Marfan’s syndrome and

related aortopathies

Shehla Mohammed

Marfan’s syndrome

• Common multisystem connective tissue disorder

• 1 in 5000

• Altered body proportions risk of aortic dissection and

rupture risk of eye problems (lens

dislocation and retinal detachment)

Marfan’s syndrome and related aortopathies

• Common multisystem connective tissue disorder

• 1 in 5000

• Altered body proportions• risk of aortic dissection and rupture

• risk of eye problems (ectopia lentis and retinal detachment)

• Mutations in Fibrillin 1 gene (FBN1)

• Variable clinical expression

• Several conditions with overlapping clinical manifestations

MULTIPLE GENES INVOVED

Current provision of testing

• Number of labs currently provide testing

* FBN1 * TGFBR1 * TGFBR2 * TAAD

•Testing criteria available for all except FBN1

UKGTN –RCP WORKSHOP

• Clinical Geneticists• Cardiologists with specialist interest• Clinical Scientists• Genetics Counsellors• Patient support group• PHG foundation

• External expert : Prof Bart Loeys

Aims of workshop – RCP Sept 2012

• Consensus TC for MFS revisions to draft testing criteria?

incorporate revised Ghent criteria (2010)

• Draw up combined clinical and testing pathways to:

facilitate and optimise targeted testingappropriate, timely managementaccommodate testing for panel approach?

• Publish agreed pathways and TC• phg foundation report

• Aortic aneurysms a major health issue• Incidence of aortopathies 10.4/ 100,000• Early identification critical for prophylactic

surgery to improve health outcomes• Communication, role of GP, early referral• Bart Loeys:

“ Does identification of FBN1 mutation equate to a diagnosis of Marfans? “

RCP workshop : key mesages

Criteria : Suspected diagnosis of Marfan syndrome REVISED GHENT CRITERIA (Loeys 2010)

Tick if this patient meets criteria

Dilated Aortic root AND Ectopia Lentis

OR: Dilated Aortic root AND Systemic score > 7 ( See Box for score)

AND Purpose for knowing mutation in this individual case must be one or more from list below… :

- affects aortic screening /clinical management

OR - allows prenatal testing

OR - enables cascade family testing

OR - avoids other investigation or seeking other clinical opinions for index case or relatives

OR - enables targeting clinical screening in relatives

OR - provides knowledge of genetic risk

Feature  Value

Wrist AND thumb sign  3

Wrist OR thumb sign  1

Pectus carinatum deformity  2

Pectus excavatum or chest asymmetry  1

Hindfoot deformity  2

Plain flat foot (pes planus)  1

Pneumothorax  2

Dural ectasia  2

Protrusio acetabulae  2

Reduced upper segment / lower segment AND increased arm span/height ratios  1

Scoliosis or thoracolumbar kyphosis  1

Reduced elbow extension  1

3 of 5 facial features  1

Skin striae  1

Myopia  1

Mitral valve prolapse  1

  

Loeys BL et al. The revised Ghent nosology for the Marfan syndrome Journal of Medical Genetics 2010; 47: 476-485

   

REVISED GHENT CRITERIA (Loeys 2010)Calculation of the Systemic Score

• Score > 7 indicates systemic involvement• Aortic root enlargement:

Z- score > 2 : > 20yrs

Z- score > 3 : < 20 yrs• Aortic size standardised to age and body size for accurate interpretation

Z score > 2.0 above 95th percentile

> 3.0 above 99th percentile

Calculation of Systemic scoreRevised Ghent Criteria ( 2010)

• Consultant Cardiologists (Adult, Paediatric)

• Clinical Geneticist

Referrals

For suspected Marfan Syndrome ± Echo / MRI

Clinical assessment using revised Ghent criteria (2010)

Aortic root dilation/

dissection

Ectopia Lentis FH of MFS Systemic scoreof ≥ 7

OR OR OR

FulfilsCriteria

Fibrillin 1 testing

If negative, refer to specialist service for assessment

If positive, continue standard MFS care

Other aortopathies to be considered such as LDS, BAV,

AOS, TAAD etc.

Recommendations

Consideration by UKGTN for approval and implementation :

Testing Criteria for Marfan’s syndrome Clinical Diagnostic pathway

Panel test for “aortopathies” : encouragement for an NHS lab to develop

Acknowledgements• All workshop participants• UKGTN project team

• Gurdeep Sagoo• Mark Kroese

• Robin and Diane RUST