Marfan Syndrome

Marfan syndrome is a heritable disorder of connective tissue caused by mutations in the FBN1 gene, which encodes fibrillin-1 — a glycoprotein essential for the formation of elastic fibres in the extracellular matrix. The condition follows an autosomal dominant inheritance pattern, meaning a single copy of the altered gene is sufficient to cause the disorder. Approximately 25% of cases arise from de novo mutations with no family history. The syndrome affects multiple organ systems, most critically the cardiovascular system, musculoskeletal system, and eyes. Dysregulation of transforming growth factor beta (TGF-β) signalling plays a central role in disease pathogenesis.

Marfan syndrome affects approximately 1 in 5,000 people worldwide, with no significant variation in prevalence across racial or ethnic groups. It occurs with equal frequency in males and females. The global burden is estimated at over 1.5 million individuals. Due to its variable expressivity and the subtlety of some clinical features, a significant proportion of cases remain undiagnosed throughout a person's lifetime.

Marfan syndrome presents with a broad spectrum of features across multiple body systems. Clinical presentation varies widely even within families sharing the same mutation. The revised Ghent nosology (2010) provides the current diagnostic criteria.

• Cardiovascular: aortic root dilatation or dissection, mitral valve prolapse, aortic regurgitation
• Musculoskeletal: tall stature, arachnodactyly (long fingers), pectus excavatum or carinatum, scoliosis, joint hypermobility, pes planus
• Ocular: ectopia lentis (lens dislocation), myopia, increased risk of retinal detachment and glaucoma
• Dural: lumbosacral dural ectasia (enlargement of the spinal dural sac)
• Pulmonary: spontaneous pneumothorax, apical blebs
• Skin and integument: striae atrophicae (stretch marks) in unusual locations, recurrent herniae

Diagnosis is based on the revised Ghent nosology, which combines clinical criteria, family history, and molecular genetic testing. In the absence of a family history, aortic root dilatation or dissection plus ectopia lentis is sufficient for diagnosis. Genetic testing for FBN1 mutations confirms the diagnosis in approximately 90–95% of cases meeting clinical criteria. Echocardiography is essential to assess the aorta. Ophthalmological slit-lamp examination assesses for lens dislocation. MRI of the lumbosacral spine may be used to evaluate for dural ectasia.

There is no cure for Marfan syndrome; management is aimed at preventing and monitoring complications. Beta-blockers (e.g., atenolol) or angiotensin II receptor blockers (e.g., losartan) are used to slow aortic root dilatation. Prophylactic aortic root surgery is recommended when the aortic diameter reaches 4.5–5.0 cm. Annual echocardiography is standard care. Physical activity restrictions are advised, particularly avoiding contact sports and isometric exercise. Corrective lenses or surgery for ocular complications. Scoliosis may require bracing or surgery. Multidisciplinary care involving cardiology, genetics, ophthalmology, and orthopaedics is recommended.

1. [1]Loeys BL, et al. (2010). The revised Ghent nosology for the Marfan syndrome. Journal of Medical Genetics, 47(7), 476–485.
2. [2]Dietz HC. (2020). Marfan Syndrome. In: Adam MP, et al. (eds). GeneReviews®. Seattle (WA): University of Washington.
3. [3]National Marfan Foundation. (2024). About Marfan Syndrome. Retrieved from marfan.org.
4. [4]Orphanet. (2024). Marfan syndrome. Orphanet Report Series: Rare Diseases collection. Orphanet #558.