Ueda Kimiko, Yaoita Masako, Niihori Tetsuya, Aoki Yoko, Okamoto Nobuhiko
Department of Medical Genetics, Osaka Women's and Children's Hospital, Osaka Prefectural Hospital Organization, Osaka, Japan.
Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.
Am J Med Genet A. 2017 Sep;173(9):2346-2352. doi: 10.1002/ajmg.a.38337. Epub 2017 Jun 26.
RASopathies are phenotypically overlapping genetic disorders caused by dysregulation of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway. RASopathies include Noonan syndrome, cardio-facio-cutaneous (CFC) syndrome, Costello syndrome, Neurofibromatosis type 1, Legius syndrome, Noonan syndrome with multiple lentigines, Noonan-like syndrome, hereditary gingival fibromatosis, and capillary malformation/arteriovenous malformation syndrome. Recently, six patients with craniosynostosis and Noonan syndrome involving KRAS mutations were described in a review, and a patient with craniosynostosis and Noonan syndrome involving a SHOC2 mutation has also been reported. Here, we describe patients with craniosynostosis and Noonan syndrome due to de novo mutations in PTPN11 and patients with craniosynostosis and CFC syndrome due to de novo mutations in BRAF or KRAS. All of these patients had cranial deformities in addition to the typical phenotypes of CFC syndrome and Noonan syndrome. In RASopathy, patients with cranial deformities, further assessments may be necessary to look for craniosynostosis. Future studies should attempt to elucidate the pathogenic mechanism responsible for craniosynostosis mediated by the RAS/MAPK signaling pathway.
RAS 病是由 RAS/丝裂原活化蛋白激酶（MAPK）信号通路失调引起的表型重叠的遗传性疾病。RAS 病包括努南综合征、心面皮肤综合征（CFC 综合征）、科斯特洛综合征、1 型神经纤维瘤病、勒吉尤斯综合征、多发雀斑样痣型努南综合征、类努南综合征、遗传性牙龈纤维瘤病以及毛细血管畸形/动静脉畸形综合征。最近，一篇综述中描述了 6 例患有颅骨缝早闭和努南综合征且涉及 KRAS 突变的患者，并且也报道了 1 例患有颅骨缝早闭和努南综合征且涉及 SHOC2 突变的患者。在此，我们描述了因 PTPN11 基因新发突变导致颅骨缝早闭和努南综合征的患者，以及因 BRAF 或 KRAS 基因新发突变导致颅骨缝早闭和 CFC 综合征的患者。所有这些患者除了具有 CFC 综合征和努南综合征的典型表型外，还存在颅骨畸形。在 RAS 病中，对于有颅骨畸形的患者，可能需要进一步评估以查找颅骨缝早闭情况。未来的研究应尝试阐明由 RAS/MAPK 信号通路介导的颅骨缝早闭的致病机制。
