i1552-5783-64-6-3_1682775854.07686

Special Issue
IMI—Management and Investigation of High Myopia in

Infants and Young Children
Ian Flitcroft,1,2 John Ainsworth,3 Audrey Chia,4 Susan Cotter,5 Elise Harb,6,12 Zi-Bing Jin,7
Caroline C. W. Klaver,8–11 Anthony T. Moore,12 Ken K. Nischal,13 Kyoko Ohno-Matsui,14
Evelyn A. Paysse,15 Michael X. Repka,16 Irina Y. Smirnova,17 Martin Snead,18
Virginie J. M. Verhoeven,8,19 and Pavan K. Verkicharla20
1
Children’s Health Ireland (CHI) at Temple Street, Dublin, Ireland
2
Centre for Eye Research Ireland, Technological University of Dublin, Dublin, Ireland
3
Birmingham Children’s Hospital, Steelhouse Lane Birmingham, United Kingdom
4
Singapore National Eye Center, Singapore
5
Southern California College of Optometry, Marshall B Ketchum University, Fullerton, California, United States
6
Wertheim School Optometry and Vision Science, Berkeley, California, United States
7
Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
8
Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands
9
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
10
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands
11
Institute of Molecular and Clinical Ophthalmology, Basel, Switzerland
12
University of California – San Francisco, School of Medicine, San Francisco, California, United States
13
UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States
14
Tokyo Medical and Dental University, Tokyo, Japan
15
Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas, United States
16
Wilmer Eye Institute, The John Hopkins University School of Medicine, Baltimore, Maryland, United States
17
Ophthalmology Center Glazka, Novosibirsk, Russia
18
Department of Vitreoretinal Research, John van Geest Centre for Brain Repair, University of Cambridge, United Kingdom
19
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
20
L V Prasad Eye Institute, Hyderabad, India
Correspondence: Ian Flitcroft, PURPOSE. The purpose of this study was to evaluate the epidemiology, etiology, clin-
Children’s Health Ireland (CHI) at ical assessment, investigation, management, and visual consequences of high myopia
Temple Street, Temple Street, (≤−6 diopters [D]) in infants and young children.
Dublin, D01 YC67, Ireland;
[email protected]. FINDINGS. High myopia is rare in pre-school children with a prevalence less than 1%.
The etiology of myopia in such children is different than in older children, with a high
Received: January 31, 2023
rate of secondary myopia associated with prematurity or genetic causes. The priority
Accepted: February 12, 2023
Published: May 1, 2023 following the diagnosis of high myopia in childhood is to determine whether there is
an associated medical diagnosis that may be of greater overall importance to the health
Citation: Flitcroft I, Ainsworth J, Chia of the child through a clinical evaluation that targets the commonest features associ-
A, et al. IMI—management and ated with syndromic forms of myopia. Biometric evaluation (including axial length and
investigation of high myopia in
infants and young children. Invest
corneal curvature) is important to distinguishing axial myopia from refractive myopia
Ophthalmol Vis Sci. 2023;64(6):3. associated with abnormal development of the anterior segment. Additional investigation
https://doi.org/10.1167/iovs.64.6.3 includes ocular imaging, electrophysiological tests, genetic testing, and involvement of
pediatricians and clinical geneticists is often warranted. Following investigation, optical
correction is essential, but this may be more challenging and complex than in older chil-
dren. Application of myopia control interventions in this group of children requires a
case-by-case approach due to the lack of evidence of efficacy and clinical heterogeneity
of high myopia in young children.
CONCLUSIONS. High myopia in infants and young children is a rare condition with a differ-
ent pattern of etiology to that seen in older children. The clinical management of such
children, in terms of investigation, optical correction, and use of myopia control treat-
ments, is a complex and often multidisciplinary process.
Keywords: high myopia, secondary myopia, syndromic myopia, myopia control, myopia
genetics
Copyright 2023 The Authors

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IMI—High Myopia in Infants and Young Children IOVS | Special Issue | Vol. 64 | No. 6 | Article 3 | 2
with high myopia.9 In a large US report from a single health

T here is a growing interest in active management of
myopia progression in children, with a range of behav-
ioral, pharmacological, and optical interventions available.1,2
insurer, the rate of high myopia at 5 to 7 years was 0.6%.10
Two US population surveys found a prevalence of myopia
Such interventions have generally been tested on children worse than −4.0 D at 5 to 6 years old of 0.6% to 0.8%.11,12 As
between 6 and 16 years old who show a conventional pattern with all forms of myopia, high myopia increases with age,
of myopia onset and progression. In such cases, myopia particularly in Asia, and this relationship is highly nonlinear.
develops after the age of 5 or 6 years and progresses for In China, the prevalence of high myopia in 15-year-olds was
a variable duration until stabilizing in the teenage or early found to be increasing over 10 years from 3.96% to 6.69%
adult years.3 More rarely, children are found to have high and rising very rapidly to 15.1% (95% confidence interval
levels of myopia in infancy or early childhood, often reach- [CI] = 6.4–23.8) by age 16 to 18 years.13,14 In a retrospective
ing the −6.0 diopter (D) threshold of high myopia.4 In report from the United Kingdom, 4.6% of children less than
such cases, there are a wide range of diagnostic, systemic 17 years old had high myopia,15 and in the United States a
health, and visual challenges that need to be considered. The rate of 4.8% for high myopia was found in 14 to 16-year-
management of such issues, at least initially, may represent old children.10 These two latter studies were clinic based
a higher clinical priority than treating any observed myopic and hence they likely overestimate population levels of
progression. myopia.
High myopia in infants and young children creates issues
in relation to optical correction to ensure normal visual ETIOLOGY OF HIGH MYOPIA IN CHILDREN
development and the avoidance of amblyopia. High myopia
in combination with behavioral or developmental issues can High myopia in children can result from both environmen-
be particularly challenging in children intolerant to wearing tal and genetic causes. Such environmental factors are often
spectacles or contact lenses, with the resulting poor vision distinct from the risk factors identified in epidemiological
often compounding behavioral issues. In addition to behav- studies,16 with prematurity being the most notable environ-
ior, visual impairment from uncorrected high myopia can mental factor in infants. There are two distinct genetic mech-
adversely impact child development. For example, the inabil- anisms that can cause high myopia, first, via the interaction
ity to see faces and hence understand the emotion of others of the hundreds of known genetic risk factors with envi-
can be profoundly isolating. The term “visual autism” has ronmental factors, such as near work and outdoor expo-
been used to describe the impact of visual isolation in such sure. Such cases can be considered extreme examples of
children.5 typical or normal myopia, often with a higher polygenic
The aim of this paper is to provide an overview of risk score of known myopia alleles.17,18 Second, early-onset
this complex, multifaceted topic, and give recommendations high myopia can result from mutations in a single gene
regarding the identification, evaluation, and management of that have a large impact on refractive development, inde-
high myopia in infants and young children. Such patients pendent of the usual environmental myopia risk factors,
may present initially to primary eye care services where such as monogenic high myopia. In monogenic forms, high
specialist multidisciplinary investigation and management myopia can be isolated, or it can be accompanied by a wide
services are not available. In such settings, a good clinical spectrum of ocular and extraocular features, a combination
history, thorough clinical examination, and recognition of that is called syndromic myopia.19 Myopia of prematurity
the features that mark such children as “out of the ordi- and monogenic forms of myopia fall within the category of
nary” are critical. This will facilitate prompt and appropriate “secondary myopia,” which has been defined as, “A myopic
onward referral. refractive state for which a single, specific cause (for exam-
This group of patients is commonly referred to hospital- ple drug, corneal disease or systemic clinical syndrome) can
based eye clinics. In such settings, the initial challenge is be identified that is not a recognized population risk factor
to correctly identify those cases that merit more detailed for myopia development.”4
investigation, such as to separate secondary, monogenic, and Studies of highly myopic children indicate that they
syndromic forms of early onset high myopia from typical or represent a distinct population. High myopia present in chil-
normal high myopia, so that the appropriate range of clini- dren before 10 years of age is associated with a much higher
cal and diagnostic services are brought to bear. The scope of risk of other ocular and systemic disorders than in children
such management may be very wide-ranging and includes without high myopia. In a hospital-based survey in 2001,
advanced ocular imaging, electrophysiology, genetic investi- 54% of the highly myopic children younger than 10 years
gations, involvement of pediatricians and clinical geneticists, of age were born prematurely, had a neurodevelopmen-
genetic counseling, customized optical correction strategies, tal delay, or had an underlying systemic disorder (includ-
and appropriate follow-up protocols for high-risk children. ing Marfan syndrome, Stickler syndrome, Noonan syndrome,
and Down syndrome). In addition, 38% of the sample
PREVALENCE OF HIGH MYOPIA IN CHILDREN had associated ocular pathology.20 The authors found that
severe developmental delay was the most common asso-
Despite the rising global numbers of myopic adults and chil- ciation at 12%. Although such patients may be uncom-
dren, the prevalence of high myopia (worse than −6.0 D) mon in some community settings, a study in the United
in children remains low. Even in high prevalence coun- Kingdom showed that 44% of community-identified chil-
tries, such as China, population surveys have shown that dren with high myopia (defined as worse than −5.0 D)
the prevalence of high myopia is low (0.03 to 0.2%) before younger than 10 years of age had either associated ocular
7 years of age.6,7 Singapore has a reported prevalence of (25%) or undiagnosed systemic conditions (18%), including
high myopia below 6 years old of 0.2%.8 In Western coun- Stickler syndrome, Weill-Marchesani syndrome, and homo-
tries, the prevalence is very low. In a population survey of cystinuria.21 High myopia in young children (worse than
728 children ages 6 to 7 years old, the most myopic cyclo- −6 D before 10 years of age) is also associated with
plegic refraction was −5.0 D, with no children identified high rates of reduced best-corrected visual acuity (78%),

strabismus (32%), and anisometropia (35%).22 Both high Premature Infants With ROP
myopia and high hyperopia are risk factors for retinal abnor-
malities in children, with cone-rod dystrophies and inner The presence of ROP greatly increases the prevalence of
retinal dysfunction being the most common retinal disorders myopia in premature infants. In very low birth weight infants
in children with high myopia.23 (<1250 g), the prevalence of myopia at 2 years of age
With increasing age there are likely fewer children with was 19% in eyes with any degree of ROP and only 6% in
secondary high myopia and more with rapidly progressive eyes without ROP.36 The prevalence increases markedly in
“normal” high myopia. There is a lack of evidence to quan- eyes with more severe disease. About 70% of high-risk pre-
tify these proportions by age. Very large sample sizes are threshold ROP eyes, which were treated with ablative ther-
necessary to identify adequate numbers of children with apy, were myopic at age 4 to 6 years. High risk eyes that
high myopia and such population studies are less likely to resolved without treatment showed a myopia prevalence of
include comprehensive genetic and clinical investigations of 45%. The prevalence of high myopia (defined as <−5.0 D,
secondary myopia. One informative study, involving 36,000 in the Early Treatment for Retinopathy of Prematurity trial
school children in Beijing,24 reported that the rate of high [ETROP]) is far more common in premature infants with
myopia was low in children less than 6 years old and rose ROP than those without. In the ETROP trial, 38% of treated
only slowly up to age 10 years. After 10 years of age, the high-risk pre-threshold ROP eyes were highly myopic by
prevalence of high myopia accelerated, in line with the age 4 years compared with 19% of eyes with regressed
overall levels of myopia. Thus, it is reasonable to propose ROP.26 In the presence of ROP, myopia can reach very high
that any high myopia in a child younger than 10 years old levels, in excess of −20.0 D, yet this myopia is not primar-
is worthy of investigation in relation to possible underly- ily axial in nature but mostly attributable to corneal, ante-
ing ocular, genetic, or systemic causes. For lower levels of rior chamber depth, and lenticular changes.37,38 A compari-
myopia, a high level of clinical suspicion is warranted for son of highly myopic premature infants with ROP and full-
children who are more myopic in diopters than their age term highly myopic children showed that those with ROP
in years. This proposal would help to identify many such had a mean refraction of −12.4 D and a mean axial length
cases, but by no means all. It is therefore important that clin- of 23.36 mm, compared with full-term children who had a
icians should be aware of the other clinical features that can mean refraction of −11.7 D and a mean axial length of 27.02
be helpful in distinguishing common forms of high myopia mm.37 The refractive difference in this study was almost
from monogenic and syndromic myopia. entirely lenticular in etiology. In addition to myopia, such
Premature children, especially those with retinopathy of infants also display high rates of astigmatism, anisometropia,
prematurity (ROP), are at high risk of developing myopia and ROP-associated posterior segment changes.39 Aggres-
and merit appropriate monitoring to ensure timely iden- sive posterior ROP has been found to be a particularly
tification and correction of visually impactful early-onset strong risk factor for high myopia, especially in Asian
myopia.25,26 Syndromic forms of myopia, particularly in the countries.40–42
absence of a clear family history, represent a far more chal- Myopia associated with ROP is further complicated by the
lenging clinical problem because they may carry specific impact of treatment on eye growth, with cryotherapy lead-
risks to vision (for example, inherited retinal disease and ing to more myopia than laser treatment.43,44 Bevacizumab
Stickler syndrome) and impact on general health to the point appears to have less impact on refraction than laser treat-
of being life-threatening (for example, connective tissues ment.45 In keeping with earlier studies, the variation in
disorders, such as Marfan syndrome, and some metabolic refractive outcomes of eyes treated for ROP is not correlated
disorders).19,27 with axial length. At 2 years of age, eyes treated with beva-
cizumab had a mean refraction of −0.98 D, as compared with
−14.38 D in eyes treated with lens sparing vitrectomy, but
the axial lengths were not significantly different (21.30 mm
Myopia of Prematurity vs. 21.85 mm).46 Another study found 14% of bevacizumab
Premature infants (defined as those born before 37 treated eyes developed spherical equivalent myopia worse
completed weeks of gestation), both with and without than −5.0 D at 1 year, supporting the concept that VEGF
ROP, are at high risk for myopia, even in the first year inhibitor treatment leads to less myopia, but some eyes still
of life. Myopia associated with prematurity is a complex develop high myopia.47
phenomenon with multiple interacting mechanisms.28,29
These include arrested anterior segment development and Monogenic Forms of Myopia
impaired emmetropization, with both mechanisms influ-
enced by the disease process of ROP and the impact Monogenic forms of myopia can be broadly categorized into
of treatment on ocular structures. Myopia of prematurity four groups: (1) ametropic retinal dystrophies; (2) connec-
(MOP) has specific biometric features that differ from typi- tive tissue disorders; (3) monogenic isolated high myopia;
cal myopia, specifically steeper corneas, shallower anterior and (4) other disorders.
chambers, thicker lenses, and shorter axial lengths than
full-term infants.30,31 The characteristic biometric features Ametropic Retinal Dystrophies
of MOP have also been reported to persist into adoles-
cence.32,33 A proportion of premature infants without ROP High myopia, and refractive errors in general, can be a first
display myopia that resolves in the first few months or or accompanying feature of an inherited retinal disease.23,48
years of life due to emmetropization, in a similar manner An analysis of a large group of genetically characterized
as what occurs in the much smaller proportion of myopic patients with inherited retinal disease has demonstrated that
full-term infants.30,34 However, emmetropization appears to four genetic subtypes, blue cone monochromacy, Bornholm
be impaired in premature infants, often resulting in persis- eye disease (both associated with OPN1LW and OPN1MW or
tent myopia.35 their regulatory regions), and retinal dystrophies caused by

RPGR and RPE65 mutations were associated with increased very typical. Family members without myopia may carry the
axial length.49 Two genes associated with albinism (such defective gene and be at risk of life-threatening but treat-
as OCA2 and TYR) also increased the risk of longer axial able cardiac complications. Diagnosis of Marfan syndrome
length. Short axial lengths are also seen in certain gene vari- in a patient without a family history therefore merits onward
ants. In terms of refraction, the range of retinal dystrophies referral of the entire family to a clinical genetics service.
that predispose to high myopia include retinitis pigmentosa Ehlers-Danlos is another connective tissue disorder that
(RP) and cone-rod dystrophies caused by mutations in the is characterized by joint hypermobility, skin hyperextensibil-
RPGR gene (15% of male patients with non-syndromic RP,50 ity, and tissue fragility, with associated ocular disorders that
congenital stationary night blindness (commonly associated include high myopia, lens opacifications, and convergence
with genes NYX and CACNA1F),51 and rare conditions, such insufficiency.61 Knobloch syndrome is also worth noting as
as blue cone monochromacy.52 a rare but commonly missed diagnosis associated with very
Metabolic disorders can also lead to high myopia. high levels of myopia.62 Features of all these syndromes
Gyrate atrophy (ornithine amino transferase [OAT] defi- are highly variable, even within the same family, and can
ciency) leads to chorioretinal atrophy and myopia. Long also be absent or subtle. Some phenotypes have primarily
chain 3-hydroxyacyl-CoA dehydrogenase deficiency (due to ocular signs, thus placing the onus on eye care practition-
mutations in HADHA), is a mitochondrial fatty acid oxidation ers who may be the first health professionals in a posi-
disorder associated with chorioretinal atrophy, myopia, and tion to make a diagnosis, which can have serious impli-
staphyloma formation.53 Homocystinuria is caused by muta- cations for a patient’s general health, risk for offspring,
tions in cystathionine beta-synthase (CBS) and can present reproductive options, and potentially for undiagnosed family
with myopia, with or without obvious lens dislocation.54 members.
Although rare, the clinical significance of these metabolic
disorders lies in the fact that dietary measures may improve
outcomes.55,56 Early diagnosis and active management in Stickler Syndrome and Allied Collagen
homocystinuria can greatly improve cognitive outcomes Vitreoretinopathies
and reduce the risk of the life-threatening thromboembolic
complications, most notably in countries without a neonatal The Stickler syndromes are an important group of connec-
screening program.57 tive tissue disorders within syndromic myopia because they
High myopia may represent the initial presenting feature are relatively common and have sight-threatening complica-
of an inherited retinal disease, placing a burden on the tions from retinal detachment for which prophylactic treat-
first eye care practitioner who sees the child to consider ments are available.63 They form part of the spectrum of
such a diagnosis. In addition to the immediate benefits to inherited vitreoretinopathies usually resulting from congen-
vision from identifying and correcting high myopia, there ital disorders of type II, IX, and XI collagen which are major
are several benefits of early diagnosis of a myopia-associated structural components of the extracellular matrix in vitreous
retinal dystrophy. The variable effects of this class of condi- and cartilage.64 The various subtypes of Stickler syndrome
tions on visual acuity, color vision, contrast sensitivity, visual are listed in Table 1.
fields, and night vision have huge implications for a child’s The clinical features may be considered under four cate-
education and their safe navigation. In addition, an accurate gories:
genetic diagnosis provides valuable prognostic information, 1. Ophthalmic
and there is now an approved therapy for at least one of The classic and pathognomonic ophthalmic feature of
the retinal dystrophy genes associated with increased axial Stickler syndromes is embryological arrest or disruption of
length (RPE65).58 vitreous embryogenesis. This is usually in association with
congenital myopia. In contrast to normal developmental
Myopia-Associated Connective Tissue Disorders myopia, the refractive error may be high, but it is usually
nonprogressive.65
High myopia is a characteristic feature in connective tissue Other recognized ophthalmic features are congenital
disorders. Stickler syndrome (incidence 1:7500–1:9000) and lamellar cataract, and a high risk of retinal detachment
Marfan syndrome (incidence 1:5000–1:10000) are two rela- and giant retinal tear. Although the congenital (refractive)
tively common heritable conditions associated with high myopia is common, it is important to recognize that approx-
myopia in children that can have a range of severe ocular and imately 15% of patients exhibit no significant refractive error,
extra-ocular manifestations. Stickler syndrome can include although many of these may still have congenital megaloph-
ocular findings, such as cataract and retinal detachment, thalmos but with associated cornea plana rendering them
and extraocular features, such as hearing loss (both conduc- refractively emmetropic – “crypto myopia.” Axial length
tive and sensorineural), midfacial underdevelopment and measurement is therefore particularly important. Recent
cleft palate (either alone or as part of the Robin sequence), research has identified a variety of genetic Stickler syndrome
and mild spondyloepiphyseal dysplasia and/or precocious mutations that may be predominantly ocular or only affect
arthritis.59 the eye, with minimal or no systemic involvement. In such
Marfan syndrome is characterized by its cardinal features cases, identification of the typical membranous (COL2A1
involving the ocular (ectopia lentis, retinal detachment, glau- mutations) or beaded (COL11A1 mutations) vitreous synere-
coma, and cataracts), skeletal (bone overgrowth and joint sis is key to making the clinical diagnosis.66
laxity, disproportionately long extremities, pectus abnormal- 2. Auditory
ities, and scoliosis), and cardiovascular system (aortic dilata- Conductive and sensorineural hearing loss (often
tion predisposing to aortic tear and rupture, and mitral combined) may be congenital and subclinical. If present, the
and/or tricuspid valve prolapse).60 Marfan syndrome is a sensorineural hearing loss tends to be nonprogressive and
dominantly inherited abnormality of fibrillin-1 (FBN1) with the conductive hearing loss which is common in childhood
high penetrance where intrafamilial phenotypic variation is becomes less prevalent with age.

TABLE 1. Known and Suspected Genetic Causes of Stickler Syndrome

Inheritance Gene Clinical Features MIM No.*
1 AD COL2A1 Membranous congenital vitreous anomaly, congenital megalophthalmos, 108300

deafness, arthropathy, cleft palate
2 AD COL2A1 Ocular only. Membranous congenital vitreous anomaly (usually), 609508
congenital megalophthalmos. No systemic features.
3 AD COL11A1 Ocular only. Membranous congenital vitreous anomaly (usually), 604841
congenital megalophthalmos. No systemic features.
4 AR COL11A1 Beaded congenital vitreous anomaly, congenital megalophthalmos, MIM not yet assigned128
arthropathy, cleft palate, profound severe congenital deafness
5 AD COL11A2 Normal vitreous and ocular phenotype, deafness, arthropathy, cleft palate 184840
6 AR COL9A1 Sensorineural deafness, myopia, vitreoretinopathy, epiphyseal dysplasia 614134
9 AD BMP4 Hypoplastic vitreous, deafness, arthropathy, cleft palate MIM not yet assigned129
10 AR LOXL3 sensorineural deafness, myopia, vitreoretinopathy, epiphyseal dysplasia MIM not yet assigned130
11 AR LRP2 sensorineural deafness, myopia, vitreoretinopathy, epiphyseal dysplasia MIM not yet assigned131
* Online Mendelian Inheritance in Man, OMIM. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore,
MD), {date}. World Wide Web URL: https://omim.org/.
3. Oro-facial (30%), or X-linked (33%), more unusual inheritance patterns

All subgroups of Stickler syndrome may be associated have been observed. The X-linked female limited inheritance
with cleft or high arch palate and/or Pierre-Robin sequence. pattern seen in ARR3 mutations, with affected female carri-
Other features include micrognathia, mid-facial hypoplasia, ers and unaffected male carriers, can make diagnosis chal-
nasal hypoplasia, anteverted nares, and long philtrum. As lenging.72,73
with other features, the variability of the phenotype means
that the lack of these features does not rule out Stickler
Other Disorders Associated With Myopia
syndrome.
4. Musculo-skeletal Other forms of syndromic myopia can be related to corneal
Patients with Stickler syndrome can suffer from joint or lens malformations. Keratoconus, a cause of predom-
hypermobility leading to secondary premature arthropa- inantly non-axial myopia, is usually isolated but linked
thy (typically but not exclusively affecting hips, knees, and with over 20 genes and 49 syndromes, including Down
lumbar spine in young adulthood). The musculo-skeletal Syndrome. Microspherophakia, characterized by a lens with
features of the allelic disorders Kniest dysplasia and spondy- reduced equatorial diameter and increased optical power,
loepiphyseal dysplasia congenita (SEDC) are more severe is associated with Weill-Marchesani syndrome (WMS) and
and associated with rhizomelic (proximal) limb shorten- linked to mutations in ADAMTS10 and FBN1 genes, but it
ing, kyphosis, and scoliosis, but similarly associated with may appear in isolation or in association with a range of
congenital myopia and megalophthalmos. An association other syndromic conditions. Another cause of myopia in
between Stickler syndrome and mitral valve prolapse has newborns is congenital glaucoma, which can cause buph-
been reported, but this was on a cohort with a clinical not thalmos and progressive myopia, and is associated mutations
genetic diagnosis.67 in the CYP1B1, LTBP2, and TEK genes.
A cohort of 78 genetically confirmed cases of Stickler
syndrome found no clinical or echocardiographic evidence
of mitral valve prolapse, suggesting that earlier studies may
CLINICAL EVALUATION OF A HIGHLY MYOPIC
have included other phenotypically similar connective tissue CHILD
disorders.68
There are many aspects to the clinical evaluation of high
myopia in children. In addition to the normal considerations
of optical correction and managing myopia progression, a
Monogenic Forms of Myopia
primary goal of investigating highly myopic children is to
Over the past few years, many genes have been iden- identify syndromic forms of myopia, as discussed above, that
tified as causing isolated monogenic high myopia, but may have additional implications for their vision and general
greater progress has been made in identifying monogenic health.
syndromic forms of myopia.69–71 Whole exome sequencing
of a cohort of patients with high myopia has demonstrated Recommended Assessment Procedures
that 20% of such cases had a causal pathogenic mutation
in a known myopia-associated gene. A genetic diagnosis Due to the increased risk of associated ocular and systemic
was more likely in cases with ocular or systemic syndromic comorbidities, high myopia in children merits a very detailed
features, being found in 35% of such cases as compared clinical evaluation. The clinical history needs to be tailored
with only 14% of cases of isolated myopia. This shows to identify possible monogenic inheritance patterns and
the diagnostic value of identifying associated ocular and the symptoms of the most significant syndromic forms of
systemic features in early-onset high myopia. Although most myopia. In addition to a detailed ocular examination of the
of these disorders display conventional inheritance patterns, cornea, lens, vitreous, and retina, attention must be given
such as autosomal dominant (30%), autosomal recessive to the non-ocular clinical signs of connective disorders.

Following cycloplegic refraction, biometric analysis is essen- such as congenital stationary night blindness and achro-
tial to determine which ocular components are contribut- matopsia, and is characterized by initial pupillary constric-
ing to the child’s myopia. This will help to distinguish tion to darkness. In older children, automated perimetry can
corneal, lenticular, axial, or mixed pattern forms of myopia. be useful to detect peripheral field loss from inherited retinal
Depending on the history and examination findings, addi- disease.
tional investigations are often merited. These may include The presence of nystagmus in combination with high
specialized ocular investigations, such as electrophysiology myopia strongly suggests the possibility of retinal dystro-
and retinal imaging. Where a systemic medical condition is phy. Clinical evaluation of the cornea, iris (for transillumina-
diagnosed clinically, or suspected, the involvement of clini- tion as a pointer to albinism), anterior chamber depth, lens
cal geneticists and pediatricians may be warranted. (curvature, size and dislocation), vitreous, and retina can be
diagnostic in certain cases, allowing identification of kera-
History toconus, anterior lens dislocation, microspherophakia, lenti-
conus, or the classical membranous or beaded features of the
The clinical history should start with a family history, inquir- vitreous in Stickler syndrome. Retinal examination can reveal
ing about refractive status and potentially significant ocular features of inherited retinal disease or neonatal treatments
and non-ocular medical conditions. Ocular factors that may for ROP that may not have been revealed during history
suggest genetic retinal disease include family members with taking. Older highly myopic children may demonstrate a
poor vision despite optical correction, color vision deficits range of structural changes, including optic nerve changes,
that include tritanopia, and poor night vision. Previous reti- myopic maculopathy, and posterior staphyloma, which carry
nal detachment surgery (especially giant retinal tears or implications for future visual impairment.
bilateral detachments) in any family member, familial deaf- Even though intraocular pressure can be difficult to
ness or hearing loss, and cleft palate are useful markers for measure in infants, this is an essential step in any myopic
Stickler syndrome. A history of heart valve surgery within infant to exclude the possibility of congenital or early-
the extended family can point to connective tissues disor- onset glaucoma. Non-contact tonometry techniques can be
ders, such as Marfan syndrome. Birth history is important performed in the clinic without the need for sedation or
in relation to the possible contribution of prematurity, and anesthesia.
assessment of milestones provides a simple test for develop-
mental delay which is a common finding in childhood high Ocular Biometry
myopia.20
Ocular biometry is essential in the evaluation of high myopia
General Clinical Examination in children because there are many conditions, such as
keratoconus and ROP, where the associated myopia is not
Prior to the ocular examination, a general examination of primarily axial. In addition to assessment of axial length,
a child by the eye care practitioner can reveal useful infor- keratometry, corneal topography, corneal thickness, anterior
mation. Assessment of their general psychomotor develop- chamber depth, and lens thickness are valuable measure-
ment, facial morphology, and limbs can indicate the need ments for assessing and monitoring corneal disorders (for
for review by a pediatrician or clinical geneticist. Facial example, keratoconus) and conditions affecting the lens
features suggestive of connective disorders, such as Stick- shape and location, such as microspherophakia and early
ler syndrome, include micrognathia, mid-facial hypoplasia, lens dislocation in Marfan syndrome.
long philtrum, and a flattened nasal contour. This is often
best appreciated from a lateral viewpoint. Ocular Imaging
Screening for joint hypermobility and skin elasticity
is useful for identifying potential cases of Ehlers–Danlos Ocular imaging using techniques, such as wide-angle
syndrome, Marfan syndrome, and Stickler syndrome. The fundus photography, fundus autofluorescence imaging, opti-
standardized method for assessing joint hypermobility is the cal coherence tomography (OCT), and optical coherence
Beighton score. A quick clinical screening can be done in tomography angiography,74 can all provide critical diagnos-
a minute or less by looking for little finger/pinkie hyper- tic information regarding possible inherited retinal diseases.
extension, testing if the thumb can touch the forearm, Wide field fundus autofluorescence imaging is particularly
elbow/knee hyperextension, and checking for elbow skin useful in children because the characteristic retinal pigmen-
elasticity. Examination of the palate for midline clefting, tary changes seen in adults with inherited retinal disease
previous cleft palate surgery, bifid uvula, or a high arched are often absent in children, but changes in fundus autoflu-
palate is easily done with light from a direct or indirect orescence are present from a young age in such cases.75 In
ophthalmoscope. older children, analysis of the ellipsoid zone (specifically
photoreceptor outer segment length) with OCT can be an
Ocular Examination effective method of objectively diagnosing and monitoring
retinal dystrophies.
Age-specific visual acuity testing and cycloplegic refraction
are essential starting points of the clinical examination. Electrophysiology
Reduced best-corrected visual acuity is rare in uncompli-
cated myopia but an important marker of retinal disease Visual electrophysiology tests are used to help diagnose
in children with high myopia.23 Color vision testing is a a variety of visual disorders, and are essential for detect-
useful screening test for cone dystrophies provided it tests ing retinal dystrophies.76 Such testing is indicated in highly
for tritan (blue-yellow) discrimination (for example, Hardy- myopic children where there is a family history of inherited
Rand-Ritter [HRR] plates or the 100-hue test). Paradoxical retinal disease, in patients with reduced best-corrected visual
pupillary reaction is a screening test for retinal diseases, acuity with or without nystagmus, color vision deficits, poor

FIGURE 1. A comprehensive guide to the assessment, investigation, diagnosis, and management of high myopia in a hospital setting.
night vision, abnormal retinal autofluorescence, or suspi- multi-focal ERG,78 on-off ERG,79 and S-cone ERG80 are valu-
cious retinal findings. Full-field electroretinogram (ERG) able additions when available. The electrooculogram, which
remains the most useful single test,77 but pattern ERG, assesses retinal pigment epithelial function, is also very

TABLE 2. Clinical Diagnostic Approach
Medical and family history

- Age of myopia onset
- Environmental risk factors: prematurity, outdoor exposure, near work
- Vision: night blindness and color blindness
- Hearing loss
- Cleft lip and/or palate (including Pierre Robin sequence)
- Joint hypermobility and skeletal abnormalities
- Cardiovascular abnormalities (aortic root dilatation or dissection)
- Developmental milestones and cognitive abilities
- Three-generation family tree, with specific enquiry about (high) myopia, hearing loss, skeletal abnormalities, cleft lip and/or palate,
cardiovascular abnormalities, visual impairment and/or blindness, retinal detachment.
Ophthalmological examination
- Visual acuity
- Cycloplegic refraction
- Color vision testing (including Tritan deficits)
- Eye movements (for nystagmus)
- Biometry including keratometry and axial length measurement at a minimum
- Fundoscopy
- Wide field fundus photography
- Fundal auto-fluorescence (if a retinal dystrophy is suspected clinically)
- Electroretinography (if a retinal dystrophy is suspected clinically)
Clinical examination for extraocular features
- Dysmorphological assessment (e.g. midfacial underdevelopment, Marfanoid habitus)
- Stature; arm span to height ratio
- Occipital skull defects, cutis aplasia
- Wrist sign, thumb sign
- Beighton hypermobility score
- Skeletal abnormalities (e.g. pectus excavatum or carinatum)
Genetic Testing and/or onward referral
- In case of a recognizable phenotype: targeted DNA analysis.
- In case of a non-recognizable ocular phenotype or broader differential diagnosis, consider next-generation sequencing or whole-exome
sequencing using gene panel for vision disorders (where available).
- In case of suspected ocular and systemic phenotype, refer to pediatric or clinical genetics services.
- Consider referral to a clinical geneticist: in case of extraocular features, when a variant of unknown significance is found, complex
pedigrees, segregation analysis.
Diagnoses to consider
- Common myopia
- Connective tissue disorder (e.g. Marfan syndrome, Stickler syndrome, Knobloch syndrome)
- Retinal dystrophy (e.g. RPGR/RPE65-related retinitis pigmentosa, congenital stationary night blindness, blue cone monochromacy,
Bornholm eye disease)
- Monogenic isolated high myopia
- Non-axial high myopia (e.g. myopia of prematurity, spherophakia, keratoconus)
helpful in specific disorders, such as Best disease, but this onset high myopia, with molecular genetic testing replacing
condition is unlikely to present as high myopia. other investigations, such as electrophysiology and detailed
retinal imaging as the initial approach to diagnosis.
Figure 1 provides a flow chart for the suggested clin-
Role of Clinical Geneticists and Genetic Testing ical evaluation, diagnosis, and management process and
Table 2 provides additional details regarding the various
If the clinical evaluation suggests a monogenic or syndromic steps. Depending on the clinical setting and age of the
form of myopia, the involvement of other medical profes- patient, this may occur over one or more visits in a single
sionals may be warranted. These may include ophthalmolo- tertiary referral site or be broken down into smaller steps
gists who specialize in inherited disease, clinical geneticists, that are performed by multiple health professionals in differ-
genetic counselors, and/or pediatricians. Ideally, this multi- ent sites.
disciplinary evaluation should be done within the context
of a well-defined care pathway.81 Traditionally, genetic test-
ing has been based on testing genes known to be involved ROLE OF PRIMARY EYE CARE PRACTITIONERS
in the suspected condition. The diagnostic yield is higher
in the context of known or suspected ocular or systemic Primary eye care providers are the first line of defense
features, but the advent of whole exome sequencing using following a failed vision screening by a pediatrician or
large panels of ocular disease genes has provided a route school program. With the advent of instrument-based vision
to a rapid genetic diagnosis in childhood high myopia. In screenings, these referrals can happen as early as 12 months
the future, reduced cost and increased availability of such of age. The American Association of Pediatric Ophthalmol-
approaches may simplify the clinical evaluation of early- ogy and Strabismus (AAPOS) recommends that infants and

FIGURE 2. Guide for identification of cases that may represent secondary or syndromic myopia in a primary eye care setting and hence
merit referral.
toddlers undergoing instrument-based vision screenings be ble of doing automated perimetry, can be performed in a
referred if myopia worse than −3.0 D is detected in children primary care setting.
younger than 48 months of age or myopia worse than High myopia has been identified as a significant risk
−2.0 D in children 48 months of age or older.82 In addi- factor for having associated ocular and systemic conditions,
tion, the primary eye care community has been at the fore- but the converse is not always true. Many significant ocular
front of introducing myopia control treatments, with many conditions typically associated with myopia (for example,
primary eye care practices offering pediatric myopia control Stickler syndrome), show marked variability and some cases
services. Therefore, the primary eye care community needs may not display high levels of myopia and the absence of
to be on heightened alert in recognizing the risk factors for myopia cannot be taken as proof that such systemic condi-
syndromic forms of myopia in children so that timely and tions are not present. Myopia levels may also be lower at the
appropriate referrals for further investigation can be made early stages of some systemic disorders.
when applicable. Once the initial diagnosis of high myopia is
made, the priority is to determine whether there is an asso-
ciated systemic or ocular disorder (as outlined in Fig. 2). CHALLENGES OF OPTICAL CORRECTION OF HIGH
The presence of one or more of the history and clinical MYOPIA IN CHILDREN
features noted in Figure 2, indicates that additional investiga-
tion and multidisciplinary clinical evaluation are warranted, High myopia in young children creates unique issues relat-
which may require referral to a pediatric tertiary eye care ing to optical correction to ensure normal visual develop-
center. ment and the avoidance of amblyopia. Although specta-
Although a comprehensive evaluation is unlikely to be cles will be the primary form of optical correction, contact
possible in a primary care setting, a clinical history (as lenses may be more appropriate for children with signifi-
described above) that targets the commonest features of cant anisometropia (such as in high anisomyopia) or where
syndromic myopia can be performed in any clinical setting craniofacial abnormalities make the wearing of conventional
and should be considered mandatory in assessing high spectacles challenging.83 Contact lenses may be useful in
myopia in young children. The clinical tests for joint hyper- improving quality of life and even visual acuity because
mobility in children are easy to learn and apply in any highly myopic spectacle lenses cause minification of the
clinical environment (see https://www.ehlers-danlos.com/ retinal images.20 Optical correction can be particularly chal-
assessing-joint-hypermobility [accessed January 2023] for a lenging in children with neuro-behavioral abnormalities, as
simple guide). Other valuable screening tests, such as look- the visual impairment associated with uncorrected myopia
ing for reduced best-corrected visual acuity, tritan color can adversely impact both their behavior and develop-
vision deficits, or visual field defects in older children capa- ment. In such cases, surgical refractive correction may

be a viable intervention when performed at centers with
BCVA, best corrected visual acuity; IOL, intraocular lens; LASEK, laser-assisted subepithelial keratectomy; NR, not reported; PRK, photorefractive keratectomy; SE, spherical equivalent;
One dislocated IOL and one
extensive pediatric experience, although this remains a
posterior capsule opacity

40% mild to moderate haze
controversial topic.84
Complications
Conventional Optical Correction of High Myopia
22% mild haze
35% mild haze

in Childhood
Whereas full correction of myopia in school-aged chil-
None
dren is appropriate based on the maximizing distance
visual acuity and avoiding accelerated myopic progres-
sion, in preschool children, it is common practice for
Improved in 2/3 of patients

Improved in 50% to 83% of
Improved by questionnaire
lower levels of myopia not to be corrected. The revised
American Academy of Ophthalmology Preferred Prac-
Improved in 88% of
Behavior
tice Guidelines published in 2022 (https://www.aao.
org/preferred-practice-pattern/pediatric-eye-evaluations-
ppp-2022 Accessed January 2023) do not explicitly address
patients
patients
Improved
the issue of high myopia in young children, but recommend
that the following levels of bilateral myopia merit optical
correction, noting that smaller amounts of refractive error
may also warrant correction depending on the clinical
Follow-Up
(mo)
situation.
12
12
12
54
17
• refractions < −5.0 D in <1 year of age
• refractions < −4.0 D from 1 year and <2 years
Postoperative
• refractions < −3.0 D from 2 years and <3 years
UCVA†
Mean
20/38
20/60
• < −2.5 from 3 years and <4 years
NR
NR
NR
refractions D
Under these guidelines, all high myopes (worse than

−6.0 D) and most significantly myopic children under
Preoperative
4 years of age merit correction. It is noted that “these values
20/133
BCVA*
Mean
20/70
20/80
3/200
20/76
were generated by consensus and are based solely on profes-
sional experience and clinical impressions because there are
no scientifically rigorous published data for guidance.” In the
absence of such evidence, an analytical approach can be a
Postoperative
1 D of goal
89% within
helpful guide. Leat provided a valuable analysis and a set of
SE (D)*
−1.4
−1.2
−3.3
0.8
questions that can be applied to a specific patient.85
1. Is the refractive error within the normal range for the
treated for anisometropia in the same study.

child’s age?
Preoperative
2. Will this child’s refractive error emmetropize?

Range: −3.8
to −11.5
SE (D)*
3. Will this level of refractive error disrupt normal visual

−10.7
−7.5
−19.1
−8
development or functional vision?

4. Will prescribing spectacles improve visual function or
functional vision?
Age Range
5. Will prescribing spectacles interfere with the normal

(Years)
1–17
1–18
3–16
1–6
process of emmetropization?
7
TABLE 3. Refractive Surgery for High Bilateral Myopia
Considering these questions for highly myopic preschool

children points to the need for optical correction.
Patients
No. of
10
11
1
13
• Question 1: Based on the prevalence of high myopia

in this age group, their refraction is certainly outside
Procedure
the normal range.

RLE/CLE
LASEK
LASEK
LASEK
PRK
• Question 2: Although low myopic errors can

† These studies include patients
UCVA, uncorrected visual acuity.

* Mean unless range is given.
emmetropize, there is little evidence regarding high

myopia86 and early onset highly myopic eyes have
2002
2004
2006
2006
2006
Year
already demonstrated a failure to emmetropize.

• Question 3: Uncorrected, or significantly undercor-
rected, high myopia could certainly disrupt visual
Tychsen and Hoekel5
function and normal visual development.

• Question 4: Correcting high myopia will undoubt-
Tychsen et al.134
Astle et al.132,†
Astle et al.133,†
Astle et al.133,†
edly improve visual function.

Author(s)
• Question 5: In lower levels of myopia undercorrec-

tion does not slow down progression or promote
emmetropization.87 There is no evidence to suggest
any benefit for undercorrection in high myopia.

TABLE 4. Refractive Surgery for High Myopic Anisometropia

Age Range No. of Preoperative Postoperative SE Preoperative Postoperative Mean Follow-Up
Author(s) Year Procedure (Years) Patients SE (D)* (D)* BCVA* UCVA† (mo) Complications
Singh135 1995 PRK 10–15 6 −12.1 −2.9 20/82 20/44 1 Haze
Nano et al.136 1997 PRK 11–14 5 −8 −1.6 20/400 20/72 12 Mild haze
Alio et al.137 1998 PRK 5–7 6 −9.6 −2 20/114 20/35 24 Severe haze (1)
IMI—High Myopia in Infants and Young Children
Rashad138 1999 LASIK 7–12 14 −7.9 −0.6 20/50 20/25 12 None

Agarwal et al.139 2000 LASIK 5–11 16 −14.9 −1.4 20/37 20/37 12 Free Flap
Nucci and Drack140 2001 PRK/LASIK 9–14 14 −8 −0.07 20/125 20/121 20 None
Nassaralla and Nassaralla141 2001 LASIK 8–15 9 −7.2 −0.2 NR NR 12 None
Astle et al.132 ,† 2002 PRK 1–6 27 −10.7 −1.4 20/70 20/40 12 Mild haze
Autrata and Rehurek142 2004 PRK/LASEK 4–7 27 −8.3 −1.6 20/95 20/26 24 Mild haze (3)
Astle et al.143 ,† 2004 LASEK 1–17 13 −8 −1.2 20/80 20/50 12 Minimal haze
Phillips et al.144 2004 LASIK 8–19 17 −9.06 −3.74 20/25 20/20 18 None
Tychsen et al.145 2005 PRK/LASIK 4–16 35 −11.5 −3 20/87 20/47 29 Minimal haze (3)
Paysse et al.146 2006 PRK 2–11 11 −13.8 −3.6 20/316 20/126 31 Minimal haze
Yin et al.147 2007 LASIK 6–14 32 −10.1 −2.2 20/50 20/33 17 Minimal haze
Ali et al.148 2007 RLE/CLE 4–20 7 −16.7 NR NR (UCVA NR (UCVA 4 Posterior capsule fibrosis (1)
20/2550) 20/130
Pirouzian and Ip149 2010 phIOL 5–11 7 −14.28 −1.1 20/4000 NR (BCVA 35 None
20/40
Lesueur and Arne150 2002 phIOL 3–16 11 −12.7 NR (range −0.75 NR (range CF NR (BCVA 21 None
to +2.00) to 20/63) 20/63)
* Mean unless range is given.
† These data include patientstreated for bilateral high myopia and high myopia after penetrating keratoplasty in the same study.
BCVA, best corrected visual acuity; UCVA, uncorrected visual acuity; LASEK, laser-assisted subepithelial keratectomy; LASIK, laser in situ keratomileusis; NR, not reported; PRK,
photorefractive keratectomy; RLE/CLE, refractive lens exchange/clear lens extraction; phIOL, phakic intraocular lens; SE, spherical equivalent.
IOVS | Special Issue | Vol. 64 | No. 6 | Article 3 | 11
Overall, until better evidence is available, such analy- creates issues for frame fitting. Contact lens fitting can
sis would appear to favor full correction of high myopia be challenging in such cases due to shallow orbits,
in young children to optimize functional vision and avoid associated lagophthalmos, and corneal exposure.98
disrupting visual development.
In all three groups, the absence of optical correction can
Management of High Anisomyopia have a negative impact on their quality of life and or visual
development. Untreated high refractive error in young chil-
High anisomyopia is a challenging condition that can dren can result in severe levels of blur-induced amblyopia
be associated with significant unilateral visual impairment akin to that found with a dense congenital cataract or corneal
from amblyopia, particularly when associated with myeli- opacity. We should therefore approach the amblyopia of
nated retinal nerve fibers (Straatsma syndrome).88,89 Opti- conventionally uncorrectable refractive errors as we would
cal correction is an essential part of the management of these other treatable causes of form vision deprivation,
anisomyopia, usually combined with amblyopia treatment. where surgical interventions are now routinely used. One
Despite the traditional view that amblyopia in the presence difference is the higher proportion of associated systemic
of myelinated nerve fibers and anisomyopia responds poorly issues in this group of patients (compared, for example, to
to occlusion therapy, some patients respond extremely well, congenital cataracts), which requires an individualized risk-
making a therapeutic trial worthwhile.90,91 benefit assessment with multidisciplinary input from a range
The intraocular difference in refraction in anisomyopia of healthcare professionals.
is often dramatic; a mean value of 9.4 D was reported in
one of the larger series,92 leading to aniseikonia with spec- Outcomes of Refractive Surgery in Children
tacle correction. As a result, contact lens correction of the
myopic eye is the preferred option. Corneal rigid lenses do Both corneal and intraocular procedures can correct refrac-
not normally have a significant impact on normal myopia tive errors. Excimer laser refractive surgery for high myopia
progression but, in high anisomyopia, several case studies associated with amblyopia has been performed for over 2
suggest a possible beneficial effect on myopic progression in decades in children, with good visual acuity and refractive
the more myopic eye.93,94 If contact lenses prove impossible, results and low levels of complications (see Tables 3, 4).
full or partial optical correction should be attempted, espe- Currently, both corneal and intraocular refractive procedures
cially in young children to minimize amblyopia. Children are are utilized “off-label” in children in most jurisdictions and
often capable of surprisingly large amounts of neuroadapta- are not approved by the US Federal Drug Administration
tion to retinal size differences.95 (FDA) in the United States.
Attempts have been made to directly reduce anisomy-
opia with myopia control interventions in the myopic eye. Improvements in Visual Function and General
A comparison of low-dose atropine and orthokeratology
Development
indicated that orthokeratology had a more beneficial effect,
but this was a retrospective series, not a controlled trial.96 Refractive surgery can be effective in children with high
A meta-analysis of multiple cohort studies came to the refractive errors and amblyopia unresponsive to standard
same conclusion, but definitive trials are required to clar- therapy. Substantial gains in visual acuity have been reported
ify whether myopia control interventions can meaningfully with refractive surgery in children, with a mean improve-
alter the natural refractive history of anisomyopia.97 ment of visual acuity of 1.6 lines (range = 0 to 7 lines, n =
28) and no loss of best corrected visual acuity in one series.99
Surgical Correction of High Myopia in Childhood A recent study reported that children aged 3 to 7 years with
severe anisomyopia treated with patching and excimer laser
Most children with high myopia wear their refractive correc- treatment (n = 27) or phakic IOL (n = 16) achieved signif-
tion because it greatly improves their vision, but compli- icantly better visual acuity than a similar group (n = 37)
ance with spectacles or contact lenses is not guaranteed in of compliant children treated with contact lenses and patch-
young children. Patience and perseverance by parents will ing.100 Development improvements have also been observed
overcome many of the challenges with conventional optical in highly myopic children with intellectual disability unable
corrections, but there are certain children with high myopia to use conventional optical corrections.101
who refuse or are unable to wear a refractive correction and
consideration should be given to possible surgical solutions.
Such children will broadly fall into one of three cate-
MANAGEMENT OF MYOPIA PROGRESSION
gories: Management of myopic progression is currently the primary
goal of myopia control in most myopic children. For the
1. Children with bilateral high ametropia who are highly myopic children discussed in this paper, tackling
noncompliant with or intolerant of optical correc- myopic progression is only a small part of their overall
tion due to neurobehavioral problems or intellec- management. However, early onset of myopia is associated
tual disability. Such children often display a profound with increased risk of high myopia in later childhood.102
tactile aversion to both spectacles and insertion of It is therefore natural that clinicians will want to try and
contact lenses. address myopia progression in such cases. A note of caution
2. Children with severe anisomyopia who are spectacle is, however, required on the basis that many of the forms
intolerant due to aniseikonia/binocular vision issues of myopia described in this paper have been excluded from
and who are also contact lens intolerant. myopia progression trials, based on the degree of myopia,
3. Children with high ametropia or anisometropia, who age, prematurity, or as a syndromic form of myopia.103
have other special circumstances, such as craniofacial The lack of evidence regarding efficacy in these
anomalies, ear deformities, or neck hypotonia, that cases makes it difficult to provide evidence-based

recommendations. In addition, secondary forms of myopia show little or no progression while others do progress.65,109
are inherently a very heterogenous group. Online Mendelian In light of the lack of evidence for effectiveness of treatments
Inheritance in Man (OMIM)104 lists over 400 conditions that and the variability in progression rates in preschool children
include myopia as a clinical feature and the genes that with high myopia, ensuring that there is myopia progression
contribute to syndromic myopia are involved in a wide and axial elongation prior to intervention is warranted.111
variety of biological processes.19 This heterogeneity makes An additional complexity is that, in certain syndromic
it very likely that the responses to myopia progression forms of myopia, the associated abnormalities may accen-
interventions will be highly variable. Clinical trials are tuate the side effects of certain treatments. Photophobia is
unlikely to be feasible for these rare conditions and pooling a common feature of cone dystrophies; hence such patients
of outcome data between clinical sites in disease registries may be intolerant of even the minimal levels of mydriasis
may be the best option for developing an evidence-based seen with low dose atropine. In conditions with potential
approach to myopia management in this complex subtype cardiac complications, such as Marfan syndrome, reducing
of myopia. Assessing pharmacological myopia treatments, cardiac output with beta-blockers is standard practice and
such as atropine, in animal models of human syndromic any treatment that could increase heart rate (for example
myopia represents another promising paradigm.105 higher dose of atropine) should be avoided.
The goals of reducing myopic progression also need to be
considered in the overall context of the patient. The primary
Myopia Progression Treatments in Myopia of justification for reducing myopia progression is maintain-
Prematurity ing good visual acuity into old age by reducing retinal and
other ocular complications associated with myopia.112 In
As previously noted, high myopia associated with prematu-
some forms of syndromic myopia, the major threat to vision
rity and ROP is not primarily axial. In such cases, there is
comes from direct retinal involvement of the condition itself,
little justification for routine use of currently available optical
not the myopia, but the two factors may interact. In retinal
or pharmacological treatments that have been developed to
dystrophies associated with RPGR mutations, high myopia is
slow axial growth. Evidence of axial elongation should there-
associated with a faster rate of decline of visual acuity with
fore be regarded as a prerequisite for any myopia control
age.113 Limiting progression of high myopia may also poten-
intervention in a child with a history of prematurity. Animal
tially reduce the myopia-related surgical risks of subretinal
studies involving infant primates have also raised the possi-
gene therapy.114 Syndromic myopia can be associated with
bility that topical atropine may lead to arrested development
behavioral abnormalities and looking after such children
of the anterior segment,106 suggesting caution over the use
already places a heavy challenge on parents and carers. This
of high concentrations of atropine for myopia control in the
may make eye drops, contact lenses, and even specialized
first year or two of life until further clinical data are avail-
spectacle lenses not feasible. Sadly, some syndromic forms of
able. This presents a particular challenge in ROP, because
myopia are also life-shortening and quality of life in the first
myopic progression appears to be most rapid in the first 3 or
decades is the priority; hence the burden of additional hospi-
4 years of life in eyes with ROP.36,41 If excessive axial growth
tal or clinic visits without a clear long-term benefit needs to
is observed in myopia associated with prematurity, active
be considered.
myopia management would be a reasonable approach, but
When considering myopia control interventions in highly
because intervention trials have generally excluded such
myopic children, a case-by-case approach is required. Where
cases, parents should be informed of the lack of evidence
myopic progression is observed and the axial length is
of efficacy in this situation.
greater than expected for the age,108 it is reasonable to
consider myopia control interventions provided no adverse
Myopia Progression Treatments in Syndromic interactions are anticipated in syndromic cases. Optical inter-
Myopia ventions are likely to have less potential for such interac-
tions, but their availability may be limited in high refrac-
Several forms of syndromic myopia are also primarily lentic- tive errors. The assessment of suitability for myopia control
ular or corneal (for example, Cohen syndrome).107 Biometric interventions also needs disclosure of the lack of evidence
analysis of corneal curvature, anterior chamber depth, lens for efficacy in syndromic cases. As a low-risk intervention,
morphology, and axial length are therefore essential in deter- advice on increased outdoor activities for all children with
mining whether the observed myopia is refractive, axial, or myopia or at risk of myopia from an identified syndrome is
a combination of both. Where an axial contribution to the appropriate.
myopia is suspected, monitoring of axial length is essential
to determine that there is faster than normal axial progres-
sion prior to considering treatment.108 COMPLICATIONS OF HIGH MYOPIA IN CHILDREN
The pattern of myopia onset and progression is often very
different in syndromic myopia compared to typical myopia. It is now well recognized that the structural complications
In many forms of syndromic myopia, high levels of myopia of myopia, as embodied in the term “pathologic myopia”4
are present by the age of 5 years and there is little progres- increase with age. In 1864, Donders wrote, “it is rare at
sion thereafter.65,109 A study of preschool myopic children in 60 years of age to find a tolerably useful eye, with myopia of
China found that those children with a spherical equivalent 1:2.5 (−15.75 D in modern units) or even 1:3 (−13.0 D).”115
refraction worse than −6.0 D showed a mean progression of This adage has been amply confirmed in recent studies.
−0.32 D/year, compared with −0.85 D/year for children with Visual impairment associated with high myopia is rare
lower levels of myopia between −0.5 D and −2.0 D.110 A low before 50 years of age and increases rapidly after 60 years
rate of progression in highly myopic children has been iden- of age.112 Ocular complications specifically associated with
tified in specific syndromes, such as Stickler syndrome and pathologic myopia, such as myopic maculopathy, poste-
congenital stationary night blindness, with many cases that rior staphyloma, and myopic traction maculopathy, show

a very similar age profile. This raises two interesting clin- In an Asian pediatric series, myopia worse than −4.0 D was
ical questions. First, are there structural changes present in the most frequent risk factor, but a high baseline prevalence
highly myopic children that could predict visual loss in later of myopia may have influenced this result.124
years? Second, will children presenting with high myopia Several syndromic forms of high myopia carry an
not display any structural issues or complications associated increased risk of rhegmatogenous retinal detachment associ-
with myopia until late adulthood? ated with retinal breaks or giant tears. These include Stickler
A recent retrospective study examined the medical syndrome (type 1 and type 2), Marshall syndrome (allelic
records of children with high myopia who were followed for with Stickler type 2), Knobloch syndrome, Kniest dyspla-
at least 20 years, looking for evidence of myopic maculopa- sia, Donnai-Barrow syndrome, Wagner vitreoretinopathy,
thy.116 Among 35 eyes with signs of myopic maculopathy spondyloepiphyseal dysplasia congenita, and Ehlers-Danlos
in adult life, 83% had shown parapapillary diffuse choroidal syndrome. In many of these syndromes, there are identified
atrophy confined to the area temporal to the optic nerve structural abnormalities in the vitreous which may repre-
head as children. The presence of parapapillary diffuse sent the primary etiological factor for retinal detachment,
choroidal atrophy in children with high axial myopia might as a proportion (10 %) of retinal detachments in Stickler
therefore be a biomarker for pathologic myopia and associ- syndrome occur in eyes without myopia.125 This is an impor-
ated visual impairment in adulthood. tant clinical finding, emphasizing that absence of myopia in
a child from a family affected by Stickler syndrome does not
rule the diagnosis or its sight-threatening complications.
Choroidal Changes in Highly Myopic Children Myopia worse than −10.0 D in children has been found
The choroid, long considered a passive vascular layer, is to be associated with reduced success of retinal detachment
now thought to play an important role in the regulation surgery when compared with surgery for eyes with myopia
of eye growth and refractive error development.117,118 In of −6.0 to −10.0 D.126 Retinal detachment associated with
non-myopic children, the choroid shows a yearly increase ROP is primarily tractional rather than rhegmatogenous, and
in thickness of 12 to 14 μm/year, whereas in myopic chil- although such eyes may be myopic, the myopia is not typi-
dren the choroid decreases in thickness with age as the axial cally axial in nature. In ROP, such tractional retinal detach-
length of the eye elongates and myopia progresses.118,119 ments are the consequence of the underlying pathophysiol-
In highly myopic children, the presence of parapapillary ogy of the condition rather than a consequence of the degree
diffuse choroidal atrophy is associated with a marked thin- of myopia.127
ning of the temporal parapapillary choroid and the subfoveal
choroid.120 CONCLUSION
The priority following the diagnosis of high myopia in child-
Posterior Staphyloma hood is to determine whether there is an associated medical
diagnosis that may be of greater overall importance to the
Although posterior staphylomas have been generally consid-
health of the child. A clinical history that targets the common
ered to be features of pathologic myopia that develop in
features of syndromic forms of myopia can be performed in
later life, a recent study using wide field OCT in highly
any clinical setting and should be considered mandatory in
myopic children aged 6 to 19 years old, revealed that 12.7%
assessing high myopia in young children. Biometric evalua-
had the initial features of posterior staphyloma.121 Similar
tion is important in distinguishing axial myopia from refrac-
to adults, these early-onset staphylomas were characterized
tive myopia associated with abnormal development of the
by choroidal thinning toward the staphyloma edge with the
anterior segment. Where suspicion has been raised during
posterior displacement of the sclera. These results show that
history taking and examination, further specialized inves-
posterior staphylomas can be present at a much younger age
tigation and multidisciplinary clinical evaluation are indi-
than generally believed. Statistical comparisons also showed
cated. Where a child has been diagnosed in a primary care
that the eyes with a staphyloma had diffuse chorioretinal
setting, this may require referral to a tertiary care facility.
atrophy, including parapapillary diffuse choroidal atrophy,
Although it is reasonable to use low risk interventions
significantly more frequently than those without a staphy-
for reducing myopia progression in childhood myopia with
loma.
proven axial progression, practitioners should consider the
Further work is required to establish the causative nature
lack of evidence of efficacy for children with high myopia
of these associations among choroidal changes, myopic
and syndromic forms of myopia. Considering the highly
maculopathy, and posterior staphyloma, and to separate
heterogenous nature of high myopia in childhood it is likely
early-onset environmental high myopia from high secondary
that the responses to interventions will be highly variable.
myopia4 from genetic or syndromic causes. However, the
When a therapeutic intervention is used, close monitoring
findings to date suggest that choroidal thickness is an impor-
of refraction and axial length is recommended. The genetic
tant initial biomarker for future development of pathologic
heterogeneity of syndromic and non-syndromic monogenic
myopia in highly myopic children. Monitoring choroidal
myopia makes randomized clinical trials of myopia inter-
changes in young children with high myopia may therefore
ventions both unpractical and unlikely. Pooling of outcome
be a valuable prognostic tool.
data between clinical sites in disease registries may be the
best option for developing an evidence-based approach to
Retinal Detachment Risk in Childhood High myopia management in this complex subtype of myopia.
Myopia
Retinal detachment is rare in childhood, representing only Acknowledgments
2 to 6% of all cases,122 with most cases arising from trauma, Supported by the International Myopia Institute. The publi-
ocular syndromes, ROP, and pediatric cataract surgery.122,123 cation and dissemination costs of the International Myopia

Institute reports were supported by donations from the Brien 10. Theophanous C, Modjtahedi BS, Batech M, Marlin DS,
Holden Vision Institute, Carl Zeiss Vision, CooperVision, Essilor- Luong TQ, Fong DS. Myopia prevalence and risk factors
Luxottica, Hoya, Thea, Alcon, and Oculus. A special acknowl- in children. Clin Ophthalmol. 2018;12:1581–1587.
edgement to Mark Bullimore for harmonization of this white 11. Multi-Ethnic Pediatric Eye Disease Study Group. Preva-
paper. lence of myopia and hyperopia in 6- to 72-month-old
African American and hispanic children: The multi-ethnic
In preparing this document, the authors received valuable feed- pediatric eye disease study. Ophthalmology. 2010;117:140–
back and support from the wide range of scientists and clini- 147.e3.
cians who have contributed to this IMI initiative and staff of the 12. Giordano L, Friedman DS, Repka MX, et al. Prevalence
IMI. Specifically acknowledged Contributors: of refractive error among preschool children in an urban
Annechien E.H. Haarman1,4 , Jan Roelof Polling1,3 , J. Willem population: The Baltimore pediatric eye disease study.
Tideman1,4 , Alberta A.H.J Thiadens1 , Anneke J.A. Kievit2 , and Ophthalmology. 2009;116:739–746.e1-4.
Tae Igarashi-Yokoi5 13. Dong L, Kang YK, Li Y, Wei W, Jonas JB. Prevalence
1
Department of Ophthalmology, Erasmus Medical Center, and time trends of myopia in children and adolescents
Rotterdam, The Netherlands in China: A systemic review and meta-analysis. Retina.
2
Department of Clinical Genetics, Erasmus Medical Center, 2020;40:399–411.
Rotterdam, The Netherlands
3
Department of Optometry and Orthoptics, Hogeschool Utrecht, 14. Li Y, Liu J, Qi P. The increasing prevalence of myopia
University of Applied Science, Utrecht, The Netherlands in junior high school students in the Haidian district of
4
Department of Epidemiology, Erasmus Medical Center, Rotter- Beijing, China: A 10-year population-based survey. BMC
dam, The Netherlands Ophthalmol. 2017;17:88.
5
Tokyo Medical and Dental University, Japan. 15. Wong K, Dahlmann-Noor A. Myopia and its progression
in children in London, UK: A retrospective evaluation.
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Johnson & Johnson Vision (C), Vyluma (C), Thea (C), Ocume- 16. Morgan IG, Wu PC, Ostrin LA, et al. IMI risk factors for
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Ainsworth, None; A. Chia, None; S. Cotter, None; E. Harb, 17. Ghorbani Mojarrad N, Plotnikov D, Williams C, Guggen-
None; Z.-B. Jin, None; C.C.W. Klaver, Bayer (C), Novartis (C), heim JA. Association between polygenic risk score and risk
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Nischal, Essilor Luxoittica (C), Ocumension (C), Graybug (C), 18. Lanca C, Kassam I, Patasova K, et al. New polygenic risk
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E.A. Paysse, None; M.X. Repka, Alcon (C), Luminopia (C); I.Y. dren. Transl Vis Sci Technol. 2021;10:26.
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Special Issue

IMI—Management and Investigation of High Myopia in

Copyright 2023 The Authors

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with high myopia.9 In a large US report from a single health

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TABLE 1. Known and Suspected Genetic Causes of Stickler Syndrome

1 AD COL2A1 Membranous congenital vitreous anomaly, congenital megalophthalmos, 108300

3. Oro-facial (30%), or X-linked (33%), more unusual inheritance patterns

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TABLE 2. Clinical Diagnostic Approach

Medical and family history

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be a viable intervention when performed at centers with

posterior capsule opacity

22% mild haze

35% mild haze

Improved in 2/3 of patients

Under these guidelines, all high myopes (worse than

1. Is the refractive error within the normal range for the

treated for anisometropia in the same study.

2. Will this child’s refractive error emmetropize?

3. Will this level of refractive error disrupt normal visual

development or functional vision?

5. Will prescribing spectacles interfere with the normal

Considering these questions for highly myopic preschool

• Question 1: Based on the prevalence of high myopia

the normal range.

• Question 2: Although low myopic errors can

UCVA, uncorrected visual acuity.

emmetropize, there is little evidence regarding high

already demonstrated a failure to emmetropize.

function and normal visual development.

edly improve visual function.

• Question 5: In lower levels of myopia undercorrec-

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Rashad138 1999 LASIK 7–12 14 −7.9 −0.6 20/50 20/25 12 None

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