Marfan Syndrome (MFS)

Updated: Aug 24, 2022
  • Author: Prashanth Inna, MBBS, MS, DNB; Chief Editor: Jeffrey D Thomson, MD  more...
  • Print

Practice Essentials

Marfan syndrome (MFS) is a spectrum of disorders caused by a heritable genetic defect of connective tissue that has an autosomal dominant mode of transmission. [1, 2, 3, 4]  The defect itself has been isolated to the FBN1 gene on chromosome 15, which codes for the connective tissue protein fibrillin. [1, 5, 6]  Abnormalities in this protein cause a myriad of distinct clinical problems, of which the musculoskeletal, cardiac, and ocular system problems predominate. [2, 7, 8]

The most severe of these clinical problems include aortic root dilatation and dissection, which have historically been the causative factors in early patient demise. [9]  Skeletal deformities such as thoracolumbar scoliosis, thoracic lordosis, and pectus excavatum, may lead to pulmonary difficulties that include restrictive airway disease and cor pulmonale if the deformities are progressive and untreated. Finally, blindness may result from unrecognized and untreated glaucomaretinal detachment, and cataracts.

The skeleton of patients with MFS typically displays multiple deformities including arachnodactyly (ie, abnormally long and thin digits), dolichostenomelia (ie, long limbs relative to trunk length), pectus deformities (ie, pectus excavatum and pectus carinatum), and thoracolumbar scoliosis. [10, 11]

In the cardiovascular system, aortic dilatation, aortic regurgitation, and aneurysms  [12]  are the most worrisome clinical findings. [1, 3, 4] Mitral valve prolapse that requires valve replacement can occur as well. Ocular findings include myopiacataractsretinal detachment, and superior dislocation of the lens. [13]

Given the variable expressivity of MFS, no single sign is pathognomic; the diagnosis is made on clinical grounds on the basis of typical abnormalities. In one study, the physical examination features with the highest diagnostic yield were as follows [14] :

  • Craniofacial characteristics
  • Thumb and wrist signs
  • Pectus carinatum
  • Severe hindfoot valgus

No specific laboratory test exists with which to make the diagnosis of MFS; however, molecular genetic testing can facilitate diagnosis of MFS in certain clinical situations. Skeletal abnormalities are assessed with radiography, computed tomography (CT), and magnetic resonance imaging (MRI). Ocular abnormalities are assessed with ultrasonography (US), slit-lamp examination, and keratometry. Cardiovascular abnormalities are assessed with electrocardiography (ECG), echocardiography, MRI, and magnetic resonance angiography (MRA).

No specific surgical procedure cures MFS; rather, specific medical and surgical interventions may ameliorate certain aspects of the syndrome. 

The majority of medical therapy as it relates to MFS has been targeted at preventing cardiovascular compromise, [9, 15, 16]  with beta blockers and afterload-reducing agents used to reduce stress on the aortic and mitral valves and the aortic root. [17]  

Mitral valve regurgitation may become so severe that medical therapy must be replaced with surgical intervention. Mitral valve repair is undertaken if possible, to delay eventual mitral valve replacement. The ascending aorta (aortic root) or the incompetent aortic valve may also require repair.

Scoliosis is the most common major skeletal deformity encountered in patients with MFS that necessitates intervention, but no specific medicinal intervention exists to treat it. Nonoperative treatments (eg, bracing) are usually unsuccessful. The major indication for surgery for the musculoskeletal system involves progression of moderate-to-severe scoliosis. Posterior spinal fusion and segmental spinal instrumentation, along with autogenous bone grafting, are the mainstay of treatment. 


Pathophysiology and Etiology

Over many years, several investigators have studied various molecules found in the extracellular matrix in attempts to elucidate the cause of MFS. [18, 16] These molecules have included collagen, elastin, hyaluronic acid, and fibrillin. Sakai et al identified fibrillin, a 350-kd protein, by using monoclonal antibodies raised against myofibrils. [19] Immunofluorescence studies were then used to compare the reactivity in both healthy subjects and those with MFS. During this period, similar technology was used to construct a genetic exclusion map that led to the localization of the defect to chromosome 15 (bands q15-q23).

Several point mutations have been identified in the fibrillin gene, most of which affect cysteine residues within the microfibril. Thus, these mutations are thought to cause defective fibrillin to be produced. Fibrillin's structure and function are altered by abnormal protein folding due to the alteration of bonding between cysteine residues, which in turn causes defective microfibril production.

Mutations in the FBN1 locus of the fibrillin gene on chromosome 15 have been linked to MFS and other distinct clinical entities with similar findings.



The estimated incidence of MFS ranges from 1 in 5000 to 2-3 in 10,000 persons. [1] The mutation in the fibrillin gene causes pleiotropic effects; thus, a wide range of phenotypic features is derived from a single gene mutation. Several other diseases have presentations similar to MFS, making it exceedingly difficult to determine the exact incidence.



Advances in the management of the cardiovascular manifestations of MFS have led to a significant decrease in the morbidity and mortality that are associated with this condition. Before the advent of pharmacologic and surgical therapy for aortic root and valvular disease, the life expectancy for patients with MFS was about two thirds that of the healthy population. Aortic dissection and congestive heart failure due to aortic and mitral valvular anomalies accounted for over 90% of the known causes of death.

Patient longevity now approaches that of persons without MFS, though cardiovascular compromise is still the most common cause of patient death, likely due to sudden death in the previously undiagnosed patient and a new diagnosis in those whose disease process has progressed beyond the scope of medical or surgical cure.