Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome
Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome
复制标题
DOI：
10.1002/ajmg.a.31815
复制
发表时间：
2007-07-01
影响因子：
2
通讯作者：
Sol-Church, Katia
中科院分区：
文献类型：
--
作者：
Gripp, Karen W.;Lin, Angela E.;Sol-Church, Katia
由于心面皮肤 (CFC) 综合征与 Costello 综合征有显着的表型重叠，因此可能难以在临床基础上做出诊断。最近发现 Costello 综合征患者的种系 HRAS 突变和 CFC 综合征患者的 BRAF、MEK1 和 MEK2 突变，揭示了基于 MAP 激酶通路内受影响基因产物的密切相互作用的共同表型发现的生物学机制。我们评估了一系列临床诊断为科斯特洛综合征的患者，或者考虑了科斯特洛和 CFC 综合征的诊断。排除 HRAS 突变后，我们确定了 BRAF 中的 8 个变化和 MEK1 中的 5 个变化。有五个突变是新的，所有变化都是在这些测试的三联体中从头发生的。对临床异常的回顾显示，具有 BRAF 或 MEK1 突变的患者与之前报告的具有 HRAS 突变的患者之间存在重要差异。尽管本文报告的 BRAF 和 MEK1 突变患者数量相对较少，但羊水过多、生长激素缺乏和存在不止一个乳头状瘤的情况仍具有统计学意义，与 HRAS 突变阳性患者相比，这些在 CFC 中较少见。尽管 CFC 和 Costello 综合征的特点是约四分之三的患者存在心脏异常，但先天性心脏缺陷 (CHD)、肥厚性心肌病 (HCM) 和心动过速的模式有所不同。 CHD，尤其是与继发孔型房间隔缺损相关的肺动脉瓣狭窄，在 CFC 中比 Costello 综合征更常见（P = 0.02）。与携带 HRAS 突变的 Costello 综合征患者相比，携带 BRAF 或 MEK1 突变的 CFC 患者房性心动过速的发生率较低 (P = 0.04)。仅在科斯特洛综合征中观察到混乱的心房节律或多灶性房性心动过速。由于 HRAS 突变，恶性肿瘤被认为是科斯特洛综合征的特征，然而，我们在此报告了一名患有恶性肿瘤（肝母细胞瘤）的患者的 MEK1 突变。尽管这表明肿瘤的存在对于具有 HRAS 突变的 Costello 综合征并不具有特异性，但值得注意的是，肿瘤组织学与 Costello 综合征中常见的肿瘤组织学不同。基于这些临床差异，我们建议携带 BRAF 和 MEK 突变的患者应诊断为 CFC 综合征，而携带 HRAS 突变的患者应诊断为 Costello 综合征。 (c) 2007 年 Wiley-Liss, Inc.
Because Cardio-facio-cutaneous (CFC) syndrome has significant phenotypic overlap with Costello syndrome, it may be difficult to establish the diagnosis on a clinical basis. The recent discoveries of germline HRAS mutations in patients with Costello syndrome and mutations in BRAF, MEK1, and MEK2 in CFC syndrome uncovered the biologic mechanism for the shared phenotypic findings based on the close interaction of the affected gene products within the MAP kinase pathway. We evaluated a series of patients who were either clinically diagnosed with Costello syndrome, or in whom the diagnoses of both Costello and CFC syndromes were considered. After excluding mutations in HRAS, we identified eight changes in BRAF and five in MEK1. Five mutations are novel, and all changes occurred de novo among those triads tested. A review of the clinical abnormalities showed important differences between patients with either a BRAF or MEK1 mutation, and those previously reported with an HRAS mutation. Statistical significance was achieved, despite the relatively small number of patients with BRAF and MEK1 mutations reported here, for polyhydramnios, growth hormone deficiency and the presence of more than one papilloma, which were less common in CFC compared to HRAS mutation positive patients. Although both CFC and Costello syndrome are characterized by cardiac abnormalities in about three-fourths of patients, the pattern of congenital heart defects (CHD), hypertrophic cardiomyopathy (HCM), and tachycardia differs somewhat. CHD, especially pulmonic stenosis associated with a secundum-type atrial septal defect, are more common in CFC than Costello syndrome (P = 0.02). Atrial tachycardia is less frequent in CFC patients with BRAF or MEK1 mutations, compared to Costello syndrome patients with HRAS mutation (P = 0.04). Chaotic atrial rhythm or multifocal atrial tachycardia was observed only in Costello syndrome. Malignant tumors have been viewed as characteristic for Costello syndrome due to HRAS mutations, however, we report here on a MEK1 mutation in a patient with a malignant tumor, a hepatoblastoma. Although this indicates that the presence of a tumor is not specific for Costello syndrome with HRAS mutation, it is noteworthy that the tumor histology differs from those commonly seen in Costello syndrome. Based on these clinical differences we suggest that patients with BRAF and MEK mutations should be diagnosed with CFC syndrome, and the diagnosis of Costello syndrome be reserved for patients with HRAS mutations. (c) 2007 Wiley-Liss, Inc.