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Microphthalmia/Anophthalmia/Coloboma Spectrum

, MS, LCGC, , MD, and , MD, FACMG.

Author Information
, MS, LCGC
GeneDx
Gaithersburg, Maryland
, MD
Department of Ophthalmology
Children's Hospital and Regional Medical Center
Seattle, Washington
, MD, FACMG
Department of Genetics
Einstein Medical Center
Philadelphia, Pennsylvania

Initial Posting: ; Last Update: July 9, 2015.

Summary

Clinical characteristics.

Microphthalmia, anophthalmia, and coloboma comprise the MAC spectrum of ocular malformations.

  • Microphthalmia refers to a globe with a total axial length that is at least two standard deviations below the mean for age.
  • Anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus).
  • Coloboma refers to the ocular malformations that result from failure of closure of the optic fissure. Chorioretinal coloboma refers to coloboma of the retina and choroid. Iris coloboma causes the iris to appear keyhole-shaped.

Microphthalmia, anophthalmia, and coloboma may be unilateral or bilateral; when bilateral they may occur in any combination.

Diagnosis/testing.

Molecular genetic testing (which can include sequence analysis, gene-targeted deletion/duplication analysis, and chromosome microarray analysis [CMA]) can identify a genetic cause in 80% of individuals with bilateral anophthalmia/severe microphthalmia and in up to 20% of all individuals with an ocular malformation in the MAC spectrum.

Management.

Treatment of MAC spectrum: Prosthetic intervention is appropriate for those with severe microphthalmia and anophthalmia. In many infants, an ocularist can start shortly after birth to expand the palpebral fissures, conjunctival cul-de-sac, and orbit using conformers of progressively increasing size. An oculoplastic surgeon can help determine the most suitable options for surgical intervention after age six months (when postnatal growth of the orbit can be assessed) and before the age that orbital dimensions are fixed (after which extensive orbital reconstruction may be required).

Children with reduced vision may benefit from visual aids and other visual resources as well as early intervention to help optimize psychomotor development, educational endeavors, life skills, and mobility. Protection of the healthy eye in those with unilateral involvement is recommended.

Genetic counseling.

When an inherited or de novo chromosome abnormality or a specific syndrome is identified either by phenotypic findings or by genetic/genomic testing, genetic counseling is indicated based on the mode of inheritance for that condition.

Definition

Microphthalmia, anophthalmia, and coloboma comprise the MAC spectrum of ocular malformations.

Microphthalmia refers to a globe with a total axial length (TAL) 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 approximately 21.0 mm.
  • In children (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 1Anterior Segment Length 2Posterior 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 on 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 <4 mm and a TAL <10 mm at birth or <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 interchangeably used for severe microphthalmia.

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

Coloboma refers to any of the ocular malformations that result from failure of closure of the optic fissure extending inferonasally from the optic disk, retina, and choroid (in the posterior portion of the eye) to the ciliary body and lens zonules and to the iris (in the anterior portion of the eye) during embyrogenesis.

Chorioretinal coloboma refers to coloboma of the retina and choroid. Iris coloboma causes the pupil to be "keyhole" shaped.

Other abnormalities of the eye that can be seen with coloboma include:

  • Sclerocornea: opacity and vascularization of portions of the normally transparent cornea which, as a result, resembles sclera
  • Cataract: opacity of the lens
  • Retinal dysplasia: histologic findings associated with developmental loss of structural and functional cellular components of the retina

Each of these three malformations may be unilateral or bilateral; when bilateral they may occur in any combination. For example:

  • Colobomatous malformations may occur in any combination within an eye or between eyes of the same individual.
  • Colobomatous malformations may occur with or without microphthalmia.
  • Colobomatous malformations in one eye may be accompanied by microphthalmia or anophthalmia in the fellow eye.
  • Anophthalmia may be bilateral or unilateral with or without colobomatous malformation of the fellow eye.

Establishing the Diagnosis of MAC Spectrum

The diagnosis of MAC 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 of MAC Spectrum

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 (OMIM 219000). 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.

Causes

Recent studies indicate that molecular genetic testing that includes sequence analysis, gene-targeted deletion/duplication analysis, and chromosome microarray analysis (CMA) can identify a genetic cause in:

  • 80% of individuals with bilateral anophthalmia/severe microphthalmia [Williamson & FitzPatrick 2014];
  • Up to 20% of all individuals with an ocular malformation in the microphthalmia, anophthalmia, coloboma (MAC) spectrum (in which the laterality and severity of MAC can vary).

Chromosome Abnormalities

Chromosome abnormalities can be identified in an estimated 25%-30% of individuals with MAC (Table 2) [Verma & Fitzpatrick 2007].

Table 2.

Common Chromosome Abnormalities Associated with Microphthalmia/Anophthalmia/Coloboma (MAC) Spectrum

Type of Chromosome AbnormalityChromosome Abnormality
AneuploidyTrisomy 9 mosaicism
Trisomy 13
Trisomy 18
TriploidyTriploidy
Deletion4p- (Wolf-Hirschhorn syndrome)
Deletion 7p15.1-p21.1
13q-, ring 13
Deletion 14q22.1-q23.2
18q-
Deletion 3q26 (includes SOX2)
DuplicationDuplication 3q syndrome (3q21-ter dup)
Duplication 4p syndrome
Duplication 10q syndrome

Single-Gene Disorders

Single-gene causes of MAC spectrum that account for 1% or more of anophthalmia/microphthalmia/coloboma are listed in Table 3A. Single-gene causes that account for less than 1% of MAC spectrum are listed in Table 3B. The microphthalmia, anophthalmia, and coloboma (MAC) spectrum is present in all disorders listed in both tables.

Of note, the co-occurrence of any of the ocular findings within the MAC spectrum may be unilateral or bilateral and may be in any combination within an eye (e.g., chorioretinal coloboma and/or iris coloboma ± microphthalmia) or between eyes of the same individual (e.g., colobomatous malformation in one eye and anophthalmia in the fellow eye).

Table 3A.

Molecular Genetics of Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum: Most Common Genetic Causes

Gene 1Disease Name% of MAC Attributed to Mutation of This GeneMOIOcular Phenotype 2Distinguishing Clinical FeaturesSelected OMIM
SOX2SOX2-related eye disorders15%-20%ADOptic nerve hypoplasiaFTT, genital abnormalities, pituitary dysfunction, DD, ataxic gait, atypical seizures, SNHL, EA±TEF184429 
206900
OTX2OTX2-related eye disorders2%-5%ADAS
RD
Optic nerve hypoplasia/aplasia 3
Pituitary anomalies/dysfunction, brain abnormalities, DD, autistic features 4600037
610125
RAXMicrophthalmia, isolated 33%ARSclerocorneaDD601881
611038
FOXE3FOXE3-related ocular disorder 52.5%ARSclerocorneaUnknown (possible DD, ASD)601094
BMP4Orofacial cleft 112%ADRD, SclerocorneaDigital anomalies, pituitary anomalies/dysfunction, learning disabilities112262
600625
PAX6PAX6-related anophthalmia 6, 72%ARAniridiaCerebellar ataxia607108
BCOROculofaciocardiodental (OFCD) syndrome 8>1%XLOFCD: CatOFCD syndrome (females only): cardiac abnormalities, tooth anomaly radiculomegaly, toe anomalies300485
300166
Lenz microphthalmia syndrome (LMS)LMS (males only) (see NAA10 in Table 3B)
CHD7CHARGE syndrome>1%ADHeart defects, choanal atresia, renal anomalies, growth retardation, ear malformations608892
214800
STRA6Microphthalmia, isolated with coloboma 8>1%ARNonsyndromic610745
601186
Microphthalmia, syndromic 9 (Matthew-Wood syndrome; PDAC)Congenital diaphragmatic hernia, lung malformations, DD
GDF6Microphthalmia, isolated 41%AD601147
613094
118100
Klippel-Feil syndrome 1Klippel-Feil anomaly, vertebral/rib anomalies, polydactyly

Pathogenic variants of any one of the genes included in this table account for ≥1% of anophthalmia/microphthalmia/coloboma (MAC).

MOI = mode of inheritance

Ocular phenotypes:

AS = anterior segment dysgenesis

Cat = cataract

RD = retinal dysplasia

Distinguishing clinical features:

FTT = failure to thrive

SNHL = sensorineural hearing loss

ID = intellectual disability

EA±TEF = esophageal atresia with or without tracheoesophageal fistula

DD = developmental delays

ASD = autism spectrum disorders

Footnotes:

1.

Genes that cause ≥2% of MAC are listed from most frequent to least frequent genetic cause; they are followed in alphabetical order by genes that cause <2% but >1% of MAC.

2.

Ocular features in addition to the typical findings in the MAC spectrum

3.

Slavotinek [2011]

4.

Schilter et al [2011]

5.

Reis et al [2010], Jimenez et al [2011], Chassaing et al [2014], Williamson & FitzPatrick [2014], Islam et al [2015]

6.

Author [personal observation]

7.

Heterozygous PAX6 pathogenic variants are associated with isolated aniridia.

8.

Also can be caused by mutation of NAA10 (see Table 3B)

Table 3B.

Molecular Genetics of Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum: Less Common Genetic Causes

Gene 1Disease NameMOIOcular Phenotype 2Distinguishing Clinical FeaturesSelected OMIM
CRYBA4Cataract 23ADCatNonsyndromic123631
610425
HCCSMicrophthalmia with linear skin defects (MIDAS syndrome)XLSclerocorneaFTT, hydrocephalus, linear pigmentary changes, cardiac & brain anomalies, genital abnormalities300056
309801
HESX1Septooptic dysplasiaADOptic nerve hypoplasiaPituitary hypoplasia, ACC, absence of septum pellucidum601802
182230
IKBKGIncontinentia pigmentiXLMAC 3
Retinal neovascularization
Skin lesions change w/age; hypodontia, alopecia, dystrophic nails, seizures, ID300248
308300
NAA10Lenz microphthalmia syndromeXLID, short stature; clavicle, skeletal, & renal anomalies300013
309800
NHSNance-Horan syndromeXLCat
Microcornea
ID, tooth anomalies, short 4th metacarpal300457
302350
PORCNFocal dermal hypoplasia
(Goltz syndrome)
XLAtrophic skin patches, cutis aplasia, pigmentary changes, nail anomalies, notched alae nasi, CL/P300651
305600
PXDNSee footnote 4ARSclerocorneaNone reported; possible developmental delay
RARBMicrophthalmia, syndromic 12ADDiaphragmatic hernia, DD, bicornuate uterus, intestinal malrotation, hypotonia180220
615524
SHHMicrophthalmia with coloboma 5ADNonsyndromic600725
611638
142945
Holoprosencephaly 5Holoprosencephaly, CL/P
SMOC1Microphthalmia with limb anomalies
(Waardenburg anophthalmia syndrome)
AROligosyndactyly, distal limb anomalies, ID608488
206920
TFAP2ABranchiooculofacial syndromeADCat
Ptosis
Branchial skin defect, cleft lip, upper lip pits malformed pinnae, hearing loss107580
113620
VSX2Isolated colobomatous microphthalmia-3ARCatNonsyndromic142993
610092
610093
Isolated microphthalmia-2

Pathogenic variants in any one of the genes listed in this table are reported in only a few families (i.e., <1% of anophthalmia/microphthalmia/coloboma (MAC).

MOI = mode of inheritance

Ocular phenotypes:

Cat = cataract

RD = retinal dysplasia

Distinguishing clinical features:

FTT = failure to thrive

SNHL = sensorineural hearing loss

ID = intellectual disability

EA±TEF = esophageal atresia with or without tracheoesophageal fistula

DD = developmental delays

ASD = autism spectrum disorders

ACC = absence of the corpus callosum

CL/P = cleft lip/palate

Footnotes:

1.

Genes are listed in alphabetical order.

2.

Ocular features in addition to the typical findings in the MAC spectrum

3.

Minić et al [2010]

4.

Khan et al [2011], Choi et al [2015]

5.

Slavotinek [2011]

Evaluation Strategy

Establishing the specific genetic cause of microphthalmia/anophthalmia/coloboma (MAC) spectrum in a given individual usually involves the following:

  • Ophthalmologic examination by an ophthalmologist familiar with MAC to document both the ocular manifestations of MAC and any additional ocular findings.
  • Ocular/brain imaging studies
    • Ultrasound examination of the orbits
    • MRI of the brain and orbits (or CT scan if unable to obtain an MRI)
  • Physical examination (including dysmorphology examination) to determine the presence of distinguishing clinical features which may identify a specific genetic cause (see Tables 3A and 3B). Additional studies that may be warranted include:
    • Endocrine evaluation
    • Dental evaluation in older child
    • Echocardiogram
    • Renal ultrasound examination
  • Family history. It is appropriate to obtain a three-generation family history of eye anomalies, including anophthalmia, microphthalmia, and coloboma. Complete eye examination of both parents is warranted.
  • Genomic/genetic testing, which can include the following:
    • Chromosomal microarray analysis (CMA) to look for evidence of aneuploidy or chromosome duplication, deletion, or rearrangement (Table 2). Note: CMA will not detect balanced chromosomal rearrangements.
    • Single-gene testing in the order in which genes are most likely to be mutated, based on the individual’s clinical findings and/or family history (see Table 3A and Table 3B). Single-gene testing should include sequence analysis as well as gene-targeted deletion/duplication analysis [Reis et al 2010, Chassaing et al 2014].
    • Use of a multi-gene panel that includes the genes of interest. Note: The genes included and the sensitivity of multi-gene panels vary by laboratory and over time.
    • Genomic testing; may be considered if serial single-gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with MAC spectrum. Such testing may include whole-exome sequencing (WES), whole-genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq). For issues to consider in interpretation of genomic test results, click here.
  • If no diagnosis is established after the initial set of examinations and tests, reevaluation within two years is recommended.

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.

When an inherited or de novo chromosome abnormality (see Table 2) or a specific syndrome is identified either by features listed in Table 3A or Table 3B or by genetic/genomic testing, genetic counseling is indicated based on the mode of inheritance for that condition.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Pregnancies known to be at increased risk for MAC spectrum due to a previous affected child and/or family history

  • If the genetic/genomic cause has been identified in the affected relative, prenatal testing relies on testing that will detect the genetic/genomic change present in the affected relative.
  • If the genetic/genomic cause has not been identified in the affected relative, prenatal testing relies on the following imaging studies:

Pregnancies not known to be at increased risk for MAC spectrum. When a MAC spectrum abnormality is detected on fetal ultrasound examination, further diagnostic work up is recommended including chromosome microarray analysis (CMA) and SOX2 sequence analysis and gene-targeted deletion/duplication analysis. Use of a multi-gene panel of genes of interest can also be considered.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which pathogenic variant(s) in a specific gene have been identified.

Resources

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)
    Email: ican@anophthalmia.org
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
    Email: 2020@nei.nih.gov
  • National Federation of the Blind (NFB)
    200 East Wells Street
    (at Jernigan Place)
    Baltimore MD 21230
    Phone: 410-659-9314
    Fax: 410-685-5653
    Email: pmaurer@nfb.org
  • eyeGENE® - National Ophthalmic Disease Genotyping Network Registry
    Phone: 301-435-3032
    Email: eyeGENEinfo@nei.nih.gov

Management

Treatment of MAC Spectrum

Prosthetic intervention is appropriate in severe microphthalmia and anophthalmia.

  • In many infants, an ocularist can start shortly after birth to expand the palpebral fissures, conjunctival cul-de-sac, and orbit using conformers of progressively increasing size. In some instances, conformers do not adequately expand the orbit, especially horizontally, causing an "hour glass" deformity.
  • An oculoplastic surgeon can help determine the most suitable options for surgical intervention after age six months (when postnatal growth of the orbit can be assessed) and before the age that orbital dimensions are fixed (after which extensive orbital reconstruction may be required).

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.

Children with reduced vision may benefit from visual aids and other visual resources as well as early intervention to help optimize psychomotor development, educational endeavors, life skills, and mobility. Protection of the healthy eye in those with unilateral involvement is recommended.

References

Literature Cited

  1. Araujo Júnior E, Kawanami TE, Nardozza LM, Milani HJ, Oliveira PS, Moron AF. Prenatal diagnosis of bilateral anophthalmia by 3D "reverse face" view ultrasound and magnetic resonance imaging. Taiwan J Obstet Gynecol. 2012;51:616–9. [PubMed: 23276567]
  2. Chassaing N, Causse A, Vigouroux A, Delahaye A, Alessandri JL, Boespflug-Tanguy O, Boute-Benejean O, Dollfus H, Duban-Bedu B, Gilbert-Dussardier B, Giuliano F, Gonzales M, Holder-Espinasse M, Isidor B, Jacquemont ML, Lacombe D, Martin-Coignard D, Mathieu-Dramard M, Odent S, Picone O, Pinson L, Quelin C, Sigaudy S, Toutain A, Thauvin-Robinet C, Kaplan J, Calvas P. Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia. Clin Genet. 2014;86:326–34. [PubMed: 24033328]
  3. Chen CP, Wang KG, Huang JK, Chang TY, Lin YH, Chin DT, Tzen CY, Wang W. Prenatal diagnosis of otocephaly with microphthalmia/anophthalmia using ultrasound and magnetic resonance imaging. Ultrasound Obstet Gynecol. 2003;22:214–5. [PubMed: 12905522]
  4. Choi A, Lao R, Ling-Fung Tang P, Wan E, Mayer W, Bardakjian T, Shaw GM, Kwok PY, Schneider A, Slavotinek A. Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis. Eur J Hum Genet. 2015;23:337–41. [PMC free article: PMC4326713] [PubMed: 24939590]
  5. Gordon RA, Donzis PB. Refractive development of the human eye. Arch Ophthalmol. 1985;103:785–9. [PubMed: 4004614]
  6. Islam L, Kelberman D, Williamson L, Lewis N, Glindzicz MB, Nischal KK, Sowden JC. Functional analysis of FOXE3 mutations causing dominant and recessive ocular anterior segment disease. Hum Mutat. 2015;36:296–300. [PubMed: 25504734]
  7. Jimenez NL, Flannick J, Yahyavi M, Li J, Bardakjian T, Tonkin L, Schneider A, Sherr EH, Slavotinek AM. Targeted 'next-generation' sequencing in anophthalmia and microphthalmia patients confirms SOX2, OTX2 and FOXE3 mutations. BMC Med Genet. 2011;12:172. [PMC free article: PMC3262754] [PubMed: 22204637]
  8. Khan K, Rudkin A, Parry DA, Burdon KP, McKibbin M, Logan CV, Abdelhamed ZI, Muecke JS, Fernandez-Fuentes N, Laurie KJ, Shires M, Fogarty R, Carr IM, Poulter JA, Morgan JE, Mohamed MD, Jafri H, Raashid Y, Meng N, Piseth H, Toomes C, Casson RJ, Taylor GR, Hammerton M, Sheridan E, Johnson CA, Inglehearn CF, Craig JE, Ali M. Homozygous mutations in PXDN cause congenital cataract, corneal opacity, and developmental glaucoma. Am J Hum Genet. 2011;89:464–73. [PMC free article: PMC3169830] [PubMed: 21907015]
  9. Lee A, Deutinger J, Bernaschek G. Three dimensional ultrasound: abnormalities of the fetal face in surface and volume rendering mode. Br J Obstet Gynaecol. 1995;102:302–6. [PubMed: 7612513]
  10. Mashiach R, Vardimon D, Kaplan B, Shalev J, Meizner I. Early sonographic detection of recurrent fetal eye anomalies. Ultrasound Obstet Gynecol. 2004;24:640–3. [PubMed: 15517557]
  11. Minić S, Obradović M, Kovacević I, Trpinac D. Ocular anomalies in incontinentia pigmenti: literature review and meta-analysis. Srp Arh Celok Lek. 2010;138:408–13. [PubMed: 20842883]
  12. Reis LM, Tyler R, Schneider A, Bardakjian T, Semina E. Examination of SOX2 in variable ocular conditions identified a recurrent deletion in microphthalmia and lack of mutations in other phenotypes. Mol Vis. 2010;16:768–773. [PMC free article: PMC2862242] [PubMed: 20454695]
  13. Schilter KF, Schneider A, Bardakjian T, Soucy JF, Tyler RC, Reis LM, Semina EV. OTX2 microphthalmia syndrome: four novel mutations and delineation of a phenotype. Clin Genet. 2011;79:158–68. [PMC free article: PMC3017659] [PubMed: 20486942]
  14. Slavotinek AM. Eye development genes and known syndromes. Mol Genet Metab. 2011;104:448–56. [PMC free article: PMC3224152] [PubMed: 22005280]
  15. Verma AS, Fitzpatrick DR. Anophthalmia and microphthalmia. Orphanet J Rare Dis. 2007;2:47. [PMC free article: PMC2246098] [PubMed: 18039390]
  16. Weiss AH, Kousseff BG, Ross EA, Longbottom J. Simple microphthalmos. Arch Ophthalmol. 1989;107:1625–30. [PubMed: 2818284]
  17. Williamson KA, FitzPatrick DR. The genetic architecture of microphthalmia, anophthalmia and coloboma. Eur J Med Genet. 2014;57:369–80. [PubMed: 24859618]
  18. Wong HS, Parker S, Tait J, Pringle KC. Antenatal diagnosis of anophthalmia by three-dimensional ultrasound: a novel application of the reverse face view. Ultrasound Obstet Gynecol. 2008;32:103–5. [PubMed: 18570241]

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

  • 9 July 2015 (me) Comprehensive update posted to live Web site – title change
  • 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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