Heart and Vessels

, Volume 31, Issue 10, pp 1717–1723 | Cite as

Variable severity of cardiovascular phenotypes in patients with an early-onset form of Marfan syndrome harboring FBN1 mutations in exons 24–32

  • Jun MaedaEmail author
  • Kenjiro Kosaki
  • Junko Shiono
  • Kazuki Kouno
  • Ryo Aeba
  • Hiroyuki Yamagishi
Case Report


A subgroup of patients with Marfan syndrome (MFS) who have mutations in exons 24–32 of the FBN1 gene manifests severe atrioventricular valve insufficiency and skeletal problems as early as the neonatal period. These patients usually die in the first 2 years of life, thus a region between exons 24 and 32 of FBN1 is recognized as a critical region for this neonatal form of MFS (nMFS). Here, we report five consecutive patients who manifested a cardiovascular phenotype until infancy with mutations in the critical region for nMFS. Although three of these patients showed severe mitral regurgitation and died before reaching 1 year of age, the remaining two patients survived for over 5 years under medical and/or surgical interventions. Two splicing mutations and one missense mutation were identified in the three deceased patients, whereas two missense mutations were found in the two survivors. Currently, the clinical severity of patients with early-onset MFS harboring mutations in the critical region for nMFS seem to be more variable than ever thought, and intensive treatments are recommended even in this subgroup of patients with MFS.


Early-onset form of Marfan syndrome Cardiovascular phenotype FBN1 mutation 



We specially thank members of the Center for Medical Genetics, Keio University School of Medicine for their molecular analysis of FBN1. We also thank Jun Yasuhara for providing critical comments on the clinical reports.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Hennekam RC (2005) Severe infantile Marfan syndrome versus neonatal Marfan syndrome. Am J Med Genet A 139:1CrossRefPubMedGoogle Scholar
  2. 2.
    Collod-Béroud G, Le Bourdelles S, Ades L, Ala-Kokko L, Booms P, Boxer M, Child A, Comeglio P, De Paepe A, Hyland JC, Holman K, Kaitila I, Loeys B, Matyas G, Nuytinck L, Peltonen L, Rantamaki T, Robinson P, Steinmann B, Junien C, Béroud C, Boileau C (2003) Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat 22:199–208CrossRefPubMedGoogle Scholar
  3. 3.
    Putnam EA, Cho M, Zinn AB, Towbin JA, Byers PH, Milewicz DM (1996) Delineation of the Marfan phenotype associated with mutations in exons 23–32 of the FBN1 gene. Am J Med Genet 62:233–242CrossRefPubMedGoogle Scholar
  4. 4.
    Faivre L, Collod-Beroud G, Callewaert B, Child A, Binquet C, Gautier E, Loeys BL, Arbustini E, Mayer K, Arslan-Kirchner M, Stheneur C, Kiotsekoglou A, Comeglio P, Marziliano N, Wolf JE, Bouchot O, Khau-Van-Kien P, Beroud C, Claustres M, Bonithon-Kopp C, Robinson PN, Adès L, De Backer J, Coucke P, Francke U, De Paepe A, Jondeau G, Boileau C (2009) Clinical and mutation-type analysis from an international series of 198 probands with a pathogenic FBN1 exons 24–32 mutation. Eur J Hum Genet 17:491–501CrossRefPubMedGoogle Scholar
  5. 5.
    Stheneur C, Faivre L, Collod-Béroud G, Gautier E, Binquet C, Bonithon-Kopp C, Claustres M, Child AH, Arbustini E, Adès LC, Francke U, Mayer K, Arslan-Kirchner M, De Paepe A, Chevallier B, Bonnet D, Jondeau G, Boileau C (2011) Prognosis factors in probands with an FBN1 mutation diagnosed before the age of 1 year. Pediatr Res 69:265–270CrossRefPubMedGoogle Scholar
  6. 6.
    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 (2010) The revised Ghent nosology for the Marfan syndrome. J Med Genet 47:476–485CrossRefPubMedGoogle Scholar
  7. 7.
    Pettersen MD, Du W, Skeens ME, Humes RA (2008) Regression equations for calculation of z scores of cardiac structures in a large cohort of healthy infants, children, and adolescents: an echocardiographic study. J Am Soc Echocardiogr 21:922–934CrossRefPubMedGoogle Scholar
  8. 8.
    Booms P, Cisler J, Mathews KR, Godfrey M, Tiecke F, Kaufmann UC, Vetter U, Hagemeier C, Robinson PN (1999) Novel exon skipping mutation in the fibrillin-1 gene: two ‘hot spots’ for the neonatal Marfan syndrome. Clin Genet 55:110–117CrossRefPubMedGoogle Scholar
  9. 9.
    Liu W, Qian C, Comeau K, Brenn T, Furthmayr H, Francke U (1996) Mutant fibrillin-1 monomers lacking EGF-like domains disrupt microfibril assembly and cause severe Marfan syndrome. Hum Mol Genet 5:1581–1587CrossRefPubMedGoogle Scholar
  10. 10.
    Tiecke F, Katzke S, Booms P, Robinson PN, Neumann L, Godfrey M, Mathews KR, Scheuner M, Hinkel GK, Brenner RE, Hövels-Gürich HH, Hagemeier C, Fuchs J, Skovby F, Rosenberg T (2001) Classic, atypically severe and neonatal Marfan syndrome: twelve mutations and genotype-phenotype correlations in FBN1 exons 24–40. Eur J Hum Genet 9:13–21CrossRefPubMedGoogle Scholar
  11. 11.
    Barnett CP, Wilson GJ, Chiasson DA, Gross GJ, Hinek A, Hawkins C, Chitayat D (2010) Central nervous system abnormalities in two cases with neonatal Marfan syndrome with novel mutations in the fibrillin-1 gene. Am J Med Genet A 152A:2409–2412CrossRefPubMedGoogle Scholar
  12. 12.
    Giusti B, Porciani MC, Brunelli T, Evangelisti L, Fedi S, Gensini GF, Abbate R, Sani G, Yacoub M, Pepe G (2003) Phenotypic variability of cardiovascular manifestations in Marfan syndrome. possible role of hyperhomocysteinemia and C677T MTHFR gene polymorphism. Eur Heart J 24:2038–2045CrossRefPubMedGoogle Scholar
  13. 13.
    Attanasio M, Lapini I, Evangelisti L, Lucarini L, Giusti B, Porciani M, Fattori R, Anichini C, Abbate R, Gensini G, Pepe G (2008) FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations. Clin Genet 74:39–46CrossRefPubMedGoogle Scholar
  14. 14.
    Nijbroek G, Sood S, McIntosh I, Francomano CA, Bull E, Pereira L, Ramirez F, Pyeritz RE, Dietz HC (1995) Fifteen novel FBN1 mutations causing Marfan syndrome detected by heteroduplex analysis of genomic amplicons. Am J Hum Genet 57:8–21PubMedPubMedCentralGoogle Scholar
  15. 15.
    Summers KM, Nataatmadja M, Xu D, West MJ, McGill JJ, Whight C, Colley A, Adès LC (2005) Histopathology and fibrillin-1 distribution in severe early onset Marfan syndrome. Am J Med Genet A 139:2–8CrossRefPubMedGoogle Scholar
  16. 16.
    Loeys B, Nuytinck L, Delvaux I, De Bie S, De Paepe A (2001) Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. Arch Intern Med 161:2447–2454CrossRefPubMedGoogle Scholar
  17. 17.
    Wang M, Wang J-Y, Cisler J, Imaizumi K, Burton BK, Jones MC, Lamberti JL, Godfrey M (1997) Three novel fibrillin mutations in exons 25 and 27: classic versus neonatal Marfan syndrome. Hum Mutat 9:359–362CrossRefPubMedGoogle Scholar
  18. 18.
    Schrijver I, Liu W, Brenn T, Furthmayr H, Francke U (1999) Cysteine substitutions in epidermal growth factor-like domains of fibrillin-1: distinct effects on biochemical and clinical phenotypes. Am J Hum Genet 65:1007–1020CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Adès LC, Haan EA, Colley AF, Richard RI (1996) Characterisation of four novel fibrillin-1 (FBN1) mutations in Marfan syndrome. J Med Genet 33:665–671CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Pepe G, Giusti B, Attanasio M, Comeglio P, Porciani MC, Giurlani L, Montesi GF, Calamai GC, Vaccari M, Favilli S, Abbate R, Gensini GF (1997) A major involvement of the cardiovascular system in patients affected by Marfan syndrome: novel mutations in fibrillin 1 gene. J Mol Cell Cardiol 29:1877–1884CrossRefPubMedGoogle Scholar
  21. 21.
    Tynan K, Comeau K, Pearson M, Wilgenbus P, Levitt D, Gasner C, Berg MA, Miller DC, Francke U (1993) Mutation screening of complete fibrillin-1 coding sequence: report of five new mutations, including two in 8-cysteine domains. Hum Mol Genet 2:1813–1821CrossRefPubMedGoogle Scholar
  22. 22.
    Takata M, Amiya E, Watanabe M, Omori K, Imai Y, Fujita D, Nishimura H, Kato M, Morota T, Nawata K, Ozeki A, Watanabe A, Kawarasaki S, Hosoya Y, Nakao T, Maemura K, Nagai R, Hirata Y, Komuro I (2014) Impairment of flow-mediated dilation correlates with aortic dilation in patients with Marfan syndrome. Heart Vessels 29:478–485CrossRefPubMedGoogle Scholar
  23. 23.
    Grewal N, Franken R, Mulder BJ, Goumans MJ, Lindeman JH, Jongbloed MR, DeRuiter MC, Klautz RJ, Bogers AJ, Poelmann RE, Groot AC (2015) Histopathology of aortic complications in bicuspid aortic valve versus Marfan syndrome: relevance for therapy? Heart Vessels. doi: 10.1007/s00380-015-0703-z PubMedPubMedCentralGoogle Scholar
  24. 24.
    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 (2013) Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. Eur Heart J 34:3491–3500CrossRefPubMedGoogle Scholar
  25. 25.
    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 (2014) Atenolol versus losartan in children and young adults with Marfan’s syndrome. N Engl J Med 371:2061–2071CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    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 P, Boileau C, Jondeau G (2015) Marfan Sartan: a randomized, double-blind, placebo-controlled trial. Eur Heart J 36:2160–2166CrossRefPubMedGoogle Scholar

Copyright information

© Springer Japan 2016

Authors and Affiliations

  • Jun Maeda
    • 1
    Email author
  • Kenjiro Kosaki
    • 2
  • Junko Shiono
    • 3
  • Kazuki Kouno
    • 1
  • Ryo Aeba
    • 4
  • Hiroyuki Yamagishi
    • 1
  1. 1.Department of PediatricsKeio University School of MedicineTokyoJapan
  2. 2.Center for Medical GeneticsKeio University School of MedicineTokyoJapan
  3. 3.Department of Pediatric CardiologyIbaraki Children’s HospitalIbarakiJapan
  4. 4.Division of Cardiovascular SurgeryKeio University School of MedicineTokyoJapan

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