Microphthalmos

Microphthalmos (also spelled microphthalmia) is a congenital eye malformation characterized by a reduction in the volume of the eye, typically defined as a corneal diameter less than 10 mm or an anteroposterior globe diameter less than 20 mm (or an axial length below 2 standard deviations for chronological age).[1][2] One or both eyes may be affected. In severe cases the eyeball may appear absent, though residual eye tissue is generally present; this severe form should be distinguished from true anophthalmia, in which no eyeball forms at all.[3] Microphthalmos exists on a phenotypic continuum with anophthalmia and coloboma, collectively referred to as the MAC spectrum (microphthalmia/anophthalmia/coloboma).[4][2]

The combined birth prevalence of anophthalmia and microphthalmia is estimated at up to 30 per 100,000 population, with microphthalmia reported in up to 11% of blind children.[5] Microphthalmia may or may not result in significant vision loss, and it can occur in isolation (nonsyndromic) or as part of a broader syndrome (syndromic) in approximately one-third to one-half of cases.[3][5]

• Coloboma — missing tissue in the iris, retina, choroid, or optic nerv*[3][4]
• Congenital cataract — the most common associated ocular anomaly, found in approximately 32% of cases in one large series[4]
• Persistent fetal vasculature (PFV) and other posterior segment anomalies[4]
• Microcornea — small, abnormally curved cornea[3]
• Anterior segment dysgenesis — corneal opacification, abnormal irides, small abnormal lenses[4]
• Narrowed palpebral fissure[3]
• Ocular motility disorders[4]

Approximately 34% of patients have an associated systemic abnormality.[4] Common systemic associations include:

• Neurological abnormalities — most common in the anophthalmic subgroup[4]
• Musculoskeletal and facial anomalies[4]
• Urological and genital anomalies — particularly seen in cases with optic fissure closure defects[4]
• Cardiac defects[6]
• Chromosomal syndromes — trisomy 13, trisomy 18, and others are found in over 20% of cases[6]

Numerous syndromes include microphthalmos as a feature (over 269 listed in the London Dysmorphology Database).[2] Notable examples include:

• Waardenburg anophthalmia syndrome
• PDAC syndrome (Pulmonary hypoplasia/agenesis, Diaphragmatic hernia, Anophthalmia/microphthalmia, Cardiac defects)
• AEG syndrome (Anophthalmia–Esophageal–Genital)[2]

• Visual impairment and blindness — microphthalmos accounts for approximately 12% of permanent blindness in children*[6]
• High hyperopia (spherical equivalent >3D)*[7]
• Angle-closure glaucoma*[7]
• Uveal effusion syndrome*[7]
• Retinal detachment*[7]
• Chorioretinal folds*[7]
• Post-surgical complications — affected eyes present significant surgical challenges with increased risk of intraoperative and postoperative sequelae*[7]
• Orbital and facial growth abnormalities — the small globe fails to stimulate normal bony orbital growth, leading to facial asymmetry*[5]

The etiology of microphthalmos is complex and heterogeneous, encompassing genetic, chromosomal, and environmental factors.[5][8]

• SOX2 — the single most commonly implicated gene and the only major causative gene identified to date*[5][8]
• PAX6 and OTX2 — important transcription factors in eye development*[9][5]
• Other monogenic causes — CHX10 (VSX2), RAX, FOXE3, STRA6, ALDH1A3, RARβ, BMP4, BMP7, SMOC1, BCOR, YAP1, TFAP2α, GDF3, GDF6, SHH, MFRP, PRSS56, among others*[9][8][3]
• Approximately 50% of patients have identifiable mutations in known genes, though more than half currently remain without a molecular diagnosis even after whole exome/genome sequencing*[6][8]

• Chromosomal duplications, deletions, and translocations*[5]
• Recognized aneuploidies including trisomy 13 and trisomy 18*[6]

• Gestational infections — rubella and other congenital infections (strongest environmental evidence)*[5][3]
• Maternal vitamin A deficiency*[5]
• Radiation exposure (X-rays)*[5]
• Teratogen exposure — thalidomide, solvent misuse*[5][3]

Microphthalmos is believed to arise from disruption of early embryonic eye development, including failure of optic vesicle formation, lens induction failure (SOX2, PAX6 pathway), failure of retinal differentiation (OTX2, CHX10, RAX pathway), or abnormalities in optic fissure closure.[5][6] The condition typically originates early in pregnancy, though at least one report has suggested identification of microphthalmia development in midpregnancy.[1]

Patients are often managed by multidisciplinary teams including ophthalmologists, paediatricians, and clinical geneticists.[5] Treatment is directed toward maximizing existing vision and improving cosmesis through stimulation of soft tissue and bony orbital growth. Mild to moderate cases are managed conservatively with conformers, while severe microphthalmos and anophthalmia may require endo-orbital volume replacement with implants, expanders, or dermis-fat grafts and soft tissue reconstruction.[5] Genetic counselling is indicated but can be challenging due to the extensive genetic heterogeneity and variable phenotypic expression.[5][8]

1. Exome sequencing identifies genetic variants in anophthalmia and microphthalmia. Li J, Yang W, Wang YJ, et al. American Journal of Medical Genetics. Part A. 2022;188(8):2376-2388. doi:10.1002/ajmg.a.62874. 2. Genetic investigation of 93 families with microphthalmia or posterior microphthalmos. Patel N, Khan AO, Alsahli S, et al. Clinical Genetics. 2018;93(6):1210-1222. doi:10.1111/cge.13239. 3. Microphthalmia. National Library of Medicine (MedlinePlus). 4. Microphthalmia, Anophthalmia, and Coloboma and Associated Ocular and Systemic Features: Understanding the Spectrum. Skalicky SE, White AJ, Grigg JR, et al. JAMA Ophthalmology. 2013;131(12):1517-24. doi:10.1001/jamaophthalmol.2013.5305. 5. Anophthalmia and Microphthalmia. Verma AS, Fitzpatrick DR. Orphanet Journal of Rare Diseases. 2007;2:47. doi:10.1186/1750-1172-2-47. 6. Epidemiology of anophthalmia and microphthalmia: Prevalence and patterns in Texas, 1999–2009. Chambers TM, Agopian AJ, Lewis RA, et al. American Journal of Medical Genetics. Part A. 2018;176(9):1810-1818. doi:10.1002/ajmg.a.40352. 7. Prevalence of Complications in Eyes With Nanophthalmos or Microphthalmos: Protocol for a Systematic Review and Meta-Analysis. Ally N, Ismail S, Alli HD. Systematic Reviews. 2022;11(1):25. doi:10.1186/s13643-022-01889-5. 8. Genetics of Anophthalmia and Microphthalmia. Part 1: Non-Syndromic Anophthalmia/Microphthalmia. Plaisancié J, Ceroni F, Holt R, et al. Human Genetics. 2019;138(8-9):799-830. doi:10.1007/s00439-019-01977-y. 9. Genetics of Anophthalmia and Microphthalmia. Part 2: Syndromes Associated With Anophthalmia-Microphthalmia. Slavotinek A. Human Genetics. 2019;138(8-9):831-846. doi:10.1007/s00439-018-1949-1.