Megalocornea is a non-progressive congenital anomaly with a horizontal corneal diameter of 13 mm or more (12 mm or more in newborns). It is usually bilateral and symmetric. The cornea is clear and corneal thickness is normal.
When the entire anterior segment is enlarged, it is called anterior megalophthalmos. It is accompanied by abnormalities of the iris, angle, and lens, with deep anterior chamber, iridodonesis, and phacodonesis.
The exact incidence of megalocornea is unknown, but it is a rare disease. Due to X-linked recessive inheritance, about 90% of cases occur in males.
It may occur as an isolated ocular disease or as part of a systemic syndrome. In HPMRS4 (hyperphosphatasia with mental retardation syndrome 4) due to PGAP3 gene mutation, megalocornea has been reported as an initial symptom misdiagnosed as congenital glaucoma2). Megalocornea associated with chromosome 13q21.33-q31.1 deletion has also been reported 5).
QHow is megalocornea different from congenital glaucoma (buphthalmos)?
A
In megalocornea, the cornea is enlarged but clear, intraocular pressure is normal, and Haab striae (rupture lines of Descemet’s membrane) are absent. In congenital glaucoma, corneal enlargement is accompanied by elevated intraocular pressure, corneal edema, Haab striae, and progressive optic disc cupping. The limbal border is distinct in megalocornea, whereas it is indistinct in congenital glaucoma, which is also useful for differentiation.
Primary megalocornea often has few subjective symptoms. Blurred vision due to refractive error may be the main complaint. Because the cornea is steep, it tends to cause with-the-rule astigmatism and myopia.
When glaucoma develops as a complication, headache and decreased vision may occur. In a reported case of a 29-year-old male, intermittent headache and progressive blurred vision prompted the visit 1).
Bilateral corneal enlargement with a horizontal corneal diameter of 13 mm or more is characteristic. The cornea is transparent, and corneal thickness is normal or slightly thinned.
Anterior Segment Findings
Deep anterior chamber: Anterior chamber depth is markedly increased. In anterior megalophthalmos, it can reach 5 mm or more 3).
Iridodonesis and phacodonesis: Enlargement of the ciliary ring stretches the zonules, resulting in iris and lens tremulousness 1).
Angle findings: The angle is wide, and increased pigmentation of the trabecular meshwork may be observed 1).
Endothelial cell density: Within normal range. This differs from corneal stretching due to congenital glaucoma.
Associated Findings
Pigment dispersion syndrome: Transillumination defects due to iris stretching predispose to pigment dispersion and pigmentary glaucoma1).
Cataract: Premature cataract has been reported. It presents as posterior subcapsular opacity or nuclear sclerosis 3).
Lens subluxation: Zonular weakness can lead to lens subluxation.
Vitreous abnormalities: Vitreous liquefaction, vitreous opacities, lattice degeneration, and other vitreoretinal abnormalities may be present 4).
In biometric measurements of anterior megalophthalmos, the axial length is within the normal range, but the anterior chamber depth is markedly deep. In one report, the anterior chamber depth reached 6.39 mm and the white-to-white diameter was 15.0 mm 3). A vitreous index (vitreous length/axial length × 100) of 69% or less is considered useful for diagnosing anterior megalophthalmos, but in atypical cases, values of 70% or more may also be observed 4).
The main cause of megalocornea is mutation in the CHRDL1 gene (Xq23). CHRDL1 encodes ventroptin (a BMP-4 antagonist). BMP-4 is a growth factor involved in anterior segment development, and ventroptin deficiency leads to uncontrolled BMP-4 signaling, resulting in overgrowth of the anterior segment.
Inheritance patterns are as follows:
X-linked recessive inheritance: Most common. About 90% occur in males.
Autosomal dominant inheritance: Rarely reported.
Autosomal recessive inheritance: Rarely reported.
Non-familial (sporadic): Sporadic cases without family history have also been reported 4).
Syndromic megalocornea is also recognized. Mutations in the PGAP3 gene (associated with GPI deficiency) present with megalocornea as part of HPMRS4 2). In cases with 13q21.33-q31.1 deletion, haploinsufficiency of the POU4F1 gene may be involved in abnormal corneal development 5).
Associations with systemic diseases include Frank-Ter Haar syndrome (skeletal dysplasia, developmental delay), Neuhauser syndrome (megalocornea-mental retardation syndrome), Marfan syndrome, and Down syndrome.
QCan women also develop megalocornea?
A
Yes, it occurs rarely in women. Although the most common inheritance pattern is X-linked recessive, which is more common in males, cases with autosomal dominant or autosomal recessive inheritance, or as part of a syndrome in females, have been reported. A female case of syndromic megalocornea due to PGAP3 gene mutation has also been reported 2).
Diagnosis of megalocornea is based on measurement of the horizontal corneal diameter and exclusion of congenital glaucoma.
Slit-lamp examination reveals increased corneal diameter, iridodonesis, and phacodonesis. Gonioscopy evaluates wide angle and trabecular meshwork pigmentation. Differentiation from congenital glaucoma requires confirmation of normal intraocular pressure, absence of Haab striae, clear cornea, and no progression of optic disc cupping.
Genetic testing (CHRDL1) is useful for definitive diagnosis. If a syndromic condition is suspected, whole exome sequencing (WES) is recommended 2)5). Systemic examination is performed to rule out syndromic associations.
In cases with PGAP3 mutations, megalocornea has been misdiagnosed as congenital glaucoma, leading to unnecessary administration of anti-glaucoma medications 2). Accurate differential diagnosis is essential for determining treatment strategy.
Treatment for megalocornea itself is not required. Long-term regular follow-up is performed, and treatment is given if complications arise. Refractive errors are corrected with glasses or contact lenses.
Cataract Surgery
Preoperative planning: Due to deep anterior chamber, zonular fragility, and large capsular bag, intraocular lens (IOL) selection is important 3). Care is needed in IOL power calculation.
Surgical technique: Access to the cataract is difficult due to the extremely deep anterior chamber. A method to reduce zonular stress by nuclear prolapse onto the capsular bag has been reported 3).
IOL selection: Standard-diameter IOLs may provide insufficient stability within the capsular bag. Options include iris-claw IOLs, iris-sutured IOLs, and custom large-diameter IOLs 3).
Postoperative management: There is a risk of IOL decentration or dislocation, requiring long-term follow-up.
Glaucoma Treatment
Medical therapy: Intraocular pressure control with eye drops is attempted first.
Surgical therapy: If medical therapy is insufficient, glaucoma drainage devices (GDD) are selected 1). Trabeculectomy is also performed, but attention is needed for postoperative choroidal detachment4).
Regular follow-up: In cases with pigment dispersion syndrome, monitoring for glaucoma development is important 1).
In intrascleral fixation of IOLs in megalocornea eyes, due to the large corneal diameter, the haptic fixation length within the scleral tunnel is insufficient, increasing the risk of IOL decentration. Trans-iris vertical intrascleral haptic fixation has been reported, where the haptic is passed through an iridotomy and guided from the posterior limbus to the scleral tunnel, achieving a longer haptic fixation length 6).
QWhat are the particular points to note in cataract surgery?
A
In cataract surgery for eyes with megalocornea, problems include difficulty of manipulation in an extremely deep anterior chamber, risk of capsular rupture and nucleus drop due to weak zonules, and instability of standard-diameter intraocular lenses due to a large capsular bag. Careful preoperative biometry and selection of an appropriate intraocular lens, such as an iris-claw IOL or large-diameter IOL, are important 3). Long-term follow-up is necessary because of the risk of postoperative IOL decentration.
The pathogenesis of megalocornea is attributed to developmental abnormalities of the anterior segment during the embryonic period.
In CHRDL1 gene mutations, ventroptin (a BMP-4 antagonist) is deficient. BMP-4 is mainly expressed in the anterior retina and regulates the development of corneal stroma and endothelium. Deficiency of ventroptin leads to disinhibition of BMP-4 signaling, resulting in overgrowth of the anterior segment. A common hypothesis is that incomplete fusion of the anterior optic cup causes the cornea to grow more than average.
Another theory suggests that delayed growth of the optic cup anteriorly during embryogenesis is the cause. Posterior displacement of the iris-lens diaphragm and normal endothelial cell density (in contrast to low density in corneal stretching due to glaucoma) support this theory.
In anterior megalophthalmos, enlargement of the ciliary ring is the essence. Malformation of the ciliary body leads to elongation and weakening of the zonules, causing instability of the iris-lens diaphragm. Stretching of the iris produces transillumination defects and increases pigment dispersion into the trabecular meshwork, predisposing to pigmentary glaucoma1).
The involvement of the POU4F1 gene in corneal development has also gained attention in recent years. POU4F1 is a transcription factor involved in the differentiation of retinal ganglion cells (RGCs). In mouse models, POU4F1 deficiency shows corneal stromal thinning, deepening of the anterior chamber, flattening of corneal curvature, and disorganization of collagen arrangement. In humans, the association between POU4F1 haploinsufficiency due to 13q21.33-q31.1 deletion and megalocornea was first reported 5).
Large-scale clinical studies on megalocornea are scarce, and most knowledge is based on case reports.
In genetic research, reports of megalocornea in HPMRS4 syndrome due to PGAP3 mutations 2) and reports of chromosome 13q deletion suggesting involvement of the POU4F1 gene in corneal development 5) are revealing the diversity of causative genes for megalocornea. With the widespread use of whole-exome and whole-genome sequencing, identification of new causative genes is expected.
In terms of surgical techniques, transiridal vertical intrascleral haptic fixation has been reported as a new approach for intraocular lens fixation in eyes with megalocornea, and a stable intraocular lens fixation method that accommodates large corneal diameters has been developed 6).
Reports of non-familial anterior megalophthalmos 4) demonstrate the clinical diversity of this disease, and elucidating the pathogenesis independent of inheritance patterns remains a future challenge.
De Leon JMS, Mangahas MAC. A 29-year-old man with bilateral megalocornea. Digit J Ophthalmol. 2021;27:30-33.
Alhaidari AI, Albakri AS, Alhumaidi SS. A Novel PGAP3 Gene Mutation-Related Megalocornea Can Be Misdiagnosed as Primary Congenital Glaucoma. Cureus. 2022;14(9):e29387.
Zaidi SBH, Stephenson KAJ, Ejaz-Ul-Haq HM, Massanna H. Management of cataract in a patient with anterior megalophthalmos. BMJ Case Rep. 2021;14:e241659.
Rao A, Dcruz RP. Atypical presentations of non-familial anterior megalophthalmos: a rare disease. BMJ Case Rep. 2021;14:e244350.
Elmakhzen B, Nedbour A, Bouguenouch L, Ahakoud M. A De Novo 13q21.33-q31.1 Interstitial Deletion in a Child With Megalocornea and Neurodevelopmental Delay: A Clinico-Genomic Correlation. Cureus. 2025;17(8):e90646.
Sinha R, Bari A, Anjum S. Trans-iris vertical intrascleral haptic fixation of 眼内レンズ: The bypass technique in eyes with megalocornea. Indian J Ophthalmol. 2025;73:446-449.
Copy the article text and paste it into your preferred AI assistant.
Article copied to clipboard
Open an AI assistant below and paste the copied text into the chat box.
