Key Points
Question
Can vision-threatening vitreoretinopathy be detected on fluorescein angiography in the eyes of patients with CTNNB1 syndrome, even if eyes appear normal on ophthalmoscopy?
Findings
In this case series study of 11 patients with CTNNB1 syndrome and previously unremarkable ophthalmoscopic examination findings who subsequently underwent an examination with fluorescein angiography under anesthesia, vitreoretinopathy was present in 5 patients. Vitreoretinopathy requiring treatment was identified in 4 patients, including 1 retinal detachment.
Meaning
Ophthalmoscopy alone may be insufficient to identify vitreoretinopathy in patients with CTNNB1 syndrome, and early identification and treatment of vitreoretinopathy could potentially lead to better long-term visual outcomes.
Abstract
Importance
Previous studies have identified familial exudative vitreoretinonpathy (FEVR) in patients with CTNNB1 syndrome based on severe congenital ocular phenotypes. However, ophthalmoscopy may not be sufficient to detect vision-threatening vitreoretinopathy in all patients.
Objective
To report a consecutive retrospective case series of 11 patients with CTNNB1 variants who had previously unremarkable ophthalmoscopic examination results and to describe their detailed ophthalmic phenotypes.
Design, Setting, and Participants
This retrospective case series was conducted at the Children’s Hospital of Philadelphia from October 2022 to November 2023 among patients with identified variants in CTNNB1 and previously documented normal results in office retinal examinations. These consecutive patients subsequently underwent an examination under anesthesia with fluorescein angiography. Detailed genotype information was analyzed for all patients, and each variant was mapped on the CTNNB1 gene to observe any associations with severity of vitreoretinopathy.
Main Outcomes and Measures
Number of patients with vitreoretinopathy and number requiring treatment for vitreoretinopathy.
Results
The mean (SD) age at the time of CTNNB1 syndrome diagnosis was 2 (1) years, and the mean (SD) age at examination was 6 (3) years for the 11 total patients. A total of 9 patients had a diagnosis of strabismus, and 5 patients had undergone strabismus surgery. FEVR was present in 5 of 11 patients and in 9 eyes. The presence of disease requiring treatment was identified in 6 eyes, including 1 retinal detachment. Detailed genotype analysis of the patients found no clearly delineated high-risk loci in CTNNB1 in association with high severity of FEVR.
Conclusions and Relevance
In this case series study, nearly all patients with CTNNB1 syndrome required ophthalmic care for refractive error and strabismus, and a subset also required treatment for FEVR. These findings support consideration of ultra-widefield fluorescein angiography among individuals with CTNNB1 syndrome when feasible, including the use of sedation if such an assessment is not possible in the office setting.
This case series of 11 patients with CTNNB1 syndrome reports the presence of familial exudative vitreoretinonpathy detected via fluorescein angiography under anesthesia, which was previously undetected on ophthalmoscopic examination.
Introduction
Encoded by CTNNB1, β-catenin is a critical molecule in the Wnt signaling pathway and is essential for embryonic development (specifically brain and eye development) and adult tissue homeostasis.1,2,3 De novo missense, nonsense, frameshift, and splice variations as well as deletions in CTNNB1 have been reported to cause microcephaly and developmental delay, referred to as CTNNB1 syndrome.2,3 Ophthalmic manifestations of the syndrome are common and include familial exudative vitreoretinopathy (FEVR).2,3,4 FEVR is a congenital progressive retinal vascular disease characterized by peripheral retinal avascularity, neovascularization, exudation, vitreoretinal traction, or, in severe cases, retinal detachment.4,5,6,7 β-Catenin is biochemically downstream of previously confirmed FEVR gene variants, including FZD4, TSPAN12, LRP5, and NDP. Thus, it is biologically plausible that FEVR would be common in patients with CTNNB1 syndrome.4
In a systematic review of studies describing the phenotype of variants in CTNNB1, Miroševič et al3 reported that 22.8% of individuals with CTNNB1 variants had FEVR. Most of these cited CTNNB1 cases had stage 4 or stage 5 FEVR, detected due to leukocoria or blindness at birth.8,9,10,11 This prevalence is therefore likely an underestimate, since detection of less advanced stages of FEVR requires a careful peripheral retinal examination with fluorescein angiography,6 which typically cannot be performed awake in children with developmental delay.
To our knowledge, there have been no reports on the absolute prevalence of FEVR in children with CTNNB1 syndrome without apparent advanced stage disease. In this article, we report a consecutive retrospective case series of 11 patients with CTNNB1 variants who had previously unremarkable findings on ophthalmoscopic examination and describe their detailed ophthalmic phenotype.
Methods
This study was approved by the Institutional Review Board of the Children’s Hospital of Philadelphia and complied with all requirements of the US Health Insurance Portability and Accountability Act of 1996 and the tenets of the Declaration of Helsinki. Due to the study’s retrospective nature and lack of identifying information, the study was deemed exempt, and informed consent was not required. This study follows the reporting guidelines stated by Kempen et al.12
Consecutive pediatric patients with identified variants in CTNNB1 and previously documented normal retinal examination results, without any findings of retinal detachment, exudation, or vascular abnormalities typical of patients with more advanced FEVR, who subsequently underwent examination under anesthesia with fluorescein angiography, were included. Patients with known retinopathy or retinal detachment were excluded. History of prior eye surgery for nonretinal diagnoses (eg, strabismus) was not part of exclusion criteria. Variants were located based on Domain predictions from UniProt, 2023 version (The UniProt Consortium), and were graphically generated in RStudio, 2020 version, using the ggplot package (Posit).
Results
A total of 11 consecutive patients were identified, and detailed demographic characteristics are available in the Table. Briefly, mean (range) age at diagnosis of CTNNB1 syndrome was 2 (1-5) years, and mean (range) age at examination was 6 (2-11) years. A total of 9 patients had a previous diagnosis of strabismus, and 6 patients had undergone strabismus surgery. All patients who wore spectacles carried hyperopic refraction.
Table. Clinical, Genetic, and Ophthalmic Data From the Cohort.
| Patient No. | Age, y | Age at CTNNB1 syndrome diagnosis, y | CTNNB1 variant details | Genetic testing | Medical history | Eye | Visual acuitya | Refraction | FEVR stage | FEVR treatment | Strabismus | Other ocular history |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 7 | 3 | De novo pathogenic variant (c.164_165delAG; p.Glu55Glyfs*10) | Exome | Microcephaly, developmental delay, hypotonia, cerebral palsy, and failure to thrive | Right | FF | + 0.50 | 2A | Laser | Intermittent exotropia, inferior oblique overaction, dissociated vertical deviation, no surgery | Chalazion excision |
| Left | FF | + 0.50 | 1 | Laser | ||||||||
| 2 | 9 | 2 | De novo variant (C.1981c > t;p.R661X (Exon 13)) | Exome | Microcephaly, developmental delay, hypotonia, and precocious puberty | Right | 20/30 | + 5.00 + 1.50 x067 | 3 | Laser, scleral buckle | Partially accommodative esotropia, s/p right medial rectus recession at 4 y | None |
| Left | 20/30 | +6.00 + 0 | 1 | Observation | ||||||||
| 3 | 5 | 1 | De novo pathogenic variant (c.1469_1488del; p.Gly490Alafs*33) | Exome | Microcephaly, developmental delay, ventricular septal defect, and hypotonia | Right | Teller 20/47 | + 2.00 | 1 | Observation | Alternating esotropia s/p bilateral medial rectus recessions at 2 y | Nystagmus |
| Left | Teller 20/47 | + 2.00 | 1 | Observation | ||||||||
| 4 | 11 | 3 | De novo pathogenic variant (c.1603C>T p.R535X) | Exome | Microcephaly, developmental delay, and failure to thrive | Right | 20/60 | + 6.25 | 0 | NA | Partially accommodative esotropia s/p bilateral medial rectus recession at 11 y | Refractive amblyopia |
| Left | 20/80 | + 6.25 + 1.50 x090 | 0 | NA | ||||||||
| 5 | 6 | 1 | Pathogenic variant (.1963dupG; p.Ala655Glyfs*10); parents not tested | Exome | Microcephaly, developmental delay, hearing loss, micrognathia, fair skin color, and fifth-finger clinodactyly | Right | 20/40 | + 5.5 | 0 | NA | Left esotropia s/p left medial rectus recession at 6 y | None |
| Left | 20/100 | + 5.75 + 0.50 x165 | 0 | NA | ||||||||
| 6 | 8 | 5 | Pathogenic variant (c.1301dupA p.N434KfsX23); parents not tested | Exome | Microcephaly, developmental delay, hypotonia, and dystonia | Right | FF | NA | 1 | Laser | Intermittent esotropia, no surgery | Nystagmus |
| Left | FF | NA | 0 | Observation | ||||||||
| 7 | 2 | 1 | Pathogenic variant (c.1925_1926del; p.E642Vfs5); parents not tested | Exome | Developmental delay and hypotonia | Right | FF | NA | 0 | NA | Partially accommodative esotropia s/p surgery at 2 yb | None |
| Left | FF | NA | 0 | NA | ||||||||
| 8 | 6 | 3 | De novo pathogenic variant (c.283C>T; p.R95X) | Exome | Developmental delay, truncal hypotonia, appendicular hypertonia, exaggerated startle, and recurrent respiratory infections | Right | FF | + 1.50 + 0.50 x066 | 0 | NA | None | Nystagmus |
| Left | FF | + 2.00 + 0.25 x138 | 0 | NA | ||||||||
| 9 | 5 | 2 | De novo pathogenic variant (c.1420C>T; p.(R474*)) | Exome | Microcephaly and developmental delay | Right | FF | NA | 0 | NA | Partially accommodative esotropia s/p surgery at 2 yb | None |
| Left | FF | NA | 0 | NA | ||||||||
| 10 | 3 | 2 | Pathogenic variant (c.998dupA p.Y333X); parents not tested | Exome | Developmental delay, premature birth ( at gestational age 31 wk), hypotonia, and pulmonic stenosis | Right | FF | + 5.75 + 2.00 x042 | 2 | Laser | Pseudostrabismus | Regressed retinopathy of prematurity |
| Left | FF | + 4.00 + 1.00 x153 | 2 | Laser | ||||||||
| 11 | 5 | 4 | De novo pathogenic variant (c.1997_1990delTCTG(p.S663RfsX15)) | Exome | Microcephaly, developmental delay, and hypotonia | Right | FF | + 1.75 | 0 | NA | Esotropia, dissociated vertical deviation, no surgery | None |
| Left | FF | + 1.50 | 0 | NA |
Abbreviations: FEVR, familial exudative vitreoretinonpathy; FF, fix and follow; NA, not applicable; s/p, status post.
Visual acuity presented in Snellen format unless otherwise specified.
Full surgical details not available.
FEVR was present in 5 patients and 9 eyes, with staging defined by Kashani et al.6 Details are included in the Table and representative images from patients with vitreoretinopathy requiring treatment are displayed in Figure 1. All patients with vitreoretinopathy are included in the eFigure in Supplement 1. Disease requiring treatment was identified in 6 eyes, including 1 retinal detachment requiring scleral buckling.
Figure 1. Example Fluorescein Angiography From Patients With Vitreoretinopathy Requiring Treatment.
Avascular peripheral retina is indicated with an asterisk; neovascularization is shown by arrowheads. D, Traction detachment is not displayed well in image.
Detailed genotype information was available for all patients, and each variant was mapped on the CTNNB1 gene to observe any associations with severity of vitreoretinopathy, as shown in Figure 2. No uniform grouping of CTNNB1 variants and severity was identified.
Figure 2. Graphic Representation of CTNNB1 Variants.
CTNNB1 variants are noted with circles. Shading colors indicate familial exudative vitreoretinopathy stage in the worse eye. Dark blue indicates stage 0, light blue indicates stage 1, orange indicates stage 2, and gray indicates stage 3. BCL9 indicates B-cell CLL/lymphoma 9 protein; VCL, vinculin.
Discussion
Previous studies have identified FEVR in patients with CTNNB1 syndrome based on severe congenital ocular phenotype, a finding supported by biologic plausibility. This study demonstrated that vision-threatening vitreoretinopathy was present even in eyes that otherwise appeared unremarkable, within the limitations of a challenging clinical examination.
Thus far, there are no clearly delineated high-risk loci in syndromic CTNNB1 regarding risk of FEVR.13 The results here, in a small case series, similarly found no generalizable genotype and phenotype correlation. Further work may be needed to better understand FEVR risk at the patient level. For each patient, other causes of vitreoretinopathy were explored. The results of genetic testing were negative for any other known FEVR gene in all patients. Significant trauma was excluded by patients’ history. Patient 10 had a history of regressed retinopathy of prematurity after gestational age of 31 weeks. It was not possible to rule out a contribution of retinopathy of prematurity to the vascular findings, although active neovascularization is unusual in former premature infants at age 3 years. Based on this case, in our opinion, additional concern for vitreoretinopathy should be present in patients with CTNNB1 syndrome with a history of prematurity.
We agree, as has been stated by other authors,11 that the vitreoretinopathy phenotype in CTNNB1 syndrome may have some unique characteristics. The supernumerary vessel pattern common in FEVR was only seen in patient 1. Characteristic arborization at vessel termini was only clearly seen in patients 1 and 2, despite the presence of substantial avascularity in patients 3 and 6 and avascularity with neovascularization in patient 10.
Limitations
This study had some limitations. The cohort in this case series study is small, and therefore the reported incidence may not represent all patients with CTNNB1 syndrome. Detailed imaging was not available from many prior reports, especially those with FEVR less severe than stages 4 or 5. Thus, larger future studies are necessary to more completely detail the vitreoretinopathy phenotypic spectrum in CTNNB1 syndrome.
Conclusions
In summary, in this case series study, nearly all patients with CTNNB1 syndrome required ophthalmic care for refractive error and strabismus, with a subset also requiring treatment for FEVR. 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.
eFigure. Retinal Images From All Patients With Vitreoretinopathy
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eFigure. Retinal Images From All Patients With Vitreoretinopathy
Data Sharing Statement