3. Marfan's Syndrome

Marfan's Syndrome

This PatientPlus article is written for healthcare professionals so the language may be more technical than the condition leaflets. You may find the abbreviations list helpful.

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.

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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 overlapped[5]
    • Steinberg's thumb sign - a flexed thumb grasped within a clenched palm protrudes beyond the ulnar border of that hand[5]
  • Facial characteristics - maxillary/mandibular retrognathia, long face and high, arched palate are important and relatively discriminating signs of the condition[6]
  • 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. However, this view was challenged at a historical conference in Cairo in 2001.[21]

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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. Phylactou LA, Kilpatrick MW; Potential therapy paradigms for Marfan syndrome. Expert Opin Investig Drugs. 1999 Jul;8(7):983-93.
  4. Rolf C, Nieschlag E; Reproductive functions, fertility and genetic risks of ageing men. Exp Clin Endocrinol Diabetes. 2001;109(2):68-74.
  5. Chen H; Marfan Syndrome. eMedicine. Updated: May 20, 2009.
  6. 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.
  7. Kiotsekoglou A, Sutherland GR, Moggridge JC, et al; The unravelling of primary myocardial impairment in Marfan syndrome by modern echocardiography. Heart. 2009 Feb 17.
  8. 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.
  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. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. Utreja A, Evans CA; Marfan syndrome-an orthodontic perspective. Angle Orthod. 2009 Mar;79(2):394-400.
  17. 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.
  18. Gray JR, Bridges AB, West RR, et al; Life expectancy in British Marfan syndrome populations. Clin Genet. 1998 Aug;54(2):124-8.
  19. 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.
  20. Robinson PN, Arteaga-Solis E, Baldock C, et al; The molecular genetics of Marfan syndrome and related disorders. J Med Genet. 2006 Oct;43(10):769-87. Epub 2006 Mar 29.
  21. Farag T; The Maladies of Celebrities The Ambassadors Online Magazine 5;1:2002
Original Author: Dr Laurence Knott Current Version:
Last Checked: 22/03/2010 Document ID: 2435  Version: 23 © EMIS

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.