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.

中文翻译：

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Noonan综合征中的先天性心脏缺陷：诊断，处理和治疗。

Noonan综合征是一种多形性遗传疾病，其中高比例的受影响个体患有心血管疾病，最常见的是各种形式的先天性心脏病（即肺动脉瓣狭窄，间隔缺损，左侧病变以及具有多种异常的复杂形式） 。护理包括对多种合并症的关注，其中一些会直接影响心脏管理（血液透析和淋巴异常）。超过50％的Noonan综合征患者携带PTPN11致病性变异，导致RAS /丝裂原活化的蛋白激酶信号转导过度激活。对于NS和与表型相关的疾病，还发现了其他几种具有相似生物学效应的疾病基因，统称为RASopathies。基因重测序小组的分子诊断现已广泛应用，但是表型变异性以及某些情况下的微妙性继续使Noonan综合征的识别变得困难。在先天性心脏病患者普遍进行基因检测之前，对Noonan综合征的广泛临床表现保持警惕仍然至关重要。建立分子诊断后，Noonan综合征的基因型与表型相关性可以为受影响的患者提供更好的预后。我们仍然缺乏针对Noonan综合征的治疗方法；但是，如果可以确定适应症（例如肺动脉瓣狭窄）的安全性和有效性，则新开发的抗癌RAS途径抑制剂可以填补这一空白。警惕Noonan综合征的广泛临床表现仍然至关重要。建立分子诊断后，Noonan综合征的基因型与表型相关性可以为受影响的患者提供更好的预后。我们仍然缺乏针对Noonan综合征的治疗方法；但是，如果可以确定适应症（例如肺动脉瓣狭窄）的安全性和有效性，则新开发的抗癌RAS途径抑制剂可以填补这一空白。警惕Noonan综合征的广泛临床表现仍然至关重要。建立分子诊断后，Noonan综合征的基因型与表型相关性可以为受影响的患者提供更好的预后。我们仍然缺乏针对Noonan综合征的治疗方法；但是，如果可以确定适应症（例如肺动脉瓣狭窄）的安全性和有效性，则新开发的抗癌RAS途径抑制剂可以填补这一空白。