The optic nerve coloboma spectrum is a group of congenital disorders characterized by excavation of the optic disc. The term “coloboma” derives from the Greek word kolobōma (meaning a mutilated or defective part).
In recent years, the unified concept of congenital optic disc anomaly (CODA) has been proposed. 6)
The main diseases included in the spectrum are the following five:
ODC is approximately equally unilateral and bilateral. There is no racial or gender predilection.
Visual acuity and symptoms vary greatly depending on the disease and severity.
Optic disc findings differ for each disease. See the comparison below.
ODC
Optic disc findings: Well-defined bowl-shaped excavation predominantly inferiorly. The superior rim of the disc remains, and the sclera appears white.
Vascular pattern: The central retinal artery branches posterior to the disc, so many arteries appear to emerge from the disc margin.
Complications: Extension to choroidal coloboma, microphthalmos. Complicated by serous retinal detachment.
MGD
Optic disc findings: Funnel-shaped excavation. A central glial tissue mass is observed. Accompanied by numerous retinal vessels radiating from the peripapillary area (annulus). Usually unilateral. 4)
Complications: Classically known association with basal encephalocele. Attention should also be paid to complications of cerebrovascular anomalies.
PPS/ODP
PPS: The optic disc itself is usually normal. Deep funnel-shaped excavation around the disc. Atrophic pigmentary changes. Reports of contractile staphyloma. 4)
ODP: Gray-white round to oval crater-like excavation, often on the temporal side. OCT shows lamina cribrosa defect, suboptic disc fluid accumulation, and intraoptic disc septal structures. 5)
Cupping due to ODC is inferiorly eccentric and non-progressive, and is not accompanied by elevated intraocular pressure or progressive visual field changes, which are the main differentiating points from glaucoma. OCT, visual field testing, and follow-up of cupping changes over time are useful for differentiation.
The root cause common to all spectrum diseases is failure of closure of the embryonal fissure.
Eye development begins with the formation of the optic sulcus at 22–25 days of gestation, differentiating into the optic vesicle and optic stalk (→ optic nerve). If the embryonal fissure does not close normally by the 7th week of gestation, coloboma occurs.
The etiology for each disease is as follows.
Most cases are sporadic, but familial cases have also been reported.
Spectrum diseases may be associated with severe systemic diseases. The table below summarizes the main associated diseases.
| Systemic Disease | Main Features | Associated Gene |
|---|---|---|
| CHARGE syndrome | Heart malformation, choanal atresia, growth retardation | CHD7 |
| Papillorenal syndrome | Renal hypoplasia, hypertension, sensorineural hearing loss | PAX2 |
| Aicardi syndrome | Agenesis of corpus callosum, infantile spasms | — |
| Meckel syndrome | Polydactyly, renal cysts | — |
In MGD, a classic association with basal encephalocele is known.
Most cases are sporadic. However, familial cases have been reported, suggesting possible triplication of the mucosal pemphigoid 19 gene or autosomal dominant inheritance in ODP. 6) Papillorenal syndrome due to PAX2 mutation is a hereditary disease and requires screening for renal complications.
ODC can be diagnosed by ophthalmoscopy alone. Characteristic findings include a downward-eccentric, well-defined bowl-shaped excavation, preservation of the superior rim of the optic disc, and visible scleral whiteness. Ultrasound, MRI, CT, and OCT are used for definitive diagnosis.
It is particularly useful for evaluating the pathology of ODP.
Swept-source OCT (SS-OCT) shows sparse and irregular scleral fibers and an opening of the subarachnoid space just behind the excavation floor in ODC.
| Differential Disease | Key Points for Differentiation |
|---|---|
| Glaucomatous optic disc cupping | Progressive, elevated intraocular pressure, visual field changes |
| Peripapillary staphyloma | Optic disc itself is normal |
| Morning glory syndrome (another name for MGD) | Radial vessels, glial tuft |
| Optic disc PFV/PHPV | Persistent fetal hyaloid artery |
ODC tends to be located inferonasally, while ODP tends to be inferotemporally, which also helps in differentiation. 5)
There is no fundamental treatment or prevention. The mainstay of treatment is amblyopia management and addressing complications.
Management of serous retinal detachment (serous RD) associated with ODC is as follows:
The main treatments for ODP maculopathy are as follows. There is no established consensus on treatment, and the choice varies depending on the facility and case.
Nadig & Ratra (2024) reported a case of a 42-year-old male with double optic disc pits treated with PPV + ILM flap inversion + fibrin glue + SF6 gas tamponade. At 3 months postoperatively, best-corrected visual acuity improved from 20/60 to 20/30, and foveal thickness decreased from 879 μm to 482 μm. 1)
In combined cases of PPS and ODP, improvement in visual acuity has been reported with PPV + laser photocoagulation at the PPS margin + SF6 gas tamponade (best-corrected visual acuity 0.2→0.7). 7)
There are multiple options including PPV (vitrectomy), laser photocoagulation, gas tamponade, macular buckling, and use of human amniotic membrane, but there is no established standard treatment. PPV is considered to have a higher success rate than laser photocoagulation, and there are reports of PPV + ILM flap inversion. 1)
Eye development begins with the formation of the optic sulcus at 22–25 days of gestation. The normal course involves differentiation into the optic vesicle → optic stalk (→ optic nerve), with closure of the embryonic fissure by 7 weeks of gestation. Incomplete closure of this fissure forms the basis for the development of various diseases.
The PAX2 gene is expressed in astrocytes and is involved in the normal differentiation and migration of precursor astrocytes. PAX2 mutations impair optic disc formation and inhibit retinal and choroidal development through abnormal angiogenesis.
Multiple pathways have been suggested for the accumulation of subretinal and intraretinal fluid in ODP.
As a pressure gradient mechanism, it has been proposed that when intracranial pressure decreases, vitreous humor is drawn into the ODP, and when intracranial pressure increases, fluid is pushed back into the eye, dissecting the subretinal and intraretinal spaces. 9)
The progression of the lesion (Lincoff sequence) is as follows:
Histologically, ODP is a herniation of retinal tissue extending into the subarachnoid space through a defect in the lamina cribrosa. 7,9)
When silicone oil is used in an ODC eye, if IOP increases, the coloboma acts as a pathway, and the pressure gradient causes oil to migrate from the vitreous cavity to the subretinal space. Cases occurring 14 months postoperatively have been reported, highlighting the importance of long-term intraocular pressure management. 3)
Betsch et al. (2021) reported two pairs of father-son familial ODP cases and showed that whole-exome sequencing did not detect mutations in PAX2, PAX6, or collagen type XVII alpha 1. 6) Candidate genes include IGSF9, MPP4, SDHA, HMCN1, and SCN3A, but causality remains unconfirmed.
The establishment of the CODA concept, which treats ODC, MGD, and ODP as diseases on the same spectrum, is progressing. Additionally, a 6 kbp triplication of the collagen type XVII alpha 1 gene (chromosome 12q) has been identified in a CODA family (Fingert 2007 → confirmed as triplication by Hazlewood 2015), and in another CODA family, 14q12-q22.1 has been reported as a new locus. 6)
Hodgkins et al. reported that all cases with frontonasal dysplasia and basal encephalocele were accompanied by PPS or MGDA, suggesting that both diseases share a common embryological origin. 4)
The hypothesis that MGDA and PPS are different forms on the phenotypic spectrum of the same disease is being supported by accumulating case reports.
PPV with ILM (internal limiting membrane) flap inversion for ODP maculopathy is gaining attention as a new surgical approach. 1) Additionally, the use of human amniotic membrane for ODP with neurosensory detachment has been reported, but both are still at a stage with limited case numbers.
