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          Institute: MPI für molekulare Genetik     Collection: Department of Human Molecular Genetics     Display Documents

ID: 411070.1, MPI für molekulare Genetik / Department of Human Molecular Genetics
Multiple giant cell lesions in patients with Noonan syndrome and cardio-facio-cutaneous syndrome
Authors:Neumann, Thomas E; Allanson, Judith; Kavamura, Ines; Kerr, Bronwyn; Neri, Giovanni; Noonan, Jacqueline; Cordeddu, Viviana; Gibson, Kate; Tzschach, Andreas; Krüger, Gabriele; Hoeltzenbein, Maria; Goecke, Timm O; Kehl, Hans Gerd; Albrecht, Beate; Luczak, Klaudiusz; Sasiadek, Maria M.; Musante, Luciana; Laurie, Rohan; Peters, Hartmut; Tartaglia, Marco; Zenker, Martin; Kalscheuer, Vera M.
Date of Publication (YYYY-MM-DD):2009-04
Title of Journal:European Journal of Human Genetics
Journal Abbrev.:Eur J Hum Genet
Issue / Number:4
Start Page:420
End Page:425
Copyright:© 2009 European Society of Human Genetics
Review Status:not specified
Audience:Experts Only
Abstract / Description: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.
Free Keywords:Noonan syndrome; Cardio-facio-cutaneous syndrome; Multiple giant cell lesions; Noonan-like/multiple giant cell lesion syndrome; RAS-MAPK signaling cascade
Comment of the Author/Creator:Correspondence: Dr. M. Zenker, Institute of Human Genetics, University Hospital Erlangen, Schwabachanlage 10, 91054 Erlangen, Germany. Tel: +49 9131 8522318; Fax: +49 9131 209297; email: mzenker@humgenet.uni-erlangen.de
External Publication Status:published
Document Type:Article
Communicated by:Hans-Hilger Ropers
Affiliations:MPI für molekulare Genetik
External Affiliations:Department of Human Genetics, University Hospital Münster, Münster, Germany
Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada
Medical Genetics, Federal University of Sao Paulo, Sao Paulo, Brazil
Royal Manchester Children's Hospital, Manchester, UK
Instituto di Genetica Medica, Universita Cattolica, Rome, Italy
Division of Cardiology, Department of Pediatrics, College of Medicine, University of Kentucky, Lexington, KY, USA
Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Rome, Italy
Genetic Health Queensland, Royal Children's Hospital, Herston, Queensland, Australia
Department of Human Genetics, University Hospital Düsseldorf, Düsseldorf, Germany
Department of Pediatric Cardiology, University Hospital Münster, Münster, Germany
Department of Human Genetics, University Hospital Essen, Essen, Germany
Department of Maxilla-Facial Surgery, Wroclaw Medical University, Wroclaw, Poland
Department of Genetics, Wroclaw Medical University, Wroclaw, Poland
Mater Pathology Services, South Brisbane, Queensland, Australia
Department of Medical Genetics, University Hospital Charité, Berlin, Germany
Institute of Human Genetics, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
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