RASopathies. Part I: Genetics and therapeutic considerations

Abstract

RASopathies are common developmental disorders caused by variants in RAS and RAS-related proteins that affect a biological signaling pathway regulating cell growth and development. Considering the genetic and biochemical basis, part I will discuss the RASopathies divided into germline and mosaic patterns. The germline RASopathies include neurofibromatosis type 1 (not discussed in detail in this review), Noonan syndrome, Noonan syndrome with multiple lentigines, Legius syndrome, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, and cardiofaciocutaneous syndrome. Mosaic RASopathies encompass a broad category including nevus sebaceus syndrome, neurocutaneous melanosis, melanocytic nevi, McCune-Albright syndrome, phacomatosis spilosebacea, epidermal nevus syndrome, and encephalocraniocutaneous lipomatosis. Due to the RAS pathway's downstream impact on cell growth, many RASopathies predispose to malignancy. Conversely, the RAS pathway is overactive in many cancers, and some oncologic therapies also benefit patients with RASopathies. Although RAS ubiquity and homology complicate the efficacy of direct inhibition, several candidate drugs carry potential for decreasing RAS activity. Continued investigation into RAS biochemistry and genetics may elucidate strategies for pharmacological targets and pathways in both RASopathies and cancers.

Keywords: CM-AVM; Costello; ECCL; HRAS; KRAS; LEOPARD; Legius; NF1; NRAS; Noonan; Noonan syndrome with multiple lentigines; RAS; RASopathies; RASopathy; Schimmelpenning; cancer; capillary malformation-arteriovenous malformation; cardiofaciocutaneous; encephalocraniocutaneous lipomatosis; epidermal nevus; genetics; inhibitor; malignancy; neurofibromatosis; nevus sebaceus; oncogene; phakomatosis pigmentokeratotica; sebaceous nevus; tumor suppressor.