Multiple giant cell lesions in patients with Noonan syndrome and cardio-facio-cutaneous syndrome

• Published in: European journal of human genetics : EJHG Vol. 17; no. 4; pp. 420 - 425
• Main 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
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.04.2009; Nature Publishing Group
• Subjects: Abnormalities, Multiple - diagnosis; Abnormalities, Multiple - genetics; Abnormalities, Multiple - pathology; Adapter proteins; Adolescent; Adult; Bioinformatics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cardiology; Child; Cohort Studies; Cytogenetics; Diseases of the osteoarticular system; Female; Fundamental and applied biological sciences. Psychology; Gene Expression; General aspects. Genetic counseling; Genes; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Genotypes; Giant Cells - pathology; Heart Diseases - congenital; Heart Diseases - pathology; Hospitals; Human Genetics; Humans; Jaw; Kinases; Leukemia; Male; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; MAP kinase; MAP Kinase Signaling System - genetics; Medical genetics; Medical sciences; Molecular and cellular biology; Mutation; Noonan Syndrome - diagnosis; Noonan Syndrome - genetics; Noonan Syndrome - pathology; Patients; Pediatrics; Phenotype; Phenotypes; ras Proteins - genetics; ras Proteins - metabolism; Signal transduction; Skin Diseases - pathology; Syndrome; Poland; Italy; Queensland Australia; Germany; RAS-MAPK signaling cascade; Noonan-like/multiple giant cell lesion syndrome; Noonan syndrome; cardio-facio-cutaneous syndrome; multiple giant cell lesions; Human; Skin disease; Nervous system diseases; Multiple; Cardio facio cutaneous syndrome; Enzyme; Transferases; Diseases of the osteoarticular system; Mitogen-activated protein kinase; Cardiovascular disease; Patient; Genetic disease; Giant cell; Noonan-like/ multiple giant cell lesion syndrome; Genetics; Lesion; Osteochondrodysplasia
• ISSN: 1018-4813; 1476-5438; 1476-5438
• DOI: 10.1038/ejhg.2008.188

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.