Genetics of Marfan Syndrome

Updated: Jun 16, 2023
  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD  more...
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Practice Essentials

Marfan syndrome (MFS) is an inherited connective tissue disorder noteworthy for its worldwide distribution, relatively high prevalence, and clinical variability. This autosomal dominant syndrome has pleiotropic manifestations involving primarily the ocular, cardiovascular, and skeletal systems. [1, 2] Classic MFS (MFS type 1, MFS1) has been considered a condition caused by the deficiency of a structural extracellular matrix protein, fibrillin-1; however, studies of Marfan mouse models and Marfan-related conditions have expanded our current understanding to a pathogenic model that involves dysregulation of cytokine-transforming growth factor beta (TGFβ) signaling. [3, 4]  Patients who have clinical findings of MFS, as well as genetic variants in the transforming growth factor-beta receptor-1 gene (TGFβR1) or the transforming growth factor-beta receptor-2 gene (TGFβR2), are designated as having MFS type 2 (MFS2). [5]

Signs and symptoms of Marfan syndrome

Clinical presentations are as follows:

  • Delayed achievement of gross and fine motor milestones due to ligamentous laxity of the hips, knees, ankles, plantar arches, wrists, and fingers
  • A decrescendo diastolic murmur from aortic regurgitation
  • An ejection click at the apex followed by a holosystolic high-pitched murmur due to mitral prolapse and regurgitation
  • Dysrhythmia (a primary feature)
  • Abrupt onset of thoracic pain, which occurs in more than 90% of patients with aortic dissection
  • Low back pain near the tailbone, burning sensation and numbness or weakness in the legs in severe dural ectasia. 
  • Joint pain in older patients
  • Dyspnea, severe palpitations, and substernal pain in significant  pectus excavatum
  • Breathlessness, often associated with chest pain, in spontaneous pneumothorax
  • Visual problems, such as vision impairment due to lens dislocation or retinal detachment

Workup in Marfan syndrome

Lab studies

Currently, the standard of care in MFS is to obtain confirmatory molecular diagnostics on patients with the syndrome and their family members, due to the variable expression of MFS and the diagnosable "look-alike" conditions.

Molecular studies of the fibrillin-1 (FBN1) gene should be performed in patients in whom MFS is suspected. Mutation analysis can identify the exact mutation in the fibrillin gene, and linkage analysis can be used to track an abnormal fibrillin gene within a family. [6]

Imaging studies

Chest radiography should be focused on apical blebs. Chest radiographs may also detect a thoracic aortic dissection by demonstrating enlargement of the aortic and cardiac silhouette. Pelvic radiography may be required if a positive finding of protrusio acetabula is needed for the diagnosis.

Standard echocardiography is valuable to assess mitral valve prolapse, left ventricular size and function, left atrial size, and tricuspid valve function.

Cross-sectional echocardiography is a common tool used to diagnose and manage aortic root dilatation. The upper limit of normal aortic root size is 1.9 cm/m2 of body surface area and is independent of the patient's sex.

Transesophageal echocardiography depicts the distal ascending and descending aorta and can provide assessment of prosthetic valves. Doppler echocardiography is useful to detect and grade the severity of aortic and mitral regurgitation.

Magnetic resonance imaging (MRI) is the best choice for assessing chronic dissection of any region of the aorta. Computed tomography (CT) scanning or MRI of the lumbosacral spine may be needed to detect dural ectasia.

Management of Marfan syndrome

General guidelines for all adults diagnosed with MFS are as follows [7, 8] :

  • Restriction of physical activity with avoidance of contact sports, isometric exercise, and activities that can cause joint injury/pain
  • Avoidance of agents that stimulate the cardiovascular system, such as decongestants and caffeine
  • Annual ophthalmologic examination - LASIK correction of refractive errors is not recommended.
  • Subacute endocarditis prophylaxis for dental work in the presence of mitral or aortic valve regurgitation
  • Annual echocardiography to evaluate the ascending aorta in cases of small aortic dimensions and/or a slow aortic dilatation rate - Echocardiography is required with greater frequency when aortic root diameter is over 4.5 cm in adults, if aortic dilatation is greater than 0.5 cm per year, and if significant aortic regurgitation is present
  • Beta-blocking treatment to reduce hemodynamic stress on the aortic wall

Key issues in cardiovascular management are as follows  [9] :

  • Beta-blocker therapy should be considered at any age if the aorta is dilated, but prophylactic treatment may be more effective in those patients with an aortic diameter of less than 4 cm.
  • Risk factors for aortic dissection include an aortic diameter of over 5 cm, aortic dilatation extending beyond the sinus of Valsalva, rapid rate of dilatation (an increase of 45% per year, or 1.5 mm per year in adults), and a family history of aortic dissection.
  • Annual cardiovascular evaluation should be offered and should include clinical history, examination, and echocardiography.
  • In children, serial echocardiography at 6- to 12-month intervals is recommended, with the frequency dependent on the aortic diameter (in relation to body surface area) and rate of aortic dilatation.
  • Prophylactic aortic root surgery should be considered when the aortic diameter at the sinus of Valsalva is over 5 cm.

Cardiovascular surgery can substantially prolong survival. Prophylactic and emergency cardiovascular surgery is needed for treatment of aortic and mitral regurgitation, aortic aneurysm, and aortic dissection. Emergency surgical replacement of the aortic root is indicated for survivors of acute proximal aortic dissection.

Severe scoliosis requires surgery. Bracing has a limited role in treating the most severe form of infantile scoliosis. Surgery should not be performed on a child younger than 4 years, because many patients with large curves before this age spontaneously die of cardiac complications. Results of spinal fusion are better in children older than 5 years.

Other types of surgery include the following:

  • Protrusio acetabuli surgery
  • Pectus excavatum repair
  • Bleb resection and pleurodesis after recurrence of pneumothorax
  • Laser surgery to restore a detached retina


Marfan syndrome (MFS) results from heterozygous mutations in the fibrillin-1 gene (FBN1; OMIM #134797), located on chromosome 15 at band q21.1 (15q21.1), which encodes for the glycoprotein fibrillin. Fibrillin is a major building block of microfibrils, which constitute the structural components of the suspensory ligament of the ocular lens and serve as substrates for elastin in the aorta and other connective tissues. Abnormalities involving microfibrils weaken the aortic wall. Progressive aortic dilatation and eventual aortic dissection occur due to the tension caused by left ventricular ejection impulses. Likewise, deficient fibrillin deposition leads to reduced structural integrity of the lens zonules, ligaments, lung airways, and spinal dura.

Production of abnormal fibrillin-1 monomers from the mutated gene disrupts the multimerization of fibrillin-1 and prevents microfibril formation. This pathogenetic mechanism has been termed dominant-negative because the abnormal fibrillin-1 disrupts microfibril formation (although other fibrillin genes still encode normal fibrillin). Evidence of this mechanism is shown in studies of cultured skin fibroblasts from patients with MFS who produce greatly diminished and abnormal microfibrils.

A study by Benarroch et al suggested that clinical variability in MFS may result from alternative splicing of FBN1. [10]

FBN1 mutations cause several Marfan-like disorders, such as the MASS (myopia, mitral valve prolapse, borderline and nonprogressive aortic enlargement, nonspecific skin and skeletal findings) phenotype and isolated ectopia lentis.

Studies have suggested that abnormalities in the transforming growth factor-beta (TGFβ)-signaling pathway may represent a common pathway for the development of the Marfan phenotype. [11] This gene defect ultimately leads to decreased and disordered incorporation of fibrillin into the connective tissue matrix.

The identification of mutations in TGFβR2 in patients with MFS type 2 (MFS2 mapped at 3p24.2-p25) provided direct evidence of abnormal TGFβ signaling in the pathogenesis of MFS.

Abnormalities in TGFβR1 and TGFβR2 were also reported to cause a new dominant syndrome similar to MFS1; it was associated with aortic aneurysm and congenital anomalies, including Loeys-Dietz syndrome (LDS). LDS is an autosomal dominant aortic aneurysm syndrome with widespread systemic involvement (LDS; OMIM #609192). [11] These results define a new group of Marfan syndrome–related connective tissue disorders, namely, TGFβ signalopathies, and include LDS1 and LDS2 (TGFβR1 and TGFβR2) and the SMAD3 and TGFβ2 disorders, with the latter two being classified as Loeys-Dietz-like (or as LDS3 and LDS4).

Shprintzen-Goldberg syndrome (SGS) has been found to be caused by a pathogenic variant in the SKI gene, which encodes a negative regulator of TGFβ signaling. There is phenotypic overlap with MFS and LDS. 

A variant of the fibrillin-2 gene, FBN2, causes congenital contractural arachnodactyly, known as Beals syndrome. [12]




United States

MFS is one of the most common single-gene malformation syndromes. MFS1 affects about 1:5000 to 1:10,000 individuals. [13, 7]  Estimates suggest that at least 200,000 people in the United States have MFS or a related connective-tissue disorder.

A study by Behr et al found that in patients presenting with a chief complaint of pectus deformity, the incidence of MFS was 5.3%, with the incidence being 20% in persons with combined type pectus deformity. [14]


No geographic predilection is known. 


Cardiovascular disease (aortic dilatation and dissection) is the major cause of morbidity and mortality in MFS. Without proper medical management, MFS can be lethal in young adulthood, with death occurring at an average age of 30-40 years.

Infant morbidity, as related to cardiovascular disease, is due to progression of mitral valve prolapse to mitral regurgitation and often occurs in conjunction with tricuspid prolapse and regurgitation. Progression to congestive heart failure is a leading cause of cardiovascular morbidity and mortality, as well as the leading indicator for cardiovascular surgery.

Death later in life is usually due to chronic aortic regurgitation and ascending aortic dissection. Dissection generally occurs at the aortic root and is uncommon in childhood and adolescence.

A Norwegian study, by Vanem et al, found that out of 84 adults with Marfan syndrome (MFS) first investigated in 2003-2004, 16 (19.0%) were deceased by 2014-2015 follow-up, including 11 (68.8%) who had died of cardiovascular causes. Standardized mortality ratios were 8.20 for men and 3.85 for women. [15]

A study by Reis et al of patients with Marfan syndrome (MFS) found that those who had an aortic root diameter of 45 mm or more at the time of diagnosis had a significantly worse survival rate over the study’s mean 12.4-year follow-up period. [16]


Marfan syndrome is panethnic.


No sex predilection is known.


MFS may be diagnosed prenatally, at birth, in childhood, during adolescence, or in adulthood. Neonatal presentation is associated with a severe clinical course.

Many clinical features are specific to age. Some features may not present until later in life, a situation that may make early diagnosis in childhood difficult.