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nanophthalmia [2026/07/27 10:20] – created Scott Larsonnanophthalmia [2026/07/27 12:08] (current) – Scott Larson
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 ===== Definition ===== ===== Definition =====
  
-Nanophthalmos is a rare developmental ocular disorder characterised by a small but structurally normal eye with a significantly shortened axial length (typically ≤20.5–21.0 mm; mean ~17.6–18.1 mm), high hyperopia (often +7 to +13 diopters), a high lens-to-eye volume ratio, shallow anterior chamber, thickened sclera, and small cornea. It represents the extreme end of the hyperopia spectrum and is distinct from microphthalmos, which involves structural ocular abnormalities.+  * Small but largely structurally normal eye 
 +  * Characterized by: 
 +    * Significantly shortened axial length (typically ≤20.5–21.0 mm; mean ~17.6–18.1 mm) 
 +    * [[high_hyperopia|High hyperopia]] (often +7 to +13 diopters),  
 +    * High lens-to-eye volume ratio 
 +    * Shallow anterior chamber 
 +    * Thickened sclera 
 +    * Small cornea.  
 +  * Distinct from [[microphthalmos|microphthalmos]], which involves structural ocular abnormalities.
  
 ===== Potential Causes / Genetics ===== ===== Potential Causes / Genetics =====
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 Nanophthalmos is a genetically heterogeneous condition. Both autosomal recessive and autosomal dominant inheritance patterns have been described. Six genes have been implicated: Nanophthalmos is a genetically heterogeneous condition. Both autosomal recessive and autosomal dominant inheritance patterns have been described. Six genes have been implicated:
  
-== Autosomal Recessive ==+=== Autosomal Recessive ===
  
-  * PRSS56 (protease serine 56) — the most commonly implicated gene (~47.6% of genetically solved cases). Associated with shorter axial length, higher hyperopia, steeper corneal curvatures, and uveal effusion.* +  * PRSS56 (protease serine 56) — the most commonly implicated gene (~47.6% of genetically solved cases). Associated with shorter axial length, higher hyperopia, steeper corneal curvatures, and uveal effusion. 
-  * MFRP (membrane-type frizzled-related protein) — the second most common (~36.5%). Associated with [retinitis pigmentosa](https://www.openevidence.com/rare-disease/retinitis-pigmentosa) / retinal dystrophy.*+  * MFRP (membrane-type frizzled-related protein) — the second most common (~36.5%). Associated with [retinitis pigmentosa](https://www.openevidence.com/rare-disease/retinitis-pigmentosa) / retinal dystrophy.
  
-== Autosomal Dominant ==+=== Autosomal Dominant ===
  
   * MYRF (myelin regulatory factor) — mapped to the NNO1 locus on chromosome 11. Can cause isolated or syndromic nanophthalmos. Associated with the thinnest retinal nerve fibre layer thickness.*   * MYRF (myelin regulatory factor) — mapped to the NNO1 locus on chromosome 11. Can cause isolated or syndromic nanophthalmos. Associated with the thinnest retinal nerve fibre layer thickness.*
   * TMEM98 (transmembrane protein 98) — associated with earlier onset of glaucoma and multiple ciliary body cysts. May play a primary role in retinal and scleral structure.*   * TMEM98 (transmembrane protein 98) — associated with earlier onset of glaucoma and multiple ciliary body cysts. May play a primary role in retinal and scleral structure.*
  
-== Other Implicated Genes ==+=== Other Implicated Genes ===
  
-  * CRB1* +  * CRB1 
-  * BEST1 (VMD2)*+  * BEST1 (VMD2)
  
 Biallelic variants in PRSS56 and MFRP are associated with more severe phenotypes compared to monoallelic variants. Genetic testing via whole exome sequencing achieves a diagnostic yield of approximately 70%. Biallelic variants in PRSS56 and MFRP are associated with more severe phenotypes compared to monoallelic variants. Genetic testing via whole exome sequencing achieves a diagnostic yield of approximately 70%.
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 ===== Associations ===== ===== Associations =====
  
-  * Syndromic associations: [Kenny-Caffey syndrome](https://www.openevidence.com/rare-disease/kenny-caffey-syndrome) type 2 (FAM111A variants); co-inheritance with [Aicardi-Goutieres syndrome](https://www.openevidence.com/rare-disease/aicardi-goutieres-syndrome) (ADAR variants) has been reported.* +  * Syndromic associations: [Kenny-Caffey syndrome](https://www.openevidence.com/rare-disease/kenny-caffey-syndrome) type 2 (FAM111A variants); co-inheritance with [Aicardi-Goutieres syndrome](https://www.openevidence.com/rare-disease/aicardi-goutieres-syndrome) (ADAR variants) has been reported. 
-  * Amblyopia — present in approximately 30% of patients.* +  * Amblyopia — present in approximately 30% of patients. 
-  * Foveal hypoplasia — more common in recessive forms (PRSS56, MFRP).* +  * Foveal hypoplasia — more common in recessive forms (PRSS56, MFRP). 
-  * Crowded optic discs / papillomacular folds — frequently observed.* +  * Crowded optic discs / papillomacular folds — frequently observed. 
-  * Retinitis pigmentosa — specifically associated with MFRP variants.* +  * Retinitis pigmentosa — specifically associated with MFRP variants. 
-  * Choroidal folds — more common in PRSS56 families.* +  * Choroidal folds — more common in PRSS56 families. 
-  * Multiple ciliary body cysts — associated with autosomal dominant genes (MYRF, TMEM98).*+  * Multiple ciliary body cysts — associated with autosomal dominant genes (MYRF, TMEM98).
  
 ===== Complications ===== ===== Complications =====
  
-  * Angle-closure glaucoma (ACG) — the most significant complication, present in 67-79% of patients. Caused by anterior segment crowding due to the high lens/eye volume ratio and shallow anterior chamber. Earlier onset is observed in autosomal dominant forms (TMEM98, MYRF). Peripheral anterior synechiae increase the odds of glaucoma (OR 3.66).* +  * Angle-closure glaucoma (ACG) — the most significant complication, present in 67-79% of patients. Caused by anterior segment crowding due to the high lens/eye volume ratio and shallow anterior chamber. Earlier onset is observed in autosomal dominant forms (TMEM98, MYRF). Peripheral anterior synechiae increase the odds of glaucoma (OR 3.66). 
-  * Uveal effusion syndrome — results from impaired transscleral fluid outflow through the abnormally thickened sclera. More common with PRSS56 variants.* +  * Uveal effusion syndrome — results from impaired transscleral fluid outflow through the abnormally thickened sclera. More common with PRSS56 variants. 
-  * Retinal detachment — a recognised spontaneous and post-operative complication.* +  * Retinal detachment — a recognised spontaneous and post-operative complication. 
-  * Choroidal detachment — may occur spontaneously or post-operatively.* +  * Choroidal detachment — may occur spontaneously or post-operatively. 
-  * Legal blindness — reported in approximately 16.7% of patients.* +  * Legal blindness — reported in approximately 16.7% of patients. 
-  * Post-surgical complications — intraocular surgery carries an extremely high complication rate, including malignant glaucoma, suprachoroidal haemorrhage, choroidal effusion, and phthisis bulbi.*+  * Post-surgical complications — intraocular surgery carries an extremely high complication rate, including malignant glaucoma, suprachoroidal haemorrhage, choroidal effusion, and phthisis bulbi.
  
-===== Treatment =====+===== Surgical Consideration =====
  
-Treatment of nanophthalmos is challenging due to the high rate of surgical complications.+Treatment of glaucoma in the setting of nanophthalmos is challenging due to the high rate of surgical complications.
  
 == Medical Management == == Medical Management ==
- +  * Glaucoma medications — effective for IOP control; however, miotics should be used with caution as they may worsen pupillary block. 
-  * Glaucoma medications — effective for IOP control; however, miotics should be used with caution as they may worsen pupillary block.* +  * Cycloplegic agents — may be used for refractive correction in children.
-  * Cycloplegic agents — may be used for refractive correction in children.*+
  
 == Laser Therapy == == Laser Therapy ==
- +  * Laser peripheral iridotomy (LPI) — first-line for angle-closure; successful in ~83% of eyes. 
-  * Laser peripheral iridotomy (LPI) — first-line for angle-closure; successful in ~83% of eyes.* +  * Laser gonioplasty — successful in ~92% of eyes. 
-  * Laser gonioplasty — successful in ~92% of eyes.* +  * Laser therapy is generally preferred over incisional surgery due to the lower complication rate.
-  * Laser therapy is generally preferred over incisional surgery due to the lower complication rate.*+
  
 == Surgical Management == == Surgical Management ==
- +  * Scleral decompression procedures (sclerectomy, sclerostomy, sclerotomy) — used for treatment and prophylaxis of uveal effusion syndrome. Concomitant sclerostomy during cataract surgery significantly reduces the occurrence of uveal effusion. 
-  * Scleral decompression procedures (sclerectomy, sclerostomy, sclerotomy) — used for treatment and prophylaxis of uveal effusion syndrome. Concomitant sclerostomy during cataract surgery significantly reduces the occurrence of uveal effusion.* +  * Cataract surgery — phacoemulsification has significantly fewer complications than manual small-incision cataract surgery (SICS). Lens extraction can also deepen the anterior chamber and help manage angle closure. 
-  * Cataract surgery — phacoemulsification has significantly fewer complications than manual small-incision cataract surgery (SICS). Lens extraction can also deepen the anterior chamber and help manage angle closure.* +  * Combined surgery (limited pars plana vitrectomy + phacoemulsification + IOL implantation + posterior capsulotomy) — reported success rate of ~89% in complex nanophthalmos, with significant IOP reduction (32.7 to 16.9 mmHg), improved visual acuity, and deepened anterior chamber. 
-  * Combined surgery (limited pars plana vitrectomy + phacoemulsification + IOL implantation + posterior capsulotomy) — reported success rate of ~89% in complex nanophthalmos, with significant IOP reduction (32.7 to 16.9 mmHg), improved visual acuity, and deepened anterior chamber.* +  * Pars plana filtration (PPF) — a newer, less invasive technique involving partial ciliary body excision to create an alternative aqueous drainage route. Early results suggest safety and efficacy, but larger studies are needed. 
-  * Pars plana filtration (PPF) — a newer, less invasive technique involving partial ciliary body excision to create an alternative aqueous drainage route. Early results suggest safety and efficacy, but larger studies are needed.* +  * Vortex vein decompression — less frequently reported; used for uveal effusion. 
-  * Vortex vein decompression — less frequently reported; used for uveal effusion.* +  * Adjunctive treatments — mitomycin C and intravitreal anti-VEGF injections have been used as adjuncts to scleral decompression surgery.
-  * Adjunctive treatments — mitomycin C and intravitreal anti-VEGF injections have been used as adjuncts to scleral decompression surgery.* +
 == Key Surgical Principles == == Key Surgical Principles ==
- +  * Surgery in nanophthalmic eyes carries an extremely high complication rate; medication and laser therapy are the procedures of choice when feasible. 
-  * Surgery in nanophthalmic eyes carries an extremely high complication rate; medication and laser therapy are the procedures of choice when feasible.* +  * Prophylactic sclerostomy should be considered when intraocular surgery is planned. 
-  * Prophylactic sclerostomy should be considered when intraocular surgery is planned.* +  * Genetic counselling is recommended, particularly for heterozygous carriers of MFRP and PRSS56 who should be screened for high hyperopia.
-  * Genetic counselling is recommended, particularly for heterozygous carriers of MFRP and PRSS56 who should be screened for high hyperopia.*+
  
 =====References===== =====References=====
  
-1. Comprehensive Genetic Landscapes and Clinical Heterogeneity in Nanophthalmos: New Insights From a Large Chinese Cohort. Xu Q, Zhou Y, Wang J, et al. Journal of Medical Genetics. 2025;:jmg-2025-110905. doi:10.1136/jmg-2025-110905. +  - [[https://pubmed.ncbi.nlm.nih.gov/40973198/|Comprehensive Genetic Landscapes and Clinical Heterogeneity in Nanophthalmos: New Insights From a Large Chinese Cohort. Xu Q, Zhou Y, Wang J, et al. Journal of Medical Genetics. 2025;:jmg-2025-110905]] 
-2. Clinical Features of Patients With Mutations in Genes for Nanophthalmos. Li X, Xiao H, Su Y, et al. The British Journal of Ophthalmology. 2024;108(12):1679-1687. doi:10.1136/bjo-2023-324931. +  - [[https://pubmed.ncbi.nlm.nih.gov/38749530/|Clinical Features of Patients With Mutations in Genes for Nanophthalmos. Li X, Xiao H, Su Y, et al. The British Journal of Ophthalmology. 2024;108(12):1679-1687]] 
-3. Clinical Spectrum and Treatment Outcomes of Patients With Nanophthalmos. Rajendrababu S, Shroff S, Uduman MS, Babu N. Eye (London, England). 2021;35(3):825-830. doi:10.1038/s41433-020-0971-4. +  - [[https://pubmed.ncbi.nlm.nih.gov/32461562/|Clinical Spectrum and Treatment Outcomes of Patients With Nanophthalmos. Rajendrababu S, Shroff S, Uduman MS, Babu N. Eye (London, England). 2021;35(3):825-830]] 
-4. The genetic and clinical landscape of nanophthalmos and posterior microphthalmos in an Australian cohort. Siggs OM, Awadalla MS, Souzeau E, et al. Clinical Genetics. 2020;97(5):764-769. doi:10.1111/cge.13722. +  - [[https://pubmed.ncbi.nlm.nih.gov/32052405/|The genetic and clinical landscape of nanophthalmos and posterior microphthalmos in an Australian cohort. Siggs OM, Awadalla MS, Souzeau E, et al. Clinical Genetics. 2020;97(5):764-769]] 
-5. Novel TMEM98, MFRP, PRSS56 Variants in a Large United States High Hyperopia and Nanophthalmos Cohort. Prasov L, Guan B, Ullah E, et al. Scientific Reports. 2020;10(1):19986. doi:10.1038/s41598-020-76725-8. +  - [[https://pubmed.ncbi.nlm.nih.gov/33203948/|Novel TMEM98, MFRP, PRSS56 Variants in a Large United States High Hyperopia and Nanophthalmos Cohort. Prasov L, Guan B, Ullah E, et al. Scientific Reports. 2020;10(1):19986]] 
-6. The Majority of Autosomal Recessive Nanophthalmos and Posterior Microphthalmia Can Be Attributed to Biallelic Sequence and Structural Variants in MFRP and PRSS56. Almoallem B, Arno G, De Zaeytijd J, et al. Scientific Reports. 2020;10(1):1289. doi:10.1038/s41598-019-57338-2. +  - [[https://www.nature.com/articles/s41598-019-57338-2|The Majority of Autosomal Recessive Nanophthalmos and Posterior Microphthalmia Can Be Attributed to Biallelic Sequence and Structural Variants in MFRP and PRSS56. Almoallem B, Arno G, De Zaeytijd J, et al. Scientific Reports. 2020;10(1):1289]] 
-7. Sclerectomies in Nanophthalmos and Idiopathic Uveal Effusion Syndrome: A Systematic Review. Braga de Sousa L, Barbosa-Breda J. Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht Von Graefes Archiv Fur Klinische Und Experimentelle Ophthalmologie. 2025;:10.1007/s00417-025-06908-4. doi:10.1007/s00417-025-06908-4. +  - [[https://pubmed.ncbi.nlm.nih.gov/40663118/|Sclerectomies in Nanophthalmos and Idiopathic Uveal Effusion Syndrome: A Systematic Review. Braga de Sousa L, Barbosa-Breda J. Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht Von Graefes Archiv Fur Klinische Und Experimentelle Ophthalmologie. 2025;:10.1007/s00417-025-06908-4]] 
-8. Effect of Combined Surgery in Patients With Complex Nanophthalmos. Wei Y, Su Y, Fang L, et al. Journal of Clinical Medicine. 2022;11(19):5909. doi:10.3390/jcm11195909. +  - [[https://www.mdpi.com/2077-0383/11/19/5909|Effect of Combined Surgery in Patients With Complex Nanophthalmos. Wei Y, Su Y, Fang L, et al. Journal of Clinical Medicine. 2022;11(19):5909]] 
-9. Nanophthalmos: A Perspective on Identification and Therapy. Singh OS, Simmons RJ, Brockhurst RJ, Trempe CL. Ophthalmology. 1982;89(9):1006-12. +  - [[https://pubmed.ncbi.nlm.nih.gov/7177565/|Nanophthalmos: A Perspective on Identification and Therapy. Singh OS, Simmons RJ, Brockhurst RJ, Trempe CL. Ophthalmology. 1982;89(9):1006-12]] 
-10. Genotype-Phenotype Spectrum in Isolated and Syndromic Nanophthalmos. Lang E, Koller S, Atac D, et al. Acta Ophthalmologica. 2021;99(4):e594-e607. doi:10.1111/aos.14615.+  - [[https://pubmed.ncbi.nlm.nih.gov/32996714/|Genotype-Phenotype Spectrum in Isolated and Syndromic Nanophthalmos. Lang E, Koller S, Atac D, et al. Acta Ophthalmologica. 2021;99(4):e594-e607]]