Ejarque Ismael, Millán-Salvador José M, Oltra Silvestre, Pesudo-Martínez José V, Beneyto Magdalena, Pérez-Aytés Antonio
Hospital La Fe, 46009 Valencia, Espana.
Rev Neurol. 2015 May 1;60(9):408-12.
Noonan syndrome (NS) and other syndromes with a similar phenotype, such as LEOPARD, cardiofaciocutaneous, Costello and Legius, are associated to mutations in genes included in the RAS/MAPK pathway (RASopathies), which is an important signalling pathway related to cell proliferation. Tonsillar descent into the upper cervical spinal canal, known as Arnold-Chiari malformation (ACM), has been reported in patients with NS and this has led some researchers to suggest that ACM could be part of the phenotypic spectrum of NS. We report two cases of NS and ACM.
Case 1: 29-year-old female with Noonan phenotype who underwent surgery at the age of nine years due to pulmonary valve stenosis. At the age of 27, she presented symptomatic ACM that required surgical decompression. She presented the c.922A>G (N308D) mutation in the gene PTPN that belongs to the RAS/MAPK pathway. Case 2: a 10-year-old female with Noonan phenotype and asymptomatic ACM detected in magnetic resonance imaging of the brain. She was a carrier of the c.923A>G (N308S) mutation in gene PTPN11.
Six patients with this association have been found in the literature, four with the Noonan phenotype and two with LEOPARD. Our two patients provide supplementary evidence that backs up the hypothesis by which ACM would be part of the phenotypic spectrum of NS. The small number of reported cases of patients with this association does not allow us to draw up recommendations about when and how often neuroimaging studies should be performed; a careful neurological examination, however, should be included in the anticipatory health guidelines in syndromes involving the RAS/MAPK pathway.
努南综合征（NS）以及其他具有相似表型的综合征，如豹皮综合征、心面皮肤综合征、科斯特洛综合征和勒吉乌斯综合征，都与RAS/丝裂原活化蛋白激酶（MAPK）信号通路中的基因突变有关（RAS病），该信号通路是与细胞增殖相关的重要信号通路。有报道称，NS患者存在扁桃体下降至颈椎上段椎管内的情况，即阿诺德-奇亚里畸形（ACM），这使得一些研究人员认为ACM可能是NS表型谱的一部分。我们报告两例NS合并ACM的病例。
病例1：一名29岁女性，具有努南表型，9岁时因肺动脉瓣狭窄接受手术。27岁时，她出现有症状的ACM，需要进行手术减压。她的PTPN基因存在c.922A>G（N308D）突变，该基因属于RAS/MAPK信号通路。病例2：一名10岁女性，具有努南表型，脑部磁共振成像检查发现无症状的ACM。她是PTPN11基因c.923A>G（N308S）突变的携带者。
文献中已发现6例这种关联的患者，4例具有努南表型，2例具有豹皮综合征表型。我们的两例患者提供了补充证据，支持了ACM是NS表型谱一部分的假说。由于报道的这种关联患者病例数量较少，我们无法就何时以及多久进行一次神经影像学检查提出建议；然而，在涉及RAS/MAPK信号通路的综合征的预期健康指南中，应包括仔细的神经系统检查。
