UK Genetic Testing Network Marfan syndrome testing guideline workshop

Transcription

1 UK Genetic Testing Network Marfan syndrome testing guideline workshop Executive summary 5 th September 2012, pm Royal College of Physicians, London Meeting report The UK Genetic Testing Network (UKGTN) invited clinical geneticists, cardiologists with a specialist interest in Marfan syndrome, molecular scientists, genetic counsellors and representatives from a patient group (Marfan Association UK) to a workshop to discuss and develop a consensus clinical diagnostic pathway for suspected Marfan syndrome and related aortopathies and testing criteria for molecular genetic testing for Marfan syndrome. This workshop was held in response to the need for formal testing criteria for Marfan syndrome in order to incorporate the recent revisions in the clinical diagnostic criteria brought about by the 2010 Ghent nosology. The 2010 Ghent criteria places greater emphasis on the two cardinal features of Marfan syndrome: ectopia lentis and aortic root aneurysm/dissection. Diagnosis is simplified, the role of genetic testing has been clarified, and differential diagnosis is improved over the previous Ghent criteria. Additional testing and/or follow-up is now formally included in the criteria with a potential Marfan syndrome label applicable to patients under the age of 20 years. The importance of making a diagnosis and offering an equitable service is vital to patients. An accurate diagnosis facilitates comprehensive genetic advice for the affected individual and at risk family members. Importantly, it enables appropriate treatment and targeted testing to be implemented for patients within a clinical pathway. Marfan Association UK, a patient advocacy group for Marfan syndrome and overlapping disorders, also highlighted the importance of educating GPs of the revised diagnostic criteria for Marfan syndrome as it is normally the GPs who are the first point of contact for patients. Consensus testing criteria for Marfan syndrome and the clinical diagnostic pathway for suspected Marfan syndrome were agreed at the meeting. Recommendations The testing criteria for Marfan syndrome should be considered for approval by the UKGTN and implemented as soon as possible within the NHS. The clinical diagnostic pathway for suspected Marfan syndrome should be considered for approval by the UKGTN and provided as guidance on the UKGTN website. It is recommended that a new panel test incorporating all the known genes for inherited conditions with aortic involvement (so called aortopathies ) should be developed for NHS evaluation and clinical use. 1

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3 REVISED GHENT CRITERIA (Loeys 2010) * Loeys BL et al. The revised Ghent nosology for the Marfan syndrome. Journal of Medical Genetics 2010; 47: Doi: /jmg Table 1. Calculation of the Systemic Score 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 Maximum total: 20 points Score 7 indicates systemic involvement US/LS= upper segment/lower segment ratio Aortic root enlargement (Z-score 2.0 in those age 20 years or 3.0 in those age <20 years). Aortic size must be standardised to age and body size for accurate interpretation. A Z-score 2.0 infers a value at or above the 95th percentile, while a Z-score 3.0 infers a value at or above the 99th percentile. 3

4 Introduction Marfan syndrome is an inherited connective tissue disorder which is inherited in an autosomal dominant manner. The disorder is caused by mutations in the Fibrillin 1 gene (FBN1). The syndrome has a prevalence of around 1 in 5,000 individuals 1 and has a high degree of clinical variability. The main features involve the ocular, cardiovascular and skeletal systems although the skin, lungs and dura may also be involved. Ocular involvement often presents as myopia and ectopia lentis (displacement of the lens from the centre of the pupil) is also a common presentation. Marfan syndrome patients are also at risk of retinal detachment, glaucoma, and early cataract formation. Cardiovascular features often involve the dilatation or dissection of the aorta and it is the cardiovascular features of Marfan syndrome that account for much of the morbidity and early mortality. Skeletal features are characterised by bone overgrowth and joint laxity with arms and legs being disproportionately long for the size of the body. Several other conditions have also been recognised which present overlapping clinical features with Marfan syndrome including ocular (e.g. ectopia lentis syndrome), cardiovascular (e.g. bicuspid aortic valve) and skeletal features (Shprintzen- Goldberg syndrome). The clinical diagnosis of Marfan syndrome is complicated by this heterogeneity and in 1996 the Ghent criteria were developed to facilitate diagnosis. The 1996 criteria employed a set of major and minor criteria with diagnosis in an index case requiring two major and at least one minor criteria to be fulfilled. The major criteria included ectopia lentis, aortic root dilatation/dissection, dural ectasia or a combination of more than four out of eight major skeletal features. If the case has a mutation in the FBN1 gene known to cause Marfan syndrome or has a first-degree relative that has been diagnosed with Marfan syndrome, then the presence of one major and one minor criteria were enough to diagnose Marfan syndrome. Although mutations in FBN1 are identifiable in the vast majority of patients diagnosed using the 1996 criteria, concerns over the sensitivity of the criteria were raised; for example not enough account being taken of the age-dependent nature of some of the clinical features which makes diagnosis in children very difficult. Concerns with the validity of some of the diagnostic criteria coupled with problems in diagnosing children and greater understanding of the variable clinical expression and differential diagnoses of conditions with overlapping features led to revised 2010 Ghent criteria 2. The new criteria places more weight on the two main features of Marfan syndrome, aortic root aneurysm/dissection and ectopia lentis. Diagnosis can be made with the presence of these two features. Other clinical features contribute towards a systemic score which when combined to give a score of greater than or equal to seven can guide diagnosis in the absence of the two main features. A more prominent role was also given to genetic testing so that the absence of one of the two main features plus the presence of a known causal mutation in FBN1 would be sufficient for a diagnosis to be made. Less specific clinical features, for example dural ectasia, were either removed or made less influential in the new criteria. The new criteria also formalised the need for additional diagnostic considerations, tests, or follow-up in patients that either did not fulfil the criteria for diagnosis but showed other unexpected findings and the use of potential Marfan syndrome in patients under the age of 20 to take into account that the phenotype may develop with age. 4

5 Many genes are known to be involved in the aetiology of inherited aortopathies. A number of laboratories provide genetic testing for these genes for example, TGFBR1 and TGFBR2 genes, as well as FBN1. The recent revisions in the clinical diagnosis of Marfan syndrome introduced by the 2010 Ghent criteria provide an opportunity to develop testing criteria for Marfan syndrome and to develop the clinical diagnostic pathway for suspected Marfan syndrome patients. This will facilitate and optimise targeted testing of FBN1 to allow the right test to be conducted for the right patient at the right time. The UK Genetic Testing Network (UKGTN) invited clinical geneticists, cardiologists with a specialist interest in Marfan syndrome, molecular scientists, genetic counsellors and representatives from a patient group (Marfan Association UK) to a workshop to discuss and develop a consensus clinical diagnostic pathway for suspected Marfan syndrome and related aortopathies and testing criteria for molecular genetic testing for Marfan syndrome. The objectives for the workshop were: To develop and publish consensus testing criteria for Marfan syndrome using the 2010 Ghent criteria To develop and publish a consensus clinical diagnostic pathway for suspected Marfan syndrome patients which captures the changes in the diagnostic criteria following acceptance of the 2010 Ghent criteria To make available a report of the workshop and the agreed clinical diagnostic pathway and testing criteria for Marfan syndrome 5

6 Summary of Presentations 1. Genetic testing in Marfan syndrome and related aortopathies Leema Robert (Guy s and St Thomas Hospital, UK) Presentation With a lack of consensus testing criteria in the UK, Guy s and St Thomas Hospital has been using its own diagnostic pathway for the last 10 years. The 1996 Ghent criteria are well established and are used in the clinical diagnosis of Marfan syndrome. These criteria are generally agreed to be very good, with a FBN1 mutation pick up rate of 97%, but are limited in that they include some non-specific findings, make no allowance for age-dependent features, are not helpful for considering differential diagnosis or planning further management, and result in difficulty in deciding whether there is cardiovascular risk in those families with just musculoskeletal features and/or ectopic lentis. However, most departments now use the revised Ghent criteria (2010 version) which are clearer, have a more precise definition of the clinical subgroups, and provide better advice for follow-up and management when applied to children with suspected Marfan syndrome. The new scoring system gives greater weight to more specific symptoms such as a positive family history of Marfan syndrome, ectopia lentis, and dilated aortic root. It is generally agreed that these new criteria are an improvement on the old 1996 criteria. Thoracic aortic aneurysm is a major health problem with potentially devastating consequences. The incidence rate of the aortopathies is roughly 10.4 per 100,000 person-years and in 20% of cases a positive family history is seen. The causes of aortopathies can be thought of as non-genetic and genetic, with genetic causes further sub-categorised into syndromic (for example Marfan syndrome) and non-syndromic (such as bicuspid aortic valve with aneurysms of the ascending aorta or tetralogy of Fallot). The research into genetic causes of aortopathies continues with several genotype-phenotype associations discovered in the last few years including further discoveries of phenotypic clinical variation within single families. This highlights the need to remain abreast of the evolving literature as it has allowed the team at Guy s to make several diagnoses following the recognition of a similar clinical phenotype in patients seen at Guy s and the ordering of appropriate testing for positive confirmation. The importance of clear and precise clinical phenotyping cannot be over stated regardless of whether it is done by the cardiologist or the clinical geneticist. It is also becoming apparent that there is significant overlap of the clinical phenotypes in aortopathies and panel testing using next generation sequencing maybe the way forward. 6

7 2. Marfan syndrome in Scotland John Dean (Aberdeen Royal Infirmary, Scotland) Presentation In Scotland there are four clinical genetics centres and although there is no formal Marfan syndrome network, there is a managed clinical network for familial arrhythmias. Scotland has had its own guideline since 2000, which made use of the Ghent 1996 criteria. The Scottish guideline states that all suspected Marfan syndrome patients should have an echocardiogram to measure the diameter of the Sinus of Valsalva relative to age and body surface area. Other investigations such as X-ray for protrusion or magnetic resonance imaging for dural ectasia are undertaken if the patient would fulfil the diagnostic criteria if the result was positive. The Ghent 1996 nosology was adapted to make clinical use easier: for example, myopia was also allowed to count as ocular involvement. Genetic testing is undertaken if a positive test would make the Marfan syndrome diagnosis. Electronic records are created and used in the clinics and these are designed as care pathways for patients with Marfan syndrome thereby allowing automated calculation of the Ghent criteria scores. The current electronic records include both the 1996 criteria and the revised 2010 criteria. The algorithm for the 1996 scoring system was easy to create but the 2010 scoring algorithm was more complex and was difficult to implement because there are gaps in the 2010 nosology into which some patients fall. Both the original criteria and the revised criteria have problems with regard to making a diagnosis in children but this is a problem with the natural history of Marfan syndrome as some phenotypes do not manifest in young children. In a review, both the 1996 and 2010 nosologies were compared in 40 index cases. 34 of these patients fulfilled the criteria for both nosologies with FBN1 mutation testing positive in 24 of 31 patients. By investigating the cases classified differently by the two nosologies, it was concluded that the 2010 revision makes it easier to diagnose Marfan syndrome when there is only information about the eyes and aorta but the 1996 criteria are more sensitive and detect some FBN1 positive cases that were missed by the 2010 revision. In conclusion, genetic testing should be routine in suspected cases but in cases referred because of family history of Marfan syndrome, caution should be exercised if the index case has not been tested. Genetic testing should include FBN1, TGFBR1 and TGFBR2, and additional tests should be considered if negative or other clinical features are involved. 3a. Cardiologist perspective Christoph Kiesewetter (Guy s and St Thomas Foundation Trust, UK) Presentation In the adult cardiac clinic, the early identification and establishment of a diagnosis is critical as it allows early prophylactic surgery that prevents aortic dissection and rupture, greatly improving health outcomes. Finding the molecular mechanism behind Marfan syndrome and related aortopathies improves diagnostic testing. The use of a multidisciplinary team during diagnosis of a patient helps to produce a correct diagnosis. The current approach involves the correct phenotyping of the various clinical manifestations using the revised 2010 criteria whereby greater diagnostic weight is given to the two cardinal features of Marfan syndrome - aortic root aneurysm/dissection and ectopia lentis - and also to molecular genetic testing. 7

8 Clinical phenotyping is a key component of diagnosis in suspected Marfan syndrome patients and their relatives and should include a multidisciplinary team including professionals with specific training and experience in Marfan syndrome and related aortopathies. The accuracy of the diagnosis is key and all investigations require a rigorous approach. One of the key investigations using transthoracic echocardiography is that of determining the diameter and searching for the dissection of the aortic root and all other parts of the aorta. Magnetic resonance imaging (or computed tomography angiography) is often necessary to complete this assessment. Careful evaluation of imaging results is required with respect to not only the size and location of the abnormal aortic root but also the shape. The key message is careful clinical phenotyping and considered evaluation using a multidisciplinary team with appropriate expertise and experience of Marfan syndrome and related aortopathies. 3b. Marfan syndrome and related aortopathies perspective from paediatric cardiac clinic Juan Pablo Kaski (Great Ormond Street Hospital and University College London, UK) Presentation The aortopathy clinic is part of the Inherited Cardiovascular Diseases Unit at Great Ormond Street Hospital. Many of the tests conducted in adults are also conducted in children, including electrocardiography, echocardiography and cardiovascular MRI. In this clinic, three broad groups of patients are seen: 1) those with known aortopathy syndromes; 2) first-degree relatives of known cases (attending for screening); and 3) children referred for investigation for possible Marfan syndrome or related disorders. The known aortopathy syndrome group include patients with clinical diagnoses of Marfan syndrome, Loeys-Dietz, and Ehlers-Danlos (type IV). The value of genetic testing in this group includes confirming molecular diagnosis, potentially providing prognostic information, guiding surveillance and management with respect to the timing of interventions and the type or necessity of pharmacological therapy. Confirmed diagnosis in this first group can also lead to cascade screening in family members (the second group). Genetic testing in this second group of patients, if positive, allows confirmation of the diagnosis and appropriate surveillance and management. If predictive genetic testing is negative, the patient can be given the all-clear and discharged from the clinic. The third group of patients those with possible Marfan syndrome have not fulfilled the Ghent criteria which, in the paediatric population, may be due to the age-dependent nature of penetrance for clinical features or because the condition exhibits incomplete expression and may have overlapping phenotypes with other related conditions. Many of these patients therefore get a non-specific connective tissue disorder diagnosis, and require ongoing follow-up. Genetic testing in this group of patients may provide a specific diagnosis which can then guide surveillance and management. This third group is also interesting for research purposes as they are the group of patients that may lead to new gene discovery. As alluded to in other presentations, the phenotyping of children is paramount and should be used as the basis on which to conduct further investigations. 8

9 4. Marfan syndrome and related aortopathies: developing consensus guidelines Bart Loeys (Antwerp University Hospital, Belgium) Presentation There is ongoing debate as to whether the identification of any gene mutation in FBN1 should equate to a diagnosis of Marfan syndrome. However, different mutations result in many different syndromes with significant differences in the clinical phenotype when compared to Marfan syndrome (for example acromicric/geleophysic dysplasia which presents as short stature and joint stiffness). Great care should be taken when thinking about making all FBN1 mutations equate to Marfan syndrome. In classical Marfan syndrome patients using the original 1996 Ghent criteria, traditional sequencing techniques are able to identify a mutation in FBN1 in around 90% of patients. The mutations in the other 10% could be due to deletions or duplications, mutations within the promoter or 3 UTR regions, or may not be detected due to the limitations of the technology currently being used. It is also possible that the causal mutation may be in other known or unknown genes (locus heterogeneity). But none of these reasons have currently been demonstrated to account for the 5-10% of unidentified mutations and further research into new areas is ongoing. The 1996 Ghent criteria have been used worldwide and have been found to be helpful in making the diagnosis of Marfan syndrome and both sensitive and specific in identifying FBN1 mutation carriers. However, in the absence of aortic dilatation, the diagnosis of Marfan syndrome in patients was found to be stigmatising, hampered career aspirations, and restricted insurance opportunities and lifestyle choices. Some of the minor diagnostic criteria used were not very specific to Marfan syndrome and had not been clinically validated. The criteria were also difficult to apply to children although this is due to the nature of the condition and so remains in the revised criteria. An evidence-based approach was used to update the criteria with greater emphasis placed on whether genetic testing impacts on clinical management and also in distinguishing between Marfan syndrome and the related disorders with improved differential diagnostics. The major and minor criteria from the 1996 were abandoned and replaced by a greater focus on the two cardinal features of aortic root dilatation/dissection and ectopia lentis. There is less emphasis now on the less specific clinical presentations of Marfan syndrome. The addition of better differential diagnosis and the addition of follow-up and surveillance of ambiguous diagnoses have led to criteria which is easier to apply. The concordance between the old and new criteria is very high with discordance between the two main clinical criteria resulting in fewer diagnoses without vascular disease and the earlier diagnosis of young children. However, the systemic score aspect of the new criteria will require prospective evaluation. The clinical utility card for FBN1 mutation screening was published in the European Journal of Human Genetics in It queries the usefulness of FBN1 testing when a clinical diagnosis of Marfan syndrome has been made. Appropriate treatment should be started regardless of FBN1 mutation status if a clinical diagnosis has been made as there is no evidence that outcomes differ based on FBN1 mutation status. However, there is no consensus at a European level with regards to the timing for the initiation of aortic treatment. FBN1 mutation testing seems useful when patients do not fulfil Ghent criteria but they do have suggestive cardiovascular features, are sporadic young cases, or the testing is taking place in familial members of a positive case. This would allow confirmation of Marfan syndrome before all clinical features have presented themselves. Testing criteria do not exist at a European 9

10 level and countries such as Belgium and the Netherlands are moving towards using a panel of genes rather than testing in a sequential manner. This is partly driven by cheaper costs but also because there is significant overlap between the clinical phenotypes which make clinical diagnosis difficult especially in young children. 5. The patient perspective Diane and Robin Rust (Marfan Association UK) Presentation The incidence of Marfan syndrome is estimated to be 1 in 3,300 which suggests that there are approximately 19,000 patients in the UK based on 2011 population figures. Although uncertainty exists regarding the actual number of patients in the UK, all patients still need clinical services and resources. The General Practitioner (GP) is a very important person to the patient and is a focal point for the patient to return to. GPs should be included as referrers for testing along with cardiology and genetic services. Patients sometimes feel that they can get locked into certain specialities due to the multidisciplinary nature of the condition and not all genetic centres deal appropriately with the family members who may also be at risk. This is not a universal problem though. Patients should be kept fully informed of tests, results and their consequences along with appropriate counselling, although it is acknowledged that this can be difficult. All diagnosed patients should also be referred to the Marfan Association UK although whether they follow this up is their choice. Inconclusive results can be both devastating and very difficult for a patient to understand and ongoing support is still required. Family cascade testing should be conducted when Marfan syndrome is diagnosed in an index case. Children will also benefit from genetic testing in order to confirm a suspected diagnosis. All involved in the care of Marfan syndrome patients should communicate with one another in order to establish good continuity of care for the patient. A lead care coordinator should be designated and the patient s own GP should be kept informed. Cardiac and pulmonary rehabilitation is not conducted in a timely manner following surgery and this places stress on both the patient and their families. Patients should be seen by all specialities involved ideally in a one-stop shop facility in order to not only minimise disruption to the patient but also to aid the diagnostic process and speed up the onset of treatment. Working in this manner in a clinic at Frimley Park Hospital made making a diagnosis easier. It was acknowledged that sometimes holding these types of clinics results in them being held less frequently but the Marfan Association UK would strongly recommend that the frequency of Marfan syndrome clinics should not be reduced. The Marfan Association UK is also worried that the removal of the tall and thin phenotype from the revised Ghent criteria would mean that GPs may miss this often obvious clinical presentation of Marfan syndrome and thus hinder the progress made to date. GPs should be educated to help them identify Marfan syndrome and should be kept informed of new developments as they are the first contact for patients. 10

11 6. Impact of emerging technology platforms Edward Blair (Oxford University Hospital NHS Trust, UK) Presentation Hypertrophic Cardiomyopathy (HCM) can be used as an example condition to assess the impact of emerging technology on genetic testing. HCM is similar to Marfan syndrome and related disorders in terms of the clinical and genetic heterogeneity. For HCM, the clinical utility of genetic testing is not always solely about making a diagnosis. Marfan syndrome can often be diagnosed without the need for genetic testing. Utility has been shown in cascade testing in family members. It has been shown to be cost-effective, identifies those at-risk and also very importantly, allows the discharge of those not at-risk. Marfan syndrome has stronger evidence for prognostic indications than HCM and thus there is greater potential use of the information from genetic testing. The challenge lies with the clinical heterogeneity, the genetic heterogeneity, and the interpretation of results which make up clinical sensitivity. With HCM, research advances have increased the number of genes associated with HCM, the cost of testing and turn-around time has reduced, and the knowledge-base has increased leading to improved interpretation of results. All these factors have improved clinical sensitivity (9-11% with the 13 gene vs 4 gene panel) with 13 genes currently being tested although a 28 gene cardiac panel is being developed. Trends over the last 10 years for HCM genetic testing show the number of referrals has gone up. Improvements in testing platforms along with reduced costs will continue to expand the knowledge-base in Marfan syndrome if used. Allied to clear and comprehensive clinical phenotyping, a panel test approach would be the best manner in which to proceed with genetic testing in the Marfan syndrome clinic setting rather than a sequential gene-by-gene approach. However, it should be noted that the analysis of results is complex and will remain so as our knowledge continues to expand. 11

12 Discussions The testing criteria for patients with Marfan syndrome and the clinical diagnostic pathway for suspected Marfan syndrome patients were discussed and all agreed that they should be simple to understand and implement. The importance of clear clinical assessment using the 2010 Ghent criteria cannot be over emphasised. It was agreed that patients would be referred for genetic testing by either the consultant clinical geneticist or the consultant cardiologist. It was also agreed that patients should be referred for FBN1 genetic testing with one of the following: aortic root dilatation/dissection; ectopia lentis; a positive family history of Marfan syndrome; or a systemic score of greater than or equal to 7 (Annex 1). If the FBN1 test is positive then the patient should continue with the standard care pathway for Marfan syndrome. If the test is negative then the patient should be referred to a specialist service for assessment where genetic testing for Marfan syndrome and the related aortopathies should be considered as appropriate (Annex 2). There is now an opportunity to significantly improve the clinical diagnostic pathway for suspected Marfan syndrome patients through the development of a test panel which will test known genes for inherited syndromes with aortic involvement. This is possible because of the development of next generation sequencing. The expected benefits of such a new genetic test includes greater efficiency of genetic testing compared to the current sequential testing approach and improved diagnosis rate. It is also envisaged that there will be a considerable reduction in the time to diagnosis for patients. NHS laboratories should be encouraged to collaborate in identifying which laboratory will lead in the development of such a test. Recommendations The testing criteria for Marfan syndrome should be considered for approval by the UKGTN and implemented as soon as possible within the NHS. The clinical diagnostic pathway for suspected Marfan syndrome should be considered for approval by the UKGTN and provided as guidance on the UKGTN website. It is recommended that a new panel test incorporating all the known genes for inherited conditions with aortic involvement (so called aortopathies ) should be developed for NHS evaluation and clinical use. 12

13 Authors Gurdeep S Sagoo, PHG Foundation Shehla Mohammed, UKGTN Mark Kroese, UKGTN and PHG Foundation The Foundation for Genomics and Population Health (PHG Foundation) was commissioned by the UKGTN to write this report. The PHG Foundation is the working name of the Foundation for Genomics and Population Health, a charitable company registered in England and Wales, charity No company No References 1. Orphanet. Prevalence of rare diseases, Orphanet Report Series, May 2012, Number 1: Listed in alphabetical order of disease or group of diseases available at orpha.net/orphacom/cahiers/docs/gb/prevalence_of_rare_diseases_by_alphabetical_ list.pdf accessed on 24/09/ Loeys BL, et al. The revised Ghent nosology for the Marfan syndrome. Journal of Medical Genetics 2010; 47: Doi: /jmg

14 Annex 1: Agreed consensus testing criteria 14

15 REVISED GHENT CRITERIA (Loeys 2010) * Loeys BL et al. The revised Ghent nosology for the Marfan syndrome. Journal of Medical Genetics 2010; 47: Doi: /jmg Table 1. Calculation of the Systemic Score 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 Maximum total: 20 points Score 7 indicates systemic involvement US/LS= upper segment/lower segment ratio Aortic root enlargement (Z-score 2.0 in those age 20 years or 3.0 in those age <20 years). Aortic size must be standardised to age and body size for accurate interpretation. A Z-score 2.0 infers a value at or above the 95th percentile, while a Z-score 3.0 infers a value at or above the 99th percentile. 15

16 Annex 2: Agreed consensus clinical pathway for suspected Marfan syndrome 16

17 Annex 3: Marfan Association UK briefing paper 17

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21 Annex 4: Meeting programme MARFAN S SYNDROME AND RELATED AORTOPATHIES: DEVELOPING CONSENSUS TESTING GUIDELINES Held on 5th September 2012 at the Council Chamber, Royal College of Physicians, London Registration and Coffee Chaired by Rosalind Skinner Introduction and welcome Rosalind Skinner Background and scope of workshop Shehla Mohammed Current practice: Clinical and testing pathway Leema Roberts The Scottish experience John Dean Perspective from the cardiac clinic Adult clinic Paediatric clinic Christoph Kiesewetter Juan Kaski European perspective Bart Loeys Patient perspective Diane and Robin Rust Lunch Impact of emerging technology platforms Edward Blair Development of recommendations on consensus referral and testing guidelines Summary and closing remarks 21

22 Annex 5: Meeting attendees Name Job Title Organisation Edward Blair Consultant Clinical Geneticist and Clinical Lead Oxford University Hospital NHS Trust Paul Brennan Clinical Director, Northern Genetics Service Newcastle Hospitals NHS Foundation Trust Glen Brice Genetics Counsellor St George s Clinical Genetics, London Sally Cottrell Clinical Scientist (Molecular Genetics) St George s Hospital, London John Dean Clinical Geneticist NHS Grampian, Aberdeen Perry Elliott Professor of Cardiovascular Medicine University College London Lucy Jenkins Head of Molecular Genetics Great Ormond Street Hospital Juan Kaski Paediatric Cardiologist in Inherited Cardiac Disease Great Ormond Street Hospital Christoph Kiesewetter Consultant ACHD Cardiologist Guy s and St Thomas Hospital Mark Kroese Public Health Advisor, UKGTN Anna Lehmann Genetic Counsellor Guy s and St Thomas Hospital Bart Loeys Clinical Geneticist Antwerp University Hospital Sarju Mehta Clinical Geneticist Addenbrookes Hospital, Cambridge Shehla Mohammed Clinical Advisor, UKGTN Nicole Motton Clinical Scientist West Midlands Regional Genetics Lab Leema Robert Consultant Clinical Geneticist Guy s and St Thomas Hospital Diane Rust Chairman/Support Coordinator Marfan Association UK Robin Rust Patient Support and D/B Management Marfan Association UK Anand Saggar Consultant in Clinical Genetics St George s Hospital, London Gurdeep Sagoo Epidemiologist PHG Foundation Saba Sharif Consultant Clinical Geneticist West Midlands Regional Genetic Service Rosalind Skinner Chair, UKGTN Su Stenhouse Fiona Stewart Jacquie Westwood Scientific Advisor, UKGTN Chair, UKGTN Genetic Test and Evaluation Working Group Director, UKGTN 22