Skip to main content
SpringerLink
Log in

Neurofibromatosis-Noonan Syndrome: A Possible Paradigm of the Combination of Genetic and Epigenetic Factors

  • Conference paper
  • First Online:
GeNeDis 2016

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 987))

Abstract

Neurofibromatosis-Noonan syndrome (NFNS) is a clinical entity possessing traits of autosomal dominant disorders neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). Germline mutations that disrupt the RAS/MAPK pathway are involved in the pathogenesis of both NS and NF1. In light of a studied Greek family, a new theory for etiological pathogenesis of NFNS is suggested. The NFNS phenotype may be the final result of a combination of a genetic factor (a mutation in the NF1 gene) and an environmental factor with the epigenetic effects of muscle hypotonia (such as hydantoin in the reported Greek family), causing hypoplasia of the face and micrognathia.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Allanson, J.E., J.G. Hall, and M.I. Van Allen. 1985. Noonan Phenotype Associated with Neurofibromatosis. American Journal of Medical Genetics 21: 457–462.

    Article  CAS  PubMed  Google Scholar 

  2. Opitz, J.M., and D.D. Weaver. 1985. The Neurofibromatosis-Noonan Syndrome. American Journal of Medical Genetics 21: 477–490.

    Article  CAS  PubMed  Google Scholar 

  3. Ferner, R.E., S.M. Huson, N. Thomas, C. Moss, H. Willshaw, D.G. Evans, M. Upadhyaya, R. Towers, M. Gleeson, C. Steiger, and A. Kirby. 2007. Guidelines for the Diagnosis and Management of Individuals with Neurofibromatosis 1. Journal of Medical Genetics44: 81–88.

    Article  CAS  PubMed  Google Scholar 

  4. Allanson, J.E. 1987. Noonan Syndrome. Journal of Medical Genetics 24: 9–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lu-Emerson, C., and S.R. Plotkin. 2009. The Neurofibromatoses. Part 1: NF1. Reviews in Neurological Diseases 6: E47–E53.

    PubMed  Google Scholar 

  6. Williams, V.C., J. Lucas, M.A. Babcock, D.H. Gutmann, B. Korf, and B.L. Maria. 2009. Neurofibromatosis Type 1 Revisited. Pediatrics 123: 124–133.

    Article  PubMed  Google Scholar 

  7. Xu, G.F., P. O’Connell, D. Viskochil, R. Cawton, M. Robertson, M. Cilver, D. Dunn, J. Stevens, R. Gesteland, and R. White. 1990. The Neurofibromatosis Type 1 Gene Encodes a Protein Related to GAP. Cell 62: 599–608.

    Article  CAS  PubMed  Google Scholar 

  8. Jorge, A.A., A.C. Malaquias, I.J. Arnhold, and B.B. Mendonca. 2009. Noonan Syndrome and Related Disorders: A Review of Clinical Features and Mutations in Genes of the RAS/MAPK Pathway. Hormone Research 71: 185–193.

    Article  CAS  PubMed  Google Scholar 

  9. Viskochil, D.H. 2011. Disorders of the RAS Pathway: An Introduction. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics 157C: 79–82.

    Article  PubMed  Google Scholar 

  10. Tartaglia, M., E.L. Mehler, R. Goldberg, G. Zampino, H.G. Brunner, H. Kremer, I. van der Burgt, A.H. Crosby, A. Ion, S. Jeffery, K. Kalidas, M.A. Patton, R.S. Kucherlapati, and B.D. Gelb. 2001. Mutations in PTPN11, Encoding the Protein Tyrosine Phosphatase SHP2, Cause Noonan Syndrome. Nature Genetics 29: 465–468.

    Article  CAS  PubMed  Google Scholar 

  11. Musante, L., H.G. Kehl, F. Majewski, P. Meinecke, S. Schweiger, G. Gillessen-Kaesbach, D. Wieczorek, G.K. Hinkel, S. Tinschert, M. Hoeltzenbein, H.-H. Ropers, and V.M. Kalscheuer. 2003. Spectrum of Mutations in PTPN11 and Genotype-Phenotype Correlation in 96 Patients with Noonan Syndrome and Five Patients with Cardiofacio-Cutaneous Syndrome. European Journal of Human Genetics 11: 201–206.

    Article  CAS  PubMed  Google Scholar 

  12. van der Burgt, I., and H. Brunner. 2000. Genetic Heterogeneity in Noonan Syndrome: Evidence for an Autosomal Recessive Form. American Journal of Medical Genetics 94: 46–51.

    Article  Google Scholar 

  13. Roberts, A.E., T. Araki, K.D. Swanson, K.T. Montgomery, T.A. Schiripo, V.A. Joshi, L. Li, Y. Yassin, A.M. Tamburino, B.G. Neel, and R.S. Kucherlapati. 2007. Germline Gain-of-Function Mutations in SOS1 Cause Noonan Syndrome. Nature Genetics 39: 70–74.

    Article  CAS  PubMed  Google Scholar 

  14. Yamamoto, G.L., M. Aguena, M. Gos, C. Hung, J. Pilch, S. Fahiminiya, A. Abramowicz, I. Cristian, M. Buscarilli, M.S. Naslavsky, A.C. Malaquias, M. Zatz, O. Bodamer, J. Majewski, A.A.L. Jorge, A.C. Pereira, C.A. Kim, M.R. Passos-Bueno, and D.R. Bertola. 2015. Rare Variants in SOS2 and LZTR1 are Associated with Noonan Syndrome. Journal of Medical Genetics 52: 413–421.

    Article  CAS  PubMed  Google Scholar 

  15. Schubbert, S., M. Zenker, S.L. Rowe, S. Boll, C. Klein, G. Bollag, I. van der Burgt, L. Musante, V. Kalscheuer, L.-E. Wehner, H. Nguyen, B. West, K.Y.J. Zhang, E. Sistermans, A. Rauch, C.M. Niemeyer, K. Shannon, and C.P. Kratz. 2006. Germline KRAS Mutations Cause Noonan Syndrome. Nature Genetics 38: 331–336.

    Article  CAS  PubMed  Google Scholar 

  16. Ferrero, G.B., G. Baldassarre, A.G. Delmonaco, E. Biamino, E. Banaudi, C. Carta, C. Rossi, and M.C. Silengo. 2008. Clinical and Molecular Characterization of 40 Patients with Noonan Syndrome. European Journal of Medical Genetics 51: 566–572.

    Article  PubMed  Google Scholar 

  17. De Filippi, P., M. Zecca, D. Lisini, V. Rosti, C. Cagioni, C. Carlo-Stella, O. Radi, P. Veggiotti, A. Mastronuzzi, A. Acquaviva, A. D’Ambrosio, F. Locatelli, and C. Danesino. 2009. Germ-Line Mutation of the NRAS Gene may be Responsible for the Development of Juvenile Myelomonocytic Leukaemia. British Journal of Haematology 147: 706–709.

    Article  PubMed  Google Scholar 

  18. Aoki, Y., T. Niihori, T. Banjo, N. Okamoto, S. Mizuno, K. Kurosawa, T. Ogata, F. Takada, M. Yano, T. Ando, T. Hoshika, C. Barnett, H. Ohashi, H. Kawame, T. Hasegawa, T. Okutani, T. Nagashima, S. Hasegawa, R. Funayama, T. Nagashima, K. Nakayama, S. Inoue, Y. Watanabe, T. Ogura, and Y. Matsubara. 2013. Gain-Offunction Mutations in RIT1 Cause Noonan Syndrome, a RAS/MAPK Pathway Syndrome. American Journal of Human Genetics 93: 173–180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pandit, B., A. Sarkozy, L.A. Pennacchio, C. Carta, K. Oishi, S. Martinelli, E.A. Pogna, W. Schackwitz, A. Ustaszewska, A. Landstrom, J.M. Bos, S.R. Ommen, G. Esposito, F. Lepri, C. Faul, P. Mundel, J.P. López Siguero, R. Tenconi, A. Selicorni, C. Rossi, L. Mazzanti, I. Torrente, B. Marino, M.C. Digilio, G. Zampino, M.J. Ackerman, B. Dallapiccola, M. Tartaglia, and B.D. Gelb. 2007. Gain of-Function RAF1 Mutations Cause Noonan and LEOPARD Syndromes with Hypertrophic Cardiomyopathy. Nature Genetics 39: 1007–1012.

    Article  CAS  PubMed  Google Scholar 

  20. Sarkozy, A., C. Carta, S. Moretti, G. Zampino, M.C. Digilio, F. Pantaleoni, A.P. Scioletti, G. Esposito, V. Cordeddu, F. Lepri, V. Petrangeli, M.L. Dentici, G.M. Mancini, A. Selicorni, C. Rossi, L. Mazzanti, B. Marino, G.B. Ferrero, M.C. Silengo, L. Memo, F. Stanzial, F. Faravelli, L. Stuppia, E. Puxeddu, B.D. Gelb, B. Dallapiccola, and M. Tartaglia. 2009. Germline BRAF Mutations in Noonan, LEOPARD, and Cardiofaciocutaneous Syndromes: Molecular Diversity and Associated Phenotypic Spectrum. Human Mutation 30: 695–702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Colley, A., D. Donnai, and D.G. Evans. 1996. Neurofibromatosis/Noonan Phenotype: A Variable Feature of Type 1 Neurofibromatosis. Clinical Genetics 49: 59–64.

    Article  CAS  PubMed  Google Scholar 

  22. Bertola, D.R., A.C. Pereira, F. Passetti, P.S. de Oliveira, L. Messiaen, B.D. Gelb, C.A. Kim, and J.E. Krieger. 2005. Neurofibromatosis–Noonan Syndrome: Molecular Evidence of the Concurrence of Both Disorders in a Patient. American Journal of Medical Genetics. Part A 136: 242–245.

    Article  PubMed  Google Scholar 

  23. Thiel, C., M. Wilken, M. Zenker, H. Sticht, R. Fahsold, G.-C. Gusek-Schneider, and A. Rauch. 2009. Independent NF1 and PTPN11 Mutations in a Family with Neurofibromatosis-Noonan Syndrome. American Journal of Medical Genetics 149A: 1263–1267.

    Article  CAS  PubMed  Google Scholar 

  24. Edman Ahlbom, B., N. Dahl, P. Zetterqvist, and G. Anneren. 1995. Noonan Syndrome with cafe-au-lait Spots and Multiple Lentigines Syndrome are not Linked to the Neurofibromatosis Type 1 Locus. Clinical Genetics 48: 85–89.

    Article  Google Scholar 

  25. Nystrom, A.M., S. Ekvall, J. Allanson, C. Edeby, M. Elinder, G. Holmstrom, M.L. Bondeson, and G. Anneren. 2009. Noonan Syndrome and Neurofibromatosis Type I in a Family with a Novel Mutation in NF1. Clinical Genetics 76: 524–534.

    Article  CAS  PubMed  Google Scholar 

  26. Meinecke, P. 1987. Evidence that the Neurofibromatosis-Noonan Syndrome is a Variant of von Recklinghausen Neurofibromatosis. American Journal of Medical Genetics 26: 741–745.

    Article  CAS  PubMed  Google Scholar 

  27. Stern, H.J., H.M. Saal, J.S. Lee, P.R. Fain, D.E. Goldgar, K.N. Rosenbaum, and D.F. Barker. 1992. Clinical Variability of Type 1 Neurofibromatosis: Is there a Neurofibromatosis-Noonan Syndrome? Journal of Medical Genetics 29: 184–187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Baralle, D., C. Mattocks, K. Kalidas, F. Elmslie, J. Whittaker, M. Lees, N. Ragge, M.A. Patton, R.M. Winter, and C. Ffrench-Constant. 2003. Different Mutations in the NF1 Gene are Associated with Neurofibromatosis–Noonan Syndrome (NFNS). American Journal of Medical Genetics 119A: 1–8.

    Article  PubMed  Google Scholar 

  29. De Luca, A., I. Bottillo, A. Sarkozy, C. Carta, C. Neri, E. Bellacchio, A. Schirinzi, E. Conti, G. Zampino, A. Battaglia, S. Majore, M.M. Rinaldi, M. Carella, B. Marino, A. Pizzuti, M.C. Digilio, M. Tartaglia, and B. Dallapiccola. 2005. NF1 Gene Mutations Represent the Major Molecular Event Underlying Neurofibromatosis–Noonan Syndrome. American Journal of Human Genetics 77: 1092–1101.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Stevenson, D.A., D.H. Viskochil, A.F. Rope, and J.C. Carey. 2006. Clinical and Molecular Aspects of an Informative Family with Neurofibromatosis Type 1 and Noonan Phenotype. Clinical Genetics 69: 246–253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yapijakis, C., N. Pachis, S. Natsis, and C. Voumvourakis. 2016. Is Neurofibromatosis Type 1-Noonan Syndrome a Phenotypic Result of Combined Genetic and Epigenetic Factors? In Vivo 30: 315–320.

    Article  PubMed  Google Scholar 

  32. Horiuchi, T., N. Hatta, M. Matsumoto, H. Ohtsuka, F.S. Collins, Y. Kobayashi, and S. Fujita. 1994. Nonsense Mutations at Arg-1947 in Two Cases of Familial Neurofibromatosis Type 1 in Japanese. Human Genetics 93: 81–83.

    Article  CAS  PubMed  Google Scholar 

  33. Andrews, J.D., D.N. Mancini, S.M. Singh, and D.I. Rodenhiser. 1996. Site and Sequence Specific DNA Methylation in the Neurofibromatosis (NF1) Gene Includes C5839T: The Site of the Recurrent Substitution Mutation in Exon 31. Human Molecular Genetics 5: 503–507.

    Article  CAS  PubMed  Google Scholar 

  34. Krkljus, S., C.R. Abernathy, J.S. Johnson, C.A. Williams, D.J. Driscoll, R. Zori, H.J. Stalker, S.A. RASmussen, F.S. Collins, B.G. Kousseff, L. Baumbach, and M.R. Wallace. 1998. Analysis of CpG C-to-T Mutations in Neurofibromatosis Type 1. Mutations in Brief no. 129. Human Mutation 11: 411.

    Article  CAS  PubMed  Google Scholar 

  35. Ainsworth, P.J., D.I. Rodenhiser, and M.T. Costa. 1993. Identification and Characterization of Sporadic and Inherited Mutations in Exon 31 of the Neurofibromatosis (NF1) Gene. Human Genetics 91: 151–156.

    Article  CAS  PubMed  Google Scholar 

  36. Estivill, X., C. Lazaro, T. Casals, and A. Ravella. 1991. Recurrence of a Nonsense Mutation in the NF1 Gene Causing Classical Neurofibromatosis Type 1. Human Genetics 88: 185–188.

    Article  CAS  PubMed  Google Scholar 

  37. Heim, R.A., L.M. Silverman, R.A. Farber, L.N.W. Kam-Morgan, and M.C. Luce. 1994. Screening for Truncated NF1 Proteins. Nature Genetics 8: 218–219.

    Article  CAS  PubMed  Google Scholar 

  38. Lazaro, C., H. Kruyer, A. Gaona, and X. Estivill. 1995. Two Further Cases of Mutation R1947X in the NF1 Gene: Screening for a Relatively Common Recurrent Mutation. Human Genetics 96: 361–363.

    Article  CAS  PubMed  Google Scholar 

  39. Klose, A., H. Peters, S. Hoffmeyer, A. Buske, A. Lüder, D. Hess, R. Lehmann, P. Nürnberg, and S. Tinschert. 1999. Two Independent Mutations in a Family with Neurofibromatosis Type 1 (NF1). American Journal of Medical Genetics 83: 6–12.

    Article  CAS  PubMed  Google Scholar 

  40. Park, K.C., H.O. Choi, K.H. Park, K.H. Kim, and H.C. Eun. 2000. A Nonsense Mutation at Arg-1947 in the NF1 Gene in a Case of Neurofibromatosis Type 1 in a Korean Patient. Journal of Human Genetics 45: 84–85.

    Article  CAS  PubMed  Google Scholar 

  41. Origone, P., A. De Luca, C. Bellini, A. Buccino, R. Mingarelli, S. Costabel, C. La Rosa, C. Garrè, D.A. Coviello, F. Ajmar, B. Dallapiccola, and E. Bonioli. 2002. Ten Novel Mutations in the Humanneurofibromatosis Type 1 (NF1) Gene in Italian Patients. Human Mutation 20: 74–75.

    Article  PubMed  Google Scholar 

  42. Yang, Q., C. Huang, X. Yang, Y. Feng, Q. Wang, and M. Liu. 2008. The R1947X Mutation of NF1 Causing Autosomal Dominant Neurofibromatosis Type 1 in a Chinese Family. Journal of Genetics and Genomics 35: 73–76.

    Article  PubMed  Google Scholar 

  43. Oguni, M., and M. Osawa. 2004. Epilepsy and Pregnancy. Epilepsia 45 (Suppl. 8): 37–41.

    Article  PubMed  Google Scholar 

  44. Rohrer, T. 2009. Noonan Syndrome: Introduction and Basic Clinical Features. Hormone Research 72 (Suppl. 2): 3–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Oral and Maxillofacial Surgery, School of Medicine, University of Athens, Attikon Hospital, Athens, Greece

    Christos Yapijakis

  2. “Cephalogenetics” Genetic Center, Athens, Greece

    Christos Yapijakis & Nikos Pachis

  3. Department of Neurology, School of Medicine, University of Athens, Eginition Hospital, Athens, Greece

    Christos Yapijakis

  4. 2nd Department of Neurology, School of Medicine, University of Athens, Attikon Hospital, Athens, Greece

    Costas Voumvourakis

Authors
  1. Christos Yapijakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nikos Pachis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Costas Voumvourakis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christos Yapijakis .

Editor information

Editors and Affiliations

  1. Department of Informatics, Bioinformatics and Human Electrophysiology Laboratory, Ionian University, Corfu, Greece

    Panayiotis Vlamos

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this paper

Cite this paper

Yapijakis, C., Pachis, N., Voumvourakis, C. (2017). Neurofibromatosis-Noonan Syndrome: A Possible Paradigm of the Combination of Genetic and Epigenetic Factors. In: Vlamos, P. (eds) GeNeDis 2016. Advances in Experimental Medicine and Biology, vol 987. Springer, Cham. https://doi.org/10.1007/978-3-319-57379-3_14

Download citation

Publish with us

Policies and ethics

Search

Navigation