Skip to main content

Neuro-kardio-fazio-kutane Syndrome

Überlappende Phänotypen mit gemeinsamem molekularem Signalweg – interdisziplinäres Betreuungskonzept

Neuro-cardio-facio-cutaneous syndromes

Overlapping phenotypes with a shared molecular pathway – interdisciplinary health management

Zusammenfassung

Neuro-kardio-fazio-kutane („neuro-cardio-facio-cutaneous“: NCFC) Syndrome wurden in den letzten Jahren als eine Gruppe von angeborenen Erkrankungen definiert, deren phänotypische Überschneidungen eine gemeinsame pathogenetische Grundlage haben. Erkrankungen aus diesem phänotypischen Spektrum gehen mit einer Überfunktion des RAS-MAPK-Signalwegs (RAS: „rat sarcoma“, MAPK mitogenaktivierte Proteinkinase) einher. Zu den neuro-kardio-fazio-kutanen Erkrankungen gehören das Noonan-, das LEOPARD-, das kardio-fazio-kutane („cardio-facio-cutaneous“: CFC) und das Costello-Syndrom, die Neurofibromatose Typ 1 sowie das Legius-Syndrom. Für eine sachgerechte medizinische Diagnostik und Behandlung sowie die notwendige psychosoziale Betreuung von Betroffenen und deren Familien ist das Zusammenwirken verschiedener Fachdisziplinen notwendig.

Abstract

Recently, neuro-cardio-facio-cutaneous (NCFC) syndromes were defined as a group of hereditary diseases with phenotypical overlap based on a similar pathogenetic mechanism. These syndromes are associated with increased signal transduction down the RAS-MAPK (RAS: rat sarcoma, MAPK: mitogen-activated protein kinase) pathway. Noonan, LEOPARD, cardio-facio-cutaneous, and Costello syndrome as well as neurofibromatosis type 1 and Legius syndrome belong to the NCFC diseases. Interdisciplinary health management is essential to determine and establish adequate medical diagnostics and treatment and to provide psychosocial support for affected patients and their families.

This is a preview of subscription content, access via your institution.

Abb. 1
Abb. 2

Literatur

  1. 1.

    Allanson JE (2007) Noonan syndrome. Am J Med Genet C Semin Med Genet 145C:274–279

    Article  PubMed  Google Scholar 

  2. 2.

    Aoki Y, Niihori T, Kawame H et al (2005) Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet 37:1038–1040

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Binder G, Neuer K, Ranke MB et al (2005) PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome. J Clin Endocrinol Metab 90:5377–5381

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Bos JL (1989) Ras oncogenes in human cancer: a review. Cancer Res 49:4682–4689

    CAS  PubMed  Google Scholar 

  5. 5.

    Brems H, Chmara M, Sahbatou M et al (2007) Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet 39:1120–1126

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Carta C, Pantaleoni F, Bocchinfuso G et al (2006) Germline missense mutations affecting KRAS isoform B are associated with a severe Noonan syndrome phenotype. Am J Hum Genet 79:129–135

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Cirstea IC, Kutsche K, Dvorsky R et al (2010) A restricted spectrum of NRAS mutations causes Noonan syndrome. Nat Genet 42:27–29

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Cordeddu V, Di Schiavi E, Pennacchio LA et al (2009) Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet 41:1022–1026

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Digilio MC, Conti E, Sarkozy A et al (2002) Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet 71:389–394

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Dorschner MO, Sybert VP, Weaver M et al (2000) NF1 microdeletion breakpoints are clustered at flanking repetitive sequences. Hum Mol Genet 9:35–46

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Feldman T, Leon MB (2007) Prospects for percutaneous valve therapies. Circulation 116:2866–2877

    Article  PubMed  Google Scholar 

  12. 12.

    Gripp KW (2005) Tumor predisposition in Costello syndrome. Am J Med Genet 137C:72–77

    Article  PubMed  Google Scholar 

  13. 13.

    Hennekam RC (2003) Costello syndrome: an overview. Am J Med Genet 117C:42–48

    Article  PubMed  Google Scholar 

  14. 14.

    Hüffmeier U, Zenker M, Hoyer J et al (2006) A variable combination of features of Noonan syndrome and neurofibromatosis type I are caused by mutations in the NF1 gene. Am J Med Genet 140:2749–2756

    Article  PubMed  Google Scholar 

  15. 15.

    Kontaridis MI, Swanson KD, David FS et al (2006) PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem 281:6785–6792

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Koudova M, Seemanova E, Zenker M (2009) Novel BRAF mutation in a patient with LEOPARD syndrome and normal intelligence. Eur J Med Genet 52:337–340

    Article  PubMed  Google Scholar 

  17. 17.

    Krab LC, Goorden SM, Elgersma Y (2008) Oncogenes on my mind: ERK and MTOR signaling in cognitive diseases. Trends Genet 24:498–510

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Lammert M, Friedman JM, Kluwe L et al (2005) Prevalence of neurofibromatosis 1 in German children at elementary school enrollment. Arch Dermatol 141:78–79

    Article  Google Scholar 

  19. 19.

    Lee DA, Portnoy S, Hill P et al (2005) Psychological profile of children with Noonan syndrome. Dev Med Child Neurol 47:35–38

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Lin AE, Grossfeld PD, Hamilton RM et al (2002) Further delineation of cardiac abnormalities in Costello syndrome. Am J Med Genet 111:115–129

    Article  PubMed  Google Scholar 

  21. 21.

    Marian AJ (2009) Contemporary treatment of hypertrophic cardiomyopathy. Tex Heart Inst J 36:194–204

    PubMed  Google Scholar 

  22. 22.

    Mautner VF Asuagbor FA, Dombi E et al (2008) Assessment of benign tumor burden by whole-body MRI in patients with neurofibromatosis 1. Neuro Oncol 10:593–598

    Article  PubMed  Google Scholar 

  23. 23.

    Mensink KA, Ketterling RP, Flynn HC et al (2006) Connective tissue dysplasia in five new patients with NF1 microdeletions: further expansion of phenotype and review of the literature. J Med Genet 43:e8

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Neumann TE, Allanson J, Kavamura I et al (2009) Multiple giant cell lesions in patients with Noonan syndrome and cardio-facio-cutaneous syndrome. Eur J Hum Genet 17:420–425

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Niihori T, Aoki Y, Narumi Y et al (2006) Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet 38:294–296

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Noordam K (2007) Expanding the genetic spectrum of Noonan syndrome. Horm Res [Suppl 5] 68:24–27

    Google Scholar 

  27. 27.

    Osio D, Dahlgren J, Wikland KA et al (2005) Improved final height with long-term growth hormone treatment in Noonan syndrome. Acta Paediatr 94:1232–1237

    Article  PubMed  Google Scholar 

  28. 28.

    Ostman-Smith I, Wettrell G, Riesenfeld T (1999) A cohort study of childhood hypertrophic cardiomyopathy: improved survival following high-dose beta-adrenoceptor antagonist treatment. J Am Coll Cardiol 34:1813–1822

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Pandit B, Sarkozy A, Pennacchio LA et al (2007) Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet 39:1007–1012

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Razzaque MA, Nishizawa T, Komoike Y et al (2007) Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet 39:1013–1017

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Roberts A, Allanson J, Jadico SK et al (2006) The cardiofaciocutaneous syndrome. J Med Genet 43:833–842

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Roberts AE, Araki T, Swanson KD et al (2007) Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet 39:70–74

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Rodriguez-Viciana P, Tetsu O, Tidyman WE et al (2006) Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science 311:1287–1290

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Sarkozy A, Digilio MC, Dallapiccola B (2008) LEOPARD syndrome. Orphanet J Rare Dis 3:13

    Article  PubMed  Google Scholar 

  35. 35.

    Schmaltz AA, Bauer U, Baumgartner H et al (2008) Medical guideline for the treatment of adults with congenital heart abnormalities of the German-Austrian-Swiss Cardiology Specialty Society. Clin Res Cardiol 97:194–214

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Schubbert S, Zenker M, Rowe SL et al (2006) Germline KRAS mutations cause Noonan syndrome. Nat Genet 38:331–336

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    Tartaglia M, Mehler EL, Goldberg R et al (2001) Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 29:465–468

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    Tartaglia M, Niemeyer CM, Fragale A et al (2003) Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 34:148–150

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Tartaglia M, Pennacchio LA, Zhao C et al (2007) Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet 39:75–79

    Article  CAS  PubMed  Google Scholar 

  40. 40.

    Tidyman WE, Rauen KA (2009) The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev 19:230–236

    Article  CAS  PubMed  Google Scholar 

  41. 41.

    Tucker T, Schnabel C, Hartmann M et al (2008) Bone health and fracture rate in individuals with NF1. J Med Genet 46: 259–265

    Article  PubMed  Google Scholar 

  42. 42.

    Tucker T, Friedman JM, Friedrich RE et al (2009) Longitudinal study of neurofibromatosis 1 associated plexiform neurofibromas. J Med Genet 46:81–85

    Article  CAS  PubMed  Google Scholar 

  43. 43.

    Vetter IR, Wittinghofer A (2001) The guanine nucleotide-binding switch in three dimensions. Science 294:1299–1304

    Article  CAS  PubMed  Google Scholar 

  44. 44.

    Wallace MR, Marchuk DA, Andersen LB et al (1990) Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249:181–186

    Article  CAS  PubMed  Google Scholar 

  45. 45.

    Zenker M, Lehmann K, Schulz AL et al (2007) Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. J Med Genet 44:131–135

    Article  CAS  PubMed  Google Scholar 

Download references

Danksagung

Die Autoren bedanken sich sehr herzlich bei den Patienten und ihren Familien für die Teilnahme an unseren Forschungsarbeiten sowie die Bereitschaft zur Publikation der Fotos.

Interessenkonflikt

Der korrespondierende Autor gibt an, dass kein Interessenkonflikt besteht.

Author information

Affiliations

Authors

Corresponding author

Correspondence to V.-F. Mautner.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Mautner, VF., Nguyen, R., Bernhard, A. et al. Neuro-kardio-fazio-kutane Syndrome. medgen 22, 10–19 (2010). https://doi.org/10.1007/s11825-010-0208-1

Download citation

Schlüsselwörter

  • Neuro-kardio-fazio-kutane Syndrome
  • Angeborene Erkrankung
  • RAS-MAPK-Signalweg
  • Multidisziplinäre Behandlung
  • Psychosoziale Betreuung

Keywords

  • Neuro-cardio-facio-cutaneous syndromes
  • Hereditary disease
  • RAS-MAPK pathway
  • Interdisciplinary health management
  • Psychosocial support