Trisomy 21/Down Syndrome
|Trisomy 21/Down Syndrome|
|Classification and external resources|
Down (or Down’s) syndrome is one of the most common genetic diseases. It is most often caused by trisomy 21. This syndrome is typically marked by a characteristic facial appearance, short stature, intellectual disability, and cardiac anomalies. Children with Down syndrome are at increased risk for a variety of ophthalmic disorders, including strabismus, high refractive error, cataracts, lacrimal duct obstruction, and blepharitis. The visual acuity of children with Down syndrome is generally less than other children of the same age. Close observation and management of disorders by a pediatric ophthalmologist is necessary as visual impairment in addition to the social, behavioral, and emotional difficulties experienced by individuals with Down syndrome can be a significant impediment to quality of life.1
- 1 Disease Entity
- 2 Diagnosis
- 3 Clinical Features
- 4 Management
- 5 Summary
- 6 Additional Resources
- 7 References
Down syndrome is caused by expression of a third copy of chromosome 21. This extra chromosomal material can be transmitted in three ways. The most common mode of transmission (90-95% of cases) is nondisjunction of either the maternal or paternal chromosome 21 pair during the first phase of meiosis leading to individuals having a complete additional chromosome. Approximately 3-4% of Down syndrome cases are caused by an unbalanced translocation, with chromosome 21 fused via its centromere to another acrocentric chromosome, usually chromosome 14. A de novo mutation leads to 75% of translocation cases, and a balanced translocation in a parent leads to 25% of these cases. In 1-2% of Down syndrome patients, mosaicism is present due to an error in cell division in the early embryonic stage, and these patients may have a less severe phenotype.2
Down syndrome is the most common chromosomal abnormality.3 Down syndrome occurs in approximately 1 in 700 births, and the frequency rises with maternal age due to an increase in nondisjunction events. Roughly 5,400 children with Down syndrome are born each year in the United States.4
The reported prevalence of ophthalmic disorders in Down syndrome patients ranges from 46% to 100%.5 The incidence of associated eye disease increases with age. Thirty eight percent of Down syndrome children < 1 year old rises to 80% of 5 to 7 year-old children with ophthalmic disorders that need monitoring or intervention.6
The diagnosis of Down syndrome is generally made by prenatal testing, such as chorionic villus sampling or aminocentesis after a positive first or second trimester screening test. When prenatal testing is not available, the diagnosis of Down syndrome is made by recognition of the phenotypic features of Down syndrome in the neonate, including hypotonia, poor reflexes, flat facial profile, slanted palpebral fissures, and a single palmar crease,7 followed by a karyotype showing trisomy 21, a translocation, or mosaicism.
Strabismus, especially esodeviation, is common in Down syndrome children. The prevalence of strabismus in Down children ranges from 5% to 47%.1,8–19 In most of these studies the strabismus type is esotropia, although in one study of Korean children, 42% of Down children with strabismus were found to have exotropia.19 Only one study of Down syndrome children mentions hyperdeviation, which was found in 7% of patients with strabismus.15
Nystagmus has been found to be present in 3% to 33% of children with Down syndrome, which is significantly more prevalent than in control patients.1,8–10,14,16–20 The form is usually a rapid horizontal nystagmus.13,21 Eighty to 89% of Down syndrome children with nystagmus have a manifest nystagmus while a smaller cohort have a latent or manifest-latent nystagmus.12,21–23 Nystagmus in Down syndrome children has been associated with lesser visual acuities.23
Refractive Error and Astigmatism
Down syndrome children have a higher prevalence of hyperopia and astigmatism and a higher magnitude of refractive error compared to age-matched controls.1,24 Refractive error outside the range of a spherical equivalent of -0.50 to +1.00 D is found in almost 80% of Down syndrome children.25 Hyperopia in Down syndrome children has been found to range from 4% to 65%.1,5,26 Although the prevalence of myopia ranges from 8% to 41% in Down syndrome children,5 it has not been found to be significantly higher than in controls.1,26 In addition, before one year of age, there is no significant difference in the prevalence of refractive error when comparing to age-matched controls.27 Failure of emmetropization has been proposed as the etiology of the increase in prevalence of refractive error after infancy.28
In infants up to 12 months old without Down syndrome, clinically significant astigmatism is common, with a prevalence ranging from 40 to 53%. The prevalence of astigmatism then declines to 10% to 18% by 4 years of age.29,30 In infants and in children up to age 4 with Down syndrome, the prevalence of astigmatism is not significantly different than with controls. However, while the rates of astigmatism decline after infancy in control patients, Down syndrome children continue to have roughly the same prevalence of astigmatism. At the primary school age (4 to 12 years), Down syndrome children have a 37.5% prevalence of astigmatism, significantly higher than in age-matched controls.27
Infants with Down syndrome generally have “with the rule” astigmatism. The type of astigmatism often changes, with 26% to 54.8% of Down children with astigmatism having an oblique type of astigmatism.28,31–33 Looking at a cross sectional population of Down syndrome children by age, the prevalence of oblique astigmatism is low in infancy, at 7.1% of children with astigmatism at one year of age, and raises to 45% of 15-year-old children with astigmatism.34 The development of oblique astigmatism has been proposed to be caused by the oblique, upslanting palpebral fissues in Down patients,35 as the axis of astigmatism has been correlated with the angle of the palpebral fissure.36
Best corrected visual acuity (BCVA) in Down syndrome patients is on average less than comparative controls. In studies of visual acuity in Down syndrome children, BCVA was found to be 20/45 on average,26 worse than 20/50 in 24% of patients,37 and below average for age for 94% of subjects, with 79% of subjects falling two standard deviations below the mean.38 There are multiple causes for this decrease in BCVA. One major cause is amblyopia, which affects 3% to 26% of Down syndrome children.15,18,21,37 As strabismus is common in Down syndrome, early and regular assessment and treatment can help minimize visual loss due to amblyopia. Nystagmus may also account for a substantial extent of visual acuity loss.23 Other common causes of decreased visual acuity in Down syndrome patients include cataracts and high refractive errors.39
Poor accommodative ability has been found in Down syndrome children. Using dynamic retinoscopy, studies have found that 32% to 100% of Down syndrome children have an abnormally low ability to accommodate, measured by accommodative response.32,40–42 Inaccurate accommodation has been found to be associated with hypermetropia and strabismus.32,43
Eyelids and Midface
The most common findings are upward slanting palpebral fissures, with a prevalence ranging from 63% to 82% in Down syndrome children,15,19 and large epicanthal folds, ranging from 31% to 97%.12,14–16,19 Blepharitis is also a common finding in Down syndrome patients. The prevalence of blepharitis in children with Down syndrome ranges from 3% to 34.5%.9,10,12–20 The wide range in prevalence may be due to differing criteria for diagnosing blepharitis.44 The high rate of blepharitis has been speculated to be due to impaired immune or due to skin abnormalities in Down syndrome individuals.15,45 Other disorders of the eyelids include epiblepharon, which has been found to be more common in a Korean population of Down syndrome patients with a prevalence of 54% (ranging from 43% at birth to the highest of 65% at ages 4 to 6).19 In comparison to a Japanese population of control patients, epiblepharon incidence at birth was 46% and decreased to 9.9% by age 18.46 However, in a Malaysian population of Down syndrome children with a mean age of 7 years old, the incidence of epiblepharon was 2%.16
Lacrimal duct obstruction is common, found to range from 3.3% to 36% in Down children.9,12–14,16–19 In one study, bilateral involvement was found in 73% of patients.47 The higher rate of nasolacrimal duct obstruction is related to the facial morphology of Down syndrome patients and may be due to an abnormal persistence of a membrane or bony obstruction blocking the nasolacrimal duct.48
Keratoconus has been associated with Down syndrome, but usually does not present until early adulthood. In most pediatric studies examining ocular abnormalities in Down syndrome children, keratoconus is not found.9,10,16,18,19,49 Only two pediatric studies found keratoconus, indicating a prevalence of 1% and 13%.20,37 In contrast, adult studies have found a prevalence which varies from 0.5% to 15.8%.28,35,44,50–53 The cornea in Down syndrome patients is steeper with higher rates of astigmatism than controls, which could explain the increase prevalence of keratoconus.24 Eye-rubbing has been thought to play a role in developing keratoconus,54,55 which patients with Down syndrome may be more prone to due to the higher rate of chronic blepharitis.44,56 Some studies have suggested a genetic link between genes on chromosome 21 and keratoconus, which could explain the increased prevalence in trisomy 21.57,58
Brushfield spots are white, gray or brown spots spaced around the periphery of the iris. They are focal areas of iris stromal tissue connective tissue hyperplasia which are of no functional importance.25 They are not pathognomonic for Down syndrome and can be seen in children without disease. Brushfield spots are more common on blue, green or hazel irides compared to dark irides.15 The prevalence of Brushfield spots differ in various ethnic populations, possibly reflecting variations in predominant iris color between ethnic groups.9 In studies of Down syndrome children in Italian, Egyptian, and South and East Asian populations, Brushfield spots were not found in any patient.10,12,14,17,19 In Slovenian, Brazilian and American studies, the prevalence was found to be 16.9%, 52%, and 81% respectively.15,44,49
The prevalence of cataracts in Down syndrome children varies from 4% to 37%.1,13–16,18,20 The prevalence ranges greatly due to differences in the diagnostic criteria and also whether both congenital and acquired cataract are included. From a large population study of children in Denmark with early cataracts, the frequency of congenital cataracts in Down syndrome patients was less than 1%, and the frequency of developing a cataract before age 18 was 1.4%.59 Another population based study found that the risk of congenital cataracts in a Down syndrome patients was almost 10-fold higher than for controls, with an incidence of 2.9 congenital cataracts per 1000 Down patients compared to 0.3 for non-Down syndrome patients.60
A common retinal finding in Down syndrome is a spoke-like appearance with a high number of vessels crossing the margin of the optic nerve. Although not associated with vision loss, studies have found that 13% to 38% of Down children have 18 or more vessels crossing the disc margin.9,19,22,61 This has been proposed to be a consequence of a deficiency in systemic angiogenesis.62 Retinoblastoma has also been speculated to be connected to Down syndrome, possibly caused by oncogenic genes overexpressed on chromosome 21, although there have only been a few recorded cases of this disease in Down patients.16,63
Optic nerve anomalies in Down syndrome are rare. Optic disk elevation has been reported in a total of thirteen patients in three case series.64–66 One case series noted a prevalence of disk elevation in 3.4% of Down syndrome children, possibly attributable to idiopathic intracranial hypertension.66 Optic nerve hypoplasia has been reported in three cases, but may represent coincidental findings.45
Glaucoma in Down children is rare.45 In most recent studies, the prevalence ranges from 0% to 1% of cases,10,13,14,18,19,49 although in one series in Malaysian Down syndrome children, the prevalence was 7%.16 In contrast, in a general pediatric population, the incidence of primary childhood glaucoma over a 40-year period was 0.38 per 100,000 children.67
Pediatric ophthalmologists should be considered part of all Down syndrome children’s healthcare team whose contributions greatly assist in allowing the patient to reach his or her full health and developmental potential. The American Academy of Pediatrics provides the following recommendations for visits to a pediatric ophthalmologist by Down syndrome children:
- Be evaluated for strabismus, cataracts, and nystagmus along with visual acuity testing within the first 6 months of life
- Followed annually until age 5 with evaluation for refractive error, strabismus, or other conditions which could result in amblyopia
- Followed biannually from 5-13 years old to evaluate for the onset of new ophthalmic disorders2
Assessment and regular follow-up by the pediatric ophthalmologist is important to detect abnormalities when they arise. Roizen et al. compared the detection of ophthalmic abnormalities in general pediatricians to pediatric ophthalmologists and noted that pediatricians missed abnormalities which were found by the ophthalmologists in 16 patients out of 47 patients, resulting in a 66% sensitivity of general pediatricians in detecting ophthalmic disease.18
The treatment of strabismus for Down syndrome children is similar to the general pediatric population. Bilateral medial rectus muscle recession on Down syndrome children with the standard surgical dosage results in similar outcomes as controls and does not typically result in overcorrection as has been thought to occur in developmentally delayed children.68,69
A fine, rapid horizontal nystagmus in patients in Down syndrome occurs frequently, is generally stable or self-resolving, and needs no specific investigation or intervention.13
Refractive Error and Astigmatism
Refractive error is treated with prescription glasses. Compliance with glasses wear is generally high, although difficulties can arise depending on the individual. The addition of bifocals due to reduced accommodative ability may be important for optimal near vision to promote learning potential.
Although visual acuity testing can be difficult in children, especially with intellectual disability, visual acuity has been measured in preverbal Down children using Teller, Keeler, and Cardiff acuity cards with success rates ranging up to 100%.11,12,23,37,38
The majority of Down syndrome children are likely visually impaired at near distances, and this may be an additional barrier to literacy and early learning in these children. Use of bifocal prescriptions significantly improved the accommodative ability for 65% of Down syndrome children, with the improvement continuing after returning to single vision lenses in 53% of these children.70 In addition, bifocals have also been found to help with accommodation when looking through the distance portion of their glasses, meaning that instead of solely being a focusing aid as with presbyopic adults, bifocals may help children better use their own accommodative ability.71 Nandakumar et al. suggests that children should first be checked for their refractive error, as they found that 79% of Down syndrome children did not have a correct prescription, possibly due to difficulties with examining this population or due to lack of adequate care for patients with developmental delays.42 Compliance with eyeglasses wear was comparable to children without disabilities, at 82% being fully compliant and 18% being partially compliant.71
Eyelids and Midface
Blepharitis can be treated similarly as with children without Down syndrome. See EyeWiki article on Blepharitis.
In the general pediatric population, probing procedures have a high rate of success, as the common reason for obstruction is failure for Hasner’s membrane to open. However, in Down syndrome, canalicular stenosis and atresia are more common reasons for obstruction. A more aggressive initial treatment may be appropriate, such as stents or balloon dilation, depending on the etiology of the obstruction.47,72
Keratoconus generally affects adult Down syndrome patients and is rare in children. Treatment can be complicated by difficulties in fitting contact lenses, excessive eye rubbing, and in patient reporting of changes in visual acuity.73 See EyeWiki article on Keratoconus.
Brushfield spots are a benign finding and require no treatment.
Neonates with known Down syndrome should be carefully checked for a robust red reflex by a pediatrician shortly after birth to screen for congenital cataracts. If a cataract is found, treatment may require surgical intervention in the near future. See EyeWiki article on Congenital Cataracts.
The blood vessel spoke-like appearance is a benign finding with no management needed. Other retinal pathology should be treated as with the general pediatric population.
Optic nerve edema, papilledema or idiopathic intracranial hypertension should be suspected in children with elevated optic disks, but they may represent transient, benign findings in Down syndrome children.64
The child should be monitored for signs of primary congenital glaucoma, and if present, medical and surgical interventions are required.
Down syndrome is a common genetic disease with a high rate of ophthalmic findings. Some manifestations are benign, such as epicanthal folds and Brushfield spots, but Down syndrome is associated with lower visual acuity due to refractive error, astigmatism, amblyopia, nystagmus, and cataracts, among other disorders. These disorders require early evaluation and follow-up by a pediatric ophthalmologist with expertise in developmentally challenged populations to provide the best visual outcome for the child.
- National Down Syndrome Society: http://www.ndss.org/Resources/Local-Support
- Global Down Syndrome Foundation: http://www.globaldownsyndrome.org/about-down-syndrome/resources/local-organizations/
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