Ophthalmoscopy Insufficient to Detect Vitreoretinopathy in CTNNB1 Syndrome

Drew Scoles, MD, PhD

Credit: LinkedIn

Nearly all patients with CTNNB1 syndrome in a recent case series needed ophthalmic care for refractive error and strabismus, with a subset of patients also requiring treatment for familial exudative vitreoretinopathy (FEVR).¹

The case series study involved patients with previously unnoticeable ophthalmoscopic examination findings, suggesting ophthalmoscopy alone is inadequate to identify vitreoretinopathy among individuals with CTNNB1 syndrome.

“These findings support consideration of ultra-widefield fluorescein angiography among individuals with CTNNB1 syndrome when feasible, including use of sedation if such an assessment is not possible in the office setting,” wrote the investigative team, led by Drew Scoles, MD, PhD, Children’s Hospital of Philadelphia.

De novo missense, nonsense, frameshift, splice variants, and deletions, in CTNNB1 have been reported to cause microcephaly and development delay, known as CTNNB1 syndrome.² Ophthalmic manifestations of CTNNB1 syndrome include FEVR, a congenital progressive retinal vascular disease, characterized by peripheral retinal avascularity, neovascularization, exudation, vitreoretinal traction, and retinal detachment in severe cases.

A previous systematic review reported up to 23% of individuals with CTNNB1 variants had FEVR.³ However, Scoles and colleagues noted this prevalence is likely underestimated, as detection of less advanced FEVR requires examination with fluorescein angiography, which typically cannot be performed awake in children with developmental delay.¹

In addition, reports are scarce on the absolute prevalence of FEVR in children with CTNNB1 syndrome without advanced-stage disease. To bridge this gap, Scoles and colleagues reported on patients with CTNNB1 variants who had previously unremarkable findings on ophthalmoscopic examinations and described their ophthalmic phenotypes.

Conducted at the investigators’ institution from October 2022 to November 2023, the case series identified 11 patients with identified variants in CTNNB1 and normal results on past office retinal examinations. These consecutive patients underwent examination under anesthesia with fluorescein angiography.

For the analysis, detailed genotype information was assessed for all patients, with each variant mapped on the CTNNB1 gene to identify a link with vitreoretinopathy severity. Primary outcomes included the number of patients with vitreoretinopathy and the number requiring treatment for vitreoretinopathy.

At the time of diagnosis, the full study population had a mean age of 2 years, with a mean age of 6 years at examination. A previous diagnosis of strabismus was identified in 9 patients, while 6 patients had previously experienced strabismus surgery.

Upon analysis, FEVR was identified in 5 patients and 9 eyes. Disease-requiring treatment was necessary for 6 of these eyes, including 1 retinal detachment requiring scleral buckling.

Scoles and colleagues indicated the detailed genotypic analysis of patients with CTNNB1 syndrome revealed no characterized high-risk loci in CTNNB1 associated with the notable severity of FEVR.

“The results here, in a small case series, similarly found no generalizable genotype and phenotype correlation,” Scoles added. “Further work may be needed to better understand FEVR risk at the patient level.”

The team added the results of genetic testing were negative for other known FEVR genes across all patients, and significant trauma was excluded by patient history.

“Based on this case, in our opinion, additional concern for vitreoretinopathy should be present in patients with CTNNB1 syndrome with a history of prematurity,” Scoles and colleagues wrote.

Reference

1. _{Bedoukian EC, Forbes G, Scoles D. Vitreoretinopathy in Asymptomatic Children with CTNNB1 Syndrome. JAMA Ophthalmol. Published online August 15, 2024.}
2. _{Kayumi S, Pérez-Jurado LA, Palomares M, et al. Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants. Genet Med. 2022;24(11):2351-2366. doi:10.1016/j.gim.2022.08.006}
3. _{Miroševič Š, Khandelwal S, Sušjan P, et al. Correlation between Phenotype and Genotype in CTNNB1 Syndrome: A Systematic Review of the Literature. Int J Mol Sci. 2022;23(20):12564. Published 2022 Oct 19. doi:10.3390/ijms232012564}