Dear Editor,
Morning glory syndrome (MGS) and optic disc coloboma (ODC) are rare congenital optic disc (OD) anomalies that can be confusing and difficult to differentiate due to their similar presentations. MGS, first described by Kindler in 1970 and named for its resemblance to the morning glory flower, is characterized by a funnel-shaped, enlarged, and excavated OD.1 Meanwhile, ODC appears as a sharply defined, white excavation within an enlarged OD and can occur in isolation or alongside other ocular anomalies, such as iris or chorioretinal coloboma (CC), particularly in patients with PAX6 mutations.2
Retinitis pigmentosa (RP) is the most common form of inherited retinal degeneration, characterized by progressive photoreceptor disorders leading to photoreceptor cell death.3 The disease can follow several modes of inheritance, including autosomal dominant, autosomal recessive, and X-linked patterns.3
Herein, we highlight a rare familial presentation involving bilateral OD anomalies in a mother and son, as well as CC in the son and RP in the father, and describe the associated genetic findings.
A family consisting of a 44-year-old woman, an 11-year-old boy, and a 40-year-old man visited our clinic. The woman came for a routine examination, while the boy presented with strabismus and the man reported low vision since childhood.
Upon evaluation, the woman’s best corrected visual acuity (BCVA) was 20/50 in the right eye and 20/20 in the left. Fundus examination revealed bilaterally excavated, enlarged OD with peripapillary atrophy (Figure 1).
The 11-year-old son’s BCVA was 20/25 bilaterally. Cycloplegic refraction revealed a bilateral hyperopic error of +2 diopters (D) in the 90-degree axis. Extraocular motility assessment indicated small-angle esotropia at distance and near fixation (10 prism diopters [PD] and 4 PD, respectively). Slit-lamp fundus examination revealed bilaterally excavated and enlarged ODs surrounded by an annulus of chorioretinal pigmentary deposition. Additionally, an area of chorioretinal atrophy was located between the OD and macula, and CC was observed inferiorly to the OD (Figure 2). His 8-year-old sibling had no detectable ocular or systemic abnormalities.
The visual acuity of the 40-year-old father was counting fingers at 2 meters bilaterally. Slit-lamp examination showed mild bilateral posterior capsular cataract. Fundus examination demonstrated attenuation of the retinal arteries, OD pallor, retinal atrophy, a bull’s eye maculopathy pattern, and bone-spicule pigmentation changes, consistent with RP (Figure 3).
To investigate these clinical findings, whole exome sequencing (WES) and targeted variant analysis were performed for the family (Figure 4). The mother and affected son were heterozygous for a variant of uncertain significance in the YAP1 gene according to the American College of Medical Genetics and Genomics (ACMG) criteria.4 The unaffected sibling did not carry this variant. Furthermore, the father was homozygous for a pathogenic variant in the BBS1 gene according to ACMG criteria. However, he exhibited no related systemic manifestations. Both the affected and unaffected sons were also heterozygous carriers of the BBS1 variant.
Although the exact type of OD anomaly could not be definitively diagnosed, the mother’s OD configuration resembled MGS, while the son’s was consistent with ODC. The pathogenesis of these conditions differs. MGS may result from a primary mesenchymal abnormality, partial development of the lamina cribrosa, or incomplete closure of the posterior scleral wall, while ODC is caused by defective closure of the embryonic fissure.1, 2 In ODC, the defect is typically decentered inferiorly, reflecting the position of the embryonic fissure and abnormal exit of retinal vessels.2 In contrast, MGS presents with central excavation and radial exit of the vessels.2
YAP1 (OMIM 606608) encodes Yes-associated protein 1, a key effector of the Hippo signaling pathway involved in the development, growth, repair, and homeostasis of multiple organs, including the eye.5, 6 Previous studies have linked YAP1 variants to various ocular anomalies. DeYoung et al.5 reported an association with uveal coloboma. Holt et al.6 described a novel frameshift variant in the YAP1 gene in a boy with bilateral CC. Meanwhile, Williamson et al.7 identified novel missense and nonsense YAP1 variants in families with both syndromic and non-syndromic coloboma. In the present case, both the mother and her affected son carried the identified YAP1 variant, whereas the 8-year-old son, who exhibited no ocular or systemic abnormalities, did not carry this variant. Unfortunately, segregation analysis could not be extended to the maternal grandparents, as they were deceased. Therefore, the clinical relevance of the identified variant remains uncertain, although it is considered likely to be associated with the observed phenotype based on the available evidence.
Pathogenic variants in the BBS1 gene associated with RP can present as mild or even nonsyndromic forms of Bardet-Biedl syndrome (BBS).3 According to WES analysis, the father was homozygous for this BBS1 variant, whereas the affected son was heterozygous. This difference may partly explain the phenotypic variability observed between the father and son.
Clinically, the CC and OD anomaly observed in the son resembled ODC. This presentation may represent a type 3 fundus coloboma with OD involvement, as described by Gopal et al.8 In addition, some studies have reported an association between RP and CC, which has been described as an autosomal dominant trait.9, 10 Meanwhile, CC has also been associated with BBS, as reported by Chattannavar et al.,11 supporting our suggestion of a potential link between the father and son.
The presence of these unusual bilateral findings in the mother and son, both carrying a YAP1 variant, along with the father’s BBS1-associated RP, makes this case unique. It underscores the diagnostic challenge of distinguishing between MGS and ODC. Our patients lacked any systemic or neurological abnormalities, particularly cranial midline anomalies. The absence of these associated findings, together with the identification of a heterozygous YAP1 variant, suggests that the observed phenotype is more consistent with ODC than MGS. Finally, the rare bilateral involvement in two family members raises the intriguing possibility that the son’s CC is associated with the father’s RP.
