SURVEY OF OPHTHALMOLOGY VOLUME 45 • NUMBER 3 • NOVEMBER–DECEMBER 2000

MAJOR REVIEW

Ocular Colobomata
Benjamin C. Onwochei, MD,1 John W. Simon, MD,2 J. Bronwyn Bateman, MD3
Kimberly C. Couture, BS,2 and Envar Mir2

1
Family Practice Departments of Schenectady Family Health Services and St. Clare’s Hospital, Schenectady, New York;
2
Department of Ophthalmology and Lions Eye Institute, Albany Medical College, Albany, New York; and 3Department of
Ophthalmology, University of Colorado, Denver, Colorado, USA

Abstract. Ocular colobomata present diagnostic and therapeutic challenges in patients of all ages, but
especially in young children. The “typical” coloboma, caused by defective closure of the fetal fissure, is
located in the inferonasal quadrant, and it may affect any part of the globe traversed by the fissure from
the iris to the optic nerve. Ocular colobomata are often associated with microphthalmia, and they may
be idiopathic or associated with various syndromes. Types and severity of complications vary depending
on the location and size of the colobomata. This article reviews the pathogeneses, categorization,
genetic bases, differential diagnoses and management of ocular coloboma. (Surv Ophthalmol 45:
175–194, 2000. © 2000 Elsevier Science Inc. All rights reserved.)

Key words. embryogenesis • genetic disorders • microphthalmia • ocular coloboma •

ocular colobomata

Ocular colobomata are caused by defective embryo-
genesis. All layers of the eye can be involved, includ-
ing the cornea,33,102 iris, zonule and ciliary body, chor-
oid, retina, and optic nerve. Eyelid “coloboma” has
been described.85,157,168 Colobomata can be “typical”
or “atypical,” and complete or incomplete; affected
eyes are frequently microphthalmic. The etiologies of
colobomata are varied, and visual prognosis is related
to location and associated features.
I. Definition and Pathogenesis
Coloboma (plural: colobomata) is derived from the
Greek koloboma,56 meaning mutilated or curtailed. The
malformation refers to a notch, gap, hole, or fissure
in any of the ocular structures.151,157 As used in this
review, the term applies primarily to embryologic de-
fects, although it is occasionally used to describe ac-
quired iris abnormalities.
The earliest report of uveal coloboma was written
in 1673 by Thomas Bartholin (Bartholin the
younger), a Danish anatomist, who described hered-
itary iris coloboma.12,14 Coloboma is frequently asso-
ciated with microphthalmia. In a prospective study
of more than 50,000 pregnancies in the United
States,192 the incidence of anophthalmia or mi-
crophthalmia or both was found to be 0.22 per 1,000
births, and the incidence of coloboma was 0.26 per
1,000. Incidence rates found in an epidemiological
study of congenital eye malformations in 131,760
consecutive births were 1.8 per 10,000 for mi-
crophthalmia, 0.3 per 10,000 for anophthalmia, and
0.7 per 10,000 for coloboma.232,260 The prevalence of
coloboma among blind adults has been calculated at
0.6–1.9%;146 among children, it accounts for a
greater proportion of blindness (3.2–11.2%).83,86 Dif-
ferences in prevalence may reflect the race or popu-
lation studied; the highest prevalence (11.2%) was
found in visually-impaired Japanese school children.86

175
© 2000 by Elsevier Science Inc. 0039-6257/00/$–see front matter
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176 Surv Ophthalmol 45 (3) November–December 2000
Colobomata generally result from a failure of the
fetal or choroidal fissure to close61,123,171,199 during
the 5th to 7th week of fetal life, at the 7–14 mm
stage.61,123,151,248,283 This is the period between the in-
vagination of the optic vesicle and the closure of the
fetal fissure. Almost any ocular structure may be in-
volved, including the cornea,33,102 iris, ciliary body,189
zonule (lens),3,15 choroid, retina, optic disk, and/or
optic nerve. Although formation of the eyelids is in-
duced by the developing globe, there is no clear evi-
dence that the presence of eyelid coloboma is sec-
ondary to globe abnormalities.85,157,168 A rare case of
coloboma involving the inferior rectus muscle has
been reported.17 Orbital involvement may occur
with cyst formation and/or reduced orbital volume
because of a microphthalmic eye. The mechanism of
cyst formation is poorly understood, but some au-
thors have speculated that it results from prolapse of
intraocular contents through a scleral defect (mi-
crophthalmia with cyst).6,134,148,266 A more plausible
explanation is that microphthalmia with cyst repre-
sents ectasia of the colobomatous globe.9
The eye develops from three embryonic layers:
neural ectoderm, neural crest, and surface ecto-
derm, with minor contribution from the mesoderm,
which gives rise to striated extraocular muscles and
vascular endothelia.183 The neural ectoderm gives
rise to the optic vesicle and optic cup. It contributes
cells for the formation of the retinal pigment epithe-
lium, the iris sphincter and dilator muscles, the pos-
terior iris neuro-epithelium, the pigmented and
nonpigmented ciliary epithelium, and the optic
nerve fibers and glia. The lens, the corneal epithe-
lium, the lacrimal gland, the surface epidermis of
the lids, and the epithelium of the adnexal glands
and conjunctiva all arise from the surface ectoderm.
The cranial neural crest is the origin of the corneal
keratocytes; the endothelium of the cornea and tra-
becular meshwork; the iris and choroidal stroma, in-
cluding pigmented and nonpigmented cells; the cili-
ary smooth muscle; the fibroblasts of the sclera; and
the optic nerve meninges.179 Orbital fibroadipose tis-
sues, the satellite cells of the extraocular muscles,
the orbital nerves and their associated Schwann
cells, the trigeminal ganglion, and the orbital carti-
lage and bone also originate from the neural crest.183
Ocular development begins at the cranial end in a
thickened zone in the differentiating central ner-
vous system, which forms the neural folds of the
early embryo. Optic pits appear about 21 days after
conception as two depressions on the surface of the
neural fold, one on each side of the neural
groove.149,183 It has been suggested that, during de-
velopment, the eye begins as a median structure, but
it is notable that the optic pits are symmetrical and
paired right from the outset.149 These optic pits give
ONWOCHEI ET AL
rise to the two optic grooves (sulci), which, by the
beginning of the fourth week, are recognizable in
the neural folds located on each side of, and parallel
to, the neural groove at the cranial end of the em-
bryo. As these folds close, neural ectoderm evagi-
nates from each groove toward the surface. The re-
sulting spherical projections from the sides of the
forebrain are recognizable by the 25th day of devel-
opment as the optic vesicles,183 thought to be in-
duced by the adjacent mesenchyme.171 Each vesicle
is connected to the forebrain by an optic stalk, the
canal for the future optic nerve and the hyaloid ves-
sels. Cells of the optic stalk eventually form the neu-
roglial supporting tissue of the actual optic nerve fi-
bers, which are axons of the developing retinal
ganglion cells, the nerve sheaths and septa being de-
rived from the surrounding mesoderm. At the same
stage, the surface ectoderm overlying each vesicle
thickens to form a lens plate (placode). Under the
sustaining influence of the adjacent optic vesicle,
this structure subsequently invaginates to form a
lens pit.81,109 The fusion of the edges of the lens pit
gives rise to the lens vesicle.
The optic vesicle then invaginates—the original
outer wall approaching the inner wall—giving rise to
a double-layered optic cup. The lens vesicle, which
by the fourth week or 9-mm stage has been “pinched
off” the surface ectoderm, comes to lie within the
optic cup (Fig.1). The simultaneous linear invagina-
tion of the ventral surface of the optic stalk and vesi-
cle results in the formation of the fetal or choroidal
fissure. Blood vessels from vascular mesoderm grow
into the mesenchyme of the choroidal fissure. These
are the hyaloid vessels of the vitreous cavity, and
their proximal portions are destined to become the
central retinal artery and vein. The margins of the
optic cup then grow around the choroidal fissure. As
invagination progresses, the fetal fissure narrows
and closes during the fifth or sixth week. Although
closure of the fetal fissure commences during the
fifth week, it may not be complete until after the
sixth week (17-mm stage).183 A permanent opening
left at the anterior end of the optic stalk permits pas-
sage of the hyaloid vessels.
Failure of a portion of the fetal fissure to close re-
sults in the defect we recognize as an ocular
coloboma; disk coloboma results from nonclosure of
the most anterior portion of the optic stalk.10,244,246
Efforts to understand the pathogenesis of aberrant
closure have included the use of animal models. In
rabbits, prospective colobomatous embryos showed
failure of the optic fissure to fuse,253 as well as defor-
mities in the shape of the entire cup. Disturbed
growth ratios of the outer and inner layers of the op-
tic cup occurred, with the outer layer lagging be-
hind. As a result, the presumptive retinal tissue be-
OCULAR COLOBOMATA
Fig. 1. Choroidal fissure at 4-week stage of normal development.
came everted around the margin of the fissure,
partially duplicating the retina in the outer layer of
the cup.120,151 In the experimental cinnamon mouse,
homozygous for the microphthalmia gene, abnor-
mal growth and invagination led to delayed apposi-
tion of fissure margins; a failure of basement mem-
brane disintegration at the margins of the fissure was
visible by electron microscopy.110 It was suggested
that phagocytic cells may be fewer in number or may
lack sufficient enzymes for breaking down basement
membrane. In any case, the combination of delayed
apposition and failure of basement membrane disin-
tegration is thought to give rise to coloboma formation.
The eyelids develop from surface mesoderm as
mesoblastic folds, which first appear at 4–5 weeks183
and extend from above and below to meet at the
palpebral fissure.149 Fusion begins in the inner can-
thus region at the 32-mm stage, extends laterally,
and is complete at the 37–45 mm stage.183 Structures
of the lid margin (Meibomian glands, glands of Moll
and Zeiss, cilia, muscle fibers, and tarsal plates) dif-
ferentiate while the lids are fused. Epithelial adhe-
sion of the lids begins to break down by the end of
the fifth month. Failure of adhesion of the lid folds
or localized breakdown of the adhesion caused by
maternal virus infection during pregnancy149 may re-
sult in coloboma. It has been suggested that symmet-
ric temporal lower eyelid coloboma may result from
a deficiency in migration or excessive death of neu-
ral crest cells.169 Eyelid coloboma may be vascular in
some cases.
177
Coloboma of the eyelids can be partial or full
thickness, presenting as a quadrilateral or triangular
gap, broadest at the lid margin; W-shaped and irreg-
ular defects are also possible.157 They may range in
size from minute, scalloped notches to absence of
most of the lid. Lid coloboma may involve the or-
bital margin with localized absence of the eyebrow;
an anomalous wedge of scalp hair has been de-
scribed extending down the forehead toward the
coloboma.157 Lacrimal drainage anomalies may be
associated.51,143,175,250
II. Clinical Features and Complications
A. TYPICAL/ATYPICAL
The “typical” coloboma is in the inferonasal quad-
rant, caused by defective closure of the fetal fissure.
It is so named because it is the most frequent. It may
affect any part of the globe traversed by the fissure
from the iris to the optic nerve. Although iris
coloboma may be an isolated phenomenon, it is fre-
quently associated with coloboma of the ciliary body,
zonule,15 choroid, retina, and optic nerve.
Coloboma located anywhere other than the infer-
onasal quadrant of the globe is termed “atypical”
(Fig.2); the embryologic basis of this malformation
is still unclear, although several theories have been
suggested. It may represent a “rotation” of the fetal
fissure or a result of an intrauterine inflammatory
process.9,152 Atypical ciliary body coloboma may be
caused by persistence of mesodermal tissue from the
178 Surv Ophthalmol 45 (3) November–December 2000
embryonic vascular system.165 This tissue may block
the forward growth of the neuroectoderm, produc-
ing a defect in the ciliary body and iris.165 Other ocu-
lar defects, such as Peters anomaly, Rieger anomaly/
syndrome, and aniridia may be associated.91,158,160,261
Optic nerve pits may be caused by a fetal fissure
malformation.137,236 These crater-like holes or inden-
tations in the surface of the optic disk occur most
frequently in the temporal aspect of the disk and, at
least, in dogs, are more commonly seen in left eyes.20
In a series reported in humans, 57% of optic pits oc-
curred in the left eye and 43% in the right.137,236 The
reported incidence is approximately 1:10,000, with
no gender predilection.236 Whether or not optic pits
are colobomatous in origin is controversial. Many au-
thors regard them as incomplete or partial colobomata
of the optic nerve head, perhaps atypical, because of
their frequent association with other colobomata
and with inferior optic nerve crescents.36,100,137
The pathogenesis of optic pits may involve the
faulty closure of an aberrant fetal fissure, although
this has been a subject of debate. They are usually
asymptomatic, but they may be associated with cen-
tral serous retinopathy or exudative retinal detach-
ment.20,136,236,239 It has been postulated that a commu-
nication between the vitreous and/or retina and the
subretinal space may develop through the pit in
such cases.
Histologically, optic nerve pits are herniations of
dysplastic retina into a collagen-lined pocket, which
often extends posteriorly into the subarachnoid
space through a defect in the lamina cribrosa.23,163
These herniations are frequently associated with ab-
errant nerve fibers and pigmented cells, which re-
semble pigment epithelium, together with glial tis-
sue and some branches of retinal or cilioretinal
blood vessels.236 Edema and cystoid degeneration of
Fig. 2. Atypical coloboma of iris.
ONWOCHEI ET AL
the outer plexiform layer have also been described
in the macula.77
In dogs, the collective term dysplasia has been ap-
plied to abnormal development of ocular embryonal
tissue.20 The phenotypic manifestation includes op-
tic nerve pits and typical colobomata, as well as the
pathological occurrence of pigmented cells within
the optic nerve and a variety of meningeal and neu-
ral tissue anomalies.20,236,271
B. COMPLETE/INCOMPLETE
A complete iris coloboma is a full thickness defect,
involving both the pigment epithelium and the iris
stroma.184 It may be total, extending to the iris root and
giving rise to the “keyhole pupil” (Fig.3), or partial, in-
volving only the pupillary margin and causing a slightly
oval pupil. Small strands of mesodermal tissue are oc-
casionally seen bridging the coloboma and forming
multiple pupils, or polycoria. Such strands may extend
to the lens as a persistent pupillary membrane.151
An incomplete iris coloboma is usually partial
thickness, involving either the pigment epithelium
or the iris stroma.123 It tends to be wedge-shaped and
is best demonstrated by iris transillumination. Het-
erochromia iridis and colobomata have occurred si-
multaneously;58 however, whether heterochromia
represents a mild form of incomplete iris coloboma
is speculative.184,260
C. LENS “COLOBOMA”
At the 26-mm stage of embryological develop-
ment, the secondary vitreous begins to form around
the primary vitreous, arising either from the termi-
nal fibers of Mueller cells or, possibly, from the
lens.60,150,282 Organization of mesodermal tissue in
the paralenticular area results in the appearance of a
specialized region of the anterior secondary vitreous
Fig. 3. Typical complete coloboma of iris.
OCULAR COLOBOMATA
called the marginal bundle of Druault, or faisceau
isthmique. The tertiary vitreous, or zonules, develop
within this structure at 3 to 4 months’ gestation
(Fig.4). However, there is no general agreement
about whether the zonules result from local conden-
sation and differentiation of the vitreous substance
or, alternatively, are “induced” by the lens and pro-
ceed across the marginal bundle.114,150,183
Segmentally defective or absent development of the
zonules results in a “coloboma” of the lens secondary
to flattening of the equator in the region of the zonu-
lar defect.3,15,64,114 The absence of zonular fibers re-
leases tension on the lens capsule, causing the lens to
contract segmentally with a notch in the affected re-
gion. Occasionally, normal lenses in young people
can be seen to have indentations at the equator be-
tween zonular insertions.69,123,162,284 The term lens
coloboma is, thus, a misnomer because there is no ac-
tual loss of lens substance. There were no associated
abnormalities in the filtration angle, iris, or uveal tract
in the series reported by Hovland and colleagues.114
On the other hand, a ciliary body coloboma is often
seen in the area where the zonules are defective. Lens
coloboma is, therefore, more accurately referred to as
coloboma of the zonule and/or ciliary body.3,15
D. POSTERIOR SEGMENT COLOBOMA
In contrast to iris malformations, posterior segment
colobomata are more closely related to visual progno-
sis. The inner layers of the fetal fissure, comprising
Fig. 4. Normal development of the zonule.
179
progenitor neuroretinal cells, are approximated at its
margins, normally closing during the 5th or 6th week
of gestation. The neuroretinal cells then completely
cover the inside of the globe. Failure of simultaneous
fusion of the outer layers—the future retinal pigment
epithelium (RPE)—leads to coloboma involving both
the RPE and the neurosensory retina. The choroid
also fails to differentiate in areas in which the RPE is
absent, although the cause and the effect of the asso-
ciated choroidal involvement are uncertain.107,151 The
defect represents an area of bare sclera devoid of
overlying normally differentiated retina or choroid.
However, undifferentiated retinal remnants may per-
sist as a membrane, sometimes with associated retinal
vessels. The sclera in the affected area may bulge
posteriorly, forming a staphyloma which may involve
the entire posterior pole.11,126
The term choroidal coloboma is synonymous with ret-
inochoroidal coloboma.258 Coloboma of the choroid is
infrequent, occurring in only 0.14% in one large hos-
pital series.126 Histological findings include absence
of the RPE.9,258 The overlying retina is hypoplastic
and gliotic, and sometimes has rosettes. Where reti-
nal tissue is recognizable, the retinal layers are re-
versed, with the rods and cones facing inward and
the nerve fiber layer adjacent to the sclera.9 Underly-
ing choroid is either hypoplastic or absent alto-
gether. On the other hand, the RPE at the edge of
the defect is hyperplastic. The thin sclera may have
cystic spaces filled with glial proliferation, sometimes
exuberant enough to resemble a neoplasm.61,210,285
180 Surv Ophthalmol 45 (3) November–December 2000
Retinochoroidal colobomata can occur as multi-
ples, with intervening areas of normal retina (Fig.
5). Clinically, they may be identified by parents or
primary care physicians because of leukocoria. They
usually appear glistening white with definable bor-
ders, frequently with irregular clumps of pigment
along the rim. The white reflex is caused by absence
of the choroid; the underlying sclera is visible be-
cause of the atrophic or absent retina and RPE.284 A
retinochoroidal coloboma is often discovered on ex-
amination that has been undertaken because of a
more obvious iris defect; in some cases, however, the
iris is not involved. Rarely, it presents in adulthood
with visual loss related to retinal detachment.211 A
typical coloboma is located in the inferonasal quad-
rant and may extend to include part or all of the op-
tic disk (see section I.E). Clinically, chorioretinal
coloboma may be totally asymptomatic, may present
early in life as leukocoria,42 or may be diagnosed
later in life because of loss of visual acuity or visual
field.
Macular colobomata can be isolated. By defini-
tion, such defects are atypical and unrelated to chor-
oidal fissure closure. Macular colobomata are usually
bilateral, symmetrical, circumscribed and excavated
defects that involve both the choroid and retina.190,
207,226
They have been classified into three main
types: pigmented macular coloboma, nonpigmented
macular coloboma, and macular coloboma associ-
ated with abnormal vessels.153 Differentiation of iso-
lated macular colobomata from inflammatory le-
sions, such as toxoplasmosis,41,153,190 and from Leber’s
congenital amaurosis28 can be difficult. A unilateral
macular “scar,” with or without pigmenation, in the
absence of a positive family history or parental con-
Fig. 5. Retinochoroidal colobomata (with bridging nor-
mal tissue).
ONWOCHEI ET AL
sanguinity, may be consistent with healed toxo-
plasma choroiditis or healed chorioretinitis second-
ary to Toxocara canis or Toxocara cati. Specific serum
antibody titers would be confirmatory.41,190 Retinal
findings in Leber’s congenital amaurosis vary from
normal appearance280 to severe pigmentary retinop-
athy.72 Evidence of a widespread photoreceptor dis-
order is provided by an absent or markedly dimin-
ished electroretinogram (ERG).156
The visual prognosis depends primarily on the in-
volvement of the optic nerve, macula, and papulo-
macular bundle. If these structures are seriously
compromised, severe visual loss is inevitable. Bilat-
eral cases may present in infancy with poor visual
function and nystagmus. Unilateral cases may de-
velop a sensory strabismus, perhaps with superim-
posed “organic amblyopia.” If the macula is spared
and the optic nerve and papulomacular bundle are
not severely involved, typical choroidal colobomata
may remain asymptomatic.
Retinochoroidal colobomata induce absolute sco-
tomata if they are severe.65 Macular colobomata are
associated with loss of central vision. Useful periph-
eral vision may be preserved if the lesion is small.
E. OPTIC NERVE
Retinochoroidal colobomata can involve both the
macula and the optic nerve to varying degrees. Iso-
lated optic disk colobomata present as enlarged,
white, sharply delineated, bowl-shaped excavations
of the disk, 2–8 diopters in depth. Usually, a rim of
neural tissue is preserved superiorly (Fig. 6).23,191 Op-
tic disk involvement has been classified into six
types, increasing in severity from a normal disk out-
side the chorioretinal coloboma as the mildest form
to a nonidentifiable disk shape with blood vessels
emerging from the superior border of a large chori-
oretinal coloboma.96 This classification is helpful for
predicting the degree of visual impairment in optic
disk colobomata, particularly in infants and young
children whose visual acuity can be difficult to mea-
sure.29 Although the visual prognosis depends on
the severity of optic nerve involvement, some eyes
with apparently extensive optic nerve damage main-
tain surprisingly good vision.54,165
Of special importance is the association of disk mal-
formations, especially the morning glory disk anom-
aly, and congenital forebrain anomalies. Basal en-
cephalocoeles, or herniations of brain tissue, can
present as pulsating exophthalmos or as a mass in the
medial portion of the upper lid with or without hyper-
telorism. Biopsy of such masses should be avoided.95
Other craniofacial associations include cleft lip and
palate, agenesis of the corpus colosum, defects in the
sella turcica, and endocrine dysfunction.7,74
OCULAR COLOBOMATA
Fig. 6. Optic disk coloboma.
F. THE MORNING GLORY DISK ANOMALY
Morning glory syndrome was first described in
1970 in ten unrelated children with an unusual con-
genital disk anomaly.130 The morning glory anomaly
appears as a large, excavated, funnel-shaped disk
with a prominent elevated rim or ring of peripapil-
lary tissue sometimes associated with peripapillary
pigmentary mottling (Fig. 7).158 The emerging ves-
sels characteristically form a radiating pattern as
they fan out from the disk, giving the appearance of
a flower—hence, the name morning glory.181,273 As
originally described, the condition occurred unilat-
erally and was associated with either strabismus or
poor visual acuity in the affected eye. However, it
may be bilateral, and it is not always associated with
markedly diminished vision.138 The precise nature of
this developmental anomaly is still debated. While
several authors presume that a different embryo-
logic fault is involved,75,242 the morning glory anom-
aly is considered by others to be a type of optic disk
coloboma,181 and optic pits are thought to be caused
by anomalous closure of the fetal fissure involving
the disk.273
Of interest are rare case reports of morning glory
syndrome with spontaneous contractile movements
of a choroidal neovascular membrane, which
change the configuration of the optic disk.43,191 The
clinical significance of this phenomenon is unclear.
The movements have been ascribed to an anoma-
lous communication between the subretinal and
subarachnoid spaces, allowing fluid flux between the
two compartments to cause variable retinal elevation
within the excavated part of the lesion.191
G. MICROPHTHALMIA/ANOPHTHALMIA AND CYST
The term microphthalmia (or microphthalmos) de-
scribes a congenital ocular malformation in which
181
Fig. 7. Morning glory disk anomaly.
the volume of the globe is smaller than normal.13 It
has been defined as an eye with an axial length at
least 2 standard deviations below the mean for that
age group.269 Simple microphthalmia refers to a
globe that is small but otherwise normal, whereas in
complex or complicated microphthalmia there are
other associated abnormalities, including retinocho-
roidal coloboma.73,270 Axial length at birth has been
estimated to be 18 mm,31 and tables of “normal val-
ues” exist for both axial length and corneal diame-
ters,106,144 although accuracy of these figures remains
a subject of debate.79 High resolution ultrasonogra-
phy, computerized tomography, and magnetic reso-
nance imaging as means of measurement should
prove helpful in defining normal values.
The microphthalmic eye has an axial length less
than 19.2 mm at 1 year of age and less than 20.9 mm
in adulthood.73 These compare with average adult
inner sagittal diameter of 22.12 mm and outer sagit-
tal diameter of 24.15 mm.67 The term clinical anoph-
thalmia (or anophthalmos) is generally applied to ex-
treme microphthalmia in which ocular structures
are identifiable only histopathologically.260
The normal development of the lens depends
upon apposition between the surface ectoderm and
the optic vesicle,81 following resorption of the inter-
vening mesenchyme. In the absence of this apposi-
tion, residual mesenchyme proliferates, with even-
tual resorption of the developing globe, causing
anophthalmia.220 If the lens has reached a critical
size, it is retained within the optic cup and the eye be-
comes microphthalmic.135,214 Vitreous volume is lost,
perhaps because it leaks into the orbit through an as-
sociated coloboma and/or, more likely, because of
decreased production.135 Studies of the homozygous
microphthalmic (mi/mi) mouse have shown that the
cause of microphthalmia was failure of secondary vit-
182 Surv Ophthalmol 45 (3) November–December 2000
reous to develop.214 Although this sequence has been
observed primarily in animal models, it is possible
that similar events occur in the human.
Microcornea frequently occurs in association with
microphthalmia. The natural history of the growth
of the cornea in microphthalmia is not known, but it
may be similar to that in the normal eye. At birth,
the normal cornea has an average horizontal diame-
ter of 9.8 mm,18 and it attains its average adult di-
mension of 11.8 mm by the age of 2 years.68,73,118 The
horizontal and vertical corneal diameters may be dif-
ferent in microphthalmia, resulting in an oval-
shaped cornea.
Animal studies and pedigree analyses of human
families62,227 support the concept that retinochoridal
coloboma and orbital cyst are the result of the same
mechanism. Both are considered parts of the clinical
spectrum, which includes anophthalmia and mi-
crophthalmia.151,266 The embryologic relationship
between coloboma and microphthalmia is such that
causes of coloboma can also result in microphthalmia;
however, the reverse is not true. Clinical anoph-
thalmia is uncommon and total anophthalmia, with
no evidence of ocular tissue on histological study,206
is extremely rare.
Orbital cysts present in a variety of forms. A poste-
rior cyst may cause proptosis of the microphthalmic
eye and orbital contents, and an anterior cyst may be
visible as a bluish bulge in the lower lid adjacent to
the microphthalmic eye.151,266 Cysts may be attached
to the optic nerve posterior to a normal globe.132,151
Histologic examination of orbital cysts reveals an
outer layer of sclera and an inner layer of variably
differentiated retina, with or without retinal folds.5,9,
134,266
A thin-walled cyst may be devoid of discernible
differentiated ocular structures.184
H. COMPLICATIONS
Retinal detachment and cataract are the most
common complications associated with retinochor-
oidal coloboma. Rhegmatogenous retinal detach-
ments have been reported in 4–40% of cases, usually
because of breaks within or adjacent to the
coloboma.126,211,170 Occasionally, breaks are remote
from the coloboma. Of all cases of retinal detach-
ment, 0.6–1.7% are associated with retinochoroidal
coloboma.258 While some detachments may be con-
genital, resulting from incomplete attachment at the
margins of the colobomatous defect,126,254 acquired
retinal detachment is more common.211,215 One fac-
tor contributing to such detachments may be ab-
sence of the normal RPE pump.59,88,165,188,196,212 Addi-
tionally, colobomatous eyes are frequently myopic
and have vitreous syneresis,258,284 which increases vit-
reous traction. Histologic sections indicate that a
central break in the inner layer of the retina and a
ONWOCHEI ET AL
break in the outer layer at the margin of the
coloboma are both necessary to produce rhegmato-
genous detachment.215 Retinal vascular ischemia or
scleral stretching could explain the break in the in-
ner layer. The outer layer break is thought to be sec-
ondary either to vitreous traction at the margin of
the coloboma or to extension of an initially isolated
detachment to the margin of the coloboma, where
there is less glial support.215
Hovland and associates114 reported eight cases of
bilateral, congenital retinal detachments in associa-
tion with nasal “coloboma of the lens.” The detach-
ments were caused by giant retinal tears ranging in
size from 90–360⬚. Other retinal holes also were lo-
cated posterior to the giant tears in four eyes. Such
tears most commonly involved the nasal quadrants
and were related to abnormal formation of the
zonules, with adherence between the peripheral ret-
ina and the lens. The authors postulated that failure
of the normal recession of the marginal bundle of
Drault, together with persistence of the tunica vascu-
losa lentis and associated mesoderm, could have
caused such adherence and prevented the normal
apposition of the inner sensory and outer pigment
epithelial layers of the optic cup.114 Retinal detach-
ment may accompany even subtle defects in the
lens/zonule/ciliary body complex, because fluid can
gain access to the subretinal space through a break
in the nonpigmented epithelium of the ciliary
body.114,211,245 Excavated defects of the optic disk, in-
cluding congenital pits, optic nerve coloboma, and
the morning glory syndrome, have all been associ-
ated with retinal detachment.30
Nonrhegmatogenous retinal detachment occurs,
usually after infancy, in two-thirds of individuals with
autosomal dominant, isolated optic nerve coloboma.208
Savell and Cook found this condition to be hetero-
geneous, the incidence of nonrhegmatogenous reti-
nal detachment varying with the type of optic nerve
coloboma. Counseling of such patients should there-
fore be guarded. The incidence of retinal detach-
ment in nonhereditary cases of optic nerve coloboma
is unknown.54,165
Eyes with optic nerve pits are especially at risk of
retinal detachment. In such cases, a hole has been
identified in tissue within the optic cup, which pre-
sumably provides an anomalous fluid communica-
tion between the developing subretinal and either
the subarachnoid space or the vitreous compart-
ment.49,123,211 Dog studies have documented congeni-
tal colobomata associated with scleral ectasia and ex-
tensive retinal detachment. In some, “crater-like
holes” were present in the optic disk.198
Retinal dysplasias are commonly noted at the bor-
der of retinochoroidal colobomata, and may be asso-
ciated with intrauterine or neonatal retinal detach-
OCULAR COLOBOMATA
ments.258 Coloboma with retinal glioma has been
described in tuberous sclerosis.139 Although both ret-
inoblastoma and uveal coloboma are part of the 13q-
deletion syndrome,180 this combination has occa-
sionally been reported in patients with a normal
karyotype.159 In addition to a high resolution karyo-
type, a molecular genetic examination may be neces-
sary to eliminate the possibility of a 13q-deletion in a
patient with retinoblastoma and microphthalmia or
coloboma.
Subretinal neovascularization causing serous mac-
ular detachment has also been reported in a num-
ber of adults and at least one infant as a complica-
tion of retinochoroidal coloboma.27,141 For unknown
reasons, the neovascular membrane tends to de-
velop at the superotemporal edge of the coloboma.27
It is comparable to the choroidal neovascularization
associated with high myopia, angioid streaks, choroi-
dal ruptures, and choroiditis.201 It is thought that the
abrupt termination and abnormal architecture of
the RPE and Bruch’s membrane at the margin may
predispose to the development of subretinal neovas-
cularization.95,145 Treatment with laser photocoagula-
tion may preserve good vision in affected eyes.145,231
A variety of cataracts have been associated with
coloboma, including isolated pigment clumping on
the lens capsule at the equator, subcapsular and cor-
tical opacification, anterior and posterior polar cata-
racts, and total opacification. Lens subluxation oc-
curs infrequently.15,114,119,245 Secondary glaucoma
(and related angle abnormalities), amblyopia, ani-
sometropia, and sensory strabismus may occur.2,40,44,
87,139,147,176,177
Finally, a large upper eyelid coloboma
may be associated with exposure keratopathy and
even corneal ulceration if left untreated.247
III. Etiology and Patterns of Inheritance263
A. ISOLATED OCULAR MONOGENIC SYNDROMES
1. Autosomal Dominant Inheritance
Autosomal dominant colobomatous microphthalmia
without associated systemic malformations has been
well established.80,184,190 Variable expressivity, from
small iris or choroidal colobomata to clinical anoph-
thalmia or orbital cyst, has been reported;80,184,266 in-
complete penetrance is common.80 The parents of
children with isolated colobomatous microphthalmia
should be examined carefully for minor ocular mal-
formations. Incomplete penetrance reduces the risk
that the offspring of an affected individual will have
colobomatous microphthalmia. In a family with an
autosomal dominant inheritance pattern, it was esti-
mated that any individual with a normal ocular ex-
amination has an 8.6% chance of having an affected
child.184 Macular coloboma may be inherited as an
autosomal dominant disorder76,207 and usually is not
183
associated with microphthalmia. Although autoso-
mal dominant transmission is most common, autoso-
mal recessive colobomatous microphthalmia has
been reported as a syndrome associated with skeletal
anomalies.241
Coloboma of the optic nerve is usually unilateral,
but some cases are bilateral and may be asymmet-
ric.121 Both optic nerve and uveal coloboma may be
inherited as autosomal dominant syndromes,208,262 as
illustrated by the colobomatous microphthalmia
with microcornea syndrome.14,186 However, autoso-
mal recessive and X-linked recessive inheritance pat-
terns have been described.121 In most cases, a heredi-
tary pattern cannot be established.
2. Autosomal Recessive Inheritance
Pedigrees supporting nonsyndromal autosomal
recessive inheritance of microphthalmia are few,
and many lack careful documentation of the ocular
status of the parents.166 Several consanguineous Is-
raeli families established this form of inheritance.192,
290
Additional evidence is from the study of more
than 1300 Japanese patients with microphthalmia;
segregation analysis indicated a recessive form of in-
heritance in 12%.86 However, there was no distinc-
tion between the colobomatous and noncoloboma-
tous forms and associated malformations were not
discussed.
B. MULTISYSTEM MONOGENIC SYNDROMES
1. Autosomal Dominant Inheritance
The basal cell nevus (carcinoma) syndrome is
characterized by multiple basal cell carcinomas, dys-
keratotic cysts of the jaw, rib and spinal anomalies,
and pits of the hands and feet; mental retardation
may be present.99 Penetrance is high; variable ex-
pressivity has been observed, and the diagnosis may
be made if two major features are present. This syn-
drome may be associated with multiple ocular anom-
alies. The basal cell carcinomas, which cannot be dif-
ferentiated histologically from nongenetic forms,
usually appear in childhood and frequently involve
the eyelids. Affected individuals should be moni-
tored for malignant transformation of nevi. Coloboma-
tous microphthalmia, as well as congenital cataract
and strabismus, have been recorded in this syn-
drome.98,256 The gene has been mapped to the long
arm of chromosome 9.50
Congenital contractural arachnodactyly, charac-
terized by a Marfanoid body habitus and multiple
congenital joint contractures, may be associated with
uveal colobomata. Dislocated lenses are not a fea-
ture of this syndrome.11 The gene defect is in the
connective tissue protein fibrillin and has been
mapped to chromosome 5.243
184 Surv Ophthalmol 45 (3) November–December 2000
Optic nerve coloboma combined with renal anom-
alies has recently been described.57,71 In addition to
renal hypoplasia and vesiclo-ureteral reflux, patients
may have genital anomalies, high-frequency hearing
loss, and central nervous system anomalies. Mutation
in the PAX 2 gene is thought to be responsible.
2. Autosomal Recessive Inheritance
The Meckel-Gruber syndrome, which consists of mi-
crocephaly; occipital encephalocele; congenital heart
defects; polydactyly; facial clefts; and polycystic disease
of the kidneys, liver, and pancreas is commonly associ-
ated with colobomatous microphthalmia.147,182 This
syndrome, phenotypically similar to trisomy 13, usually
is fatal during the first few weeks of life. Mi-
crophthalmia, with or without coloboma, occurs in
approximately 15% of patients.97
The Sjogren-Larsson syndrome, described in 1949,
is characterized by colobomatous microphthalmia
and mental retardation.224 This syndrome is not asso-
ciated with other systemic abnormalities. Few subse-
quent reports have appeared.223
Humeroradial synostosis, characterized by re-
duced or absent flexion and extension at the elbow,
may be associated with microcephaly, occipital men-
ingocele, and colobomatous microphthalmia.209
The inheritance pattern has not yet been confirmed,
although an autosomal recessive form has been
suggested.129,195
Hunter and colleagues117 have described two sib-
lings, a boy and a girl, with multiple minor dysmor-
phic features (frontal bossing, high arched palate,
anteverted nares, hypertelorism, and carp mouth),
colobomatous microphthalmia, congenital hepatic
fibrosis, polycystic kidney disease, and diffuse en-
cephalopathy. Autosomal recessive inheritance is
presumed. However, the nonocular manifestations
may be similar to those found in both the Zellweger
and the Meckel-Gruber syndromes; the Zellweger
syndrome has not been associated with uveal
coloboma.
Cohen and coworkers48 described several children
with mental retardation and retinitis pigmentosa,
who also had hypotonia, obesity, prominent incisors,
and colobomatous microphthalmia. Inheritance was
presumed to be autosomal recessive, as male and fe-
male siblings were affected.
An autosomal recessive form of the oral-facial-digi-
tal syndrome (type VIII) may be associated with
uveal colobomata.124
Rarely, colobomatous microphthalmia may be as-
sociated with an autosomal recessive chondrodyspla-
sia punctata syndrome.241
Walker-Warburg syndrome, or type II (Walker) lis-
sencephaly, includes optic nerve colobomata, hydro-
cephalus, and agyria. Other ocular anomalies include
ONWOCHEI ET AL
Peters anomaly, persistent hyperplastic primary vitre-
ous, retinal dysplasia, retinal detachment, and optic
nerve hypoplasia. Magnetic resonance imaging shows
a smooth cerebral surface and cerebellar hypoplasia
with absence of the posterior vermis. The disorder is
usually fatal before the first birthday.24,74
3. X-Linked Inheritance
The Lenz microphthalmia syndrome is inherited
as an X-linked recessive disorder. Carrier females
are not phenotypically identifiable, although they
may have early cataracts. Microphthalmia, with or
without coloboma, is a fundamental manifestation
of the disorder; congenital cataracts and clinical
anophthalmia113,142 also have been reported. The oc-
ular manifestations are relatively consistent within a
family, as are short stature, cylindrical thorax, and
widely spaced teeth. Additional features in affected
males may include mental retardation, microcephaly,
asymmetric or dysmorphic ears, and dental anoma-
lies. Genitourinary abnormalities, such as renal agen-
esis or hypospadias, also have been described. It is
not yet clear whether more than one genetic locus is
involved or whether the variability reflects different
alleles (mutations) at the same site.37,94,113
The Aicardi syndrome includes optic disk and/or iris
colobomata in association with chororetinal lacunae.
Other ocular abnormalities include microphthalmia,
orbital cyst, pseudoglioma or retinal detachment,
and cataract. Systemic findings include vertebral
anomalies, dysmorphic features, microcephaly, and
mental retardation. The inheritance is thought to be
X-linked dominant, the mutation lethal in males.25,65,
95
Focal dermal hypoplasia is an X-linked dominant
disorder characterized by linear regions of dermal
atrophy that become progressively hyperpigmented,
mucous membrane papillomas, and abnormalities
of the extremities, particularly syndactyly, polydac-
tyly, or oligodactyly.28,264 Most affected individuals
are female and it has been postulated that the trait is
lethal in males. Colobomatous microphthalmia is a
common manifestation.
MIDAS syndrome (an acronym for microphthalmia,
dermal aplasia, and sclerocornea) is a term that has
been proposed105 for an X-linked dominant male-
lethal trait distinct from focal dermal hypoplasia.
The gene defect can be assigned to Xp22.3. Clinical
features include bilateral microphthalmia with ble-
pharophimosis, linear lesions of dermal aplasia in-
volving the face, and microcephaly; major congenital
heart defects also may be associated.105 It is often
called the MLS syndrome (microphthalmia with lin-
ear skin defects).8,164
The Catel-Manzke syndrome, characterized by in-
dex finger hyperphalangy with the Pierre-Robin se-
OCULAR COLOBOMATA 185

quence, has been associated with colobomata.275 An
X-linked recessive pattern has been postulated.
A male with an X-linked recessive oto-palatal-digi-
tal syndrome (type II) with cerebellar hypoplasia/
hydrocephalus and iris colobomata has been re-
ported.233 The patient had two similarly affected ma-
ternal uncles, who died as neonates. The authors
postulated a chromosomal deletion, but this could
not be confirmed microscopically.
Many individuals with the Pai syndrome have
colobomatous microphthalmia.204 Affected individu-
als have medial cleft of the upper lip, cutaneous fa-
cial polyps, and lipoma of the corpus callosum; the
inheritance pattern is uncertain and may be autoso-
mal dominant.
Frontonasal dysplasia may be associated with men-
tal retardation and uveal colobomata.240

5. Chromosomal Aberrations
4. Unknown Etiology
Multiple chromosomal aberrations that have been
The CHARGE association derives its acronym associated with colobomatous microphthalmia125,265
from the nonrandom grouping of a series of fea- are summarized in Table 1.
tures: colobomatous microphthalmia, heart defects, Although some disorders, such as trisomy 13 or
choanal atresia, retarded growth, genital anomalies, the 4p-syndrome, have specific clinical features that
and ear anomalies or deafness. Generally, at least may alert the physician to the diagnosis, many of
three of the features are necessary for the diagno- these syndromes are nonspecific. The physician,
sis.104,185,259 Cranial nerve paresis or palsy is com- whether an ophthalmologist or a primary care physi-
mon.34 The cardiac defects are varied and may be le- cian, should consider the possibility of a chromo-
thal. It has been postulated that the syndrome is somal disorder in individuals who have coloboma-
caused by an insult during the second month of tous microphthalmia with developmental delay or
gestation185 or that it is genetic with autosomal domi- any other malformation. A high resolution karyo-
nant inheritance.167 Sporadic and autosomal recessive type should be performed.
inheritance patterns also have been described.111,249
Some chromosomal syndromes, including trisomies
13 (Patau syndrome) and 18 (Edwards syndrome),
4p- (Wolf-Hirschhorn syndrome), and the cat-eye TABLE 1
syndrome, exhibit some similar features and a chro- Chromosomal Aberrations That Have Been Associated with
mosomal analysis should be performed. Colobomatous Microphthalmia
The epidermal nevus syndrome (also known as
Triploidy44,87
the linear sebaceous nevus syndrome, or nevus sebaceous Trisomies
of Jadassohn) is characterized by one or more linear Trisomy 1345
epidermal nevi. Some individuals also have a seizure Trisomy 18173
disorder and developmental delay. The diagnosis Trisomy 224
Duplications
usually is evidenced at birth by the presence of the
Duplication 4q⫹278
sebaceous nevus, a yellowish lesion with abundant Duplication 7q⫹251
sebaceous glands and immature hair follicles. A mid- Duplication 9p⫹197
line lesion on the face is common. At puberty, papil- Duplication 9p⫹q⫹216
lomatous epidermal hyperplasia develops. Malig- Duplication 13q⫹115
Duplication 14q⫹1
nant transformation may occur in the postpubertal
Duplication 22q⫹255,289
period.230 Rarely, colobomatous microphthalmia Deletions
may be an associated finding.155 Deletion 2p22268
Colobomatous microphthalmia may occur un- Deletion 4p⫺274
commonly in association with the Rubinstein-Taybi Deletion 4del110 (q12q12.1)53
Deletion 4r38
syndrome.89,101,202,203 Affected individuals have char-
Deletion 5(q15q22)288
acteristic facies, including a broad nasal bridge, Deletion Dq⫺35
prominent forehead, beaked nose, broad thumbs Deletion Dr229
and first toes, and mental retardation. The etiology Deletion 11q⫺78
is unknown and none of the affected individuals Deletion 13q⫺180,279
Deletion 13r⫺205
have reproduced offspring.
Deletion 18q⫺213
Two unrelated children with macrosomia, obe- Deletion 18r286
sity, macrocrania, and colobomata have been de- Pericentric Inversions
scribed.172 The acronym MOMO was suggested and Inv(6)(p23q23.1)272
the authors postulated an autosomal dominant form XY Anomalies
XYY131
of inheritance.
186 Surv Ophthalmol 45 (3) November–December 2000 ONWOCHEI ET AL

C. ENVIRONMENTAL CAUSES AND IV. Evaluation and Treatment

INTRAUTERINE INSULTS
A. EYELIDS
Although environmental influences would seem
Congenital defects in the eyelid are not related to
plausible in sporadic cases of colobomatous mi-
the fetal fissure. Upper lid colobomata are more
crophthalmia, few specific embryopathic agents
common and, with the exception of an association
have been identified. To date, thalidomide “A” is the
with Goldenhar syndrome, are generally isolated.32,
only documented environmental cause of coloboma 193
They occur at the junction of the inner and mid-
in humans with or without phocomelia.225 A pro-
dle thirds, tend to be full thickness, and have normal
spective study of individuals with established thalido-
adjacent lid margins.51,143 In contrast, lower lid
mide embryopathy documented two patients with
colobomata, sometimes symmetrical,169 are often as-
isolated coloboma of the optic disk, and another
sociated with mandibulofacial dysostosis (Treacher-
with coloboma of both the uvea and optic disk.235
Collins Syndrome).32,39 They occur most frequently
The effect of thalidomide was thought to have oc-
at the junction of the middle and lateral thirds, and
curred early in the teratogenic period, perhaps dur-
tend to be partial thickness, involving preferentially
ing the 4th week of development.
the anterior lamella.175 Notably, eyelid colobomata
Intrauterine vitamin A deficiency in humans also
have not been associated with focal dermal hypopla-
has been implicated.140 This observation has been
sia (Goltz-Gorlin syndrome), which affects tissues of
supported by the finding of colobomatous mi-
meso-ectodermal origin, despite its ocular associa-
crophthalmia in the offspring of rats deprived of vi-
tions that include other lid abnormalities.103,154
tamin A during pregnancy.277
Treatment of eyelid defects depends on the extent
Use of anticonvulsants in pregnancy, notably
of involvement and the risk of corneal decompensa-
diphenyl hydantoin and carbamazapine, has been
tion.143,175 Infants generally tolerate relatively large
associated with increased risk of systemic and ocular
defects well,287 especially if only the lower lid is in-
abnormalities, including cardiovascular and renal
volved.187 Initial therapy should be conservative, con-
defects, cleft lip and palate, hyperteliorism, ptosis,
sisting of topical lubricants, bandage contact lenses,
strabismus, and retinochoroidal colobomata.238,257
and/or moisture chambers fabricated with plastic
A variety of ocular anomalies have also been related
food wrap and ointment. Surgical repair is war-
to the fetal alcohol syndrome, including microph-
ranted if corneal decompensation is caused by dehy-
thalmia, microcornea, and uveal colobomata.234
dration and/or trichiasis. Eyelid sharing procedures
Infectious embryopathic agents, such as cytomega-
should be considered carefully in young children be-
lovirus,84,112,161 Epstein-Barr virus,93 varicella-zoster
cause of the risk of occlusion amblyopia during the
virus, and herpes virus,228 may be associated with
healing phase.39,133,143,175,187 Small defects can be
noncolobomatous microphthalmia. Although their
closed in a one-stage procedure by direct apposition
causality is controversial, maternal fever during
of the edges after they are mobilized and “fresh-
pregnancy and prenatal irradiation have been impli-
ened.” A moderate sized coloboma, up to 70% of the
cated.82,122 In animal models, ocular teratogens caus-
lid, can be closed by fashioning a pentagonal lid de-
ing noncolobomatous microphthalmia have in-
fect to facilitate reapproximation; a lateral cantholy-
cluded folic acid deficiencies (rat),92 irradiation
sis may be required. Closure of larger defects may
(rat),276 exposure to nickel carbonyl (rat),237 and ele-
necessitate a sliding myocutaneous flap or a full-
vated incubation temperatures (chick).178
thickness lid-sharing operation, such as the Cutler-
Several mechanisms have been proposed for the
Beard procedure or modifications.32,64,133,143,175
formation of lid colobomata in utero. The craniofa-
cial and limb abnormalities in the amniotic band
syndrome are caused by constrictive intrauterine B. IRIS
bands. Pressure over the eyelid and eye may cause an Because the iris defects themselves impose no vi-
eyelid coloboma or microphthalmia.128 As described sual defect, treatment is indicated only for cosmesis.
in the Goldenhar syndrome, eyelid hematomas may One useful approach is to fit a cosmetic contact lens
be responsible for asymmetric eyelid defects.193,219 Bi- (Fig.8) that resembles a normal iris and is designed
lateral defects are more likely to have a genetic basis. to match the fellow eye in appearance.46 Such lenses
The gene for Treacher-Collins syndrome has been can be optically corrective. Cosmetic contact lenses
cloned and encodes a low complexity protein;55,281 also are useful for microcornea associated with
lower lid coloboma is often associated. Other possi- coloboma and microphthalmia.
ble causes include infections or inflammation,200 fail- Surgical treatment of iris colobomata may be un-
ure of fusion of the eyelid folds,66,193 compromised dertaken as part of cataract extraction or penetrat-
placental circulation,200 vitamin A toxicity,193 and vi- ing keratoplasty at any age.19,252,267 Surgical repair is
tamin deficiency.200 not generally performed unless other intraocular
OCULAR COLOBOMATA
Fig. 8. Colobomatous microphthalmia with cosmetic
contact lens.
surgery is indicated. After implantation, the
coloboma may be repaired with nonabsorbable su-
tures. Posterior chamber lens implantation in the
capsular bag is preferred by many cataract sur-
geons.16,116,252 If zonular integrity is insufficient, sul-
cus placement or anterior chamber implantation
could be considered. Ideally, haptics should be
placed 90 degrees from the defect to stabilize the im-
plant, and larger lens implants are preferred to min-
imize glare.218,288 Repair of iris colobomata is helpful
to provide a stable platform for anterior chamber
lens implantation and may prevent progressive syne-
chia formation and secondary angle closure.47,218,288
Intraocular surgery in patients with cataract and
microphthalmia may be complicated by postopera-
tive uveal effusion, retinal detachment, intraocular
hemorrhage, and malignant glaucoma. Prophylac-
tic previous or simultaneous sclerotomy or sclerec-
tomy has been advocated to reduce the incidence of
postoperative uveal effusion.21,22,127
C. ZONULE AND CILIARY BODY
“Coloboma” of the lens is secondary to zonular
and ciliary body defects; no lens tissue is missing. In
rare cases, coloboma affecting the zonule is associ-
ated with superior lens subluxation.245 Lens extrac-
tion is indicated for cataract or subluxation if visual
function is sufficiently compromised.52,123,245 Coloboma
is the most common congenital defect in the ciliary
body,165 involving both mesodermal and neuroecto-
dermal elements.63,165 Ciliary body coloboma may be
visible through the overlying iris coloboma as white
lesions with varying degrees of pigmentation at the
margins related to hyperplasia of pigment epithelial
cells.45,63,165
There is no specific treatment for ciliary body
colobomata and restoration of defective zonules is
187
not possible.180 Lens implant surgery may be higher
risk because of absent zonules.
D. RETINOCHOROIDAL
Retinal detachments have long been a recognized
risk of retinochoroidal cholobomata, with an inci-
dence of 23–42%.126,188 In patients under 30 years of
age, coloboma-associated retinal detachments are
more common in males.258 The incidence of retinal
breaks is doubtless higher, as many of these may be
asymptomatic and unassociated with detachments.
Most holes are atrophic, without operculae, and may
be hidden near the edge of the coloboma or under a
hemorrhage.126,253 These breaks may therefore be
difficult to localize, because there is little contrast in
the colobomatous area, and patients may have nys-
tagmus.221,258 Additional technical difficulties in-
clude ectatic sclera, absence of choroid, and thinned
retina.
Prophylactic laser treatment applied posteriorly
along the edge of the coloboma and cryopexy anteri-
orly has been recommended.188 A complication of
such treatment is the creation of nerve fiber bundle
defects in eyes with already compromised visual
fields.188,211,258
In cases requiring surgery, the preferred initial
treatment is laser photocoagulation. Vitrectomy and
air-fluid exchange with a buckle may be indicated
subsequently, and are more successful than scleral
buckling alone.258 Colobomatous eyes tolerate buck-
ling surgery poorly, with success rates ranging from
37% to 70%.258 One useful technique to localize reti-
nal holes during vitrectomy is to aspirate subretinal
fluid from within the vitreous; the yellow color indi-
cates the location of the break.188 The prognosis fol-
lowing vitrectomy is better in older patients, who are
able to tolerate the face-down head positioning after
surgery. Optic nerve sheath fenestration has report-
edly led to reattachment in a few cases of optic nerve
pit associated detachment;54,211 however, these suc-
cesses are difficult to validate, because spontaneous
retinal reattachment can occur.217
In cases with associated severe microphthalmia,
treatment during infancy with cosmetic scleral shells
may be helpful. With periodic refitting, this method
may promote the development of symmetrical ocu-
lar appearance without the need for surgery.194
In colobomatous microphthalmia the size of the
orbit varies from normal or near normal to very
small. An eye with normal function is more likely to
have normal-sized fornices and orbit.174 When indi-
cated, gradual expansion of the fornices may be ac-
complished by the use of progressively enlarged
ring-type prostheses from the age of a few months,
so that a specially shaped normal size prosthesis can
eventually be fitted in the socket.174 Orbital growth
188 Surv Ophthalmol 45 (3) November–December 2000
has been successfully induced by the implantation of
a 4-ml spherical intraorbital tissue expander with a
remote saline injection port in a series of patients
between the ages of 4 months and 8 years.70 Dermis-
fat graft implantation108 and intraorbital balloon
techniques90 also have been employed.
E. OPTIC NERVE
Colobomata, pits, and morning glory malforma-
tion of the optic nerve have all been associated with
serous retinal detachments. These detachments are
nonrhegmatogenous, and spontaneous reattach-
ment has been known to occur. Optic nerve sheath
fenestration has been advocated by some.54,211
F. GENERAL
Evaluation should be performed expeditiously if
there is a threat of corneal decompensation from an
eyelid coloboma. Meticulous evaluation of infants
with colobomata is typically difficult, given their lack
of cooperation, nystagmus and micropthalmos. In-
deed, effective examination may be impossible with-
out general anesthesia. Slit-lamp examination can
then aid in defining anterior segment manifesta-
tions. Choroidal, retinal, and optic nerve involve-
ment can be studied with direct and indirect oph-
thalmoscopy. Accurate refraction is essential, as
amblyopia can be induced by anisometropia or by
bilateral high ametropia. Computerized tomography
or magnetic resonance imaging can be useful in de-
fining microphthalmia and associated CNS malfor-
mations. Axial length can be measured by high reso-
lution ultrasonography. Older patients can have
their visual fields assessed. Inferior retinal colobomata
are associated with superior defects.222
Fundamental in the treatment of children with
colobomata is a determination regarding visual
prognosis. It is advisable for the parents to be in-
cluded in this discussion from an early stage, and for
them to have the benefit of second opinions if it is
determined that an eye will not be visually useful.
Such determination, however, can facilitate cos-
metic treatment of severe microphthalmia with
scleral shells. With periodic refitting, this method
may promote the development of symmetrical ocu-
lar appearance without the need for surgery.194
When indicated, gradual expansion of the fornices
may be accomplished by the use of ring-type pros-
theses.174 Orbital growth has also been induced by
the implantation of spherical intraorbital tissue ex-
panders with remote saline injection ports,70 intraor-
bital balloon devices,90 and dermis grafts.108
Children with severely limited visual prognosis in
one eye should be fitted with safety glasses by the
ONWOCHEI ET AL
time they are independently active, and should wear
goggles for sports. Although amblyopia may be un-
treatable, in some cases a trial of part-time occlusion
may help to show the parents the inevitability of
poor vision in the affected eye. Strabismus can be
treated surgically if necessary. In some cases, specta-
cle correction of hyperopia in the normal eye may
correct accommodative esotropia. Children with nys-
tagmus can be treated surgically, especially if a com-
pensatory face turn is induced.221
V. Differential Diagnosis
Colobomata of the eyelids can be mistaken for
congenital amniotic band syndrome, eyelid trauma,
entropion and, in cases presenting with involvement
of the lacrimal drainage system, blocked tear ducts.
Iris abnormalities in aniridia, heterochromia irides,
iris nevi, iris trauma, iris atrophy, and Rieger syn-
drome can mimic a coloboma. In young people, nor-
mal lenses with indentations at the equator between
zonular insertions can be mistaken for “coloboma”
of the lens.69,162 Retinochoroidal colobomata are eas-
ily differentiated from inflammatory lesions and all
the other causes of leukocoria.
The morning glory disk anomaly has been occasion-
ally confused with optic nerve coloboma.181 A differen-
tial diagnosis has been published by Brodsky, Baker,
and Hammed.26 Morning glory disks are surrounded
by an annular zone of pigmentary disturbance,
whereas colobomatous disks have a paracentral defect,
typically inferior, with minimal parapapillary pigmen-
tary disturbance. Morning glory disks have anoma-
lous retinal vessels and a central glial tuft, neither of
which is typical of colobomatous disks.
Congenital optic pits and optic nerve staphylo-
mata can also be confused with optic nerve
colobomata. A staphyloma is a deep fundus excava-
tion surrounding the optic disk, which itself may be
normal or show only mild temporal pallor.26 Optic
pits are round or oval gray, white, or yellowish de-
pressions within the substance of the optic nerve.
Some believe they are similar to colobomata in that
they may represent anomalous closure of the fetal
fissure involving the disk.273
Optic nerve coloboma, congenital optic pits, and the
morning glory disk anomaly may be confused with
each other and with staphyloma of the optic nerve.
In most cases the diagnosis is made clinically
based on the appearance of the lesions themselves.
Imaging studies are sometimes required. In the case
of inflammatory lesions, specific titers or appropri-
ate cultures can be helpful diagnostically.
VI. Conclusion
Ocular colobomata are often associated with mi-
crophthalmia. They are common congenital malfor-
OCULAR COLOBOMATA
mations which may occur as an isolated ocular
anomaly or in association with multisystem anoma-
lies. Although most cases are idiopathic, there are
many associated syndromes.
There is wide variation in severity, ranging from a
small iris coloboma to a defect that causes profound
visual impairment. Treatment is dependent on loca-
tion and severity. A genetic evaluation is warranted
in all cases.
Method of Literature Search
Medline and Ovid were used to search literature
from 1966 to the present. Supplemental sources in-
cluded Index Medicus and references in identified
articles. Key words used were coloboma, microphthalmia,
and named syndromes. One Russian article was trans-
lated. The English abstracts of other foreign lan-
guage articles were used.
References
1. Abeliovich D, Yagupsky P, Bashan N: 3:1 meiotic disjunc-
tion in a mother with a balanced translocation, 46, XX, t(5,
14)(p15;q13) resulting in tertiary trisomy and tertiary
monosomy offspring. Am J Med Genet 12:83–9, 1982
2. Allderdice PW, Davis JG, Miller OJ, et al: The 13q-deletion
syndrome. Am J Hum Genet 21:499–512, 1969
3. Amari F, Segawa K, Ando F: Lens coloboma and Alport-like
glomerulonephritis. Eur J Ophthalmol 4:181–3, 1994
4. Antle CM, Pantzar JT, White VA: The ocular pathology of
trisomy 22: report of two cases and review. J Pediatr Oph-
thalmol Strabismus 27:310–4, 1990
5. Arstikaitis M: A case report of bilateral microphthalmos
with cysts. Arch Ophthalmol 82:480–2, 1969
6. Bakir M, Sarialioglu F, Bilgic S, Akhan O: Microphthalmos
with bilateral colobomatous orbital cyst accompanied by
polycystic kidney disease and vacuolization of myeloid pro-
genitor cells. Acta Paediatr 81:1054–7, 1992
7. Bakri SJ, Siker D, Masaryk T, et al: Ocular malformations,
moyamoya disease, and midline cranial defects: a distinct
syndrome. Am J Ophthalmol 127:356–7, 1999
8. Ballabio A: MLS, Aicardi and Goltz syndromes: how many
genes involved? [letter]. Am J Med Genet 59:100, 1995
9. Barber AN: Embryology of the Human Eye. St. Louis, CV
Mosby, 1955, pp 50–63
10. Barber AN: Embryology of the Human Eye. St. Louis, CV
Mosby, 1955, pp 105–115
11. Bard LA: Congenital contractual arachnodactyly and in-
traocular colobomas. Birth Defects: Original Article Series
XV-5B:189–205, 1979
12. Bartholin T: Acta Medica et Philosophica Hafniensia.
Hafnie Sumptibus Petri Haubold, 1673, pp 62–63
13. Bateman JB: Microphthalmos. Int Ophthalmol Clin 24: 87–
107, 1984
14. Bateman JB, Maumenee IH: Colobomatous macrophthalmia
with microcornea. Ophthalmic Paediatr Genet 4:59–66, 1984
15. Bavbek T, Ogut MS, Kazokoglu H: Congenital lens coloboma
and associated pathologies. Doc Ophthalmol 83:313–22, 1993
16. Binkhorst CD: Corneal and retinal complications after cat-
aract extraction. The mechanical aspect of endophthalmo-
donesis. Ophthalmology 87:609–17, 1980
17. Block RL, Weseley AC: Chorioretinal coloboma with hypo-
plasia of the inferior rectus muscle in a microphthalmic
eye. J Pediatr Ophthalmol Strabismus 35:53–4, 1998
18. Blomdahl S: Ultrasonic measurements of the eye in the
newborn. Acta Ophthalmol (Copenh) 57:1048–56, 1979
19. Boruchoff SA: Penetrating Keratoplasty, in Albert DM, Ja-
kobiec FA (eds): Principles and Practice of Ophthalmology
189
Clinical Practice, Vol 1. Philadelphia, WB Saunders, 1994,
pp 325–36
20. Briziarelli G, Abrutyn D: Atypical coloboma in the optic
disc of a beagle. J Comp Pathol 85:237–40, 1975
21. Brockhurst RJ: Cataract surgery in nanophthalmic eyes.
Arch Ophthalmol 108:965–7, 1990
22. Brockhurst RJ: Nanophthalmos with uveal effusion: a new
clinical entity. Arch Ophthalmol 93:1289–99, 1975
23. Brodsky MC: Congenital optic disk anomalies [see com-
ments] [published erratum appears in Surv Ophthalmol
1995 Sep–Oct;40(2):172]. Surv Ophthalmol 39: 89–112, 1994
24. Brodsky MC, Baker RS, Hammed LM: Pediatric Neuro-
Ophthalmology. New York, Springer, 1996, pp 444–6
25. Brodsky MC, Baker RS, Hammed LM: Pediatric Neuro-
Ophthalmology. New York, Springer, 1996, p 63
26. Brodsky MC, Baker RS, Hammed LM: Pediatric Neuro-
Ophthalmology. New York, Springer, 1996, pp 42–75
27. Brodsky MC, Ford RE, Bradford JD: Subretinal neovascular
membrane in an infant with a retinochoroidal coloboma
[letter]. Arch Ophthalmol 109:1650–1, 1991
28. Broughton WL, Weaver JE, Bibro MC, White BJ: Focal der-
mal hypoplasia: ocular manifestations in a male. J Pediatr
Ophthalmol Strabismus 19:314–7, 1982
29. Brown GC: Discussion of Gopal L, et al: Optic disc in fun-
dus coloboma. Ophthalmology 103:2126–7, 1996
30. Brown GC, Brown MM: Repair of retinal detachment asso-
ciated with congenital excavated defects of the optic disc.
Ophthalmic Surg 26:11–5, 1995
31. Brown NP, Koretz JF, Bron AJ: The development and main-
tenance of emmetropia. Eye 13:83–92, 1999
32. Bullock JD, Goldberg SH: Eyelid coloboma, in Fraunfelder
FT, Roy FH (eds): Current Ocular Therapy. Philadelphia,
WB Saunders Co, 1990, ed 3, p 507
33. Buzna E: Coloboma of the cornea. Rev Chir Oncol Radiol
ORL Oftalmol Stomatol Ser Oftalmol 30:125–8, 1986
34. Byerly KA, Pauli RM: Cranial nerve abnormalities in
CHARGE association [see comments]. Am J Med Genet 45:
751–7, 1993
35. Cagianut B, Theiler K: Bilateral colobomas of iris and chor-
oid. Association with partial deletion of a chromosome of
group D. Arch Ophthalmol 83:141–4, 1970
36. Calhoun FP: Bilateral coloboma of the optic nerve associ-
ated with holes in the disk and a cyst of the optic sheath.
Arch Ophthalmol 3:71–79, 1930
37. Capella JA, Kaufman HE, Lill FJ, Cooper G: Hereditary cat-
aracts and microphthalmia. Am J Ophthalmol 56:454–458,
1963
38. Carter R, Baker E, Hayman D: Congenital malformations
associated with a ring 4 chromosome. J Med Genet 6:224–
7, 1969
39. Casey TA: Congenital colobomata of the eyelids. Trans
Ophthalmol Soc UK 96:65–8, 1976
40. 40. Chemke J, Czernobilsky B, Mundel G, Barishak YR: A
familial syndrome of central nervous system and ocular
malformations. Clin Genet 7:1–7, 1975
41. Chen MS, Yang CH, Huang JS: Bilateral macular coloboma
and pigmented paravenous retinochoroidal atrophy. Br J
Ophthalmol 76:250–1, 1992
42. Cheng KP, Hiles DA, Biglan AW: The differential diagnosis
of leukokoria. Pediatr Ann 19:376–83, 386, 1990
43. Chuman H, Nao-i N, Sawada A: A case of morning glory
syndrome associated with contractile movement of the op-
tic disc and subretinal neovascularization. Nippon Ganka
Gakkai Zasshi 100:705-9, 1996
44. Cogan DG: Congenital anomalies of the retina. Birth De-
fects Orig Artic Ser 7:41–51, 1971
45. Cogan DG, Kuwabara T: Ocular pathology of the 13-15 tri-
somy syndrome. Arch Ophthalmol 72:246–253, 1964
46. Cogger TJ: Correction with hard contact lenses, in Duane
TD (ed): Clinical Ophthalmology, Vol 1. Philadelphia,
Harper & Row, 1993, pp 2–6
47. Cohen EJ, Kenyon KR, Dohlman CH: Iridoplasty for pre-
vention of post-keratoplasty angle closure and glaucoma.
Ophthalmic Surg 13:994–6, 1982
190 Surv Ophthalmol 45 (3) November–December 2000
48. Cohen MM Jr, Hall BD, Smith DW, et al: A new syndrome
with hypotonia, obesity, mental deficiency, and facial, oral,
ocular, and limb anomalies. J Pediatr 83:280–4, 1973
49. Coll GE, Chang S, Flynn TE, Brown GC: Communication
between the subretinal space and the vitreous cavity in the
morning glory syndrome [see comments]. Graefes Arch
Clin Exp Ophthalmol 233:441–3, 1995
50. Compton JG, Goldstein AM, Turner M, et al: Fine mapping
of the locus for nevoid basal cell carcinoma syndrome on
chromosome 9q. J Invest Dermatol 103:178–81, 1994
51. Conlon MR, Sutula FC: Congenital eyelid anomalies, in Al-
bert DM, Jakobec FA (eds): Principles and Practice of Oph-
thalmology Clinical Practice, Vol 3. Philadelphia, WB Saun-
ders, 1994, pp 1693–702
52. Cummings C, Polomeno RC, McAlpine PJ: Autosomal
dominant cataracts, coloboma, and microphthalmia. Ex-
cerpta Medica, International Congress Series 426:87, 1977
53. Curtis MA, Quarrell OW, Cobon AM, Cummins M: Intersti-
tial deletion of chromosome 4, del(4)(q12q21.1), in a
child with multiple congenital abnormalities. J Med Genet
27:64–5, 1990
54. DeJuan E Jr, Noorily: Retinal detachments in infants, in
Glaser BM, Stephen RJ (eds): Retina, Vol. 3. St. Louis, CV
Mosby, 1994, ed 2, pp 2513–4
55. Dixon J, Loftus SK, Gladwin AJ, et al: Cloning of the hu-
man heparan sulfate-N-deacetylase/N-sulfotransferase gene
from the Treacher Collins syndrome candidate region at
5q32-q33.1. Genomics 26:239–44, 1995
56. Dorland’s Illustrated Medical Dictionary, 27th Edition.
Philadelphia, WB Saunders, 1988, p 359
57. Dressler GR, Woolf AS: Pax2 in development and renal dis-
ease. Int J Dev Biol 43:463–8, 1999
58. Drews RC, Pico G: Heterochromia associated with
coloboma of the iris. Am J Ophthalmol 72:827, 1971
59. Dufour R: Survey of statistics on juvenile detachment. Bibl
Ophthalmol 79:358, 1969
60. Duke-Elder S: System of Ophthalmology, Vol 3, Part 1. St.
Louis, CV Mosby, 1963, pp 141–55
61. Duke-Elder S: System of Ophthalmology, Vol 3, Part 2. St.
Louis, CV Mosby, 1963, pp 456–72
62. Duke-Elder S: System of Ophthalmology, Vol 3, Part 2. St.
Louis, CV Mosby, 1963, pp 463, 487
63. Duke-Elder S: System of Ophthalmology, Vol 3. St. Louis,
CV Mosby, 1963, pp 470, 606–7
64. Duke-Elder S: System of Ophthalmology, Vol 3, Part 2. St.
Louis, CV Mosby, 1963, pp 706–9
65. Duke-Elder S: System of Ophthalmology, Vol 3, Part 2. St.
Louis, CV Mosby, 1963, p 616
66. Duke-Elder S: Congenital Deformities. System of Ophthal-
mology, Vol. 3, Part 2. St. Louis, CV Mosby, 1963, pp 836–40
67. Duke-Elder S: System of Ophthalmology, Vol 2. St. Louis,
CV Mosby, 1961, pp 75–82
68. Duke-Elder S: System of Ophthalmology, Vol 2. St. Louis,
CV Mosby, 1961, pp 92–4
69. Duke-Elder S: System of Ophthalmology, Vol 2. St. Louis,
CV Mosby, 1961, pp 311, 325–38
70. Dunaway DJ, David DJ: Intraorbital tissue expansion in the
management of congenital anophthalmos. Br J Plast Surg
49:529–35, 1996
71. Eccles MR, Schimmenti LA: Renal-coloboma syndrome: a
multi-system developmental disorder caused by PAX2 mu-
tations. Clin Genet 56:1–9, 1999
72. Edwards WC, Macdonald R Jr, Price WD: Congenital amauro-
sis of retinal origin (Leber). Am J Ophthalmol 72:724–8, 1971
73. Elder MJ: Aetiology of severe visual impairment and blind-
ness in microphthalmos. Br J Ophthalmol 78:332–4, 1994
74. Eustis HS, Sanders MR, Zimmerman T: Morning glory syn-
drome in children. Association with endocrine and central
nervous system anomalies. Arch Ophthalmol 112:204–7, 1994
75. Eustis HS, Sanders MR, Zimmerman T: Morning glory syn-
drome in children. Association with endocrine and central
nervous system anomalies. Arch Ophthalmol 112:204–7, 1994
76. Evans PJ: Familial macular colobomata. Br J Ophthalmol
21:503–6, 1937
ONWOCHEI ET AL
77. Ferry AP: Macular detachment associated with congenital
pit of the optic nerve head. Arch Ophthalmol 70:346–57,
1963
78. Ferry AP, Marchevsky A, Strauss L: Ocular abnormalities in
deletion of the long arm of chromosome 11. Ann Ophthal-
mol 13:1373–7, 1981
79. Fledelius HC, Christensen AC: Reappraisal of the human
ocular growth curve in fetal life, infancy, and early child-
hood. Br J Ophthalmol 80:918–21, 1996
80. Francois J: Heredit des affections colobomoateuses du
globe oculaire. Ann Ocul (Paris) 199:545–73, 1966
81. Franz T, Besecke A: The development of the eye in ho-
mozygotes of the mouse mutant Extra-toes. Anat Embryol
(Berl) 184:355–61, 1991
82. Fraser FC, Skelton J: Possible teratogenicity of maternal fe-
ver. Lancet 2:634, 1978
83. Fraser GR, Friedman AL: The Causes of Blindness in Child-
hood. Baltimore, Johns Hopkins Press, 1967
84. Frenkel LD, Keys MP, Hefferen SJ, et al: Unusual eye ab-
normalities associated with congenital cytomegalovirus in-
fection. Pediatrics 66:763–6, 1980
85. Fuente del Campo A, Martinez Elizondo M, Arnaud E:
Treacher Collins syndrome (mandibulofacial dysostosis).
Clin Plast Surg 21:613–23, 1994
86. Fujiki K, Nakajima A, Yasuda N: Genetic analysis of mi-
crophthalmos. Ophthalmic Paediatr Genet 1:139, 1982
87. Fulton AB, Howard RO, Albert DM, et al: Ocular findings
in triploidy. Am J Ophthalmol 84:859–67, 1977
88. Gailloud C: Juvenile retinal detachment. Mod Probl Oph-
thalmol 8:157–82, 1969
89. Ge N, Crandall BF, Shuler JD, Bateman JB: Coloboma asso-
ciated with Rubinstein-Taybi syndrome. J Pediatr Ophthal-
mol Strabismus 32:266–8, 1995
90. Ghestem M, Guilbert F, Dhellemmes-Defoort S, Pellerin P:
Congenital microphthalmos. Orbital and palpebral expan-
sion. Rev Stomatol Chir Maxillofac 92:77–83, 1991
91. Ghose S, Kishore K, Patil ND: Oculoauricular dysplasia syn-
drome of Goldenhar and Peters anomaly: a new associa-
tion. J Pediatr Ophthalmol Strabismus 29:384–6, 1992
92. Giroud A, Delmas A, Lefebvras J, Probst H: Etude de mal-
formations ocularies chez le foetus de rat deficient en
acide folique. Arch Anat Microse 43:21, 1954
93. Goldberg GN, Fulginiti VA, Ray CG, et al: In utero Epstein-
Barr virus (infectious mononucleosis) infection. JAMA 246:
1579–81, 1981
94. Goldberg MF, McKusick VA: X-linked colobomatous mi-
crophthalmos and other congenital anomalies. A disorder
resembling Lenzs dysmorphogenetic syndrome. Am J Oph-
thalmol 71:1128–33, 1971
95. Goldhammer Y, Smith JL: Optic nerve anomalies in basal
encephalocele. Arch Ophthalmol 93:115–8, 1975
96. Gopal L, Badrinath SS, Kumar KS, et al: Optic disc in fun-
dus coloboma [see comments]. Ophthalmology 103:2120–
6; discussion 2126–7, 1996
97. Gorlin RJ, Cohen MM Jr, Levin LS: Syndromes of the Head
and Neck. New York, Oxford University Press, 1990, ed 3,
pp 724–7
98. Gorlin RJ, Goltz RW: Multiple nevoid basal-cell epithe-
lioma, jaw cysts and bifid rib. A syndrome. N Engl J Med
262:908–12, 1960
99. Gorlin RJ, Sedano HO: The multiple nevoid basal cell car-
cinoma syndrome revisited. Birth Defects Orig Artic Ser 7:
140–8, 1972
100. Greear JM: Pits, or crater-like holes, in the optic disk. Arch
Ophthalmol 28:467-483, 1942
101. Guion-Almeida ML, Richieri-Costa A: Callosal agenesis, iris
coloboma, and megacolon in a Brazilian boy with Rubin-
stein-Taybi syndrome. Am J Med Genet 43:929–31, 1992
102. Gunderson CA, Stone R, Peiffer R, Freedman S: Corneal
coloboma, aphakia and retinal neovascularization with an-
terior segment dysgenesis (Peters anomaly). Ophthalmo-
logica 210:361–6, 1996
103. Gunduz K, Gunalp I, Erden I: Focal dermal hypoplasia
(Goltzs syndrome). Ophthalmic Genet 18:143–9, 1997
OCULAR COLOBOMATA
104. Hall BD: Choanal atresia and associated multiple anoma-
lies. J Pediatr 95:395–8, 1979
105. Happle R, Daniels O, Koopman RJ: MIDAS syndrome (mi-
crophthalmia, dermal aplasia, and sclerocornea): an X- linked
phenotype distinct from Goltz syndrome [see comments].
Am J Med Genet 47:710–3, 1993
106. Harayama K, Amemiya T, Nishimura H: Development of
the eyeball during fetal life. J Pediatr Ophthalmol Strabis-
mus 18:37–40, 1981
107. Hayreh SS, Cullen JF: Atypical minimal peripapillary chor-
oidal colobomata. Br J Ophthalmol 56:86–96, 1972
108. Heher KL, Katowitz JA, Low JE: Unilateral dermis-fat graft
implantation in the pediatric orbit. Ophthal Plast Reconstr
Surg 14:81–8, 1998
109. Henry JJ, Grainger RM: Early tissue interactions leading to
embryonic lens formation in Xenopus laevis. Dev Biol 141:
149–63, 1990
110. Hero I, Farjah M, Scholtz CL: The prenatal development of
the optic fissure in colobomatous microphthalmia. Invest
Ophthalmol Vis Sci 32:2622–35, 1991
111. Hertzberg BS, Kliewer MA, Lile RL: Antenatal ultrasono-
graphic findings in the CHARGE association. J Ultrasound
Med 13:238–42, 1994
112. Hittner HM, Desmond MM, Montgomery JR: Optic nerve
manifestations of human congenital cytomegalovirus infec-
tion. Am J Ophthalmol 81:661–5, 1976
113. Hoefnagel D, Keenan M, Allen FH Jr: Heredofamilial bilat-
eral anophthalmia. Arch Ophthalmol 69:760–764, 1963
114. Hovland KR, Schepens CL, Freeman HM: Developmental
giant retinal tears associated with lens coloboma. Arch
Ophthalmol 80:325–31, 1968
115. Hsu LY, Kim HJ, Sujansky E, et al: Reciprocal translocation ver-
sus centric fusion between two No. 13 chromosomes. A case of
46, XX,-13,⫹t(13;13)(p12;q13) and a case of 46, XY,-13,⫹t(13;
13)(p12;p12). Cytogenet Cell Genet 12:235–44, 1973
116. Hu BV, Shin DH, Gibbs KA, Hong YJ: Implantation of pos-
terior chamber lens in the absence of capsular and zonular
support. Arch Ophthalmol 106:416–20, 1988
117. Hunter AG, Rothman SJ, Hwang WS, Deckelbaum RJ: He-
patic fibrosis, polycystic kidney, colobomata and encephal-
opathy in siblings. Clin Genet 6:82–9, 1974
118. Hymes C: The postnatal growth of the cornea and palpe-
bral fissure and the projection of the eyeball in early life. J
Comp Neurol 48:415–440, 1929
119. Iijima Y, Wagai K, Matsuura Y, et al: Retinal detachment
with breaks in the pars plicata of the ciliary body [pub-
lished erratum appears in Am J Ophthalmol 1989 Dec 15;
108(6):752]. Am J Ophthalmol 108:349–55, 1989
120. Jackson CG: Prenatal development of the microphthalmic
eye in the golden hamster. J Morphol 167:65–90, 1981
121. Jacobs M, Taylor D: The systemic and genetic significance
of congenital optic disc anomalies. Eye 5:470–5, 1991
122. Jacobson L, Mellemgaard L: Anomalies of the eye in de-
scendants of women irradiated with small x-ray doses dur-
ing age of fertility. Acta Ophthalmol (Copenh) 46:252,
1968
123. Jakobiec FA: Ocular Anatomy Embryology and Teratology.
Philadelphia, Harper & Row, 1982, pp 1027, 1052–7
124. Jamieson R, Collins F: Oral-facial-digital syndrome and reti-
nal abnormalities with autosomal recessive inheritance [let-
ter; comment]. Am J Med Genet 47:304–6, 1993
125. Jay M: The Eye in Chromosome Duplications and Deficien-
cies. New York, Marcel Dekker, 1977
126. Jesberg DO, Schepens CL: Retinal detachment associated
with coloboma of the choroid. Arch Ophthalmol 65:163–
73, 1961
127. Jin JC, Anderson DR: Laser and unsutured sclerotomy in
nanophthalmos. Am J Ophthalmol 109:575–80, 1990
128. Jones KL, Smith KW, Hall JD: A pattern of craniofacial and
limb defects secondary to aberrant tissue bands. J Pediatr
84:90, 1974
129. Keutel J, Kindermann I, Mockel H: A probable autosomal
recessive hereditary skeletal malformations with humerora-
dial synostosis. Humangenetik 9: 43–53, 1970
191
130. Kindler P: Morning glory syndrome: unusual congenital
optic disk anomaly. Am J Ophthalmol 69:376–84, 1970
131. Kitsiou S, Bartsocas CS: Unusual association of XYY chro-
mosomal constitution with colobomas of iris, myopia, in-
creased lipoproteins, mental retardation and convulsions.
Ann Genet 29:264–5, 1986
132. Kleberger E, Stolowsky RB: Eine aussergewohnlich grosse
Orbitalzyste mit machtiger Erweiterung der knochernen
Orbita. Klin Monatsbl Augenheilkd 133:218, 1958
133. Kohn R: Textbook of Ophthalmic Plastic and Reconstruc-
tive Surgery. Philadelphia, Lea & Febiger, 1988, pp 58–9
134. Kok-van Alphen CC, Manschot WA, Frederiks E, van
Beuseko GT : Proceedings: Microphthalmus and orbital
cyst. Ophthalmologica 167:389–92, 1973
135. Konyukhov BV, Bugrilova RS: The growth-inhibiting factor
in embryos of mutant stock brachypodism-H mice. Gene-
tika 14:65–9, 1968
136. Kranenburg E: Crater-like holes in the optic disc and cen-
tral serous retinopathy. Arch Ophthalmol 64:912–24, 1960
137. Kranenburg EW: Crater-like holes in the optic disc and
central serous retinopathy. Arch Ophthalmol 64:912–24,
1960
138. Krause U: Three cases of the morning glory syndrome.
Acta Ophthalmol (Copenh) 50:188–98, 1972
139. Lagos JC, Gomez MR: Tuberous sclerosis: reappraisal of a
clinical entity. Mayo Clin Proc 42:26–49, 1967
140. Lamba PA, Sood NN: Congenital microphthalmos and
colobomata in maternal vitamin A deficiency. J Pediatr
Ophthalmol 5:115, 1968
141. Leff SR, Britton WA Jr, Brown GC, et al: Retinochoroidal
coloboma associated with subretinal neovascularization.
Retina 5:154–6, 1985
142. Lenz W: Recessivheschiechtsgebundene Mikrophthalmie
mit multiplen Missbildungen. Z Kinderheilkd 77:348, 1955
143. Leone CR Jr: Plastic Surgery, in Spaeth GL (ed): Oph-
thalmic Surgery Principles and Practice. Philadelphia, WB
Saunders, 1990, ed 2, pp 606–7
144. Luyckx J, Delmarcelle Y: Contribution of ultrasonography
to the study of microcornea and megalocornea, in Gitter
KA, Keeney AH, Sarin LK, Meyer D (eds): Ophthalmic Ul-
trasound, Proceedings of the Fourth International Con-
gress of Ultrasonography in Ophthalmology, Philadelphia,
Pennsylvania. St. Louis, CV Mosby, 1969, pp 149–57
145. Maberley AL, Gottner MJ, Antworth MV: Subretinal
neovascularization associated with retinochoroidal colobo-
mas. Can J Ophthalmol 24:172–4, 1989
146. MacDonald AE: Causes of blindness in Canada: an analysis
of 24,605 cases registered with the Canadian National Insti-
tute for the Blind. Can Med Assoc J 92:264, 1965
147. MacRae DW, Howard RO, Albert DM, Hsia YE: Ocular
manifestations of the Meckel syndrome. Arch Ophthalmol
88:106–13, 1972
148. Makley TA Jr, Battles M: Microphthalmos with cyst. Report of
two cases in the same family. Surv Ophthalmol 13:200–6, 1969
149. Mann I: The development of the human eye. New York,
Grune and Stratton, 1969, pp 259–69
150. Mann I: The Development of the Human Eye. New York,
Grune and Stratton, 1969, pp 150–88
151. Mann I: Developmental abnormalities of the eye. Philadel-
phia, Lippincott, 1957, ed 2, pp 81–103
152. Mann I, Ross JA: A case of atypical coloboma associated
with abnormal retinal vessels. Br J Ophthalmol 13:608–12,
1929
153. Mann IC: On certain abnormal conditions of the macular
region usually classed as colobomata. Br J Ophthalmol 11:
99–116, 1927
154. Marcus DM, Shore JW, Albert DM: Anophthalmia in the fo-
cal dermal hypoplasia syndrome. Arch Ophthalmol 108:
96–100, 1990
155. Marden PM, Venters HD Jr: A new neurocutaneous syn-
drome. Am J Dis Child 112:79–81, 1966
156. Margolis S, Scher BM, Carr RE: Macular colobomas in Leb-
ers congenital amaurosis. Am J Ophthalmol 83:27–31, 1977
157. Marles SL, Greenberg CR, Persaud TV, et al: New familial
192 Surv Ophthalmol 45 (3) November–December 2000
syndrome of unilateral upper eyelid coloboma, aberrant
anterior hairline pattern, and anal anomalies in Manitoba
Indians. Am J Med Genet 42:793–9, 1992
158. Martyn LJ, DiGeorge A: Selected eye defects of special im-
portance in pediatrics. Pediatr Clin North Am 34:1517–42,
1987
159. Mauger TF, Makley TA, Davidorf FH, Rogers GL: Retino-
blastoma, microphthalmia, coloboma, and neuroepithe-
lioma of the pineal body. Ann Ophthalmol 24:290–4, 1992
160. Maumenee IH, Mitchell TN: Colobomatous malformations
of the eye. Trans Am Ophthalmol Soc 88:123–32; discus-
sion 133-5, 1990
161. McCarthy RW, Frenkel LD, Kollarits CR, Keys MP: Clinical
anophthalmia associated with congenital cytomegalovirus
infection. Am J Ophthalmol 90:558–61, 1980
162. McCulloch C: The zonule: its origin, course, and insertion,
and its relation to neighboring structures. Trans Am Oph-
thalmol Soc 52:525–85, 1954
163. McDonald HR, Schatz H, Johnson RN: Treatment of reti-
nal detachment associated with optic pits. Int Ophthalmol
Clin 32:35–42, 1992
164. McKussick VA, Francomano CA, Antonarakis SE: Mendel-
lian Inheritance in Man: Catalogues of Autosomal Domi-
nant, Autosomal Recessive, and X-Linked Phenotypes, 10th
Edition. Baltimore, The Johns Hopkins University Press,
1992
165. McMahon RT: Anatomy, congenital anomalies, and tu-
mors, in Peyman GA, Sanders DR, Goldberg MF (eds):
Principles and Practice of Ophthalmology, Vol. 2, Part 6.
Philadelphia, WB Saunders Co, 1980, pp 1510–4
166. McMilliam L: Anophthalmia and maldevelopment of the
eyes; four cases in the same family. Br J Ophthalmol 5:121,
1921
167. Metlay LA, Smythe PS, Miller ME: Familial CHARGE syn-
drome: clinical report with autopsy findings. Am J Med
Genet 26:577–81, 1987
168. Meythaler H, Koniszewski G: Colobomas of the eyelids.
Fortschr Ophthalmol 82:391–2, 1985
169. Miller MT, Deutsch TA, Cronin C, Keys CL: Amniotic
bands as a cause of ocular anomalies. Am J Ophthalmol
104:270–9, 1987
170. Mollenbach CJ: Medfodte defekter I ojets indre hinder.
Thesis, Copenhagen. Nyt Nord Forleg. 1947 (summary in
English)
171. Moore K: The Developing Human. Philadelphia, WB Saun-
ders Co, 1977, ed 2, p 359
172. Moretti-Ferreira D, Koiffmann CP, Listik M, et al: Macro-
somia, obesity, macrocephaly and ocular abnormalities
(MOMO syndrome) in two unrelated patients: delineation
of a newly recognized overgrowth syndrome. Am J Med
Genet 46:555–8, 1993
173. Mullaney J: Ocular pathology in trisomy 18 (Edwards syn-
drome). Am J Ophthalmol 76:246–54, 1973
174. Mustarde JC: Repair and Reconstruction in the Orbital Re-
gion. A Practical Guide. Edinburgh, Churchill Livingstone,
1991, ed 3, pp 351–60
175. Mustarde JC: Repair and Reconstruction in the Orbital Re-
gion. A Practical Guide. Edinburgh, Churchill Livingstone,
1991, ed 3, pp 500, 525–30
176. Nevin NC, Pearce WG: Diagnostic and genetical aspects of
tuberous sclerosis. J Med Genet 5:273–80, 1968
177. Newell, F: Ophthalmology Principles and Concepts. St.
Louis, CV Mosby, 1982, ed 5, p 326
178. Nilsen NO: Eye malformations in chick embryos exposed
to elevated incubation temperatures. Acta Ophthalmol
(Copenh) 46:322–8, 1968
179. O’Rahilly R: The early development of the eye in staged hu-
man embryos. Contrib Embryol Carneg Inst 38:1–42, 1966
180. O’Grady RB, Rothstein TB, Romano PE: D-group deletion
syndromes and retinoblastoma. Am J Ophthalmol 77:40–5,
1974
181. Okada K, Sakata H, Shirane M, et al: Computerized tomog-
raphy of two patients with morning glory syndrome. Hi-
roshima J Med Sci 43:111–3, 1994
ONWOCHEI ET AL
182. Opitz JM, Howe JJ: The Meckel syndrome (dysencephalia
splanchnocystica, the Gruber syndrome). Birth Defects 2:
167–79, 1969
183. Ozanics V, Jacobiec FA: Prenatal development of the eye
and its adnexa, in Jacobiec FA (ed): Ocular Anatomy, Em-
bryology and Teratology. Philadelphia, Harper & Row,
1982, pp 11–96
184. Pagon RA: Ocular coloboma. Surv Ophthalmol 25:223–36,
1981
185. Pagon RA, Graham JM Jr, Zonana J, Yong SL: Coloboma,
congenital heart disease, and choanal atresia with multiple
anomalies: CHARGE association. J Pediatr 99:223–7, 1981
186. Pallotta R, Fusilli P, Sabatino G, et al: Confirmation of the
colobomatous macrophthalmia with microcornea syn-
drome: report of another family. Am J Med Genet 76:252–
4, 1998
187. Patipa M, Wilkins RB, Guelzow KW: Surgical management
of congenital eyelid coloboma. Ophthalmic Surg 13:212–6,
1982
188. Patnaik B, Kalsi R: Retinal detachment with coloboma of
the choroid. Indian J Ophthalmol 29:345–9, 1981
189. Patrinely JR, Font RL, Campbell RJ, Robertson DM: Hamar-
tomatous adenoma of the nonpigmented ciliary epithelium
arising in iris-ciliary body coloboma. Light and electron mi-
croscopic observations. Ophthalmology 90:1540–7, 1983
190. Phillips CI: Hereditary macular coloboma. J Med Genet 7:
224–6, 1970
191. Pollock S: The morning glory disc anomaly: contractile
movement, classification, and embryogenesis. Doc Oph-
thalmol 65:439–60, 1987
192. Porges Y, Gershoni-Baruch R, Leibu R, et al: Hereditary mi-
crophthalmia with colobomatous cyst. Am J Ophthalmol
114:30–4, 1992
193. Poswillo D: Pathogenesis of craniofacial syndromes exhibit-
ing colobomata. Trans Ophthalmol Soc UK 96:69–72, 1976
194. Price E, Simon JW, Calhoun JH: Prosthetic treatment of se-
vere microphthalmos in infancy. J Pediatr Ophthalmol
Strabismus 23:22–4, 1986
195. Ramer JC, Ladda RL: Humero-radial synostosis with ulnar
defects in sibs. Am J Med Genet 33:176–9, 1989
196. Rendahl I: The electroretinogram of juvenile patients with
retinal detachment. Bibl Ophthalmol 79:351–7, 1969
197. Rethore MO, Larget-Piet L, Abonyi D, et al: 4 cases of tri-
somy for the short arm of chromosome 9. Individualization
of a new morbid entity. Ann Genet 13:217–32, 1970
198. Roberts SR: Congenital posterior ectasia of the sclera in
collie dogs. Am J Ophthalmol 50:451–65, 1960
199. Roch LM, Petrucci JV, Barber AN: Studies on the develop-
ment of the eye in the 13-15 trisomy syndrome. Am J Oph-
thalmol 60:1067–74, 1965
200. Roper Hall MJ: Congenital colobomata of the lids. Trans
Ophthalmol Soc UK 88:557–66, 1968
201. Rouland JF, Hochart G, Constantinides G: Chorioretinal
coloboma and neovascular membrane. Bull Soc Ophtalmol
Fr 90:643–4, 1990
202. Roy FH, Summitt RL, Hiatt RL, Hughes JG: Ocular mani-
festations of the Rubinstein-Taybi syndrome. Case report
and review of the literature. Arch Ophthalmol 79:272–8,
1968
203. Rubinstein JH, Taybi H: Broad thumbs and toes and facial
abnormalities. Am J Dis Child 105:88, 1963
204. Rudnik-Schoneborn S, Zerres K: A further patient with Pai
syndrome with autosomal dominant inheritance? J Med
Genet 31:497–8, 1994
205. Saraux H, Rethore MO, Aussannaire M, et al: Ocular ab-
normalities of phenotype DR (ring D chromosome). Ann
Ocul (Paris) 203:737–48, 1970
206. Sassani JW, Yanoff: Anophthalmos in an infant with multi-
ple congenital anomalies. Am J Ophthalmol 83:43–8, 1977
207. Satorre J, Lopez JM, Martinez J, Pinera P: Dominant macu-
lar colobomata. J Pediatr Ophthalmol Strabismus 27:148–
52, 1990
208. Savell J, Cook JR: Optic nerve colobomas of autosomal-
dominant heredity. Arch Ophthalmol 94:395–400, 1976
OCULAR COLOBOMATA
209. Say B, Balci S, Atasu M: Humeroradial synostosis. A case re-
port. Humangenetik 19:341–3, 1973
210. Scheie HG, Yanoff M: Peters anomaly and total posterior
coloboma of retinal pigment epithelium and choroid. Arch
Ophthalmol 87:525–30, 1972
211. Schepens CL: Retinal detachment and Allied diseases. Phil-
adelphia, WB Saunders, 1983, pp.58–62, 615–32
212. Schepens CL, Jesberg DO: Retinal detachments associated
with colobomata of the choroid. Arch Ophthalmol 65:163–
173, 1961
213. Schinzel A, Hayashi K, Schmid W: Structural aberrations of
chromosome 18. II. The 18q- syndrome. Report of three
cases. Humangenetik 26:123–32, 1975
214. Scholtz CL, Chan KK: Complicated colobomatous mi-
crophthalmia in the microphthalmic (mi/mi) mouse. De-
velopment 99:501–8, 1987
215. Schubert HD: Schisis-like rhegmatogenous retinal detach-
ment associated with choroidal colobomas. Graefes Arch
Clin Exp Ophthalmol 233:74–9, 1995
216. Schwanitz G, Schamberger U, Rott HD, Wieczorek V: Par-
tial trisomy 9 in the case of familial translocation 8/9 mat.
Ann Genet 17:163–6, 1974
217. Shami M, McCartney D, Benedict W, Barnes C: Spontane-
ous retinal reattachment in a patient with persistent hyper-
plastic primary vitreous and an optic nerve coloboma [let-
ter]. Am J Ophthalmol 114:769–71, 1992
218. Shin DH: Repair of sector iris coloboma. Closed-chamber
technique. Arch Ophthalmol 100:460–1, 1982
219. Shokeir MH: The Goldenhar syndrome: a natural history.
Birth Defects 13:67–83, 1977
220. Silver J, Hughes AF: The relationship between morphoge-
netic cell death and the development of congenital anoph-
thalmia. J Comp Neurol 157:281–301, 1974
221. Simon JW, Calhoun JH: A Child’s Eyes: A Guide to Pediat-
ric Primary Care. Gainsville, Florida, Triad Publishing
Company, 1998, pp 129–134
222. Simon JW, Calhoun JH: A Child’s Eyes: A Guide to Pediat-
ric Primary Care. Gainsville, Florida, Triad Publishing
Company, 1998, pp 30–42
223. Sjogren T, Larsson T: A clinical and genetic study of oligo-
phrenia in combination with congenital ichthyosis and
spastic disorders. Acta Psychiatr Neurol Scand 32 (Supp
113): 1–112, 1957
224. Sjogren T, Larsson T: Microphthalmos and anophthalmos
with or without coincident oligophrenia. A clinical and ge-
netic-statistical study. Acta Psychiatr Neurol Scand Supp 56,
1949:
225. Smithells RW: Defects and disabilities of thalidomide chil-
dren. Br Med J 1:269–72, 1973
226. Sorsby A: Congenital coloboma of the macula: together
with an account of the familial occurrence of bilateral mac-
ula coloboma in association with apical dystrophy of the
hands and feet. Br J Ophthalmol 19:65–90, 1935
227. Sorsby A: Ophthalmic Genetics. New York, Appleton Cen-
tury Crofts, 1970, ed 2, pp 17–29
228. South MA, Tompkins WA, Morris CR, Rawls WE: Congenital
malformation of the central nervous system associated with
genital type (type 2) herpesvirus. J Pediatr 75:13–8, 1969
229. Sparkes RS, Carrel RE, Wright SW: Absent thumbs with a
ring D2 chromosome: a new deletion syndrome. Am J Hum
Genet 19:644–59, 1967
230. Stavrianeas NG, Katoulis AC, Stratigeas NP, et al: Develop-
ment of multiple tumors in a sebaceous nevus of Jadas-
sohn. Dermatology 195:155–8, 1997
231. Steahly LP: Laser treatment of a subretinal neovascular
membrane associated with retinochoroidal coloboma. Ret-
ina 6:154–6, 1986
232. Stoll C, Alembik Y, Dott B, Roth MP: Epidemiology of con-
genital eye malformations in 131,760 consecutive births.
Ophthalmic Paediatr Genet 13:179–86, 1992
233. Stratton RF, Bluestone DL: Oto-palatal-digital syndrome
type II with X-linked cerebellar hypoplasia/hydrocephalus.
Am J Med Genet 41:169–72, 1991
234. Stromland K, Hellstrom A: Fetal alcohol syndrome—an
193
ophthalmological and socioeducational prospective study.
Pediatrics 97:845–50, 1996
235. Stromland K, Miller MT: Thalidomide embryopathy: revis-
ited 27 years later. Acta Ophthalmol (Copenh) 71:238–45,
1993
236. Sugar HS: Congenital pits in the optic disc and their equiv-
alents (congenital colobomas and colobomalike excava-
tions) associated with submacular fluid. Am J Ophthalmol
63:298–307, 1967
237. Sunderman FW Jr, Allpass PR, Mitchell JM, et al: Eye mal-
formations in rats: induction by prenatal exposure to
nickel carbonyl. Science 203:550–3, 1979
238. Sutcliffe AG, Jones RB, Woodruff G: Eye malformations as-
sociated with treatment with carbamazepine during preg-
nancy. Ophthalmic Genet 19:59–62, 1998
239. Tabacchi G, Meoldia G: Corio-retinite maculare associata a
fossetta Colobomatosa epipapillare. Annali di ottalmolog-
ica e clinica oculistica 91:21–28, 1965
240. Temple IK, Brunner H, Jones B, et al: Midline facial defects
with ocular colobomata. Am J Med Genet 37:23–7, 1990
241. Toriello HV, Higgins JV, Miller T: Provisionally unique au-
tosomal recessive chondrodysplasia punctata syndrome.
Am J Med Genet 47:797–9, 1993
242. Traboulsi EI: Morning glory disc anomaly or optic disc
coloboma? [letter; comment]. Arch Ophthalmol 112:153,
1994
243. Tsipouras P, Del Mastro R, Sarfarazi M, et al: Genetic link-
age of the Marfan syndrome, ectopia lentis, and congenital
contractural arachnodactyly to the fibrillin genes on chro-
mosomes 15 and 5. The International Marfan Syndrome
Collaborative Study. N Engl J Med 326:905–9, 1992
244. Tucker S, Jones B, Collin R: Systemic anomalies in 77 pa-
tients with congenital anophthalmos or microphthalmos.
Eye 10:310–4, 1996
245. Uemura A, Uto M: Bilateral retinal detachment with large
breaks of pars plicata associated with coloboma lentis and
ocular hypertension. Jpn J Ophthalmol 36:97–102, 1992
246. van Dalen JT, Delleman JW, Yogiantoro M: A discussion of
61 cases of optic nerve coloboma. Doc Ophthalmol 56:177–
81, 1983
247. Vaughan D, Asbury T, Riordan-Eva P: General Ophthalmol-
ogy. Norwalk, Appleton and Lange, 1995, ed 14, pp 81, 341
248. Vaughan D, Asbury T, Tabbara K: General Ophthalmology.
New York, Lange and Company, 1989, ed 12, pp 13–4
249. Venetikidou A: The CHARGE association: report of two
cases. J Clin Pediatr Dent 17:243–51, 1993
250. Vistnes LM, Sergott TJ: Surgical reconstruction of a difficult
orbital cleft. Ophthal Plast Reconstr Surg 2:179–82, 1989
251. Vogel W, Siebers JW, Reinwein H: Partial trisomy 7q. Ann
Genet 16:277–80, 1973
252. Volcker HE, Tetz MR, Daus W: Cataract surgery in eyes
with colobomas. Dev Ophthalmol 22:94–100, 1991
253. von Szily A: Uber die Ontogenesis der idiotypischen (erbli-
chen) Spaltbildung des Auges, des Mikrophthlmus und der
Orbitalzysten. Z Anat Entwicklungsgesch 74:1–232, 1924
254. Wagener HP, Gipner JF: Coloboma of iris, choroid and op-
tic disc with detachment of the retina. Am J Ophthalmol 8:
694–7, 1925
255. Walknowska J, Peakman D, Weleber RG: Cytogenetic inves-
tigation of cat-eye syndrome. Am J Ophthalmol 84:477–86,
1977
256. Wallace DC, Murphy KJ, Kelly L, Ward WH: The basal cell
naevus syndrome. Report of a family with anosmia and a
case of hypogonadotrophic hypopituitarism. J Med Genet
10:30–3, 1973
257. Wallar PH, Genstler DE, George CC: Multiple systemic and
periocular malformations associated with the fetal hydan-
toin syndrome. Ann Ophthalmol 10:1568–72, 1978
258. Wang K, Hilton GF: Retinal detachment associated with
coloboma of the choroid. Trans Am Ophthalmol Soc 83:
49–62, 1985
259. Warberg M: Ocular coloboma and multiple congenital
anomalies: the CHARGE association. Ophthalmic Paediatr
Genet 2:189–99, 1983
194 Surv Ophthalmol 45 (3) November–December 2000
260. Warburg M: Classification of microphthalmos and
coloboma. J Med Genet 30:664–9, 1993
261. Warburg M: Update of sporadic microphthalmos and
coloboma. Non-inherited anomalies. Ophthalmic Paediatr
Genet 13:111–22, 1992
262. Warburg M: An update on microphthalmos and coloboma.
A brief survey of genetic disorders with microphthalmos
and coloboma. Ophthalmic Paediatr Genet 12:57–63, 1991
263. Warburg M: Genetics of microphthalmos. Int Ophthalmol
4:45–65, 1981
264. Warburg M: Focal dermal hypoplasia. Ocular and general
manifestations with a survey of the literature. Acta Ophthal-
mol (Copenh) 48:525, 1970
265. Warburg M, Friedrich U: Coloboma and microphthalmos
in chromosomal aberrations. Chromosomal aberrations
and neural crest cell developmental field. Ophthalmic Pae-
diatr Genet 8:105–18, 1987
266. Waring GO 3d, Roth AM, Rodrigues MM: Clinicopatho-
logic correlation of microphthalmos with cyst. Am J Oph-
thalmol 82:714–21, 1976
267. Watt RH: Inferior congenital iris coloboma and IOL im-
plantation. J Cataract Refract Surg 19:669–71, 1993
268. Webb GC, Keith CG, Campbell NT: Concurrent de novo
interstitial deletion of band 2p22 and reciprocal transloca-
tion (3;7) (p21;q22). J Med Genet 25:124–7, 1988
269. Weiss AH, Kousseff BG, Ross EA, Longbottom J: Simple mi-
crophthalmos. Arch Ophthalmol 107:1625–30, 1989
270. Weiss AH, Kousseff BG, Ross EA, Longbottom J: Complex
microphthalmos. Arch Ophthalmol 107:1619–24, 1989
271. Weisse I, Stotzer H. Hypoplasie des Nervus opticus und
Kolo: 86:1–3, 1973
272. Wenstrom KD, Muilenburg AC, Patil SR, Hanson JW: Unique
phenotype associated with a pericentric inversion of chromo-
some 6 in three generations. Am J Med Genet 39:102–5, 1991
273. Wiggins RE, von Noorden GK, Boniuk M: Optic nerve
coloboma with cyst: a case report and review. J Pediatr
Ophthalmol Strabismus 28:274–7, 1991
274. Wilcox LM Jr, Bercovitch L, Howard RO: Ophthalmic fea-
tures of chromosome deletion 4p- (Wolf-Hirschhorn syn-
drome). Am J Ophthalmol 86:834–9, 1978
275. Wilson GN, King TE, Brookshire GS: Index finger hyper-
phalangy and multiple anomalies: Catel-Manzke syn-
drome? Am J Med Genet 46:176–9, 1993
276. Wilson JG, Karr JW: Effects of irradiation on embryonic de-
velopment:1. X-rays on the tenth day of gestation in the rat.
Am J Anat 88:1–33, 1951
277. Wilson JG, Roth CB, Warkany J: An analysis of the syn-
drome of malformations induced by maternal vitamin A
deficiency. Effects of restoration of vitamin A at various
times during gestation. Am J Anat 92:189–217, 1953
278. Wilson MG, Towner JW, Coffin GS, Forsman I: Inherited
pericentric inversion of chromosome no. 4. Am J Hum
Genet 22:670, 1970
279. Wilson WG, Campochiaro PA, Conway BP, et al: Deletion
(13)(q14.1q14.3) in two generations: variability of ocular
manifestations and definition of the phenotype. Am J Med
Genet 28:675–83, 1987
280. Winkelman JE, Horstein GPM: Congenital blindness in the
presence of a normal fundus. Ophthalmologica 137:423–5,
1959
281. Wise CA, Chiang LC, Paznekas WA, et al: TCOF1 gene en-
codes a putative nucleolar phosphoprotein that exhibits
mutations in Treacher Collins Syndrome throughout its
coding region. Proc Natl Acad Sci USA 94:3110–5, 1997
282. Worgul BV: Lens, in Jacobiec FA (ed): Ocular Anatomy,
Embryology, and Teratology. Philadelphia, Harper & Row,
1982, pp 355–89
ONWOCHEI ET AL
283. Wright S, Levy IS: White sponge naevus and ocular
coloboma. Arch Dis Child 66:514–6, 1991
284. Yanoff M, Fine BS: Ocular Pathology: A Text and Atlas.
Philadelphia, Harper & Row, 1982, ed 2, pp 402–4
285. Yanoff M, Fine BS: Ocular Pathology: A Text and Atlas.
Hagerstown, Harper & Row, 1975, pp 329–32
286. Yanoff M, Rorke LB, Niederer BS: Ocular and cerebral ab-
normalities in chromosome 18 deletion defect. Am J Oph-
thalmol 70:391–402, 1970
287. Yeo LM, Willshaw HE: Large congenital upper lid
coloboma—successful delayed conservative management. J
Pediatr Ophthalmol Strabismus 34:190–2, 1997
288. Yung JF, Williamson N, Salafsky I, Hoo JJ: Deletion of band
5q21 in association with a de novo translocation involving
2p and 5q. J Med Genet 25:570–2, 1988
289. Zellweger H, Ionasescu V, Simpson J, Burmeister L: The
problem of trisomy 22. A case report and a discussion of
the variant forms. Clin Pediatr 15:601–6, 617–8, 1976
290. Zlotogora J, Legum C, Raz J, et al: Autosomal recessive
colobomatous microphthalmia. Am J Med Genet 49:261–2,
1994
Outline
I. Definition and pathogenesis
II. Alinical features and complications
A. Typical/atypical
B. Complete/incomplete
C. Lens “coloboma”
D. Posterior segment coloboma
E. Optic nerve
F. The morning glory disk anomaly
G. Microphthalmia/Anophthalmia and cyst
H. Complications
III. Etiology and patterns of inheritance
A. Isolated ocular monogenic syndromes
1. Autosomal dominant inheritance
2. Autosomal recessive inheritance
B. Multisystem monogenic syndromes
1. Autosomal dominant inheritance
2. Autosomal recessive inheritance
3. X-linked inheritance
4. Unknown etiology
5. Chromosomal aberrations
C. Environmental causes and intrauterine insults
IV. Presentation and treatment
A. Eyelids
B. Iris
C. Zonule/Ciliary body
D. Retinochoroidal
V. Differential diagnosis
VI. Conclusion
The authors would like to thank Leanore Barror for her contri-
bution in the painstaking preparation of this manuscript.
The authors have no proprietary or commercial interest in any
product or concept discussed in this article.
Reprint address: John W. Simon, MD, Albany Medical College,
Department of Ophthalmology, Lions Eye Institute, 35 Hackett
Blvd., Albany NY 12208 USA.