Microphthalmia (microphthalmos) is a congenital ocular developmental anomaly in which the axial length is at least 2 standard deviations (SD) below the age-adjusted mean. In adults, an axial length less than 21 mm is indicative; in 1-year-olds, less than 19 mm is the threshold 5). It is a rare disease with a frequency of 1–3 per 10,000 individuals, and no curative treatment has been established. There is no sex predilection, and bilateral and unilateral cases occur with equal frequency.
Microphthalmia is classified as follows based on morphology and the presence of complications.
According to Duke-Elder’s classification, microphthalmos is classified into (1) nanophthalmos, (2) microphthalmos with coloboma, (3) microphthalmos with congenital ocular anomalies, and (4) microphthalmos with systemic diseases. According to Majima’s embryopathological classification, it is classified into seven types: optic vesicle developmental disorder, optic cup formation disorder, anterior segment mesenchymal dysgenesis, lens-induced, vitreous-induced, failure of embryonic fissure closure, and ocular wall developmental disorder.
According to Relhan et al., nanophthalmos (NO) and posterior microphthalmos (PM) are distinguished based on a corneal diameter of 11 mm. In NO, the corneal diameter is 10.06 mm, anterior chamber depth 2.68 mm, lens thickness 4.77 mm, and the complication rate of angle-closure glaucoma reaches 69%. In contrast, in PM, the corneal diameter is 11.39 mm, anterior chamber depth 3.20 mm, lens thickness 3.93 mm, and the complication rate of angle-closure glaucoma is 0%2).
The estimated birth prevalence is 0.2 to 1.7 per 10,000 people, with regional differences. The prevalence of microphthalmia is reported to be about 1/7,000, and anophthalmia about 1/30,0005). Bilateral cases are more common, and patients with bilateral involvement are more likely to have systemic diseases. There is no difference in incidence by sex or race, and it accounts for 3–12% of visually impaired children.
Microphthalmos refers to cases with anatomical malformations (such as coloboma, cataract, etc.), while nanophthalmos refers to a uniformly small eye without malformations. Nanophthalmos carries a particularly high risk of high hyperopia and angle-closure glaucoma. For details, see the “Causes and Risk Factors” section.
Nanophthalmos is characterized by the following findings:
A comparison of biometric measurements between nanophthalmos (NO) and posterior microphthalmos (PM) is shown below.
| Parameter | NO | PM |
|---|---|---|
| Corneal diameter | 10.06 mm | 11.39 mm |
| Anterior chamber depth | 2.68 mm | 3.20 mm |
| Lens thickness | 4.77 mm | 3.93 mm |
| Angle-closure glaucoma | 69% | 0% |
In a histological study of 4 cases by Rajendrababu et al., the sclera of nanophthalmic eyes showed irregular arrangement of collagen fibers, fraying, and overexpression of fibronectin6). In cases with axial length <17 mm, severe disruption of the scleral lamellar structure was observed, whereas in those with axial length >17 mm, the lamellar structure was preserved6).
33–50% are syndromic and may be associated with the following systemic abnormalities5). Systemic abnormalities are more often bilateral, and a Japanese survey reported central nervous system abnormalities/developmental delay in 13%, multiple malformations/syndromes in 9%, and chromosomal abnormalities in 4%.
Related syndromes include CHARGE syndrome, Lenz microphthalmia syndrome4), Fraser syndrome, Lowe syndrome, Meckel-Gruber syndrome, TORCH syndrome (congenital infection), Hallermann-Streiff syndrome, and oculodentodigital syndrome. Collaboration with pediatrics and genetics is essential.
Most cases are sporadic, but autosomal dominant, autosomal recessive, and X-linked inheritance patterns have been reported. More than 100 genetic traits associated with microphthalmia and coloboma have been identified.
Major causative genes are listed below.
| Inheritance Pattern | Main Causative Genes |
|---|---|
| Autosomal dominant | SOX2, OTX2, BMP4, CHD7, GDF6, RARB, SHH |
| Autosomal recessive | PAX6, STRA6, FOXE3, RAX, SMOC1, VSX2 |
| X-linked | BCOR, HCCS, NAA10 |
Among these, SOX2 and PAX6 have been identified as major causative genes.
There is a detailed genetic classification into three groups: syndromic, nonsyndromic, and coloboma-associated. In syndromic cases, BMP4, MAB21L2, OTX2, SOX2 (autosomal dominant) and STRA6 (autosomal recessive) have been reported; in nonsyndromic cases, MFRP, PRSS56 (autosomal recessive); and in coloboma-associated cases, TENM3 (autosomal recessive) and GDF3, GDF6 (autosomal dominant) have been reported.
The following individual gene mutations have been reported.
Frequently observed in patients with trisomy 13 or trisomy 18.
Most cases are sporadic, but autosomal dominant (e.g., SOX2, OTX2), autosomal recessive (e.g., PAX6, STRA6), and X-linked (e.g., BCOR, HCCS) inheritance patterns have been reported. Over 100 associated genes have been identified, and the inheritance pattern varies depending on the causative gene.
Fetal orbits can be detected by 11–12 weeks of gestation. Ultrasound is used to measure the length of the eyeball. If clinically suspected, genetic evaluation such as chromosomal microarray analysis via amniocentesis may be considered.
Comprehensive screening using a 78-gene MAC panel is employed7). Whole genome sequencing (WGS) is useful for identifying mutations that are difficult to detect by exome sequencing3).
The fetal orbits can be detected by ultrasound at 11–12 weeks of gestation, and eye size can be measured. If suspected, genetic evaluation is performed by chromosomal microarray analysis of amniotic fluid.
If retinal function is present, refractive correction and amblyopia treatment are most important. True microphthalmia presents with high hyperopia exceeding +20D, making early refractive correction essential. Microphthalmia is associated with high refractive errors, so early initiation of regular spectacle use is important to promote visual development. In bilateral mild cases, complications such as cataract and glaucoma should be diagnosed early, and surgery and amblyopia treatment should be performed. Generally, cases with corneal diameter ≤6 mm or marked asymmetry result in visual acuity less than 0.02. However, because organic amblyopia due to retinal nerve fiber layer abnormalities is also a factor, achieving normal visual acuity is often difficult. For amblyopia, occlusion therapy is performed. In cases with severe visual impairment, low vision care should be initiated from infancy.
Reduced ocular volume due to microphthalmia affects normal development of the face and orbit. Treatment strategy is determined based on axial length.
Axial length 16 mm or more
Orbital growth: Likely to be near normal.
Timing of expansion therapy: Can be adjusted according to social and aesthetic needs.
Method: Insertion of conformers that gradually increase in size. Exchange interval averages every 1 week to 1 month.
Axial length less than 16 mm
Orbital growth: Natural growth is unlikely.
Timing of expansion therapy: Start early to prevent asymmetry due to growth.
Method: In addition to conformers, implants, expanders, and dermal fat grafts are needed. In the most severe cases, orbital osteotomy is performed.
After age 3, children may resist wearing the conformer, so it is desirable to fit it before that age.
Microphthalmic eyes are prone to serious complications in infancy to young adulthood. Frequent complications include cataract (34%), glaucoma (13%), and retinal detachment (7%). All are difficult to treat, and lifelong management of complications is necessary to preserve visual function.
When eyeball atrophy or corneal opacity occurs, prosthetic eye fitting is recommended for cosmetic issues.
In severe cases with axial length <16 mm, natural orbital growth is unlikely, so initiation within the first few weeks of life is recommended. For axial length ≥16 mm, timing can be adjusted according to social and aesthetic needs. Since fitting becomes difficult after age 3, early initiation is desirable.
Microphthalmia results from improper development of the optic vesicle, anterior neural tube, or orbit during early embryogenesis. Incomplete closure of the embryonic fissure leads to coloboma. Reduced size of the optic cup, changes in vitreous proteoglycans, low intraocular pressure, abnormal growth factor production, and insufficient secondary vitreous production are also contributing factors.
In nanophthalmos, abnormalities in scleral collagen and decreased chondroitin sulfate have been reported. This leads to scleral thickening, causing vortex vein outflow obstruction, and choroidal fluid accumulation leading to exudative retinal detachment.
Histologically, irregular arrangement and fraying of scleral collagen fibers, and overexpression of fibronectin have been confirmed 6). In cases with axial length <17 mm, severe disruption of the scleral lamellar structure is observed, while in those with axial length >17 mm, the lamellar structure is preserved 6).
DeYoung et al. (2022) identified a de novo YAP1 mutation (c.178dupG) by whole-genome sequencing (WGS) in a 1-year-old boy with bilateral coloboma and right microphthalmia 3). This mutation was difficult to detect by exome analysis, demonstrating the utility of WGS. The same mutation was not found in the parents, confirming de novo occurrence.
Gholami Yarahmadi et al. (2022) reported a homozygous splice site mutation (c.5069-1G>C) in TENM3 in an Iranian male 5). Known mutations in TENM3 include 7 mutations across 6 families; this case adds a new mutation. Many reports come from consanguineous families, supporting autosomal recessive inheritance.
Javidi et al. (2022) identified a homozygous SIX6 mutation (c.1A>G) using a 78-gene MAC panel in a 3-week-old male from a consanguineous family 7). Corneal diameter was 8.0×8.5/8.5×8.5 mm, and axial length on MRI was 19/17.5 mm. This is the first case of combined microphthalmia and coloboma due to SIX6 mutation.
Rajendrababu et al. (2022) performed cataract surgery with prophylactic scleral fenestration in 4 nanophthalmos cases (mean axial length 17.60±1.40 mm) and evaluated the excised scleral tissue by light microscopy 6). Immunohistochemistry confirmed overexpression of fibronectin, indicating that diagnosis is possible without the use of expensive electron microscopy. IOL power ranged from 36 to 54 D.
Adeel et al. (2023) reported a case of MFRP gene-related PMPRS (47-year-old female, axial length 18.37/18.00 mm, +10 D) 1). WTW 12.0/12.4 mm, extinguished electroretinogram, foveoschisis, and sclerochoroidal thickening were observed, demonstrating the phenotypic diversity of MFRP mutations.
