Marfan's Syndrome

oPatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.

Synonyms: Marfan syndrome, MFS, MFS1

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

Marfan's syndrome 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 inherited 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.

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The diagnosis is usually established using the Ghent criteria which evaluate family history, molecular data and six organ systems.[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.

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 overlapped.
    • Steinberg's thumb sign - a flexed thumb grasped within a clenched palm protrudes beyond the ulnar border of that hand.
  • Facial characteristics - maxillary/mandibular retrognathia, long face and high, arched palate are important and relatively discriminating signs of the condition.[5]
  • 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.[6]
  • MRI scanning of spinal column: consider this if headache/sacral pain is potentially attributable to dural ectasia.[7]
  • Pelvic X-ray: this may demonstrate protrusion of the acetabulum into the pelvic cavity (protrusio acetabula). It is present in about 50% of cases.

Management requires a multidisciplinary 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]
  • The 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 have been used to reduce mean arterial pressure and pulse rate significantly.[11] 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.[12] Furthermore, angiotensin-converting enzyme (ACE) inhibitors have been shown to have comparable or improved efficacy.[13] 

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 Marfan's syndrome.[14] Studies are currently underway to assess the benefits of losartan in humans with Marfan's syndrome.[15] 

Surgical

With progressive aortic disease (dilatation of the ascending aorta and valve ring), composite valve conduit/aortic root graft replacement should be considered.[16] Some advocate medical therapy and aortic valve-sparing surgery where possible, due to the risks of having to anticoagulate after valve replacement.[17] 

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 intraocular lens placement is a technique often used following lens removal.[18] 

Surgery may be indicated for associated orthopaedic problems, including scoliosis.[19] 

Orthodontic treatment may be required to prevent or manage periodontal disease.[20]

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 intrapartum care. Where aortic root dilatation does occur, highly-specialised surgical care and caesarean delivery are advocated.[21]

The main cause of death is cardiovascular disease and other vascular complications. Early use of propranolol and new surgical procedures are improving this prognosis.[9] Patients with Marfan's syndrome requiring surgery during childhood have a relatively favorable long-term outcome.[22] 

Further reading & references

  1. Marfan Syndrome, MFS; Online Mendelian Inheritance in Man (OMIM)
  2. Grimes SJ, Acheson LS, Matthews AL, et al; Clinical consult: Marfan syndrome. Prim Care. 2004 Sep;31(3):739-42, xii.
  3. Ammash NM, Sundt TM, Connolly HM; Marfan syndrome-diagnosis and management. Curr Probl Cardiol. 2008 Jan;33(1):7-39.
  4. Keane MG, Pyeritz RE; Medical management of Marfan syndrome. Circulation. 2008 May 27;117(21):2802-13. doi: 10.1161/CIRCULATIONAHA.107.693523.
  5. De Coster P, De Pauw G, Martens L, et al; Craniofacial structure in Marfan syndrome: a cephalometric study. Am J Med Genet A. 2004 Dec 15;131(3):240-8.
  6. Kiotsekoglou A, Sutherland GR, Moggridge JC, et al; The unravelling of primary myocardial impairment in Marfan syndrome by modern echocardiography. Heart. 2009 Feb 17.
  7. Rosser T, Finkel J, Vezina G, et al; Postural headache in a child with Marfan syndrome: case report and review of the literature. J Child Neurol. 2005 Feb;20(2):153-5.
  8. Judge DP, Dietz HC; Marfan's syndrome. Lancet. 2005 Dec 3;366(9501):1965-76.
  9. Raanani E, Ghosh P; The multidisciplinary approach to the Marfan patient. Isr Med Assoc J. 2008 Mar;10(3):171-4.
  10. Fusar-Poli P, Klersy C, Stramesi F, et al; Determinants of quality of life in Marfan syndrome. Psychosomatics. 2008 May-Jun;49(3):243-8.
  11. Williams A, Davies S, Stuart AG, et al; Medical treatment of Marfan syndrome: a time for change. Heart. 2008 Apr;94(4):414-21.
  12. Selamet Tierney ES, Feingold B, Printz BF, et al; Beta-blocker therapy does not alter the rate of aortic root dilation in pediatric patients with Marfan syndrome. J Pediatr. 2007 Jan;150(1):77-82.
  13. Yetman AT, Bornemeier RA, McCrindle BW; Usefulness of enalapril versus propranolol or atenolol for prevention of aortic dilation in patients with the Marfan syndrome. Am J Cardiol. 2005 May 1;95(9):1125-7.
  14. Matt P, Habashi J, Carrel T, et al; Recent advances in understanding Marfan syndrome: should we now treat surgical patients with losartan? J Thorac Cardiovasc Surg. 2008 Feb;135(2):389-94.
  15. Braverman AC; Medical management of thoracic aortic aneurysm disease. J Thorac Cardiovasc Surg. 2013 Mar;145(3 Suppl):S2-6. doi: 10.1016/j.jtcvs.2012.11.062. Epub 2012 Dec 20.
  16. Zehr KJ, Matloobi A, Connolly HM, et al; Surgical management of the aortic root in patients with Marfan syndrome. J Heart Valve Dis. 2005 Jan;14(1):121-8; discussion 128-9.
  17. Kim SY, Martin N, Hsia EC, et al; Management of aortic disease in Marfan Syndrome: a decision analysis. Arch Intern Med. 2005 Apr 11;165(7):749-55.
  18. Morrison D, Sternberg P, Donahue S; Anterior chamber intraocular lens (ACIOL) placement after pars plana lensectomy in pediatric Marfan syndrome. J AAPOS. 2005 Jun;9(3):240-2.
  19. Di Silvestre M, Greggi T, Giacomini S, et al; Surgical treatment for scoliosis in Marfan syndrome. Spine (Phila Pa 1976). 2005 Oct 15;30(20):E597-604.
  20. Utreja A, Evans CA; Marfan syndrome-an orthodontic perspective. Angle Orthod. 2009 Mar;79(2):394-400.
  21. Sakaguchi M, Kitahara H, Seto T, et al; Surgery for acute type A aortic dissection in pregnant patients with Marfan syndrome. Eur J Cardiothorac Surg. 2005 Aug;28(2):280-3; discussion 283-5.
  22. Everitt MD, Pinto N, Hawkins JA, et al; Cardiovascular surgery in children with Marfan syndrome or Loeys-Dietz syndrome. J Thorac Cardiovasc Surg. 2009 Jun;137(6):1327-32; discussion 1332-3. Epub 2009 Apr 11.

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.

Original Author:
Dr Laurence Knott
Current Version:
Peer Reviewer:
Dr Adrian Bonsall
Last Checked:
10/12/2013
Document ID:
2435 (v24)
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