Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
Curr Opin Pediatr. 2011 Aug;23(4):443-51. doi: 10.1097/MOP.0b013e32834881dd.
Recent advances in molecular genetic research have led to the definition of the new group of genetic syndromes, the RAS-mitogen-activated protein kinase (MAPK) pathway disorders or 'RASopathies'. They comprise Noonan syndrome and related disorders (cardio-facio-cutaneous and Costello syndromes), as well as neurofibromatosis type 1. This review summarizes the recent literature with a special focus on genotype-phenotype correlations.
Although the picture is still incomplete, and additional genes are likely to exist, the underlying genetic alteration can now be found in a large majority of patients with a RASopathy phenotype. The most recently discovered novel genes for Noonan syndrome or Noonan syndrome-like disorders, NRAS, SHOC2, and CBL, account for small fractions of the patient population. The increasing knowledge about the spectrum of gene mutations and associated clinical manifestations has led to a refinement of genotype-phenotype correlations. Recent studies have added new insights into tumor predisposition and prenatal manifestations. Model systems are being developed to investigate innovative treatment approaches.
Constitutional overactivation at various levels of the RAS-MAPK pathway causes overlapping syndromes, comprising characteristic facial features, cardiac defects, cutaneous abnormalities, growth deficit, neurocognitive delay, and predisposition to malignancies. Each syndrome also exhibits unique features that probably reflect genotype-related specific biological effects.
分子遗传学研究的最新进展导致了新的遗传综合征群——RAS-丝裂原活化蛋白激酶（MAPK）途径疾病或“RAS 病”的定义。它们包括努南综合征和相关疾病（心面肢综合征和 Costello 综合征）以及神经纤维瘤病 1 型。本综述总结了最近的文献，特别关注了基因型-表型相关性。
尽管情况仍不完整，并且可能存在其他基因，但现在可以在大多数具有 RAS 病表型的患者中发现潜在的遗传改变。最近发现的努南综合征或努南综合征样疾病的新基因 NRAS、SHOC2 和 CBL 仅占患者人群的一小部分。关于基因突变和相关临床表现谱的知识不断增加，导致了基因型-表型相关性的细化。最近的研究增加了对肿瘤易感性和产前表现的新见解。正在开发模型系统以研究创新的治疗方法。
RAS-MAPK 途径的各种水平的结构激活导致重叠的综合征，包括特征性的面部特征、心脏缺陷、皮肤异常、生长缺陷、神经认知延迟和恶性肿瘤易感性。每种综合征还表现出独特的特征，这可能反映了基因型相关的特定生物学效应。
