Noonan syndrome spectrum disorders are a group of phenotypically related conditions, resembling Noonan syndrome, caused by germline pathogenic variants in genes within the Ras/mitogen-activated protein kinase (Ras/MAPK) signalling pathway. Lymphatic dysplasia with a clinical lymphatic abnormality is one of the major features. We performed a systematic review to get more insight in (1) the prevalence of clinically lymphatic abnormalities in patients with a genetically proven Noonan syndrome spectrum disorder, (2) if a genotype-lymphatic phenotype relation can be found and describe the clinical presentation and course of the lymphatic abnormality. Most studies report patients with Noonan syndrome. Prenatally, the prevalence of increased nuchal translucency differs from 7% in patients with pathogenic PTPN11 variants to 38% in patients with pathogenic RIT1 variants, and the prevalence of pleural effusions differed from 7% in patients with pathogenic SOS1 to 29% in patients with pathogenic RIT1 variants. Postnatally, the prevalence of lymphedema differs from 16% in patients with pathogenic PTPN11 variants to 44% in patients with pathogenic SOS1 variants, and the prevalence of acquired chylothorax is 4% in patients with pathogenic RIT1 variants. Lymphatic abnormalities do occur in patients with cardiofaciocutaneous syndrome and Costello syndrome. In conclusion, Noonan syndrome spectrum disorders, Noonan syndrome in particular, are associated with lymphatic abnormalities. Combining the available published literature about genetically proven Noonan syndrome spectrum disorders, it appears likely that the lifetime prevalence of these abnormalities in Noonan syndrome is higher than the 20% that were generally accepted so far. This is increasingly important, because the activation of the RAS/MAPK pathway can be inhibited by RAS/MAPK inhibitors, and clinically severe lymphatic abnormalities may improve.
Mol Syndromol

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Noonan 综合征谱系疾病的淋巴异常：系统评价

Noonan 综合征谱系障碍是一组表型相关的疾病，类似于 Noonan 综合征，由 Ras/丝裂原活化蛋白激酶 (Ras/MAPK) 信号通路内基因的种系致病变异引起。伴有临床淋巴异常的淋巴发育不良是主要特征之一。我们进行了系统评价，以更深入地了解 (1) 经基因证实的 Noonan 综合征谱系障碍患者临床淋巴异常的患病率，(2) 是否可以找到基因型-淋巴表型关系并描述临床表现和病程的淋巴异常。大多数研究报告患有 Noonan 综合征的患者。产前，致病性PTPN11患者颈部透明带增加的患病率与 7% 不同致病性RIT1变异患者的 s变异至 38% ，胸腔积液的患病率从致病性 SOS1 患者的 7%到致病性RIT1变异患者的 29%不同。出生后，淋巴水肿的患病率从致病性PTPN11变异患者的 16% 到致病性 SOS1 变异患者的 44%，而致病性RIT1患者的获得性乳糜胸患病率为 4 %变体。心脏面部皮肤综合征和科斯特洛综合征患者确实会出现淋巴异常。总之，Noonan 综合征谱系障碍，尤其是 Noonan 综合征，与淋巴异常有关。结合现有已发表的关于基因证实的 Noonan 综合征谱系障碍的文献，Noonan 综合征中这些异常的终生患病率似乎高于目前普遍接受的 20%。这一点越来越重要，因为 RAS/MAPK 抑制剂可以抑制 RAS/MAPK 通路的激活，临床上严重的淋巴异常可能会得到改善。
摩尔综合症