OVERVIEW: What every practitioner needs to know

Are you sure your patient has Marfan syndrome? What are the typical findings for this disease?

The diagnosis of Marfan syndrome is made according to guidelines established by the 2010 Revised Ghent Nosology.

The most important features of Marfan syndrome (the cardinal features) are aortic root dilation or dissection, dislocation of the ocular lenses, and a postive family history for Marfan syndrome. In the presence of one of the cardinal features but the absence of the other two, the diagnosis of Marfan syndrome may be made if a systemic score of 7 or more is established.

Systemic score for Marfan syndrome

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Points are allocated for various systemic findings, which include the wrist and thumb signs (3 points), wrist or thumb sign (1 point), pectus carinatum (2 points), pectus excavatum or asymmetric chest wall (1 point), hindfoot deformity (2 points), pes planus (1 point), pneumothorax, dural ectasia, or protusio acetabulo (2 points each), reduced upper-lower segment ratio, and increased arm span-height ratio (1 point), and 1 point each for the following: scoliosis or thoracolumbar kyphosis, reduced elbow extension, three of five facial features, skin striae, mitral valve prolapse, and myopia.

Facial features

Facial features include dolichocephaly, enophthalmos, down-slanting palpebral fissures, retrognathia, malar hypoplasia.

What other disease/condition shares some of these symptoms?

In patients younger than 20 years of age, the differential diagnosis includes a nonspecific connective tissue disorder and potential Marfan syndrome, if a FBN1 mutation has been established in a first-degree relative but the aortic root size remains less than a
z score of 3.

In patients older than 20 years, the differential diagnosis includes ectopia lentis syndrome, mitral valve prolapse syndrome, and MASS phenotype (mitral, aortic, skin and skeleton). There are also a number of familial aneurysm syndromes that may be considered in the presence of aortic aneurysm if the diagnostic criteria for Marfan syndrome are not fulfilled.

Loeys-Dietz syndrome (LDS) shares features with Marfan syndrome, including aneurysms of the ascending aorta, craniofacial features (downward slanting palpebral fissues, high-arched palate, malar hypoplasia, retrognathia, and/or micrognathia), scoliosis, arachnodactyly, and dural ectasia. Features seen in LDS that are not typically seen in Marfan syndrome include ocular hypertelorism, bifid uvula, Chiari malformation, craniosynostosis, generalized arterial tortuosity, and aneurysms, with dissection throughout the arterial tree (not limited to the aorta).

Shprintzen-Goldberg syndrome manifests with skeletal features similar to those seen in Marfan syndrome, but with additional features not seen in Marfan syndrome, including craniofacial features such as ocular hypertelorism and craniosynostosis, as well as cognitive impairment.

Other connective tissue disorders, including Ehlers-Danlos syndrome, Stickler syndrome, congenital contractural arachnodactyly, homocystinuria, and the fragile X syndrome demonstrate musculoskeletal features that overlap with those seen in Marfan syndrome.

What caused this disease to develop at this time?

Marfan syndrome is a hereditary disorder of connective tissue caused by mutations in the fibrillin-1 (FBN1) gene. It is inherited in an autosomal dominant manner, meaning that the presence of a single disease-causing FBN1 mutation in a an individual’s genome is sufficient to cause the Marfan syndrome.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Echocardiography: The presence of aortic root dilation with a
z score of more than 3 is one of the cardinal features of Marfan syndrome.

Ophthalmic evaluation: The presence of ectopia lentis is one of the cardinal features of Marfan syndrome.

DNA analysis of the FBN1 gene. The presence of a causal
FBN mutation is a cardinal feature of Marfan syndrome. Consultation with a medical geneticist familiar with the diagnosis of Marfan syndrome is encouraged to interpret results of FBN1 gene sequencing.

Would imaging studies be helpful? If so, which ones?

Echocardiography to look for aortic root dilation

Hip radiography to look for protrusio acetabuli

Magnetic resonance imaging of the lumbar spine to look for dural ectasia

If you are able to confirm that the patient has Marfan syndrome, what treatment should be initiated?

Cardiovascular management: This consists of aggressive blood pressure control and routine imaging of the ascending aorta, with consideration of prophylactic aortic root replacement if the diameter exceeds 4.5 cm at the sinuses of Valsalva. Beta-blockade has long been the standard for blood pressure management. As of 2011, ongoing studies are looking at the efficacy of angiotensin II blockade by losartan in preventing and stabilizing aortic root dilation.

Ocular management: Slit-lamp examination should be performed with the pupil maximally dilated to look for lens subluxation. Monitor for development of ectopia lentis, amblyopia, and glaucoma. Educate the patient about signs of retinal detachment. Rarely, ocular lens removal may be necessary if the lens is dislocated and obstructing the field of vision. Affected children are at risk of amblyopia; aggressive refraction and visual correction is essential.

Orthopedic management: Monitor for progressive scoliosis, bracing for scoliosis between 20 and 40 degrees, and consideration of surgery if the scoliosis is greater than 40-50 degrees because of pulmonary implications of severe scoliosis. Severe pectus excavatum may require surgical intervention. Arch supports for pes planus may improve foot pain, but children may also find them irritating; use should be left to individual preference unless the ankle pronation is severe. Musculoskeletal pain may be related to muscle spasm and/or myofascial pain related to joint hypermobility. Interventions aimed at muscle relaxation and toning/strengthening muscles around lax joints may be helpful.

Whenever possible, patients with Marfan syndrome should be managed by a multidisciplinary team familiar with the diagnosis and treatment of this disorder. Ideally, this team will include a geneticist, cardiologist, ophthalmologist, orthopedist, and cardiovascular surgeon.

What are the adverse effects associated with each treatment option?

Some patients are unable to tolerate aggressive management of blood pressure. Patients with asthma or chronic obstructive pulmonary disease may not tolerate beta-blockade.

What are the possible outcomes of this disease?

In the absence of a diagnosis and diligent screening and management, persons with Marfan syndrome have an average life expectancy of 40-45 years. However, with appropriate screening for aortic dilation and prophylactic surgery, the life expectancy of affected persons approaches that of the general public.

Continued monitoring of the thoracic and abdominal aorta is warranted because distal aneurysms may develop after an aneurysm of the aortic root has been surgically corrected.

What causes this disease and how frequent is it?

Marfan syndrome affects approximately 1 in every 5000 individuals. Men and women are affected equally. Persons of all races and ethnic groups may be affected.

Marfan syndrome is caused by mutations in the gene encoding fibrillin-1 (FBN1). Approximately 75% of affected persons inherit the condition from an affected parent, but 25% have a new mutation, meaning they are the first affected person in their family.

How do these pathogens/genes/exposures cause the disease?

Mutations in FBN1 cause Marfan syndrome by interfering with the integrity of fibrillin in the connective tissue and disrupting the transforming growth factor-β (TGF-β) signaling pathway.

What complications might you expect from the disease or treatment of the disease?

Aortic dissection or rupture is the most important and life-threatening complication of Marfan syndrome. In young children, valvular dysfunction leading to congestive heart failure is the leading indication for cardiovascular surgery. Dilation of the pulmonary artery is also observed.

Prophylactic replacement of the aortic root has long been accomplished by replacement of the aortic valve and the aortic root, traditionally with a composite graft. Persons who have gone through this surgery must be treated with warfarin for life. The advent of valve-sparing surgery to replace the aortic root without replacing the aortic valve so that anticoagulation is not necessary has been a welcome addition to the therapeutic armamentarium.

Dural ectasia, or enlargement of the dural sac, usually in the lumbar region, may lead to bone erosion and nerve entrapment, both of which can cause significant pain.

Dislocation of the ocular lens is seen in approximately 60% of affected persons.

Are additional laboratory studies available; even some that are not widely available?

Laboratories testing for mutations in the FBN1 gene may be found at genetests.org.

How can this disease be prevented?

Children of affected persons are at 50% risk of inheriting the condition. If the disease-causing FBN1 mutation is known, prenatal or preimplantation diagnosis may be offered to the family.

What is the evidence?

Brook, BS, Habashi, JP, Judge, DP. “Antiotensin II blockade and aortic root dilation in Marfan's syndrome”. N Engl J Med. vol. 358. 2008. pp. 2787-95. (Discusses the rationale for angiotensin II blockage and the TGF-β pathway in Marfan syndrome.)

Dietz, HC. “Marfan Syndrome”. In at GeneTests: Medical Genetics Information Resource (database online). 1997-2011. (GeneReviews provides structured, updated, authoritative information about genetic disorders.)

Dietz, HC, Pyeritz, RE, Scriver, CR, Beaudet, AL, Sly, WS. “Marfan syndrome and related disorders”. 2000.

Loeys, BL, Dietz, HC, Braverman, AC. “The revised Ghent nosology for the Marfan syndrome”. J Med Genet. vol. 47. 2010. pp. 476-85. (This paper outlines the criteria for the diagnosis of Marfan syndrome according to the most recent guidelines.)

Milewicz, DM, Dietz, HC, Miller, CD. “The management of aortic disease in patient with Marfan syndrome”. Circulation. vol. 111. 2005. pp. e150-7. (Summarizes recommendations on cardiovascular management from experts on the Professional Advisory Board of the National Marfan Foundation.)