Research

Original Investigation | CLINICAL SCIENCES

Microphthalmia, Anophthalmia, and Coloboma and

Associated Ocular and Systemic Features
Understanding the Spectrum
Simon E. Skalicky, MPhil; Andrew J. R. White, FRANZCO; John R. Grigg, FRANZCO; Frank Martin, FRANZCO;
Jeremy Smith, FRANZCO; Michael Jones, FRANZCO; Craig Donaldson, FRANZCO; James E. H. Smith, FRANZCO;
Maree Flaherty, FRANZCO; Robyn V. Jamieson, FRACP

IMPORTANCE Microphthalmia, anophthalmia, and coloboma form an interrelated spectrum of

congenital eye abnormalities.

OBJECTIVE To document the ocular and systemic findings and inheritance patterns in
patients with microphthalmia, anophthalmia, and coloboma disease to gain insight into the
underlying developmental etiologies.

DESIGN, SETTING, AND PARTICIPANTS This retrospective consecutive case series was
conducted at a tertiary referral center. Included in the study were 141 patients with
microphthalmia, anophthalmia, and coloboma disease without a recognized syndromic
etiology who attended the Westmead Childrens Hospital, Sydney, from 1981-2012.

EXPOSURE Cases were grouped on the basis of the presence or absence of an optic fissure
closure defect (OFCD); those with OFCD were further subdivided into microphthalmic and
nonmicrophthalmic cases. Anophthalmic cases were considered as a separate group.

MAIN OUTCOMES AND MEASURES Associated ocular and systemic abnormalities and
inheritance patterns were assessed.

RESULTS Of 141 cases, 61 (43%) were microphthalmic non-OFCD (NOFCD), 34 (24%)

microphthalmic OFCD, 32 (23%) nonmicrophthalmic coloboma (OFCD), 9 (6%)
anophthalmic, and 5 (4%) were unclassified. Sixty-three (45%) had bilateral disease.
Eighty-four patients (60%) had an associated ocular abnormality; of these, cataract
(P < .001) and posterior segment anomalies (P < .001) were most common in the NOFCD
group. Forty-eight (34%) had an associated systemic abnormality, most commonly
neurological, musculoskeletal and facial, urological and genital, or cardiac. Neurological
abnormalities were most common in the anophthalmic group (P = .003), while urological
abnormalities were particularly seen in the OFCD groups (P = .009). Familial cases were
identified in both the OFCD and NOFCD groups, with a likely autosomal dominant inheritance
pattern in 9 of 10 families.

CONCLUSIONS AND RELEVANCE This series indicated that the OFCD/NOFCD distinction may
be useful in guiding evaluation for ocular and systemic associations, as well as the direction
and analysis of genetic investigation.

Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Author: Robyn V.
Jamieson, FRACP, Eye and
Developmental Genetics Research
Group, Western Sydney Genetics
Program, The Childrens Hospital at
Westmead, Sydney, New South
JAMA Ophthalmol. 2013;131(12):1517-1524. doi:10.1001/jamaophthalmol.2013.5305 Wales, Australia 2145 (rjamieson
Published online October 31, 2013. @cmri.org.au).

1517

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 Research Original Investigation
M
icrophthalmia, anophthalmia, and coloboma (MAC)
are related structural, congenital eye malforma-
tions that display a spectrum of severity and can oc-
cur in isolation or as part of a syndrome.1-3 They account for a
significant proportion of childhood visual impairment
worldwide.4 Anophthalmia is the complete absence of the eye.
Microphthalmia is a small eye most usefully defined in terms
of axial length and corneal diameter. The optic fissure clo-
sure defect (OFCD) of coloboma is a segmental ocular defect,
affecting some or all of the iris, choroid, retina, and optic
nerve.5,6 Microphthalmia may also be found in association with
congenital cataracts, or when there is disruption of normal an-
terior segment formation leading to abnormal irides, corneal
opacification, and small abnormal lenses.1,7,8
Reported birth prevalence ranges from 0.6 to 4.2 per
100 000 births for anophthalmia4,9-15; 2 to 17 per 100 000 births
for microphthalmia4,9-16; and 2 to 14 per 100 000 births for
coloboma.4,5,10,11,15,17 In Australia, the incidence of MAC is ap-
proximately 6 to 13 per 100 000 births.18
The genetic etiology of MAC spectrum disease is not well
understood. Clinical and experimental evidence increasingly
suggests a heterogenous genetic basis including a local dis-
ruption in eye development or as part of a more generalized
developmental anomaly.1,16,19,20 The early development of the
eye is controlled by a complex network of diffusible signaling
molecules, transcription factors, and downstream targets in-
cluding cell-cycle regulators, structural proteins, and adhe-
sion factors.21-23 The molecular signals in early eye develop-
ment interact in specific pathways, which may be tissue- and
time-specific in their action. This complexity helps explain the
overlapping clinical phenotypes and the underlying genetic
heterogeneity in these conditions.19
In some cases, such as CHARGE (coloboma, heart de-
fects, choanal atresia, retarded growth and development, geni-
tal abnormalities, and ear anomalies) syndrome24 or anoph-
thalmia associated with pulmonary hypoplasia,25 syndrome
identification or the presence of a chromosomal anomaly or
microdeletion may guide investigations. However, for most pa-
tients, no syndrome or chromosomal anomaly is detected. In
these cases, molecular diagnosis can be especially challeng-
ing because many genes have been identified that are indi-
vidually responsible for a small number of cases. Currently, the
2 most frequently mutated genes known to cause monogenic
MAC are SOX2 and OTX2, accounting for 10% and 3% of cases,
respectively, when anophthalmia or severe microphthalmia is
present.19,26-31 Mutations in VSX2 (CHX10),32 PAX6,33 RAX,34
FOXE3,35 BMP4,36 and GDF631 are less commonly detected. Fa-
milial clustering and successful linkage analysis in a small num-
ber of families have demonstrated segregation in autosomal
recessive37 or autosomal dominant38 patterns. X-linked reces-
sive or dominant inheritance is associated with some syn-
dromic forms of MAC.39,40 Many patients are the first af-
fected individual in their family and this, in combination with
the lack of availability of a route to clear-cut genetic diagno-
sis, hampers informative recurrence risk counseling.
A classification system based on embryological develop-
ment of the eye may be useful. Morrison et al16 classified MAC
based on the presence or absence of an OFCD. In this study,
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Microphthalmia, Anophthalmia, and Coloboma
this classification system was applied to a cohort of patients
with MAC to determine the proportions of patients that may
fall into these groupings and the associated ocular and sys-
temic features. Cases without a known genetic or syndromic
etiology were primarily investigated to determine pheno-
typic and inheritance patterns. With the advent of broadly tar-
geted next-generation and whole-genome approaches in ge-
netic diagnosis,35,41,42 clear phenotypic characterization will
be critical to determine the likelihood that particular molecu-
lar variations are disease causing. This clinical knowledge will
be useful in directing investigations for possible associated sys-
temic features and for genetic information for affected fami-
lies.
Methods
We performed a retrospective case report study of medical rec-
ords at the Childrens Hospital, Westmead, Sydney, Australia,
from between 1981 and 2012. Ethics approval was prospec-
tively granted by the Childrens Hospital, Westmead, re-
search ethics committee. Because data were collected retro-
spectively via a database, informed consent was not obtained
from patients; all data collected were de-identified from hos-
pital notes. Consecutive cases of microphthalmia, anophthal-
mia, and coloboma were obtained from the medical records.
Inpatient files, outpatient clinic files, and separate files from
the Department of Clinical Genetics at the Childrens Hospi-
tal, Westmead, were identified via computer database. The
search keywords were microphthalmia/microphthalmos, an-
ophthalmia/anophthalmos, nanophthalmia/nanophthal-
mos, coloboma, and anterior segment dysgenesis (including
sclerocornea).
Cases irrelevant to the study, including Axenfield-Rieger
spectrum anomalies, Peters anomaly, aniridia, retinopathy of
prematurity, and Morning Glory anomaly, were excluded. Cases
with a recognized syndrome associated with MAC, such as
CHARGE, oculo-auriculo-vertebral spectrum disease, or Jou-
bert syndrome, were excluded.
All cases were reviewed by a senior pediatric ophthalmolo-
gist as were first-degree relatives, when possible. The embryo-
logical classification proposed by Morrison et al16 was ex-
tended as follows: cases were grouped into microphthalmia
with OFCD, microphthalmia without OFCD (NOFCD), microph-
thalmia unclassified, coloboma isolated in 1 or both eyes (OFCD
with normal axial length), and anophthalmia in 1 or both eyes,
in keeping with similar studies. Coloboma was defined as a pre-
dominantly inferior deficiency of iris, chorioretinal, or optic
disc tissue. An iris coloboma was a full-thickness iris defect or
anterior stromal deficiency, a chorioretinal coloboma was an
area of absent chorioretinal tissue that may or may not ex-
tend continuously or discontinuously to the optic disc, and an
optic disc coloboma was a focally enlarged optic disc with de-
ficiency of neuroretinal tissue.5 Microphthalmia was defined
as an abnormally small eye or cornea (microcornea) (axial
length <16 mm at birth and <19 mm at 12 months of age; and
corneal diameter <10 mm at birth).15 Anophthalmia was de-
fined as no evidence of a globe or ocular tissue in the orbit on
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 Microphthalmia, Anophthalmia, and Coloboma Original Investigation Research

clinical examination since birth.15,16 Cases were deemed un-

Table 1. Patient Characteristics and Treatment Data
classifiable if the presence or absence of an OFCD was unable
to be ascertained; for example, if there was an opaque cornea Characteristic Patients, No. (%)
or indeterminate on ultrasonography. Age at diagnosis, median (range), mo 11.0 (0-72)

Cases were further assessed on the basis of the presence Better-eye visual acuity, mean (range), LogMAR 0.88 (0.2 to 4)
or absence of the following features: congenital cataract, an- Sex
terior or posterior segment morphological abnormality, glau- Male 73 (52)
coma, persistent fetal vasculature (PFV), orbital or nasolacri- Female 68 (48)
mal duct abnormality, ocular motility disorder, and systemic Laterality
abnormalities. Anterior segment abnormality included sclero- Unilateral 78 (55)
cornea (defined as a congenital nonprogressive, noninflamma- Bilateral 63 (45)
tory scleralization of the peripheral and sometimes entire cor- MAC group
nea, without underlying iris or angle abnormality or iridocorneal Anophthalmia 9 (6)
adhesion), abnormal iris (excluding iris coloboma), and disor- Microphthalmic NOFCD 61 (43)
ganized angle. Posterior segment abnormality included cho- Microphthalmic OFCD 34 (24)
rioretinal or optic disc abnormalities (excluding PFV and cho- Nonmicrophthalmic OFCD 32 (23)
rioretinal and/or optic nerve coloboma); examples included Microphthalmic unclassified 5 (4)
vascular abnormality, chorioretinal atrophy, and hypoplastic
Ocular anomaly
and dysplastic optic discs. Visual acuity data were converted
Anterior segment abnormality 21 (15)
into logarithm of the minimal angle of resolution; the visual acu-
Cataract 45 (32)
ity of the better eye was recorded for each patient.
PFV 16 (11)
A detailed systemic clinical evaluation was performed on
Posterior segment abnormality, non-PFV 19 (13)
all patients by a senior pediatrician; further investigation for
Orbital or nasolacrimal abnormality 7 (5)
systemic abnormality was determined by clinical findings.
Oculomotility disorder 38 (27)
Significance testing was performed using the 2 Fisher ex-
Total 84 (59)
act probability test and analysis of variance across groups. Pedi-
gree analysis was performed to study the pattern of inheri- Nil 57 (41)

tance. Systemic abnormality

Neurological 22 (16)
Musculoskeletal 16 (11)
Cardiac 9 (6)
Results Urological 13 (9)
Case Selection Integumentary 7 (5)
A total of 182 case files were examined, of which 41 were ex- Other systemic abnormality 5 (4)
cluded from the study because they did not have MAC spec- Total 48 (34)
trum disease. Of those excluded, 19 were anophthalmic sec- Nil 93 (66)
ondary to enucleation due to an unrelated cause such as Ocular surgery
retinoblastoma. A further 22 cases were excluded because they Bilateral lensectomy 16
had either a documented congenital infection (3 cases) or a rec- Unilateral lensectomy 13
ognized genetic syndrome (19 cases: 7 with CHARGE syn- Intraocular lens insertion 18
drome, 2 with oculo-auriculo-vertebral spectrum disease, and Pupilloplasty 3
1 each of Aicardi Syndrome, Gorlin Syndrome, Jacobsen Syn-
Glaucoma surgery 8
drome, Nance-Horan Syndrome, Rubenstein-Taybi Syn-
Strabismus surgery 3
drome, Waardenburg Syndrome, Norrie Disease, Down Syn-
Orbital and eyelid surgery 6
drome, Velocardiofacial Syndrome, and Joubert Syndrome),
Enucleation 1
leaving 141 cases in the study. Based on Australian Institute
Total 38 (27)
of Health and Welfare data,18 approximately 235 live births with
Nil 103 (73)
MAC would be expected in New South Wales during the study
period, indicating a 60% capture rate of all New South Wales Abbreviations: MAC, microphthalmia, anophthalmia, and coloboma; NOFCD,
nonoptic fissure closure defect; OFCD, optic fissure closure defect; PFV,
cases in this study.
persistent fetal vasculature.

Descriptive Data
Most cases were detected in the first 18 months of life, with
the median age at presentation being 11 months (Table 1). The
mean better-eye visual acuity corresponded to Snellen 6/45
(range, 6/4.5 to no light perception). The sex distribution was
broadly equal, with 73 males and 68 females. There were 63
bilateral and 78 unilateral cases. There were 61 cases (43%) with
microphthalmic NOFCD and 66 cases with OFCD, in whom 34
(24%) had an eye size meeting the definition for microphthal-
mia and 32 (23%) where the eye size did not meet the microph-
thalmia definition. In 5 cases, the presence or absence of an
OFCD could not be determined. Nine patients had anophthal-
mia; this was bilateral in 7 cases. In the 2 patients with unilat-

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 Research Original Investigation
Table 2. Relative Prevalence of Associated Ocular Abnormalities Within MAC Subgroups
Microphthalmic
NOFCD OFCD Unclassified
Ocular Abnormality (n = 61) (n = 34) (n = 5)
Anterior segment 11 (18) 7 (21)
Cataract 37 (61) 7 (21)
Posterior segment 27 (44)a 6 (18)
Glaucoma 10 (16) 1 (3)
Orbital/nasolacrimal duct 3 (5) 2 (6)
Ocular motility 23 (38) 10 (30)
Any ocular abnormality 53 (87) 20 (59)
eral anophthalmia, the other eye had an OFCD in one patient
and there was an NOFCD in the other eye in the other patient.
Eighty-four patients (60%) had an associated ocular abnor-
mality in their involved eye(s); 48 (34%) had an associated sys-
temic abnormality. Thirty-eight individuals received surgical
intervention, the most common procedure being a lensec-
tomy.
MAC Subgroup Analysis
There were no differences between MAC subgroups in terms
of bilaterality; however, on subgroup analysis of the NOFCD
group, microphthalmic eyes with PFV had fewer bilaterally af-
fected cases (P < .007). Table 2 demonstrates the distribution
of associated ocular abnormalities within the subgroups. As-
sociated ocular abnormalities were most common in the
NOFCD (53 of 61) and microphthalmic OFCD (20 of 34) groups,
and they were less common in the nonmicrophthalmic OFCD
group (7 of 32) (P < .001). The most common abnormality was
congenital cataract (45 of 141), which was the most fre-
quently associated ocular anomaly in the NOFCD group (37 of
61). However, it was also present in some cases in both the mi-
crophthalmic (7 of 34) and nonmicrophthalmic (1 of 32) OFCD
groups, indicating some overlap in phenotypic features be-
tween the groups. Other associated ocular features in the
NOFCD group were posterior segment anomalies (27 of 61), in-
cluding persistent fetal vasculature, and anterior segment ab-
normalities, such as opacifications of the cornea in 11 of 61 pa-
tients. Ocular motility disorders were least prevalent in the
nonmicrophthalmic coloboma (OFCD) group (P = .04).
An associated systemic abnormality was identified in 34%
of cases. The frequency and type of systemic abnormality did
not vary between unilateral and bilateral cases. The distribu-
tion of systemic abnormalities found in our cohort is shown in
Table 3, and several patients had more than 1 associated sys-
temic feature. The most common abnormalities were neuro-
logical, musculoskeletal and facial, and urological and genital.
Neurological abnormality was most common in the anophthal-
mic subgroup (5 of 9) and least in the nonmicrophthalmic OFCD
group (1 of 32) (P = .003). Urological and genital abnormality was
most common in the microphthalmic (5 of 34) and nonmicroph-
thalmic (7 of 32) OFCD groups and least common in the anoph-
thalmic group (0 of 9) (P = .009). Cardiac abnormality was not
detected in the NOFCD group (0 of 61) and was present in all
other groups in small numbers (P = .04).
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Microphthalmia, Anophthalmia, and Coloboma
No. (%)
Nonmicrophthalmic
OFCD
(n = 32) P Value
1 (20) 2 (6) NS
0 (0) 1 (3) <.001
Abbreviations: MAC, microphthalmia,
1 (20) 1 (3) <.001
anophthalmia, and coloboma;
1 (20) 1 (3) NS NOFCD, nonoptic fissure closure
1 (20) 1 (3) NS defect; NS, not significant; OFCD,
optic fissure closure defect.
2 (40) 3 (9) .04
a
Including 16 cases with persistent
4 (80) 7 (22) <.001
fetal vasculature.
Sibling Recurrence
Microphthalmia, anophthalmia, and coloboma disease was re-
corded in 23 individuals from 10 families in our cohort. Expres-
sion within families remained consistently either NOFCD or
OFCD; however, within families, some individuals were mi-
crophthalmic and others had normal ocular size. This indi-
cates variable phenotypic expression of the genetic defect. Six
of the families had NOFCD, with cataracts and microphthal-
mia running in an autosomal dominant inheritance pattern. Off-
spring in 1 of these families had associated features of iridocor-
neal adhesions and sclerocornea. Four of the familial cases had
OFCD and these followed an autosomal dominant inheritance
pattern in 3 cases. In the other OFCD family, nonconsanguine-
ous unaffected parents had 2 affected children, 1 female and 1
male. This may be owing to autosomal recessive inheritance or
to germline mosaicism with or without somatic mosaicism in 1
of the phenotypically unaffected parents.
Discussion
There have been a variety of classification systems for MAC
spectrum disorders43,44 but, to our knowledge, few have at-
tempted to classify the phenotypic features based on embry-
ology and possible genetic etiology.16 The early embryology
of the eye includes several important events (optic vesicle for-
mation, optic cup formation, and optic fissure closure), which
provide points for consideration of the responsible molecu-
lar signals, pathways, and genetic coordinators.3,21-23 From a
clinical perspective, the microphthalmic NOFCD group may
represent either a very severe phenotype suggesting disrup-
tion at the optic vesicle or optic cup stage or, if mild, then in-
terruption to differentiation and maturation. The presence of
OFCD implies disruption to events around the time of optic fis-
sure closure. There has been some epidemiological evidence
for subclassifying MAC spectrum disorders according to the
presence or absence of a coloboma.9
There have been recent advances in our understanding of
the genetic etiology of microphthalmia and anophthalmia spec-
trum disorders largely through family studies,25,26,32 and clini-
cal molecular testing for some candidate genes is now
available.19,27,28,30,33,35,45 Because microphthalmia and anoph-
thalmia spectrum has a heterogenous genetic etiology with a
variety of phenotypic expressions, specific candidate genes for
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 Microphthalmia, Anophthalmia, and Coloboma Original Investigation Research

Table 3. Relative Prevalence of Associated Systemic Abnormalities Within MAC Subgroups

Systemic Anophthalmia NOFCD
Abnormality (n = 9) (n = 61)
Neurological 5 (56): Hypoplastic optic 8 (13): Sensorineural hear-
nerves and tracts; ing loss and atrophic optic
septooptic chiasm; sensorineural
dysplasia; occipital hearing loss;
encephalocele; bilateral sensorineural
frontal encephalocele; hearing impairment;
bilateral sensorineural congential right cerebral
hearing loss and hypoplasia, bifid
absent septum pituitary, and small
pellucidum corpus callosum; severe
developmental delay;
hypotonia; hydrocephalus;
midline hypothalamus and
optic chiasm anomaly
Musculoskeletal 1 (11): Absent right ear, 5 (8): Short palpebral
and facial cleft lip, and palate fissures, microcephalus,
wide nasal bridge, small
posteriorly rotated ears and
syndactyly of toes 2-3;
limb overgrowth;
polydactyly; abnormal
dentition, right facial
microsomia, malar
hypoplasia, small jaw,
redundant upper eyelids,
downsloping palpebral
fissures, fused C2-3,
scoliosis, and nasal
deformity; 11 ribs
bilaterally, sacral
hemivertebrae,
tracheo-esophageal
fistula, low rotated ears,
flat facies, fused eyelids
Cardiac 1 (11): Hemitruncus 0 (0)
arteriosum,
ventricular septal
defect, and pulmonary
hypertension
Urological and 0 (0) 1 (2): Hydrocele
genital
Integumentary 1 (11): Linear 2 (3): Hypopigmented skin
scleroderma patches; hirsutism
Other systemic 0 (0) 3 (5): Reduced growth
abnormality hormone; congenital
cystic adenoid
malformation of lung type
II and duodenal atresia;
obstructive sleep apnea
Total 6 (67) 15 (25)
No. (%)
Microphthalmic
OFCD
(n = 34)
7 (21): Sensorineural
hearing loss; hydrocephalus; Cerebral
basal encephalocele, corpus palsy
callosum agenesis; absent
septum pellucidum with
dilated lateral ventricles,
hydrocephalus, and atrophic
corpus callosum; occult
spina bifida; involuntary arm
movements; epilepsy
8 (24): Facial
dysmorphology, down
slating palpebral fissures,
wide nasal bridge, short
nose, micrognathia, rotated
ears, and nuchal thickening;
bilateral 5th finger
clinodactyly and override
toes 2-3; snub nose, low set
ears, cleft palate, redundant
neck folds, micrognathia,
syndactyly of toes 2-3; right
webbed toes, right
anomalous pinna;
hypoplastic left femur;
bilateral limb anomalies,
exomphalos; bilateral
inguinal hernias; cleft palate
5 (15): Ventricular septal
defect; patent ductus
arteriosus; pulmonary
atresia, ventricular septal
defect, atrial septal defect;
ventricular septal defect,
atrial septal defect, patent
ductus arteriosus; atrial-
ventricular septal defect
5 (15): Anterior anus and
hypoplastic labia majora;
vesicoureteric reflux; renal
pelvic dilatation; micropenis
and absent scrotum; neuro-
genic bladder and renal
reflux
1 (3): Caf au lait spot on
left shoulder
0 (0)
13 (38)
Nonmicrophthalmic
Unclassified (OFCD) P
(n = 5) (n = 32) Value
1 (20): 1 (3): Absent cerebellar .003
vermis and expressive
dysphasia
0 (0) 2 (6): Fused C2-3, .13
postaxial polydactyly
both upper limbs and left
lower limb; cleft palate,
hyperflexible thumb
joints, Klippel-Fiel
anomaly C2-C4, high
nasal bridge, protuberant
lower lip, pectus
excavatum, malar
hypoplasia and long feet
1 (20): 2 (6): Subaortic stenosis; .04
Tetralogy ventricular septal defect
of Fallot
1 (20): 7 (22): Undescended .009
Congenital left testes; severe
testicular vesicoureteric reflux;
torsion medullary sponge
kidneys; single kidney;
cryptorchidism;
dysplastic kidney;
bladder abnormalities,
dysplastic kidneys
0 (0) 1 (3): Dry skin, sparse .56
hair
0 (0) 4 (12): Inguinal hernia; .60
2-vessel umbilicus with
hernia; plagiocephaly;
hepatosplenomegaly
2 (40) 12 (38) .13

Abbreviations: MAC, microphthalmia, anophthalmia, and coloboma; NOFCD, nonoptic fissure closure defect; OFCD, optic fissure closure defect.

microphthalmia and anophthalmia can only be isolated in a
minority of cases.16,19 In the near future, whole-exome se-
quencing, with interpretation guided by an understanding of
the overlapping roles of developmental genes in OFCD and
NOFCD, will lead to increased yield in diagnostic testing in
these conditions (Figure). This is likely to significantly en-
hance our understanding of the genetic etiology of these
disorders.46
The Australian prevalence of MAC is comparable with other
countries: 1 to 17 per 100 000 births for microphthalmia,4,9-18,47,48
with variability largely based on different inclusion/exclusion
criteria.4,9-11,13,14,16,17 The sex distribution of our cases was ap-
proximately equal, in keeping with other studies.13-15 It is pos-
sible that these were the more severe cases in this spectrum of
disorders or they may have had concomitant problems leading
to a referral for management.

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 Research Original Investigation Microphthalmia, Anophthalmia, and Coloboma

possible nonsyndromic systemic associations, this cohort may

Figure. Disease Genes in Patients With Optic Fissure Closure Defect
(OFCD) and Nonoptic Fissure Closure Defect (NOFCD) Phenotypes
Optic fissure Nonoptic fissure
closure defect closure defect
SOX2/SOX2
BMP4/BMP4
PAX6/PAX6 FOXE3
SHH/SHH OTX2 PITX3
STRA6/STRA6 VSX2 NHS/NHS
GDF6/GDF6 ATOH7 GJA1
CHD7 RAX BCOR
NDP HCCS
SMOC1
Mutations in some genes are specifically seen in patients with OFCD or NOFCD.
Some patients with OFCD can have associated NOFCD features, such as
cataract and anterior or posterior segment abnormality, and at least 9 of the
genes (eg, SOX2, BMP4, and PAX6) can be mutated in patients with OFCD,
NOFCD, or OFCD with associated ocular defects. For genes in bold, there may
be systemic features in patients with mutations in at least 13 genes, and a
mutation in these genes causes a syndromic ocular condition. For genes not in
bold, a mutation causes isolated ocular abnormality. For all genes, a mutation
may cause isolated ocular abnormality or ocular and systemic abnormality.
Epidemiological studies have suggested that cataract is of-
ten found in association with microphthalmia.8,49 Our finding
that cataract was the most frequently associated eye abnormal-
ity in the NOFCD cohort (Table 2) and can be found in relatives
of patients with NOFCD is consistent with these reports. There
have been previous instances of pedigrees with this pairing of
eye abnormalities.50 Anterior segment anomalies were more
common in the microphthalmic OFCD group than the nonmi-
crophthamic OFCD group. This may reflect an increased inci-
dence of corneal abnormality and anterior segment disorgani-
zation in microphthalmic eyes. Glaucoma (an important
comorbidity) affected a small number of patients in all groups.
Ocular motility abnormalities were present in all microphthal-
mic groups, consistent with a higher incidence of poor vision
in microphthalmic eyes and subsequent sensory tropia.
Similar to previous studies,9,16,49,51,52 a large proportion of
our cases (34%) had an associated systemic abnormality, most
commonly neurological, musculoskeletal and facial, or uro-
logical and genital. Neurological abnormality was relatively
more common in the anophthalmic group followed by the mi-
crophthalmic OFCD and NOFCD groups (Table 3). This is in
keeping with previous studies where neurological abnormal-
ity, especially midline anomalies, have been found, particu-
larly when the eyes are more severely affected.33,53 Optic
fissure closure defect cases, both microphthalmic and non-
microphthalmic, showed an increased predisposition to uro-
logical abnormalities compared with NOFCD cases. By exclud-
ing cases with known syndromic etiology to provide clues to
reflect a reduced incidence of systemic abnormalities associ-
ated with MAC.
In this series, most pedigrees had an autosomal domi-
nant inheritance pattern. However, most cases did not have a
known family history. Sibling recurrence is a significant risk
and must be explained to affected families. In this series, there
were familial cases in both the NOFCD (6 families) and OFCD
(4 families) groups. There was marked variability within some
families. For example, there was 1 family where a father had
coloboma with normal size eyes, while his child had colo-
boma and microphthalmia. Three NOFCD families had indi-
viduals with microphthalmia and cataracts, whose relatives
(typically earlier generations) had pediatric cataract with nor-
mal globe size.
Persistent fetal vasculature, traditionally considered a sepa-
rate clinical entity,54,55 has been included as a subset of NOFCD
within this cohort. With increasing identification of causative
genes, there may be an etiological overlap between PFV and
other noncolobomatous cases of microphthalmia.56 When com-
pared with non-PFV cases in the NOFCD group, those with PFV
had similar frequencies of systemic and ocular abnormalities;
however, there was a higher prevalence of unilateral cases.
Five of the cases classified as microphthalmic on the basis
of small corneal diameters were subsequently shown to have
normal axial lengths when this was measured in later child-
hood. Each of these cases had associated bilateral congenital
cataracts and had developed glaucoma or had an affected fam-
ily member with congenital cataract and microphthalmia. These
cases represent a distinct clinical subset that requires recogni-
tion by the pediatric ophthalmologist and geneticist. Patients
with the phenotype of cataract and microcornea, with or with-
out reduction in axial length, may have mutations in cataract-
related genes such as GJA8, GJA3, CRYBA4, and CRYGC.57,58
This study provided useful clues for clinicians and geneti-
cists involved in the management of these patients. First, the
phenotypic expression of MAC spectrum abnormalities is vari-
able (even within families) and a significant proportion of the
patient population has associated eye and systemic abnormali-
ties and careful examination must be made for these. Some of
these, such as NOFCD with cataract and OFCD with urological
abnormalities, cluster together and this serves as an aid to the
clinician in recognizing these associations. While the inheri-
tance pattern is complex and incompletely understood, it is clear
that cases of bilateral MAC abnormalities and those NOFCD cases
with cataract may be particularly associated with a familial pat-
tern of inheritance. Expression of MAC spectrum disorders is
not uniform, so the clinical delineation of phenotypic features
is important to aid interpretation of exome and whole-
genome data in these patients as this becomes increasingly avail-
able. This will lead to improved prospects for genetic diagno-
sis and information for these patients and families.

ARTICLE INFORMATION
Submitted for Publication: February 28, 2013;
final revision received May 9, 2013; accepted May
17, 2013.
Published Online: October 31, 2013.
doi:10.1001/jamaophthalmol.2013.5305.
Author Affiliations: Discipline of Ophthalmology,
University of Sydney, New South Wales, Australia
(Skalicky, White, Grigg, Martin, Jones, Jamieson);
Eye and Developmental Genetics Research Group,
Western Sydney Genetics Program, The Childrens
Hospital at Westmead, Sydney, New South Wales,
Australia (White, Grigg, Flaherty, Jamieson);
Department of Ophthalmology, The Childrens

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Copyright 2013 American Medical Association. All rights reserved.

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 Microphthalmia, Anophthalmia, and Coloboma
Hospital at Westmead, Sydney, New South Wales,
Australia (Skalicky, White, Grigg, Martin, J. Smith,
Jones, Donaldson, J.E. Smith, Flaherty); Childrens
Medical Research Institute, Westmead, Sydney,
New South Wales, Australia (Jamieson); Discipline
of Paediatrics and Child Health, University of
Sydney, Sydney, New South Wales, Australia
(Jamieson).
Author Contributions: Dr Jamieson had full access
to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Skalicky, White, Grigg,
Jamieson.
Acquisition of data: Skalicky, White, Martin,
Donaldson, J. E. H. Smith, Flaherty.
Analysis and interpretation of data: Skalicky, White,
J. Smith, Jones, Jamieson.
Drafting of the manuscript: Skalicky, Grigg,
Jamieson.
Critical revision of the manuscript for important
intellectual content: Skalicky, White, Martin, J.
Smith, Jones, Donaldson, J. E. H. Smith, Flaherty,
Jamieson.
Statistical analysis: Skalicky, Grigg.
Obtained funding: Grigg.
Administrative, technical, or material support:
Skalicky, Grigg, Donaldson.
Study supervision: Grigg, Martin, Jones, Donaldson,
J. E. H. Smith, Jamieson.
Conflict of Interest Disclosures: None reported.
Additional Contributions: We acknowledge the
contribution of Stephen Hing, FRANZCO, and Neil
Rowe, FRANZCO, in the management of many
patients in this series.
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