Congenital heart defects in Noonan syndrome: Diagnosis, management, and treatment.
Congenital heart defects in Noonan syndrome: Diagnosis, management, and treatment.
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DOI：
10.1002/ajmg.c.31765
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发表时间：
2020-03
期刊：
影响因子：
--
通讯作者：
Gelb BD
中科院分区：
文献类型：
--
作者：
Linglart L;Gelb BD
努南综合征是一种多形性遗传性疾病，其中很高比例的患者有心血管受累，最常见的是各种形式的先天性心脏病(即肺动脉瓣狭窄、间隔缺陷、左侧病变和复杂形式的多种异常)。护理包括注意几种合并症，其中一些直接影响心脏管理(出血疾病和淋巴异常)。超过50%的Noonan综合征患者存在PTPN11致病变异，导致RAS/丝裂原活化蛋白激酶信号的过度激活。其他几个具有类似生物效应的疾病基因已经在NS和表型相关疾病中被发现，统称为Rasopathies。利用基因重测序面板进行分子诊断现已广泛可用，但表型的变异性和某些情况下的微妙，继续使努南综合征的识别变得困难。在基因检测在先天性心脏病患者中普及之前，对努南综合征广泛的临床表现保持警惕仍然至关重要。当建立分子诊断时，Noonan综合征的基因型-表型关联能够更好地预测受影响的患者。我们仍然缺乏针对Noonan综合征的特异性治疗；然而，如果能为诸如肺动脉瓣狭窄等适应症确定安全性和有效性，新开发的抗癌RAS途径抑制剂可以填补这一空白。
Noonan syndrome is a pleomorphic genetic disorder, in which a high percentage of affected individuals have cardiovascular involvement, most prevalently various forms of congenital heart disease (i.e., pulmonary valve stenosis, septal defects, left-sided lesions, and complex forms with multiple anomalies). Care includes attentiveness to several comorbidities, some directly impacting cardiac management (bleeding diatheses and lymphatic anomalies). More than 50% of patients with Noonan syndrome harbor PTPN11 pathogenic variation, which results in hyperactivation of RAS/mitogen-activated protein kinase signaling. Several other disease genes with similar biological effects have been uncovered for NS and phenotypically related disorders, collectively called the RASopathies. Molecular diagnosis with gene resequencing panels is now widely available, but phenotype variability and in some cases, subtlety, continues to make identification of Noonan syndrome difficult. Until genetic testing becomes universal for patients with congenital heart disease, alertness to Noonan syndrome’s broad clinical presentations remains crucial. Genotype-phenotype associations for Noonan syndrome enable better prognostication for affected patients when a molecular diagnosis is established. We still lack Noonan syndrome-specific treatment; however, newly developed anticancer RAS pathway inhibitors could fill that gap if safety and efficacy can be established for indications such as pulmonary valve stenosis.
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