Iris
Keyhole pupil: Typically, the defect is located inferonasally, causing the pupil to deform into a keyhole shape.
Inferotemporal location: It may also occur in atypical positions.
Coloboma (Ocular Defect)
Key Points at a Glance
Section titled “Key Points at a Glance”1. What is Coloboma (Ocular Defect)?
Section titled “1. What is Coloboma (Ocular Defect)?”Coloboma derives from the Greek word meaning “defect” and is a congenital disease in which tissue defects occur in various parts of the eye due to incomplete closure of the embryonic fissure. It can occur in the eyelids, iris, lens, ciliary body, choroid, retina, and optic nerve. The defect is typically located inferonasally and is often accompanied by microphthalmia.
The prevalence is reported to be 0.5–2.2 per 10,000 births. In the United States, it is approximately 2.6 per 10,000 births 4), and in Europe, 4–19 per 100,000 births 6). It accounts for about 11% of childhood blindness, and the genetic diagnostic rate remains below 30% 6). The prevalence of eyelid coloboma is 0.2–0.8 per 10,000 births. It accounts for 0.07% of congenital eye malformations and 3.2–11.2% of visually impaired children.
Coloboma can be classified into typical and atypical types. Typical coloboma results from incomplete closure of the embryonic fissure and is located inferonasally, whereas atypical coloboma occurs in other locations and is thought to have a different developmental mechanism.
ICD-10 codes are Q10.3 (eyelid), Q13.0 (iris), Q12.2 (lens), H47.319 (optic nerve), and Q14.8 (choroid/retina).
Q
Is coloboma hereditary?
A
Both sporadic and hereditary forms exist. Various inheritance patterns including autosomal dominant, autosomal recessive, and X-linked have been reported. Multiple causative genes such as PAX2, CHD7, and FZD5 have been identified, but the genetic diagnostic rate is less than 30% 6). Genetic counseling is recommended if there is a family history.
2. Main symptoms and clinical findings
Section titled “2. Main symptoms and clinical findings”
Lingam G, et al. Ocular coloboma-a comprehensive review for the clinician. Eye (Lond). 2021. Figure 2. PMCID: PMC8302742. License: CC BY.
Anterior segment photograph showing incomplete iris coloboma, with a notch at the lower pupillary margin and a partial-thickness iris defect near the iris root (arrow). This corresponds to iris coloboma discussed in the section “2. Main symptoms and clinical findings.”
Subjective symptoms
Section titled “Subjective symptoms”Visual acuity varies widely from no light perception to normal, depending on the location and extent of the defect.
- Decreased visual acuity: Prominent when the macula or optic nerve is involved.
- Nystagmus and strabismus: Occur due to poor vision from macular or optic nerve coloboma. Deprivation amblyopia may also develop.
- Photophobia (glare): Occurs when the iris coloboma reduces the light-blocking function of the iris 4).
- White pupil (leukocoria): May be observed in extensive choroidal coloboma.
Clinical findings
Section titled “Clinical findings”Coloboma presents characteristic findings in each part of the eye.
Choroid and Retina
Yellow-white lesion: A well-defined round to fan-shaped defect where the sclera is visible.
Risk of retinal detachment: Incidence 23–40%7). Regular follow-up is necessary.
Optic Nerve and Lens
Enlarged optic disc cupping: Varies in severity, from unilateral to bilateral.
Flattening of the lens equator: Occurs due to zonular defects. Observed under dilated pupils.
Eyelid
Defect in the upper eyelid medially: Full-thickness tissue defect.
Association with systemic malformations: May occur alone or with systemic anomalies.
Ciliary body coloboma rarely occurs alone and is often found contiguous with a large choroidal coloboma.
Q
Does coloboma always cause vision loss?
A
Visual acuity ranges from no light perception to normal. If the coloboma is limited to the iris, vision is often preserved. When the macula or optic nerve is involved, poor visual acuity is common.
3. Causes and Risk Factors
Section titled “3. Causes and Risk Factors”The main cause of coloboma is failure of closure of the embryonic fissure.
Developmental Process
Section titled “Developmental Process”The embryonic fissure (optic fissure) forms at 4 weeks of gestation and is completed by 5 weeks. Closure begins at 6 weeks and is completed by 7 weeks. If this closure process is disrupted for any reason, coloboma occurs. Involvement of vitamin A has also been suggested.
Related Genes
Section titled “Related Genes”Multiple genes involved in the development of coloboma have been identified.
| Gene | Associated Disease/Phenotype |
|---|---|
| PAX2 | Renal coloboma syndrome5) |
| CHD7 | CHARGE syndrome |
| FZD5 | Syndromic OC + microcornea6) |
| TENM3 | MCOPS15 (microcornea + developmental delay) 8) |
| FAT1 | Coloboma + nephropathy 9) |
| YAP1 | Coloboma-related |
| ABCB6 | Coloboma-related |
| SALL2 | Coloboma-related |
Associated syndromes
Section titled “Associated syndromes”Coloboma can be associated with the following systemic syndromes.
- CHARGE syndrome: A multiple malformation syndrome caused by CHD7 gene mutation. Characterized by coloboma, heart defects, choanal atresia, growth retardation, genital hypoplasia, and ear abnormalities.
- Aicardi syndrome: Characterized by the triad of agenesis of the corpus callosum, infantile spasms, and chorioretinal coloboma.
- Goldenhar syndrome and Treacher Collins syndrome: Craniofacial developmental anomalies that may be accompanied by eyelid and iris coloboma.
Q
What is CHARGE syndrome?
A
It is a multiple malformation syndrome caused by mutations in the CHD7 gene. The name is an acronym for coloboma (C), heart defects (H), choanal atresia (A), growth and developmental retardation (R), genital hypoplasia (G), and ear abnormalities (E). Diagnosis is based on a combination of these findings.
4. Diagnosis and testing methods
Section titled “4. Diagnosis and testing methods”Ophthalmic examination
Section titled “Ophthalmic examination”- Ophthalmoscopy: Essential for evaluating choroidal, retinal, and optic nerve colobomas. Performed under pupil dilation.
- Slit-lamp examination: Used to evaluate iris and lens colobomas.
- OCT (Optical Coherence Tomography): Useful for detailed evaluation of retinal structure. Can assess macular involvement.
- Ultrasound (Echography): Used when the fundus is poorly visible or to search for retinal detachment.
- Ultrasound Biomicroscopy (UBM): Useful for evaluating anterior segment structures. Also used to confirm scleral defects 1).
- Head MRI/CT: Necessary for evaluating optic nerve coloboma and central nervous system complications.
Genetic testing
Section titled “Genetic testing”Comprehensive genetic testing such as whole exome sequencing (WES) is performed, but the diagnostic rate remains below 30% 6).
Differential diagnosis
Section titled “Differential diagnosis”Coloboma requires differentiation from the following diseases depending on the site.
| Site | Main differential diagnoses |
|---|---|
| Eyelid | Amniotic band syndrome, trauma |
| Iris | Aniridia, traumatic iris dialysis |
| Optic nerve | Morning glory syndrome, optic nerve hypoplasia |
5. Standard treatment
Section titled “5. Standard treatment”There is no curative treatment for coloboma; management focuses on symptomatic treatment and complication management according to the site.
Eyelid coloboma
Section titled “Eyelid coloboma”- Corneal protection: Prevention of corneal dryness with lubricants (artificial tears).
- Surgical repair: Eyelid reconstruction with end-to-end sutures or skin flaps.
- Amblyopia prevention: Early amblyopia treatment is important in pediatric cases.
Iris and Lens Coloboma
Section titled “Iris and Lens Coloboma”- Refractive correction: Correction with glasses or contact lenses.
- Cataract surgery: When cataract is associated with lens coloboma, intraocular lens (IOL) implantation is performed. Due to zonular defects, the use of a capsular tension ring (CTR) is useful 4).
Castilla-Martinez et al. (2024) performed femtosecond laser-assisted cataract surgery (FLACS) combined with pupilloplasty and placed a CTR in a case of iris, lens, and zonular coloboma with cataract. Postoperative visual acuity improved to logMAR 0.2 4).
Choroidal and Retinal Coloboma
Section titled “Choroidal and Retinal Coloboma”- Amblyopia treatment: In pediatric cases, amblyopia treatment such as patching of the healthy eye is performed.
- Retinal detachment monitoring: Regular examinations every 6 to 12 months are recommended. The incidence of retinal detachment is high at 23–40% 7).
- Prophylactic laser photocoagulation: Prophylactic laser to the coloboma margin may be considered in some cases.
Optic Nerve Coloboma
Section titled “Optic Nerve Coloboma”In optic nerve coloboma, due to lamina cribrosa dysplasia, the central retinal artery and vein already branch posterior to the optic disc, and retinal vessels originate from multiple sites at the disc margin. Chorioretinal atrophy associated with incomplete closure of the embryonic fissure is often seen inferior to the disc.
- Serous retinal detachment: There is no established treatment strategy, and some cases resolve spontaneously.
- Rhegmatogenous retinal detachment: Surgery (vitrectomy and photocoagulation around the excavation) is required. Causes of retinal detachment include a break within the excavation as well as cerebrospinal fluid inflow due to communication between the excavation and the subarachnoid space.
Q
What is the treatment for retinal detachment in eyes with coloboma?
A
Vitrectomy is performed for rhegmatogenous retinal detachment. Surgical techniques such as retinopexy with fibrin glue 7) and endophotocoagulation with gas tamponade 3) have been reported. For serous retinal detachment, spontaneous resolution may occur, and treatment is decided on a case-by-case basis.
6. Pathophysiology and Detailed Mechanisms
Section titled “6. Pathophysiology and Detailed Mechanisms”Formation and Closure of the Embryonic Fissure
Section titled “Formation and Closure of the Embryonic Fissure”The optic cup forms from the neuroectoderm at 4 weeks of gestation. On the ventral side of the optic cup, the embryonic fissure (optic cup fissure) develops, through which the hyaloid artery passes. This fissure is completed at 5 weeks, and closure begins at 6 weeks. Closure starts near the equator and proceeds anteriorly (toward the iris) and posteriorly (toward the optic nerve), completing at 7 weeks.
Epithelial-mesenchymal transition (EMT) is involved in the closure process. Neuroretinal epithelial cells at the edges of the embryonic fissure degrade the basement membrane, acquire mesenchymal characteristics, and fuse. Disruption of this process leads to coloboma.
Molecular Mechanisms
Section titled “Molecular Mechanisms”The FZD5 gene encodes a receptor in the Wnt signaling pathway. Loss-of-function mutations in FZD5 cause abnormal Wnt signaling, leading to failure of embryonic fissure closure and microcornea 6).
Neural crest cells (NCCs) are also involved in coloboma development. NCCs differentiate into mesenchymal tissue around the optic cup and play an important role in the closure of the embryonic fissure 2). Impaired NCC migration leads to abnormalities in iris and choroid development.
Mechanisms by Site
Section titled “Mechanisms by Site”- Iris coloboma: Results from incomplete closure of the anterior end of the embryonic fissure. Typically presents as a keyhole-shaped defect in the inferonasal quadrant.
- Choroidal coloboma: Caused by incomplete closure of the central portion of the embryonic fissure. The retinal pigment epithelium and choroid are absent, and the sclera is visible.
- Optic nerve coloboma: Occurs due to incomplete closure of the posterior end of the embryonic fissure. Observed as an enlarged excavation of the optic disc.
7. Latest Research and Future Perspectives (Reports at Research Stage)
Section titled “7. Latest Research and Future Perspectives (Reports at Research Stage)”Identification of novel causative genes
Section titled “Identification of novel causative genes”Cortes-Gonzalez et al. (2024) reported that a homozygous missense mutation (p.M160V) in FZD5 causes syndromic ocular coloboma and microcornea 6). It shows an autosomal recessive inheritance pattern, and functional analysis confirmed impaired ligand-dependent activation of the Wnt signaling pathway. The genetic diagnostic rate for coloboma is less than 30%, and identification of novel causative genes is expected to improve diagnosis.
Zhou et al. (2022) reported that compound heterozygous mutations in the TENM3 gene cause MCOPS15 (microcornea, iris-choroidal coloboma, and global developmental delay) 8). TENM3 encodes a transmembrane protein involved in cell adhesion and neurodevelopment.
Esmaeilzadeh et al. (2022) reported that FAT1 gene mutations were identified in an Iranian family with iris coloboma and nephropathy 9). FAT1 is a member of the cadherin superfamily involved in cell polarity and tissue morphogenesis.
Hu et al. (2024) reported that a c.76delG frameshift mutation in PAX2 was identified in a family with focal segmental glomerulosclerosis (FSGS) 5). This finding suggests that the phenotypic spectrum of renal coloboma syndrome is broader than previously thought.
New surgical techniques
Section titled “New surgical techniques”Jain et al. (2024) reported a case of coloboma-related retinal detachment treated with fibrin glue-assisted retinopexy 7). Fibrin glue was applied around the retinal tear at the coloboma margin to enhance adhesion, and final visual acuity improved to 20/50.
Ratra et al. (2023) reported successful treatment of a case of atypical choroidal coloboma complicated by post-traumatic scleral fistula using vitrectomy, endolaser photocoagulation, and gas tamponade 3).
Scemla et al. (2021) reported a case of a 19-year-old male with hypotony (4 mmHg) due to transscleral filtration at the site of choroidal coloboma 1). Scleral defect was confirmed by ultrasound biomicroscopy. Spontaneous recovery occurred within 6 weeks, maintaining intraocular pressure of 11 mmHg and visual acuity of 1.0.
8. References
Section titled “8. References”- Scemla B, Duroi Q, Duraffour P, Souedan V, Brezin AP. Transscleral filtration revealing a chorioretinal coloboma. Am J Ophthalmol Case Rep. 2021;21:101003.
- Rajshri H, Nagesha CK, Arthi M. Combined choroidal vitiligo and retinochoroidal coloboma. BMJ Case Rep. 2023;16:e253854.
- Ratra D, Mohan S, Nadig R, Kashyap H. The deceptive coloboma. Indian J Ophthalmol. 2023;71(6):2632.
- Castilla-Martinez G, Fernandez-Martinez C, Pardo-Lopez S, Toledano-Martos R, Hernandez-Artola F. FLACS combined with pupiloplasty in iris-lens coloboma. Am J Ophthalmol Case Rep. 2024;34:102039.
- Hu X, Lin W, Luo Z, Zhong Y, Xiao X, Tang R. Frameshift Mutation in PAX2 Related to FSGS. Mol Genet Genomic Med. 2024;12:e70006.
- Cortes-Gonzalez V, Rodriguez-Morales M, Ataliotis P, et al. Homozygosity for a hypomorphic mutation in FZD5 causes syndromic ocular coloboma with microcornea. Hum Genet. 2024;143:1509-1521.
- Jain KS, Upadhyaya A, Raval VR. Fibrin-glue-assisted retinopexy for coloboma-associated retinal detachment. Indian J Ophthalmol. 2024.
- Zhou Y, Xu K, Gu W, Huang Y. TENM3 pathogenic variants causing microcornea, iris and choroidal coloboma, and global developmental delay. Mol Genet Genomic Med. 2022;10:e1948.
- Esmaeilzadeh E, Ghaderi Z, Moradi A, Khorram Khorshid HR. Causative gene mutation in coloboma and nephropathy. CEN Case Rep. 2022;11:404-407.