SECTION X - MARFAN SYNDROME

Part I - Background Information

Definition

Marfan syndrome is an autosomal dominantly inherited disorder of connective tissue in which cardiovascular, skeletal, ocular, and other abnormalities may be present to a highly variable degree. Prevalence has been estimated to be 1 in 3000-5000.

 
Part II - Prevalence and Genetics

New mutations account for 25-30% of cases. The clinical features are the result of a weakening of the supporting tissues, due to defects in fibrillin-1, a glycoprotein and a principal component of the extracellular matrix microfibril. The gene for fibrillin-1 (FBN1) is located on chromosome 15. More than 200 mutations in FBN1 have been described. The phenotype presents to a highly variable degree due to varying genotype expression (136-138).

 
Part III - History and Management of Unoperated Patients

Prognosis of patients with Marfan syndrome is mainly determined by aortic root abnormalities, which predispose to progressive dilation and dissection, and lead to aortic regurgitation. The mean survival of untreated patients is 40 years, but the variance is large. Not only the aortic root, but also other parts of the aorta and "elastic" arteries may be dilated and may dissect or rupture, but much less commonly. Patients with a dilated aorta are usually asymptomatic. The presence of aortic regurgitation or mitral valve prolapse with regurgitation may lead to signs or symptoms of left ventricular volume overload.

Both medical and surgical therapies have improved life expectancy substantially, from a mean survival of 40 years in 1972 (139) to approximately 60 years in 1993 (140). The risk of type A dissection clearly increases with increasing aortic root diameter. Nonetheless, patients with no or only mild aortic dilation occasionally dissect. A beneficial effect of ß-adrenergic blockade has been shown in slowing the rate of aortic dilation and reducing the risk of dissection (141,142).

To reduce aortic and arterial stress, the following is recommended: [1] the use of beta-blockade; [2] the avoidance of maximal and isometric exertion, and contact sports.
Grade: C	Level: V	Refs: 141,142

 
Part IV - Diagnostic Work-up

An adequate diagnostic workup:

• Documents the basis for the diagnosis of Marfan syndrome, using the "Ghent criteria" (143) (see Table 1).
• Determines the diameter and searches for dissection of the aortic root and all other parts of the aorta.
• Determines if aortic regurgitation is present.
• Determines the presence of mitral valve prolapse, mitral regurgitation, calcification of the mitral annulus, presence of tricuspid valve prolapse, tricuspid regurgitation, and the diameter of the main pulmonary artery.

Accuracy of diagnosis is critical, and requires a rigorous approach. To this point, the diagnosis of Marfan syndrome is made on clinical grounds. Because of the variability in clinical expression, a multidisciplinary evaluation in a centre for Marfan screening is recommended for a complete evaluation of a patient and for screening of the patient's relatives for Marfan syndrome.

A definite diagnosis requires occurrence of major manifestations in two different categories and involvement (presence of criteria) of a third category (see table 1).
Grade: Consensus		Ref: 143

When the diagnosis of Marfan syndrome has been established the diagnostic workup should include at a minimum:

• A thorough clinical assessment.
• ECG.
• Chest x-ray.
• Echo-Doppler evaluation especially for measurements of the ascending aorta and degree of mitral regurgitation.
• MRI for measurements of the entire aorta and its branches and for lumbosacral dural ectasia, or abdominal ultrasound for the abdominal aorta; or CT scanning for any of the above.

A diagnostic workup may require:

• Coronary arteriography in patients over the age of 40 years (or younger if there are severe risk factors for coronary artery disease) in whom surgery is being planned.
• Transesophageal echocardiography if aortic dissection is suspected.

Table 1. Diagnostic Criteria for Marfan Syndrome

Criteria	Major	Minor
Family history	independent diagnosis in parent, child, sibling	none
Genetics	mutation FBN1	none
Cardiovascular	aortic root dilation dissection of ascending aorta	mitral valve prolapse calcification of the mitral valve(< 40 yrs.) dilation pulmonary artery dilation/dissection of descending aorta
Ocular	ectopia lentis	(2 needed): flat cornea myopia elongated globe
Skeletal (144)	(4 needed): pectus excavatum needing surgery pectus carinatum pes planus wrist and thumb sign scoliosis > 20 º or spondylolisthesis arm span-height ratio > 1.05 protrusio acetabulae (xray, MRI) diminished extension elbows (< 170 º)	(2-3 major, or 1 major and 2 minor signs): flat cornea moderate pectus excavatum high narrowly arched palate typical facies joint hypermobility
Skeletal (144)	(4 needed): pectus excavatum needing surgery pectus carinatum pes planus wrist and thumb sign scoliosis > 20 º or spondylolisthesis arm span-height ratio > 1.05 protrusio acetabulae (xray, MRI) diminished extension elbows (< 170 º)	(2-3 major, or 1 major and 2 minor signs): flat cornea moderate pectus excavatum high narrowly arched palate typical facies joint hypermobility
Pulmonary		spontaneous pneumothorax apical bulla
Skin		unexplained stretch marks (striae) recurrent or incisional herniae
Central nervous system (144,145)	lumbosacral dural ectasia (CT or MRI)

 
Part V - Indications for Intervention

The following situations warrant surgical intervention: A maximal aortic root diameter > 55 mm. A maximal aortic root > 50 mm in patients with a family history of dissection, rapid aortic root growth > 2 mm per year or severe aortic and/or mitral valve regurgitation that requires surgery. Maximal aortic root diameter of > 45-50 mm if the surgeon believes the aortic valve can be spared (a more aggressive view, especially if an aortic valve-sparing procedure is planned). A maximum aortic root dimension > 44 mm if pregnancy is desired. Progressive dilation or a diameter of approximately 50 mm of other parts of the aorta. Severe mitral regurgitation associated with symptoms or progressive LV dilation/dysfunction.
Grade: C	Level: IV	Refs: 146-150

 
Part VI - Surgical Options

For aortic root replacement the surgical options include: [1] a composite graft repair (modified Bentall procedure - using a mechanical, bioprosthetic, or homograft aortic valve prosthesis) (146); [2] an aortic valve-sparing procedure (150). If necessary, all other parts of the aorta can be replaced. Surgery should be performed in a centre and by surgeons with substantial experience with these types of surgery.

 
Part VII- Surgical Outcomes

Five and 10 year survival after aortic root replacement is 80% and 60% respectively (148). This relatively poor outlook is mainly caused by the necessity for re-operation of the aorta because of the presence of pre-existing type 1 dissection, or development of new dilation or dissection of other parts of the aorta. A recent study reports a high survival rate at 5 years for selected Marfan patients who had aortic-valve sparing surgery (150). Longer term data is not yet available.

 
Part VIII - Arrhythmias

These are not a feature of Marfan syndrome itself. They may occur as a consequence of mitral regurgitation, myocardial ischemia/infarction due to dissection, or ventricular dysfunction.

 
Part IX - Pregnancy

For women with Marfan syndrome, pregnancy presents a two-fold problem: [1] the genetic problem (a 50% chance that the child will be affected), and [2], an increased (but unquantified) risk of aortic dissection during pregnancy and for up to 6 months post-partum.

Women with an aortic diameter above 44 mm should be strongly discouraged from becoming pregnant without repair. An aortic diameter below 40 mm rarely presents a problem, although a completely safe diameter does not exist.
Grade: C	Level: V	Refs: 151,152

 
Part X - Follow Up

Whenever possible, Marfan patients should be under the care of professionals with specific training/experience in Marfan syndrome. Ideally, this should be through a multidisciplinary clinic. All patients with Marfan syndrome should be advised to take beta-adrenergic blocking agents, and to remain on them unless intolerable side effects preclude their use. This is especially true, usually in association with other BP lowering agents, if dissection has occurred. During follow-up the aortic root and the entire aorta should be regularly evaluated with echocardiography, MRI, CT and/or abdominal ultrasound examinations. This is particularly true if a dissection remains and its stability is being monitored. Patients with mitral valve prolapse and moderate mitral regurgitation should also be followed with yearly echocardiography. Endocarditis prophylaxis is recommended for 6 months following aortic root replacement or for life if any residual gradient/lesions persist or in the presence of prosthetic valve or mitral regurgitation.
Grade: Consensus		Refs: 148,150