Down syndrome (DS) is a chromosomal abnormality caused by an extra copy of chromosome 21 (trisomy 21) and is the most common chromosomal disorder. The incidence is approximately 1 in 700 live births (range 1 in 600 to 800).
Genetic types include nondisjunction (90–95%), translocation (3–4%), and mosaicism (1–2%). The frequency increases with maternal age.
Systemic features include characteristic facial appearance (upslanting palpebral fissures, flat nasal bridge, epicanthal folds), congenital heart disease, hypotonia, and intellectual disability.
Muñoz-Ortiz et al. (2022) reported in a systematic review of 22 studies that the weighted prevalence of ocular findings in children with Down syndrome is 85%1).
The frequency of ocular complications increases with age, reaching 38% in children under 1 year old and 80% in those aged 5–7 years.
According to a systematic review, the weighted prevalence of ophthalmic findings in children with Down syndrome is 85%. It is 38% in infants under 1 year old, increases with age, and reaches 80% in those aged 5–7 years. Regular eye screening enables early detection and treatment.
Anterior Segment Findings
Upward slanting of the palpebral fissures: Present in 63–82% of cases. Part of the characteristic facial appearance of Down syndrome.
Epicanthal folds: 31–97%. There are ethnic differences.
Entropion (inward turning of eyelashes): Reported in 54% of cases in a Korean study.
Blepharitis: 3–34.5%.
Brushfield spots: 47.15%1). Focal hyperplasia of the iris stroma, with no effect on visual function.
Refraction and motility findings
Refractive errors: Approximately 80%. Hyperopia 36.4%, myopia 21.5%, astigmatism 37.2% (oblique astigmatism is characteristic)1). Lack of emmetropization is the background. Hyperopia, which easily causes amblyopia, accounts for about 70%, and astigmatism of 2D or more is seen in about 60%; overall, about 90% require glasses. Myopia is not numerous but has a wide distribution, including some up to -10D.
Accommodative insufficiency: Decreased in 32–100%.
Strabismus: 33.5%. Esotropia is the most common (27.7%), while exotropia is 4.7%1). Seen in about 35%, with esotropia and inferior oblique overaction being frequent.
Nystagmus: 15.6%1). Some reports indicate a complication rate of about 25%. Torticollis 9.9%, of which 37.3% have nystagmus2).
Posterior segment and others
Keratoconus: 20.8–32%. Risk is about 30 times that of the general population4). Association with eye rubbing is noted.
Cataract: 10.9%1). Congenital cataract is 2.2%, about 300 times the general rate. Blue cataract is seen in 50%. Posterior lenticonus may be associated.
Nasolacrimal duct obstruction: 14.5%1). 73% bilateral.
Retina and optic nerve: Foveal hypoplasia (OCT findings), optic nerve head radial appearance (13–38%). Risk of retinopathy of prematurity (ROP) is low.
Glaucoma: Rare at 0–1%, classified as non-acquired systemic disease-related glaucoma3).
| Ophthalmic finding | Prevalence | Notes |
|---|---|---|
| Refractive error | Approximately 80% | Oblique astigmatism is characteristic |
| Brushfield spots | 47.2% | Iris hyperpigmentation, no effect on visual function |
| Blepharoconjunctivitis | 42.5% | 31% in infants under 1 year |
| Astigmatism | 37.2% | — |
| Hyperopia | 36.4% | — |
| Strabismus (overall) | 33.5% | Esotropia 27.7%, exotropia 4.7% |
| Keratoconus | 20.8–32% | Onset in adolescence, stabilizes around age 30 |
| Myopia | 21.5% | — |
| Nystagmus | 15.6% | — |
| Nasolacrimal duct obstruction | 14.5% | 73% bilateral |
| Amblyopia | 13.3% | — |
| Cataract | 10.9% | Congenital cataract 2.2% |
Brushfield spots are caused by localized hyperplasia of the iris stroma and do not affect visual function. They are a characteristic finding in about 47% of individuals with Down syndrome and do not require treatment. Their frequency varies by ethnicity.
The cause of trisomy 21 is a numerical abnormality of chromosome 21.
Nondisjunction type (90–95%)
Nondisjunction during meiosis results in three copies of chromosome 21. Advanced maternal age is the main risk factor. It is sporadic and usually not inherited.
Translocation type (3–4%)
The long arm of chromosome 21 translocates to chromosome 14 or 21. It can be inherited from a carrier parent. About half of translocation cases (approximately 2% of all cases) are inherited from a parent with a balanced translocation.
Mosaic type (1–2%)
Only some somatic cells show trisomy 21. The phenotype is generally milder.
The development of ocular complications involves overexpression of genes on chromosome 21 (HSA21). Overexpression of HSA21 genes leads to anti-angiogenic properties, which is thought to contribute to a reduced risk of retinopathy of prematurity and age-related macular degeneration in individuals with Down syndrome.
In recent years, non-invasive prenatal testing (NIPT) using maternal blood has become widespread, allowing assessment of the possibility of trisomy 21 in early pregnancy. Definitive diagnosis requires conventional karyotyping via chorionic villus sampling or amniocentesis. After birth, suspicion arises from characteristic phenotypes, and diagnosis is confirmed by karyotyping of peripheral blood.
Based on recommendations from the AAP (American Academy of Pediatrics) and AAPOS, eye screening is performed according to the following schedule 1).
| Timing | Examination Content |
|---|---|
| Newborn | Red reflex test (to rule out congenital cataract) |
| 6–12 months | Assessment of strabismus and fixation |
| 1–3 years | Refraction test (under cycloplegia) |
| 3–5 years | Visual acuity test, refraction test, ocular alignment assessment |
| 5 years and older | Annual visual acuity, refraction, and keratoconus screening |
Check the red reflex in the newborn period (to rule out congenital cataract), assess strabismus and fixation at 6–12 months, perform cycloplegic refraction at 1–3 years, and start visual acuity testing at 3–5 years. From age 5 onward, annual visual acuity, refraction, and keratoconus screening are recommended.
Treatment for each ocular complication is as follows.
Surgery is performed under general anesthesia, so preoperative evaluation of any associated cardiac disease is necessary.
Strabismus surgery for esotropia in children with Down syndrome achieves similar results as in typical children with standard surgical doses. The risk of overcorrection is comparable, and if accommodative esotropia is present, spectacle correction should be tried first.
Ocular complications in Down syndrome involve multifactorial pathogenesis.
Studies in Ts65Dn mouse models have shown that the gene dosage effect of chromosome 21 causes abnormal development of neural crest cells 1). Abnormalities in neural crest-derived tissues (corneal stroma, iris, orbital bones) underlie the diverse anterior segment findings.
In children with Down syndrome, the postnatal emmetropization process is impaired 1). Normally, axial length and corneal curvature change coordinately with growth, converging toward emmetropia. In Down syndrome, this coordination is lacking, resulting in a high prevalence of hyperopia, myopia, and astigmatism.
Accommodative dysfunction is observed in 32–100% of patients and contributes to the development of esotropia. Currently, impairment of sensory pathways (abnormal processing of visual input) is considered the leading cause, but morphological abnormalities of the ciliary muscle and innervation disorders have also been proposed.
Overexpression of genes on HSA21 leads to increased production of anti-angiogenic factors. This property is associated with a reduced risk of solid tumors, retinopathy of prematurity, and age-related macular degeneration in patients with Down syndrome.
The high frequency of keratoconus in patients with Down syndrome involves both genetic predisposition and the habit of eye rubbing 4). Difficulty in self-control due to intellectual disability promotes eye rubbing, leading to accumulation of mechanical stress on the cornea. It tends to develop during adolescence and stabilize around age 30.
Studies using optical coherence tomography (OCT) have shown that many children with Down syndrome have foveal hypoplasia. Analysis of the depth of the foveal pit and the residual pattern of the inner retinal layers is advancing the understanding of the mechanisms underlying reduced visual acuity.
The anti-angiogenic properties resulting from overexpression of HSA21 genes are being explored as therapeutic targets for retinal vascular diseases and tumors. Elucidating the mechanisms by which patients with Down syndrome have a lower risk of angiogenic eye diseases may contribute to the development of novel anti-angiogenic drugs.
The exact mechanism of accommodative dysfunction remains unclear. Although sensory pathway impairment is considered a leading hypothesis, multiple hypotheses are being tested, including morphological factors of the ciliary body and lens, and abnormalities in neural control of the autofocus function. Elucidating the mechanism may lead to the development of more effective accommodative aids for children with Down syndrome.
