Axenfeld-Rieger Anomaly (ARA) and Axenfeld-Rieger Syndrome (ARS): for professionals

• Overview
• Clinical phenotype
• Genetics
• Key investigations
• Diagnosis
• Management
• Current research
• Further information and support
• References
• Axenfeld-Rieger Syndrome (ARS): for patients

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Overview

Prevalence	1:50,000 – 100,000
Inheritance	De novo sporadic (50-70%)[1] Autosomal dominant
Genes involved (OMIM No.)	FOXC1 (#601090) and PITX2 (#601542) are major causative genes (approx. 40% of ARS cases) Remaining 60% has unknown aetiology is unknown but other genes associated include: PAX6, COL4A1, CPAMD8 and CYP1B1[1-4]
Signs	Bilateral involvement is most common; Unilateral and asymmetric presentation may occur: Highly variable clinical features Isolated ocular or syndromic phenotypes Posterior embryotoxon Peripheral iris adhesions Iris hypoplasia Polycoria Corectopia Glaucoma is the most common and serious co-morbidity Squint may be the only feature due to sensory deprivation amblyopia
Symptoms	Variable severity Ranges from asymptomatic with incidental detection of raised IOP and VF loss in later life to buphthalmos and photophobia in infancy due to congenital glaucoma
Systemic features	Most common: Dental defects, craniofacial dysmorphism, and redundant periumbilical skin Other reported associations: genitourinary anomalies, cardiovascular outflow tract defects, brain maldevelopment, hearing loss and skeletal anomalies[1,5]
Key investigations	Orthoptic assessment and refraction Ultrasound biomicroscopy and/or anterior segment OCT in the presence of corneal haziness Glaucoma assessment (tonometry, pachymetry, perimetry, goniscopy if indicated and optic disc OCT) B-scan ultrasound to measure axial length Electrophysiology to assess level of vision in pre-/non-verbal patients Systemic assessment with a paediatrician and other relevant specialists
Molecular diagnosis	Next generation sequencing Targeted gene panels (ASD) Whole genome sequencing
Management	Ocular Monitor and treat glaucoma Systemic Multidisciplinary approach Dental and maxillofacial input to manage dental and craniofacial abnormalities Abdominal ultrasound to aid differentiation of redundant periumbilical skin from umbilical hernia
Therapies under research	None at present

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Clinical phenotype

The components of Axenfeld-Rieger anomaly and Axenfeld-Rieger syndrome are historically described as four distinct phenotypes:

• Axenfeld anomaly—Posterior embryotoxon with peripheral anterior iris adhesions
• Rieger anomaly—Axenfeld anomaly with iris hypoplasia, polycoria and corectopia
• Axenfeld syndrome or Reiger syndrome—Axenfeld or Reiger anomalies with systemic features

These four separate entities are now believed to be part of a spectrum with overlapping features, and the terms Axenfeld-Rieger anomaly (ARA) and Axenfeld-Rieger syndrome (ARS) may be more appropriate. ARA refers to an isolated ocular phenotype while ARS is used to describe ARA with extra-ocular manifestations.^[1,3,5,6]

Main ocular features

Axenfeld-Rieger anomaly (ARA)

Posterior embryotoxon describes the anterior insertion of Schwalbe’s line. It is commonly associated with ARA but it can also be found in other anterior segment dysgenesis disorders as well such as Alagille syndrome. Interestingly, it has also been reported as an isolated finding in approximately 15% of the normal population.^[7,8] Other ocular features that may be present include peripheral anterior iris adhesions, iris hypoplasia, polycoria and corectopia.

Ocular features usually present bilaterally, however unilateral, and asymmetric presentations have been reported.^[1] There is intra- and inter-familial variability in terms of clinical findings and severity, which is reflected by the variable age of diagnosis. While some cases are diagnosed in infancy with striking ocular abnormalities noticed by parents or care providers, such as iris abnormalities or signs of congenital glaucoma including tearing, photosensitivity, corneal clouding and buphthalmos; others with milder phenotypes may present more insidiously in later life with reduced vision, a squint (due to sensory deprivation amblyopia) or incidentally identified raised intraocular pressures (IOP).

Associated extraocular features

Dental defects, craniofacial anomalies and redundant periumbilical skin are the most frequently associated extraocular features of ARS. However, several other systemic manifestations have also been described and are summarised below:

• Dental defects (micro-, hypo-, oligo-, and/or anodontia, taurodontism, enamel hypoplasia, shortened roots, delayed eruption and cone-shaped teeth)^[1,9,10]
• Craniofacial anomalies (prominent forehead, hypertelorism, telecanthus, mid-face hypoplasia, broad flat nasal root, maxillary and mandibular hypoplasia, short philtrum, thin upper lip, and a larger everted lower lip)^[1,5]
• Redundant periumbilical skin
• Genitourinary anomalies (kidney abnormalities ^[1] ,hypospadias^[5])
• Cardiovascular outflow tract defects
• Brain maldevelopment
• Auditory problems (sensorineural hearing loss^[5])
• Skeletal anomalies (flattening of femoral and humeral epiphyses, shortening of femoral neck, club feet and other positional joint abnormalities^[5,11])

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Genetics

The two major causative genes for ARS are FOXC1 and PITX2, contributing to approximately 40% of cases.^[1,2] Amongst molecularly diagnosed patients, 50 – 70% have a de novo mutation.^[1] Isolated ocular involvement are more commonly associated with FOXC1 mutations (Rieger syndrome type 3; OMIM 602482), whilst dysmorphic systemic features are more commonly observed with PITX2 mutations (Rieger syndrome type 1; OMIM 180500).^[3,4]

The genetic cause is unknown in the remaining 60% of ARS patients. However, associations with ARA have been reported in patients harbouring pathogenic mutations in PAX6, COL4A1, CPAMD8 and CYP1B1.^[1,3,5]

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

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Key investigations

Ocular

1) Orthoptic assessment and refraction

To assess current level of vision and determine if amblyopia therapy and/or refractive correction are required to optimise vision.

2) Ultrasound biomicroscopy and B-scan ultrasound

Ultrasonography can be utilised to examine the anterior and posterior segments, which may be difficult in the presence of corneal oedema in paediatric glaucoma or in small children. Axial length and corneal diameter measurements should be taken as part of the assessment.

3) Anterior segment optical coherence tomography (AS-OCT)

AS-OCT can be used to document and visualise anterior segment structures and help with characterisation and identification of iris defects which may not be easily identified on clinical examination. Corneal thickness measurement can also be achieved with AS-OCT.

4) Intraocular pressure (IOP) and gonioscopy

IOP should be assessed regularly and lifelong, as patients are at increased risk of developing glaucoma. Gonioscopy should be performed if tolerated to assess for any angle abnormalities and to identify any peripheral anterior adhesions.

5) Disc OCT imaging and perimetry

Enable assessment and monitoring of glaucomatous optic nerve changes and the corresponding visual field defects.

6) Electrophysiology

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

Systemic

Dental and maxillofacial input is required to address dental and craniofacial anomalies. 

Children should be referred to a paediatrician for investigations which may include:

• Ultrasound abdomen – to help differentiate redundant periumbilical skin in ARS from an umbilical hernia which requires surgical intervention
• Echocardiogram – to assess for cardiovascular outflow tract defects
• Audiology
• MRI brain imaging – brain abnormalities reported in ARS include small pars intermedia and pineal cysts, adenohypophyseal hypoplasia, steep clival angle, and sellar bridging.^[12]

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Diagnosis

ARA and ARS can be diagnosed clinically. Genetic testing should be undertaken to obtain a molecular diagnosis which can help in directing further clinical management, particularly in those harbouring mutations in FOXC1 and PITX2 due to the higher incidence of glaucoma among these patients. A group has observed that ARS caused by FOXC1 duplications and PITX2 mutations are associated with an earlier-onset and more severe glaucoma.^[13] Furthermore, a molecular diagnosis can aid in genetic counselling and providing accurate advice on prognosis and future family planning.

This can be achieved through a variety of next generation sequencing (NGS) methods:

• Targeted gene panels (ASD)
• Whole genome sequencing

Clinicians should be aware that only 40% of patients are identified to have mutations in PITX2 or FOXC1, and the remaining 60% may not receive a genetic diagnosis or are found to have mutations in other genes.

Related links

• Genomics England PanelApp for glaucoma
• Clinical genetic testing: for professionals

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Management

Ocular

1) Glaucoma

Glaucoma is the main ocular co-morbidity associated with ARA/ARS and affects up to half of the patients (up to 75% are affected in those with FOXC1 and PITX2 mutations).^[2,6] Therefore, patients should have frequent reviews to ensure glaucoma is identified and managed early to preserve visual function.

Treatment can be achieved with medical and surgical interventions. Medical treatment includes:

• Alpha agonists (use with caution in young children due to potential CNS depression^[14]; may exacerbate cardiac outflow defects in ARS patients^[1])
• Beta blockers
• Carbonic anhydrase inhibitors
• Osmotic agents
• Parasympathomimetics agonists
• Prostaglandin analogues (poor response in ARS patients possibly due to the role of FOXC1 in lantanorprost signaling^[15])

Topical treatment is often considered first line management in patients diagnosed in late childhood or early adulthood. Surgery is often required later on to further lower the IOP but despite this, only 18% of patients have good response to medical or surgical treatment (solely or in combination).^[13]

Infants presenting with congenital glaucoma are usually managed surgically with trabeculectomy and mitomycin C instead of goniotomy due to the presence of corneal oedema and peripheral anterior adhesions.^[5] However, it involves more frequent follow-ups after surgery and examination under anaesthesia may sometimes be required in poorly co-operative children, which can be complicated by the presence of craniofacial anomalies and cardiac outflow defects in some ARS patients. Aqueous shunts and cyclo-ablative lasers are alternatives but are less effective in lowering IOP. Medical intervention is only used temporarily to lower IOP until surgery is performed.

Related links

• Management of congenital glaucoma

2) Supportive ocular management

• Correcting any associated refractive errors
• Close monitoring of vision with rapid initiation of amblyopia treatment if detected
• Referral to low vision services
• Directing patients and families to supporting organisations  
• Encourage the use of assistive technology that may improve quality of life

Systemic

A multidisciplinary approach is usually required due to the various systemic manifestations associated with ARS. New patients diagnosed with ARA should be referred to a paediatrician to screen for any systemic associations and managing them symptomatically if present.

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 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.

Family management and counselling

ARS/ARS has been reported to be inherited in the following manner:

• De novo sporadic (50-70%)
• Autosomal dominant

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.

Emotional and social support

Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the 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

• Coping with sight loss
• Education and learning
• Family support service

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 ARA/ARS

The genetic basis for approximately 60% of ARS remains unknown. With increasing availability of genetic testing, it is hoped that more novel genes can be identified through its implementation in routine ophthalmological management.^[16] A rare disease patient registry (NCT 01793168) is also available for patients to enrol and researchers to access.

Glaucoma is the most common ocular complication of ARA/ARS, and although often not primarily researched and developed for the purpose of ARS, future advances in glaucoma therapies can impact on the management and therefore visual prognosis of patients affected by ARA/ARS.

Related links

• Research Opportunities at Moorfields Eye Hospital UK
• Searching for current clinical research or trials

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Further information and support

• Glaucoma UK
• Glaucoma Research Foundation
• Royal National Institute of Blind People (RNIB)
• Guide Dogs for the Blind Association
• Look UK
• Scottish Sensory Centre 

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References

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