Marfan’s syndrome

Doctor of PhysiotherapyCR11

Meg Edmonston, Alex Bond & Jordan Gauder

Introduction

• Pathophysiology

• Aetiology

• Signs & symptoms

• Diagnosis

• Clinical presentation

• Medical management

• Evidence-based physiotherapy intervention

• Conclusion

Quick Facts

•Marfan syndrome is a condition in which your body's connective tissue is abnormal.

•Estimated prevelance of MFS ranges from 1 in 5000 effecting each sex equally.

•Largest cause of death in MFS is aortic dilatation aneurysm.

•Life expectancy is primarily determined by the severity of cardiovascular involvement, and has improved substantially in the past 30 years as a result of improved medical and surgical management.

Pathophysiology

• The majority of cases of MFS are caused by the mutation in the FBN-1 gene.

• Fibrillin-1 is a glycoprotein widely distributed in elastic and non elastic tissues. Fibrillin-1 associate to form microfibrils which form part of elastic fibres. (Keane et al. 2008)

• It is thought that the changes in structural properties of Fibrillin-1 causes lens luxation, dural ectasia, or joint hyperlaxity- explained by weak connective tissue (Dean, 2002).

•Recent studies have suggested that abnormalities in the transforming growth factor-beta (TGF β )-signaling pathway may represent a final pathway in the development of the Marfan phenotype (Dean, 2002).

•The gene defect ultimately leads to decreased and disordered incorporation of fibrillin into the connective tissue matrix.

•Abnormally increased TGF-B signalling may cause disproportionate growth, impaired pulmonary alveolar septation, thickening of mitral valve and eventually an aortic root aneurysm.

•The pathophysiological consequence of the elastic fibre degeneration seen in the aorta is reduced distensibility in response to the pulse pressure wave or increased stiffness (Dean, 2002).

•The normal aorta dilates gradually with age, and becomes stiffer, but these changes are more notable at any age in Marfan syndrome (Dean, 2002).

Aetiology• Mutations in the FBN1 locus of the fibrillin gene on

chromosome 15 have been linked to (Marfan Syndrome) MFS (Dean, 2002).

• In most cases, Marfan syndrome is inherited. The pattern is called “autosomal dominant,” meaning it occurs equally in men and women and can be inherited from just one parent with Marfan syndrome (Loeys et al. 2009).

• People who have Marfan syndrome have a 50 percent chance of passing along the disorder to each of their children (Dean, 2002).

• 26% of all new MFS diagnoses result from a new mutation (Dean, 2002).

Signs & symptomsSystem of body Clinical manifestation

1. Skeletal

Joint laxity, tall in stature, spine abnormality (scoliosis, kyphosis), pectus excavatum/pectus carinatum, long, thin limbs, flat feet, crowded

teeth

2. OcularMyopia, retinal detachment, lens dislocation,

early cataracts, early glaucoma

3. CardiovascularAortic aneurysm and dissection, mitral valve

prolapse (MVP) & regurgitation & aortic regurgitation

4. PulmonaryDecreased lung compliance, spontaneous

pneumothorax

5. Integumentary Stretch marks, inguinal hernias, dural ectasia

Diagnosis

• No specific laboratory test exists with which to make the diagnosis of MFS (Loeys et al. 2009).

Molecular Genetic Testing can be performed to assist in making the diagnosis of MFS in the following 2 clinical situations (Dean, 2002):

• First, if the specific FBN1 mutation is known in an individual diagnosed with MFS, this information can be applied to help diagnose family members.

• Second, linkage analysis can be performed in families with several individuals who are affected with MFS to assess involvement in the remaining undiagnosed relatives.

• Imaging tests are used to view abnormalities with the skeletal system and CV system, and other diagnostic tests such as MRI/ECG/CT/Echocardiogram.

(Dean, 2002)

Pectus excavatum

Chest x-ray: elongated thorax,large-volume lungs & heart in shifted to left. The aortic arch is

slightly dilated.

A. Steinberg sign B. Walker-Murdoch sign

Clinical Presentation

Chest x-ray: severe scoliosis

Medical Management

•No cure, but Rx can minimise and prevent complications.

•Annual exams for systems affected are most beneficial

• Ie Detecting changes in eyesight or spinal column (especially during adolescence).

• Exercise: Avoiding contact sports & isometric exercises. However, with modification, exercise can be a beneficial aspect of medical Mx.

• Exercise of low-moderate intensity can safely increase HR, SV & cardiac output while decreasing peripheral resistance.

• Patients should not exceed 50% of their aerobic capacity and not exceed a heart rate of 110 bpm.

• Cardiovascular: Regular exams & echocardiograms.

• Medication: Pts with heart valve issues are given beta-blockers to reduce the stress on the aorta. Research has shown that an angiotensin receptor blocker(ARB), Losartan, can prevent aortic growth in special Marfan mice. A clinical trial is underway to compare this to beta-blockers in individuals who have Marfan syndrome.

Medical management

•Surgery is sometimes required to replace or repair an affected valve or aorta.•Common types of surgery with those with Marfan’s (will vary):

•Spinal fusion (for severe scoliosis)•Cardiovascular: aortic root replacement/reconstruction or repair of mitral valve

Physiotherapy Interventions for MFSProblem Rx Tool / Intervention Evidence

Joint Hypermobility Isometric exercises through range.

This is contraindicated throughout other publications.

Adib et al. 2004Cohort Study

Level II Evidence

Impaired ROM & Joint Hypermobility

High repetitions and light resistance. Aerobic Conditioning at a light intensity. Shoulder and Hip strength focus.

Dennison & Certo 2006Case Study

Level IV Evidence

Poor Posture Posture retraining: sitting, standing and sleeping. Use of bracesStretching and Strengthening

Brigham & Women’s Hospital 2007Case StudyLevel IV Evidence

More physiotherapy management for MFS should be addressed and researched.

Post-op Physiotherapy Management: For those patient’s whom undergo surgery- normal surgical Physiotherapy management has been

documented.

ConclusionClinical Implications

For Physiotherapy, being aware of the multi-faceted way in which MFS presents in each individual. Treatment protocols will differ dependent on this.

MFS patients live a relatively normal life if their condition is well managed! Michael Phelps has been suggested to have been diagnosed MFS!

The Cardiovascular aspects are the main cause of mortality. Patients are advised to have their condition regularly checked

Questions?

References• Keane, M. G & Pyeritz, R. E. Medical Management of Marfan syndrome. Circulation 117, 2802-2813 (2008)

• El-Hamamsy, I & Yacoub, M. H. Cellular and molecular mechanisms of thoracic aortic aneurysms. Nat. Rev. Cardiol 6, 771-786 (2009)

• Neptune. E. R. et al. Dysregulation of TGF-beta activation contributed to pathogensis in Marfan syndrome. J.Clin. Invest. 114, 172-181 (2004)

• Loeys, B, Dietz, B & Braverman, H 2009, ‘The Revised Ghent Nosology for Marfan Syndrome’, J Med Genet, vol. 47, no. 1, pp 476-485.

• Dean, J 2002, ‘Management of Marfan Syndrome’, Heart Journal, vol. 88, pp. 97-103.

• Brigham & Women’s Hospital, 2007. Standard of Care: Marfan Syndrome.[online] Available at:http://www.brighamandwomens.org/Patients_Visitors/pcs/rehabilitationservices/Physical%20Therapy%20Standards%20of%20Care%20and%20Protocols/General%20-%20Marfan%20Syndrome.pdf. [Accessed 2 September 2011].

• Dennison, A.D. & Certo, C., (2006). Exercise for Individuals with Marfan Syndrome. Cardiopulmonary Physical Therapy Journal, 17 (3), pp. 110-115.

• National Marfan Foundation, 2011. Living with Marfan syndrome. [online] Available at:http://www.marfan.org/marfan/. [Accessed 2 September 2011].