DOI: https://doi.org/10.14710/jbtr.v4i2.3560

Marfan Syndrome, A Review

VU University Medical Center, Netherlands

Received: 7 Nov 2018; Published: 31 Dec 2018.
Open Access Copyright (c) 2018 Journal of Biomedicine and Translational Research

Citation Format:
Abstract

Marfan syndrome is named after the French pediatrician Antoine Bernard-Jean Marfan who described in 1896 a girl with arachnodactyly and long limbs1. The patient also had congenital contractures of the elbows and would not fulfill the current criteria for Marfan syndrome. She probably was suffering from a condition that we now call contractural arachnodactyly, caused by mutations in the FBN2 gene.

The clinical features of Marfan syndrome affect many systems of the body. The most obvious are the skeletal features, long limbs, tall stature, long thin fingers (arachnodactyly or spider fingers). The skeletal features can be scored objectively as: arm span more than 1.05 x body length; wrist sign (thumb and index finger can encircle the wrist of the other hand with at least one digit overlap) and thumb sign (when making a fist around the thumb, one digit of the thumb sticks out). The main neurological symptom is dural ectasias. The most severe symptoms are cardiovascular: mitralis valve prolapse, aortic dilatation and thoracic aortic aneurysms and dissections, which may lead to sudden death5. However, I noticed in discussions with patients that they often consider the ocular symptoms, severe myopia and lens luxation, the worst for themselves, because the latter may lead to blindness.
Fulltext View|Download
Keywords: Marfan syndrome; FBN1; aortic aneurysm, losartan

Article Metrics:

Article Info
Section: Review Articles
Language : EN
Recent articles
The Effects of Zinc Supplementation on Immune Response of Obese Children With Family History of Atopy Factors Affecting Parents' Acceptance towards Children with Familial Intellectual Disability (ID) Malaria, hepatitis B and HIV /AIDS, and their co-infection among Patients Visiting Health Centres in Akure, Nigeria A rare case of trisomy 18 with split-hand/split-foot malformation (SHFM) Marfan Syndrome, A Review More recent articles
  1. Marfan, AB. Un cas de déformation congénitale des quartre membres, plus prononcée aux extrémitiés, caractérisée par l'allongement des os avec un certain degré d'amincissement. Bulletins et memoires de la Société medicale des hôspitaux de Paris. 1896;13 (3rd series): 220–226
  2. Groth KA, Stochholm K, Hove H, Andersen NH, Gravholt CH. Causes of Mortality in the Marfan Syndrome(from a Nationwide Register Study). Am J Cardiol. 2018 Oct 1;122(7):1231-1235. doi: 10.1016/j.amjcard.2018.06.034.Epub2018Jul21
  3. Ergoren MC, Turkgenc B, Terali K, Rodoplu O, Verstraeten A, Van Laer L, Mocan G, Loeys B, Tetik O, Temel SG. Identification and characterization of a novel FBN1 gene variant in an extended family with variable clinical phenotype of Marfan syndrome. Connect Tissue Res. 2018 May 28:1-9. doi: 10.1080/03008207.2018.1472589.[Epubaheadofprint]
  4. Aalberts JJ, Schuurman AG, Pals G, Hamel BJ, Bosman G, Hilhorst-Hofstee Y, Barge-Schaapveld DQ, Mulder BJ, van den Berg MP, van Tintelen JP. Recurrent and founder mutations in the Netherlands: Extensive clinical variability in Marfan syndrome patients with a single novel recurrent fibrillin-1 missense mutation. Neth Heart J. 2010 Feb;18(2):85-9
  5. Li Y, Xu J, Chen M, Du B, Li Q, Xing Q, Zhang Y. A FBN1 mutation association with different phenotypes of Marfan syndrome in a Chinese family. Clin Chim Acta. 2016 Sep 1;460:102-6. doi: 10.1016/j.cca.2016.06.031.Epub2016Jun25
  6. Beighton P, de Paepe A, Danks D, Finidori G, Gedde-Dahl T, Goodman R, Hall JG, Hollister DW, Horton W, McKusick VA, Opitz JM, Pope FM, Pyeritz RE, Rimoin DL, Sillence D, Spranger JW, Thompson E, Tsipouras P, Viljoen D, Winship I, Young James I, Reynolds F. International nosology of heritable disorders of connective tissue, Berlin, 1986. Am J Med Genet. 1988 Mar;29(3):581-94. doi: 10.1002/ajmg.1320290316
  7. De Paepe A1, 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. doi: 10.1136/jmg.2009.072785
  8. Loeys BL, Dietz HC, 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 Jul;47(7):476-85. doi: 10.1136/jmg.2009.072785
  9. Attanasio M, Pratelli E, Porciani MC, Evangelisti L, Torricelli E, Pellicanò G, Abbate R, Gensini GF, Pepe G. Dural ectasia and FBN1 mutation screening of 40 patients with Marfan syndrome and related disorders: role of dural ectasia for the diagnosis. Eur J Med Genet. 2013 Jul;56(7):356-60. doi: 10.1016/j.ejmg.2013.04.006.Epub2013May15
  10. Franken R, den Hartog AW, van de Riet L, Timmermans J, Scholte AJ, van den Berg MP, de Waard V, Zwinderman AH, Groenink M, Yip JW, Mulder BJ. Clinical features differ substantially between Caucasian and Asian populations of Marfan syndrome. Circ J. 2013;77(11):2793-8. Epub 2013 Aug 29
  11. Yoo EH, Woo H, Ki CS, Lee HJ, Kim DK, Kang IS, Park P, Sung K, Lee CS, Chung TY, Moon JR, Han H, Lee ST, Kim JW. Clinical and genetic analysis of Korean patients with Marfan syndrome: possible ethnic differences in clinical manifestation. Clin Genet. 2010 Feb;77(2):177-82. doi: 10.1111/j.1399-0004.2009.01287.x.Epub2009Oct23.Erratumin:ClinGenet.2010Nov;78(5):505.doi: 10.1111/j.1399-0004.2009.01287.x. Epub 2009 Oct 23. Erratum in: Clin Genet. 2010 Nov;78(5):505.
  12. Faivre L, Collod-Beroud G, Callewaert B, Child A, Loeys BL, Binquet C, Gautier E, Arbustini E, Mayer K, Arslan-Kirchner M, Kiotsekoglou A, Comeglio P, Grasso M, Beroud C, Bonithon-Kopp C, Claustres M, Stheneur C, Bouchot O, Wolf JE, Robinson PN, Adès L, De Backer J, Coucke P, Francke U, De Paepe A, Boileau C, Jondeau G. Pathogenic FBN1 mutations in 146 adults not meeting clinical diagnostic criteria for Marfan syndrome: further delineation of type 1 fibrillinopathies and focus on patients with an isolated major criterion. Am J Med Genet A. 2009 May;149A(5):854-60 doi: 10.1002/ajmg.a.32809
  13. Dietz HC Cutting GR Pyeritz RE . Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. . Nature . 1991;352:337–339. doi: 10.1038/352337a0
  14. Loeys B, De Backer J, Van Acker P, Wettinck K, Pals G, Nuytinck L, Coucke P, De Paepe A. Comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical Marfan syndrome. Hum Mutat. 2004 Aug;24(2):140-6. doi: 10.1002/humu.20070
  15. Teixeira LV, Lezirovitz K, Pereira LV, Perez AB. Candidate gene linkage analysis indicates genetic heterogeneity in Marfan syndrome. Braz J Med Biol Res. 2011 Aug;44(8):793-800
  16. Groth KA, Hove H, Kyhl K, Folkestad L, Gaustadnes M, Vejlstrup N, Stochholm K, Østergaard JR, Andersen NH, Gravholt CH. Prevalence, incidence, and age at diagnosis in Marfan Syndrome. Orphanet J Rare Dis. 2015 Dec 2;10:153. doi: 10.1186/s13023-015-0369-8
  17. Penpattharakul W, Pithukpakorn M. Revised Ghent Criteria is Comparable to Original Diagnostic Criteria for Marfan Syndrome with Increased Ability to Clinically Diagnose Related Disorders. J Med Assoc Thai. 2016 Jan;99(1):34-9
  18. de Vries BB, Pals G, Odink R, Hamel BC. Homozygosity for a FBN1 missense mutation: clinical and molecular evidence for recessive Marfan syndrome. Eur J Hum Genet. 2007 Sep;15(9):930-5. doi: 10.1038/sj.ejhg.5201865
  19. Van Dijk FS, Hamel BC, Hilhorst-Hofstee Y, Mulder BJ, Timmermans J, Pals G, Cobben JM. Compound-heterozygous Marfan syndrome. Eur J Med Genet. 2009 Jan-Feb;52(1):1-5. doi: 10.1016/j.ejmg.2008.11.004.Epub2008Nov27
  20. Isogai Z, Ono RN, Ushiro S, Keene DR, Chen Y, Mazzieri R, Charbonneau NL, Reinhardt DP, Rifkin DB, Sakai LY. Latent transforming growth factor beta-binding protein 1 interacts with fibrillin and is a microfibril-associated protein. J Biol Chem. 2003 Jan 24;278(4):2750-7. doi: 10.1074/jbc.M209256200
  21. Davis MR1, Summers KM. Structure and function of the mammalian fibrillin gene family: implications for human connective tissue diseases. Mol Genet Metab. 2012 Dec;107(4):635-47. doi: 10.1016/j.ymgme.2012.07.023.Epub2012Aug3
  22. Hubmacher D, Apte SS. ADAMTS proteins as modulators of microfibril formation and function. Matrix Biol. 2015 Sep;47:34-43. doi: 10.1016/j.matbio.2015.05.004.Epub2015May7
  23. Gabriel LA Wang LW Bader H. ADAMTSL4, a secreted glycoprotein widely distributed in the eye, binds fibrillin-1 microfibrils and accelerates microfibril biogenesis. Invest Ophthalmol Vis Sci . 2012;53:461–469. doi: 10.1167/iovs.10-5955
  24. Beroud C Collod-Beroud G Boileau C Soussi T Junien C. UMD (Universal mutation database): a generic software to build and analyze locus-specific databases. Hum Mutat . 2000;15:86–94. doi: 10.1002/(SICI)1098-1004(200001)15:1<86::AID-HUMU16>3.0.CO;2-4
  25. Hilhorst-Hofstee Y, Hamel BC, Verheij JB, Rijlaarsdam ME, Mancini GM, Cobben JM, Giroth C, Ruivenkamp CA, Hansson KB, Timmermans J, Moll HA, Breuning MH, Pals G. The clinical spectrum of complete FBN1 allele deletions. Eur J Hum Genet. 2011 Mar;19(3):247-52. doi: 10.1038/ejhg.2010.174.Epub2010Nov10
  26. Furtado LV, Wooderchak-Donahue W, Rope AF, Yetman AT, Lewis T, Plant P, Bayrak-Toydemir P. Characterization of large genomic deletions in the FBN1 gene using multiplex ligation-dependent probe amplification. BMC Med Genet. 2011 Sep 21;12:119. doi: 10.1186/1471-2350-12-119
  27. Mátyás G, Alonso S, Patrignani A, Marti M, Arnold E, Magyar I, Henggeler C, Carrel T, Steinmann B, Berger W. Large genomic fibrillin-1 (FBN1) gene deletions provide evidence for true haploinsufficiency in Marfan syndrome. Hum Genet. 2007 Aug;122(1):23-32. doi: 10.1007/s00439-007-0371-x
  28. Yang H, Ma Y, Luo M, Zhao K, Zhang Y, Zhu G, Sun X, Luo F, Wang L, Shu C, Zhou Z. Identification of gross deletions in FBN1 gene by MLPA. Hum Genomics. 2018 Oct 4;12(1):46. doi: 10.1186/s40246-018-0178-y
  29. Dordoni C, Ciaccio C, Santoro G, Venturini M, Cavallari U, Ritelli M, Colombi M. Marfan syndrome: Report of a complex phenotype due to a 15q21.1 contiguos gene deletion encompassing FBN1, and literature review. Am J Med Genet A. 2017 Jan;173(1):200-206. doi: 10.1002/ajmg.a.37975.Epub2016Sep12
  30. Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 2002 Jun 15;30(12):e57
  31. Knott V, Downing AK, Cardy CM, Handford P. Calcium binding properties of an epidermal growth factor-like domain pair from human fibrillin-1. J Mol Biol. 1996 Jan 12;255(1):22-7
  32. iCn3D [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information. 2016 – available from:
  33. https://www.ncbi.nlm.nih.gov/structure/icn3d/icn3d.html.
  34. Hilhorst-Hofstee Y, Rijlaarsdam ME, Scholte AJ, Swart-van den Berg M, Versteegh MI, van der Schoot-van Velzen I, Schäbitz HJ, Bijlsma EK, Baars MJ, Kerstjens-Frederikse WS, Giltay JC, Hamel BC, Breuning MH, Pals G. The clinical spectrum of missense mutations of the first aspartic acid of cbEGF-like domains in fibrillin-1 including a recessive family. Hum Mutat. 2010 Dec;31(12):E1915-27. doi: 10.1002/humu.21372
  35. Exome Aggregation Consortium. Analysis of protein-coding genetic variation in 60,706 humans . http://dx.doi.org/10.1101/030338. doi: 10.1038/nature19057
  36. Bresters D, Nikkels PG, Meijboom EJ, Hoorntje TM, Pals G, Beemer FA. Clinical, pathological and molecular genetic findings in a case of neonatal Marfan syndrome. Acta Paediatr. 1999 Jan;88(1):98-101
  37. ter Heide H, Schrander-Stumpel CT, Pals G, Delhaas T. Neonatal Marfan syndrome: clinical report and review of the literature. Clin Dysmorphol. 2005 Apr;14(2):81-4
  38. Baudhuin LM, Kotzer KE, Lagerstedt SA. Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events. Genet Med. 2015 Mar;17(3):177-87. doi: 10.1038/gim.2014.91.Epub2014Aug7
  39. den Hartog AW, Franken R, Zwinderman AH, Timmermans J, Scholte AJ, van den Berg MP, de Waard V, Pals G, Mulder BJ, Groenink M. The risk for type B aortic dissection in Marfan syndrome. J Am Coll Cardiol. 2015 Jan 27;65(3):246-54. doi: 10.1016/j.jacc.2014.10.050
  40. Franken R, Groenink M, de Waard V, Feenstra HM, Scholte AJ, van den Berg MP, Pals G, Zwinderman AH, Timmermans J, Mulder BJ. Genotype impacts survival in Marfan syndrome. Eur Heart J. 2016 Nov 14;37(43):3285-3290. doi: 10.1093/eurheartj/ehv739
  41. Franken R, Teixido-Tura G, Brion M, Forteza A, Rodriguez-Palomares J, Gutierrez L, Garcia Dorado D, Pals G, Mulder BJ, Evangelista A. Relationship between fibrillin-1 genotype and severity of cardiovascular involvement in Marfan syndrome. Heart. 2017 Nov;103(22):1795-1799. doi: 10.1136/heartjnl-2016-310631.Epub2017May3
  42. den Hartog AW, Franken R, van den Berg MP, Zwinderman AH, Timmermans J, Scholte AJ, de Waard V, Spijkerboer AM, Pals G, Mulder BJ, Groenink M. The effect of losartan therapy on ventricular function in Marfan patients with haploinsufficient or dominant negative FBN1 mutations. Neth Heart J. 2016 Nov;24(11):675-681. doi: 10.1007/s12471-016-0905-8
  43. Franken R, den Hartog AW, Radonic T, Micha D, Maugeri A, van Dijk FS, Meijers-Heijboer HE, Timmermans J, Scholte AJ, van den Berg MP, Groenink M, Mulder BJ, Zwinderman AH, de Waard V, Pals G. Beneficial Outcome of Losartan Therapy Depends on Type of FBN1 Mutation in Marfan Syndrome. Circ Cardiovasc Genet. 2015 Apr;8(2):383-8. doi: 10.1161/CIRCGENETICS.114.000950.Epub2015Jan22
  44. Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, Myers L, Klein EC, Liu G, Calvi C, Podowski M, Neptune ER, Halushka MK, Bedja D, Gabrielson K, Rifkin DB, Carta L, Ramirez F, Huso DL, Dietz HC. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006 Apr 7;312(5770):117-21.DOI: 10.1126/science.1124287
  45. Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, Meyers J, Leitch CC, Katsanis N, Sharifi N, Xu FL, Myers LA, Spevak PJ, Cameron DE, De Backer J, Hellemans J, Chen Y, Davis EC, Webb CL, Kress W, Coucke P, Rifkin DB, De Paepe AM, Dietz HC. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005 Mar;37(3):275-81DOI: 10.1038/ng1511
  46. Akhurst RJ. The paradoxical TGF-ß vasculopathies. Nat Genet. 2012 Jul 27;44(8):838-9.DOI: 10.1038/ng.2366
  47. Loeys BL. Angiotensin receptor blockers: a panacea for Marfan syndrome and related disorders?. Drug Discov Today. 2015 Feb;20(2):262-6. DOI: 10.1016/j.drudis.2014.09.022
  48. Franken R, Radonic T, den Hartog AW, Groenink M, Pals G, van Eijk M, Lutter R, Mulder BJ, Zwinderman AH, de Waard V; COMPARE study group.. The revised role of TGF-ß in aortic aneurysms in Marfan syndrome. Neth Heart J. 2015 Feb;23(2):116-21 doi: 10.1007/s12471-014-0622-0
  49. van Dijk FS, Meijers-Heijboer H, Pals G. Angiotensin II blockade in Marfan's syndrome. N Engl J Med. 2008 Oct 16;359(16):1733
  50. Radonic T, de Witte P, Groenink M, de Waard V, Lutter R, van Eijk M, Jansen M, Timmermans J, Kempers M, Scholte AJ, Hilhorst-Hofstee Y, van den Berg MP, van Tintelen JP, Pals G, Baars MJ, Mulder BJ, Zwinderman AH. Inflammation aggravates disease severity in Marfan syndrome patients. PLoS One. 2012;7(3):e32963. doi: 10.1371/journal.pone.0032963.Epub2012Mar30
  51. Groenink M, den Hartog AW, Franken R, Radonic T, de Waard V, Timmermans J, Scholte AJ, van den Berg MP, Spijkerboer AM, Marquering HA, Zwinderman AH, Mulder BJ. Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. Eur Heart J. 2013 Dec;34(45):3491-500doi: 10.1093/eurheartj/eht334.Epub2013Sep2
  52. Lacro RV, Dietz HC, Sleeper LA, Yetman AT, Bradley TJ, Colan SD, Pearson GD, Selamet Tierney ES, Levine JC, Atz AM, Benson DW, Braverman AC, Chen S, De Backer J, Gelb BD, Grossfeld PD, Klein GL, Lai WW, Liou A, Loeys BL, Markham LW, Olson AK, Paridon SM, Pemberton VL, Pierpont ME, Pyeritz RE, Radojewski E, Roman MJ, Sharkey AM, Stylianou MP, Wechsler SB, Young LT, Mahony L; Pediatric Heart Network Investigators. Atenolol versus losartan in children and young adults with Marfan's syndrome. N Engl J Med. 2014 Nov 27;371(22):2061-71.doi: 10.1056/NEJMoa1404731.Epub2014Nov18
  53. Milleron O, Arnoult F, Ropers J, Aegerter P, Detaint D, Delorme G, Attias D, Tubach F, Dupuis-Girod S, Plauchu H, Barthelet M, Sassolas F, Pangaud N, Naudion S, Thomas-Chabaneix J, Dulac Y, Edouard T, Wolf JE, Faivre L, Odent S, Basquin A, Habib G, Collignon P15, Boileau C16, Jondeau G17. Marfan Sartan: a randomized, double-blind, placebo-controlled trial. Eur Heart J. 2015 Aug 21;36(32):2160-6.doi: 10.1093/eurheartj/ehv151.Epub2015May2
  54. Teixido-Tura G, Forteza A, Rodríguez-Palomares J, González Mirelis J, Gutiérrez L, Sánchez V, Ibáñez B, García-Dorado D, Evangelista A. Losartan Versus Atenolol for Prevention of Aortic Dilation in Patients With Marfan Syndrome. J Am Coll Cardiol. 2018 Oct 2;72(14):1613-1618doi: 10.1016/j.jacc.2018.07.052
  55. Gao L, Chen L, Fan L, Gao D, Liang Z, Wang R, Lu W. The effect of losartan on progressive aortic dilatation in patients with Marfan's syndrome: a meta-analysis of prospective randomized clinical trials. Int J Cardiol. 2016 Aug 15;217:190-4. doi: 10.1016/j.ijcard.2016.04.186.Epub2016May4

Last update:

No citation recorded.

Last update:

No citation recorded.