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Microphthalmia, anophthalmia, coloboma (MAC): for patients

Overview

  • Microphthalmia—Underdeveloped or small eye
  • Anophthalmia—Absence of the eye
A short animation explaining MAC

Microphthalmia, anophthalmia and coloboma (MAC) are a group of birth eye conditions that affect 3 to 30 per 100,000 newborns.[1] Together they are the most common cause of childhood sight impairment registration in England and Wales (18.4% of children).[2] Of the three, coloboma is the most common condition in the MAC spectrum, affecting 1 in 5000 newborns.[1]

MAC can affect one (unilateral) or both (bilateral) eyes. Patients may have one of, or a combination of microphthalmia, anophthalmia and coloboma. It might be associated with other eye conditions (such as cataract and anterior segment dysgenesis) and other organs in the body might be affected as well. There can be a high degree of difference in the severity among individuals even within the same family. There is no treatment available for MAC currently.

Although we do not know the exact cause for MAC conditions, both genetic and environmental factors (such as exposure to certain medications, maternal alcohol intake, infections and Vitamin A deficiency during pregnancy) have been identified.

So far, more than 90 different genes have been identified which may cause various forms of MAC. Most cases develop spontaneously during pregnancy without prior family history. However, in those with affected family members, it can be inherited through dominant inheritance (autosomal dominant) where one parent has a faulty gene, recessive inheritance (autosomal recessive) where both parents have the faulty gene or X-linked recessive inheritance which only affects boys as it is caused by a faulty gene on the X-chromosome.

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The condition

MAC are often considered as a spectrum of birth eye conditions where anophthalmia is the most severe form, followed by microphthalmia and coloboma. It can present in various combinations and either one (unilateral) or both (bilateral) eyes can be affected:  

  • Isolated (having one of the MAC conditions only)
  • Mixed (a combination of the MAC conditions) such as microphthalmia and coloboma
  • Complex (associated with other eye conditions such as cataract and anterior segment dysgenesis)
  • Syndromic (affecting other body systems such as the brain, skull and facial bones, limbs, heart, lungs, kidneys, genitals and overall development)
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 complex microphthalmia. The right eye has an odd-shaped pupil with underdeveloped iris tissue while the left cornea is hazy and has a smaller than usual size.

The type and severity of MAC can differ within families. For instance a parent may have unilateral microphthalmia but their child has bilateral microphthalmia and coloboma. Sometimes it can even differ within individuals with bilateral involvement. For example, one eye may be affected by anophthalmia while the other may have microphthalmia and coloboma. As a result, some individuals are greatly affected with limited visual potential while others have no apparent symptoms.

About 60% of individuals tend to have the syndromic form whereby craniofacial (the bones and tissues in the face and skull) clefts are most commonly seen.[3] Individuals with bilateral conditions are at increased risk of having syndromic MAC.  

Symptoms

1) Visual impairment

Microphthalmia and anopthalmia

Patients with anophthalmia will have no vision in the affected eye.

In those with microphthalmia, the effect on vision depends on the severity, size of the eye, if one or both eyes are affected and if there are any associated eye conditions such as the following:

  • Cataract (most common)[4]
  • Changes in the development of the structures at the front of the eye such as the cornea, iris and lens (anterior segment dysgenesis)
  • Glaucoma
  • Coloboma
  • Changes in the development of the retina (retinal dysplasia)
  • Under-developed optic nerve (optic nerve hypoplasia)

Coloboma

Coloboma can affect one or more structures in the eye with a cleft or a gap, typically found at the 5-7 o’clock position of the eye. The size of the cleft can vary from person to person.

The severity of visual impairment depends on the structures affected and size of the cleft. It can be classified as the following:

  • Iris coloboma — While people with just iris coloboma often have relatively good vision, they are more likely to be affected by light sensitivity (photophobia). This is because the iris controls the amount of light entering the eye by changing the size of the pupil. If a part of the iris is missing, too much light can enter the eye which can cause glare and discomfort in bright light.
A child with bilateral iris coloboma
This is an eye showing the iris, a circular structure that gives the eye colour, and the pupil which is the black hole in the middle of the iris.
The pupil constricts (becomes small) with light, dilates (becomes big) in dark
  • Ciliary body coloboma — The ciliary body contains muscles which the supporting fibres of the lens (known as lens zonules) are attached to. The zonules hold the lens firmly in place. In ciliary body or lens coloboma, the zonules are not firmly anchored and therefore, the lens is no longer held as strongly as it normally would. This alters the shape of the lens giving it a notched appearance. As a result, vision can be affected. Formation of cataract can cause further visual deterioration.
  • Chorioretinal coloboma — This means the coloboma is affecting the retina, RPE and choroid, a layer of tissue behind the retina rich with blood vessels keeping the retina nourished and healthy. Patients may not notice any symptoms if the size of the chorioretinal coloboma is small. However, if there is a large portion of tissue missing, vision is likely to be poor. Patients with chorioretinal coloboma are at increased risk of retinal detachment.
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.
A patient with bilateral coloboma. The right eye is more severely affected compared to the left eye.
  • Optic disc coloboma — Isolated optic disc coloboma can appear quite similarly to other birth conditions of the optic disc such as morning glory disc anomaly, a condition which is associated with structural changes and poor blood circulation in the brain. Children with optic disc coloboma tend to have very poor vision.

Coloboma may affect only one structure in isolation but this is a minority. A UK-wide study found that more than 50% of patients have a coloboma in more than one location in the same eye.[3] The same study also noted that chorioretinal coloboma is the most common.

In very young children, it can be hard to tell the effect coloboma has on their vision. Doctors will have a better idea as they get older as more accurate tests can be used and they are able to verbalise their difficulties. As coloboma typically affects the lower part of the eye (5-7 o’clock position), children with extensive chorioretinal coloboma may complain of visual loss in their upper peripheral field of vision. This is because our brain processes image in an inverted manner.

2) Dysfunction or under development of other organs

60% of MAC patients have other organs affected apart from the eye, some of which form recognised syndromes. Here are some examples:

  • Craniofacial (face and skull) differences and asymmetry

This is the most common condition found among MAC patients, particularly those affected by anophthalmia or microphthalmia. Birth conditions affecting the ears, nose, lips, roof of the mouth (palate) or jaw may be present. The most common conditions are cleft lip and cleft palate.

Individuals with anophthalmia and microphthalmia are also at risk of developing facial asymmetry (where one side of the face doesn’t mirror the other). This is because after birth, our eyeball continues to grow which allows the bones and soft tissues around the eye socket to grow and develop. In children without an eye or a small eye, the bones and soft tissue may not be able to develop properly. 

  • Neurological and sensory conditions

Structural differences of the brain can lead to a wide range of difficulties such as seizures and restricted growth. A child’s growth is severely affected if there is abnormality with the pituitary gland (a structure in the brain that secretes hormones to regulate bodily functions. One of the hormones secreted is the growth hormone) is affected. In addition, MAC patients also experience hearing loss quite frequently.[3]

  • Functional impact

Affected children may experience developmental delays, learning difficulties and autism.

  • Heart conditions
  • Digestive tract conditions
  • Limb and skeletal conditions

Individuals may have extra fingers or toes (polydactyly), webbed fingers or toes (syndactyly) or the fifth finger or toe curving towards the fourth (clinodactyly). The rib cage, long bones (arms and legs) and spine can display anomalies as well.[4]

  • Kidney and genital conditions
  • CHARGE syndrome

This is the most common form of syndromic coloboma. CHARGE is an acronym used to describe the main features of the condition, which are Coloboma, Heart conditions, Choanal atresia (narrowing of the nasal passage from birth which results in breathing difficulty), Genital and Ear anomalies.

  • SOX2 anophthalmia syndrome

This is characterised by bilateral anophthalmia or severe microphthalmia, seizures, brain disorders, restricted growth, hearing loss, delayed development of motor skills, learning disabilities, oesophageal atresia and tracheoesophageal fistula and genital anomalies.

Cause

Formation of the eye during pregnancy is a complex process where many different genes interact with each other. Any disruption to this process, either from genetic faults, external environmental influence or a combination of both can lead to under development of the eye.

The severity of the birth conditions seen in MAC depends on which stage this developmental process was disrupted. As a result, a variety of presentations can occur even among family members with the same faulty gene. Some family members may only be mildly affected and have no symptoms while others might be severely affected.

Genetic causes of MAC:

  • Can be due to either anomalies in a chromosome or a gene
  • About 25-30% of MAC cases are due to chromosomal anomalies
  • Over 90 genes have been identified to date
  • SOX2 gene is the most commonly genetic cause (15-40% of MAC cases)[5] 
  • OTX2 gene is the second most common genetic cause (2-5% of MAC cases)[6]
  • At least 60% of bilateral MAC cases are due to changes in either the SOX2 or OTX2 gene[5,7]
  • Changes in the CHD7 gene causes CHARGE syndrome

External environmental factors during pregnancy known to increase the risk of MAC:

  • Alcohol consumption
  • Maternal exposure to certain medications that may cause developmental delays (such as isotretinoin, warfarin or thalidomide)
  • Maternal vitamin A deficiency[8]
  • Maternal womb infections (the rubella virus is a common cause)[8,9]

Maternal risk factors associated with microphthalmia

  • Maternal age over 40 years old
  • Multiple births
  • Infants with low birthweight (less than 2.5kg)[10]
  • Infants delivered earlier than 38 weeks of pregnancy[10]

How is it diagnosed?

1) Eye examination

Anophthalmia, severe microphthalmia and iris coloboma are usually detected during the newborn screening. Milder forms of microphthalmia may be more subtle and not noticed at birth. Depending on size, chorioretinal or optic disc coloboma may not cause any symptoms and go undetected, or a child may display unusual visual behaviour or parents might pick up an unusual white reflection from the retina when taking pictures, called the white reflex (Compared to the ‘red eye’ reflection or red reflex you often see on photographs where a flash has been used).

Microphthalmia is diagnosed by measuring the size of the eyeball using an ultrasound scan. This is a non-invasive procedure and does not contain any harmful radiations, similar to “tummy scans” during pregnancy.

Chorioretinal and optic disc coloboma can only be detected by examining the retina. This is usually done after putting eye drops to dilate the pupil.

Some cases of anophthalmia can be detected during pregnancy with ultrasound scanning during the second trimester, especially when structural changes in other organs are being monitored but this is not always the case.

2) General medical assessment

As the genes involved in eye development also have a role in the development of other organs as well, an assessment by a paediatrician is essential to exclude any syndromes or other conditions. The examination usually includes an MRI (magnetic resonance imaging) of the brain, ultrasound scans of the heart and kidneys and other tests deemed appropriate by the paediatrician. Other specialists may be involved depending on the examination findings and test results.

3) Genetic testing

Genetic testing will help identify if there is a faulty gene so that families can have more informed genetic counselling. It can also help the medical team to refer you to the appropriate specialist for monitoring.   

It is important to be aware that a faulty gene may not be found as MAC can be caused by a combination of genetic and environmental factors. A faulty 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.[11]

How is it inherited?

Many children are the first in the family to be affected as most MAC cases occur spontaneously. This means that the change occurs when the child was still just a ball of cells developing in the womb during pregnancy, and the condition was not passed down by parents. However, it can also be inherited in an autosomal recessive, autosomal dominant or X-linked recessive manner depending on the gene involved. Genetic testing will be able to provide a clearer picture.

If your child is affected by MAC, it is advisable to see a genetic counsellor to obtain more information and advice on inheritance and family planning options.

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Treatment

There is currently no treatment for MAC in terms of restoring normal vision. Management is mainly focused on changing facial appearance, maximising remaining vision and looking after the child’s general wellbeing. This often requires a team consisting of specialists from different areas.

1) Changing facial appearance

In anophthalmia and microphthalmia, early and gradual eye socket expansion during the first year of life is recommended to achieve the best outcome because the eye socket and the eyelids undergo most of their growth in the first three years of life and is particularly fast in the first year.

If children are referred in the first year of life then the expansion can start with little expanders that absorb water and slowly grow on their own; these may need replacing for larger ones. Some specialist centres just use shells or prosthetics in the first year of life and obtain very good cosmetic results, however, this does mean more visits to the prosthetics team during that period.   

After the age of one, an impression of the socket can made by using a special substance, which are also used by dentists to make impressions of teeth. This process is called moulding and is not painful because the prosthetics team usually use anaesthetic drops if required. A custom-made painted prosthesis or a clear shell can then be produced using this mould. The prosthesis can then be further modified during a ‘fitting’ process to ensure comfortable and stable wear.

Some acrylic shells/prostheses that are custom-made and painted to look like the unaffected eye.
Custom-made painted prostheses

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

The prosthesis or shell is used to help make the eyes look like each other and can also be used to help the socket grow. A painted prosthesis is usually matched to the other side or, if both eyes need a prosthesis, with those of a family member. The process of making and fitting a new prosthesis will happen more frequently in the first three to four years of life and then will become less frequent thereafter.

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-sided anophthalmia fitted with a custom-made prosthesis which is painted to look like the normal right eye.

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

Important information about the care of the prosthesis, including its removal, cleaning and replacement is given by the prosthetics team; they are also there to guide families and troubleshoot for common issues. Sometimes other teams may be required to treat occasional issues such as irritation or infection of the socket.  A little bit of sticky discharge from the socket is normal but if the team feels that this is beyond the normal level then medical treatments, such as drops, may be required. Sometimes an increase in discharge could mean it is time for the prosthesis to be changed;  the doctors and prosthetics team look for clues, such as ‘spinning’ of the prosthesis, to make these decisions.

In most patients, a prosthesis is usually sufficient to encourage good eye socket growth and achieve symmetry between the eyes. Sometimes, surgery to the eye socket may be required so that a prosthesis can fit in a more comfortable and stable way. These surgeries are tailored to the sockets of each patient and could involve tissues being brought from other areas of the body such as the fat from the buttock or lining from the mouth; these procedures are called grafts.

Artificial implants may also be used inside the socket to help boost the socket size and help support prosthesis wear. In a small group of patients, eyelid surgery may be required to further improve the comfort and look of the prosthesis; these operations are usually performed later on in childhood such as during early teens.  

A small group of patients with microphthalmia or anophthalmia may also be born with a ‘cyst’ within the socket. These cysts are sometimes only picked up on scans whereas some can be seen in the socket or the eyelids. They can be left alone in most patients if they are not causing any damage to the socket or eyelids and most are useful to have in the socket as they can make the socket grow. If they need to be removed then this is usually done with an operation.

2) Maximising remaining vision

If the eye affected by microphthalmia or coloboma is considered to have visual potential, several measures could be taken to encourage optimum visual development:

(a) Patching treatment

The eye with better vision is patched if the affected eye has become “lazy” (not reaching full visual potential)

(b) Correcting long or short sightedness

Any long or short sightedness should be corrected with glasses to make the best of the child’s vision

(c) Monitoring for associated eye abnormalities and potential complications

Due to the complex relationship between each structure in the eye during development, children with MAC may be affected by other eye disorders as well, with the two most common conditions being cataract and anterior segment dysgenesis, which may lead to glaucoma. Individuals with chorioretinal coloboma are also at risk of developing a detached retina (about 30% risk).[12] Because of this, children should be monitored regularly so that, if needed, treatment can be started quickly as these conditions can severely impact vision.

The risks of any treatment are weighed against the potential benefits, so patients will have individual treatment plans and these may have to be modified later on.

3) Looking after the child’s general health

As MAC is frequently associated with both functional (e.g developmental delays, learning difficulties and autism) and physical disabilities, specialists from many different teams are often involved. One key member is a paediatrician who specialises in child development that can monitor your child’s physical and functional growth. Qualified Teachers of children and young people with Visual Impairment (QTVI) are also crucial in helping visually impaired children in school.

Through regular monitoring, early intervention can be introduced if needed to help your child reach his/her full potential. The Developmental Journal for babies and young children with visual impairment (DJVI), developed by Great Ormond Street Hospital Developmental Vision team is a structured early intervention programme designed to track developmental and vision progress in children 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 visual impairment (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 or other specialist developmental services for further management.

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Current research in MAC

Human eye development during pregnancy is a complex process. We have not yet identified all the genes involved and their role in conditions. Because of this research currently focuses on understanding the causes and mechanisms which result in MAC.

Once the full range of genes is known, researchers can then study each gene closely to identify potential targets for intervention and develop new treatments. The genes involved can be investigated in two ways:  

  • Using animal models to assess the role of specific genes in eye development
  • Growing early eye cups using stem cells of MAC patients (modified from skin cells). This will help scientists understand how normal eye development is disrupted in these patients
A short animation showing how our skin cells can be used to grow early eye cups for research

Related links

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Practical advice

Living with MAC

Depending on the severity, some patients are still able to lead relatively independent lives through maximising their available vision and having access to social support. Here are some ideas:

  • Attending the low vision clinic which provides access to low vision specialists, Eye Clinic Liaison Officers (ECLOs), visual aids and visual rehabilitation services
  • Utilising assistive technologies that can improve quality of life
  • Contacting the local council’s social services department for access to rehabilitation services and assessment of your individual needs to help you remain independent
  • Getting in touch with the local education authority for access to qualified teachers for children with visual impairment (QTVI) and special educational needs co-ordinator (SENCO)
  • Registering as sight impaired (SI) or severely sight impaired (SSI) if eligible for access to social support and financial concessions
  • Getting in touch with national or local charities for advice and peer support

Related links

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Referral to a specialist centre

If you are based in the UK and would like to be seen in the nearest specialist centre for your eye condition, either to receive a more comprehensive genetic management or just to find out more about current research, you can approach your GP to make a referral or alternatively arrange for a private appointment. 

More information can be found in our “How to see a genetic eye specialist?” page.

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Further information and support

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A patient’s perspective

John talking to the MACS charity about his personal experience with the condition
Ellie’s father talking to the MACS charity about his experience with his daughter’s condition

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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.  Mitry D, Bunce C, Wormald R, et al. Causes of certifications for severe sight impairment (blind) and sight impairment (partial sight) in children in England and Wales. Br J Ophthalmol. 2013;97(11):1431-1436
  3.  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
  4.  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
  5.  Williamson KA, FitzPatrick DR. The genetic architecture of microphthalmia, anophthalmia and coloboma. Eur J Med Genet. 2014;57(8):369-380
  6.  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
  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.  O’Keefe M, Webb M, Pashby RC, Wagman RD. Clinical anophthalmos. Br J Ophthalmol. 1987;71(8):635-638
  9.  Vermeif-Keers C. Primary congenital aphakia and the rubella syndrome. Teratology. 1975;11(3):257-265
  10.  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
  11.  Harding P, Moosajee M. The Molecular Basis of Human Anophthalmia and Microphthalmia. J Dev Biol. 2019;7(3)
  12.  Hussain RM, Abbey AM, Shah AR, Drenser KA, Trese MT, Capone A, Jr. Chorioretinal Coloboma Complications: Retinal Detachment and Choroidal Neovascular Membrane. J Ophthalmic Vis Res. 2017;12(1):3-10

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Updated on November 30, 2020
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