Nanophthalmos derives its name from the Greek word “nano,” meaning “dwarf.” It is a developmental anomaly resulting from arrested growth of the eye after closure of the embryonic fissure, classified as complete microphthalmos with shortening of both the anterior and posterior segments 1).
It is characterized by the absence of other obvious ocular malformations or congenital anomalies. In addition to sporadic cases, autosomal dominant (NNO1, NNO3) and autosomal recessive (NNO2) inheritance patterns have been reported.
The prevalence of microphthalmos overall is estimated at 0.002–0.017% in the UK and 0.0009% in China 1). The incidence of uveal effusion syndrome (UES) is extremely rare, approximately 1.2 cases per 10 million population per year in the UK 4).
An axial length of 20.5 mm or less is defined as true microphthalmos, and Duke-Elder defined it as an ocular volume of two-thirds or less of normal. According to Majima’s diagnostic criteria, the axial length is 0.87 or less of the age-normal value, with criteria of 20.4 mm or less for adult males and 20.1 mm or less for adult females. The normal axial length by age and the axial length in microphthalmos are as follows (A-mode ultrasound measurements).
After birth
2 years
6–7 years
13 years to adult
Normal (male)
16.85mm
20.60mm
22.00mm
23.40mm
Normal (female)
16.60mm
20.29mm
21.68mm
23.06mm
Microphthalmic (male)
14.70mm
17.97mm
19.19mm
20.42mm
Microphthalmic (female)
14.44mm
17.65mm
18.86mm
20.06mm
QWhat is the difference between nanophthalmos and posterior microphthalmos?
A
Nanophthalmos involves shortening of both the anterior and posterior segments, accompanied by microcornea and shallow anterior chamber. In posterior microphthalmos, only the posterior segment is short, while anterior segment parameters are normal to slightly small.
High hyperopia: Presents with high hyperopia of +8D to +25D, requiring thick glasses or contact lenses from early childhood.
Bilateral amblyopia: Caused by high hyperopia from birth. Best corrected visual acuity (BCVA) rarely exceeds 20/40 (0.5). Due to an organic amblyopia component involving retinal nerve fiber layer dysplasia, achieving normal vision is often difficult.
Acute glaucoma attack: Presents with eye pain, headache, blurred vision, and redness. Attacks can occur at a young age (20s). Because of high hyperopia, patients often have amblyopia, making it difficult to notice the onset of chronic glaucoma.
Clinical Findings (Findings Confirmed by Physician Examination)
QWhy is it rare for best-corrected visual acuity in nanophthalmos to exceed 20/40?
A
In addition to anatomical limitations due to underdevelopment of the foveal avascular zone (FAZ) and macular hypoplasia, bilateral amblyopia associated with high hyperopia from birth further restricts vision. Complications (glaucoma, retinal detachment, cystoid macular edema) also secondarily reduce visual acuity.
Most cases of nonsyndromic nanophthalmos are sporadic, but autosomal dominant (AD) and autosomal recessive (AR) inheritance patterns have also been reported.
Inheritance Pattern
Locus/Gene
Chromosome
AD (NNO1)
Unidentified
11p
AD (NNO3)
Unidentified
2q11-q14
AR (NNO2)
MFRP
11q23
AR
PRSS56
2q37.1
AD
MYRF
—
AD
TMEM98
17p12-q12
MFRP: 13 exons, 579 amino acids. It has a frizzled family homologous transmembrane domain and is involved in eye development via WNT signaling. It is selectively expressed in the retinal pigment epithelium (RPE) and ciliary body.
PRSS56: 13 exons, 603 amino acids. It contains a serine protease domain and is expressed in the neural retina, cornea, sclera, and optic nerve.
MYRF (myelin regulatory factor) mutations are involved in familial nanophthalmos, and animal models have shown that they cause reduced density and structural disruption of the zonules of Zinn3).
Abnormalities in collagen and decreased chondroitin sulfate in the sclera are thought to be involved in the pathogenesis.
Syndromic nanophthalmos includes retinitis pigmentosa, foveal schisis, and optic disc drusen syndrome, oculodentodigital syndrome (ODD), and ADVIRC, among others.
Among complications, acute angle-closure glaucoma was the most common at 33.3%, followed by malignant glaucoma (14.9%) and uveal effusion (10.4%)5).
QWhy do more than half of nanophthalmos patients develop glaucoma?
A
An increase in the lens-to-eye volume ratio (LEVR) pushes the iris forward, causing relative pupillary block. With aging, peripheral anterior synechiae (PAS) progress, impairing aqueous outflow. Additionally, ciliochoroidal effusion due to scleral thickening rotates the ciliary processes forward, exacerbating the blockage. For details, see the “Pathophysiology” section.
The diagnosis of nanophthalmos is made by confirming bilateral, symmetric microphthalmos and comprehensively evaluating the following biometric parameters.
Axial length measurement: Measured using A-scan and B-scan ultrasound, or optical biometry (e.g., IOLMaster). Many studies use axial length <21.00 mm as a diagnostic criterion, but thresholds such as <20.50 mm or <20.00 mm are not standardized1).
Corneal diameter: Many studies use <11.00 mm as a diagnostic criterion1).
B-scan ultrasound: Retinal-choroidal-scleral (RCS) complex thickness >1.70 mm is useful for diagnosis1).
The most important differential diagnosis is posterior microphthalmos. In posterior microphthalmos, the axial length is short and hyperopia is present, but anterior segment parameters are normal to only slightly small. Differentiation from anterior microphthalmos, where only the anterior segment is small, is also necessary.
Start full correction of refractive errors early. Provide the full value obtained under cycloplegic refraction and correct with glasses or contact lenses.
If unilateral amblyopia is identified, eye patching (occlusion therapy) is recommended. Due to anatomical crowding of the anterior segment, atropine penalization should be avoided from a safety perspective.
There may also be an element of organic amblyopia associated with retinal nerve fiber layer abnormalities, making it difficult to achieve normal visual acuity in many cases. Since children dislike wearing a conformer after age 3, early initiation is desirable.
Angle-closure glaucoma is difficult to manage; the degree of shallow anterior chamber and narrow angle is more severe than in primary angle-closure glaucoma, and scleral thickening and microcornea further complicate treatment.
Medical therapy: Response to intraocular pressure is often poor. An example prescription for ciliary block (malignant glaucoma) includes atropine 1% eye drops once daily, timoptol 0.5% eye drops twice daily, Diamox 250mg tablets 2 tablets twice daily after meals, and Uralit combination tablets 4 tablets twice daily after meals. Use hyperosmotic agents intravenously to reduce vitreous volume and cycloplegics to relax the ciliary muscle to attempt to relieve the block.
Laser therapy: Iridotomy, iridoplasty. In pseudophakic eyes, perform anterior vitreolysis after Nd:YAG laser posterior capsulotomy.
Surgical therapy: filtering surgery, lens reconstruction. As a radical treatment, there is lens capsule removal with peripheral iridectomy and anterior vitrectomy.
Advances in phacoemulsification have improved safety, but the risk of postoperative complications (uveal effusion, cystoid macular edema) remains high. 88.2% of patients require an intraocular lens of +30D or more, and lens selection is also challenging 1).
Zonular weakness has been reported; a literature review found zonular defects in 15 of 184 eyes (8.2%) 3). Since a sudden drop in intraocular pressure during surgery can worsen suprachoroidal fluid accumulation, careful manipulation is necessary 3).
Surgical pearls to improve outcomes include anterior vitrectomy, pharmacologic vitreous dehydration, and scleral lamellar resection.
Management of Uveal Effusion and Exudative Retinal Detachment
First-line: Scleral decompression surgery shows the most sustained therapeutic effect 4).
Surgical technique: Extensive scleral resection of 90–95% depth in all four quadrants is effective2)3). It is performed over 280–300 degrees from the muscle insertions to the vortex veins.
Visual recovery: Even in lens-contact total retinal detachment, recovery from preoperative light perception to a postoperative median of 20/100 has been reported3).
Vitrectomy
Second-line treatment: Should only be performed in cases where scleral surgery is ineffective6).
Risks: Complications are frequent, including iatrogenic retinal breaks and the need for silicone oil tamponade.
Comparison: In reports comparing both eyes of the same patient, scleral resection was safer and had better anatomical and functional outcomes6).
Non-surgical treatment (high-dose systemic steroids) is considered ineffective for uveal effusion in nanophthalmos4). Vortex vein decompression is technically difficult and carries the risk of vortex vein puncture4).
QWhat are the points to note in cataract surgery for nanophthalmos?
A
The main concerns are the fragility of the zonules of Zinn (defects reported in 8.2% of cases) and the risk of suprachoroidal fluid accumulation due to sudden intraocular pressure drop during surgery. A high-power intraocular lens of +30 D or more is required in many cases, and lens selection is also challenging.
MFRP protein is selectively expressed in the retinal pigment epithelium (RPE) and ciliary body, and is concentrated on the apical side of RPE cells. In fetal eyes, expression is detected in the RPE at 20 weeks of gestation, indicating that it begins to function relatively late in ocular development. MFRP is essential for emmetropization and regulation of axial length, and patients with complete deficiency have no identifiable lesions outside the eye.
Heterozygous carriers of MFRP do not show hyperopia, but their corneal curvature and anterior chamber depth differ significantly from the general population, indicating semidominance.
Scleral Abnormalities and Mechanism of Uveal Effusion
In all three layers of the sclera, abnormal collagen fibers with fraying and tearing are observed, and deposition of abnormal proteoglycans has also been reported1). This abnormality causes scleral inelasticity, leading to uveal effusion and retinal detachment through the following mechanisms.
Scleral thickening → outflow obstruction from the vortex vein system
Mansour et al. (2024) cited findings from computer modeling and reported that in nanophthalmos, the thickened peripapillary choroid deforms the optic nerve head tissue, causing a “compartment syndrome” that leads to compressive optic neuropathy. Peripapillary choroidal thickness decreased from 726 μm preoperatively to 645 μm postoperatively, and visual acuity fully recovered from 20/100 to 20/40 within two weeks after 95% deep sclerectomy combined with nasal posterior radial scleral incisions2).
In mouse models with MYRF (myelin regulatory factor) mutations, shallow anterior chamber and reduced density and structural disruption of Zinn zonule fibers were observed. It is thought that the function of the MFRP gene during the embryonic period is necessary for the eye to reach normal size, and that mutation-induced failure of ciliary ring expansion leads to lens hypertrophy and “dwarfing” of the Zinn zonules3).
7. Latest Research and Future Perspectives (Investigational Reports)
Mansour et al. (2024) reported complete visual recovery after deep sclerectomy for compressive optic neuropathy due to peripapillary pachychoroid associated with nanophthalmos. They demonstrated that decompression of choroidal congestion can reverse optic neuropathy and proposed potential application to other peripapillary pachychoroid-related optic neuropathies2).
Surgical Treatment for Long-standing Retinal Detachment
In a case series of 5 patients by Mansour et al. (2024), deep sclerectomy for lens-contact total retinal detachment (duration 24–48 months) resulted in visual recovery from preoperative light perception to postoperative 20/100–20/150. This suggests that surgical intervention may be possible even in cases previously considered irreversible over the long term3).
Systematic Review of Scleral Decompression Surgery
Braga de Sousa and Barbosa-Breda (2025) conducted a systematic review of 28 studies and confirmed that sclerectomy is effective in treating and preventing uveal effusion. However, they noted a lack of large-scale comparative trials and indicated that the efficacy of adjuvant therapies such as mitomycin C (MMC) and anti-VEGF agents requires further investigation 4).
Rajendrababu et al. (2025) reported a glaucoma prevalence of 51.88% in nanophthalmos based on a meta-analysis of 44 studies and 1397 eyes. They emphasized the importance of biometric screening and the need for individualized management strategies based on anatomical characteristics 5).
The axial length cutoff values for nanophthalmos vary across studies, including <21mm, <20.5mm, <20mm, and <18mm, and establishing a grading system that addresses complication risks remains a challenge 1).
Yang N, Zhao LL, Liu J, Ma LL, Zhao JS. Nanophthalmos: An Update on the Biological Parameters and Fundus Abnormalities. J Ophthalmol. 2021;2021:8853811.
Mansour AM, Lopez-Guajardo L, Özdek Ş, Popov I, Parodi Battaglia M. Surgical Approaches to Serous Retinal Detachment With Retina-Lens Touch in Eyes With Nanophthalmos. J VitreoRetinal Dis. 2024;8(2):173-180.
Braga de Sousa L, Barbosa-Breda J. Sclerectomies in nanophthalmos and idiopathic uveal effusion syndrome: a systematic review. Graefes Arch Clin Exp Ophthalmol. 2025;263:2709-2722.
Rajendrababu S, Berendschot TTJM, Senthilkumar VA, et al. Risk factors for glaucoma in nanophthalmos — a systematic review and meta-analysis. BMC Ophthalmol. 2025;25:617.
Popov I, Popova V, Krasnik V. Comparing the Results of Vitrectomy and Sclerectomy in a Patient with Nanophthalmic Uveal Effusion Syndrome. Medicina. 2021;57:120.
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