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.
| Original language | English |
|---|---|
| Pages (from-to) | 420-425 |
| Number of pages | 6 |
| Journal | European Journal of Human Genetics |
| Volume | 17 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2009 |
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ASJC Scopus subject areas
- Genetics(clinical)
- Genetics
Cite this
Multiple giant cell lesions in patients with Noonan syndrome and cardio-facio-cutaneous syndrome. / 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.
In: European Journal of Human Genetics, Vol. 17, No. 4, 2009, p. 420-425.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Multiple giant cell lesions in patients with Noonan syndrome and cardio-facio-cutaneous syndrome
AU - Neumann, Thomas E.
AU - Allanson, Judith
AU - Kavamura, Ines
AU - Kerr, Bronwyn
AU - Neri, Giovanni
AU - Noonan, Jacqueline
AU - Cordeddu, Viviana
AU - Gibson, Kate
AU - Tzschach, Andreas
AU - Krüger, Gabriele
AU - Hoeltzenbein, Maria
AU - Goecke, Timm O.
AU - Kehl, Hans Gerd
AU - Albrecht, Beate
AU - Luczak, Klaudiusz
AU - Sasiadek, Maria M.
AU - Musante, Luciana
AU - Laurie, Rohan
AU - Peters, Hartmut
AU - Tartaglia, Marco
AU - Zenker, Martin
AU - Kalscheuer, Vera
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=62849124342&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=62849124342&partnerID=8YFLogxK
U2 - 10.1038/ejhg.2008.188
DO - 10.1038/ejhg.2008.188
M3 - Article
C2 - 18854871
AN - SCOPUS:62849124342
VL - 17
SP - 420
EP - 425
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
SN - 1018-4813
IS - 4
ER -