The RASopathies

Abstract

The RASopathies are a clinically defined group of medical genetic syndromes caused by germline mutations in genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. These disorders include neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentigines, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, and Legius syndrome. Because of the common underlying Ras/MAPK pathway dysregulation, the RASopathies exhibit numerous overlapping phenotypic features. The Ras/MAPK pathway plays an essential role in regulating the cell cycle and cellular growth, differentiation, and senescence, all of which are critical to normal development. Therefore, it is not surprising that Ras/MAPK pathway dysregulation has profound deleterious effects on both embryonic and later stages of development. The Ras/MAPK pathway has been well studied in cancer and is an attractive target for small-molecule inhibition to treat various malignancies. The use of these molecules to ameliorate developmental defects in the RASopathies is under consideration.

Figure 1

The Ras/MAPK signal transduction pathway. The MAPK signaling pathway of protein kinases is critically involved in cellular proliferation, differentiation, motility, apoptosis, and senescence. The RASopathies are medical genetic syndromes caused by mutations in genes that encode components or regulators of the Ras/MAPK pathway (indicated by dashed lines). These disorders include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), capillary malformation–ateriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facio-cutaneous syndrome (CFC), and Legius syndrome.

Figure 2

Clinical images of patients with RASopathies. (a) A young boy who has a clinical diagnosis of neurofibromatosis type 1. (b) A young girl with Noonan syndrome who has a PTPN11 mutation. (c) A young adult woman with Costello syndrome who has the common p.G12S HRAS mutation. (d) A school-age boy with cardio-facio-cutaneous syndrome who has a MEK2 mutation.