| Aniridia | |
|---|---|
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| A man with aniridia | |
| Specialty | Medical genetics  |
Aniridia is a condition characterized by the absence or near absence of theiris, the colored, muscular ring in the eye that controls the size of the pupil and regulates the amount of light entering the eye. This absence results in a primarily black appearance of the central eye. Aniridia can becongenital, typically affecting both eyes, or caused by a penetrant injury.[1] Congenital aniridia is not simply an iris defect but a more complex condition affecting multiple parts of the eye, withmacular andoptic nerve hypoplasia,cataract, andcorneal changes.[2] Vision may be severely compromised and the disorder is frequently associated with several other ocular complications, includingnystagmus,amblyopia,buphthalmos, andcataract.[1] In some cases, aniridia occurs as part of a broader syndrome, likeWAGR syndrome (kidney nephroblastoma, genitourinary anomalies and intellectual disability) orGillespie syndrome (cerebellar ataxia).
ThePAX6 gene, located within the AN2 region on the short arm ofchromosome 11 (11p13), plays a crucial role in the development of the eye and other structures. This gene, named for its "PAired boX" sequence, regulates a cascade of other genetic processes involved in eye formation.[3] Remarkably, the PAX6 gene exhibits high evolutionary conservation, sharing approximately 95% similarity with thepax gene found inzebrafish, a species whose evolutionary lineage diverged from humans around 400 million years ago.
Defects in the PAX6 gene cause aniridia-like ocular defects inmice (as well asDrosophila). Aniridia is aheterozygous disorder, meaning that only one of the twochromosome 11 copies is affected. When both copies are altered (homozygous condition), the result is a uniformly fatal condition with near complete failure of entire eye formation. In 2001, two cases of homozygous aniridia patients were reported; the fetuses died prior to birth and had severe brain damage. In mice, homozygoussmall eye defect (mouse Pax-6) leads to loss of the eyes and nose and the murine fetuses sustain severe brain damage.[4]
Aniridia may be broadly divided into hereditary and sporadic forms. Hereditary aniridia is usually transmitted in anautosomal dominant manner (each offspring has a 50% chance of being affected), although rareautosomal recessive forms (such asGillespie syndrome) have also been reported. Sporadic aniridiamutations may affect the WT1 region adjacent to the AN2 aniridia region, causing a kidney cancer callednephroblastoma (Wilms tumor). These patients often also have genitourinary abnormalities andintellectual disability (WAGR syndrome).
Several different mutations may affect the PAX6 gene. Some mutations appear to inhibit gene function more than others, with subsequent variability in the severity of the disease. Thus, some aniridic individuals are only missing a relatively small amount of iris, do not havefoveal hypoplasia, and retain relatively normalvision. Presumably, the genetic defect in these individuals causes less "heterozygous insufficiency," meaning they retain enough gene function to yield a milderphenotype.
Molecular (DNA) testing for PAX6 gene mutations (bysequencing of the entirecoding region anddeletion/duplication analysis) is available for isolated aniridia and the Gillespie syndrome. For the WAGR syndrome,high-resolution cytogenetic analysis andfluorescence in situ hybridization (FISH) can be utilized to identify deletions within chromosome band 11p13, where both the PAX6 and WT1 genes are located.[5]
Aniridia can cause many symptoms, such as:
In May 2018, the U.S. Food and Drug Administration approved the CustomFlex Artificial Iris, the firstsynthetic iris for use in adults and children with congenital aniridia or iris defects related to other conditions, such asalbinism, traumatic injury, or surgical removal due toocular melanoma. The artificial iris is a surgically implanted device made of thin, foldable, medical-gradesilicone and is custom-sized and colored for each individual patient. The prosthetic iris is held in place by the anatomical structures of the eye or, if needed, by sutures.[7]
8. Neethirajan G, Hanson IM, Krishnadas SR, Balasubramanian D, Sowdhamini R, Radha V, et al. A novel PAX6 gene mutation in an Indian aniridia patient. Mol Vis. 2003;9:205-9.
9. Neethirajan G, Vijayalakshmi P, Krishnadas SR, Balasubramanian D, Shashikant S, Shashikant C, et al. PAX6 gene variations associated with aniridia in South India. BMC Med Genet. 2004;5:37.
10. Neethirajan G, Collinson JM, Krishnadas SR, Vijayalakshmi P, Soni R, Hanson IM. De novo deletions in the paired domain of PAX6 in south Indian aniridic patients. J Hum Genet. 2004;49(12):647-9.
11. Neethirajan G, Krishnadas SR, Vijayalakshmi P, Anupkumar AN, Balasubramanian D, Hanson IM. Identification of novel mutant PAX6 alleles in Indian cases of familial aniridia. BMC Ophthalmol. 2006;6:28.
12. Neethirajan G, Krishnadas SR, Vijayalakshmi P, Shetty S, Sundaresan P. Semi-Quantitative Analysis of PAX6 Gene in Ocular and Non-Ocular Tissues. New Vis Med Med Sci. 2024;3:47–59
