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

ABSTRACT

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.

KEYWORDS:

• Costello syndrome
• RASopathies
• eye manifestations
• strabismus
• refractive errors
• optic nerve hypoplasia

Acknowledgments

Costello Syndrome Family Network (CSFN)

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

This work was supported by Children’s Miracle Network Endowed Chair in Pediatric Genetics (to SPS). This work was also supported by the National Eye Institute/National Institutes of Health [R01EY018246]; a University of Wisconsin Centennial Scholars Award [to TLY]; and an unrestricted grant from Research to Prevent Blindness, Inc. to the UW-Madison Department of Ophthalmology and Visual Sciences [to TLY]