Ophthalmic Manifestations in RASopathies

RASopathies are a group of multisystem developmental disorders caused by pathogenic variants in the RAS/MAPK genes that disrupt the RAS pathway. These include Neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), cardio-facio-cutaneous syndrome (CFC), Costello syndrome (CS), Legius Syndrome (LS), capillary malformation-arteriovenous malformation (CM-AVM), central conducting lymphatic anomalies (CCLA), and SYNGAP1 syndrome. Clinical characteristics include distinct facial features, cardiac issues, hypotonia and other neurological problems, developmental delays, dermatologic manifestations (café au lait macules, lentigines), a predilection to tumors, hematologic and immunologic problems, and ophthalmic and hearing issues. The RAS pathway is essential for cell growth and differentiation and plays an important role in ocular development. Dysfunction of this pathway due to pathogenic variants in the RAS genes results in a number of ophthalmic issues including strabismus, refractive errors, ptosis, nystagmus, optic nerve glioma, optic nerve hypoplasia, and atrophy. Rarely, vascular/lymphatic malformations, keratoconus, cataracts, glaucoma, and retinal dystrophies have been reported. This chapter provides an overview of the orbital and ocular findings observed in RASopathies emphasizing their clinical presentations and potential therapeutic interventions to prevent visual morbidity and improve the overall quality of life for individuals with RASopathies.