Skip to main content

Advertisement

SpringerLink
Log in

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

  • Case Report
  • Published:
Heart and Vessels Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Hennekam RC (2005) Severe infantile Marfan syndrome versus neonatal Marfan syndrome. Am J Med Genet A 139:1

    Article  PubMed  Google Scholar 

  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 22:199–208

    Article  PubMed  Google Scholar 

  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 62:233–242

    Article  CAS  PubMed  Google Scholar 

  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 17:491–501

    Article  CAS  PubMed  Google Scholar 

  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 69:265–270

    Article  PubMed  Google Scholar 

  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 47:476–485

    Article  CAS  PubMed  Google Scholar 

  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 21:922–934

    Article  PubMed  Google Scholar 

  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 55:110–117

    Article  CAS  PubMed  Google Scholar 

  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 5:1581–1587

    Article  CAS  PubMed  Google Scholar 

  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 9:13–21

    Article  CAS  PubMed  Google Scholar 

  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:2409–2412

    Article  PubMed  Google Scholar 

  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 24:2038–2045

    Article  CAS  PubMed  Google Scholar 

  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 74:39–46

    Article  CAS  PubMed  Google Scholar 

  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 57:8–21

    CAS  PubMed  PubMed Central  Google Scholar 

  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 139:2–8

    Article  CAS  PubMed  Google Scholar 

  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 161:2447–2454

    Article  CAS  PubMed  Google Scholar 

  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 9:359–362

    Article  CAS  PubMed  Google Scholar 

  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 65:1007–1020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Adès LC, Haan EA, Colley AF, Richard RI (1996) Characterisation of four novel fibrillin-1 (FBN1) mutations in Marfan syndrome. J Med Genet 33:665–671

    Article  PubMed  PubMed Central  Google Scholar 

  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 29:1877–1884

    Article  CAS  PubMed  Google Scholar 

  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 2:1813–1821

    Article  CAS  PubMed  Google Scholar 

  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 29:478–485

    Article  PubMed  Google Scholar 

  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

    PubMed  PubMed Central  Google Scholar 

  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 34:3491–3500

    Article  CAS  PubMed  Google Scholar 

  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 371:2061–2071

    Article  PubMed  PubMed Central  Google Scholar 

  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 36:2160–2166

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Jun Maeda, Kazuki Kouno & Hiroyuki Yamagishi

  2. Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan

    Kenjiro Kosaki

  3. Department of Pediatric Cardiology, Ibaraki Children’s Hospital, Ibaraki, Japan

    Junko Shiono

  4. Division of Cardiovascular Surgery, Keio University School of Medicine, Tokyo, Japan

    Ryo Aeba

Authors
  1. Jun Maeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kenjiro Kosaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Junko Shiono
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kazuki Kouno
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ryo Aeba
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroyuki Yamagishi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jun Maeda.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Maeda, J., Kosaki, K., Shiono, J. et al. Variable severity of cardiovascular phenotypes in patients with an early-onset form of Marfan syndrome harboring FBN1 mutations in exons 24–32. Heart Vessels 31, 1717–1723 (2016). https://doi.org/10.1007/s00380-016-0793-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00380-016-0793-2

Keywords

Search

Navigation