Journal Mobile Options
Table of Contents
Vol. 72, Suppl. 2, 2009
Issue release date: December 2009
Section title: Paper
Horm Res 2009;72(suppl 2):57–63
(DOI:10.1159/000243782)

Genetic and Pathogenetic Aspects of Noonan Syndrome and Related Disorders

Zenker M.
Institute of Human Genetics, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, and Institute of Human Genetics, University Hospital Magdeburg, Otto-von-Guericke University, Magdeburg, Germany

Do you have an account?

Register and profit from personalized services (MyKarger) Login Information

Please create your User ID & Password





Contact Information









I have read the Karger Terms and Conditions and agree.

Register and profit from personalized services (MyKarger) Login Information

Please create your User ID & Password





Contact Information









I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in

Buy

  • FullText & PDF
  • Unlimited re-access via MyKarger (new!)
  • Unrestricted printing, no saving restrictions for personal use
  • Reduced rates with a PPV account
read more

Direct: USD 38.00
Account: USD 26.50

Select

Rent/Cloud

  • Rent for 48h to view
  • Buy Cloud Access for unlimited viewing via different devices
  • Synchronizing in the ReadCube Cloud
  • Printing and saving restriction apply

Rental: USD 8.50
Cloud: USD 20.00

Select

Subscribe

  • Automatic perpetual access to all articles of the subscribed year(s)
  • Unlimited re-access via Subscriber Login or MyKarger
  • Unrestricted printing, no saving restrictions for personal use
read more

Subcription rates


Select


Article / Publication Details

First-Page Preview
Abstract of Paper

Published online: 12/22/2009

Number of Print Pages: 7
Number of Figures: 2
Number of Tables: 0

ISSN: 1663-2818 (Print)
eISSN: 1663-2826 (Online)

For additional information: http://www.karger.com/HRP

Abstract

Noonan syndrome (NS) and the clinically overlapping disorders cardio-facio-cutaneous syndrome, LEOPARD syndrome, Costello syndrome and Neurofibromatosis-Noonan syndrome share the clinical features of short stature, the same spectrum of congenital heart defects, and a similar pattern of craniofacial anomalies. It is now known that all these disorders are caused by mutations in components of the RAS-MAPK signaling pathway. This pathway was previously known for its involvement in tumorigenesis. This article reviews the current knowledge on underlying genetic alterations and possible pathogenetic mechanisms responsible for NS and related disorders. It discusses the relationship between a group of developmental disorders and oncogenes. Potential future treatment prospects are based on the possibility of inhibiting RAS-MAPK signaling by pharmaceuticals.


Article / Publication Details

First-Page Preview
Abstract of Paper

Published online: 12/22/2009

Number of Print Pages: 7
Number of Figures: 2
Number of Tables: 0

ISSN: 1663-2818 (Print)
eISSN: 1663-2826 (Online)

For additional information: http://www.karger.com/HRP


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Noonan JA: Hypertelorism with Turner phenotype: a new syndrome with associated congenital heart disease. Am J Dis Child 1968;116:373–380.
  2. Allanson JE: Noonan syndrome. Am J Med Genet C Semin Med Genet 2007;145C:274–279.
  3. van der Burgt I: Noonan syndrome. Orphanet J Rare Dis 2007;2:4.
  4. Kratz CP, Niemeyer CM: Juvenile myelomonocytic leukemia. Hematology 2005;10(suppl 1):100–103.
  5. Reynolds JF, Neri G, Herrmann JP, et al: New multiple congenital anomalies/mental retardation syndrome with cardio-facio-cutaneous involvement – the CFC syndrome. Am J Med Genet 1986;25:413–427.
  6. Roberts A, Allanson J, Jadico SK, et al: The cardiofaciocutaneous syndrome. J Med Genet 2006;43:833–842.
  7. Costello JM: A new syndrome: mental subnormality and nasal papillomata. Aust Paediatr J 1977;13:114–118.
  8. Hennekam RC: Costello syndrome: an overview. Am J Med Genet C Semin Med Genet 2003;117:42–48.

    External Resources

  9. Gripp KW: Tumor predisposition in Costello syndrome. Am J Med Genet C Semin Med Genet 2005;137:72–77.
  10. Sarkozy A, Digilio MC, Dallapiccola B: LEOPARD syndrome. Orphanet J Rare Dis 2008;3:13.
  11. Huffmeier U, Zenker M, Hoyer J, et al: A variable combination of features of Noonan syndrome and neurofibromatosis type I are caused by mutations in the NF1 gene. Am J Med Genet A 2006;140:2749–2756.

    External Resources

  12. Colley A, Donnai D, Evans DG: Neurofibromatosis/Noonan phenotype: a variable feature of type 1 neurofibromatosis. Clin Genet 1996;49:59–64.
  13. Brems H, Chmara M, Sahbatou M, et al: Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet 2007;39:1120–1126.
  14. Bentires-Alj M, Kontaridis MI, Neel BG: Stops along the RAS pathway in human genetic disease. Nat Med 2006;12:283–285.
  15. Wittinghofer A: Signal transduction via Ras. Biol Chem 1998;379:933–937.
  16. Bos JL: ras oncogenes in human cancer: a review. Cancer Res 1989;49:4682–4689.
  17. Tartaglia M, Cordeddu V, Chang H, et al: Paternal germline origin and sex-ratio distortion in transmission of PTPN11 mutations in Noonan syndrome. Am J Hum Genet 2004;75:492–497.
  18. van Der Burgt I, Brunner H: Genetic heterogeneity in Noonan syndrome: evidence for an autosomal recessive form. Am J Med Genet 2000;94:46–51.
  19. Tartaglia M, Mehler EL, Goldberg R, et al: Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 2001;29:465–468.
  20. Tartaglia M, Niemeyer CM, Fragale A, et al: Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 2003;34:148–150.
  21. Aoki Y, Niihori T, Kawame H, et al: Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet 2005;37:1038–1040.
  22. Schubbert S, Zenker M, Rowe SL, et al: Germline KRAS mutations cause Noonan syndrome. Nat Genet 2006;38:331–336.
  23. Niihori T, Aoki Y, Narumi Y, et al: Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet 2006;38:294–296.
  24. Rodriguez-Viciana P, Tetsu O, Tidyman WE, et al: Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science 2006;311:1287–1290.
  25. Roberts AE, Araki T, Swanson KD, et al: Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet 2007;39:70–74.
  26. Tartaglia M, Pennacchio LA, Zhao C, et al: Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet 2007;39:75–79.
  27. Pandit B, Sarkozy A, Pennacchio LA, et al: Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet 2007;39:1007–1012.
  28. Razzaque MA, Nishizawa T, Komoike Y, et al: Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet 2007;39:1013–1017.
  29. Nava C, Hanna N, Michot C, et al: Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome. J Med Genet 2007;44:763–771.
  30. Narumi Y, Aoki Y, Niihori T, et al: Clinical manifestations in patients with SOS1 mutations range from Noonan syndrome to CFC syndrome. J Hum Genet 2008;53:834–841.
  31. Nystrom AM, Ekvall S, Berglund E, et al: Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders. J Med Genet 2008;45:500–506.
  32. Zenker M, Horn D, Wieczorek D, et al: SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome. J Med Genet 2007;44:651–656.
  33. Kontaridis MI, Swanson KD, David FS, et al: PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem 2006;281:6785–6792.
  34. Tartaglia M, Martinelli S, Stella L, et al: Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet 2006;78:279–290.
  35. Oishi K, Zhang H, Gault WJ, et al: Phosphatase-defective LEOPARD syndrome mutations in PTPN11 have gain-of-function effects during Drosophila development. Hum Mol Genet 2008;18:193–201.
  36. Krenz M, Gulick J, Osinska HE, et al: Role of ERK1/2 signaling in congenital valve malformations in Noonan syndrome. Proc Natl Acad Sci USA 2008;105:18930–18935.
  37. Kim SO, Jiang J, Yi W, et al: Involvement of the Src homology 2-containing tyrosine phosphatase SHP-2 in growth hormone signaling. J Biol Chem 1998;273:2344–2354.
  38. Binder G, Neuer K, Ranke MB, et al: PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome. J Clin Endocrinol Metab 2005;90:5377–5381.
  39. Aoki Y, Niihori T, Narumi Y, et al: The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum Mutat 2008;29:992–1006.
  40. Schulz AL, Albrecht B, Arici C, et al: Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome. Clin Genet 2008;73:62–70.
  41. Zenker M, Lehmann K, Schulz AL, et al: Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. J Med Genet 2007;44:131–135.
  42. Kratz CP, Niemeyer CM, Zenker M: An unexpected new role of mutant Ras: perturbation of human embryonic development. J Mol Med 2007;85:227–235.
  43. Lee K, Williams B, Roza K, et al: PTPN11 analysis for the prenatal diagnosis of Noonan syndrome in fetuses with abnormal ultrasound findings. Clin Genet 2009;75:190–194.
  44. Kratz CP, Niemeyer CM, Castleberry RP, et al: The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan Syndrome/myeloproliferative disease. Blood 2005;106:2183–2185.
  45. Li W, Cui Y, Kushner SA, et al: The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1. Curr Biol 2005;15:1961–1967.
  46. Krab LC, de Goede-Bolder A, Aarsen FK, et al: Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: a randomized controlled trial. JAMA 2008;300:287–294.