Sleutjes Julia, Kleimeier Lotte, Leenders Erika, Klein Willemijn, Draaisma Jos
Department of Pediatrics, Radboud University Medical Center, Radboud Institute for Health Sciences, Amalia Children's Hospital, Nijmegen, The Netherlands.
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Mol Syndromol. 2022 Feb;13(1):1-11. doi: 10.1159/000517605. Epub 2021 Sep 10.
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 variant to 38% in patients with pathogenic variants, and the prevalence of pleural effusions differed from 7% in patients with pathogenic to 29% in patients with pathogenic variants. Postnatally, the prevalence of lymphedema differs from 16% in patients with pathogenic variants to 44% in patients with pathogenic variants, and the prevalence of acquired chylothorax is 4% in patients with pathogenic 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.
努南综合征谱系障碍是一组表型相关的疾病，与努南综合征相似，由Ras/丝裂原活化蛋白激酶（Ras/MAPK）信号通路中的基因种系致病变异引起。伴有临床淋巴管异常的淋巴发育异常是主要特征之一。我们进行了一项系统综述，以更深入了解：（1）基因确诊的努南综合征谱系障碍患者中临床淋巴管异常的患病率；（2）是否能发现基因型-淋巴管表型关系，并描述淋巴管异常的临床表现和病程。大多数研究报告的是努南综合征患者。产前，致病变异患者中颈部透明带增厚的患病率从7%到致病变异患者中的38%不等，胸腔积液的患病率从致病患者中的7%到致病变异患者中的29%不等。产后，致病变异患者中淋巴水肿的患病率从16%到致病变异患者中的44%不等，致病变异患者中后天性乳糜胸的患病率为4%。心脏颜面皮肤综合征和科斯特洛综合征患者也会出现淋巴管异常。总之，努南综合征谱系障碍，尤其是努南综合征，与淋巴管异常有关。综合有关基因确诊的努南综合征谱系障碍的现有已发表文献，努南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通路的激活可被RAS/MAPK抑制剂抑制，临床上严重的淋巴管异常可能会得到改善。
