Ophthalmic manifestations in Costello syndrome caused by Ras pathway dysregulation during development

Background Costello syndrome (CS) is a multisystem developmental disorder caused by germline pathogenic variants in HRAS resulting in dysregulation of the Ras pathway. A systematic characterization of ophthalmic manifestations provides a unique opportunity to understand the role of Ras signal transduction in ocular development and guide optimal ophthalmic care in CS individuals. Methods Visual function, ocular features and genotype/phenotype correlations were evaluated in CS individuals harboring HRAS pathogenic variants, by cross-sectional and retrospective studies, and were recruited through the Costello Syndrome Family Network (CSFN) between 2007 and 2020. Results Fifty-six molecularly diagnosed CS individuals including 34 females and 22 males, ages ranging from 0.5 to 37 years were enrolled. The most common ophthalmic manifestations in the cross-sectional study were lack of stereopsis (96%), refractive errors (83%), strabismus (72%), nystagmus (69%), optic nerve hypoplasia or pallor (55%) and ptosis (13.7%) with higher prevalence than in the retrospective data (refractive errors (41%), strabismus (44%), nystagmus (26%), optic nerve hypoplasia or pallor (7%) and ptosis (11%)). Visual acuities were found to ranged from 20/25 to 20/800 and contrast sensitivity from 1.6% to 44%. HRAS pathogenic variants included p.G12S (84%), p.G13C (7%), p.G12A (5.4%), p.G12C (1.8%) and p.A146V (1.8%). Conclusion Majority of individuals with CS have refractive errors, strabismus, nystagmus, absent stereopsis, and optic nerve abnormalities suggesting that HRAS and the Ras pathway play a vital role in visual system development. Ptosis, refractive errors and strabismus are amenable to treatment and early ophthalmic evaluation is crucial to prevent long-term vision impairment and improve overall quality of life in CS.