Isolated Aniridia

Disease Overview

Summary

Aniridia is a rare condition characterized by abnormal development of the iris of the eye. The iris is the circular, colored part in the middle of the eyeball. The center of the iris is known as the pupil. The iris can control the size of the pupil, which regulates the amount of light that enters the eye. In aniridia the iris is either partly or completely missing.

Aniridia can be isolated (aniridia without problems in other organs of the body) or can be a part of several genetic syndromes, such as WAGR syndrome and Gillespie syndrome. Aniridia can also be acquired and occur after trauma or ocular surgery. This report discusses isolated aniridia.

Most forms of isolated aniridia are caused by changes (pathogenic variants or mutations) in the PAX6 gene.

Treatment is focused on preserving and improving vision and may include the use of an artificial iris, medication and surgery.

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Synonyms

irideremia

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Signs & Symptoms

Aniridia is the partial or complete absence of the iris of the eye. Vision is preserved in some patients with mild cases of aniridia. This condition occurs when the iris fails to develop normally before birth in one or both eyes. Typically, aniridia can be diagnosed at birth. Aniridia can be isolated, i.e., occur as a single abnormality or can be one of many symptoms in an underlying condition.

Isolated aniridia is the partial or complete absence of the iris from birth. Some people with this type of aniridia may be unaware of any eye problems because pupils appear normal and usually only one eye is mildly affected. In more severe cases, isolated aniridia can cause vision problems later in life. Other symptoms can make vision cloudy or blurry and may include:

Clouding of the crystalline lens of the eye (cataracts)
Gradual loss of vision due to increased pressure inside the eyeball which may be accompanied by varying degrees of pain (glaucoma)
Superficial clouding of the cornea (corneal pannus)
Rapid involuntary movement of the eyeball (nystagmus)
Underdevelopment of the fovea area of the retina (which controls acute vision)

Aniridia may be part of an underlying condition such as Gillespie syndrome, which includes aniridia, intellectual disability and ataxia among other features, and WAGR syndrome, characterized by a kidney tumor known as Wilm’s tumor and other anomalies such as genital and urinary anomalies and intellectual disability.

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Causes

Most forms of isolated aniridia are caused by variants in the PAX6 gene. The PAX6 gene belongs to a family of genes that are important for the correct formation of tissues and organs during embryonic development and for maintaining the normal function of certain cells after birth.

The PAX6 gene codes for the PAX6 protein, which is thought to turn on (activate) genes involved in the formation of the eyes, brain and spinal cord (central nervous system), and the pancreas. Additionally, researchers believe that the PAX6 protein controls many aspects of eye development before birth. After birth, the PAX6 protein likely regulates the expression of various genes in many structures of the eyes.

Aniridia caused by PAX6 gene variants (PAX6-related aniridia) occurs either as an isolated eye (ocular) abnormality or as part of the Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome (see below).

About 13% to 33% of people with aniridia have sporadic aniridia, caused by a new (de novo) gene variant that was not inherited from the parents. About 25% to 33% of people with sporadic congenital aniridia may develop nephroblastoma before 3 years of age, as a part of WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and intellectual disability). In WAGR syndrome there is a partial deletion of the short arm of chromosome 11 involving both the PAX6 and WT1 genes.

A few cases of isolated aniridia are caused by variants in other genes including the ELP4 gene and the TRIM44 gene. Isolated aniridia caused by variants in the PAX6 gene is classified as aniridia type 1 (the most common form), aniridia caused by variants in the ELP4 gene, a gene that encodes a regulator of the PAX6 gene, is classified as aniridia type 2 and aniridia caused by variants in the TRIM44 gene is classified as aniridia type 3.

In almost all cases, isolated aniridia follows an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause a particular disease. The gene variant can be inherited from either parent or can be the result of a new changed gene in the affected individual. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

Sometimes a genetic cause for isolated aniridia cannot be identified.

Acquired aniridia can occur after eye trauma or surgery.

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Affected populations

All types of aniridia affect males and females in equal numbers. This disorder is thought to occur in approximately 1 in 40,000 to 96,000 livebirths in the United States.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of aniridia. Comparisons may be useful in helping a doctor make a diagnosis:

Irido goniodysgenesis is a genetic eye structure disorder. People with this disorder are born with underdevelopment of the foundation substance (stroma) of the iris. Glaucoma may also occur, followed by the iris changing to a lighter color. It may result in varying degrees of pain.

Rieger syndrome, also known as Irido gonodysgenesis with somatic anomalies, is characterized by incorrect development of the middle layer of the cornea and iris. There may also be abnormalities in the pupil, which is the opening that regulates the amount of light entering the eyeball. The edges of the cornea are clouded at birth and glaucoma also occurs.

Hereditary juvenile glaucoma is a genetic vision disorder which may be present at birth. However, onset of symptoms can occur later in childhood or adolescence. Glaucoma is characterized by diminished clear vision along with increased pressure with possible and variable pain inside the eyeball.

Aniridia can be a part of several conditions such as:

Gillespie syndrome, characterized by aniridia, intellectual disability and ataxia (lack of coordination of muscle movements). It is caused by variants in the ITPR1 gene and follows an autosomal recessive pattern in most patients. (For more information choose “Gillespie” as your search term in the Rare Disease Database.)

WAGR syndrome: WAGR stands for Wilms’ tumor (a type of kidney tumor), Aniridia, Genitourinary abnormalities, and Retardation (now called Intellectual disability). WAGR syndrome can also be associated with obesity. WAGR syndrome can present with some or all of these symptoms. WAGR syndrome is mainly caused by missing genetic information on chromosome 11. As commented before, this missing genetic information sometimes includes the PAX6 and WT1 genes. WAGR syndrome gene deletions can occur in a dominant pattern. WAGR syndrome gene deletions can also occur for the first time in the affected individual (de novo variants) without other affected family members. (For more information choose “WAGR” as your search term in the Rare Disease Database.)

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Diagnosis

Diagnosis can be made based on the family history and a detailed physical and eye examination by an ophthalmologist. Diagnosis can be confirmed by genetic testing that identifies a gene variant that can cause aniridia. About two-thirds of people with isolated aniridia have other relatives with this condition. The doctor needs to do a careful slit-lamp examination on other family members before establishing that the patient has a de novo gene variant that was not inherited.

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Standard Therapies

Treatment

Treatment of aniridia is usually directed at improving and preserving vision. Drugs or surgery may be helpful for glaucoma and/or cataracts. Contact lenses may be beneficial for some patients. When a genetic cause cannot be identified, patients should be evaluated for the possibility of Wilms’ tumor development. (For more information on this disorder, please choose “Wilms” as your search term in the Rare Disease Database.)

Children with aniridia who are younger than eight years of age should have ophthalmologic evaluations every four to six months for refractive errors and amblyopia and an annual ophthalmology follow up to detect issues such as corneal changes, raised intraocular pressure and cataracts.

Children with aniridia due to WAGR syndrome or children who do not have an identified genetic cause should have kidney (renal) ultrasound examinations every 3 months and should be followed up by a pediatric oncologist until age eight years. Because of the increased risk for kidney impairment in WAGR syndrome (especially in those with bilateral Wilms tumor), lifelong evaluation of renal function is recommended.

In 2018, the FDA approved the first artificial iris, a surgically implanted device to treat adults and children with aniridia. This device may help to reduce light sensitivity and glare and improve the cosmetic appearance of the eye.

Genetic counseling is recommended. Other treatments are symptomatic and supportive.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact: https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS
Lauderdale JD. Aniridia. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:640.

REVIEW ARTICLES
Wawrocka A, Krawczynski MR. The genetics of aniridia – simple things become complicated. J Appl Genet. 2018;59(2):151‐159.

Lim H, Kim D, Kim H. PAX6 aniridia syndrome. Curr Opin Ophthalmol. 2017;28(5):436-447.

Hingorani M, Hanson I, van Heyningen V. Aniridia. Eur J Hum Genet. 2012;20(10):1011-1017. doi:10.1038/ejhg.2012.100

JOURNAL ARTICLES
Hall HN, Williamson KA, FitzPatrick DR. The genetic architecture of aniridia and Gillespie syndrome. Hum Genet. 2019;138(8-9):881-898. doi:10.1007/s00439-018-1934-8.

Saying aye to the artificial iris. Nat Biotechnol. 2018;36(7):565.

Sannan NS, Gregory-Evans CY, Lyons CJ, et al. Correlation of novel PAX6 gene abnormalities in aniridia and clinical presentation. Can J Ophthalmol. 2017;52(6):570-577. doi:10.1016/j.jcjo.2017.04.006

Weissbart SB, Ayres BD. Management of aniridia and iris defects: an update on iris prosthesis options. Curr Opin Ophthalmol. 2016;27(3):244-249. doi:10.1097/ICU.0000000000000253

Ahmed NR, Tando R & Vanathi M. Diagnosis and Management of Aniridia. November 2014. Opthalmic Pearls.

Laghmari M, et al. Bilateral congenital aniridia: 5 case reports. J Fr Ophthalmol. 2004;27:385-91.

Zumkeller W, Orth U, Gal A. Three novel PAX6 mutations in patients with aniridia. Mol Pathol. 2003;56:180-3.

Churchill AJ, et al. Prenatal diagnosis of aniridia. Ophthalmology. 2000;107:1153-56.

Chao LY, et al. Mutation in the PAX6 gene in twenty patients with aniridia. Hum Mutat. 2000;15:332-39.

Hartmann RW Jr, et al. Picture of the month. Congenital aniridia. Arch Pediatr Adolesc Med. 2000;154:525-26.

Tanzer DJ, et al. Black iris-diaphragm intraocular lens for aniridia and aphakia. J Cataract Refract Surg. 1999;25:1548-51.

Osher RH, et al. Cataract surgery combined with implantation of an artifical iris. J Cataract Refract Surg. 1999;25:1540-47.

Chen TC, et al. Goniosurgery for prevention of aniridic glaucoma. Arch Ophthalmol. 1999;117:1144-48.

INTERNET

Moosajee M, Hingorani M, Moore AT. PAX6-Related Aniridia. 2003 May 20 [Updated 2018 Oct 18]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1360/ Accessed Feb 5, 2024.

Aniridia 1. McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 106210; Last Update: 10/4/2016. https://www.omim.org/entry/106210# Accessed Feb 5, 2024.

Ross M. Aniridia. Medscape. April 6, 2023. https://emedicine.medscape.com/article/1208379-overview Accessed Feb 14, 2024.

Isolated Aniridia. Orphanet. March 2012. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=250923 Accessed Feb 14, 2024.

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