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Original article

Vol. 150 No. 1314 (2020)

Marfan syndrome and related connective tissue disorders in the current era in Switzerland in 103 patients: medical and surgical management and impact of genetic testing

  • Elisa Bombardieri
  • Marianne Rohrbach
  • Matthias Greutmann
  • Gabor Matyas
  • Roland Weber
  • Jovana Radulovic
  • Margrit Fasnacht Boillat
  • André Linka
  • Gabriella De Pasquale
  • Francesca Bonassin
  • Christine H. Attenhofer Jost
Cite this as:
Swiss Med Wkly. 2020;150:w20189



Marfan syndrome (MFS) and related connective tissue disorders (CTDs) are increasingly recognised. Genetic testing has greatly improved the diagnostic outcome/power over the last two decades. In this study we describe a multicentre cohort of adults with MFS and related CTDs, with a particular focus on results from genetic testing.


All patients with MFS and related CTDs were identified from the databases of five centres in the canton of Zurich. Echocardiographic and clinical findings including systemic Marfan score, use of medication and genetic results were retrospectively analysed. MFS was diagnosed using the revised Ghent criteria (including FBN1 genetic testing if available); other CTDs (Loeys-Dietz syndrome) were diagnosed by genetic testing only.


A cohort of 103 patients were identified (62 index patients, 41 relatives of family members): 96 patients with MFS and 7 patients with other CTD, 54 males (52%), median age 23 years (range 1–75). The median systemic Marfan score was 5 (range 0–18). Only 40 patients (40/103, 39%) fulfilled criteria for systemic involvement (≥7 points). A history of aortic dissection was present in 14 out of 103 patients (14%). Echocardiographic data were available for all: aortic root enlargement (Z-score ≥2 in adults, Z-score ≥3 in children) was found in 49 patients (48%) and mitral valve prolapse in 64 (62%). Genetic testing had been performed in 80 patients (78%); FBN1 mutations were present in 69 patients (86%); other pathogenic mutations could be identified in seven patients (9%); no disease-causing mutation was found in four patients, three of them fulfilling the Ghent criteria of MFS. Of the mutation-positive patients, 33 had a systemic score of ≥7 and 43 had a systemic score of ≥5. Revised Ghent criteria were fulfilled in 70 patients: in 69 patients with FBN1 mutations and 1 patient with another CTD. Recommended treatment (beta-blocker, angiotensin receptor blocker) was taken by 63% of patients.


In this cohort a high percentage of patients fulfilling the revised Ghent criteria for MFS underwent genetic testing, often leading to or confirming the diagnosis of MFS. Other CTDs could be discriminated best by genetic testing. With respect to the diagnosis of MFS and related CTDs, the usefulness of the systemic score is limited, showing the importance of genetic testing, which enabled definitive diagnosis in 95% of tested patients. Patient education on medical treatment still has to be improved. (Trial registration no: KEK-ZH-Nr. 2013-0241)


  1. Kainulainen K, Pulkkinen L, Savolainen A, Kaitila I, Peltonen L. Location on chromosome 15 of the gene defect causing Marfan syndrome. N Engl J Med. 1990;323(14):935–9. doi:.
  2. Vollbrandt T, Tiedemann K, El-Hallous E, Lin G, Brinckmann J, John H, et al. Consequences of cysteine mutations in calcium-binding epidermal growth factor modules of fibrillin-1. J Biol Chem. 2004;279(31):32924–31. doi:.
  3. Faivre L, Collod-Beroud G, Loeys BL, Child A, Binquet C, Gautier E, et al. Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Am J Hum Genet. 2007;81(3):454–66. doi:.
  4. Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 1991;352(6333):337–9. doi:.
  5. Pyeritz RE, McKusick VA. The Marfan syndrome: diagnosis and management. N Engl J Med. 1979;300(14):772–7. doi:.
  6. Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010;47(7):476–85. doi:.
  7. Attenhofer Jost CH, Greutmann M, Connolly HM, Weber R, Rohrbach M, Oxenius A, et al. Medical treatment of aortic aneurysms in Marfan syndrome and other heritable conditions. Curr Cardiol Rev. 2014;10(2):161–71. doi:.
  8. Devereux RB, de Simone G, Arnett DK, Best LG, Boerwinkle E, Howard BV, et al. Normal limits in relation to age, body size and gender of two-dimensional echocardiographic aortic root dimensions in persons ≥15 years of age. Am J Cardiol. 2012;110(8):1189–94. doi:.
  9. Campens L, Demulier L, De Groote K, Vandekerckhove K, De Wolf D, Roman MJ, et al. Reference values for echocardiographic assessment of the diameter of the aortic root and ascending aorta spanning all age categories. Am J Cardiol. 2014;114(6):914–20. doi:.
  10. Mátyás G, De Paepe A, Halliday D, Boileau C, Pals G, Steinmann B. Evaluation and application of denaturing HPLC for mutation detection in Marfan syndrome: Identification of 20 novel mutations and two novel polymorphisms in the FBN1 gene. Hum Mutat. 2002;19(4):443–56. doi:.
  11. Mátyás G, Arnold E, Carrel T, Baumgartner D, Boileau C, Berger W, et al. Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders. Hum Mutat. 2006;27(8):760–9. doi:.
  12. Mátyás G, Alonso S, Patrignani A, Marti M, Arnold E, Magyar I, et al. Large genomic fibrillin-1 (FBN1) gene deletions provide evidence for true haploinsufficiency in Marfan syndrome. Hum Genet. 2007;122(1):23–32. Published online May 10, 2007. doi:.
  13. Attenhofer Jost CH, Connolly HM, Scott CG, Ammash NM, Bowen JM, Schaff HV. Aortic Root Surgery in Marfan Syndrome: Medium-Term Outcome in a Single-Center Experience. J Heart Valve Dis. 2017;26(1):45–53.
  14. Price J, Magruder JT, Young A, Grimm JC, Patel ND, Alejo D, et al. Long-term outcomes of aortic root operations for Marfan syndrome: A comparison of Bentall versus aortic valve-sparing procedures. J Thorac Cardiovasc Surg. 2016;151(2):330–8. doi:.
  15. Erbel R, Aboyans V, Boileau C, Bossone E, Bartolomeo RD, Eggebrecht H, et al., The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. Eur Heart J. 2014;35(41):2873–926. doi:.
  16. Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE, Jr, et al.; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines; American Association for Thoracic Surgery; American College of Radiology; American Stroke Association; Society of Cardiovascular Anesthesiologists; Society for Cardiovascular Angiography and Interventions; Society of Interventional Radiology; Society of Thoracic Surgeons; Society for Vascular Medicine. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation. 2010;121(13):e266–369.
  17. Meester JAN, Verstraeten A, Schepers D, Alaerts M, Van Laer L, Loeys BL. Differences in manifestations of Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome. Ann Cardiothorac Surg. 2017;6(6):582–94. doi:.
  18. Schoenhoff FS, Mueller C, Czerny M, Matyas G, Kadner A, Schmidli J, et al. Outcome of aortic surgery in patients with Loeys-Dietz syndrome primarily treated as having Marfan syndrome. Eur J Cardiothorac Surg. 2014;46(3):444–9, discussion 449. doi:.
  19. Veldhoen S, Stark V, Mueller GC, Derlin T, Bley TA, Weil J, et al. Pediatric patients with Marfan syndrome: frequency of dural ectasia and its correlation with common cardiovascular manifestations. RoFo Fortschr Geb Rontgenstr Nuklearmed. 2014;186(1):61–6.
  20. Maumenee IH. The eye in the Marfan syndrome. Birth Defects Orig Artic Ser. 1982;18(6):515–24.
  21. Coselli JS, Volguina IV, LeMaire SA, Sundt TM, Connolly HM, Stephens EH, et al.; Aortic Valve Operative Outcomes in Marfan Patients Study Group. Early and 1-year outcomes of aortic root surgery in patients with Marfan syndrome: a prospective, multicenter, comparative study. J Thorac Cardiovasc Surg. 2014;147(6):1758–1767.e4. doi:.
  22. Schoenhoff FS, Langhammer B, Wustmann K, Reineke D, Kadner A, Carrel T. Decision-making in aortic root surgery in Marfan syndrome: bleeding, thromboembolism and risk of reintervention after valve-sparing or mechanical aortic root replacement. Eur J Cardiothorac Surg. 2015;48(6):931–5, discussion 935–6. doi:.
  23. Böckler D, Meisenbacher K, Peters AS, Grond-Ginsbach C, Bischoff MS. Endovascular treatment of genetically linked aortic diseases. Gefasschirurgie. 2017;22(S1, Suppl 1):1–7. doi:.
  24. Treasure T, Takkenberg JJ, Pepper J. Republished review: Surgical management of aortic root disease in Marfan syndrome and other congenital disorders associated with aortic root aneurysms. Postgrad Med J. 2016;92(1084):112–7. doi:.
  25. Sung S-H, Tsai YL, Lee C-W. Emergent MitraClip to Rescue Patient with Acute Chordae Rupture and RV Failure. J Am Coll Cardiol. 2017;69(16, Supplement):S360–1. doi:.
  26. Schoenhoff FS, Jungi S, Czerny M, Roost E, Reineke D, Matyas G, et al. Acute aortic dissection determines the fate of initially untreated aortic segments in Marfan syndrome. Circulation. 2013;127(15):1569–75. doi:.
  27. Rylski B, Bavaria JE, Beyersdorf F, Branchetti E, Desai ND, Milewski RK, et al. Type A aortic dissection in Marfan syndrome: extent of initial surgery determines long-term outcome. Circulation. 2014;129(13):1381–6. doi:.
  28. Rylski B, Pacini D, Beyersdorf F, Quintana E, Schachner T, Tsagakis K, et al.; EACTS Vascular Domain, EJCTS and ICVTS Editorial Committees. Standards of reporting in open and endovascular aortic surgery (STORAGE guidelines). Eur J Cardiothorac Surg. 2019;56(1):10–20. doi:.
  29. Halpern BL, Char F, Murdoch JL, Horton WB, McKusick VA. A prospectus on the prevention of aortic rupture in the Marfan syndrome with data on survivorship without treatment. Johns Hopkins Med J. 1971;129(3):123–9.
  30. Shores J, Berger KR, Murphy EA, Pyeritz RE. Progression of aortic dilatation and the benefit of long-term beta-adrenergic blockade in Marfan’s syndrome. N Engl J Med. 1994;330(19):1335–41. doi:.
  31. Rossi-Foulkes R, Roman MJ, Rosen SE, Kramer-Fox R, Ehlers KH, O’Loughlin JE, et al. Phenotypic features and impact of beta blocker or calcium antagonist therapy on aortic lumen size in the Marfan syndrome. Am J Cardiol. 1999;83(9):1364–8. doi:.
  32. Salim MA, Alpert BS, Ward JC, Pyeritz RE. Effect of beta-adrenergic blockade on aortic root rate of dilation in the Marfan syndrome. Am J Cardiol. 1994;74(6):629–33. doi:.
  33. Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006;312(5770):117–21. doi:.
  34. Mueller GC, Stierle L, Stark V, Steiner K, von Kodolitsch Y, Weil J, et al. Retrospective analysis of the effect of angiotensin II receptor blocker versus β-blocker on aortic root growth in paediatric patients with Marfan syndrome. Heart. 2014;100(3):214–8. doi:.
  35. Forteza A, Evangelista A, Sánchez V, Teixidó-Turà G, Sanz P, Gutiérrez L, et al. Efficacy of losartan vs. atenolol for the prevention of aortic dilation in Marfan syndrome: a randomized clinical trial. Eur Heart J. 2016;37(12):978–85. doi:.
  36. den Hartog AW, Franken R, van den Berg MP, Zwinderman AH, Timmermans J, Scholte AJ, et al. The effect of losartan therapy on ventricular function in Marfan patients with haploinsufficient or dominant negative FBN1 mutations. Neth Heart J. 2016;24(11):675–81. doi:.
  37. Chiu HH, Wu MH, Wang JK, Lu CW, Chiu SN, Chen CA, et al. Losartan added to β-blockade therapy for aortic root dilation in Marfan syndrome: a randomized, open-label pilot study. Mayo Clin Proc. 2013;88(3):271–6. doi:.
  38. Lacro RV, Dietz HC, Sleeper LA, Yetman AT, Bradley TJ, Colan SD, et al.; Pediatric Heart Network Investigators. Atenolol versus losartan in children and young adults with Marfan’s syndrome. N Engl J Med. 2014;371(22):2061–71. doi:.
  39. Habashi JP, Doyle JJ, Holm TM, Aziz H, Schoenhoff F, Bedja D, et al. Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism. Science. 2011;332(6027):361–5. doi:.
  40. Doyle JJ, Doyle AJ, Wilson NK, Habashi JP, Bedja D, Whitworth RE, et al.; GenTAC Registry Consortium; MIBAVA Leducq Consortium. A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome. eLife. 2015;4:e08648. doi:.
  41. Caspar SM, Dubacher N, Kopps AM, Meienberg J, Henggeler C, Matyas G. Clinical sequencing: From raw data to diagnosis with lifetime value. Clin Genet. 2018;93(3):508–19. doi:.
  42. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP ; STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies. Int J Surg. 2014;12(12):1495–9. doi:.

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