Marfan's syndrome

Synonyms: Marfan syndrome

What is Marfan's syndrome?

Marfan's syndrome is an inherited connective tissue disorder with characteristic skeletal, dermatological, cardiac, aortic, ocular and dura mater malformations. Although Marfan's syndrome is a severe, chronic and life-threatening disease, most patients with Marfan's syndrome (MFS) who receive optimal medical care now have a near-normal life expectancy.¹

Marfan's syndrome epidemiology²

MFS is caused by a variety of mis-sense mutations in gene encoding for fibrillin 1, an elastin-matrix glycoprotein essential for the formation of cellular microfibrils and regulation of transforming growth factor beta (TGF-ß), dysregulation of which leads to the morphological changes seen in MFS. The gene is located on chromosome 15q21. The pattern of transmission is autosomal dominant with complete penetrance. There are over 1,000 genetic mutations, almost all unique to an affected family. Phenotype varies within and between families with the same genetic abnormality, leading to protean and variable manifestations of the condition in given individuals.³

Prevalence

This is 2-3 per 10,000 of population, affecting both sexes equally. The prevalence is similar worldwide, regardless of geography or ethnicity.⁴ Marfan's syndrome is the most common inherited disorder of connective tissue. Prior to the availability of Marfan's syndrome treatment, life expectancy was severely curtailed: 50% of men died by the age of 40 and 50% of women by the age of 48; the average age of death was 32.⁴ Despite medical advances, the leading cause of death remains cardiovascular disease, primarily progressive aortic root dilation and dissection, which still occurs in about 1 in 10 patients and carries a high mortality.⁵

Marfan's syndrome risk factors

Around two thirds of Marfan's syndrome cases are due to familial transmission. In the remainder there are sporadic mutations, associated with advanced paternal age.

Presentation

Marfan's syndrome diagnosis is usually established using the Ghent criteria, which were revised in 2010. The clinical diagnostic criteria are family history and systemic features, particularly the presence of ectopia lentis and an increased diameter of the aortic root, plus molecular genetic testing.⁴ Basing diagnosis solely on molecular data is not possible, as mutation detection is far from perfect and some mutations of fibrillin do not cause the syndrome.

Marfan's syndrome symptoms

Marfan's syndrome can be asymptomatic. Patients with Marfan's syndrome are disproportionately tall and thin with unusually long arms and legs compared to their trunk (dolichostenomelia) and a 'cadaverous' physique. They often have long 'spidery' fingers and toes (arachnodactyly).

Marfan's syndrome signs

The main clinical features of Marfan's syndrome are:⁴

• Skin - striae, especially thoracolumbar and sacral.

• Cardiovascular - thoracic aortic dilatation/rupture/dissection (usually asymptomatic), aortic regurgitation, mitral valve prolapse, mitral regurgitation, abdominal aortic aneurysm, cardiac dysrhythmia.

• Lungs - pleural rupture causing pneumothorax

• Eyes - lens dislocation, closed-angle glaucoma, high myopia.

• Skeleton - arachnodactyly, hypermobility, arthralgia, joint instability, finger contractures, pectus excavatum or carinatum deformities, misshapen chest, kyphoscoliosis, protrusio acetabuli and hindfoot deformity.

• Nervous system - dural ectasia hernias presenting with low back pain and symptoms akin to cauda equina syndrome or chronic postural headache due to CSF leakage

• Facial characteristics - maxillary/mandibular retrognathia, long face (dolichocephaly) and high, arched palate, enophthalmos, downslanting palpebral fissures and malar hypoplasia.⁶

Arachnodactyly - the following signs may be used to demonstrate this:

• Walker's (wrist) sign - the patient encircles the wrist of their opposite hand with the little finger and thumb, which overlap.

• Steinberg's thumb sign - a flexed thumb grasped within a clenched palm protrudes beyond the ulnar border of that hand.

Investigations⁷

• Echocardiography: repeated annually, with careful monitoring of aortic root width and the function of the heart valves is recommended. Echocardiography is also being used to evaluate the function of the myocardium which is also thought to be affected.⁸
  

• Cardiovascular magnetic resonance (CMR) or computerised tomography (CT): should be performed in every patient, showing the entire aorta. This should be repeated every five years, or annually if there is aneurysmal formation beyond the aortic root.

• Holter monitoring: should be performed in symptomatic patients, as ventricular arrhythmias, conduction disturbances, and sudden cardiac death can occur.

• MRI scanning of the spinal column: consider this if headache/sacral pain is potentially attributable to dural ectasia.⁹

• Pelvic X-ray: this may demonstrate protrusion of the acetabulum into the pelvic cavity (protrusio acetabula). It is present in about 50% of cases.

Marfan's syndrome differential diagnosis^{10 11}

• Ehlers-Danlos syndrome.

• Fragile X syndrome.

• Gigantism and acromegaly.

• Hyperpituitarism.

• Hyperthyroidism.

• Klinefelter's syndrome.

• Homocystinuria.

• Loeys-Dietz aortic aneurysm syndrome.

• Shprintzen-Goldberg syndrome.

• Other causes of arachnodactyly, aortic dissection, ectopic lentis and mitral valve prolapse.

Marfan's syndrome management^{7 12}

Management requires a multidisciplinary team which should include a geneticist, an ophthalmologist, a cardiologist and an orthopaedic surgeon.¹³

Non-drug

• Psychological support may be required in order to help patients cope with the fact that they have a chronic disease which may shorten their life and affect offspring. Many patients also have poor self-esteem and impaired relationships/sex lives due to concerns about their bodily appearance.¹⁴

• The patient should be advised to avoid exertion at maximal capacity, vigorously competitive or contact sports (fatal aortic dissection and rupture in young adults is often due to MFS). Scuba diving, weightlifting, climbing steep inclines and gymnastics should be avoided due to dangers of raised intra-thoracic/intra-aortic pressures.

Drugs

Prophylactic beta-blockers are used to reduce mean arterial pressure and pulse rate significantly.¹⁵ Studies have suggested that introducing them at an early age under the supervision of a paediatrician or cardiologist lowers the risk of aortic rupture and slowed aortic root dilatation. However, two meta-analyses have found conflicting results regarding the value of long-term beta-blockers.^{16 17}

The TGF-ß pathway is stimulated by angiotensin. The angiotensin-II receptor antagonist losartan has been shown to prevent and possibly reverse aortic root dilatation, mitral valve prolapse, lung disease and skeletal muscle dysfunction in a mouse model of MFS.¹⁸ In the same model losartan has also been shown to slow aortic root enlargement more effectively than propranolol.

A randomised controlled trial of 608 children and young adults under the age of 25 with MFS, compared losartan with atenolol over a three-year period.¹⁹ The primary outcome was the rate of aortic root dilation. Somewhat unexpectedly the study found no advantage of losartan over atenolol. There are several other similar trials underway and, to clarify what the effects are of angiotensin-II receptor antagonists and beta-blockers on patients with MFS, a prospective, collaborative meta-analysis based on individual patient data from these trials has been proposed.²⁰ It is expected to include individual patient data from over 2,000 people.

Surgical

Prophylactic aortic root surgery is the only definitive treatment for the prevention of aortic dissection in Marfan's syndrome. In patients with anatomically normal aortic valves and low-grade regurgitation, a valve-sparing aortic root replacement by a Dacron® prosthesis and reimplantation of the coronary arteries into the prosthesis (David procedure) has become the preferred surgical procedure with good long-term outcome. Composite graft replacement, usually with a mechanical valve, is a more durable alternative but does require lifelong anticoagulation.

Emergency presentations of ocular manifestations may include lens dislocation, retinal detachment, or sudden-onset glaucoma. If increased intraocular pressure occurs due to dislocated lens, vitreolensectomy is necessary to save the eye. Urgent referral to an ophthalmologist is important.

Surgery may be indicated for associated orthopaedic problems, including scoliosis.

Orthodontic treatment may be required to prevent or manage periodontal disease.

Managing pregnancy⁷

Expert input is required, as the risk of aortic rupture is vastly increased. There is also a 50% chance that the baby will be affected. Therefore genetic counselling is needed.

• Women with an aortic root diameter >45 mm are strongly discouraged from becoming pregnant without prior repair because of the increased risk of dissection.

• An aortic root diameter <40 mm rarely presents a problem, although a completely safe diameter does not exist.

• With an aortic root 40-45 mm, previous aortic growth and family history are important factors when considering repair prior to pregnancy.

• After repair of the ascending aorta, Marfan patients remain at risk for dissection of the residual aorta.

Marfan's syndrome prognosis and complications

The main cause of death with Marfan's syndrome is cardiovascular disease and other vascular complications. Early use of propranolol and new surgical procedures have improved life expectancy substantially.¹³ Patients with MFS requiring surgery during childhood have a relatively favourable long-term outcome.²¹

Marfan's syndrome is associated with a risk of redissection and recurrent aneurysm in the distal aorta, especially in patients with previous dissection. With improved life expectancy, these complications now occur more frequently.⁷