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• Re:Comments on the revised Ghent nosology for Marfan syndrome
  Bart L. Loeys
  Published on: 27 April 2016
• Comments on the revised Ghent nosology for Marfan syndrome
  Raoul C.M. Hennekam
  Published on: 27 April 2016
• Reply to: The revised Ghent nosology for the Marfan Syndrome
  jan maarten cobben
  Published on: 27 April 2016

• Published on: 27 April 2016

  Re:Comments on the revised Ghent nosology for Marfan syndrome

  • Bart L. Loeys, clinical geneticist

  We would like to thank Dr. Hennekam for his comments but would like to reply to several points made by him. We agree with Dr. Hennekam that there is a good correlation between the current nosology and the FBN1 mutation uptake, but an important goal for the new nosology is to make it simpler and more easily applicable (which is not always true for the current one). There is also an important focus on the cardiovascular a...

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  We would like to thank Dr. Hennekam for his comments but would like to reply to several points made by him. We agree with Dr. Hennekam that there is a good correlation between the current nosology and the FBN1 mutation uptake, but an important goal for the new nosology is to make it simpler and more easily applicable (which is not always true for the current one). There is also an important focus on the cardiovascular aspect of the disease which remains the most important for the life expectancy.

  Dr. Hennekam suggests that the five major changes in the revised nosology have severe shortcomings. However, we believe there are many more reasons mentioned in the paper that played a role in the revision. Since physicians associate the diagnosis of "Marfan syndrome", above all else, with risk for aortic aneurysm/dissection, it can be detrimental to diagnose MFS in patients without tangible evidence of such risk. Avoidable consequences associated with misdiagnosis of MFS include: restriction of career aspirations or access to insurance benefits; additional financial burden associated with frequent medical care; anxiety or situational depression; unfounded marital or reproductive decisions; loss of health benefits or psychosocial stigmatization associated with exercise restriction, a particularly important issue during childhood. The challenge is to balance such concerns with the paramount need to maintain good health through proper counseling and application of sound anticipatory medical practices. Toward this objective, it is also important to avoid the diagnosis of MFS when clinical or molecular observations could reveal alternative (and often more severe) diagnoses that mandate specialized counseling or management protocols.

  We agree that the focus of the current nosology is on the cardiovascular and the ocular complications, which from a medical perspective are still the most objective and have the greatest medical implications. As such it is logical to start from those two symptoms. We agree with Dr Hennekam that according to the patient survey the skeletal features may be subjectively more important but we believe this very important for the management aspect but not so much for the diagnostic decision making process. Individual skeletal findings do not bear great sensitivity but as a whole they are indeed important. As such, we did not abandon the skeletal findings but these are put more in the context of all systemic findings and the more important skeletal findings do get a greater weight in this systemic score. Other major criteria that have not been validated such as dural ectasia do get lower weight. For eg do we really want a patient with skeletal findings and dural ectasia and striae be called MFS ? We believe there is a major difference between clinical characteristics to make a diagnosis and on the other side characteristics that are important in the clinical management. Skeletal features in themselves rarely allow to make a MFS diagnosis.

  We agree that there will always be patients with TGFBR1/2 mutations that resemble Marfan syndrome but we prefer to distinguish two categories based on the gene (FBN1 versus TGFBR1/2) because of the different medical implications. Again this is a choice made from a practical viewpoint to create a clear situation even though we recognize that also within the TGFBR1/2 patients there is a spectrum of disease.

  We agree that there is poor genotype (FBN1)-phenotype correlation and this also reflected in the current nosology. For eg. we do stress that certain FBN1 mutations do not have cardiovascular implications and that ectopia lentis syndrome is possible with FBN1 mutations. For eg we also abandon the use of neonatal MFS; this represents the severe end of a phenotypic spectrum. With the current nosology, it is very important to distinguish TGFBR1/2 mutants because they have a more severe natural history. A nosology should also be made for the great majority of patients, not for the exceptions and with the current technology an FBN1 mutation is found in close to 95%

  The combination of aortic root dilation and ectopia lentis is very specific; there is no other diagnosis than Marfan syndrome. In the current literature there is no consensus on the definition and most optimal technique to determine dural ectasia. Until there is better data on the specificity of dural ectasia, we have opted to include it in the systemic score. We had hours of discussion with ophthalmologists on the methods and cut-offs that could be used. We believe the majority of the ophthalmologist do no not measure axial globe length or corneal flattening. Although we agree that these might be interesting to study the different ocular findings for their specificity. Again there are no good data in the literature about sensitivity and specificity of the ocular findings. The pulmonary artery dilation, again has no standard measurement method or cut-off; moreover the clinical relevance of this finding is very low.

  The key point is that physicians should not only look for the features specific for Marfan syndrome but also for other relevant differential diagnostics; this is specifically true for Loeys-Dietz syndrome, Shprintzen-Goldberg syndrome and vascular Ehlers-Danlos syndrome. There are criteria for vascular Ehlers-Danlos syndrome (although they also need better validation) and for Loeys-Dietz syndrome it is too early in the discovery to define good criteria, but we will continue to work on that.

  There is many other points that are made in the introduction of the paper; eg children, psychosocial burden,... that also call for changes not only in the five sections that are now quoted by Dr Hennekam. We also do now define specific diagnostic categories for children and define alternative diagnoses such as MASS, MVPS (mitral valve prolapse) and ELS (ectopia lentis syndrome) in individuals older than 20 years.

  Prof Dr Bart Loeys Prof Dr Harry Dietz Prof Dr Anne De Paepe

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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• Published on: 27 April 2016

  Comments on the revised Ghent nosology for Marfan syndrome

  • Raoul C.M. Hennekam, Professor of Pediatrics and Translational Genetics

  The Ghent criteria as proposed in 1996 are world-wide well accepted to define the diagnostic criteria for Marfan syndrome. The criteria are easy to use and work extremely well, shown by finding causative FBN1 Mutations in 97% of cases. Indeed this specificity of diagnostic criteria is amongst the highest reported in any syndromic entity. A large group of superb Marfan specialists have now suggested a revision of these cr...

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  The Ghent criteria as proposed in 1996 are world-wide well accepted to define the diagnostic criteria for Marfan syndrome. The criteria are easy to use and work extremely well, shown by finding causative FBN1 Mutations in 97% of cases. Indeed this specificity of diagnostic criteria is amongst the highest reported in any syndromic entity. A large group of superb Marfan specialists have now suggested a revision of these criteria (1). Unfortunately the suggested five major changes in the revision have severe shortcomings:

  1. More weight to aortic root aneurysm/dissection and ectopia lentis. Marfan syndrome is a systemic entity, in which many body parts are involved. There is no ratio to increase some of these manifestations (aorta; eye) or decrease others (skeleton). None has a complete sensitivity, none is 100% specific. The authors may argue that the eye and cardiovascular manifestations have the most significant implications. However, the use of new management strategies may well change this in the near future. More importantly, medical implications should not be of importance in establishing diagnostic criteria: sensitivity and specificity should be leading here. In this respect it is useful mentioning that the specificity of aortic root aneurysm/dissection is likely to be lower than the specificity of dural ectasia. One may also consider what individuals having Marfan syndrome themselves consider as the most important manifestations. Indeed, in a questionnaire study of 857 European Marfan patients it was found that not the vascular or visual problems were the most important issues for the patients themselves but this was their body build (2). In fact from a patient perspective this argues to tag more importance to the skeletal findings than any other manifestation.

  2. More prominent role of FNB1 and TGFB1/2 testing. The genotype- phenotype correlation of Marfan syndrome with FBN1 mutations is weak. There are patients with a FBN1 mutation who do not have Marfan syndrome and there are patients who have all manifestations of Marfan syndrome who do not have a (detectable) FBN1 or TGFB1/2 mutation. As has been shown in many other entities it may still be that Marfan syndrome will be genetically heterogeneous. Therefore it is doubtful whether it is wise to put more emphasis on any molecular results than was already done in the existing Ghent criteria.

  3. Removal or downgrading of less specific manifestations. Dural ectasia is downgraded as it may be ..sensitive but is not specific.. . However, as stated above it may well be that it is more specific than enlargement of the aortic root or ectopia lentis, and it is easily and reliably determinable (3, 4). Increased globe length and corneal flattening are removed as ..they have an unclear specificity and are not routinely measured by ophthalmologists.. . No one doubts these eye manifestations form part of the multisystemic manifestations of Marfan syndrome. It seems more logical to perform studies reliably determining the specificity of global length and corneal flattening in Marfan syndrome, and to instruct ophthalmologist to perform these (not difficult and cheap) investigations than to remove the manifestations from the criteria. Pulmonic artery dilatation is removed as ..it is not specific to this diagnosis. In addition complications ... occur rarely.. . Beyond doubt pulmonic manifestations are however a manifestation of the vascular system in Marfan syndrome and therefore can be useful. In addition, whether or not a manifestation provides complications is not influencing its usefulness as a diagnostic criterion. Surely there are still subjective qualifiers in the present proposal (such as mitral valve prolaps or pectus carinatum) but this remains inescapable in describing the human phenotype.

  4. Differentiation from other connective tissue disorders. This is very valuable. However, the diagnostic criteria of one entity should not be influenced by diagnostic criteria of other entities. The similarity of Marfan syndrome to entities such as Loeys-Dietz syndrome and Shprintzen- Goldberg syndrome would simply urge for reliable diagnostic criteria of each of these entities, as comparing the criteria with those in Marfan syndrome would help best in allowing such differentiation.

  5. Providing context-specific recommendations for patient counselling and follow-up. This is an excellent point and surely needs attention. However in itself such recommendations are no reason to change the diagnostic criteria, and can easily be published separately.

  I conclude that the reasoning to change the existing diagnostic criteria contains significant flaws, and suggest keeping using the existing Ghent criteria. The points mentioned by the authors do not ask for adaptation of the Ghent criteria: they ask for amendments regarding entities from which Marfan syndrome should be differentiated by defining these entities better; they ask for separate recommendations for counselling and follow-up. Specific attention to the age dependent nature of some manifestations can be added too, as this is now added only for the aortic root enlargement. Suggestions for additional studies of specific manifestations can be made or the studies can be initiated by the authors themselves.

  The present Ghent criteria function extremely well and are well incorporated in the care for Marfan patients: with limited amendments, the criteria can remain unchanged and even function better.

  References 1. Loeys B, Harry C Dietz, Braverman AC, Callewaert BL, De Backer J, Devereux RB, Hilhorst-Hofstee Y, Jondeau G, Faivre L, Milewicz DM, Pyeritz RE, Sponseller PD, Wordsworth P, De Paepe AM. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010;47:476-485. 2. De Bie S, De Paepe A, Delvaux I, Davies S, Hennekam RC. Marfan syndrome in Europe. Community Genet 2004;7:216-225. 3. Lundby R, Rand-Hendriksen S, Hald JK, Lilleas FG, Pripp AH, Skaar S, Paus B, Geiran O, Smith HJ. Dural ectasia in Marfan syndrome: a case control study. AJNR 2009;30:1534-1540. 4. Sznajder M, Krug P, Taylor M, Moura B, Leparc JM, Boileau C, Jondeau G, Chevallier B, Pelage JP, Stheneur C. Spinal imaging contributes to the diagnosis of Marfan syndrome. Joint Bone Spine 2010 May 7. [Epub ahead of print]

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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• Published on: 27 April 2016

  Reply to: The revised Ghent nosology for the Marfan Syndrome

  • jan maarten cobben, clinical geneticist
  • Other Contributors:
    • Baars MJH, van Tintelen JP

  To the editor

  In the July issue, Loeys and colleagues present new diagnostic criteria for Marfan Syndrome (MFS) in their manuscript "The revised Ghent nosology for the Marfan Syndrome"[1]. After publication of these Revised Ghent Marfan criteria, a manuscript was published which in part supports their opinions[2]. After complimenting Loeys et.al. with the result of their multidisciplinary effort, we would like...

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  To the editor

  In the July issue, Loeys and colleagues present new diagnostic criteria for Marfan Syndrome (MFS) in their manuscript "The revised Ghent nosology for the Marfan Syndrome"[1]. After publication of these Revised Ghent Marfan criteria, a manuscript was published which in part supports their opinions[2]. After complimenting Loeys et.al. with the result of their multidisciplinary effort, we would like to comment on two issues:

  First, the authors allocate more importance to genetic criteria for making a diagnosis of MFS and much less importance to the clinical feature "dural ectasia", compared to the 1996 "Revised diagnostic criteria for Marfan Syndrome". In our opinion this is a prudent decision, as in clinical practice a group of patients emerged after 1996, who had one major criterium for the diagnosis of Marfan Syndrome (usually aortic dilatation) as well as dural ectasia. Combined with even the slightest involvement of other organ systems (usually the skeletal system), patients in this group fulfilled the former diagnostic criteria for MFS[3], while in our hospitals most of these cases are non-familial and without FBN1 or TGFBR1/2 mutation. Although dural ectasia was once seen as an important and discriminating feature of MFS[4], different measurement methods of dural ectasia have been the subject of debate[5], and a recent study corroborated the role of dural ectasia as a non-specific marker for connective tissue disease[2]. In the now presented Revised Ghent criteria, cases with dural ectasia need substantial more other symptomatology to fulfil the criteria for Marfan Syndrome, which is in line with one of the aims of the paper, preventing overdiagnosis of Marfan Syndrome.

  Second, a maybe minor point, is that the authors propose to label the term "potential Marfan Syndrome" to young individuals in whom a FBN1 mutation is identified, but in whom "aortic measurements are still below Z=3". This seems contradictory with the rest of their manuscript, as the fulfilment of criteria needed for an unequivocal diagnosis of Marfan Syndrome, does not depend on the aortic root diameter alone, but on other developing symptoms as well. Furthermore, the term "potential" means "possible"[6] and as such is confusing in this context, as the penetrance of FBN1 mutations/Marfan Syndrome is 100% at adult age. Terminology like "latent MFS" or "subclinical MFS" seems more appropriate, but in our opinion there is no need to make things more complicated then they already are: In our experience, children with a (pathogenic) FBN1 mutation but with no or only minimal clinical symptoms, are labelled by their families and doctors as having "MFS" or "carrier of MFS", without problems or confusion.

  Reference List

  (1) Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De BJ, Devereux RB, Hilhorst-Hofstee Y, Jondeau G, Faivre L, Milewicz DM, Pyeritz RE, Sponseller PD, Wordsworth P, De Paepe AM. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010 Jul;47(7):476-85.

  (2) Sheikzadeh S, Rybczynski M, Habermann CR, Bernhardt AMJ, Arslan- Kirchner M, Keyser B, Kaemerrer H, Mir TS, Staebler A, Oezdal N, Robinson PN, Berger J, Meinertz T, von Kodolitsch Y. Dural ectasia in individuals with Marfan-like features but exclusion of mutations in the genes FBN1, TGFBR1 and TGFBR2. Clin Genet 2010 Jun 23;doi:10.1111/j.1399- 0004.2010.0194.x.

  (3) De PA, Devereux RB, Dietz HC, Hennekam RC, Pyeritz RE. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996 Apr 24;62(4):417-26.

  (4) Fattori R, Nienaber CA, Descovich B, Ambrosetto P, Reggiani LB, Pepe G, Kaufmann U, Negrini E, von KY, Gensini GF. Importance of dural ectasia in phenotypic assessment of Marfan's syndrome. Lancet 1999 Sep 11;354(9182):910-3.

  (5) Weigang E, Ghanem N, Chang XC, Richter H, Frydrychowicz A, Szabo G, Dudeck O, Knirsch W, von SP, Langer M, Beyersdorf F. Evaluation of three different measurement methods for dural ectasia in Marfan syndrome. Clin Radiol 2006 Nov;61(11):971-8.

  (6) Internet Communication, 03-08-2010. http://dictionary.reference.com/browse/potential

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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