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BioMed Central
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Orphanet Journal of Rare Diseases
Open Access
Review
Anophthalmia and microphthalmia
Amit S Verma and David R FitzPatrick*
Address: MRC Human Genetics Unit, Edinburgh, UK
Email: Amit S Verma - Amit.Verma@hgu.mrc.ac.uk; David R FitzPatrick* - David.Fitzpatrick@hgu.mrc.ac.uk
* Corresponding author
Abstract
Anophthalmia and microphthalmia describe, respectively, the absence of an eye and the presence
of a small eye within the orbit. The combined birth prevalence of these conditions is up to 30 per
100,000 population, with microphthalmia reported in up to 11% of blind children. High-resolution
cranial imaging, post-mortem examination and genetic studies suggest that these conditions
represent a phenotypic continuum. Both anophthalmia and microphthalmia may occur in isolation
or as part of a syndrome, as in one-third of cases. Anophthalmia/microphthalmia have complex
aetiology with chromosomal, monogenic and environmental causes identified. Chromosomal
duplications, deletions and translocations are implicated. Of monogenic causes only SOX2 has been
identified as a major causative gene. Other linked genes include PAX6, OTX2, CHX10 and RAX.
SOX2 and PAX6 mutations may act through causing lens induction failure. FOXE3 mutations,
associated with lens agenesis, have been observed in a few microphthalmic patients. OTX2, CHX10
and RAX have retinal expression and may result in anophthalmia/microphthalmia through failure of
retinal differentiation. Environmental factors also play a contributory role. The strongest evidence
appears to be with gestational-acquired infections, but may also include maternal vitamin A
deficiency, exposure to X-rays, solvent misuse and thalidomide exposure. Diagnosis can be made
pre- and post-natally using a combination of clinical features, imaging (ultrasonography and CT/MR
scanning) and genetic analysis. Genetic counselling can be challenging due to the extensive range of
genes responsible and wide variation in phenotypic expression. Appropriate counselling is indicated
if the mode of inheritance can be identified. Differential diagnoses include cryptophthalmos,
cyclopia and synophthalmia, and congenital cystic eye. Patients are often managed within multi-
disciplinary teams consisting of ophthalmologists, paediatricians and/or clinical geneticists,
especially for syndromic cases. Treatment is directed towards maximising existing vision and
improving cosmesis through simultaneous stimulation of both soft tissue and bony orbital growth.
Mild to moderate microphthalmia is managed conservatively with conformers. Severe
microphthalmia and anophthalmia rely upon additional remodelling strategies of endo-orbital
volume replacement (with implants, expanders and dermis-fat grafts) and soft tissue
reconstruction. The potential for visual development in microphthalmic patients is dependent upon
retinal development and other ocular characteristics.
Published: 26 November 2007
Orphanet Journal of Rare Diseases 2007, 2:47 doi:10.1186/1750-1172-2-47
Received: 25 July 2007
Accepted: 26 November 2007
This article is available from: http://www.OJRD.com/content/2/1/47
© 2007 Verma and FitzPatrick; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Orphanet Journal of Rare Diseases 2007, 2:47 http://www.OJRD.com/content/2/1/47
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Disease names
Anophthalmia (OMIM 206900), Microphthalmia
(OMIM 309700)
Synonyms
Anophthalmos, microphthalmos, nanophthalmos, nano-
phthalmia
Definition and diagnostic criteria
The mean maximum axial lengths in the neonatal and
adult human eye are approximately 17 and 23.8 mm
respectively. Most of the post-natal growth of the eye
occurs within the first three years with posterior segment
expansion accounting for over 90% of post-natal growth.
The International Clearinghouse for Birth Defects Moni-
toring Systems defines anophthalmia and microphthal-
mia as "anophthalmos/microphthalmos: apparently
absent or small eyes. Some normal adnexal elements and
eyelids are usually present. In microphthalmia, the cor-
neal diameter is less than 10 mm, and the antero-poste-
rior diameter of the globe is less than 20 mm" [1].
Epidemiology
The birth prevalence of anophthalmia and microphthal-
mia has been generally estimated to be 3 and 14 per
100,000 population respectively, although other evidence
puts the combined birth prevalence of these malforma-
tions at up to 30 per 100,000 population [2,3]. Epidemi-
ological data suggests risk factors for these conditions are
maternal age over 40, multiple births [4,5], infants of low
birth weight and low gestational age [6]. There is no pre-
dilection with regards to race or gender [4,5]. Both anoph-
thalmia and microphthalmia are more commonly
bilateral; the exception appears to be isolated microph-
thalmia, which is usually unilateral [5]. Microphthalmia
is reported in 3.2 – 11.2% of blind children [7].
Clinical description
Anophthalmia refers to the absence of ocular tissue in the
orbit. In the absence of clinically apparent ocular tissue,
histological sectioning has shown residual neuroecto-
derm in some cases and hence terms such as 'true anoph-
thalmia', 'clinical anophthalmia' and 'extreme
microphthalmia' may in fact refer to what is in reality a
phenotypic range between anophthalmia and microph-
thalmia (figure 1). Clinically it seems reasonable to use
the term microphthalmia for an eye with axial length two
standard deviations below that of the population age-
adjusted mean; this typically correlates to an axial length
below 21 mm in adult eyes. Simple microphthalmia refers
to a structurally normal, small eye, and has been used
interchangeably with 'nanophthalmia' (though the latter
is particularly used when referring to a small eye with
microcornea, axial length <18 mm, and = 8D hyper-
metropia). The increased thickness of the sclera in these
eyes and the subsequent changes in blood flow are
believed to be responsible for the increased incidence of
uveal effusions and choroidal detachments seen. Micro-
phthalmia may also be associated with other ocular disor-
ders, in which case it is termed complex microphthalmia.
These ocular disorders may affect the anterior segment
(for example, sclerocornea and Peters anomaly) and/or
the posterior segment (for example, persistent hyperplas-
tic primary vitreous and retinal dysplasias). Both anoph-
thalmia and microphthalmia can occur in isolation or be
syndromic, as in about one-third of cases (see additional
files 1 and 2 for a review of syndromes associated with
Clinical appearance of anophthalmia (upper picture) and microphthalmia (lower picture)Figure 1
Clinical appearance of anophthalmia (upper picture) and
microphthalmia (lower picture).
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anophthalmia and microphthalmia respectively). Learn-
ing disabilities are seen in approximately one-fifth of cases
[2]. Complex microphthalmia, in particular, exhibits wide
phenotypic variability.
Aetiology
The precise pathogenesis of anophthalmia and microph-
thalmia remains unknown. Mann [8] suggested anoph-
thalmia has its genesis early in gestation as a result of
failure of development of the anterior neural tube (second-
ary anophthalmia) or optic pit(s) to enlarge and form
optic vesicle(s) (primary anophthalmia). A third category,
consecutive or degenerative anophthalmia was applied to
cases where optic vesicles have degenerated and disap-
peared subsequent to formation. Observations of optic
nerves, chiasm, and/or tracts with anophthalmia may
indicate the regression of a partially developed eye rather
than aplasia of the optic vesicle(s), a view supported by
observations in an apparently anophthalmic orbit of
extraocular muscle insertion into a fibrous mass, possibly
representing an aborted eye [9]. Following observations
that the posterior segment of microphthalmic eyes are
more affected than the anterior, Weiss and colleagues
[10,11] suggested that post-natal ocular growth is crucial
and speculated that decreased size of the optic cup, altered
proteoglycans in the vitreous, low intraocular pressure
and abnormal growth factor production may all or in part
have a bearing on the pathogenesis of simple microph-
thalmia; whilst inadequate production of secondary vitre-
ous may result in complex microphthalmia. Some cases of
microphthalmia may be associated with a cyst; these are
believed to result from failure of the optic fissure to close
[12].
Epidemiological studies have predicted both heritable
and environmental factors in causing anophthalmia and
microphthalmia. This review focuses on heritable causes
as the evidence for environmental causes is both more cir-
cumstantial and accounts for a smaller proportion of
cases. Chromosomal duplications, deletions and translo-
cations have been implicated in both anophthalmia and
microphthalmia, and are typically associated with charac-
teristic syndromes (table 1). Of monogenic causes (table
2 shows selected genes with mutations linked to anoph-
thalmia/microphthalmia), only SOX2 has to date been
identified as a major causative gene for anophthalmia/
microphthalmia. Cytogenetic studies placed the locus at
3q26.3, and de novo heterozygous loss-of-function point
mutations have been shown to account for 10–20% of
severe bilateral anophthalmia/microphthalmia [13], the
most common phenotype being bilateral anophthalmia.
The 'SOX2 anophthalmia syndrome' encompasses sclero-
cornea, cataracts, persistent hyperplastic primary vitreous
and optic disc dysplasia as well as non-ocular features like
mental retardation, neurological abnormalities, facial
dysmorphisms, post-natal growth failure, oesophageal
pathology and anomalies of male genitalia [14,15].
PAX6, on chromosome 11p13, has been studied more
extensively than most other eye genes. In humans, heter-
Table 1: Chromosomal abnormalities associated with anophthalmia/microphthalmia [55,7].
Chromosomal Abnormality Other Features
Duplication 3q syndrome (3q21-ter dup) Learning difficulties, growth deficiency, hypertrichosis, craniosynostosis, cardiac defects, chest
deformities, genital abnormalities, umbilical hernia
4p- (Wolf-Hirschhorn syndrome) Growth deficiency, microcephaly, ocular hypertelorism, cranial asymmetry, learning difficulties,
epilepsy, cleft lip/palate, anterior segment dysgenesis
Duplication 4p syndrome Learning difficulties, epilepsy, growth deficiency, obesity, microcephaly, characteristic faces, genital
abnormalities, kyphoscoliosis
Deletion 7p15.1-p21.1 Cryptophthalmos, cleft lip/palate, choanal atresia
Trisomy 9 mosaic syndrome Joint contractures, congenital heart defects, prenatal growth deficiency, learning difficulties,
micrognathia, kyphoscoliosis
Duplication 10q syndrome Ptosis, short palpebral fissures, camptodactyly, learning difficulties, prenatal growth deficiency,
microcephaly, heart and kidney malformations
13q-, 13 ring Microcephaly, learning difficulties, bilateral retinoblastoma, cardiac defects, hypospadias,
cryptorchidism
Trisomy 13 (Patau syndrome) Holoprosencephaly, moderate microcephaly, coloboma, retinal dysplasia, cyclopia, cleft lip/palate,
cardiac defects, genital abnormalities, 86% die within one year.
Deletion 14q22.1-q23.2 Pituitary hypoplasia.
18q- Midface hypoplasia, small stature, learning difficulties, hypotonia, nystagmus, conductive deafness,
microcephaly, midface hypoplasia, genital abnormalities
Trisomy 18 (Edwards syndrome) Polyhydramnios, single umbilical artery, small placenta, low foetal activity, learning difficulties,
hypertonicity, hypoplasia of skeletal muscle, subcutaneous, adipose tissue, prominent occiput, low-
set malformed auricles, micrognathia, cardiac defects
Triploidy syndrome Large placenta with hydatidiform changes, growth deficiency, syndactyly, congenital heart defects,
brain anomalies/holoprosencephaly
Orphanet Journal of Rare Diseases 2007, 2:47 http://www.OJRD.com/content/2/1/47
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ozygous loss-of-function mutations typically produce ani-
ridia (OMIM 106210), a congenital panocular
malformation associated with severe visual impairment;
however PAX6 was also the first gene implicated in
human anophthalmia [16]. Although PAX6 mutations are
an extremely rare cause of anophthalmia, there has
recently been interest in a possible co-operative role
between PAX6 and SOX2. Kondoh and colleagues [17]
have shown that PAX6 and SOX2 co-bind to a regulatory
element driving lens induction in the chick, which sug-
gests that lens induction failure could be responsible for
microphthalmia in patients with mutations in these genes
[9]. PAX6 and SOX2 interactions have since been shown
to also drive lens induction in mammals through their
action on the γ-crystallin gene (V van Heyningen, personal
communication). Ultrasound bimicroscopy studies are
required to determine if aphakia is commonly associated
in microphthalmic SOX2 cases. As expected with genes
expressed in the developing brain, patients with inherited
PAX6 and SOX2 mutations exhibit CNS malformations in
addition to dominantly inherited anophthalmia/micro-
phthalmia [18,9]. Interestingly mutations within the
FOXE3 gene (on chromosome 1p32), associated with
congenital primary aphakia (OMIM 610256), were
observed in three siblings with microphthalmia; in all
three cases the phenotype was believed to be secondary to
lens agenesis [19].
Mutations in three genes with retinal expression are asso-
ciated with anophthalmia/microphthalmia, possibly
through failure of retinal differentiation. Heterozygous
loss-of-function mutations of OTX2 (on chromosome
14q22, autosomal dominant inheritance) have been
shown to be associated with a wide range of ocular disor-
ders from anophthalmia and microphthalmia to retinal
defects. CNS malformations and mental retardation are
common in patients with OTX2 mutations [20,9]. RAX,
located on chromosome 18q21.32, is linked to about 2%
of inherited anophthalmia/microphthalmia [21]. Simi-
larly, CHX10 mutations (chromosome 14q24.3) account
for about 2% of isolated microphthalmia [22]; mutations
in both genes characteristically presenting with recessively
inherited phenotypes.
Two syndromes with broad phenotypes have been
described recently in association with anophthalmia.
GLI2 mutations had originally been described in the con-
text of holoprosencephaly and polydactyly, however there
has been a case reporting a missense mutation in a patient
with asymmetrical genu and callosal agenesis co-existing
with anophthalmia, thereby extending the phenotype
[23]. Anophthalmia with congenital heart defects, pulmo-
nary abnormalities, diaphragmatic hernia and learning
difficulties have been described in patients with muta-
tions of the STRA6 gene [24]. Our knowledge of genes
associated with microphthalmia has also increased; com-
plex microphthalmia in association with genetic cataracts
has been attributed to mutations in the CRYBA4 gene
[25]. In addition to these putative genes, several loci have
been identified with autosomal dominant microphthal-
mia mapping to 15q12-15 [26], autosomal recessive
microphthalmia mapping to 14q32 [27,28] and X-linked
anophthalmia mapping to Xq27-28 [29].
Over the past several years, there has been an increased
awareness of environmental factors associated with ano-
phthalmia/microphthalmia. In 1993, the UK media
reported clusters of anophthalmia and microphthalmia
patients, speculating that these conditions may be con-
nected to the pesticide Benomyl. Studies specifically
designed to look at this issue found no definitive causal
link [30-33]. The strongest evidence for environmental
causes is for gestational-acquired infections, with rubella,
toxoplasmosis, varicella and cytomegalovirus implicated
[30,34]. Other viruses in the herpes-zoster family have
also been linked, as have parvovirus B19, influenza virus,
and coxsackie A9 [35,36]. Non-infectious causes have
been postulated and include maternal vitamin A defi-
ciency [37], fever, hyperthermia, exposure to X-rays, sol-
vent misuse and exposure to drugs like thalidomide,
warfarin and alcohol [30].
Diagnostic methods
The diagnosis is usually based upon clinical and imaging
criteria, and may be confirmed on histology if post-mor-
tem is performed. Establishing a specific cause involves
undertaking a comprehensive medical history, physical
Table 2: Ocular phenotypes associated with gene mutations linked to anophthalmia/microphthalmia.
Gene Locus (Inheritance) Major (and selected less common) Human Ocular Phenotype(s) OMIM [54]
SOX2 3q26.3-q27 (AD) Anophthalmia/microphthalmia 184429
PAX6 11p13 (AD) Aniridia, (Peters anomaly, autosomal dominant keratopathy, foveal hypoplasia, optic
nerve malformations, anophthalmia)
607108
OTX2 14q22 (AD) Anophthalmia/microphthalmia, (retinal dysplasia, optic nerve malformations) 600037
RAX 18q21.3 (AR) Anophthalmia/microphthalmia 601881
CHX10 14q24.3 (AR) Microphthalmia 142993
FOXE3 1p32 Anterior segment dysgenesis, congenital primary aphakia 601094
CRYBA4 22q11.2-q13.1 (AD) Autosomal dominant cataract, (microphthalmia) 123631
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examination, family history, karyotyping and molecular
genetic testing, imaging, renal ultrasonography, and audi-
ology.
Ophthalmological assessment
Anophthalmia can potentially be a difficult clinical diag-
nosis to make. Microphthalmia is usually diagnosed by
inspection and palpation of the eye through the lids. The
diagnosis is aided by measurements of corneal diameter,
which ranges from 9–10.5 mm in neonates and 10.5–12
mm in adults. Microphthalmia with cyst usually presents
with lower lid bulging. Electrodiagnostic tests may be val-
uable, particularly in cases of microphthalmia where reti-
nal development has been unaffected. Eye examination of
both parents should be undertaken and a careful family
history of eye anomalies sought.
Paediatric and clinical genetics assessment
Because of the wide phenotypic spectrum associated with
anophthalmia/microphthalmia, it is vital to assess these
patients within multi-disciplinary teams that include pae-
diatricians and clinical geneticists. Further investigations
are dependent upon the clinical picture. If no syndrome is
identified in infancy, further examination after another
three or four years is desirable as many syndromes
become more apparent by this age.
Imaging
Ultrasound is most commonly used to determine the
length of the globe in microphthalmic eyes.
CT and MR scans facilitate the diagnosis of anophthalmia.
Both scans show the absence of a globe within the orbit
although soft amorphous tissue may be discerned (inter-
mediate T1 signal intensity and low T2 signal intensity on
MR scan, intermediate density on CT scan). Neural tissue
forming the visual pathway and extraocular muscles are
variably present (figure 2) [38-40]. Orbital dimensions
and volume are both reduced [38]. Simple microphthal-
mia shows as a normal albeit small globe, with normal
signal/density characteristics of lens and vitreous, in a
smaller orbit than normal.
Differential diagnosis
Cryptophthalmos refers to completely fused eyelid margins,
without lashes. These cases can be associated with both
microphthalmia and microcornea. It is often bilateral and
may be syndromic.
Cyclopia (total) and synophthalmia (partial) represent
degrees of fusion of the optic vesicles thereby preventing
the development of separate eyes. They correspond to
neural maldevelopments incompatible with life.
In contrast to microphthalmia with cyst, which results
from failure of the optic fissure to close, a congenital cystic
eye may develop from failure of the optic vesicle to invagi-
nate [12]. At birth, the cystic eye may resemble anophthal-
mia, however with post-natal expansion, a bulge may
appear behind the eyelids.
Genetic counselling
Genetic counselling is challenging both from the perspec-
tive of the extensive range of genes responsible for anoph-
thalmia/microphthalmia and the wide variation in
phenotypic expression. Only SOX2 has thus far been iden-
tified as a major anophthalmia/microphthalmia gene,
with mutations primarily arising de novo. The picture is
further complicated by observations of phenotypically
normal parents carrying loss of function SOX2 or OTX2
mutations [41,20]. Mosaicism and/or variable penetrance
render prediction of recurrence risk difficult in these
monogenic anophthalmia/microphthalmia cases. In gen-
eral, if the mode of inheritance can be identified, then
appropriate counselling is indicated. The empiric risk to
siblings without a clear aetiology or family history is
10–15%, assuming inheritance accounts for half of cases
with the other half occurring sporadically [7]. Chromo-
somal abnormalities associated with anophthalmia/
microphthalmia tend to be associated with distinct co-
morbidities and give rise to specific syndromes. If a
patient has a numerical chromosomal abnormality, the
parents can be expected to be entirely normal whilst sib-
T2-weighted MR scan of a patient with unilateral anophthal-miaFigure 2
T2-weighted MR scan of a patient with unilateral
anophthalmia. Note the presence of amorphous tissue and
structures resembling extraocular muscles within the anoph-
thalmic right orbit. The right optic nerve/chiasm junction
appears attenuated rather than absent suggesting possible
residual optic nerve neural tissue.
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lings are at a slightly increased risk of having a similar
chromosomal abnormality, with similar or dissimilar
phenotype [7]. If a patient has a structurally unbalanced
chromosomal constitution, the parents may have bal-
anced chromosomal rearrangements and other siblings
will be at a higher risk, though this will depend upon the
specific rearrangement. If neither parent has any rear-
rangement, the risk to siblings is virtually negligible [7].
Antenatal diagnosis
Chromosome analysis
Cytogenetic studies are possible upon amniotic fluid foe-
tal cells (usually withdrawn after 14 weeks of gestation) or
on chorionic villus sampling specimens (at about 10 to 12
weeks). The power of these techniques in facilitating the
pre-natal diagnosis of anophthalmia/microphthalmia
was elegantly demonstrated by Guichet and colleagues
(2004) [42]. In a foetus with severe intrauterine growth
retardation and bilateral anophthalmia on a 24-week
ultrasound scan, they demonstrated a 46, XX,
del(3)(q26.3q28) interstitial deletion of the long arm of
chromosome 3 on 650 band karyotype. FISH analysis
confirmed the interstitial deletion of 3q27 encompassing
the SOX2 locus.
Ultrasonography
It is possible to detect anophthalmia/microphthalmia by
early second trimester [43], though more recent reports
place the limit at about 12 weeks with trans-vaginal ultra-
sound [44,45]. Foetal eyes are best scanned in the coronal,
axial and corono-axial planes and appear as symmetrical
structures on either side of the nose. Lenses appear as
smooth circular lines with hypoechogenic content on
axial and coronal views. Eye size can be measured upon
visualising the maximum coronal or axial planes of the
orbit, and compared against established eye growth charts
[46,47].
MRI
where available can be used to supplement ultrasonogra-
phy.
Management
Conservative
Detectable retinal function may be present in microph-
thalmia cases, particularly those associated with SOX2
mutations. It is important to refract these eyes and treat
any underlying amblyopia. In unilateral cases, the 'good'
eye must be protected and any visual deficit managed
appropriately.
Surgical
Surgical management can form the mainstay of anoph-
thalmia/microphthalmia treatment. The globe triples in
volume between birth and adolescence. The growth of the
bony orbit reflects growth of the globe [48]. Both congen-
ital anophthalmia and microphthalmia result in a small
volume orbit compared to age-matched controls [49],
potentially leading to the appearance of hemifacial asym-
metry. There is also evidence that enucleation (removal of
the globe) produces a reduction in orbital volume in both
children and adults [50,51]. Reconstructive strategies rely
upon the simultaneous management of both soft tissue
hypoplasia and asymmetric bone growth [52].
Treatment is usually started early to maximise the overall
development of these children. Mild/moderate microph-
thalmia is generally managed conservatively with inser-
tion of a conformer (like a prosthetic eye but not painted),
periodically increasing in size to allow for growth of the
orbit. Treatment for severe microphthalmia and anoph-
thalmia are usually started within weeks of life using con-
formers to enlarge the palpebral fissure, conjunctival cul-
de-sac and orbit [48]. Endo-orbital volume replacement
using implants of progressively increasing size can be used
to stimulate expansion of the developing bony orbit, usu-
ally after six months of age. Volume replacement using
implants and expanders can also be supplemented by the
use of dermis-fat grafts. Static orbital implants may need
to be changed between three and five times before puberty
and are associated with problems of wound dehiscence,
extrusion or inadequate stimulation of bony growth.
Expandable orbital implants were introduced as an effica-
cious means of stimulating bony growth and socket
enlargement. Inflatable expanders are limited by difficulty
maintaining orbital fixation for sustained expansion and
controlling the direction of expansion, whilst self-expand-
ing hydrogel spheres lose expansion force once fully
hydrated. Orbital osteotomies are indicated in more
severe cases [48,52]. Ocular prostheses are used when the
orbit has developed adequately, and are changed regularly
with further orbital expansion. Conjunctival sac and lid
reconstruction may be beneficial to the overall cosmetic
effect. Microphthalmia with cyst is often treated around
the age of five permitting the ophthalmic surgeon to take
advantage of the orbital expansion properties of the cyst
until the orbit is about 90% of the adult volume, whilst
allowing removal for cosmetic reasons at about the time
the child starts school. Surgical excision with preceding
decompression is commonly performed, the cyst may also
be aspirated but the recurrence rate is higher [53].
Prognosis
The potential for visual development depends upon the
degree of retinal development and other ocular character-
istics in microphthalmic patients. Therapy aims to max-
imise existing vision and enhance cosmetic appearances
rather than improve sight.
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Unresolved issues
The aetiology of anophthalmia/microphthalmia under-
lies the entire developmental biology of ocular formation
and remains a field where our knowledge is increasing
exponentially. Despite the progresses made, much work is
still needed to understand the processes underlying these
complex diseases, which are a significant cause of child-
hood blindness. Even if these processes are elucidated in
the future, novel therapeutic approaches to prevent these
conditions from occurring could still be precluded by very
early ocular development in the foetus.
Abbreviations used
AD (autosomal dominant);
AR (autosomal recessive);
CNS (central nervous system);
CT (computerised tomography);
MR (magnetic resonance);
MRI (magnetic resonance imaging);
OMIM (Online Mendelian Inheritance in Man [54]).
Competing interests
The author(s) declare that they have no competing inter-
ests.
Authors' contributions
ASV drafted the manuscript and both authors subse-
quently revised the manuscript for intellectual content.
Additional material
Acknowledgements
We gratefully acknowledge those patients who have permitted the usage of
their clinical pictures to illustrate the manuscript.
References
1. International Clearinghouse for Birth Defects Monitoring Systems:
Annual Report 2003 Rome: International Centre on Birth Defects;
2003.
2. Morrison D, FitzPatrick D, Hanson I, Williamson K, van Heyningen V,
Fleck B, Jones I, Chalmers J, Campbell H: National study of micro-
phthalmia, anophthalmia, and coloboma (MAC) in Scotland:
investigation of genetic aetiology. J Med Genet 2002, 39:16-22.
3. Campbell H, Holmes E, MacDonald S, Morrison D, Jones I: A cap-
ture-recapture model to estimate prevalence of children
born in Scotland with developmental eye defects. J Cancer Epi-
demiol Prev 2002, 7:21-28.
4. Shaw GM, Carmichael SL, Yang W, Harris JA, Finnell RH, Lammer EJ:
Epidemiologic characteristics of anophthalmia and bilateral
microphthalmia among 2.5 million births in California,
1989–1997. Am J Med Genet A 2005, 137:36-40.
5. Kallen B, Robert E, Harris J: The descriptive epidemiology of
anophthalmia and microphthalmia. Int J Epidemiol 1996,
25:1009-1016.
6. Forrester MB, Merz RD: Descriptive epidemiology of anoph-
thalmia and microphthalmia, Hawaii, 1986–2001. Birth Defects
Res A Clin Mol Teratol 2006, 76:187-92.
7. Anophthalmia/Microphthalmia Overview [http://www.gene
clinics.org/profiles/anophthalmia-ov/index.html]
8. Mann I: The Developmental Basis of Eye Malformations. Phil-
adelphia: JB Lippincott; 1953.
9. Fitzpatrick DR, van Heyningen V: Developmental eye disorders.
Curr Opin Genet Dev 2005, 15:348-353.
10. Weiss AH, Kousseff BG, Ross EA, Longbottom J: Simple microph-
thalmos. Arch Ophthalmol 1989, 107:1625-1630.
11. Weiss AH, Kousseff BG, Ross EA, Longbottom J: Complex micro-
phthalmos. Arch Ophthalmol 1989, 107:1619-1624.
12. Guthoff R, Klein R, Lieb WE: Congenital cystic eye. Graefes Arch
Clin Exp Ophthalmol 2004, 242:268-271.
13. Fantes JA, Ragge NK, Lynch SA, McGill NI, Collin JRO, Howard-Pee-
bles PN, Hayward C, Vivian AJ, Williamson KA, van Heyningen V, Fit-
zPatrick DR: Mutations in SOX2 cause anophthalmia. Nat Genet
2003, 33:461-463.
14. Ragge NK, Lorenz B, Schneider A, Bushby K, de Sanctis L, de Sanctis
U, Salt A, Collin JR, Vivian AJ, Free SL, Thompson P, Williamson KA,
Sisodiya SM, van Heyningen V, Fitzpatrick DR: SOX2 anophthalmia
syndrome. Am J Med Genet A 2005, 135:1-8.
15. Williamson KA, Hever AM, Rainger J, Rogers RC, Magee A, Fiedler Z,
Keng WT, Sharkey FH, McGill N, Hill CJ, Schneider A, Messina M,
Turnpenny PD, Fantes JA, van Heyningen V, FitzPatrick DR: Muta-
tions in SOX2 cause anophthalmia-esophageal-genital
(AEG) syndrome. Hum Mol Genet 2006, 15:1413-1422.
16. Glaser T, Jepeal L, Edwards JG, Young SR, Favor J, Maas RL: PAX6
gene dosage effect in a family with congenital cataracts, ani-
ridia, anophthalmia and central nervous system defects. Nat
Genet 1994, 7:463-471.
17. Kondoh H, Uchikawa M, Kamachi Y: Interplay of Pax6 and SOX2
in lens development as a paradigm of genetic switch mecha-
nisms for cell differentiation. Int J Dev Biol 2004, 48:819-827.
18. Sisodiya SM, Ragge NK, Cavalleri GL, Hever A, Lorenz B, Schneider
A, Williamson KA, Stevens JM, Free SL, Thompson PJ, van Heyningen
V, Fitzpatrick DR: Role of SOX2 mutations in human hippoc-
ampal malformations and epilepsy. Epilepsia 2006, 47:534-542.
19. Valleix S, Niel F, Nedelec B, Algros MP, Schwartz C, Delbosc B,
Delpech M, Kantelip B: Homozygous nonsense mutation in the
FOXE3 gene as a cause of congenital primary aphakia in
humans. Am J Hum Genet 2006, 79:358-364.
20. Ragge NK, Brown AG, Poloschek CM, Lorenz B, Henderson RA,
Clarke MP, Russell-Eggitt I, Fielder A, Gerrelli D, Martinez-Barbera JP,
Ruddle P, Hurst J, Collin JR, Salt A, Cooper ST, Thompson PJ, Sisodiya
SM, Williamson KA, FitzPatrick DR, van Heyningen V, Hanson IM:
Heterozygous mutations of OTX2 cause severe ocular mal-
formations. Am J Hum Genet 2005, 76:1008-1022.
21. Voronina VA, Kozhemyakina EA, O'Kernick CM, Kahn ND, Wenger
SL, Linberg JV, Schneider AS, Mathers PH: Mutations in the human
Additional file 1
Syndromes associated with anophthalmia. A description of the clinical
syndromes known to be associated with anophthalmia. This table also
includes known (or postulated) genetic associations.
Click here for file
[http://www.biomedcentral.com/content/supplementary/1750-
1172-2-47-S1.doc]
Additional file 2
Syndromes associated with microphthalmia. A description of the clinical
syndromes known to be associated with microphthalmia. This table also
includes known (or postulated) genetic associations.
Click here for file
[http://www.biomedcentral.com/content/supplementary/1750-
1172-2-47-S2.doc]
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RAX homeobox gene in a patient with anophthalmia and
sclerocornea. Hum Mol Genet 2004, 13:315-322.
22. Ferda Percin E, Ploder LA, Yu JJ, Arici K, Horsford DJ, Rutherford A,
Bapat B, Cox DW, Duncan AM, Kalnins VI, Kocak-Altintas A, Sowden
JC, Traboulsi E, Sarfarazi M, McInnes RR: Human microphthalmia
associated with mutations in the retinal homeobox gene
CHX10. Nat Genet 2000, 25:397-401.
23. Rahimov F, Ribeiro LA, de Miranda E, Richieri-Costa A, Murray JC:
GLI2 mutations in four Brazilian patients: how wide is the
phenotypic spectrum? Am J Med Genet A 2006, 140:2571-2576.
24. Pasutto F, Sticht H, Hammersen G, Gillessen-Kaesbach G, Fitzpatrick
DR, Nurnberg G, Brasch F, Schirmer-Zimmermann H, Tolmie JL, Chi-
tayat D, Houge G, Fernandez-Martinez L, Keating S, Mortier G, Hen-
nekam RC, von der Wense A, Slavotinek A, Meinecke P, Bitoun P,
Becker C, Nurnberg P, Reis A, Rauch A: Mutations in STRA6
cause a broad spectrum of malformations including anoph-
thalmia, congenital heart defects, diaphragmatic hernia,
alveolar capillary dysplasia, lung hypoplasia, and mental
retardation. Am J Hum Genet 2007, 80:550-560.
25. Billingsley G, Santhiya ST, Paterson AD, Ogata K, Wodak S, Hosseini
SM, Manisastry SM, Vijayalakshmi P, Gopinath PM, Graw J, Heon E:
CRYBA4, a novel human cataract gene, is also involved in
microphthalmia. Am J Hum Genet 2006, 79:702-709.
26. Morle L, Bozon M, Zech JC, Alloisio N, Raas-Rothschild A, Philippe C,
Lambert JC, Godet J, Plauchu H, Edery P: A locus for autosomal
dominant colobomatous microphthalmia maps to chromo-
some 15q12-q15. Am J Hum Genet 2000, 67:1592-1597.
27. Bessant DA, Khaliq S, Hameed A, Anwar K, Mehdi SQ, Payne AM,
Bhattacharya SS: A locus for autosomal recessive congenital
microphthalmia maps to chromosome 14q32. Am J Hum Genet
1998, 62:1113-1116.
28. Bessant DA, Anwar K, Khaliq S, Hameed A, Ismail M, Payne AM,
Mehdi SQ, Bhattacharya SS: Phenotype of autosomal recessive
congenital microphthalmia mapping to chromosome 14q32.
Br J Ophthalmol 1999, 83:919-922.
29. Graham CA, Redmond RM, Nevin NC: X-linked clinical anoph-
thalmos. Localization of the gene to Xq27-Xq28. Ophthalmic
Paediatr Genet 1991, 12:43-48.
30. Dolk H, Busby A, Armstrong BG, Walls PH: Geographical varia-
tion in anophthalmia and microphthalmia in England,
1988–94. BMJ 1998, 317:905-909.
31. Spagnolo A, Bianchi F, Calabro A, Calzolari E, Clementi M, Mastroi-
acovo P, Meli P, Petrelli G, Tenconi R: Anophthalmia and beno-
myl in Italy: a multicenter study based on 940,615 newborns.
Reprod Toxicol 1994, 8:397-403.
32. Bianchi F, Calabro A, Calzolari E, Mastroiacovo PP, Petrelli G, Spag-
nolo A, Tenconi R: Clusters of anophthalmia. No link with ben-
omyl in Italy. BMJ 1994, 308:205.
33. Kristensen P, Irgens LM: Clusters of anophthalmia... or in Nor-
way. BMJ 1994, 308:205-206.
34. Warburg M: An update on microphthalmos and coloboma. A
brief survey of genetic disorders with microphthalmos and
coloboma. Ophthalmic Paediatr Genet 1991, 12:57-63.
35. Weiland HT, Vermey-Keers C, Salimans MM, Fleuren GJ, Verwey RA,
Anderson MJ: Parvovirus B19 associated with fetal abnormal-
ity. Lancet 1987, 1(8534):682-683.
36. Knox EG, Lancashire RJ: Epidemiology of congenital malforma-
tions. London: HMSO; 1991.
37. O'Keefe M, Webb M, Pashby RC, Wagman RD: Clinical anophthal-
mos. Br J Ophthalmol 1987, 71:635-638.
38. Albernaz VS, Castillo M, Hudgins PA, Mukherji SK: Imaging findings
in patients with clinical anophthalmos. Am J Neuroradiol 1997,
18:555-561.
39. Sanjari MS, Ghasemi Falavarjani K, Parvaresh MM, Kharazi HH, Kashk-
ooli MB: Bilateral aplasia of the optic nerve, chiasm, and
tracts in an otherwise healthy infant. Br J Ophthalmol 2006,
90:513-514.
40. Aktekin M, Oz O, Saygili MR, Kurtoglu Z: Bilateral congenital ano-
phthalmos and agenesis of the optic pathways. Yonsei Med J
2005, 46:296-299.
41. Faivre L, Williamson KA, Faber V, Laurent N, Grimaldi M, Thauvin-
Robinet C, Durand C, Mugneret F, Gouyon JB, Bron A, Huet F, Hay-
ward C, Heyningen V, Fitzpatrick DR: Recurrence of SOX2 ano-
phthalmia syndrome with gonosomal mosaicism in a
phenotypically normal mother. Am J Med Genet A 2006,
140:636-639.
42. Guichet A, Triau S, Lepinard C, Esculapavit C, Biquard F, Descamps
P, Encha-Razavi F, Bonneau D: Prenatal diagnosis of primary
anophthalmia with a 3q27 interstitial deletion involving
SOX2. Prenat Diagn 2004, 24:828-832.
43. Bronshtein M, Zimmer E, Gershoni-Baruch R, Yoffe N, Meyer H, Blu-
menfeld Z: First- and second-trimester diagnosis of fetal ocu-
lar defects and associated anomalies: report of eight cases.
Obstet Gynecol 1991, 77:443-449.
44. Chen CP, Wang KG, Huang JK, Chang TY, Lin YH, Chin DT, Tzen CY,
Wang W: Prenatal diagnosis of otocephaly with microphthal-
mia/anophthalmia using ultrasound and magnetic resonance
imaging. Ultrasound Obstet Gynecol 2003, 22:214-215.
45. Mashiach R, Vardimon D, Kaplan B, Shalev J, Meizner I: Early sono-
graphic detection of recurrent fetal eye anomalies. Ultrasound
Obstet Gynecol 2004, 24:640-643.
46. Blazer S, Zimmer EZ, Mezer E, Bronshtein M: Early and late onset
fetal microphthalmia. Am J Obstet Gynecol 2006, 194:1354-1359.
47. Jeanty P, Dramaix-Wilmet M, Van Gansbeke D, van Regemorter N,
Rodesch F: Fetal ocular biometry by ultrasound. Radiology 1982,
143:513-516.
48. Clauser L, Sarti E, Dallera V, Galiè M: Integrated reconstructive
strategies for treating the anophthalmic orbit. J Craniomaxillo-
fac Surg 2004, 32:279-290.
49. Kennedy RE: Growth retardation and volume determinations
of the anophthalmic orbit. Trans Am Ophthalmol Soc 1972,
70:277-297.
50. Kennedy RE: The Effect of Early Enucleation on the Orbit in
Animals and Humans. Trans Am Ophthalmol Soc 1964, 62:459-510.
51. Hintschich C, Zonneveld F, Baldeschi L, Bunce C, Koornneef L: Bony
orbital development after early enucleation in humans. Br J
Ophthalmol 2001, 85:205-208.
52. Tse DT, Pinchuk L, Davis S, Falcone SF, Lee W, Acosta AC, Hernan-
dez E, Lee E, Parel JM: Evaluation of an integrated orbital tissue
expander in an anophthalmic feline model. Am J Ophthalmol
2007, 143:317-327.
53. McLean CJ, Ragge NK, Jones RB, Collin JR: The management of
orbital cysts associated with congenital microphthalmos and
anophthalmos. Br J Ophthalmol 2003, 87:860-863.
54. Online Mendelian Inheritance in Man [http://
www.ncbi.nlm.nih.gov/Omim]
55. Brooks BP, Traboulsi EI: Congenital Malformations of the Eye.
In Duane's Clinical Ophthalmology on CD-ROM 2005 Edition Foundation
Volume 1, Chapter 40 Edited by: Tasman W, Jaeger EA. Philadelphia:
Lippincott.
