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Axenfeld-Rieger syndrome: for patients

Overview

Axenfeld-Rieger Syndrome (ARS) is a rare condition that primarily affects the eye, leading to the development of glaucoma in approximately 50% of the affected individuals.[1] Glaucoma may present at birth or shortly after (also known as congenital glaucoma), or later in life during childhood, adolescence or even adulthood. About 1 in 50,000 to 100,000 people are affected by ARS.

The condition is caused by genetic mutations leading to the abnormal development of the structures in the front part of the eye (anterior segment), which encompasses the sclera, cornea, iris, trabecular meshwork and the lens. The structures that are primarily affected in ARS are the cornea, iris and trabecular meshwork, leading to a variety of features that characterise ARS. Some examples include:

  • Clouding of the cornea
  • Enlargement of the eyeball known as buphthalmos (Greek word for “ox eye”)
  • Incomplete or poorly developed iris (iris hypoplasia)
  • An off-centre pupil (the central black hole of the eye) known as corectopia
  • Extra pupils (polycoria)
This is a three dimensional illustration of the eye. The structures are listed from front to back. The anterior segment, highlighted in a blue box consists of the sclera, cornea, pupil, iris and lens. The posterior segment, highlighted by a green box consists of the retina, macula, optic disc and the optic nerve.
The anterior and posterior segments of the eye
The right eye of an infant is enlarged due to primary congenital glaucoma
A child affected by primary congenital glaucoma presenting with buphthalmos

Credit: Prof Sir PT Khaw, consultant ophthalmologist, Moorfields Eye Hospital, London

In some individuals with ARS, other parts of the body can be affected as well. Many have distinctive facial features, dental abnormalities and extra folds of skin around the belly button (redundant periumbilical skin) but other less common features such as hearing difficulties, heart issues and genital abnormalities may also be present.

The severity of the condition (both eye and systemic symptoms) differs significantly between individuals, even among members of the same family. As a result, the age at which ARS is diagnosed, whether other parts of the body are affected and its prognosis is highly variable.

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The condition

Symptoms

1) Visual

Axenfeld-Reiger syndrome predominantly affects the eyes but the symptoms experienced among affected individuals are highly variable, depending on the structures affected and the age at which these symptoms start. Some may have no symptoms at all, while others may experience light sensitivity from the iris abnormalities, excessive tearing and/or blurry vision (from clouding of the cornea).

More importantly, about 50% of ARS patients develop glaucoma, which can cause further impairment of vision (due to damage to the optic nerve) if not detected and treated quickly. Glaucoma can present at any age in ARS; when it presents during infancy (also known as congenital glaucoma), the affected child usually has haziness in the cornea and buphthalmos, which prompt parents to seek urgent medical attention. Glaucoma that develops later in life (childhood, adolescence or adulthood) tend to present more insidiously, with blurry vision, a sudden squint or a raised eye pressure (known medically as intraocular pressure) detected on routine eye check-ups. If left untreated, individuals may initially notice blurriness in their side (peripheral) vision, which slowly creeps in to the centre, eventually leading to “tunnel vision”.

A person driving a car with normal peripheral vision is able to see the girl in a red dress on the left. If the driver has a loss of peripheral vision, the same girl is not noticeable.
Peripheral vision loss
Seeing from the perspective of someone with tunnel vision. The person can see buildings from a small central area of his/her vision but the side vision around the central area is blurry.
Tunnel vision

2) Systemic (other body systems)

In some individuals with ARS, other parts of the body can be affected as well. Many have distinctive facial features which include:

  • Wide prominent forehead
  • Widely spaced eyes (hypertelorism)
  • Flattening of mid-face and a short upper lip
  • Broad and flat nasal bridge

In addition, some may have dental abnormalities such as unusually small teeth (microdontia), less than average number of teeth (oligodontia), decreased number of evenly spaced teeth (hypodontia) and extra folds of skin around the belly button (redundant periumbilical skin), which can be mistaken as a hernia of the umbilicus.

Other less common features of ARS include[2]:

  • Hearing loss
  • Genital abnormalities such as hypospadias (the opening of the penis is not at the tip)
  • Heart abnormalities
  • Joint and bone abnormalities

Cause

So far, only two genes, FOXC1 and PITX2 have been identified to cause ARS. About 40% of ARS cases are attributed to mutations in these two genes, while the other 60% are caused by changes in genes that are yet to be identified.[1,3]  Both of these genes play an important role in the normal development of the eye, particularly structures in the anterior segment, and other organs in the body when we are still developing in the womb. FOXC1 and PITX2 are part of a network of genes that closely interact with each other during this critical period. Hence, mutations in these genes can lead to the features seen in ARS.  

Individuals with mutations in the PITX2 gene tend to have other parts of the body affected along with ocular (eye) features, while patients with FOXC1 mutations usually only have isolated ocular features. These findings are however variable among affected individuals.[4,5]

How is it diagnosed?

1) Eye examination

The ocular features associated with ARS can be detected by an ophthalmologist through examination. However, in infants presenting with congenital glaucoma, he/she may need to be examined under general anaesthetic as carrying out a detailed evaluation in this age group can be challenging. The examination usually involves checking the eye pressure (tonometry), assessing the architecture of the drainage channels of the eye including the trabecular meshwork (gonioscopy) and taking a photograph of the optic nerve (for future comparisons to detect glaucoma progression). Once a child is old enough (usually about the age of 7 years), automated measurements of the side vision (perimetry) are performed as well to monitor visual function.  

In individuals with only mild symptoms of ARS and not affected by glaucoma initially, they should still be monitored on a regular basis by either an ophthalmologist (usually for children) or an optometrist (for adults) given the high risk of glaucoma development.  

2) General medical assessment

As ARS may involve other parts of the body as well, an assessment by a paediatrician may need to be carried out to detect if there are any systemic involvement and whether treatment is required.

3) Genetic testing

Genetic testing will help identify if there is a faulty gene so that families can have a better-informed genetic counselling session and more accurate advice on prognosis. It can also help the medical team to refer you/your child to the appropriate specialist for monitoring.

Families should be aware that a faulty gene may not be identified as the genes causing majority of ARS cases (~60%) have still not been identified, or not attributed to mutations in FOXC1 and PITX2.[2-4]

How is it inherited?

1) Autosomal dominant inheritance

Only one faulty gene copy (inherited from either parent) is required to cause disease. This means that each newborn of the patient has a 50% chance of inheriting the condition regardless of gender.

The faulty gene copy is present in the father while the mother is not affected. Each newborn of this couple has a 50% chance to be affected by the condition.
Autosomal dominant inheritance

2) Sporadic (occuring spontaneously)

About 50-70% of cases occur in this manner.[3] This means that the genetic mutation causing ARS arose by chance, and the affected individual is usually the first person in the family to have this condition. Given the marked variation in the severity of ARS, even among members of the same family, first degree relatives of a presumed sporadic case should be examined to detect subtle features and undergo genetic testing to assess if they carry the same mutation. The genetic findings may have an impact on family planning.

If you/your child is affected by ARS, 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

Is there any treatment?

There is currently no treatment for the underlying genetic changes and structural abnormalities associated with ARS. However, there are effective treatment options for glaucoma. Management is tailored to the symptoms present and is mainly focused on maximising remaining vision, lowering eye pressure and looking after the child’s general wellbeing. This often requires a team of specialists from different areas.

1) Glaucoma

High eye pressure accelerates optic nerve damage in glaucoma. Therefore, glaucoma treatment is centred on lowering the eye pressure to a level where damage to the optic nerve is halted or slowed down significantly. Treatment options vary depending on the age of onset and its severity. For infants affected by congenital glaucoma, an operation is usually required. There are a few types of procedure that can be performed to lower eye pressure in congenital glaucoma, all of which your child’s ophthalmologist will be able to explain to you in further detail. Eye drops or oral medications may be started initially but these options are usually temporary, as they are not as effective as surgery in reducing the eye pressure in this age group. Occasionally, eye drops may still be required after surgery to achieve better control of the eye pressure.

In later-onset glaucoma, eye drops are usually the first line treatment and tend to be used lifelong. Affected individuals may sometimes be using more than one type of glaucoma drop to lower the eye pressure. If the eye pressure remains too high despite using eye drops, an operation may be required to lower the eye pressure further. Your ophthalmologist will be able to advise you better on this as glaucoma treatment is highly personalised.

Patients with ARS features but not affected by glaucoma should be monitored for glaucoma indefinitely given its strong association with ARS.

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2) Supportive treatment

In addition to treating and monitoring for glaucoma, other supportive measures can be used to relieve associated symptoms and maximise visual potential. These include:

  • Regular monitoring of visual function and prescribing glasses (if required) to optimise development of remaining vision
  • Referral to low vision services
  • Utilising visual aids and assistive technology to improve quality of life
  • Having a healthy diet consisting of fresh fruits and green leafy vegetables
  • Using tinted glasses or coloured/tinted/artificial pupil contact lenses to help with light sensitivity from pupil abnormalities

3) Looking after the child’s general health and wellbeing

As ARS can be associated with both functional and physical disabilities, specialists from many different teams may be involved, depending on the affected body system(s). In addition, early-onset 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 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 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 ARS

Human eye development during pregnancy is a complex process. We have not yet identified all the genes involved in this process and their role in various conditions. Research currently focuses on identifying the remaining genes and understanding how mutations in these genes result in ARS and other birth anomalies of the eye.

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 using animal models to assess their role in eye development.[6] Furthermore, advances in glaucoma therapies can also improve the visual prognosis of ARS patients affected by glaucoma.

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Practical advice

Living with ARS

Depending on the severity, some patients are still able to lead a relatively independent life 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 your child 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

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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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References

  1.  Ito YA, Walter MA. Genomics and anterior segment dysgenesis: a review. Clin Exp Ophthalmol. Jan-Feb 2014;42(1):13-24
  2.  Chang TC, Summers CG, Schimmenti LA, Grajewski AL. Axenfeld-Rieger syndrome: new perspectives. The British journal of ophthalmology. Mar 2012;96(3):318-22
  3.  Seifi M, Walter MA. Axenfeld-Rieger syndrome. Clinical genetics. Jun 2018;93(6):1123-1130
  4.  Ma AS, Grigg JR, Jamieson RV. Phenotype-genotype correlations and emerging pathways in ocular anterior segment dysgenesis. Human genetics. Sep 2019;138(8-9):899-915
  5.  Tümer Z, Bach-Holm D. Axenfeld-Rieger syndrome and spectrum of PITX2 and FOXC1 mutations. European journal of human genetics : EJHG. Dec 2009;17(12):1527-39
  6.  Hjalt TA, Semina EV. Current molecular understanding of Axenfeld-Rieger syndrome. Expert Rev Mol Med. Nov 8 2005;7(25):1-17

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Updated on November 30, 2020
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