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Title: Multiple giant cell lesions in patients with Noonan syndrome and cardio-facio-cutaneous syndrome
Authors: Neumann, Thomas E.
Allanson, Judith
Kavamura, Ines [UNIFESP]
Kerr, Bronwyn
Neri, Giovanni
Noonan, Jacqueline
Cordeddu, Viviana
Gibson, Kate
Tzschach, Andreas
Krueger, 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
Univ Erlangen Nurnberg
Univ Hosp Munster
Childrens Hosp Eastern Ontario
Universidade Federal de São Paulo (UNIFESP)
Royal Manchester Childrens Hosp
Univ Cattolica
Univ Kentucky
Ist Super Sanita
Royal Childrens Hosp
Max Planck Inst Mol Genet
Univ Hosp Rostock
Univ Hosp Dusseldorf
Univ Hosp Essen
Wroclaw Med Univ
Mater Pathol Serv
Univ Hosp Charite
Keywords: Noonan syndrome
cardio-facio-cutaneous syndrome
multiple giant cell lesions
Noonan-like/multiple giant cell lesion syndrome
RAS-MAPK signaling cascade
Issue Date: 1-Apr-2009
Publisher: Nature Publishing Group
Citation: European Journal of Human Genetics. London: Nature Publishing Group, v. 17, n. 4, p. 420-425, 2009.
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.
ISSN: 1018-4813
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