Marfan Syndrome

Marfan syndrome is a genetic condition with autosomal dominant inheritance. Marfan syndrome affects the elasticity of connective tissues throughout the body, most notably in the cardiovascular, ocular, and musculoskeletal systems. The skin, lungs, and central nervous system are also affected. Patients are usually tall with long limbs, fingers, and toes, and hypermobile joints. Associated conditions include aortic aneurysm or dissection, mitral valve prolapse, and lens dislocation. Diagnosis is made clinically with set criteria, and genetic testing is done only when it may affect the management. Medical or surgical management is based on clinical manifestations. Cardiovascular involvement is followed closely, as it is the main cause of mortality.

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Epidemiology and Genetics


  • Incidence: 1 in 5,000 live births 
  • Affects men and women in all ethnic and racial groups


  • Most commonly due to a mutation in the FBN1 gene on chromosome 15 
    • Affects the connective tissue protein, fibrillin-1
      • Fibrillin-1 is the main component of microfibrils, which form elastic fibers in connective tissue.
      • Mutation in FBN1 gene → impaired fibrillin protein → defective microfibrils → ↓ elasticity in tissues
    • Affects connective tissues throughout the body:
      • Organs
      • Blood vessels 
      • Eyes 
      • Skin
      • Skeletal components  
  • Inheritance pattern: autosomal dominant
    • 75% of patients have affected parents.
    • 25% of cases are de novo mutations (idiopathic).
  • Penetrance: complete
  • Expressivity: variable
Marfan syndrome in Iranian family

Family members with Marfan’s syndrome

Image: “Family members with Marfan’s syndrome” by Birjand Atherosclerosis and Coronary Artery Research Centre, Birjand University of Medical Sciences, Birjand, Iran. License: CC BY 3.0

Clinical Presentation


  • Tall stature with disproportionately long extremities:
    • ↓ upper segment to lower segment ratio (US/LS)
    • ↑ arm span to height ratio
  • Long fingers and toes (arachnodactyly):
    • Positive thumb sign (Steinberg’s sign): The distal phalanx of the adducted thumb extends beyond the ulnar border of a clenched fist palm.
    • Positive wrist sign (Walker sign): The thumb and 5th finger of the hand overlap with each other when wrapped around the contralateral wrist. 
  • Joint laxity
  • Elbows may lack full extension mobility.
  • Vertebral column abnormalities:
    • Scoliosis 
    • Kyphosis 
  •  Chest abnormalities:
    • Pectus excavatum (funnel chest)
      • Sternum protrudes inward.
      • Looks “caved in”
    • Pectus carinatum (pigeon chest or sternal kyphosis): Sternum protrudes outward.
  • Hindfoot valgus:
    • Heel points outward away from midline.
    • Associated with pes planus (flat foot)
  • Protrusio acetabuli (acetabular protrusion)
  • High-arched palate
  • Characteristic facial features:
    • Dolichocephaly (↓ head width:length ratio)
    • Enophthalmos (posterior displacement of the eyeball within the orbit)
    • Downslanting palpebral fissures (area between open eyelids)
    • Malar hypoplasia (malar or zygomatic bone is small or absent)
    • Retrognathia (lower jaw set back further than upper jaw)


  • Aortic disease is the main cause of morbidity and mortality in Marfan syndrome (MFS) patients, and is due to degeneration of the media of the vessel walls.
    • Dilation or aneurysm of the aorta
      • Present in 50% of children 
      • Dilation may involve thoracic aorta, abdominal aorta, or root of pulmonary artery.
      • Dilation of the aortic root present in 60%–80% of adults with MFS
    • Aortic regurgitation
      • Often occurs with aortic dilation 
      • Valve leaflets prevented from closing properly
      • Diastolic heart murmur on exam
    • Aortic dissection
      • Tear in the intima (innermost layer) of the aorta, allowing blood between the intima and media (middle layer)
      • Life-threatening condition
      • Presents with sudden, severe, chest pain that radiates to the back
      • MFS patients account for 50% of those with aortic dissection under 40 years of age. 
      • ↑ risk of dissection during pregnancy and postpartum
  • Mitral valve prolapse 
    • Valve leaflets bulge (prolapse) into left atrium during heart systole
    • More frequently seen with ↑ age and in women
    • Systolic heart murmur and midsystolic click on exam
    • Can lead to mitral regurgitation
  • Dilation of carotid and cranial arteries 
    • Much less common
    • Berry (saccular) aneurysms are typically at the exit of the circle of Willis.
    • Rupture of a cranial artery can cause subarachnoid hemorrhage.


  • Dislocation of the lens (ectopia lentis)
    • Impaired supporting ciliary zonules fail to keep the lens in place.
    • Upward and temporal displacement
    • Occurs in 50%–80% of patients
    • Iridodonesis can be seen on inspection (vibration of the iris with eye movement).
    • Seen on slit lamp examination
  • Myopia (nearsightedness)
  • Retinal tears or detachment
    • Often bilateral in MFS patients
    • Associated with proliferative retinopathy
  • Glaucoma
  • Early cataract formation

Other manifestations

  • Skin: striae atrophicae (stretch marks) 
    • Not associated with weight changes or pregnancy
    • Often in uncommon areas:
      • Upper arms
      • Axillary area
      • Mid and lower back
      • Thighs
  • Pulmonary: emphysematous changes in the lungs 
    • Lung bullae predominantly in the upper lobes
    • ↑ risk for spontaneous pneumothorax
  • Central nervous system (CNS): lumbosacral dural ectasia 
    • Dilation of the dural sac surrounding the spinal cord
    • Symptoms: 
      • Lower back pain
      • Radicular pain
      • Paresthesias
      • Bowel and bladder dysfunction
      • Headaches


  • Revised Ghent criteria
    • Complex scoring system based on the presence of characteristic Marfan syndrome manifestations
    • Requires varying combinations of: 
      • Aortic root dilatation
      • Ectopia lentis
      • FBN1 gene mutation
      • Systemic score > 7 (see table below)
    • The presence, or absence, of a family history of MFS is factored in.
  • Genetic testing for the FBN1 mutation is done on a case-by-case basis if it will affect management.
  • Imaging is used to evaluate for complications of MFS.
    • Radiographs → pneumothorax, protrusio acetabuli, scoliosis
    • Echocardiography (echo) → valvular and aortic root defects 
    • Computed tomography (CT) of chest, abdomen, and pelvis with intravenous (IV) contrast → aortic dissection
    • Magnetic resonance imaging (MRI) → dural ectasia, aortic dilation
Table: Systemic score for the revised Ghent criteria (a score ≥ 7 indicates major systemic involvement)
Wrist and thumb sign
  • 3 points (both)
  • 1 point (1)
Pectus carinatum deformity2 points
Pectus excavatum or chest asymmetry1 point
Hindfoot deformity2 points
Plain pes planus1 point
Pneumothorax2 points
Dural ectasia2 points
Protrusio acetabuli2 points
↓ US/LS and ↑ arm span/height and no severe scoliosis1 point
Scoliosis or kyphosis1 point
↓ elbow extension1 point
Facial features (at least 3 of 5)
  • Dolichocephaly
  • Enophthalmos
  • Downslanting palpebral fissures
  • Malar hypoplasia
  • Retrognathia
1 point
Skin striae1 point
Myopia1 point
Mitral valve prolapse1 point
This table does not need to be memorized, but provides insight into the important clinical findings and the complexity of the diagnosis.


The management of MFS is based on the clinical manifestations. A multidisciplinary team of cardiologists, ophthalmologists, orthopedists, and cardiovascular surgeons is needed.


  • Avoid: 
    • Caffeine
    • Stimulants
    • Strenuous exercise
    • Contact sports
    • Activities that entail the Valsalva maneuver
    • Scuba diving
  • Genetic and preconception counseling
    • 50% risk of transmission to children
    • High-risk pregnancy due to ↑ risk of aortic dissection and rupture


  • Scoliosis treatment
    • Bracing
    • Surgery if the curve > 40 degrees
  • Physical therapy
  • Surgery may be needed for other skeletal anomalies (e.g., pectus deformities), if severe. 


  • Echocardiography 
    • Upon initial diagnosis and every 6–12 months
    • Evaluate and monitor aortic dilation.
    • Monitoring frequency is based on the rate of growth over time.
  • Cardiac CT or MRI 
    • Used to confirm echo findings
    • Assess for additional aortic or vascular defects not seen on echo.
  • Medications for strict blood pressure control 
    • Beta blockers 
    • Angiotensin receptor blockers (ARBs)
    • Avoid calcium channel blockers, as these may ↑ risk of aortic complications.
  • Surgery
    • Elective aortic repair or replacement surgery is indicated if:
      • Diameter ≥ 50 mm
      • Rapid growth
      • Family history of dissection
      • Progressive aortic regurgitation
      • Patients considering pregnancy
    • Surgery or medical management for aortic dissection depends on whether the ascending aorta is involved.
    • Mitral valve repair or replacement is recommended for:
      • Severe mitral regurgitation
      • Progressive left ventricular dilation or systolic dysfunction


  • Annual ophthalmologic exams
  • Myopia → vision correction
  • Retinal tears or detachment → photocoagulation
  • Urgent ophthalmologic assessment for sudden vision changes

Differential Diagnosis

  • Homocystinuria: autosomal recessive disorder of homocysteine metabolism. Affected individuals have marfanoid body habitus and ectopia lentis, characterized by a downward and inward dislocation. Individuals may also have intellectual disability, megaloblastic anemia, and thrombotic events (strokes and myocardial infarction). Measurement of homocysteine levels aids in diagnosis. Management is via a low-methionine diet and vitamin supplementation. 
  • Ehlers-Danlos syndrome: an autosomal dominant connective tissue disorder affecting collagen. The syndrome has 13 subtypes, and the inheritance pattern can be autosomal dominant or recessive. The cardiovascular system, musculoskeletal system, eyes, and skin are affected. Easy bruising or bleeding and dental abnormalities are also seen. The syndrome is a clinical diagnosis, but genetic testing may be beneficial. Management is symptomatic and based on manifestations. 
  • Loeys-Dietz syndrome: an autosomal dominant connective tissue disorder with similar presentation to MFS but affecting a different gene. Unlike MFS, features of hypertelorism (widely spaced eyes), split uvula, cleft palate, easy bruising, keloid formation, and arterial tortuosity are present. Vascular features may be more aggressive, with aortic aneurysms seen at an early age. Genetic testing can help differentiate between Loeys-Dietz syndrome and MFS. Management is similar to MFS.
  • Multiple endocrine neoplasia, type 2B (MEN 2B): an autosomal dominant syndrome associated with medullary thyroid carcinoma, pheochromocytoma, oral mucosal neuromas, and intestinal ganglioneuromas. Affected individuals also have a marfanoid body habitus with skeletal abnormalities; however, the cardiovascular system and eyes are usually not affected. Genetic testing helps in diagnosis. Surgery is required to remove the neoplasms. 
  • Congenital contractural arachnodactyly: also known as Beals syndrome. An autosomal dominant condition affecting the fibrillin-2 protein. Affected individuals also have a marfanoid body habitus and cardiovascular manifestations. Flexion contractures in many joints restrict movement. The skin is not affected. The condition is diagnosed with clinical criteria and genetic testing. Management is based on the clinical manifestations. 


  1. Wright, M.J. & Connolly, H.M. (2016). Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders. UpToDate. Retrieved December 7, 2020, from
  2. Marfan Syndrome. MedlinePlus.
  3. Wright, M.J. & Connolly, H.M. (2020). Management of Marfan syndrome and related disorders. UpToDate. Retrieved December 8, 2020, from
  4. Inna, P. (2020). Marfan syndrome (MFS). In Thomson, J.D. (Ed.), Medscape. Retrieved December 11, 2020, from
  5. Pessler, F. (2020). Marfan syndrome. [online] MSD Manual Professional Version. Retrieved December 11, 2020, from

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