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Congenital eye anomalies
Alex V. Levin, MD, MHSc, FAAP, FAAO, FRCSC*
Departments of Ophthalmology, Pediatrics, and Genetics, The Hospital for Sick Children,
University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada
Malformations of the eye and its surrounding tissues may occur in isolation, in
combination, or as part of a systemic malformation syndrome. For some eye
anomalies the responsible gene may be known, whereas for others, the chro-
mosomal location may be identified without knowledge of the exact gene. In
some cases, the genetic etiology may remain completely obscure. Either germ
line or somatic mutations can cause eye abnormalities. One must, however,
differentiate those eye abnormalities that result from disruption (eg, a lid cleft
caused by an amniotic band), deformation (eg, craniofacial asymmetry caused by
oligohydramnios), intrauterine infection, or teratogenic exposure from true
congenital malformations, because only true congenital malformations are
heritable. Some ocular malformations have significant visual consequences,
whereas others may have only cosmetic significance, and still others are noticed
only serendipitously on routine eye examination with no import to the patient.
Congenital abnormalities of the periocular tissues
Measuring periocular tissues
A fundamental principle of dysmorphology is to distinguish normal from
abnormal. The standard measurements for the tissues around the eyes include the
inner canthal distance (ICD), outer canthal distance (OCD), interpupillary
distance (IPD), and palpebral fissure length. One can also describe the slant of
the palpebral fissure. Measuring the periocular tissues in a child can be quite
challenging. If the child is squirming, it may be difficult to get a measuring tape
or ruler close enough to the face, thus inducing error and parallax. Crying also
distorts the facial measurements. In Treacher Collins syndrome, an abnormal
0031-3955/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved.
doi:10.1016/S0031-3955(02)00113-X
* Department of Ophthalmology M158, The Hospital for Sick Children, University of Toronto,
555 University Avenue Toronto, Ontario M5G 1X8 Canada.
E-mail address: [email protected]
Pediatr Clin N Am 50 (2003) 55–76
attachment of the lateral canthal ligament results in abnormal foreshortening of
the palpebral fissure during crying. One must also be careful not to damage the
eyeball accidentally with a ruler when an uncooperative child moves suddenly.
Congenital malformations of the lids, such as a lid coloboma, may make
landmarks difficult to identify.
Inner canthal distance
The measurement from medial canthus to medial canthus is called the inner
canthal distance. The measurement should be taken from the point at which the
upper and lower lids join medially. In the presence of epicanthus (discussed
later), one must be sure to find the true medial canthus beneath the epicanthus.
The true medial canthus may be found by pinching the bridge of the nose gently,
taking care not to distort the position of the medial canthus. Standard tables for
age-related normal values are available [1,2].
Outer canthal distance
The measurement from lateral canthus to lateral canthus is called the outer
canthal distance. It is not acceptable to double the measurement from one lateral
canthus to the midline, because the face may be asymmetric, causing the
measurements to be unequal on either side. Standard tables for age related
normal values are available [1,2].
Interpupillary distance
The distance between the pupils may be measured or calculated. Direct
measurement is particularly prone to error because the child may focus on the
examiner or ruler, thus activating the normal near convergence that will bring the
eyes closer together. Distance fixation is essential to obtain an accurate mea-
surement. Other sources of error include rapid eye movements in an uncooper-
ative child, nystagmus, and strabismus. In strabismus, one can only estimate the
interpupillary distance by doubling the measurement from the center of the pupil
of the fixing (straight) eye to the midline. Although tables with age-related values
are available [1,2], one must know whether the values were obtained by direct
measurement or calculation [3]. The formula for calculation is
IPD ¼ 0:7þ ð0:59� ICDÞ þ ð0:41� OCDÞ
Palpebral fissure length
The measurement from the medial canthus to lateral canthus of one eye
determines the length of the palpebral fissure. Standard tables for age-related
normal values are available, but one must also consider racial variation [2,4].
Slanting
If the lateral canthus is below the medial canthus relative to the horizon, then the
fissure is downslanting. If the lateral canthus is higher than normal, the fissure is
upslanting. The terms Mongoloid or anti-Mongoloid slanting are no longer used.
A.V. Levin / Pediatr Clin N Am 50 (2003) 55–7656
Hypertelorism and hypotelorism
The terms hyper- and hypotelorism refer to the relative distance between the
anterior medial edge of two bony orbits (interlacrimal distance) as determined
from a plain film radiograph or computed tomographic (CT) scan. In hyper-
telorism the orbits are further apart than the normal values for age. There may be
an associated defect in the cribiform plate with or without anterior encephalocele.
Hypotelorism refers to orbits that are closer together than normal values for age,
as may be seen in association with holoprosencephaly.
Telecanthus
If the distance between the two medial canthi is relatively large as compared to
the distance between the orbits, the child is said to have telecanthus. An increased
ICD does not necessarily imply telecanthus or hypertelorism. Rather, telecanthus
is defined by a Mustarde ratio (ICD/IPD) greater than 0.55 [5]. The IPD value
should be directly measured in keeping with the original description. One should
suspect telecanthus when the lower lid puncta and its elevated papilla lie lateral to
the medial edge of the iris in the straight-ahead position of gaze. Normally, this
puncta should be medial to the medial iris edge.
Epicanthus
There are four types of epicanthal folds: inversus, tarsalis, palpebralis, and
supraciliaris [6]. Epicanthus inversus arises from the lower lid. It is the type seen
in blepharophimosis. Epicanthus tarsalis and palpebralis are the most commonly
seen, with the former being the typical fold in patients of East Asian descent.
Epicanthus supraciliaris arise from the upper lid close to the eyebrows.
Epicanthal folds are virtually never of visual significance and are so common
that, with the exception of the inversus type, they are rarely of great syndromic
diagnostic significance.
Epiblepharon
Epiblepharon is a common minor malformation that occurs when an extra
ridge of skin is found just below the lid margin of one or both lower lids, causing
the lashes to be redirected upward or back towards the cornea where trichiasis
may result in corneal damage (Fig. 1). Epiblepharon is more common in certain
countries in the Far East but may be seen in any ethnic group worldwide. With
age, the lashes tend to return to a more normal position. If the cornea is becoming
damaged, earlier surgical intervention may be necessary. Less commonly, the
upper lid may be involved.
Congenital ptosis
Children may be born with varying degrees of unilateral or bilateral ptosis
(Fig. 2). The more severe forms are characterized by a minimal or absent lid
crease reflecting the hypoplasia of the levator palpebrae muscle. These children
A.V. Levin / Pediatr Clin N Am 50 (2003) 55–76 57
have little or no ability to raise their upper affected lids and may maintain an
anomalous head position with the chin up to see out from under the droopy lids.
Affected children may also use their forehead muscles to achieve some lid
elevation, causing a typical arching of the eyebrows. These findings may occur
with either bilateral or unilateral ptosis. In the latter case, these compensatory
signs are a reassuring indication that the child is trying to use both eyes together
but does not absolutely rule out the possibility that one eye may be amblyopic.
Referral to an ophthalmologist is indicated if the margin of the upper lid is at
or lower than the center of the pupil (ie, the visual axis), a chin-lifting position for
straight ahead viewing is present, vision is subnormal on screening, other eye or
Fig. 1. Epiblepharon. Note extra skin fold (arrows) below lashes on medial aspect of lower lid. Lashes
are pointing upward instead of outward.
Fig. 2. Bilateral congenital ptosis (in Cornelia de Lange syndrome) with chin-up head posture. Note
absence of normal upper lid creases and compensatory brow arching.
A.V. Levin / Pediatr Clin N Am 50 (2003) 55–7658
lid malformations are present, the eye is red, or the child’s appearance is of
concern. Children with severe ptosis may experience lagophthalmia while
sleeping, causing the inferior cornea to be exposed and at risk of desiccation
or ulceration. Severe chin lifts may make ambulation difficult. If vision and
mobility are unimpaired, surgery may be deferred. Later surgery may have better
long-term outcomes. One must also be conscious of the need to reconstruct the
child’s appearance to normal if there is evidence of psychoemotional harm. Mild
ptosis may not cause significant impairment of lid function or appearance.
Approximately 5% to 6% of children with congenital ptosis will also exhibit
Marcus Gunn jaw winking. Because of an anomalous wiring from the motor
division of the trigeminal nerve (destined for the muscles of mastication) to the
levator palpebrae muscle in the upper lid, movement of the jaw may result in an
elevation of the lid. This movement can be observed in infancy during breast or
bottle-feeding. As children get older they may learn to hide this manifestation
through subtle compensatory maneuvers. Surgery may be performed but usually
is not required, because the appearance can improve with age. Marcus Gunn jaw
winking can be unilateral or bilateral.
Ptosis may also be associated with congenital eye-movement disorders. In
particular, one must look for deficiency of upgaze caused by either a monocular
elevation deficit or a more widespread abnormality of eye movement such as
congenital palsy of the third cranial nerve or congenital fibrosis of the extraocular
muscles. Acquired ptosis is of much more concern and should lead to consid-
eration of intracranial pathology, myasthenia gravis, and other causes of myopa-
thy such as Kearn Sayres syndrome, which is associated with heart block and
retinal dystrophy
Blepharophimosis
The combination of bilateral congenital ptosis, horizontally short palpebral
fissures, and epicanthus inversus is called blepharophimosis. The small aperture
for viewing often causes the patients to adopt a chin-up head posture, as discussed
previously. Surgery is available to correct the ptosis, elongate the fissures, and
remove the epicanthus. Strabismus may be associated with this condition.
Although the terminology in the medical literature is often used incorrectly, one
should not use the term blepharophimosis interchangeably with ptosis or with the
synonym for ptosis, blepharoptosis. Type I blepharophimosis is isolated, whereas
type II is associated with female infertility. Both types are inherited in an
autosomal dominant fashion (although type II is transmitted only by males) and
have been mapped to 3q22-23. A contiguous gene deletion syndrome at the same
locus that causes developmental delay and other features is also recognized.
Lid coloboma
Either the upper or the lower lid may have a congenital notch of the lid
margin. When the upper lid is affected, the defect is usually more medial or
A.V. Levin / Pediatr Clin N Am 50 (2003) 55–76 59
central and may have a rectangular shape. Upper-lid coloboma may be associ-
ated with attachments between the lid and the globe. It can be seen in isolation
or in association with syndromes such as the oculo-auricular-vertebral spectrum
(eg, Goldenhar syndrome). Upper-lid coloboma is usually not a cause of visual
loss. The more common lower-lid coloboma, however, may lead to exposure
damage to the inferior portion of the cornea. Lid coloboma is less of a problem
in infancy. Lower lid coloboma may occur in isolation or in association with
syndromes such as Treacher Collins syndrome (mandibulofacial dysotosis), in
which the coloboma has a typical downsweeping followed more laterally with a
sharp upsweep to the lateral canthus (Fig. 3). There may also be absence of the
lower lashes and abnormalities of the nasolacrimal system with epiphora.
Ankyloblepharon
Ankyloblepharon is an uncommon malformation, is usually seen in isolation,
and is only rarely associated with a systemic syndrome. Ankyloblepharon refers
to a residual connection between the upper and lower lid margins. Although
usually lateral to the visual axis and quite thin (Fig. 4), more extensive
ankyloblepharon may occur and obstruct vision. One must resist the temptation
simply to separate a thin strand manually. Surgical remedies have better results.
Congenital abnormalities of the anterior segment
Anterior segment dysgenesis
There are a wide variety of congenital dysgenic abnormalities of the anterior
segment in addition to aniridia and Peters anomaly. The most common (albeit
still uncommon disorder) is the Axenfeld-Reiger spectrum of disorders wherein
there may be a variety of abnormalities including a peripheral white ring on the
Fig. 3. Lower lid colobomas in Treacher Collins syndrome. Note absence of eyelashes in coloboma.
A.V. Levin / Pediatr Clin N Am 50 (2003) 55–7660
inner surface of the cornea called posterior embryotoxon (Fig. 5), abnormalities
of the pupil shape or location (Fig. 6A), polycoria (full-thickness iris defects in
addition to the pupil), or irido-corneal adhesions. There is a high association with
glaucoma, and all patients should be screened periodically by an ophthalmologist
including a consultation at first detection. The Axenfeld-Reiger spectrum of
ocular abnormalities may be part of a multisystem disorder characterized by
facial dysmorphism, redundant periumbilical skin (Fig. 6B), and dental anom-
alies (Fig. 6C). When isolated or in combination with the systemic findings,
the inheritance pattern is autosomal dominant. Multiple genes and loci have
been recognized.
Fig. 5. Posterior embryotoxon (arrows).
Fig. 4. Ankyloblepharon (arrow).
A.V. Levin / Pediatr Clin N Am 50 (2003) 55–76 61
Peters anomaly
If the separation of the lens vesicle from the surface ectoderm does not
proceed normally, the child will be born with a whitish corneal scar termed Peters
anomaly (Fig. 7). The scar is usually central and avascular, but eccentric
or vascularized variants may occur. Usually, there are also underlying irido-
corneal adhesions. The lens may be anteriorly displaced and cataractous. Peters
Fig. 6. Axenfeld-Reiger syndrome. (A) Abnormal pupil. (B) Redundant periumbilical skin.
(C) Dental malformation.
Fig. 7. Central corneal opacity in Peters anomaly. (See also Color Plate 1.)
A.V. Levin / Pediatr Clin N Am 50 (2003) 55–7662
anomaly may occur in isolation, as part of a wider ocular malformation (such as
aniridia or microphthalmia), or as part of a systemic syndrome called Peters plus
syndrome. A variety of malformations can occur in Peters plus syndrome,
including, but not limited to, skeletal dysplasia with short stature and devel-
opmental delay. A variety of genetic defects have been associated with Peters
anomaly including the PAX6 gene and a gene for congenital glaucoma, CYP1B1
[7]. Even when bilateral, however, Peters anomaly is not usually heritable.
Patients with Peters anomaly have a high risk for developing glaucoma with or
without surgery.
This opacity is almost always visually threatening, and surgery is indicated
unless other ocular malformations portend a grim prognosis. Surgical manage-
ment by corneal transplantation is complicated by the need to balance the desire
to proceed as early as possible to avoid the onset of irreversible amblyopia during
the critical first weeks of vision development with the advantages of delaying
surgery to obtain better grafting results [8]. Cataract or lens extraction may be
necessary as well. Some surgeons prefer to remove a large segment of iris (sector
iridectomy, optical iridectomy) to allow the child to see around the corneal scar
through the unaffected edges of the cornea.
Other congenital corneal opacities
There are a wide variety of congenital corneal opacities that are beyond the
scope of this article. A cornea that is not clear at birth requires urgent attention by
an ophthalmologist. If the cornea also appears large in size, one must be
concerned about the presence of congenital glaucoma. Primary abnormalities
of the cornea include congenital hereditary endothelial dystrophy (CHED) and
congenital hereditary stromal dystrophy (CHSD), both of which present as
bilateral, gray-white opacification as opposed to the more white, and often
vascularized, appearance of sclerocornea or corneal dermoid. Limbal dermoids,
most commonly seen in the oculo-auricular-vertebral spectrum, appear as raised
white masses that may have hairs emanating from their surface (Fig. 8). Although
limbal dermoids are not usually in the visual axis, they can cause amblyopia by
inducing astigmatism or ocular discomfort. Surgical excision may be required.
Congenital corneal haze may also be a secondary phenomenon caused by an
underlying systemic disorder such as metabolic storage diseases (rarely present-
ing with significant corneal haze at birth), cystinosis, congenital infection
(eg, herpes simplex virus), or by birth trauma or amniocentesis trauma. Forceps
delivery can be associated with a break in the inner corneal layer (Descemet
membrane) that can result in lost corneal clarity because of corneal edema. This
manifestation is almost always unilateral.
Persistent pupillary membranes
Persistent pupillary membranes represent an incomplete resorption of the
normal intrauterine pupillary membrane strands. Many individuals will be found
A.V. Levin / Pediatr Clin N Am 50 (2003) 55–76 63
incidentally to have visually tiny, insignificant strands attached to the collarette of
the iris, either floating in the anterior chamber or still attached across the pupil. If
a more extensive network remains (Fig. 9), vision could potentially be affected,
although, remarkably, this is usually not the case. More often, the normal
pupillary dilation and constriction to varying levels of ambient light will cause
a gradual lysing of the strands over time. Pharmacologic dilation may also be
helpful in severe cases in which there is concern about vision. If there is also
attachment to the lens with either severe miosis or cataract, surgery may be
Fig. 8. Limbal dermoid in a patient with oculo-auricular-vertebral spectrum (Goldenhar syndrome).
Note hair emanating from surface of lesion.
Fig. 9. Persistent pupillary membrane. Pupil has been pharmacologically dilated.
A.V. Levin / Pediatr Clin N Am 50 (2003) 55–7664
indicated. Persistent pupillary membranes warrant a referral to an ophthalmolo-
gist when the red reflex is significantly obscured.
Congenital cysts of the pupil margin
Congenital cysts of the pupil margin involve the posterior pigmented epithe-
lium of the iris at the pupil margin and will give the pupil margin a scalloped,
chocolate-brown appearance that is also readily noted in the red reflex. Oph-
thalmologic referral is needed only if the central visual axis is involved. The cysts
usually collapse over time and rarely require surgical intervention. Pharmacologic
dilation of the pupil may be helpful but is rarely needed.
Physiologic anisocoria
Approximately 20% to 25% of the normal population has a difference in pupil
sizes of up to 2 mm. Sometimes this difference is noticed only on careful
inspection. When the anisocoria is physiologic, the relative difference in pupillary
size will remain constant in bright and dim illumination. For example, if one
pupil is 4 mm and the other 5 mm (ie, the larger pupil is 25% bigger), then one
would expect the pupil sizes to be, respectively, 2 mm and 2.5 mm in bright light
and 6 mm and 7.5 mm in dim light. The pupils will be round, normally located,
and briskly reactive. Anisocoria, however, may also be a sign of serious ocular or
intracranial disease, and ophthalmologic consultation is advisable should there be
any doubt about the diagnosis.
Congenital cataract
Congenital cataract is found in 1:4000 to 1:10,000 live-born infants. It may be
unilateral or bilateral, isolated, or part of a long list of systemic diseases including
chromosomal aberrations, multisystem syndromes, metabolic diseases, or infec-
tious processes. It can, rarely, result from birth trauma or amniocentesis injury.
Cataract may also be part of a broader ocular malformation syndrome such as
aniridia or Peters anomaly. Radiation and steroids are common causes of acquired
cataract later in childhood. Developmental or juvenile cataract may also occur
anytime in the pediatric years. Although some authors recommend wide-ranging,
expensive testing protocols for every child with congenital cataract, this author
prefers to send the patient for further testing only when other abnormalities are
found on careful physical examination by a pediatrician. Perhaps screening for
galactosemia may be indicated in children with otherwise unexplained nuclear or
lamellar cataracts, because galactosemia is reversible with proper dietary inter-
vention. TORCH studies are notoriously unfruitful in the absence of other
supportive findings of intrauterine infection. Examination of parents and siblings
may detect visually asymptomatic cataracts that indicate a familial condition or
possibly even previously undetected visually significant cataracts in siblings.
This finding may lead to needed intervention as well as to improved genetic
A.V. Levin / Pediatr Clin N Am 50 (2003) 55–76 65
counseling. If the cataract is part of an ocular or multisystem syndrome, however,
the genetic counseling must be based on the primary diagnosis. The absence of
cataract does not rule out the possibility of a nonpenetrant carrier.
Any opacity in the lens is a cataract. If the opacity does not involve the visual
axis, the cataract may be visually insignificant and essentially harmless. Even
when central, a cataract smaller than 3 mm in size might be amenable to treatment
using an accommodation-sparing dilating drop (phenylephrine 2.5%) with or
without patching of the unaffected eye as indicated by visual progress. Cataracts
also vary in their morphology depending on the part of the lens that is opacified.
Cataracts on the anterior surface of the lens (anterior polar) include dot anterior
polar cataract (Fig. 10), anterior lenticonus (bowing forward of the anterior lens
associated with Alport syndrome), anterior pyramidal cataract, anterior subcap-
sular cataract, and anterior capsular opacity associated with persistent pupillary
membrane strands. Posterior cataracts include posterior lenticonus, posterior
polar cataract, and posterior subcapsular cataract (the most common cataract
seen in iritis or secondary to steroids). Cataracts within the lens more centrally
include nuclear cataracts (central opacities) (Fig. 11) and lamellar cataract
(involving just one layer of the onionskin-like lens layers). A discussion all of
the cataract phenotypes is beyond the scope of this article, but a wide variety of
responsible genes are being identified, including autosomal dominant, autosomal
recessive, and X-linked recessive inheritance patterns.
Visually significant congenital cataracts must be removed as early as possible,
even in the first days of life, to ensure the optimal visual outcome. Pediatricians
are critical in the early detection of cataract through their use of the red reflex test
that should be performed at every well-child visit [9]. Any abnormality of the red
reflex (asymmetry between the two eyes, white reflex, or black reflex) should
result in a prompt referral to an ophthalmologist. Cataracts cause either com-
Fig. 10. Dot anterior polar cataracts. These opacities were visually insignificant and did not require
any therapeutic interventions.
A.V. Levin / Pediatr Clin N Am 50 (2003) 55–7666
pletely black or partially black red reflexes (Fig. 12). When the red reflex is found
to be black, pediatricians may chose to instill dilating drops (phenylephrine 2.5%
or cyclopentolate 1%) and recheck the reflex 20 minutes later. If the abnormality
is still present, the child needs referral. Suspicion of cataracts in the first 3 months
of life, and in particular in the first 6 weeks, should be considered emergent,
because delayed referral can lead to permanent, irreversible failure in visual
development even with surgical intervention. In children between 3 months and
up to 1 year of age, the referral should still be considered urgent. In fact, any
Fig. 11. Visually significant nuclear cataract.
Fig. 12. Abnormal red reflex in left eye caused by congenital cataract.
A.V. Levin / Pediatr Clin N Am 50 (2003) 55–76 67
cataract during the years of visual development (up to 9–11 years old) may
benefit from expedited attention.
If the cataract is visually significant and is not amenable to pupillary dilation
and patching, surgery is the only option. Cataract surgery involves total removal
of the lens, thus rendering the patient aphakic. Visual rehabilitation involves
replacement of the lens function either through the use of glasses, contact lenses
(inserted and removed by the parents), or placement of an intraocular lens (IOL)
implant at the time of surgery. Although the use of IOL is still the subject of some
controversy [10], particularly in infants and young toddlers, most centers world-
wide are now using IOL implantation for children 2 years old or older in the
absence of iritis or other contraindications. Early attempts at IOL implantation in
infants have been very discouraging [11]. Visual outcome has been the same for
both contact lenses and IOL implantation in older children. In fact, parents are
remarkable in their ability to manage contact lenses [12]. The hardest part of
aphakic rehabilitation remains the need to patch the phakic eye in unilateral cases
[13]. Affected patients and their families may wish to consult with the Pediatric
Glaucoma and Cataract Family Association for information and support
(www.pgcfa.org).
Persistent hyperplastic primary vitreous
The intraocular fetal vasculature (hyaloid system) that runs in utero from the
optic nerve head to the back of the lens may fail to resorb, leading to a vascularized
plaque on the back of the lens (Fig. 13) termed persistent hyperplastic primary
vitreous (PHPV). Some authors have suggested that PHPV is only one variant of a
wide spectrum of disorders related to a failure of resorption of the vascular
Fig.13. Vascularized plaque on back of lens caused by persistent hyperplastic primary vitreous
(PHPV). Note also dragged-in ciliary processes. (See also Color Plate 2.)
A.V. Levin / Pediatr Clin N Am 50 (2003) 55–7668
structures surrounding the intrauterine lens [14]. The term persistent fetal circula-
tion (PFC) has been suggested as a more appropriate designation. The cause of this
malformation is unknown. It may occur in isolation or in association with other
ocular malformations. It is not considered genetic and is usually unilateral.
Bilateral cases should prompt suspicion of other ocular diagnoses or systemic
syndromes. Common features of PHPV include microphthalmia, glaucoma, miosis
with poor pupillary dilation in response to pharmacologic agents, shallow anterior
chamber (anterior bulging of the iris), and ciliary body processes drawn in towards
the pupil (Fig. 13). Special surgical techniques may be needed to enhance the
outcome [15]. Although classic teaching for many years has been that the visual
prognosis is poor, modern diagnostic and therapeutic techniques, along with early
diagnosis and prompt intervention, can result in good visual outcomes. If the retina
is involved either by scarring or detachment, however, the prognosis is poor.
Microphthalmia and coloboma
The axial length of the globe increases in a direct relationship with age until a
child is approximately 8 years old [16]. The eyeball increases 2.86- to 3.25-fold
between birth and adulthood [17,18]. The most rapid portion of this growth
occurs in the first 40 weeks of postnatal life [19]. After the age of 2 years there is
less significant growth. In fact, the globe size in a 2-year-old child is approx-
imately 80% to 90% of the adult eye size. When the axial length is shorter than
normal, the eye is said to have microphthalmia. The corneal diameter may be
small or normal. Likewise, microcornea can occur as an isolated form of anterior
segment malformation or as a manifestation of microphthalmia. One uncommon
form of bilateral microphthalmia, nanophthalmia, is caused by an autosomal
dominant disorder with abnormally thick sclera and a predisposition to the
spontaneous development of subretinal fluid with retinal detachment.
Microphthalmia may be unilateral or bilateral and may represent an isolated
primary ocular disorder, a secondary manifestation of a craniofacial disorder such
as the lateral facial dysplasias, a condition caused by intrauterine infection, or part
of a wide variety of multisystem syndromic disorders (eg, trisomy 13 and trisomy
18). Mild, isolated microphthalmia is not necessarily vision threatening. More
severe microphthalmia may indeed result in untreatable visual impairment. The
most common ocular malformations associated with microphthalmia are congen-
ital cataract (in particular nuclear cataract and PHPV) and coloboma. Coloboma
is the most commonly associated malformation and when present is probably the
primary cause of microphthalmia.
Coloboma represents a failure of fusion of the embryonic fissure (choroidal
fissure) [20]. A wide variety of multisystem syndromes may have coloboma as a
feature, perhaps the most notable of which is CHARGE association. The optic
nerve, inferior nasal fundus, or inferior iris may be involved. In its mildest form,
an optic nerve coloboma may present as a visually insignificant enlargement of
the optic disc with a large optic nerve cup. If the coloboma extends a bit more
A.V. Levin / Pediatr Clin N Am 50 (2003) 55–76 69
anteriorly, there may be an inferior disc extension with pigmentary disruption
(Fig. 14). More anterior colobomatous disruption of the fundus appears as a white
area usually surrounded by a hyperpigmented rim (Fig. 14). The primary defect in
coloboma of the fundus is a failure of the retinal pigmented epithelium (RPE,
derived from the outer layer of the optic vesicle) to fuse. Choroid does not form
over an area that is missing this RPE layer, and as a result there are no pigmented
cells (normally present in RPE and choroid) within the coloboma. The white
sclera is immediately apparent. Overlying this white sclera is dysplastic retina and
retinal blood vessels. This retina within the coloboma is prone to spontaneous
defects that may lead to retinal detachment. Therefore it is recommended that
these children be screened one or twice yearly by an ophthalmologist. If the
coloboma is large, it may encompass the macula, fovea, or optic nerve simulta-
neously, thus portending a poor visual prognosis. Sometimes, the retina and optic
nerve may be completely spared, with coloboma only of the iris resulting in a
keyhole-shaped pupil (Fig. 15). This coloboma is visually insignificant unless the
superior edge of the pupil is drawn down below the usual central location of the
visual axis, and one side is more affected than the other. All patients should have
a full early eye exam. Even in this situation, the visual outcome may be surpris-
ingly good without surgical intervention. Although surgical procedures are
available to close the defect to reconstruct the patient’s appearance, a normal
appearance can be achieved more easily by a cosmetic contact lens.
If the size of the globe is markedly smaller than normal, orbital growth may be
secondarily impaired. If there is no useful vision in the eye, a prosthetic eye
(scleral shell) may be fashioned to fit over the existing microphthalmic eye, to
provide some force to encourage growth of the orbital bones and lids. In more
severe cases, intraorbital balloon expanders may be necessary. In mild cases, use
Fig. 14. Coloboma of inferior optic nerve and, more inferiorly, retina and choroid. White area
represents sclera visible through dysplastic retina in the absence of retinal pigmented epithelium
and choroid.
A.V. Levin / Pediatr Clin N Am 50 (2003) 55–7670
of spectacles that magnify the appearance of the eye may be enough to achieve
the desired normalization of appearance.
Both isolated microphthalmia and coloboma may be inherited as autosomal
dominant conditions and, less commonly, as autosomal recessive conditions.
Although molecular genetic testing is not readily available at the time of this
writing, careful examination of parents and siblings may detect visually asymp-
tomatic coloboma that will indicate a familial condition. If these disorders are part
of an ocular or multisystem syndrome, however, then the genetic counseling must
be based on the primary diagnosis. The absence of clinical findings in a family
member does not rule out the possibility of a nonpenetrant carrier.
Congenital abnormalities of the optic nerve
Optic nerve hypoplasia
Optic nerve hypoplasia (ONH) may be an isolated unilateral or bilateral
condition or may occur in combination with abnormalities of the central nervous
system and pituitary axis (septo-optic dysplasia). When characteristic facial
dysmorphism, open anterior fontanel, and other features are present along with
septo-optic dysplasia, the term De Morsier syndrome is used, although in
common parlance this term is used interchangably with septo-optic dysplasia,
whether or not other features are present. Mutations in the HESX1 homeobox
gene have been associated with septo-optic dysplasia in some patients. The
diagnosis of ONH is made by the finding of a small optic nerve disc. Mild cases
may be visually insignificant and escape detection. More significant hypoplasia is
characterized by an absent optic nerve head cup, optic atrophy, anomalous
vascular branching patterns off the disc, and a ‘‘double-ring sign’’ representing
Fig. 15. Iris coloboma
A.V. Levin / Pediatr Clin N Am 50 (2003) 55–76 71
the intended scleral canal through which a normal sized optic nerve would have
passed (Fig. 16). When the diagnosis is in question, other studies that may be
useful are neuroimaging to evaluate optic nerve size, radiographs of the optic
canals that may be small, and examination of the nature of the macula and the
position of the fovea relative to the disc.
When the pituitary axis is involved, MR imaging may demonstrate an absent
infindibular stalk, an ectopic bright spot (representing the posterior pituitary cells)
in the stalk or hypothalamus, deficiency of the corpus callosum or septum
pellucidum, or neuronal migration defects of the cerebral cortex [21,22]. Patients
may present with poor vision, strabismus, nystagmus, growth retardation,
seizures, and manifestations of pituitary axis disruption. Sudden death, presum-
ably related to corticotropin deficiency, has also been reported [23]. Thyroid
testing is recommended. In unilateral disease, the chance of central nervous
system involvement is lower, but such involvement may occur. Patients with
unilateral ONH may respond to patching of the unaffected eye, thus reversing any
superimposed amblyopia that is contributing to visual loss.
Peripapillary pigmentary abnormalities
It is common for the optic nerve head to be partially or completely surrounded
by a hyperpigmented ring (Fig. 17). This ring represents a normal variant
developmental anomaly without functional significance. This pigmentation
may be associated with an area of retinochoroidal atrophy. When located on
the temporal side of the disc, it is referred to as a temporal crescent. Crescents are
more common in myopia.
Tilted discs
In myopic individuals, the globe is elongated. As a result, the optic nerve
enters the eye at a more oblique angle, because it comes from the nasal side of
Fig. 16. Optic nerve hypoplasia. Note anomalous vascular pattern and double-ring sign (arrows). (See
also Color Plate 3.)
A.V. Levin / Pediatr Clin N Am 50 (2003) 55–7672
the posterior pole. This exaggerated orientation causes the temporal side of the
optic nerve head to tilt away from the examiner. This malformation can
sometimes occur in the absence of myopia. It is usually not visually signifi-
cant. The malformation may make it difficult to judge the optic nerve cup
size, however.
Fig. 17. Peripapillary hyperpigmented crescent.
Fig. 18. Physiologic cupping of the optic nerve. Cup size approximately 0.70 (cup occupies
approximately 70% of the disc surface).
A.V. Levin / Pediatr Clin N Am 50 (2003) 55–76 73
Physiologic cupping
Although an increase in the cup size of the optic nerve may indicate the
presence of optic nerve disease, in particular glaucoma, it is more common in
childhood to see physiologic cupping that does not represent a disease process.
The physiologic enlarged cup usually has very sharp edges and is well demar-
cated in the optic nerve head (Fig. 18). The size of the cup may range up to 0.8
(80% of the optic nerve head surface) in some cases. The vessels may be
somewhat splayed to the edge of the cup. The finding is usually bilateral and
symmetrical but, uncommonly, can be unilateral or asymmetric. Examination of
the parents can be of great diagnostic significance, because this normal variant
may be inherited in an autosomal dominant fashion. It is important to rule out
glaucoma, and consultation with an ophthalmologist may be indicated.
Morning glory disc
Some authorities believe the morning glory disc anomaly is a coloboma
variant of the optic disc. It is characterized by an enlarged optic nerve, vessels
splayed out in a spoked-wheel configuration, and a central tuft of glial tissue over
the optic cup (Fig. 19). Although the appearance is highly abnormal, the visual
prognosis may be surprisingly good. Patching of the unaffected eye is often
needed to reverse superimposed amblyopia. Ultrasound or CT scan will dem-
onstrate a funnel-shaped, enlarged optic nerve at its entrance to the globe [20].
Fig. 19. Morning glory disc malformation.
A.V. Levin / Pediatr Clin N Am 50 (2003) 55–7674
Rarely, a morning glory disc may be a sign of a basal encephalocele, particularly
when the patient also has a notch of the central lower lip. The morning glory disc
is almost always unilateral.
Pseudopapilledema
Some normal individuals, with no evidence of increased intracranial pressure,
may have a tight- or full-appearing optic nerve that may give the illusion of
papilledema. This finding is more common in children with significant farsight-
edness (hyperopia). The nerve head may appear smaller than normal but without
the double-ring sign or other features of ONH. The disc edges may be blurry, and
the disc may appear slightly elevated, but other features of papilledema are
absent. Unlike papilledema, the blood vessels in pseudopapilledema are seen
clearly as they pass across the disc surface; the vessels are not engorged; there are
no disc or retinal hemorrhages or exudates; and there are no signs of visual
abnormality (although persons with early papilledema may also have normal
vision). Pseudopapilledema may also be caused by the presence of buried drusen;
calcific deposits in the nerve head that may give an irregular, lumpy appearance
to the nerve head or may be detectable by only ultrasound or CT scan. Rarely,
drusen of the optic nerve head can be associated with visual field defects or fluid
leakage under the retina.
Summary
Any part of the eye and its surrounding tissues may be affected by congenital
malformation. Anomalies may occur in isolation, in combination, or as part of a
systemic malformation syndrome. Early identification is essential to remove
potential obstructions to visual development and to identify potential underlying
multisystem disease. Recognition of congenital eye anomalies can also improve
parental understanding and genetic counseling.
Acknowledgement
The author is grateful for the invaluable assistance of ophthalmic
photographers Leslie MacKeen and Cynthia VandenHoven in the creation of
the images that accompany this article.
References
[1] Feingold M, Bossert WH. Normal values for selected parameters: an aid to syndrome delinea-
tion. The National Foundation/March of Dimes. Birth Defects: Original Article Series. 1974;10:
1–15.
[2] Jones KL. Smith’s recognizable patterns of human malformation, 5th edition. Toronto: WB
Saunders; 1997.
A.V. Levin / Pediatr Clin N Am 50 (2003) 55–76 75
[3] Levin AV, Seidman DJ, Nelson LB, et al. Ophthalmologic findings in the Cornelia de Lange
syndrome. J Pediatr Ophthalmol Strabismus 1990;27(2):94–102.
[4] Chouke KS. The epicanthus or Mongolian fold in Caucasian children. Am J Phys Anthropol
1929;13:255–79.
[5] Mustarde J. Epicanthal folds and the problem of telecanthus. Trans Ophthalmol Soc U K 1963;
83:397–411.
[6] Jordan DR, Anderson RL. Epicanthal folds: a deep tissue approach. Arch Ophthalmol 1989;107:
1532–5.
[7] Vincent A, Billingsley G, Priston M, et al. Phenotypic heterogeneity of CYP1B1: mutations in a
patient with Peters anomaly. J Med Genet 2001;38(5):324–36.
[8] Dana MR, Schaumberg DA, Moyes AL, et al. Corneal transplantation in children with Peters
anomaly and mesenchymal dysgeneses. Ophthalmology 1997;104:1580–6.
[9] American Academy of Pediatrics. Red reflex examination in infants. Pediatrics 2002;109(5):
980–1.
[10] Levin AV. IOL’s, innovation and ethics in pediatric ophthalmology: let’s be honest. J AAPOS.
[11] Plager DA, Yang S, Neely D, et al. Complications in the first year following cataract surgery with
and without IOL in infants and older children. J AAPOS 2002;6(3):133–5.
[12] Levin AV, Edmonds SA, Nelson LB, et al. Extended wear contact lenses in the treatment of
pediatric aphakia. Ophthalmology 1988;95:1107–13.
[13] Ma JK, Morad Y, Mau E, et al. Contact lenses for the treatment of pediatric cataracts. Oph-
thalmology, in press.
[14] Goldberg MF. Persistent fetal vasculature (PFV): an integrated interpretation of signs and symp-
toms associated with persistent hyperplastic primary vitreous (PHPV). LIV Edward Jackson
Memorial Lecture. Am J Ophthalmol 1997;124(5):587–625.
[15] MacKeen LD, Nischal KK, Lam WC, et al. High frequency ultrasound findings in persistent
hyperplastic primary vitreous. J AAPOS 2000;4(4):217–23.
[16] Kushner BJ, Lucchese NJ, Morton GV. Variation in axial length and anatomical landmarks in
strabismic patients. Ophthalmology 1991;98:400–6.
[17] Morin JD, Hill JC, Anderson JE, et al. A study of growth in the interorbital region. Am J
Ophthalmol 1963;56:895–901.
[18] Wilmer HA, Scammon RE. Growth of the components of the human eyeball. I. Diagrams,
calculations, computation and reference tables. Arch Ophthalmol 1950;43:599–619.
[19] Fledelius HC, Christensen AC. Reappraisal of the human ocular growth curve in fetal life,
infancy, and early childhood. Br J Ophthalmol 1996;80:918–21.
[20] Onwochei BC, Simon JW, Bateman JB, et al. Ocular colobomata. Surv Ophthalmol 2000;45:
175–94.
[21] Brodsky MC, Glasier CM. Optic nerve hypoplasia: clinical significance of associated central
nervous system abnormalities on magnetic resonance imaging. Arch Ophthalmol 1993;111:
66–74.
[22] Kaufman LM, Miller MT, Mafee MF. Magnetic resonance imaging of pituitary stalk hypoplasia:
a discrete midline anomaly associated with endocrine abnormalities in septo-optic dysplasia.
Arch Ophthalmol 1989;107:1485–9.
[23] Brodsky MC, Conte FA, Taylor D, et al. Sudden death in septo-optic dysplasia: report of 5 cases.
Arch Ophthalmol 1997;115:66–70.
A.V. Levin / Pediatr Clin N Am 50 (2003) 55–7676