Marfan's Syndrome

Synonyms: Marfan syndrome, MFS, MFS1

This is an inherited connective tissue disorder with characteristic skeletal, dermatological, cardiac, aortic, ocular and dural malformations.

Marfan's 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. The gene is located on the long arm of chromosome 15. The pattern of transmission is autosomal dominant with complete penetrance. There is much variation in genotype. Phenotype varies within and between families with the same genetic abnormality, leading to protean and variable manifestations of the condition in given individuals.¹

Prevalence

This is 2-3 per 10,000 of population, affecting both sexes equally. The prevalence is similar worldwide, regardless of geography or ethnicity.² It is the most common genetic disorder of connective tissue.³

Risk factors

Around two-thirds of cases are due to familial transmission. In the remainder there are sporadic mutations, associated with advanced paternal age.⁴ Fathers of children with sporadic mutations are, on average, 5-10 years older than the mean.

The diagnosis is usually established using the Ghent criteria which evaluate family history, molecular data and 6 organ systems.⁵ 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. There are two major sets of diagnostic criteria, each with its own proponents.⁵

Symptoms

The condition can be asymptomatic. Patients 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).

Signs

The main clinical features are:

• Skin - striae, especially thoracolumbar and sacral
• Heart and blood vessels - thoracic aortic dilatation/rupture/dissection, aortic regurgitation, mitral valve prolapse, mitral regurgitation, abdominal aortic aneurysm, cardiac dysrhythmia
• Eyes - lens dislocation, closed angle glaucoma, high myopia
• Joints - hypermobility, arthralgia, instability
• Skeleton - pectus excavatum or carinatum deformities, misshapen chest, kyphoscoliosis
• Arachnodactyly - the following signs may be used to demonstrate this:
  • Walker's (wrist) sign - the patient encircles their wrist with the little finger and thumb of the opposite hand overlapped⁵
  • Steinberg's thumb sign - a flexed thumb grasped within a clenched palm protrudes beyond the ulnar border of that hand⁵
• Facial characteristics - maxillary/mandibular retrognathia, long face and high, arched palate are important and relatively discriminating signs of the condition⁶
• Miscellaneous - dural ectasia hernias (present with low back pain and symptoms akin to cauda equina syndrome or chronic postural headache due to CSF leakage), pleural rupture causing pneumothorax, finger contractures

• ECG and echocardiography: regular careful monitoring of aortic root width and the function of the heart valves is required. Echocardiography is also being used to evaluate the function of the myocardium which is also thought to be affected. Ultrasound scanning may also be helpful in assessing myocardial involvement.⁷
• MRI scanning of spinal column: consider this if headache/sacral pain is potentially attributable to dural ectasia.⁸
• Pelvic X-ray this may demonstrate protrusion of the acetabulum into the pelvic cavity (protrusio acetabula). It is present in about 50% of cases.

• Ehlers-Danlos syndrome
• Fragile X syndrome
• Gigantism and acromegaly
• Hyperpituitarism
• Hyperthyroidism
• Klinefelter's syndrome
• Congenital contractural arachnodactyly
• Familial aortic dissection
• Familial arachnodactyly
• Familial ectopic lentis
• Familial Marfan-like (Marfanoid) habitus
• Familial mitral valve prolapse syndrome
• Familial thoracic aortic aneurysm/dissection
• Myopia, mitral valve prolapse, mild aortic dilatation, skin and skeletal (MASS) phenotype
• Shprintzen-Goldberg syndrome (craniosynostosis,abdominal hernia, arachnodactyly)
• Stickler's syndrome (distinctive facial appearance, eye abnormalities, hearing loss, joint problems)
• XYY syndrome

Management requires a multi-disciplinary team which should include a geneticist, an ophthalmologist, a cardiologist and an orthopaedic surgeon.⁹

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 suffer poor self-esteem and have impaired relationships/sex lives due to concerns about their bodily appearance.¹⁰
• Patient should be advised to avoid vigorously competitive or contact sports (fatal aortic dissection and rupture in young adults is often due to Marfan's syndrome). 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 reduce mean arterial pressure and pulse rate significantly. Previous studies suggested that introducing them at an early age under the supervision of a paediatrician or cardiologist lowered the risk of aortic rupture and gradual aortic root dilatation. Recent trials however have questioned this value of long-term beta blockers.¹¹ Furthermore, ACE inhibitors have been shown to have comparable or improved efficacy.¹²

Surgical

With progressive aortic disease (dilatation of the ascending aorta and valve ring) composite valve conduit/aortic root graft replacement should be considered.¹³ Some advocate medical therapy and aortic-valve sparing surgery where possible, due to the risks of having to anticoagulate after valve replacement.¹⁴

Dislocated optic lens often occurs in early childhood. Removal of the lens is only indicated if cataract or secondary glaucoma intervene or there is greatly reduced visual acuity that cannot be corrected with glasses. Anterior chamber intra-ocular lens placement is a technique often used following lens removal.¹⁵

Orthodontic treatment may be required to prevent or manage periodontal disease.¹⁶

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. Regular echocardiography (every 6-10 weeks) is recommended, along with adaptations of anaesthetic and intra-partum care. Where aortic root dilatation does occur, highly-specialised surgical care and Caesarean delivery are advocated.¹⁷

The main cause of death is cardiovascular disease and other vascular complications. Between 1970 and 1990 in Wales and Scotland median age at death was 45 ±16.5 years.¹⁸ Early use of propranolol and new surgical procedures are improving this prognosis.⁹ Patients with Marfan's or Loeys-Dietz syndrome requiring surgery during childhood have a favorable long-term outcome.¹⁹ The average life span is now 70 years.⁵

Research into the role of growth factor signalling and of fibrillin and fibrillin-rich microfibres in the construction of the cell matrix has led to novel approaches to treatment. The most promising development currently under investigation is the use of angiotensin II type 1 receptor blockers such as losartan, which attenuate the activity of cytokines ('local hormones') of the transforming growth factor β (TGF-β) family.²⁰

It is widely believed that the iconic American President Abraham Lincoln suffered from Marfan's syndrome. The image of his commemorative statue in central Manchester demonstrates that he did appear to have dolichostenomelia and arachnodactyly along with characteristic facial features.²¹ However, this view was challenged at a historical conference in Cairo in 2001.²²