Primary congenital glaucoma: for professionals

• Overview
• Clinical phenotype
• Genetics
• Key investigations
• Diagnosis
• Management
• Current research
• Further information and support
• References
• Primary congenital glaucoma: for patients

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Overview

Incidence	1:10,000 in Western countries[1] 1:2,500 in Saudi Arabia 1:1,250 in Slovakian Roma populations Higher prevalence in consanguineous marriages
Inheritance	Autosomal recessive (most common) Autosomal dominant de novo sporadic
Genes involved (OMIM No.)	CYP1B1 (#601771) — most common causative gene LTBP2 (#602091) MYOC (#601652) FOXC1 (#601090) TEK (#600221) — rare autosomal dominant form The causative gene(s) have not been identified yet in the GLC3B and GLC3C loci
Symptoms	Usually detected by parents due to striking ocular features in neonates/infants Photophobia Epiphora Blepharospasm Visual impairment of variable severity depending on age of onset, severity and response to treatment
Ocular features	Usually bilateral involvement with asymmetrical disease Buphthalmos (if present before age of 3 years) Haab striae (breaks in the Descemet’s membrane) Corneal oedema Increased disc cupping which is reversible with treatment Progressive myopia
Systemic features	Dependent on the causative gene Axenfeld-Reiger syndrome may be present in children with FOXC1 mutations Marfan-like phenotypes with LTBP2 mutations
Key investigations	Examination under anaesthesia (EUA) to establish findings and direct clinical management Corneal diameter Gonioscopy B-scan ultrasound to measure axial length Baseline optic disc images Ultrasound biomicroscopy and/or anterior segment OCT to assess anterior segment anatomy Orthoptic assessment and refraction Perimetry (when age appropriate) Systemic assessment with a paediatrician and other relevant specialists if concerns about extraocular involvement or based on genetic testing result
Molecular diagnosis	Next generation sequencing Targeted gene panels (ASD) Whole genome sequencing
Management	Ocular Surgery (goniotomy, trabeculotomy, trabeculectomy, drainage devices or cyclodiode laser) is the predominant treatment Medical treatment (topical and/or oral) is a temporising measure while awaiting surgery or adjunct to surgical treatment Systemic Multidisciplinary approach if systemic features are present Symptomatic relieve based on affected systems
Therapies under research	Advances in glaucoma therapies in general may improve visual outcomes

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Clinical phenotype

Primary congenital glaucoma (PCG) is characterised by the presence of photophobia, epiphora and blepharospasm in a neonate or infant. It is typically associated with the following signs:

• Buphthalmos (usually occurring in children presenting before 3 years of age due to stretching of the elastic sclera from raised intraocular pressure [IOP])
• Haab striae (breaks in the Descemet’s membrane)
• Corneal oedema
• Optic disc cupping (can be reversible with treatment)
• Progressive myopia

PCG tends to present at birth or shortly after with bilateral involvement (approximately 70% of cases) and asymmetrical disease.^[2] It is classified based on the age of disease onset^[3]:

• Neonatal onset (0-1 month)
• Infantile onset (1 month- 2 years)
• Late onset (>3 years)

Some patients can present as spontaneously arrested cases where buphthalmos and Haab striae are evident but the discs and IOP are normal.^[4]

The visual prognosis for PCG is highly variable among patients, depending on the age of onset, disease severity at diagnosis (particularly corneal oedema), response to surgical management and IOP stabilisation. Generally, early-onset disease is associated with a worse outcome.^[5]

Related links

• Anterior segment dysgenesis

Associated extraocular features

PCG is usually an isolated ocular pathology as most familial cases are caused by mutations in the CYP1B1 gene (~90%).^[6] However, due to the genetic heterogeneity and phenotypic variability in PCG, clinicians should be aware of potential systemic associations and a referral to a paediatrician for screening may be indicated based on history taking, clinical assessment and/or genetic findings. For instance, children harbouring FOXC1 mutations may be affected by Axenfeld-Reiger syndrome or a Marfan-like phenotype with congenital cardiac abnormalities associated with homozygosity of the common p.R299X variant in the LTBP2 gene.^[7]

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Genetics

The genes that have been identified to be associated with PCG are:

• CYP1B1 (mostly missense variants; commonest cause of familial PCG)
• LTBP2 (the p.R299X nonsense variant is the most common; homozygosity of this variant usually results in a more severe clinical phenotype and worse visual outcome despite surgeries^[8])
• TEK (a rare autosomal dominant form with incomplete penetrance and variable expressivity)^[9]
• FOXC1 (commonly associated with Axenfeld-Reiger syndrome or Peters anomaly)
• MYOC

The causative gene(s) in two chromosomal loci associated with PCG, GLC3B (chromosome 1p36.2-p36.1, autosomal recessive) and GLC3C (chromosome 14q24.3) have not been identified yet.

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

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Key investigations

Ocular

Examination under anaesthetic (EUA) is often required in this age group for clinical assessment to establish a diagnosis and/or need for surgery.

1) Orthoptic assessment and refraction

To assess current level of vision and determine if refractive correction is required to optimise vision.

2) Ultrasound biomicroscopy and B-scan ultrasound

Ultrasonography can be utilised to examine the anatomy of the anterior segment, which may be difficult in the presence of corneal oedema. Axial length and corneal diameter measurements should be taken as part of the assessment.

3) Intraocular pressure (IOP) and gonioscopy

On gonioscopy, the angle tends to appear to have arrested development with a high flat iris insertion, peripheral scalloping and circumferential iris vessels.^[10]

4) Disc imaging and perimetry

The baseline optic disc appearance should be recorded to determine clinical progression. Automated SITA standard perimetry should be performed from the age of 7 years old onwards.

5) Electrophysiology

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

6) Examination of other family members

The siblings and/or offspring of an affected individual with a family history of consanguinity should be examined for signs of glaucoma or anterior segment dysgenesis.

Systemic

Children should be referred to a paediatrician if there are any concerns of systemic involvement or based on the results of genetic testing.

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Diagnosis

PCG can be diagnosed clinically. Genetic testing should be undertaken to obtain a molecular diagnosis which can help in directing further clinical management, 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

The genetic cause in about 13-25% of PCG cases (some in combination with anterior segment dysgenesis) are identified using targeted gene panels (containing known genes for glaucoma or anterior segment dysgenesis) or whole genome sequencing.^[9,11]

Related links

• Genomics England PanelApp for glaucoma (developmental)
• Clinical genetic testing: for professionals

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Management

Ocular

1) Surgical management

Surgical intervention is the main treatment in PCG to control IOP. There are currently no large randomised control trials that evaluate the effectiveness and safety of surgical treatments for paediatric glaucoma. The main surgical options are:

• Angle surgery (goniotomy and trabeculotomy)—associated with a high success rate (70-90%) with few complications^[6]; a clear cornea is required for goniotomy but can be achieved with alcohol-assisted epithelial debridement
• Trabeculectomy augmented with anti-fibrotic agents– 67% success rate at 5 years; may require further EUAs after surgery for suture removal and risk of bleb-related complications (bleb-related endophthalmitis, fibrosis, failure)^[12], which can be minimised with the Moorfields Safer Surgery System
• Glaucoma drainage devices—53% success rate at 5 years but high likelihood of requiring further procedures due to implant-related complications (erosion, migration, corneal decompensation)^[13]
• Cyclodiode laser—can be considered in cases with failed drainage/filtering surgery or those that are unable to have surgery due to other co-morbidities^[6]

Patients may require adjunctive topical treatment after surgery to achieve adequate IOP control.

2) Medical management

Topical or systemic medical management are not as effective in lowering IOP as in adults. It is normally used as a temporising measure while waiting for surgery or as an adjunct to surgery to achieve better IOP control.

The options for medical treatment include:

• Beta blockers
• Carbonic anhydrase inhibitors
• Prostaglandin analogues (poor response in patients with FOXC1 mutations possibly due its role in lantanorprost signaling^[14])
• Alpha agonists (use with caution in young children due to potential CNS depression^[15], bradycardia and hypotension); brimonidine should be avoided in patients under the age of 7 years

3) 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 (if indicated)
• Directing patients and families to supporting organisations
• Encourage the use of assistive technology that may improve quality of life

Systemic

A multidisciplinary approach involving other specialties is required if there are any systemic associations. Furthermore, 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

PCG has been reported to be inherited in the following manner:

• Autosomal recessive (most common)
• De novo sporadic
• Autosomal dominant

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional 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

• 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 PCG

The genetic basis and pathophysiology of PCG are not fully understood yet. As genetic testing becomes increasingly available through its implementation in routine ophthalmological management, it is hoped that more novel genes can be identified and large cohorts of molecularly confirmed patients can be established to help identify any genotype-phenotype correlations.^[16]

There is currently no gene-based therapy that can reverse the structural malformations induced by the genetic changes. It is possible that such therapeutic approaches may be able to improve aqueous outflow mechanisms in the future. Further advances in glaucoma therapies can potentially lead to further improvement of outcomes in children affected by PCG.

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

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References

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