1. ¹Department of Human Genetics, University Hospital Münster, Münster, Germany
2. ²Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada
3. ³Medical Genetics, Federal University of Sao Paulo, Sao Paulo, Brazil
4. ⁴Royal Manchester Children's Hospital, Manchester, UK
5. ⁵Instituto di Genetica Medica, Universita Cattolica, Rome, Italy
6. ⁶Division of Cardiology, Department of Pediatrics, College of Medicine, University of Kentucky, Lexington, KY, USA
7. ⁷Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Rome, Italy
8. ⁸Genetic Health Queensland, Royal Children's Hospital, Herston, Queensland, Australia
9. ⁹Max Planck Institute for Molecular Genetics, Berlin, Germany
10. ¹⁰Medical Genetics Unit, Department of Pediatrics, University Hospital Rostock, Rostock, Germany
11. ¹¹Department of Human Genetics, University Hospital Düsseldorf, Düsseldorf, Germany
12. ¹²Department of Pediatric Cardiology, University Hospital Münster, Münster, Germany
13. ¹³Department of Human Genetics, University Hospital Essen, Essen, Germany
14. ¹⁴Department of Maxilla-Facial Surgery, Wroclaw Medical University, Wroclaw, Poland
15. ¹⁵Department of Genetics, Wroclaw Medical University, Wroclaw, Poland
16. ¹⁶Mater Pathology Services, South Brisbane, Queensland, Australia
17. ¹⁷Department of Medical Genetics, University Hospital Charité, Berlin, Germany
18. ¹⁸Institute of Human Genetics, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany

Correspondence: Dr M Zenker, Institute of Human Genetics, University Hospital Erlangen, Schwabachanlage 10, 91054 Erlangen, Germany. Tel: +49 9131 8522318; Fax: +49 9131 209297; E-mail: mzenker@humgenet.uni-erlangen.de

Received 11 June 2008; Revised 8 August 2008; Accepted 27 August 2008; Published online 15 October 2008.

Abstract

Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFCS) are related developmental disorders caused by mutations in genes encoding various components of the RAS-MAPK signaling cascade. NS is associated with mutations in the genes PTPN11, SOS1, RAF1, or KRAS, whereas CFCS can be caused by mutations in BRAF, MEK1, MEK2, or KRAS. The NS phenotype is rarely accompanied by multiple giant cell lesions (MGCL) of the jaw (Noonan-like/MGCL syndrome (NL/MGCLS)). PTPN11 mutations are the only genetic abnormalities reported so far in some patients with NL/MGCLS and in one individual with LEOPARD syndrome and MGCL. In a cohort of 75 NS patients previously tested negative for mutations in PTPN11 and KRAS, we detected SOS1 mutations in 11 individuals, four of whom had MGCL. To explore further the relevance of aberrant RAS-MAPK signaling in syndromic MGCL, we analyzed the established genes causing CFCS in three subjects with MGCL associated with a phenotype fitting CFCS. Mutations in BRAF or MEK1 were identified in these patients. All mutations detected in these seven patients with syndromic MGCL had previously been described in NS or CFCS without apparent MGCL. This study demonstrates that MGCL may occur in NS and CFCS with various underlying genetic alterations and no obvious genotype–phenotype correlation. This suggests that dysregulation of the RAS-MAPK pathway represents the common and basic molecular event predisposing to giant cell lesion formation in patients with NS and CFCS rather than specific mutation effects.