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Microphthalmia, anophthalmia, coloboma (MAC): for professionals


Overview

Incidence
  • 3 to 30 per 100,000 newborns[1]
Inheritance
  • de novo sporadic (in most cases)
  • Autosomal dominant
  • Autosomal recessive
  • X-linked recessive
  • X-linked dominant
Genes involved (OMIM No.)Over 90 genes have been identified, the most common being:
  • SOX2 (#184429)
  • OTX2 (#600037)
  • STRA6 (#610745)
  • Mutations in these 3 genes account for 75% of bilateral anophthalmia/severe microphthalmia
Symptoms
  • Visual impairment of variable severity
  • Photophobia with iris coloboma
  • Superior visual field loss in severe chorioretinal coloboma
Ocular featuresUnilateral or bilateral in various combinations:
  • Isolated
  • Mixed (e.g. combination of microphthalmia and coloboma)
  • Complex (associated with other ocular abnormalities such as cataract, anterior segment dysgenesis and vitreoretinal dysplasia)
  • Syndromic
  • Coloboma typically appears in the inferior-nasal aspect
Systemic featuresAbout 60% of patients have extraocular manifestations:
  • Craniofacial anomalies (most common)
  • Midline structural anomalies
  • Neurological anomalies
  • Heart anomalies
  • Gastrointestinal anomalies
  • Genitourinary anomalies
  • Skeletal anomalies
  • Developmental delays in various aspects
Key investigations
  • B-scan USS to measure axial length to document microphthalmia
  • VEP, full-field and pattern ERG studies to determine level of vision
  • MRI brain and orbit
  • Systemic assessment with a paediatrician and other relevant specialists
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (MAC)
  • Whole genome sequencing
ManagementOcular
  • Gradual socket expansion with enlarging ocular prostheses or hydrophilic expanders
  • Cosmesis (painted prostheses/clear shells/contact lens)
  • Surgery for socket reconstruction such as mucous membrane grafting, dermis fat grafting or alloplastic orbital implants
  • Monitoring for socket health and development
  • Correct refractive errors, prevent amblyopia
  • Monitor for and treat associated complications such as retinal detachment, squint etc.
Systemic
  • Multidisciplinary approach
  • Monitor global neurodevelopment
  • Early involvement of practitioners familiar with developmental surveillance and intervention for children with visual impairment (VI) is crucial to optimise development
Therapies under research
  • None at present

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Clinical phenotype

Presenting features

Together, MAC form a spectrum of congenital ocular developmental defects which may have unilateral or bilateral involvement, and may present in various combinations:

  • Isolated
  • Mixed (a combination of MAC conditions)
  • Complex (associated with other ocular abnormalities)
  • Syndromic (MAC with extraocular features)
A patient with bilateral complex microphthalmia. The right eye has an odd shaped and underdeveloped iris while there is haziness in the left cornea (the clear window of the eye).
A patient with bilateral SOX2 complex microphthalmia demonstrating clinical variability within the same individual. The right eye has associated iris hypoplasia while the left eye has microcornea and keratopathy

Over 90 causative genes have been identified so far and as a result, there is significant interfamilial variability in terms of clinical findings and severity. Additionally, intrafamilial variability has been observed, for instance, a parent may have unilateral microphthalmia but their child might present with bilateral microphthalmia and coloboma instead. This might be due to non-penetrance and variable expressivity of certain variants, as a result of genetic modifiers or variation in environmental factors such as maternal vitamin A.[2]

Overall, the MAC conditions account for up to 20% of visual impairment in children.[3] Visual function of patients depends on a few factors:

  • Unilateral (majority of cases) or bilateral involvement
  • Size of the eye (in microphthalmic patients)
  • Associated ocular malformations  
  • Extent of the coloboma (i.e. those with isolated iris coloboma usually have better visual function compared to someone with a large chorioretinal and optic nerve coloboma)

Main ocular features

Anophthalmia and microphthalmia

“True anophthalmos” refers to the absence of the eye, optic nerve and chiasm when eye development is aborted at the stage of the developing optic vesicle, at around 3-4 weeks of gestation.[4] More frequently, development is aborted after the optic vesicle is formed which subsequently degenerates, leaving a small cystic remnant that manifests as a hypoplastic optic nerve, chiasm or tract.[5] This is termed “clinical anophthalmos” and overlaps phenotypically with severe microphthalmia.

Microphthalmia refers to a decreased size of the eye and is defined as having a total axial length (AL) of <19mm at 1 year of age or <21mm in an adult measured on B-scan ultrasound.[6] It is frequently associated with microcornea, defined as having a horizontal corneal diameter of <9 mm in a newborn or <10mm in children older than 2 years.[6] Even within microphthalmia, there is a spectrum of severity and subsets based on the AL, corneal diameter and the dimensions of the anterior and posterior segments, which can be classified as:

  • Severe microphthalmia: Corneal diameter <4mm associated with a total AL of <10mm at birth or <12mm at 1 year of age[4]
  • Posterior microphthalmia: Short total AL with normal anterior segment dimensions (corneal diameter, anterior chamber depth and anteroposterior length of the lens)[3]
  • Nanophthalmia: Both anterior and posterior segment dimensions are reduced, with thickening of the sclera, lens and choroid together with severe hypermetropia (+7.00D to +13.00D); function of the eye is relatively preserved but at high risk of developing angle closure glaucoma[3]

Bilateral anophthalmia or severe microphthalmia is a rare subset, where at least 60% of cases are due to SOX2 and OTX2 mutations.[7,8] 

Ocular coloboma

Coloboma is the most common condition among the MAC spectrum, affecting 1 in 5,000 newborns.[1] It occurs due to incomplete fusion of the optic fissure at around 5-7 weeks of gestation. Colobomata is typically located at the inferior-nasal quadrant and may affect one or more structures along the length of the eye:

  • Iris
  • Ciliary body
  • Choroid, retina and the RPE (chorioretinal coloboma)
  • Optic disc (which may look similar to other disc anomalies such as morning glory disc anomaly)

The majority (>50%) of ocular coloboma cases involve more than one ocular structure, with chorioretinal coloboma being the most frequently encountered.[9] 

A child with a cleft in the iris (the coloured bit of the eye) of both eyes. The gap is shaped like a keyhole and is located at the lower half of the eye.
Bilateral iris coloboma
Pictures of the right and left retina of a patient with bilateral chorioretinal coloboma. There is a large white cleft in the lower half of the right retina while the cleft is much smaller in the lower half of the left retina.
Bilateral chorioretinal coloboma. The right eye is more severely affected compared to the left

Other associated ocular features

Isolated MAC is rare[6] and are normally associated with other ocular abnormalities such as:

Associated extraocular features

Approximately 60% of MAC patients have systemic features, and are more common in patients with bilateral involvement.[9] Systemic manifestations include:

  • Craniofacial anomalies (microcephaly, small and posteriorly rotated ears, wide nasal bridge, short nose, micrognathia, cleft lip, cleft palate and facial asymmetry due to impaired orbital growth)
  • Midline structural anomalies (pituitary hypoplasia/aplasia, corpus callosum hypoplasia/aplasia and absent septum pellucidum)
  • Neurological anomalies (sensorineural hearing loss, seizures)
  • Skeletal anomalies (polydactyly, syndactyly, clinodactyly, abnormalities in the rib cage, long bones and spine)[10] 
  • Heart anomalies (atrial/ventricular septal defects, patent ductus arteriosus, Tetralogy of Fallot)
  • Gastrointestinal anomalies (oesophageal atresia, tracheo-oesophageal fistula, duodenal stenosis, hypoplastic or absent spleen)
  • Genitourinary anomalies (micropenis, hypospadias, cryptorchidism, bicornate/absent/hypoplastic uterus, ovarian agenesis, vesicoureteric reflux, pelvic/duplicated/horseshoe kidney)
  • Developmental delays in various aspects (learning difficulties, motor delay, growth retardation)

Genes associated with syndromic MAC

PhenotypeGenes
Non-syndromic or syndromic MACALDH1A3, BMP4, CHD7, GDF3, GDF6, OTX2, PAX6, PTCH1, RAX, RBP4, SHH, SIX6, SOX2, STRA6, TENM3, TMX3, VSX2, YAP1
Exclusively/predominantly syndromic MACB3GALNT2, BCOR, BMP7, C12orf57, CEP290, COL4A1, CRYBA4, CSPP1, FAM111A, FKTN, FNBP4, FRAS1, FREM1, FREM2, GJA1, GRIP1, HCCS, HMGB3, HMX1, KMT2D, LRP5, MAB21L2, MAPRE2, MITF, NAA10, NHS, PAX2, PDE6D, PITX3, POMGNT1, POMT1, POMT2, PORCN, PQBP1, PXDN, RAB18, RAB3GAP1, RAB3GAP2, RARB, RERE, RPGRIP1L, SALL1, SALL4, SIX3, SMO , SMOC1, SMCHD1, SRD5A3, TBC1D20, TBC1D32, TCTN2, TFAP2A, TMEM216, VAX1, ZEB2

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Genetics

Eye development is a complex process regulated by multiple interacting genes. Any dysregulation of this process during the early stages of pregnancy (first trimester), either via genetic changes, external environmental influence or a combination of both can lead to ocular maldevelopment. [3] In addition, inherent maternal risk factors also play a role in the pathogenesis of MAC.

Genetic changes, either in the form of chromosomal abnormalities or monogenic variants, are a major cause of ocular maldevelopment. Chromosomal abnormalities usually cause syndromic MAC and account for 25-30% of cases, while pathogenic variants in over 90 genes are known to cause all forms of MAC.[4,8,11,12] The most common genes associated with MAC are[8,11]:

Most of the genes associated with MAC either regulate gene expression (transcription factor/gene expression regulator) or are involved in cell signalling to induce specific processes during eye organogenesis (signalling pathway component).

General functionGenes
Transcription factor/gene expression regulatorALX1, ATOH7, BCOR, FOXC1, FOXE3, FOXL2, GLI2, GRIP1, HMX1, MITF, OTX2, PAX2, PAX6, PITX3, RAX, RERE, SALL1, SALL4, SIX3, SIX6, SOX2, TFAP2A, VAX1, VSX2, YAP1, ZEB2
Signalling pathway component (e.g. retinoic acid, hedgehog, frizzled, GTP)ALDH1A3, DOCK6, LRP5, MFRP, NDP, PTCH1, RAB18, RAB3GAP1, RAB3GAP2, RARB, RBP4, SHH, SMO, STRA6, TBC1D20, TBC1D32
Growth factorBMP4, BMP7, GDF3, GDF6
DNA structure/repairCHD7, ERCC1, ERCC5, ERCC6, HDAC6, KMT2D, SMCHD1
Post-translational modificationB3GALNT2, CRPPA, FANCL, FKRP, FKTN, NAA10, POMGNT1, POMT1, POMT2
OtherSRD5A3, ABCB6, ACTB, ACTG1, C12orf57, CC2D2A, CEP290, CLDN19, COL4A1, CRIM1, CRYAA, CRYBA4, CSPP1, DAG1, DHX38, FADD, FAM111A, FNBP4, FRAS1, FREM1, FREM2, GJA1, HCCS, HMGB3, IPO13, KIF11, MAB21L2, MAPRE2, NHS, PDE6D, PORCN, PQBP1, PRSS56, PXDN, RPGRIP1L, SEMA3E, SLC25A24, SLCT1, SMG9, SMOC1, SNX3, SRD5A3, TCTN2, TENM3, TMEM67, TMEM98, TMEM216, TMX3, TUBB

Further information about each gene can be found on OMIM and Medline Plus.

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Environmental and maternal risk factors

Some environmental and maternal risk factors have been implicated to cause MAC, either in isolation or in combination with genetic causes. Examples include:

  • Alcohol consumption during pregnancy
  • Maternal exposure to teratogenic medications (e.g. isotretinoin, warfarin, nitrofurantoin or thalidomide)
  • Maternal vitamin A deficiency[13]
  • Maternal womb infections (e.g. rubella virus, CMV or influenza)[13,14]
  • Maternal age over 40 years old
  • Multiple births
  • Infants with low birthweight (less than 2.5kg)[12]
  • Infants delivered earlier than 38 weeks of pregnancy[12]

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Key investigations

Ocular

1) Clinical examination

Anophthalmia, severe microphthalmia and iris coloboma can be easily detected during newborn screening. Anophthalmia may be detected antenatally during the second trimester, usually as a result of monitoring structural defects in extraocular structures. Milder forms of microphthalmia may be subtle and are not detected at birth.

Depending on the extent of the chorioretinal or optic disc coloboma, some children may be asymptomatic while others can present with poor visual behaviour or a white reflex. If an iris coloboma is detected, it is essential to perform a dilated fundal examination to detect for posterior involvement as ocular colobomas tend to affect more than one structure.  

2) B-scan ultrasound

A diagnosis of microphthalmia is given if the total AL is at least 2 standard deviations below normal, which usually means <19mm at 1 year of age or <21mm in an adult. The mean AL for a full-term neonate is 17mm and for an adult is 23.8mm.[4] Anterior segment dimensions including corneal diameter, anterior chamber depth and anteroposterior length of the lens can also be measured to diagnose posterior microphthalmia.  

3) Electrophysiology

Visual evoked potentials, full-field and pattern electroretinogram (ERG) should be done to assess the child’s level of vision.  

Systemic

With almost 60% of MAC patients having systemic manifestations, babies and children should be referred to a paediatrician for an assessment which usually include:

  • General physical examination including assessment of height, weight (BMI), head circumference and plotting of growth chart
  • MRI brain and orbit imaging (pituitary window should be requested due to the high incidence of midline defects)
  • Echocardiogram
  • Renal ultrasound
  • Developmental assessment

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Diagnosis

New patients should be under joint care with a paediatrician to investigate for any systemic associations and monitoring the child’s development. Genetic testing should be undertaken to obtain a molecular diagnosis and direct future management. This can be achieved through a variety of next generation sequencing (NGS) methods:

  • Targeted gene panel (MAC)
  • Whole genome sequencing

Cytogenetic testing with microarray-based comparative genomic hybridization (array-CGH) may be incorporated with NGS to detect chromosomal deletions or duplications.

It is important to be aware that a causative gene may not be found despite testing with NGS techniques. A causative gene is usually found in approximately 60-70% of bilateral anophthalmia or severe microphthalmia cases while it is only identified in 10% of unilateral cases.[2] 

Related links

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Management

Ocular

1) Socket expansion

Patients with anophthalmia or severe microphthalmia should be referred to an adnexal specialist for socket expansion. This is usually achieved using gradually enlarging clear conformer or painted prostheses while the socket and periocular tissues are developing in the first decade of life. A hydrophilic expander is occasionally required if the socket is very small (either in delayed patient presentations or very young babies) or if the parents cannot travel for regular exchange of their child’s prosthesis.

Images showing different sizes of clear shells that fit into the socket of the eye and two painted eye prostheses.
Clear conformers of various sizes (left) and some painted prostheses (right)

Credit: Miss Sri Gore, consultant ophthalmologist, Moorfields Eye Hospital (London)

A custom-made clear shell or prosthesis is developed from an impression taken from the anterior surface of the socket and the eye if present; this process is called ‘moulding’. Once the prosthesis is fashioned it may then be further modified during the ‘fitting’ process. The moulding and fitting processes may need to occur quite frequently (several times a year) when the periocular tissues are developing but are required less regularly after the age of around five or six years. Each patient has to have a tailored approach to socket expansion due to the following factors:

  • Spectrum of microphthalmia and anophthalmia 
  • Varying ages of presentation to a specialist 
  • The socket’s response to prosthetic treatment 
  • Patient and family’s response to the treatment  

A prosthesis is usually sufficient to encourage orbital and periocular tissue growth, but in a small subset of patients, surgery may be required to reconstruct the volume or the mucosal lining of the socket. There are alloplastic (artificial) and autologous grafts and/or implants that can be used for this purpose. In a smaller subset of patients still, craniofacial surgery may be required to allow patients to wear a stable prosthesis and afford better aesthetic symmetry.

For non-seeing eyes, a cosmetic shell or coloured contact lens can be used to match the contralateral eye whereas those with visual potential a clear conformer may be used. Patients with mild microphthalmic eyes can also have prosthesis or conformers fitted but the care for these are different to patients with more severe microphthalmia or anophthalmia. For example the prosthesis/conformer will have to be removed on a daily basis and the ocular surface of the eye checked more regularly by clinicians.

A patient with no eye ball in the left socket (anophthalmia) fitted with a custom-made prosthesis which is patient to look almost identical to his normal right eye.
A patient with left anophthalmia fitted with a custom-made prosthesis to match his right eye

Credit: Miss Sri Gore, consultant ophthalmologist, Moorfields Eye Hospital (London)

In about 16% of cases, patients with microphthalmia or anophthalmia may have a developmental cyst within the socket.  These cysts are sometimes only detected on scans and can be left alone in the majority of patients; they can also shrink or increase in size. The cysts usually provide useful volume inside the socket and can act like an in-built expander so they can be left inside the socket if they are not distorting the orbital and periorbital anatomy. However, they may need to be removed surgically if they are causing distortion.

2) Management of other ocular co-morbidities

Management depends on the visual potential of the eye and the risks of the treatment involved. These can include: –

  • Correcting any refractive errors
  • Surgical/medical treatment of glaucoma
  • Surgical/medical correction of squints
  • Surgical correction of cataracts or retinal detachments
  • Close monitoring of vision with rapid initiation of amblyopia treatment if detected
  • Referral to low vision services
  • Directing patients and families to supporting organisations

Systemic

A multidisciplinary approach is required if a child is affected by syndromic MAC.

Monitoring of a child’s growth is important as there might be associated pituitary abnormalities. Furthermore, visual impairment can have a negative impact on a child’s early general development. Therefore, timely referral to practitioners familiar with developmental surveillance and intervention for children with visual impairment (VI), such as developmental paediatricians as well as a Qualified Teacher of children and young people with Visual Impairment (QTVI) is crucial to optimise their developmental potential.

The Developmental Journal for babies and young children with visual impairment (DJVI) is a structured early intervention programme designed to track developmental and vision progress from birth to three years of age. It is mainly used by qualified healthcare professionals working in services providing support to babies and young children with VI in conjunction with the child’s parents.

Children with VI may be referred to specialist services such as the developmental vision clinic in the Great Ormond Street Hospital for Children for further management.

Family management and counselling

MAC can be inherited in the following manner:

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis. Due to the extensive range of disease-causing genes, variable expressivity, large number of de novo variants and mosaicism, counselling might be challenging but it should not be an obstacle to support families in making informed medical and personal decisions.

Emotion and social support

Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients in clinic. They provide emotional and practical support to help patients deal with their diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

Referral to a specialist centre

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.

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Current research in MAC

Much of the current research is mainly focused on understanding the causes and disease mechanisms of MAC. As eye development involves such a complex interplay between a multitude of genes, the primary goal now is to identify the full repertoire of genes involved in this process. Once this is achieved, candidate gene(s) can be studied in further detail to identify potential therapeutic avenues by using the following to recapitulate the clinical phenotype of the investigated gene:  

  • Animal models such as mouse, chick and zebrafish. For example, a recent study using zebrafish identified 4 novel ocular coloboma genes ANK3, BMPR1B, PDGFRA, and CDH4 through evolutionary conserved vertebrate gene analysis. These genes were found to cause the coloboma phenotype in human subjects.
  • Early optic vesicles cultured from patient-derived induced pluripotent stem cells

Current clinical studies focus more on genotype-phenotype correlations and best practice for management. Studies include:

Related links

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Further information and support

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References

  1.  Harding P, Moosajee M. Isolated microphthalmia-anophthalmia-coloboma. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=2542. Published 2019. Updated November 2019. Accessed 11 February 2020
  2.  Harding P, Moosajee M. The Molecular Basis of Human Anophthalmia and Microphthalmia. J Dev Biol. 2019;7(3)
  3.  Plaisancié J, Ceroni F, Holt R, et al. Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia. Human Genetics. 2019;138(8):799-830
  4.  Verma AS, Fitzpatrick DR. Anophthalmia and microphthalmia. Orphanet J Rare Dis. 2007;2:47
  5.  Schneider A, Bardakjian T, Reis LM, Tyler RC, Semina EV. Novel SOX2 mutations and genotype-phenotype correlation in anophthalmia and microphthalmia. Am J Med Genet A. 2009;149a(12):2706-2715
  6.  Richardson R, Sowden J, Gerth-Kahlert C, Moore AT, Moosajee M. Clinical utility gene card for: Non-Syndromic Microphthalmia Including Next-Generation Sequencing-Based Approaches. Eur J Hum Genet. 2017;25(4)
  7.  Gerth-Kahlert C, Williamson K, Ansari M, et al. Clinical and mutation analysis of 51 probands with anophthalmia and/or severe microphthalmia from a single center. Mol Genet Genomic Med. 2013;1(1):15-31
  8.  Williamson KA, FitzPatrick DR. The genetic architecture of microphthalmia, anophthalmia and coloboma. Eur J Med Genet. 2014;57(8):369-380
  9.  Shah SP, Taylor AE, Sowden JC, et al. Anophthalmos, microphthalmos, and Coloboma in the United kingdom: clinical features, results of investigations, and early management. Ophthalmology. 2012;119(2):362-368
  10.  Skalicky SE, White AJ, Grigg JR, et al. Microphthalmia, anophthalmia, and coloboma and associated ocular and systemic features: understanding the spectrum. JAMA Ophthalmol. 2013;131(12):1517-1524
  11.  Bardakjian T, Weiss A, Schneider A. Microphthalmia/Anophthalmia/Coloboma Spectrum. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews((R)). Seattle (WA)2015
  12.  Forrester MB, Merz RD. Descriptive epidemiology of anophthalmia and microphthalmia, Hawaii, 1986-2001. Birth Defects Res A Clin Mol Teratol. 2006;76(3):187-192
  13.  O’Keefe M, Webb M, Pashby RC, Wagman RD. Clinical anophthalmos. Br J Ophthalmol. 1987;71(8):635-638
  14.  Vermeif-Keers C. Primary congenital aphakia and the rubella syndrome. Teratology. 1975;11(3):257-265

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Updated on January 31, 2024
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