Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome:: Overlapping clinical manifestations with Costello syndrome
Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome:: Overlapping clinical manifestations with Costello syndrome
复制标题
DOI：
10.1002/ajmg.a.31658
复制
发表时间：
2007-04-15
影响因子：
2
通讯作者：
Matsubara, Yokhi
中科院分区：
文献类型：
--
作者：
Narumi, Yoko;Aoki, Yoko;Matsubara, Yokhi
面部皮肤综合征（CFC）是一种多发性先天性异常/智力低下综合征，其特征在于心脏缺陷、独特的面部外观、外胚层异常和智力低下。临床上，它与努南综合征和科斯特洛综合征重叠，这两种综合征分别由PTPN 11和HRAS两个基因突变引起。最近，我们在43例CFC综合征患者中的19例中发现了KRAS和BRAF突变，这表明RAS/RAF/MEK/ERK通路的失调是CFC综合征的分子基础。本研究对56例CFC综合征患者进行综合性突变分析，探讨基因型与表型的相关性。我们分析了13例新发CFC患者的KRAS、BRAF和MAP 2K 1/2（MEK 1/2），并在9例患者中发现了5种BRAF和1种MAP 2K 1突变。我们在先前研究中没有KRAS或BRAF突变的24名患者中，在3名患者中检测到1个MAP 2K 1突变，在4名患者中检测到4个新的MAP 2K 2突变[Niihori et al.，2006年]。在21例无任何突变的患者中未发现MAPK 3/1（ERKI/2）突变。总体而言，56例CFC综合征患者中有35例（62.5%）存在突变（KRAS 3例，BRAF 24例，MAP 2K 1/2 8例）。3例KRAS阳性患者、16例BRAF阳性患者和6例MAP 2K 1/2阳性患者的临床表现无显著差异。在30-40%的突变阳性CFC患者中观察到手掌和脚掌起皱、色素沉着过度和关节过度伸展，这些在Costello综合征中常见，但在CFC综合征中不常见，这表明这两种综合征之间存在显著的临床重叠。(c)2007 Wiley-Liss，Inc.
Cardio-facio-cutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by heart defects, a distinctive facial appearance, ectodermal abnormalities and mental retardation. Clinically, it overlaps with both Noonan syndrome and Costello syndrome, which are caused by mutations in two genes, PTPN11 and HRAS, respectively. Recently, we identified mutations in KRAS and BRAF in 19 of 43 individuals with CFC syndrome, suggesting that dysregulation of the RAS/RAF/MEK/ERK pathway is a molecular basis for CFC syndrome. The purpose of this study was to perform comprehensive mutation analysis in 56 patients with CFC syndrome and to investigate genotype-phenotype cot-relation. We analyzed KRAS, BRAF, and MAP2K1/2 (MEK1/2) in 13 new CFC patients and identified five BRAF and one MAP2K1 mutations in nine patients. We detected one MAP2K1 mutation in three patients and four new MAP2K2 mutations in four patients out of 24 patients without KRAS or BRAF mutations in the previous study [Niihori et al., 2006]. No mutations were identified in MAPK3/1(ERKI/2) in 21 patients without any mutations. In total, 35 of 56 (62.5%) patients with CFC syndrome had mutations (3 in KRAS, 24 in BRAF, and 8 in MAP2K1/2). No significant differences in clinical manifestations were found among 3 KRAS-positive patients, 16 BRAF-positive patients, and 6 MAP2K1/2-positive patients. Wrinkled palms and soles, hyperpigmentation and joint hyperextension, which have been commonly reported in Costello syndrome but not in CFC syndrome, were observed in 30-40% of the mutation-positive CFC patients, suggesting a significant clinical overlap between these two syndromes. (c) 2007 Wiley-Liss, Inc.