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
1Department of Human Genetics, University Hospital Münster, Münster, Germany.
Eur J Hum Genet. 2009 Apr;17(4):420-5. doi: 10.1038/ejhg.2008.188. Epub 2008 Oct 15.
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.
努南综合征（NS）和心脏-颜面-皮肤综合征（CFCS）是由编码RAS-MAPK信号级联反应各种组分的基因突变引起的相关发育障碍。NS与PTPN11、SOS1、RAF1或KRAS基因的突变相关，而CFCS可能由BRAF、MEK1、MEK2或KRAS基因的突变引起。NS的表型很少伴有颌骨的多发性巨细胞病变（MGCL）（努南样/ MGCL综合征（NL/MGCLS））。PTPN11突变是迄今为止在一些NL/MGCLS患者以及一名患有豹皮综合征和MGCL的个体中报道的唯一遗传异常。在一组先前检测PTPN11和KRAS基因无突变的75例NS患者中，我们在11例个体中检测到SOS1突变，其中4例有MGCL。为了进一步探讨异常RAS-MAPK信号传导在综合征性MGCL中的相关性，我们分析了3例伴有符合CFCS表型的MGCL患者中导致CFCS的既定基因。在这些患者中鉴定出BRAF或MEK1突变。在这7例综合征性MGCL患者中检测到的所有突变先前已在无明显MGCL的NS或CFCS中描述过。这项研究表明，MGCL可能发生在具有各种潜在基因改变的NS和CFCS中，且没有明显的基因型-表型相关性。这表明RAS-MAPK通路失调代表了NS和CFCS患者中易发生巨细胞病变形成的常见和基本分子事件，而非特定的突变效应。
