Marfan syndrome

Marfan syndrome is an inherited connective tissue disorder that is transmitted as an autosomal dominant trait (Only one of the two genes to be defective for disease onset. In other words, one affected parent is sufficient to pass on the disorder to the child). Connective tissue, one of the four tissue types, is found throughout various body systems. It has two fold functions (1) as cementing material that provides a framework for tissue assembly and (2) as a lubricant in bone joints. Being a connective tissue disorder, Marfan syndrome affects almost all of the body’s systems, including the skeletal, cardiovascular, nervous, skin, and pulmonary systems. 

Marfan syndrome involves a defect in a single copy of a gene called fibrillin-1 (FBN1) located on chromosome 15 (King, 2010).  This defect is autosomal, as opposed to resulting from the two sex-determining chromosomes (X or Y).  Three-quarters of the patients with this condition have an affected parent (family history), with the remaining quarter representing a newly acquired genetic mutation (de novo – of unknown origin).  It is among the most common single-gene malformations in the realm of medicine, with the single "hit" affecting the glycoprotein fibrillin-1.  This particular glycoprotein is integral for the formation of tissues within the periosteum (a fibrous sheath that encases the bones), aorta (the major blood vessel that exits the heart to distribute blood to the rest of the body), tendons (structures that connect muscles to the bones), muscles, and the supporting structures that hold the lens in place on the eye (Andreoli, 2001, King, 2010).  Fibrillin-1 is also a primary building block for formation of suspensory ligaments of the ocular lens (Chen, 2010).  Abnormalities in the fibrillin and elastin result in the aortic dissection and dislocation of the lens of the eye, two of the key features seen in Marfan syndrome patients.

Recently, there has been evidence that transforming growth factor beta (TGF-β)-signaling pathways and receptors are also implicated in the development of Marfan syndrome (Chen, 2010).  This family of proteins is involved in the process of blood cell formation, as well as the development of heart, kidneys, bones, liver, gastrointestinal tract, and blood vessels (Kalluri, 2008).  They are also integral to normal tissue development and maintenance within the adult.  Two members of the TGF-β protein family, TGFBR1 and TGFBR2, have been reported to cause Loeys-Dietz aortic aneurysm syndrome which is very similar to Marfan syndrome.  Another mechanism that is closely tied to the TGF-β pathway involves angiotensin II, a powerful vasoconstrictor (chemical that causes the arterioles to become narrower, thus increasing the blood pressure) (Chen, 2010). 

A second syndrome closely related to Marfan syndrome is referred to as the MASS phenotype (mitral valve prolapse, aortic dilation, skin and skeletal findings); this particular Marfan-like syndrome also results from mutation of the fibrillin-1 gene (Chen, 2010).


The prevalence of Marfan syndrome in the United States ranges from 10 to 30 per 100,000 populations (Chen, 2010). Many of the subtle forms of this condition result in misdiagnosis for some other similar disorder.  Therefore, the incidence rates stated above may be skewed, with many cases remaining undiagnosed.  There does not appear to be a racial or gender predilection with this condition.  The prognosis for patients with Marfan syndrome generally includes reduction of the lifespan to approximately 32 years of age, primarily as a result of aortic dissection, rupture or cardiac failure (Kodolitsch and Rybczynski, 2004). Regular follow-up visits to the family physician are highly recommended to monitor and prevent the condition from getting worse (Crawford, 2006). The regularity of the visits depends on the severity of the condition and associated complication. Precise statistics for the incidence of Marfan syndrome in India are not readily available.


The diagnosis of Marfan syndrome is made based on a combination of family/genetic factors and physical features in the patient (Chen, 2010).  A positive family history, as evidenced by a first-order family member with Marfan syndrome, is considered to be a major criterion for diagnosis, as is detection of the fibrillin-1 mutation via genetic testing.  The Ghent criteria, established in 1996, emphasizes genetic and family history, in addition to the obvious musculoskeletal findings that are prevalent in patients with this condition. 

Most patients with Marfan syndrome have very tall slender body statures with extremities that are very long and disproportionate to the trunk (Andreoli, 2001).  There is typically a pronounced degree of scoliosis within the thoracic spine, with a curvature commonly exceeding 20-degrees (Chen, 2010).  The rib cage is commonly concave in appearance (termed pectus excavatum).  The fingers and toes of a Marfan patient are characteristically long and spindly, resembling the legs of a spider and giving rise to the moniker arachnodactyly (spider-fingers).  The fingers can be wrapped completely around the opposing wrist, frequently overlapping (positive Walker's sign) and when enclosed within the clenched fist, the thumb protrudes beyond the ulnar border (positive Steinberg sign).  Additionally, the inner bony prominence of the ankle is commonly displaced inward and the arch of the foot is severely blunted, a finding referred to as pes planus.

Due to the systemic nature of this condition, and the importance of fibrillin and elastin in normal tissue development, most of the body's systems are affected.  The heart is commonly involved, with the ascending aorta developing aneurysms (weakening and bulging of the blood vessel) and leaving the patient prone to spontaneous dissection (tearing of the inner layer of the aortic vessel wall; the number one cause of death in such patients). Other cardiac findings include aortic valvular insufficiency (leakage of the aortic valve due to failure of the leaflets to come together during diastole) and mitral valve prolapse, where the mitral valve leaflets protrude backward into the left atrium during systole (Otto, 2007). The tall, thin body structure, as well as weak spots within the adhering tissues of the lungs (blebs) renders these patients prone to spontaneous collapse of the lungs (pneumothorax). Ocular derangements can include ectopia lentis, in which the lens becomes dislocated (Chen, 2010).  Stretch marks or striations, similar to those noted in persons who have had radical changes in weight, following pregnancy, or with adrenal insufficiency conditions, are another common, albeit nonspecific, feature in patients with Marfan syndrome.

There has been a recent proposal to revise the Ghent criteria in diagnosing Marfan syndrome (Loeys, 2010).  This new methodology involves placing more emphasis on the two primary findings associated with this condition:  aortic root dilation and ectopia lentis.  This revision also assigns a more prominent role to molecular genetic testing of fibrillin-1 and other relevant genes, such as TGFBR1 and TGFBR2.  The other, less specific, manifestations noted above are viewed as less influential in making a diagnosis of Marfan syndrome, although the presence of enough of them should aid in such conclusions.  The revised Ghent criteria for Marfan syndrome include:

1.    The combined presence of aortic root dilatation or dissection and ectopia lentis is considered to be unequivocal manifestations for diagnosis of Marfan syndrome.

2.    The presence of aortic root dilatation or dissection and the identification of a valid mutation in the fibrillin-1 gene are also considered to be sufficient to make the diagnosis of this condition, even in the absence of ectopia lentis.

3.    The presence of aortic root dilatation or dissection with a fibrillin-1 genetic mutation status that is either unknown or negative, as well as the absence of ectopia lentis, could lead to the diagnosis of Marfan syndrome if there are several of the less specific findings, such as dural ectasia, pneumothorax, wrist and thumb signs, and skin striations.

4.    If ectopia lentis is noted, but aortic root dilatation or dissection is absent, then there must be conclusive identification of the fibrillin-1 genetic mutation in order to make the diagnosis of this condition.

Evaluation of patients with Marfan syndrome commonly involves various imaging studies. Echocardiography allows for documentation of the cardiac features, as well as a means to provide serial evaluation of potential changes in aortic root diameter or other complications that tend to dramatically shorten the lifespan of such patients (Habermann, 2008).Computed tomography or magnetic resonance imaging can also be used to evaluate the integrity and measurements of the ascending aorta, as well as dural ectasia (an enlargement of the dural sac and spinal canal with associated herniation of the nerve roots at the base of the spine) (Chen, 2010).

Clinical Management:

Treatment of patients with Marfan syndrome primarily revolves around minimizing the potential complications.  Patients should be educated on lifestyle modifications and pregnancy risks, with counseling about the elevated risk of aortic root dilatation associated with pregnancy, as well as the enhanced risk of transmitting this condition to their offspring.  Restrictions in activities should include avoiding potentially dangerous activities such as competitive and contact sports due to the inherent aortic wall weaknesses and dilation, ocular anomalies, and skeletal complications.  Avoidance of rapid decompressions from such activities as quickly ascending elevators, scuba diving, or flying in unpressurized aircraft are helpful in reducing the risk of spontaneous pneumothorax.  Due to the substantial increases in systolic blood pressures associated with isometric activities, patients should be advised to abstain from weightlifting, gymnastics, climbing steep inclines, and performing calisthenics, such as push-ups and pull-ups.  They should be encouraged to engage in nonstrenuous activities, such as golfing, walking, and fishing, which might prove to be both physically and emotionally beneficial to the patient.

Beta-blockers have become the standard of care in patients with Marfan syndrome in order to reduce the tension against the aortic wall, thus delaying aortic expansion and progression to rupture or dissection (Chen, 2010).  This class of medication also has the added benefit of inhibiting the rises in heart rate and contractile force of the heart that accompany drops in blood pressure from other vasodilating medications.  This group of medications has led to a substantial reduction in the incidence for surgical replacement of the dilated aortic segments over the past decade.  Because of the connection of the angiotensin II pathway to Marfan syndrome, another potentially beneficial class of medications that can be used to decrease the tension against the aortic walls, thus slowing the progression of dilation and dissection, are angiotensin-converting enzyme (ACE) inhibitors (Kalluri, 2008).  Patients with Marfan syndrome should be advised to take prophylactic antibiotics prior to procedures such as dental cleanings and surgeries to avoid infections within the inner linings of the heart and aorta.  Surgical therapies include resection and replacement of the dilated segments of the aorta (typically when the diameter exceeds 50 mm) and refractive surgery for myopia (Chen, 2010).  Orthotics may be useful for patients with excessively flattened feet.  Ayurvedic medical systems offer alternative treatment options to manage the skeletal, cardiac, and nervous system disorders encountered by Marfan syndrome patients. 

Marfan syndrome is named after the French pediatrician Antonin Bernard Marfan, who first summarized the symptoms in 1892. 

Worldwide, there are many support groups for individuals with Marfan syndrome.  Patients and their families should be encouraged to seek guidance, counseling, and emotional comfort by meeting with others afflicted with this condition.  Within India, one such member of the International Federation of Marfan Syndrome ( Organization is located in the state of Assam.

Contact: Mr. Chirarnjib Nath

South Hazarapar, Tezpur, 784001

Assam, India.

References and further readings:

Andreoli, T. E., Carpenter, C. C. J., Griggs, R. C., & Loscalzo, J. (2001).  Cecil Essentials of Medicine, 5th ed.  W. B. Saunders, Philadelphia, et al.

Cañadas V, Vilacosta I, Bruna I, Fuster V. Marfan syndrome. Part 1: pathophysiology and diagnosis. Nat Rev Cardiol. 2010;7:256-65

Chen, H. (2010).  "Marfan Syndrome" accessed on August 20, 2010 from

Crawford, M.H., Srivathson, K., & McGlothlin, D.P. (2006).  Current Consult Cardiology.  Lange Medical Books / McGraw-Hill, New York, et al.

Gonzales EA. Marfan syndrome. J Am Acad Nurse Pract. 2009;21:663-70.

Habermann, T. M. & Ghosh, A. K. (2008).  Mayo Clinic Internal Medicine:  Concise Textbook.  Mayo Foundation for Medical Education and Research, Rochester, MN.

Kalluri R, Han Y. Targeting TGF-beta and the extracellular matrix in Marfan's syndrome. Dev Cell. 2008;15:1-2.

King, M.W. (2010).  “Marfan Syndrome”  accessed on October 01, 2010 from

Kodolitsch YV and Rybczynski M (2004), Cardiovascular Aspects of the Marfan Syndrome—A Systematic Review. In: Marfan Syndrome: A Primer for Clinicians and Scientists. Edited by: Robinson P and Godfrey M, Landes Bioscience, Austin, TX, USA. ISBN: 978-0-306-48238-0

Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, Hilhorst-Hofstee Y, Jondeau G, Faivre L, Milewicz DM, Pyeritz RE, Sponseller PD, Wordsworth P, De Paepe AM. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010;47:476-85.

Otto, C. M. (2007).  The Practice of Clinical Echocardiography, 3rd ed.  Saunders / Elsevier, Philadelphia.

Contributors: Sean Marcus Hancock, RDCS (AE), RCS, RCSA, RCIS

Staff Cardiovascular Technician and Clinical Educator

Naval Hospital Bremerton, Washington


Pochi R. Subbarayan PhD

University of Miami

December 2010