- Clinical phenotype
- Key investigations
- Current research
- Further information and support
- Anterior segment dysgenesis: for patients
Anterior segment dysgenesis (ASD) is an umbrella term which describes a spectrum of disorders originating from maldevelopment of the anterior segment and usually associated with an increased risk of glaucoma. Anatomically, the anterior segment encompasses the cornea, anterior chamber, trabecular meshwork, iris, ciliary body, and lens. ASDs can present as an isolated abnormality of one structure of the anterior segment, or more commonly as a combination of congenital abnormalities (e.g. Axenfeld-Reiger anomaly). It can also be associated with systemic features (e.g. Peters Plus syndrome and Alagille syndrome).
Due to the complex interplay between a number of genes during normal development of the anterior segment, pathogenic mutations in any one of these genes can consequently lead to a broad spectrum of overlapping phenotypes, making it challenging to assign a clinical diagnosis. With an increasing understanding in genetics and genotype-phenotype correlations, a move towards a genetic diagnosis to support a clinical presentation is important to better understand ASD, and to identify individuals who may be eligible for clinical trials.
There is significant heterogeneity in terms of clinical features and disease severity although several well characterised phenotypes have been described. Some notable examples include:
- Alagille syndrome
- Axenfeld-Rieger syndrome
- Primary congenital glaucoma
- Congenital cataracts
- Corneal dystrophies
- Peters anomaly and Peters Plus Syndrome
Most patients affected by ASD have a combination of anterior segment abnormalities and in some, it may be associated with other congenital ocular disorders such as microphthalmia, foveal hypoplasia and optic nerve dysplasia. Importantly, patients with ASD are at increased risk of developing glaucoma due to abnormalities of the angle drainage system. Approximately 50% of ASD patients develop glaucoma, but up to 75% has been reported in those with Axenfeld-Rieger anomaly due to FOXC1 and PITX2 mutations.[1,4,5] Hence, regular glaucoma monitoring is recommended. Given the wide genetic heterogeneity associated with ASD, it can present either as non-syndromic or syndromic cases.
The normal development of the anterior segment is a complex process regulated by multiple interacting genes and tissue components. Several genes have been identified and associated with a clinical diagnosis, which are listed in the following table. This list is not exhaustive.
|Gene (OMIM no.)||Ocular Phenotypes||Inheritance|
|FOXE3 (#601094)||AD or AR|
- Genetics of corneal dystrophy
- Genetic of congenital cataracts
- Genetics of primary congenital glaucoma
- Genetics of aniridia
The following are general ocular investigation modalities that are usually required for ASD cases. Please refer to the individual condition pages for more focused ocular and systemic investigations.
1) Refraction and orthoptic assessment
Monitoring of visual function in children is important, and refractive errors should be corrected to optimise vision and minimise the development of amblyopia.
2) Ocular ultrasonography
In ASD conditions where the anterior and/or posterior segment is not visualised (e.g. corneal opacity), ultrasonography enables evaluation of these ocular structures. Axial length and corneal diameter measurements can also be established, which is important for paediatric glaucoma assessment and to exclude microphthalmia.
3) Anterior segment OCT (AS-OCT)
AS-OCT also provides visualisation of the anterior segment and help identify any abnormalities which may not be easily detected on clinical examination.
4) Corneal thickness measurement
This can be achieved in a number of ways and the method of choice is dependent on the tolerability of the patient. A handheld pachymeter, or ultrasound assisted measurements of the cornea may be suitable for younger patients, whilst older patients may have their corneal thickness established with Pentacam, Orbscan, or AS-OCT.
Gonioscopy should be performed if tolerated to assess angle architecture. In patients who are unable to tolerate gonioscopy such as infants or young children, examination under anaesthetic is usually required (e.g. for primary congenital glaucoma).
Intraocular pressures should be monitored regularly as patients are at high risk of developing glaucoma.
7) Disc imaging and perimetry
Enables assessment and monitoring for glaucomatous optic nerve changes, but also to identify optic nerve hypoplasia which can be seen in aniridia. Perimetry should be performed to monitor glaucoma progression. Children as young as 6 years of age are usually competent to perform automated tests, although the results become more accurate as they get older.
8) Macula OCT
Foveal hypoplasia is seen in patients with aniridia. A macula OCT scan can help identify this feature easily and facilitate the grading of its severity. A correlation between the severity of foveal hypoplasia and visual acuity has been reported.
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 or those experiencing developmental delays.
Although ASD can occasionally be diagnosed clinically, the wide array of presentations and overlapping features often makes it difficult to make a diagnosis from clinical features alone. Genetic testing should be undertaken to obtain a molecular diagnosis which can help in directing further clinical management, facilitating 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
- Whole genome sequencing
Cytogenetic testing with microarray-based comparative genomic hybridization (array-CGH) may be incorporated with NGS to detect chromosomal deletions or duplications as these structural changes can be associated other extraocular features.
- Genomic England PanelApp for glaucoma (developmental)
- Genomic England PanelApp for cataracts
- Genomic England PanelApp for corneal abnormalities
- Clinical genetic testing: for professionals
This section covers the general management approaches for ASD. Further details can be obtained from the associated webpages outlined in the “Clinical phenotypes” section.
Family management and counselling
ASD can be inherited in the following manner depending on the associated genotype:
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.
Referral to a specialist service
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.
The genetic basis and pathophysiology of ASD 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.
Once the full repertoire of genes involved in the development of the anterior segment is identified, candidate gene(s) can then be studied in further detail to identify potential therapeutic avenues through animal or cell models. Some advances have been made in certain ASD phenotypes, which are discussed in more detail in their respective pages. Moreover, given the prevalence of glaucoma among ASD patients, further development in glaucoma therapies will also improve their visual outcome.
- Current research in aniridia
- Current research in corneal dystrophies
- Current research in congenital cataracts
- Current research in primary congenital glaucoma
- Current research in Alagille syndrome
- Research Opportunities at Moorfields Eye Hospital UK
- Searching for current clinical research or trials
- Glaucoma UK
- Glaucoma Research Foundation
- The Corneal Dystrophy Foundation
- Royal National Institute of Blind People (RNIB)
- Guide Dogs for the Blind Association
- Look UK
- Ito YA, Walter MA. Genomics and anterior segment dysgenesis: a review. Clinical & experimental ophthalmology. 2014;42(1):13-24
- Sowden JC. Molecular and developmental mechanisms of anterior segment dysgenesis. Eye (London, England). 2007;21(10):1310-1318
- Ma AS, Grigg JR, Jamieson RV. Phenotype-genotype correlations and emerging pathways in ocular anterior segment dysgenesis. Human genetics. 2019;138(8-9):899-915
- Alward WL. Axenfeld-Rieger syndrome in the age of molecular genetics. American journal of ophthalmology. 2000;130(1):107-115
- Strungaru MH, Dinu I, Walter MA. Genotype-phenotype correlations in Axenfeld-Rieger malformation and glaucoma patients with FOXC1 and PITX2 mutations. Investigative ophthalmology & visual science. 2007;48(1):228-237
- Patel A, Hayward JD, Tailor V, et al. The Oculome Panel Test: Next-Generation Sequencing to Diagnose a Diverse Range of Genetic Developmental Eye Disorders. Ophthalmology. 2019;126(6):888-907
- Jackson D, Malka S, Harding P, Palma J, Dunbar H, Moosajee M. Molecular diagnostic challenges for non-retinal developmental eye disorders in the United Kingdom. Am J Med Genet C Semin Med Genet. 2020;184(3):578-589
- Thomas MG, Kumar A, Mohammad S, et al. Structural grading of foveal hypoplasia using spectral-domain optical coherence tomography a predictor of visual acuity? Ophthalmology. 2011;118(8):1653-1660
- Black GC, MacEwen C, Lotery AJ. The integration of genomics into clinical ophthalmic services in the UK. Eye. 2020;34(6):993-996