Pi is 003139550200113 x

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.


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


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.


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).


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.)


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


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.


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


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.


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.


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.)


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


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.


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


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.)


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).


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.


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.

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