Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway:: genotype-phenotype relationships and overlap with Costello syndrome
Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway:: genotype-phenotype relationships and overlap with Costello syndrome
复制标题
DOI：
10.1136/jmg.2007.050450
复制
发表时间：
2007-12-01
影响因子：
4
通讯作者：
Cave, Helene
中科院分区：
文献类型：
--
作者：
Nava, Caroline;Hanna, Nadine;Cave, Helene
面部皮肤（CFC）综合征、努南综合征（NS）和科斯特洛综合征（CS）是临床相关的发育障碍，最近被认为与RAS/MEK/ERK信号通路的突变有关。该研究是对总共130例患者（40例临床诊断为CFC的患者，20例来自法国Costello家庭支持组的无HRAS突变的患者，以及70例无PTPN 11或SOS 1突变的NS患者）的KRAS、BRAF、MEK 1和MEK 2基因的突变分析。在14/40（35%）CFC患者和8/20（40%）HRAS阴性CS患者中发现BRAF突变。KRAS突变在CFC组1/40（2.5%），HRAS阴性CS组2/20（10%），NS组4/70（5.7%）。MEK 1基因突变见于CFC患者4/40例（10%），HRAS阴性的CS患者4/20例（20%），NS患者3/70例（4.3%），MEK 2基因突变见于CFC患者4/40例（10%）。主要表型特征的分析表明CS和CFC之间存在显著的临床重叠。与MEK突变相关的表型似乎不太严重，并且与正常的智力发育相容。被认为是CS独特的特征也被发现与BRAF或MEK突变相关。由于其特殊的癌症风险，术语“科斯特洛综合征”应仅用于已证实HRAS突变的患者。这些结果证实KRAS是NS的次要贡献者，并表明MEK参与了某些NS病例，证明了临床实体之间的表型连续性。虽然某些相关的特征似乎是特定基因的特征，但没有简单的规则可以轻易区分NS和CFC。
Cardio-facio-cutaneous (CFC) syndrome, Noonan syndrome (NS), and Costello syndrome ( CS) are clinically related developmental disorders that have been recently linked to mutations in the RAS/MEK/ERK signalling pathway. This study was a mutation analysis of the KRAS, BRAF, MEK1 and MEK2 genes in a total of 130 patients ( 40 patients with a clinical diagnosis of CFC, 20 patients without HRAS mutations from the French Costello family support group, and 70 patients with NS without PTPN11 or SOS1 mutations). BRAF mutations were found in 14/40 (35%) patients with CFC and 8/20 (40%) HRAS-negative patients with CS. KRAS mutations were found in 1/40 (2.5%) patients with CFC, 2/20 (10%) HRAS-negative patients with CS and 4/70 patients with NS (5.7%). MEK1 mutations were found in 4/40 patients with CFC ( 10%), 4/20 (20%) HRAS-negative patients with CS and 3/70 (4.3%) patients with NS, and MEK2 mutations in 4/40 (10%) patients with CFC. Analysis of the major phenotypic features suggests significant clinical overlap between CS and CFC. The phenotype associated with MEK mutations seems less severe, and is compatible with normal mental development. Features considered distinctive for CS were also found to be associated with BRAF or MEK mutations. Because of its particular cancer risk, the term "Costello syndrome'' should only be used for patients with proven HRAS mutation. These results confirm that KRAS is a minor contributor to NS and show that MEK is involved in some cases of NS, demonstrating a phenotypic continuum between the clinical entities. Although some associated features appear to be characteristic of a specific gene, no simple rule exists to distinguish NS from CFC easily.