the most dangerous form because of spontaneous arterial, uterine and bowel rupture. The diagnosis is made clinically and confirmed by COL3A1 genetic testing, and elective invasive procedures are avoided where possible.
When is prophylactic aortic surgery considered in Marfan syndrome?
Prophylactic aortic root surgery is generally considered when the root reaches about 5 cm, or earlier if growth is rapid or a family history of dissection exists. Beta-blocker or losartan therapy continues while the root is followed by echocardiography.