1. Marfan’s syndrome and related aortopathies Shehla Mohammed

2. 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)

3. 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

4. Current provision of testing Number of labs currently provide testing * FBN1 * TGFBR1 * TGFBR2 * TAAD Testing criteria available for all except FBN1

5. UKGTN –RCP WORKSHOP Clinical Geneticists Cardiologists with specialist interest Clinical Scientists Genetics Counsellors Patient support group PHG foundation External expert : Prof Bart Loeys

6. 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 testing appropriate, timely management accommodate testing for panel approach? Publish agreed pathways and TC phg foundation report

7. 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

8. 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

9. 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

10. 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 95 th percentile > 3.0 above 99 th percentile Calculation of Systemic score Revised Ghent Criteria ( 2010)

11. Consultant Cardiologists (Adult, Paediatric) Clinical Geneticist Referrals

12. For suspected Marfan Syndrome ± Echo / MRI Clinical assessment using revised Ghent criteria (2010) Aortic root dilation/ dissection Ectopia Lentis FH of MFS Systemic score of ≥ 7 Systemic score of ≥ 7 OR Fulfils Criteria 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.

13. 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

14. Acknowledgements All workshop participants UKGTN project team Gurdeep Sagoo Mark Kroese Robin and Diane RUST