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Anophthalmia/Microphthalmia Overview

, MS, CGC, , MD, and , MD, FACMG.

Author Information
Department of Genetics
Albert Einstein Medical Center
Philadelphia, Pennsylvania
, MD
Department of Ophthalmology
Children's Hospital and Regional Medical Center
Seattle, Washington
Department of Genetics
Albert Einstein Medical Center
Philadelphia, Pennsylvania

Initial Posting: ; Last Update: May 26, 2006.


Clinical characteristics.

Anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age. Classification of microphthalmia is according to the anatomic appearance of the globe and severity of axial length reduction. Severe microphthalmia refers to a globe with a corneal diameter less than 4 mm and a TAL less than 10 mm at birth or less than 12 mm after age one year. Simple microphthalmia refers to an eye that is anatomically intact except for its short TAL. Complex microphthalmia refers to an eye with anterior segment dysgenesis and/or posterior segment dysgenesis. Anophthalmia/microphthalmia (A/M) can be unilateral or bilateral. A/M is a heterogenous condition with various etiologies. It can be isolated or can occur with other anomalies or as part of a well-defined syndrome. One-third of individuals with A/M have associated malformations. Heritable causes of A/M include chromosome abnormalities and syndromic or nonsyndromic single gene disorders.


The diagnosis of anophthalmia/microphthalmia (A/M) is based on clinical examination and imaging studies including: A-scan ultrasonography to measure total axial length; B-scan ultrasonography to evaluate the internal structures of the globe; and CT scan or MRI of the brain and orbits to evaluate the size and internal structures of the globe, the optic nerve and extraocular muscles, and brain anatomy. Evaluation for other malformations, assessment of hearing, chromosome analysis, family history, and parental eye examinations may help establish the underlying cause. Mutations in the following genes are associated with A/M: SIX3, HESX1, BCOR, SHH, PAX6, RAX, CHD7 (CHARGE syndrome), IKBKG (incontinentia pigmenti), NDP (Norrie disease), SOX2 (SOX2-related eye disorders), POMT1 (Walker-Warburg syndrome), and SIX6.

Genetic counseling.

If a proband has an inherited or de novo chromosome abnormality or a specific syndrome associated with A/M, genetic counseling, and possibly genetic testing, for that condition is indicated. Rarely, isolated anophthalmia may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Assuming that one-half of cases are sporadic and one-half inherited, the empiric risk for sibs without a clear etiology or family history is 10%-15%. Prenatal diagnosis for pregnancies at increased risk for chromosome abnormalities and some syndromic forms of A/M is possible. Transvaginal ultrasound examination may detect the eyes from 12 weeks' gestation onward; in most reports, eye malformations are detected only after 22 weeks' gestation. The sensitivity of transvaginal ultrasound examination in detecting A/M is not known. Three-dimensional and four-dimensional ultrasound examination may be used in some centers to detect complex malformations of the face, including A/M. MRI may be a useful adjunct to ultrasound examination in detection of anophthalmia.


Treatment may include evaluation by an oculoplastic surgeon. Prosthetic intervention and surgery are appropriate in severe microphthalmia and anophthalmia. Early intervention and therapy to optimize psychomotor development, educational endeavors, life skills, and mobility are essential in children with unilateral or bilateral involvement. Protection of the healthy eye in children with unilateral involvement is important. Children with reduced vision in one or both eyes may benefit from visual aids and other visual resources. Surveillance consists of re-evaluation of children by a medical geneticist at age four to five years to look for features of a syndrome that may have become more apparent over time.


Clinical Manifestations

Anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus).

Microphthalmia refers to a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age (see Table 1). For an adult eye, the lower 2.5% confidence limit for the TAL is about 21.0 mm. In a child in whom postnatal ocular growth continues into adolescence, the lower 2.5% confidence limit must be derived from a normative plot of TAL versus age [Gordon & Donzis 1985, Weiss et al 1989].

Table 1.

Length of the Neonatal and Adult Eye

AgeMean Length
Total Axial Length 1 Anterior Segment Length 2 Posterior Segment Length 3
Neonate17 mm6.8 mm10.2 mm
Adult23.8 mm7.3 mm16.5 mm

1. Total axial length (TAL) is the axial distance (in mm) from the corneal apex to the back of the globe.

2. Anterior segment length (ASL) is the axial distance (in mm) from the cornea to the back of the lens.

3. Posterior segment length (PSL) is the axial distance (in mm) from the back of the lens to the back of the globe.

In microphthalmic eyes, measurements of ASL and PSL indicate that ASL is within or below the normal range, whereas PSL is uniformly at least two standard deviations below the mean for age [Weiss et al 1989].

Most postnatal growth of the eye occurs in the first three years of life, particularly during the first year. Growth of the posterior segment accounts for 60% of the prenatal and more than 90% of the postnatal increase in TAL. Although TAL is reduced at birth, the microphthalmic eye can grow by a variable amount in the postnatal period depending upon the severity of the underlying malformation.

Classification of microphthalmia is according to the anatomic appearance of the globe and severity of axial length reduction.

  • Severe microphthalmia refers to a globe that is severely reduced in size, with a corneal diameter less than 4 mm and a TAL less than 10 mm at birth or less than 12 mm after age one year. Although the globe is inconspicuous on clinical examination, CT or MRI reveals remnants of ocular tissue, an optic nerve, and extraocular muscles. Without orbital imaging studies, severe microphthalmia can be mistaken for anophthalmia; thus, the term "clinical anophthalmia" is often inappropriately used for severe microphthalmia.
  • Simple microphthalmia refers to an eye that is anatomically intact except for its short TAL. Decreases in TAL are usually mild in simple microphthalmia. Simple microphthalmia is suspected in the presence of high hyperopia (≥8 diopters) or microcornea, which is present in about 15% of affected individuals. A subset of individuals can have visual loss resulting from posterior segment abnormalities including papillomacular folds, macular hypoplasia, cystoid macular edema, and uveal effusion [Khairallah et al 2002].

    Nanophthalmos is a subtype of simple microphthalmia characterized by microcornea, TAL less than 18 mm, and high hyperopia (≥8 diopters). Angle-closure glaucoma is common.
  • Complex microphthalmia refers to an eye with anterior segment dysgenesis and/or posterior segment dysgenesis. Decreases in TAL can be mild, moderate, or severe.
    • Anterior segment dysgenesis includes a spectrum of developmental abnormalities of the cornea, iris, iridocorneal angle, and ciliary body:
      • Axenfeld-Rieger anomaly. Axenfeld anomaly (a prominent and centrally displaced Schwalbe's line [posterior embryotoxon] with bands of iris tissue bridging the iridocorneal angle) combined with a spectrum of central iris defects including diffuse iris hypoplasia with a normally positioned or eccentric pupil (corectopia) or segmental iris aplasia resulting in multiple pupils (polycoria)

        Note: The term "anomaly" designates the ocular findings alone, whereas the term "syndrome" includes systemic findings such as dental anomalies, maxillary hypoplasia, ocular hypertelorism, cutis navel, and heart defects.
      • Peters anomaly. Circumscribed opacification of the central cornea, the posterior surface of which is bound circumferentially by iris strands and sometimes apposed centrally to the lens
      • Sclerocornea. Opacity and vascularization of portions of the normally transparent cornea which, as a result, resembles sclera
    • Posterior segment dysgenesis includes the following:
      • Cataract
      • Persistent fetal vasculature (previously known as persistent hyperplastic primary vitreous (PHPV). Abnormal persistence of the fetal hyaloid vasculature, overgrowth of the surrounding mesoderm, and inadequate development of the secondary vitreous and lens zonules [Goldberg 1997]

        In anterior PHPV, the persistent hyaloid vessel emerging from the optic disk extends axially and terminates in a fibrovascular membrane integrated with the posterior aspect of the lens. Anterior PHPV is the most frequent cause of unilateral lens opacification and microphthalmia.

        In posterior PHPV, the persistent hyaloid vessel is radially oriented but confined to the epiretinal plane, creating a falciform retinal fold. As a rule, the anterior segment structures are normal except for microcornea, and more than two thirds of cases are microphthalmic.
      • Chorioretinal coloboma. A gap in the ocular tissues extending inferonasally from the optic disk, retina, and choroid posteriorly to the ciliary body and lens zonules and to the iris anteriorly. Iris colobomas cause the pupil to be "key hole" shaped, similar to a "cat's eye."
      • Retinal dysplasia. Histologic findings associated with developmental loss of structural and functional cellular components of the retina

Establishing the Diagnosis

The diagnosis of anophthalmia/microphthalmia is based on the following:

Clinical examination

  • Gross inspection looking for evidence of a cornea/globe and palpation of the orbit to obtain an estimate of globe size
  • Measurement of corneal diameter, which normally ranges from 9.0 to 10.5 mm in neonates and 10.5 to 12.0 mm in adults

Imaging study

  • A-scan ultrasonography to measure total axial length and anterior and posterior segment lengths
  • B-scan ultrasonography to evaluate the internal structures of the globe
  • CT scan or MRI of the brain and orbits to evaluate the size and internal structures of the globe, presence of optic nerve and extraocular muscles, and brain anatomy

Differential Diagnosis

Microphthalmia needs to be distinguished from mild microcornea with a normal-sized globe. Anophthalmia needs to be distinguished from severe microphthalmia, cryptophthalmos, and cystic eye.

  • Cryptophthalmos ("hidden eye") refers to abnormal fusion of the entire eyelid margin with absence of eyelashes, resulting in a continuous sheet of skin extending from the forehead to the cheek. Failure of eyelid separation can be associated with maldevelopment of the underlying cornea and microphthalmia. Cryptophthalmos is usually bilateral and occurs in association with other multiple malformations collectively referred to as Fraser Syndrome. Inheritance is autosomal recessive.
  • Cystic eye refers to a cyst of neuroglial tissue that lacks normal ocular structures. At birth, the cyst may be small, the palpebral fissures narrow, and orbital volume reduced, suggesting anophthalmia. Postnatal expansion of the cyst can lead to distention of the cyst with bulging behind the eyelids. Orbital imaging shows an intraorbital cyst with attached extraocular muscles but no optic nerve. Cystic eye should be distinguished from the cyst associated with colobomatous microphthalmia.


Between 3.2% and 11.2% of blind children have microphthalmia [Fujiki et al 1982, Fraunfelder et al 1985, Traboulsi 1999].

Combining data from three large registers of congenital malformations (central-east France, Sweden, and California), Kallen et al [1996] found a prevalence for anophthalmia/microphthalmia of 1.5 per 10,000.

Between 1984 and 1998, prevalence of anophthalmia/microphthalmia in England was 1.0 per 10,000 births [Busby et al 1998, Dolk et al 1998].

A national study of all live births in Scotland over a 16-year period showed a prevalence of 19 per 100,000 [Morrison et al 2002].

A statewide birth defects monitoring program in California reported that the prevalence of anophthalmia/bilateral microphthalmia was 0.40 per 10,000 between 1989 and 1997 [Shaw et al 2005].

The Alberta Congenital Anomalies Surveillance System noted a mean prevalence for anophthalmia/microphthalmia of 1.4 per 10,000 between 1991 and 2001 [Lowry et al 2005].


Anophthalmia/microphthalmia may be isolated (i.e., with no other systemic involvement) or may be part of a syndrome with other associated anomalies.

Causes can be divided into environmental, heritable, or unknown.

Environmental Causes

Prenatal exposures associated with anophthalmia/microphthalmia include rubella, alcohol, thalidomide, retinoic acid [Fraunfelder et al 1985, Lammer et al 1985], hydantoin [Hampton & Krepostman 1981], and LSD.

Heritable Causes

Chromosome Abnormalities

Deletions and apparently balanced de novo translocations are significant because they may help identify regions in which to search for candidate genes for anophthalmia/microphthalmia.


Trisomy 13 is a severe intellectual disability multiple congenital anomaly syndrome with a mean life expectancy of 130 days; 86% of affected children die within the first year of life. Findings include: holoprosencephaly, cleft lip and palate, scalp skin defects, polydactyly, congenital heart disease, and renal anomalies. Cyclopia (the presence of a single eye [located in the area normally occupied by the root of the nose] and a missing nose or a nose in the form of a proboscis [a tubular appendage located above the eye]), microphthalmia, and coloboma are described.

Mosaic trisomy 9 has been associated with anophthalmia/microphthalmia and other eye anomalies [Kaminker et al 1985, Ginsberg et al 1989].

Deletions. Reported deletions in chromosomal numerical order:

Rearrangements. Apparently balanced de novo translocations seen in individuals with anophthalmia/microphthalmia:

  • 46,XX,t(1;2)(p31.2;q23). Unilateral microphthalmia with cyst and an optic nerve coloboma in the other eye
  • 46,XY,t(8;12)(q22;q21). Bilateral anophthalmia and frontofacionasal dysplasia [Habecker-Green et al 2000]
  • 46,XX,inv(2)(p21q31) de novo. Bilateral microphthalmia in a single individual associated with unusual cataracts and nystagmus. Growth, psychomotor development, and the remainder of the physical examination were normal [Weaver et al 1991]. SIX3 is in this region.
  • 46,XY,t (2;6)(q31;q24). Bilateral severe microphthalmia, intellectual disability, and cerebral palsy [Hirayama et al 2005]

Single Gene Disorders

Syndromic Anophthalmia

Table 2.

Syndromic Anophthalmia: Molecular Genetics

Disease NameGene Chromosomal LocusProtein Name
SOX2-related eye disorders SOX2 3q26.33Transcription factor SOX-2
PAX6-related anophthalmiaPAX6 11p13Paired box protein Pax-6

SOX2-related eye disorders are characterized by bilateral anophthalmia and/or microphthalmia, learning disability, delayed motor development, postnatal growth failure, and cryptorchidism and/or micropenis in males. Esophageal atresia with or without tracheoesophageal fistula [Petrackova et al 2004, Bardakjian & Schneider 2005, Hill et al 2005, Morini et al 2005] are now known to be part of the spectrum of anomalies as Williamson et al [2006] reported heterozygous loss-of-function mutations in SOX2 in three individuals with the anophthalmia-esophageal atresia-genital abnormalities (AEG) syndrome.

Individuals with SOX2-related eye disorders have been reported with deletion of SOX2 associated with a de novo translocation involving 3q27 [Male et al 2002, Fantes et al 2003]. Using sequence analysis, 8%-15% of individuals with bilateral severe eye malformations and fewer than 3% of individuals with unilateral eye involvement have a heterozygous loss-of-function mutation in the coding region of SOX2 [Fantes et al 2003; Hagstrom et al 2005; Ragge et al 2005; FitzPatrick, personal observation]. Inheritance is autosomal dominant.

PAX6 mutations. Heterozygous PAX6 mutations are associated with isolated aniridia. In the rare cases of homozygous PAX6 mutation, severe craniofacial abnormalities, anophthalmia, absent or malformed nose, absent adrenal glands, central nervous system malformations, and fetal or neonatal death have occurred [Hodgson & Saunders 1980, Glaser et al 1994, Graw 1996, MacDonald & Wilson 1996].

Waardenburg anophthalmia syndrome is characterized by anophthalmia, limb abnormalities, growth delays, and intellectual disability. Limb anomalies include syndactyly, oligodactyly, elbow and hip dislocation, bowed tibia, and absence or hypoplasia of fibulae. Inheritance is autosomal recessive.

Oculocerebrocutaneous syndrome (Delleman syndrome). Anophthalmia and, more commonly, congenital cystic eye are associated with cerebral malformations, accessory skin tags, and focal dermal hypoplasia or aplasia. Cerebral malformations mainly include multiple fluid-filled cysts in the cortex and agenesis of the corpus callosum, but occipital meningoencephalocele and cerebellar hypoplasia can occur. Cleft lip/palate has been noted in 15% [Angle & Hersh 1997]. Leichtman et al [1994] reported an extended form of Delleman syndrome that included panhypopituitarism and seizure disorder. Inheritance is autosomal recessive.

"Anophthalmia-plus" syndrome. Bilateral anophthalmia was reported in two sibs, one of whom had bilateral cleft lip/palate and sacral neural tube defect. The second sib did not have extraocular anomalies [Fryns et al 1995].

Anophthalmia/microphthalmia has been reported in association with pulmonary hypoplasia. One of two affected sibs had a cleft palate [Seller et al 1996].

Syndromic Microphthalmia with Anterior Segment Dysgenesis

Microphthalmia with linear skin defects (MLS), also called MIDAS (microphthalmia, dermal aplasia and sclerocornea) and Gazali-Temple syndrome [al-Gazali et al 1990]. Oncocytic cardiomyopathy with conduction defects was described by Stratton et al [1998] in a 46,XX male and complex congenital heart disease with ASD and VSD was described by Lindor et al [1992]. This X-linked dominant male-lethal condition is caused by deletion of a critical region in Xp22.31 [Temple et al 1990, Happle et al 1993, Prakash et al 2002]. Males reported with this disorder tend to have a 46,XX karyotype and to be SRY positive (see 46,XX Testicular Disorder of Sex Development). The ocular phenotype has been expanded to include Peter's anomaly, anophthalmia, and normal-sized globes [Cape et al 2004, Morleo et al 2005].

Syndromic Microphthalmia with Cataract

Cerebro-oculo-facial-skeletal syndrome (COFS) (see Cockayne syndrome), originally described by Pena & Shokeir [1974], is characterized by multiple congenital contractures, microcephaly, hypotonia, failure to thrive, microphthalmia, characteristic facies with prominent nose, large ears, overhanging upper lip, micrognathia, kyphoscoliosis, and osteoporosis. The first reported family with COFS has a mutation in ERCC6 [Meira et al 2000]; therefore, COFS or Pena-Shokeir syndrome type 2 is allelic to, but clinically more severe than, Cockayne syndrome type II. Inheritance is autosomal recessive.

Nance-Horan syndrome (cataract dental syndrome) is characterized by congenital cataracts with microcornea, mild or moderate intellectual disability, crown-shaped anomalies of the teeth, long and narrow face, prominent nasal bridge and nose, large anteverted ears, and shortened fourth metacarpals. Both interfamilial and intrafamilial variability occur. Some carrier females have cataract or mild dental abnormalities. The Nance-Horan syndrome locus has been refined to an interval of 1.3 Mb on Xp22.13 [Toutain et al 1997, Toutain et al 2002, Burdon et al 2003]. Inheritance is X-linked.

Micro syndrome is characterized by congenital membranous cataracts, microcornea (corneal diameter 5.5 mm to 7.5 mm) microphthalmia, 1-2 mm pupils, and persistent pupillary membrane. Lens diameter is 3-4 mm (normal: 6.0 mm). After surgery, visual acuity remains severely reduced despite a normal-appearing fundus, except for mild optic nerve pallor. Electrophysiologic studies demonstrate a normal photopic (light-adapted) and scotopic (dark-adapted) ERG but severely reduced pattern VEP, findings consistent with cortical visual impairment. Brain MRI reveals hypoplasia of the corpus callosum and variable presence of lissencephaly, pachygyria, and cerebellar hypoplasia. Other findings are intrauterine growth retardation, microcephaly, developmental delay, truncal hypotonia with limb spasticity, and hypogenitalism in males [Ainsworth et al 2001].

Syndromic Microphthalmia with Coloboma

Table 3.

Syndromic Microphthalmia with Coloboma: Molecular Genetics

Disease NameGene Symbol (Locus Name)Chromosomal LocusProtein Name
CHARGE syndrome CHD7 8q12.1-q12.2Chromodomain-helicase-DNA-binding protein 7
Papillorenal syndromePAX2 10q24.31Paired box protein Pax-2
Lenz microphthalmia syndrome (ANOP1)Xq27-q28
BCOR Xp11.4BCL-6 corepressor
Branchiooculofacial syndromeUnknownUnknownUnknown
Goltz syndromeX chromosome
Aicardi syndrome

CHARGE syndrome. CHARGE is a mnemonic for coloboma, heart defects, choanal atresia, retarded growth and development and/or CNS anomalies, genital anomalies in males (cryptorchidism and micropenis), and ear anomalies/deafness. Other findings commonly observed are unilateral or bilateral facial nerve palsy, cleft lip and palate, cleft palate only, and sucking and swallowing problems. Anophthalmia has been seen in individuals with CHARGE syndrome. The ear has a characteristic appearance. Hearing loss may be sensorineural or mixed sensorineural and conductive, ranging from mild to profound. CNS anomalies may be severe; developmental delay is variable. About 50%-60% of individuals with CHARGE syndrome have mutations in CHD7 [Vissers et al 2004]; in those individuals inheritance is autosomal dominant.

Papillorenal (renal coloboma) syndrome is characterized by bilateral optic disk anomalies associated with hypoplastic kidneys and/or vesicoureteral reflux that can be associated with end-stage renal disease (ESRD). The optic disk is excavated, central retinal vessels are absent or few in number, and multiple cilioretinal vessels emerge from the disk margins. Papillorenal syndrome is the preferred name because it reflects the specturm of optic disk anomalies. PAX2 mutations have been identified in only four (10%) of 40 individuals with oculorenal abnormalities, suggesting genetic heterogeneity [Sanyanusin et al 1996, Schimmenti et al 1997]. Inheritance is autosomal dominant.

Lenz microphthalmia syndrome (LMS) is characterized by unilateral or bilateral microphthalmia and/or anophthalmia with malformations of the ears, teeth, fingers, skeleton, or genitourinary system. Microphthalmia is often accompanied by microcornea and glaucoma. Coloboma is present in approximately 60% of microphthalmic eyes, with severity ranging from iris coloboma only to coloboma of the ciliary body, choroid, and optic disk. Ears may be low set, anteverted, posteriorly rotated, simple, cup shaped, or abnormally modeled. Hearing loss has been observed. Dental findings include irregularly shaped, missing, or widely spaced teeth. Long cylindrical thorax with sloping, narrow shoulders, kyphoscoliosis, and exaggerated lumbar lordosis are common. Genitourinary anomalies include hypospadias, cryptorchidism, renal hypoplasia/aplasia, and hydroureter. Approximately 60% of affected males have mild-to-severe intellectual disability or developmental delay. Two loci on the X chromosome, ANOP1 (Xq27-q28) and BCOR (Xp11.4-p21.2), are associated with a phenotypic spectrum ranging from isolated microphthalmia to typical LMS [Ng et al 2002]. Mutations in BCOR are also associated with oculo-facio-cardio-dental (OFCD) syndrome which shares overlapping clinical features with LMS, suggesting that the two disorders are allelic [Ng et al 2004, Horn et al 2005]. Inheritance is X-linked.

Branchiooculofacial syndrome (BOF). Anophthalmia and/or microphthalmia in association with colobomas is present in about 50% of affected individuals. Skin defects in the infra-auricular or cervical area are pathognomonic and may be associated with draining sinus fistulae. Renal malformations are common. Cardiac and central nervous system abnormalities are unusual. Developmental delay and hypotonia with visual, hearing, and speech problems are described [Lin et al 1995]. Inheritance is autosomal dominant.

Goltz syndrome is characterized by focal areas of skin hypoplasia and reddish-brown, linear, erythematous, raised and depressed macules that follow the lines of Blaschko. Other features are dystrophic nails, tooth hypoplasia and late eruption, syndactyly of fingers/toes (especially 3rd-4th fingers), oligodactyly, papillomatous lip lesions, strabismus, coloboma, and microphthalmia. Typical features include asymmetry of the face with mild hemiatrophy, low-set protruding ears, a narrow nasal bridge, a broad nasal tip with unilateral notch of the alae nasi, and a pointed chin. Variable expression results from varying degrees of X-chromosome inactivation. Inheritance is X-linked.

Aicardi syndrome is characterized by agenesis of the corpus callosum, chorioretinal lacunae, infantile spasms, intellectual disability, and vertebral segmentation defects. The pathognomonic chorioretinal lacunae are circumscribed defects in the retinal pigment epithelium and underlying choroid. The chorioretinal lacunae can be smaller or larger than the optic disk. Additional ocular abnormalities include dysplastic or hypoplastic optic disks, chorioretinal and optic nerve coloboma, persistent pupillary membrane, microphthalmia, and, rarely, anophthalmia [Hoyt et al 1978, Donnenfeld et al 1989, Menezes et al 1996]. Visual impairment is related to involvement of the macula and optic nerve. All individuals described have been female or males with Klinefelter syndrome with karyotype 47,XXY. The syndrome is believed to be caused by an X-linked dominant, male-lethal mutation in a gene located on the short arm of the X chromosome. Inheritance is X-linked.

Syndromic Microphthalmia with Retinal Dysplasia

Table 4.

Syndromic Microphthalmia with Retinal Dysplasia: Molecular Genetics

Disease NameGene Symbol (Locus Name)Chromosomal LocusProtein Name
Walker-Warburg syndromePOMT1 9q34.13Protein O-mannosyl-transferase 1
Meckel-Gruber syndrome(MKS1)17q22Meckel syndrome type 1 protein
MKS3 8q21.13-q22.1Meckelin
Norrie disease NDP Xp11.3Norrin
Incontinentia pigmenti IKBKG Xq28NF-kappa-B essential modulator

Walker-Warburg syndrome (WWS) (see Congenital Muscular Dystrophy Overview). This disorder is characterized by a congenital muscular dystrophy associated with malformations of the brain and eye. Lissencephaly and cerebellar vermis hypoplasia are uniformly present. Ocular abnormalities of the posterior segment include retinal dysplasia, chorioretinal coloboma, persistence of fetal vasculature, optic nerve hypoplasia, and variable presence of microphthalmia. Anterior segment dysgenesis and cataract are reported. The condition is usually lethal before one year of age. Mutations in the gene POMT1 encoding the protein O-mannasyltransferase were identified in 20% of unrelated individuals with WWS [Beltrán-Valero de Bernabé et al 2002]. Inheritance is autosomal recessive.

Meckel-Gruber syndrome is characterized by CNS malformation (posterior encephalocele, cerebral and cerebellar hypoplasia), polycystic or hypoplastic kidneys, preaxial or postaxial polydactyly, and early demise. Additional findings include cleft lip and palate, ambiguous genitalia, microcephaly, and microphthalmia. Ocular histopathology reveals retinal dysplasia, coloboma, cataract, and corneal dysgenesis. Two loci have been mapped and one gene, MKS3, identified [Smith et al 2006]. Inheritance is autosomal recessive.

Norrie disease (ND) is characterized by a spectrum of fibrous and vascular changes of the retina at birth that progress through childhood or adolescence to cause varying degrees of visual impairment. The most severe retinal findings are grayish-yellow fibrovascular masses, which occur in the first few months of life and progress to phthisis bulbi (shrinking of the globe), resulting in total blindness. Norrie disease is inherited in an X-linked recessive manner. About 85% of affected males have an identifiable mutation in NDP. Inheritance is X-linked.

Incontinentia pigmenti (IP) is an X-linked dominant disorder that is usually male lethal. The pathognomonic finding is the evolution of skin changes along Blaschko's lines in four stages: vesiculobullous, verrucous, swirled hyperpigmentation, and patchy atrophic hypopigmentation. Additional organ involvement includes the hair, teeth, skeleton, and central nervous system (seizures, hemiparesis, spasticity, intellectual disability, microcephaly, and cerebellar ataxia). Ocular abnormalities are reported in 35% of individuals with IP and include incomplete retinal vascularization and postnatal neovascularization, foveal hypoplasia, pigment epithelial mottling, microphthalmia, and, rarely, anophthalmia. Mutations in the NF-kappa B essential modulator gene (IKBKG) have been identified in about 80% of affected individuals. Inheritance is X-linked dominant, usually male lethal.

Table 5 lists in order by chromosome the genes known to be involved in syndromic microphthalmia/anophthalmia.

Table 5.

Syndromic Microphthalmia/Anophthalmia

Gene Chromosomal LocusProtein NameRegulatory Function in the EyeOcular PhenotypeSystemic Findings
SIX3 1 2p21Homeobox protein SIX3Differentiation of retinal precursorsMicrophthalmia, coloboma, PHPVHoloprosencephaly, cleft lip/palate
HESX1 3p14.3Homeobox expressed in ES cells 1Developmental patterning of forebrainSeptooptic dysplasiaPituitary hypoplasia, agenesis of corpus callosum and septum pellucidum
SHH 2 7q36.3Sonic hedgehog proteinDevelopmental patterning of ventral eyeColobomatous microphthalmia, anophthalmiaHoloprosencephaly, cleft lip/palate normal
SIX6 14q23.1Homeobox protein SIX6Development of eye, pituitary, and hypothalamusAnophthalmia (heterozygote)Pituitary hypoplasia
VSX2 3 14q24.3Homeobox protein CHX10Proliferation of neuroretinal progenitor cellsMicrophthalmia, cataract, iris colobomaNone
RAX18q21.32Retinal homeobox protein RxEstablishment and/or proliferation of retinal progenitor cellsAnophthalmia, microphthalmiaUnknown

SIX6. Individuals with bilateral anophthalmia and pituitary anomalies with interstitial deletions of chromosome 14q were reported by Gallardo et al [1999]. The possibility that the phenotype is related to the loss of additional genes in this region cannot be excluded. In a study of 173 individuals with anophthalmia, microphthalmia, or coloboma, Aijaz et al [2004] found no intragenic mutations in SIX6.

RAX. Molecular analysis of 75 individuals with anophthalmia/microphthalmia identified a single individual with unilateral anophthalmia who was a compound heterozygote for mutations within the DNA-binding homeodomain of RAX [Voronina et al 2004]. Parents and grandparents, who were clinically normal, were heterozygotes. Inheritance is autosomal recessive.

Nonsyndromic Microphthalmia/Anophthalmia

Isolated nonsyndromic microphthalmia and anophthalmia with or without coloboma have been described. No specific genes have been identified in many of these families.

Isolated anophthalmia has been considered to be autosomal recessive in most cases. Occurrence of anophthalmia in several consanguineous families has been reported.

Unknown Causes

Oculo-auriculo-vertebral spectrum (also known as Goldenhar syndrome, hemifacial microsomia, facio-auriculo-vertebral spectrum) is a complex malformation syndrome involving structures derived from the first and second branchial arches, sometimes accompanied by ocular and/or vertebral anomalies. The first pair of arches contribute extensively to the formation of facial bones (maxilla, zygoma, squamous portion of the temporal bone, mandible, hyoid, and the ear ossicles), related muscles and ligaments, aortic arches, and cranial nerves V and VII. The phenotype is highly variable because of the multiple derivatives of the pharyngeal arches, variable combination of abnormalities, and lateralizing asymmetry (70% of cases are unilateral). Cardinal features include maxillary and zygomatic hypoplasia, microtia, preauricular tags and/or pits, middle-ear anomaly with deafness, macrostomia, hypoplasia of facial musculature, malfunction of soft palate and tongue, epibulbar dermoids, and vertebral anomalies. Occasional ocular abnormalities include eyelid coloboma and chorioretinal coloboma, sometimes associated with microcornea and microphthalmia ipsilateral to the hemifacial microsomia. Estimated incidence is 1:3000-1:5000 live births with 3:2 male predominance.

Other. Unilateral and bilateral anophthalmia have been reported in association with basal encephalocele and other CNS anomalies (primarily gray-matter heterotopia, agenesis of corpus callosum), midline oronasal cleft with absence of nasal septum and columella, ocular hypertelorism, intellectual disability, and growth retardation [Tada 1985, Guion-Almeida & Richieri-Costa 1999].

Unilateral and bilateral anophthalmia/microphthalmia has been reported in combination with many different birth defects including abnormalities of the kidneys and GU system, heart, ear (including hearing loss), vertebrae, and brain. Developmental delay and autism are also seen more frequently than in the general population [Bardakjian & Schneider 2005].

Many of these cases do not fit a known syndrome.

Evaluation Strategy

Establishing the specific cause of anophthalmia/microphthalmia in a given individual usually involves medical history, physical examination, family history, neuroimaging, renal ultrasound examination, hearing screen, and karyotype. More studies may be warranted based on findings from physical examination or family history.

Family history. It is appropriate to obtain a three-generation family history of eye anomalies, including anophthalmia, microphthalmia, and coloboma. Complete eye examinations of both parents are warranted.

Physical examination. It is appropriate to examine a proband for evidence of a syndrome associated with anophthalmia/microphthalmia. If no specific syndrome is identified in infancy, re-examination by a medical geneticist after four to five years is warranted because features of several syndromes are more obvious as the child grows and develops.


Molecular genetic testing is possible for mutations in numerous genes associated with anophthalmia/microphthalmia.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Syndromic anophthalmia/microphthalmia. If a proband has an inherited or de novo chromosome abnormality or a specific syndrome associated with anophthalmia/microphthalmia, genetic counseling for the mode of inheritance of that condition is indicated.

Risk to Family Members — Empiric Recurrence Risk

Rarely, isolated anophthalmia may be inherited in an autosomal dominant [Griepentrog & Lucarelli 2004], autosomal recessive, or X-linked manner. In such cases, genetic counseling for the identified mode of inheritance is indicated. Assuming that one-half of cases are sporadic and one-half inherited, the empiric risk for sibs without a clear etiology or family history is 10%-15% [I Maumenee, personal communication].

Risk to Family Members — Chromosomal

Anophthalmia can be the result of an inherited or de novo chromosome abnormality in an individual who has other congenital malformations.

Parents of a proband

Sibs of a proband

  • Sibs of a proband with a numerical chromosome abnormality have a slightly increased risk of having a similar chromosome abnormality (depending upon the specific abnormality and the age of the mother) with either a similar or different phenotype.
  • The risk to sibs of a proband with a structural unbalanced chromosome constitution depends upon the chromosome findings in the parents.
  • If neither parent has a structural chromosome rearrangement, the risk to sibs is negligible.
  • If a parent has a balanced structural chromosome rearrangement, the risk to sibs is increased and is dependent upon the specific chromosome rearrangement and other possible variables.

Offspring of a proband. Individuals with anophthalmia/microphthalmia and an unbalanced chromosome rearrangement are unlikely to reproduce.

Carrier Detection

If a parent of the proband has a balanced chromosome rearrangement, at-risk family members can be tested by chromosome analysis.

Related Genetic Counseling Issues

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Chromosome analysis. Prenatal diagnosis for pregnancies at increased risk for chromosome abnormalities is possible. Chromosome analysis is performed on fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Molecular genetic testing. If the disease-causing mutation(s) have been identified in an affected family member, prenatal testing for at-risk pregnancies is possible through laboratories offering either prenatal testing for the gene of interest or custom testing.

Imaging studies

  • Transvaginal ultrasound examination may detect the eyes from 12 weeks' gestation onward [Chen et al 2003, Mashiach et al 2004]. In most reports, eye malformations are detected only after 22 weeks' gestation. The sensitivity of transvaginal ultrasound examination in detecting anophthalmia/microphthalmia is not known.
  • Three-dimensional and four-dimensional ultrasound examination may be used in some centers to detect complex malformations of the face, including anophthalmia/microphthalmia [Lee et al 1995].
  • MRI may be a useful adjunct to ultrasound examination in detection of anophthalmia.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • International Children's Anophthalmia and Microphthalmia Network (ICAN)
    c/o Center for Developmental Medicine and Genetics
    5501 Old York Road
    Genetics, Levy 2 West
    Philadelphia PA 19141
    Phone: 800-580-4226 (toll-free)
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
  • National Federation of the Blind (NFB)
    200 East Wells Street
    (at Jernigan Place)
    Baltimore MD 21230
    Phone: 410-659-9314
    Fax: 410-685-5653
  • eyeGENE® - National Ophthalmic Disease Genotyping Network Registry
    Phone: 301-435-3032


Evaluations Following Initial Diagnosis

Following diagnosis of anophthalmia/microphthalmia based on examination by an ophthalmologist, ultrasound examination of the globe and CT or MRI of the brain and orbit to help establish the presence or absence of eye tissue optic nerve is recommended.

Treatment of Manifestations

Evaluation by an oculoplastic surgeon may be helpful in determining the best course of action in each individual.

Prosthetic intervention is appropriate in severe microphthalmia and anophthalmia. In many cases, an ocularist can start shortly after birth to expand the palpebral fissures, conjunctival cul-de-sac, and orbit by fitting the infant with conformers of progressively increasing size. In some cases, conformers do not adequately expand the orbit, especially horizontally, causing an "hour glass" deformity.

Surgery is appropriate in severe microphthalmia and anophthalmia. Surgical options include placement of orbital implants of fixed dimensions at one or more surgeries; placement of expandable implants (silicone balloon, hydrophilic polymers); or use of a dermis-fat graft, which has the capability of post-surgical growth. Considerations for surgical intervention are best made after six months of age when postnatal growth of the orbit can be assessed. Older individuals in whom the orbital dimensions are fixed or individuals with previous orbital irradiation may require extensive orbital reconstruction.

Early intervention and therapy to optimize psychomotor development, educational endeavors, life skills and mobility are essential in children with unilateral or bilateral involvement.

Protection of the healthy eye in children with unilateral involvement. Children with reduced vision in the fellow eye as a result of coloboma or other malformation may benefit from visual aids and other visual resources.


Individuals not seen since infancy should be re-evaluated by a medical geneticist at age four to five years for features of a syndrome that may have become more apparent over time.


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  75. Voronina VA, Kozhemyakina EA, O'Kernick CM, Kahn ND, Wenger SL, Linberg JV, Schneider AS, Mathers PH. Mutations in the human RAX homeobox gene in a patient with anophthalmia and sclerocornea. Hum Mol Genet. 2004;13:315–22. [PubMed: 14662654]
  76. Wallis DE, Roessler E, Hehr U, Nanni L, Wiltshire T, Richieri-Costa A, Gillessen-Kaesbach G, Zackai EH, Rommens J, Muenke M. Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nat Genet. 1999;22:196–8. [PubMed: 10369266]
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Suggested Reading

  1. Warburg M. Classification of microphthalmos and coloboma. J Med Genet. 1993;30:664–9. [PMC free article: PMC1016495] [PubMed: 8411053]

Chapter Notes

Revision History

  • 15 February 2007 (cd) Revision: testing for mutations in RAX clinically available
  • 26 May 2006 (me) Comprehensive update posted to live Web site
  • 29 January 2004 (me) Overview posted to live Web site
  • 7 March 2003 (as) Original submission
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