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- Overview
- Clinical phenotype
- Genetics
- Key investigations
- Diagnosis
- Management
- Current research
- Further information and support
- References
- Aniridia: for patients
Overview
Prevalence | 1:40,000-100,000[1] |
Inheritance |
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Genes involved (OMIM no.) | |
Symptoms |
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Ocular features |
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Systemic features | |
Key investigations |
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Molecular diagnosis |
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Management | Ocular
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Therapies under research | Nonsense suppression therapy (phase 2) |
Clinical phenotype
Presenting features
Aniridia is a pan-ocular disorder with iris hypoplasia being most characteristic. Most children present at birth with an obvious iris or pupillary abnormality or during infancy with nystagmus. Visual acuity is usually impaired due to foveal hypoplasia but the severity can vary between and within families, with some displaying subtle changes to the iris architecture, good vision, and normal foveal structure. Affected individuals tend to have symmetrical ocular findings.

Other ocular features
Apart from iris hypoplasia, aniridia can be associated with the following features[2] :
- Microphthalmia, anophthalmia, coloboma (MAC) spectrum
- Strabisumus
- Aniridia-related keratopathy leading to progressive corneal opacification
- Secondary glaucoma but congenital glaucoma can rarely occur[3]
- Cataract
- Lens subluxation
- Exudative vascular retinopathy
- Choroidal degeneration
- Optic nerve hypoplasia

Associated extraocular features
Contiguous deletion of PAX6 and the adjacent WT1 gene causes WAGR syndrome. However, mutations in PAX6 alone can be associated with the following systemic features[2],[4-6]:
- Central auditory processing deficits
- Behavioural problems
- Sleep disorders
- Obesity
- Glucose intolerance
Genetics
1) Gene: PAX6 (11p13)
OMIM no.: #607108
Protein: Paired Box 6
Location of expression: Ubiquitously expressed, mainly in the brain and eye
Function: A highly conserved transcription regulator that is involved in the early development of the eye, brain, olfactory bulb, neural tube, pancreas and gutin the embryo[1] 99%[2] of isolated aniridia are due to mutations in PAX6.
2) Gene: ELP4 (11p13)
OMIM no.: #606985
Protein: Elongator acetyltransferase complex subunit 4
Location of expression: Ubiquitously expressed throughout body
Function: An ultra-conserved PAX6 cis-regulatory element (SIMO) that is critical in maintaining the transcription of the PAX6 gene during embryonic development.[2]
3) Gene: WT1 (11p13)
OMIM no.: #607102
Protein: Wilms tumour 1
Location of expression: Developing kidneys and gonads
Function: Development of kidneys and gonads before birth. Postnatally, the WT1 protein regulates renal cell division, differentiation and apoptosis. Deletion of the WT1 gene leads to unregulated cell cycle and thus increases the risk Wilms tumour formation.[7]
Key investigations
Ocular
1) Optical coherence tomography (OCT)
OCT can be used to detect fovea hypoplasia and support a clinical diagnosis especially where iris defects may be subtle. Anterior segment OCT is able to help delineate anterior segment structures even in the presence of corneal opacity.[8]

2) High-frequency ultrasound biomicroscopy (UBM)
This is usually performed in infants (under general anaesthesia) presenting with corneal opacity or corneal oedema associated with congenital glaucoma. It is able to assess for iris hypoplasia and/or absence.
3) Ultrasound B-scan
This should be performed routinely to assess axial length (AL) due to the association with microphthalmia. It is defined as AL < 19mm in infants at 1 year of age or <21mm in adults.
4) Electrophysiology
To assess level of vision and exclude other causes of nystagmus such as ocular or oculocutaneous albinism.
Systemic
Children should be referred to a paediatrician for investigation of systemic features which include:
- Serial 3 monthly renal ultrasound for children under the age of 8 whilst awaiting genetic results
- Audiology
- MRI brain imaging
- Endocrine assessment (if indicated)
- Sleep assessment (if indicated)
Diagnosis
New patients should be under joint care with a paediatrician and have genetic testing done urgently either by a clinical geneticist or an ophthalmologist specialising in genetic eye disease as follows:
- Chromosomal microarray to exclude deletions of PAX6 and WT1 (WAGR syndrome)
- Direct sequencing of PAX6 and rarely ELP4 if a chromosomal deletion is not detected
- Whole genome sequencing to identify novel mutations in genes or non-coding regulatory elements
Related links
Management
Ocular
Supportive management:
- Observe visual development, treat amblyopia if present
- Regular refraction
- Advise tinted/photochromic lenses. Contact lens might not be suitable due to ARK
- Regular monitoring by glaucoma specialists
- Cataract surgery if indicated
- Referral to corneal specialists if evidence of limbal stem cell deficiency
- Referral to low vision services
- Direct patients to supporting organisations
- Consider registration if criteria met

Systemic
Children diagnosed with WAGR syndrome require serial 3 monthly renal ultrasound monitoring by paediatricians until the age of 8 due to the increased risk of developing Wilms tumour (90% of patients develop by age 4 and 98% develop by 7 years old).[9] They will need to be managed by the appropriate multidisciplinary team due to other systemic issues.
For children that did not receive genetic testing or refused to, they need to be monitored similarly as children with confirmed WT1 deletion until the age of 8. If WT1 deletion is negative, regular renal ultrasound monitoring is not required.[2]
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
- Proband with positive family history
It will be inherited in an autosomal dominant pattern.[2]
- Proband with negative family history (sporadic aniridia)
Careful examination of both parents is required due to phenotypic variability among family members. Genetic testing of both parents is recommended to confirm a sporadic case.
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
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.
Current research in aniridia
1) Nonsense suppression therapy
Nonsense suppression therapy is a new drug-based genetic treatment that can override the effect of nonsense mutations within the coding region of a gene. It promotes “read-through” of premature termination codons (PTC) during translation to continue protein production.
Nonsense mutations account for up to 40%[10] of the disease-causing mutations in aniridia. Ataluren (or TranslarnaTM) eye drops has been shown to reverse ocular defects associated with aniridia in mouse models when given at a specific time frame after birth.[11][12] These proof-of-concept studies led to the development of a phase 2 randomized, double-masked, placebo-controlled study of oral ataluren in patients with aniridia caused by nonsense mutations (NCT 02647359) which is currently underway.
2) Limbal stem cell transplant
(a) Role of limbal stem cells
Limbal stem cells reside in a specialised microenvironment called the limbal niche. It is characterised by extracellular matrix, signalling molecules and various supporting cells (fibroblasts, melanocytes and vascular cells).[13] The stem cells are dependent on the limbal niche to function optimally and maintain corneal epithelium homeostasis.
(b) Role of PAX6 mutation in ARK
PAX6 mutation causes dysfunction of the limbal stem cells, its associated niche and the limbal barrier.[13][14] Consequently, this affects corneal epithelial healing, corneal epithelial integrity and conjuntivalisation of the cornea. Patients with ARK may require surgery if the central corneal opacity is severely impacting vision.
(c) Types of transplant
- Allografts
Penetrating keratoplasty alone usually results in graft failure as limbal stem cell deficiency is not addressed.[1] As a result, limbal stem cell allografts (due to bilateral nature of aniridia), either in the form of cultured stem cell sheet or direct tissue transplant are indicated.[15]However, these therapies have variable long term results[16][17] and lifelong systemic immunosuppression might be required to prevent rejection.
- Cultivated oral mucosal epithelial transplantation (COMET)
To avoid systemic immunosuppression use, COMET has been used instead to achieve ocular surface stability. However, the associated visual outcomes are sub-optimal as the transplanted epithelium does not convert to a corneal phenotype, producing a thicker and more opaque epithelium.[18] The long term outcome of this technique is not available yet.
The variable outcomes associated with the above treatment strategies is in part due to the failure of restoring the dysfunctional limbal niche.[18] In addition, the amniotic membranes used as limbal stem cell scaffolds are biologically variable and carries a small risk of infectious disease transmission.[19] Due to these challenges, RAFT was developed as an alternative extracellular matrix scaffold. It is a type 1 collagen hydrogel based substrate cast moulded to mimic the limbal niche architecture.Proper alignment of the niche was demonstrated with the detection of corneal epithelium on the surface, limbal stem cell markers in the basal layer and limbal fibroblasts in the stroma.[19] While amniotic membranes rely on suitable donors, RAFT plates can be manufactured consistently with low risk of infection. Its success in pre-clinical studies led to the planning of a phase 1/2 clinical trial for ARK which is due to start in 2020.
3) Artificial iris prosthesis
These devices aim to improve visual acuity, alleviate photophobia and improve cosmetic appearance. Although studies have demonstrated functional and anatomic improvement in patients (mainly traumatic aniridia), we do not advocate implanting these devices in congenital aniridia patients due to the following reasons[20]:
- Variable visual outcome—associated ocular co-morbidities might limit visual improvement
- Development/progression of glaucoma and ARK
- Prolonged anterior uveitis
- Hypotony
- Retinal/choroidal detachment, vitreous haemorrhage, cystoid macular oedema development
- Endophthalmitis
- Implant malposition—Surgical repositioning of implant is rare but can lead to aniridic fibrosis syndrome
The three main types of prosthesis are:
- CustomFlex Artificial Iris (HumanOptics AG)–recent FDA approval in 2018
- Morcher Iris diaphragm (Morcher® GmbH)
- 311 Aniridia Lens II (Ophtec)
The prosthesis can be broadly categorised into three groups:
- Iris-lens diaphragm (Morcher and Ophtec)
- Endocapsular tension ring-based (Morcher)
- Customised artificial iris (HumanOptics)
These devices are inserted into aphakic or pseudophakic eyes, either as a separate procedure or combined with cataract surgery. They are mainly inserted either into the capsule or in the sulcus with transcleral fixation sutures.
Related links
- Research Opportunities at Moorfields Eye Hospital UK
- Searching for current clinical research or trials
Further information and support
- Aniridia Network
- International WAGR Syndrome Association (IWSA)
- Royal National Institute of Blind People (RNIB)
- Guide Dogs for the Blind Association
- Look UK
References
- Hingorani M, Hanson I, Van Heyningen V. Aniridia. European Journal of Human Genetics. 2012;20(10):1011.
- Moosajee M, Hingorani M, Moore AT. PAX6-Related Aniridia. In: GeneReviews®[Internet]. University of Washington, Seattle; 2018.
- Gramer E, Reiter C, Gramer G. Glaucoma and frequency of ocular and general diseases in 30 patients with aniridia: a clinical study. Eur J Ophthalmol. 2012;22(1):104-110.
- Bamiou DE, Free SL, Sisodiya SM, et al. Auditory inter-hemispheric transfer deficits, hearing difficulties, and brain magnetic resonance imaging abnormalities in children with congenital aniridia due to PAX6 mutations. Arch Pediatr Adolesc Med. 2007;161(5):463-469
- Yasuda T, Kajimoto Y, Fujitani Y, et al. PAX6 mutation as a genetic factor common to aniridia and glucose intolerance. Diabetes. 2002;51(1):224-230.
- Lim HT, Kim DH, Kim H. PAX6 aniridia syndrome: clinics, genetics, and therapeutics. Curr Opin Ophthalmol. 2017;28(5):436-447.
- US National Library of Medicine. WT1 gene. https://ghr.nlm.nih.gov/gene/WT1. Published 2019. Updated September 2018. Accessed 30/10/19.
- Majander AS, Lindahl PM, Vasara LK, Krootila K. Anterior segment optical coherence tomography in congenital corneal opacities. Ophthalmology. 2012;119(12):2450-2457
- Beckwith JB. Nephrogenic rests and the pathogenesis of Wilms tumor: developmental and clinical considerations. Am J Med Genet. 1998;79(4):268-273.
- Lee H, Khan R, O’Keefe M. Aniridia: current pathology and management. Acta Ophthalmol. 2008;86(7):708-715.
- S Gregory-Evans CY, Wang X, Wasan KM, Zhao J, Metcalfe AL, Gregory-Evans K. Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects. J Clin Invest. 2014;124(1):111-116
- Wang X, Gregory-Evans K, Wasan KM, Sivak O, Shan X, Gregory-Evans CY. Efficacy of Postnatal In Vivo Nonsense Suppression Therapy in a Pax6 Mouse Model of Aniridia. Mol Ther Nucleic Acids. 2017;7:417-428.
- Shortt AJ, Secker GA, Munro PM, Khaw PT, Tuft SJ, Daniels JT. Characterization of the limbal epithelial stem cell niche: novel imaging techniques permit in vivo observation and targeted biopsy of limbal epithelial stem cells. Stem Cells. 2007;25(6):1402-1409.
- Ramaesh K, Ramaesh T, Dutton GN, Dhillon B. Evolving concepts on the pathogenic mechanisms of aniridia related keratopathy. Int J Biochem Cell Biol. 2005;37(3):547-557.
- Fernandez-Buenaga R, Aiello F, Zaher SS, Grixti A, Ahmad S. Twenty years of limbal epithelial therapy: an update on managing limbal stem cell deficiency. BMJ Open Ophthalmol. 2018;3(1):e000164.
- Baylis O, Figueiredo F, Henein C, Lako M, Ahmad S. 13 years of cultured limbal epithelial cell therapy: a review of the outcomes. J Cell Biochem. 2011;112(4):993-1002.
- Shortt AJ, Secker GA, Notara MD, et al. Transplantation of ex vivo cultured limbal epithelial stem cells: a review of techniques and clinical results. Surv Ophthalmol. 2007;52(5):483-502.
- Yazdanpanah G, Haq Z, Kang K, Jabbehdari S, Rosenblatt ML, Djalilian AR. Strategies for reconstructing the limbal stem cell niche. Ocul Surf. 2019;17(2):230-240.
- Levis HJ, Kureshi AK, Massie I, Morgan L, Vernon AJ, Daniels JT. Tissue Engineering the Cornea: The Evolution of RAFT. J Funct Biomater. 2015;6(1):50-65.
- Srinivasan S, Ting DS, Snyder ME, Prasad S, Koch HR. Prosthetic iris devices. Can J Ophthalmol. 2014;49(1):6-17