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    Aniridia (Isolated Aniridia)

    Aniridia[1]

    Aniridia is a rare ocular condition most often caused by a mutation in the PAX6 gene located on the short arm of chromosome 11.

    Aniridia stems from the following process: congenital.

    Presentation

    • Iris: Abnormalities of the iris range from mild hypoplasia to almost complete absence [1]. In the most severe cases, the iris may be reduced to a small portion of residual tissue found only on ultrasound biomicroscopy or gonioscopy [2][4]. The mildest phenotypes may show a normal pupil size with the iris present but abnormal [2] [4]. There may also be loss of the surface architecture [1] [13]. Other changes in the iris can include iris ectropion, colobomatous lesions, and eccentric pupil [14] [15].
    • Lens: Cataracts are present in 50-85% of cases [2] and frequently occur at a young age [16][3]. Lens dislocations infrequently occur [1]. Opacities can be due to the persistence of the pupillary membrane or remnant foetal vascularization within the anterior lens capsule [2].
    • Cornea: Approximately 20% of patients have keratopathy associated with aniridia [17]. Keratopathic changes begin with peripheral vascularization and thickening that gradually spreads to involve the whole of the cornea [3] [18] and resulting in corneal ulceration, subepithelial fibrosis and erosions [4].
    • Optic nerve and retina: Hypoplasia of the optic nerve is reported in up to 10% of cases [5].
    • GlaucomaThe incidence of glaucoma in aniridia is common and ranges from 6-75% [1], with the risk generally accepted as 50% [4]. Congenital glaucoma is rare [19].
    • Strabismus, ptosis and refractive errors: Ptosis is found in up to 10% of cases [2], with strabismus presenting as esotropia also common [18]. Myopia and hypermetropia are not uncommon [1].

    Systemic defects

    • Hearing: Difficulties can arise from auditory processing deficits due to abnormal interhemispheric transfer [1].
    • CNS: Olfactory deficits are the most common [20], and abnormalities of the cerebellum, corpus callosum, anterior commissure, olfactory bulb and pineal gland have also been demonstrated [20] [21].
    • WAGR syndrome: This syndrome is the most common of the aniridia syndromes and involves Wilms tumor, genitourinary abnormalities and mental retardation [1] [4].
    • Gillespie syndrome: A rare variant, these cases are associated with mental retardation and cerebellar ataxia [22].

    Entire body system
    Fishing
    • Hybridation in situ en fluorescence FISH Pr Patrick Calvas CHU Purpan Toulouse France Exemple d' étude FISH : "FISH studies in patients with aniridia reveals 35% with chromosome abnormalities including five cryptic 3 PAX6 deletions.[snof.org]
    • For the WAGR syndrome, high-resolution cytogenetic analysis and fluorescence in situ hybridization (FISH) can be utilized to identify deletions within chromosome band 11p13, where both the PAX6 and WT1 genes are located.[en.wikipedia.org]
    • Large gross chromosomal deletion can be detected by cytogenetic analysis, fluorescent in situ hybridization (FISH) and oligo array Comparative Genomic Hybridization (oligo aCGH) analysis.[genedx.com]
    • In this case we used FISH to map both breakpoints.[journals.plos.org]
    • Rarely an asymptomatic parent may be mosaic for such a deletion; thus, it is appropriate to offer FISH testing or deletion testing to both parents.[eyewiki.aao.org]
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  • neurologic
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  • musculoskeletal
    Short Arm
    • Each chromosome has a short arm designated "p" and a long arm designated "q".[cigna.com]
    • The AN2 region of the short arm of chromosome 11 (11p13) includes the PAX6 gene (named for its PAired boX status), whose gene product helps regulate a cascade of other genetic processes involved in the development of the eye (as well as other non-ocular[en.wikipedia.org]
    • Aniridia occurs as the following: An identifiable chromosome deletion of the short arm of chromosome 11, including band p13 [12] Sporadic case The exact defect in iris morphogenesis giving rise to aniridia is unknown.[emedicine.medscape.com]
    • It is due to a mutation in the short arm of chromosome 11 (11p13) and affects the PAX6 gene.[aapos.org]
    • There are various genes that may be affected; however, by far the most common is a genetic error on the short arm of the chromosome 11p13 involving the PAX 6 gene.[aniridia.net]
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  • Workup

    Renal ultrasounds are indicated up to 8 years of age for children exhibiting WAGR or sporadic aniridia without chromosomal abnormality [1]. Cytogenetic testing is used to detect chromosomal abnormalities [2]. The severity of ocular involvement can be assessed by measuring visual acuity, and ophthalmoscopy used to determine iris/pupil abnormalities, optic nerve/foveal hypoplasia and the presence of glaucoma or cataracts [4] [1].

    Differential diagnosis includes Peters and Reiger type 1 syndrome, albinism, Gillespie syndrome, iris coloboma and congenital cataract [4] [1].

    Laboratory

    Serum
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  • Treatment

    Glaucoma

    A lifelong combination of medical and surgical treatment is required to control intraocular pressure [4]. Medical treatment can involve the use of topical miotics, carbonic anhydrase inhibitors and sympathomimetics [3] [1]. Surgical treatments include the following: goniotomy, trabeculectomy with or without antimetabolites, filtration procedures and trabeculoplasty, but no one treatment has been reliable or shown high efficacy [1] [4].

    Cornea

    The treatment approach depends on the degree of keratopathy of the ocular surface [4]. Mucolytics, lubricants and drops without preservatives have been shown to be useful [3]. Surgical treatments have a poor prognosis [1] and are reserved for cases with severe reduction of vision [4]. Results of penetrating keratoplasty are very poor [4], and transplantation of amniotic membrane has shown good but only temporary results [4]. Homologous lamellar limbokeratoplasty has given high success rates due in part to the use of systemic immunosuppressants [23]. Use of the Type 1 Boston keratoprosthesis has been very successful [24], but the development or worsening of glaucoma after transplantation limits the long-term success [4].

    Lens

    Severe opacification necessitates extraction [3] [1], which may be accompanied by an intraocular lens implant [1]. Surgical improvements to vision are limited by other ocular defects [1] and postoperative complications including macular oedema and uveitis [25], determine the surgical technique of choice [1].

    Iris

    Various techniques have been used to relieve the effects of iris hypoplasia, including contact lenses, eyelid surgery, tattooing of the cornea and implantation of artificial iris devices[3][4]. The development of silicone implants personalized to the colour of the other eye means they can be inserted via a minimal incision in the cornea [4].

    Nystagmus and photophobia

    These can be relieved by the use tinted spectacles, tinted intraocular lenses and tinted contact lenses [3] [1].

    Prognosis

    Even with early diagnosis and proper management, aniridia has a poor visual prognosis.

    Complications

    Diabetes Mellitus
    • The PAX6 gene mutation was also associated with early-onset diabetes mellitus and aniridia.[jpediatricsreview.com]
    • Compound heterozygosity for mutations in PAX6 in a patient with complex brain anomaly, neonatal diabetes mellitus, and microophthalmia.[eyewiki.aao.org]
    Glaucoma
    • glaucoma filtration surgery in aniridic glaucoma.[glaucomatoday.com]
    • This type of glaucoma is called congential glaucoma and is not the most common form of glaucoma in aniridia.[aniridia.ru]
    • Glaucoma Although glaucoma or ocular hypertension associated with aniridia has been reported in between 6% and 75% of patients, the risk of developing glaucoma is generally accepted to be around 50%.[hindawi.com]
    • Glaucoma surgical procedures are frequently necessary in patients who develop refractory glaucoma Treatment of photophobia and nystagmus Cataract surgery should be approached with caution because of accompanying zonular dehiscence and/or lens subluxation[dro.hs.columbia.edu]
    • ., cataract), and glaucoma frequently develops before adolescence.[tsbvi.edu]
    Microcornea
    • Aniridia associated with microcornea and subluxated lenses.[meajo.org]
    • Online Mendelian Inheritance in Man (OMIM) 106210 AN Online Mendelian Inheritance in Man (OMIM) 106220 Aniridia and absent patella Online Mendelian Inheritance in Man (OMIM) 106230 Aniridia, microcornea, and spontaneously reabsorbed cataract Online Mendelian[en.wikipedia.org]
    • Microcornea : underdeveloped or small cornea.[rnib.org.uk]
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  • Etiology

    Haploinsufficiency of the PAX6 gene is detectable in about 90% of cases, resulting from genic mutations in two-thirds and chromosomal rearrangements in one-third of cases [4]. Both copies of this gene are required for normal eye development, as it regulates genesis of most of the ocular tissues. PAX6 also regulates development of the olfactory bulb, multiple regions throughout the brain, the gut, pancreas and neural tube [6] [7].

    Epidemiology

    The incidence of aniridia has been reported between 1:40 000 to 1:100 000 [6] and no significant gender or racial bias has been shown [2]. Familial cases of aniridia with dominant inheritance account for approximately two-thirds of patients, with almost complete penetration but variable phenotype [3]. The remaining one-third are sporadic cases [1] [9].

    Sex distribution
    Age distribution

    Pathophysiology

    The pathophysiology underlying aniridia is not known with certainty [10]. The epithelium of the normal iris derives from the neuroectoderm of the anterior rim of the optic cup, while the stroma is derived from the mesenchymal tissue of the neural crest [11]. Both stroma and epithelium are deficient in aniridia so defects in the development of either tissue may prevent normal maturation of the other [3]. Another theory suggests that aniridia may result from excessive remodelling, with regular iris formation being followed by inappropriate iris tissue regression [12].

    Prevention

    There are no guidelines for the prevention of this inherited disorder.

    Summary

    Aniridia is a rare, panocular, congenital disorder of the tissues of the eye, and results in progressive and severe sight disruption [1]. Characterized by extreme hypoplasia of the iris, aniridia often presents with foveal hypoplasia and nystagmus [2] [3]. Related ocular conditions including glaucoma, cataracts, strabismus and optic nerve hypoplasia result in a variety of visual problems [4] [5].

    Aniridia usually presents in infancy [2], and although wide-ranging cerebral defects have been shown [3], hearing and olfactory abnormalities are the most common associated functional deficits [1]. Approximately two-thirds of cases show familial dominant inheritance while the other one-third are sporadic [6]. Sporadic aniridia may show only ocular abnormality, or present in association with a number of systemic disorders [4]. The most common of these is WAGR syndrome that describes the association with Wilms tumor, urogenital abnormalities and mental retardation [1] [3].

    All patients have reduced visual function, and regular monitoring is required for early management of a range of debilitating long-term outcomes [2]. Due to the inheritance pattern, genetic counselling is appropriate [1].

    Patient Information

    Definition

    Aniridia is a rare genetic eye condition that is present at birth. It typically affects both eyes and occurs in approximately 1 in 60,000 births.  Rarely, aniridia is caused by trauma to the eye, or sometimes it is not inherited but develops by chance.

    Aniridia results in the incomplete formation of the iris (the coloured part of the eye that surrounds the pupil). Aniridia can also affect other parts of the eye including the retina, the cornea and the lens, and causes a wide variety of visual problems.

    Cause

    • Inherited

    Most often, aniridia is inherited and congenital, meaning it is passed from parent to child through their genes and is present at birth. Genes are present in pairs and one of each pair is inherited from each of your parents. A parent can carry one normal and one faulty gene but not develop aniridia because the normal gene makes up for the faulty one. The gene responsible for aniridia is called PAX6. If PAX6 is missing or wrong, it prevents the proper formation of parts of the eye, especially the iris, prior to birth.

    Children can inherit genetic conditions through either a dominant or recessive pattern. Dominant conditions are inherited from only one parent. If a parent who carries the aniridia gene has children with a partner who does not carry the gene, there is a 50% chance that any child will have aniridia. A child who does not inherit aniridia cannot pass it on to their children. Nearly two-thirds of congenital cases are caused by a faulty gene inherited this way.

    Recessive conditions are inherited from both parents. You would need to inherit the aniridia gene from both parents to develop a recessive type of aniridia. If two parents who carry the gene (but don’t have aniridia) have a child, there is a 25% chance that the child will develop aniridia. Only a very small number of cases of aniridia are caused by a faulty gene inherited this way. Gillespie syndrome is a rare recessive condition that causes aniridia and problems with writing, speech and walking.

    • Spontaneous

    Approximately one-third of congenital cases occur spontaneously and are not inherited from either parent. The faulty gene starts for the first time in the affected child, and these children are at risk of developing other associated conditions, WAGR syndrome or Miller syndrome.

    WAGR are the initials of the problems that can occur in this syndrome:
    W: Wilms Tumour is a childhood tumour involving the kidney that usually develops before age 5.
    A: Aniridia
    G: Genitourinary problems.
    R: Retardation (Mental).

    Boys and girls can develop WAGR Syndrome, and not all children with the syndrome will have the same types of problems.

    Miller syndrome can cause cleft palate and other developmental problems with the face and the limbs. For most children, the eyes are the only affected parts of the body.

    Symptoms

    The symptoms of aniridia are highly variable and depend on which parts of the developing eye are affected, and some conditions may only develop later on. Some of the more common include:

    • Poor vision: Aniridia patients usually have a visual acuity measurement of between 20/80 and 20/200. Some may be legally blind while others are able to drive a car.
    • Dry eye: related to problems with tear production, this causes the eyes to feel sore and gritty.
    • Amblyopia: Otherwise known as ‘lazy eye’, the image produced by one eye is better than the other.
    • Photophobia: Sensitivity to light.
    • Nystagmus: Uncontrolled movements of the eyes, usually from side to side. This is very common with aniridia and affects detailed vision. Distance vision is affected more than near vision.
    • Glaucoma develops in about 50% of patients, often as they get older and causes damage to the optic nerve due to abnormally high pressure within the eye.
    • Fovea hypoplasia: Fovea hypoplasia can make it difficult for children to read and write and see fine detail. 
    • Cataract: this is clouding of the lens and can blur vision, and can develop in 50-85% of patients with aniridia.

    Diagnosis

    Aniridia is usually picked up by a paediatrician during a routine examination, and the child is referred to an ophthalmologist for proper diagnosis. Blood tests may be taken for genetic screening and confirmation of the diagnosis. Children at risk of developing a Wilms tumor will have a regular abdominal ultrasound at least until they are 10 years old. Wilms tumor can be treated successfully if detected early.

    Treatment

    Treatment depends on the type and severity of the problems, and may include:

    • Sunglasses can be used to help with photophobia and glare.
    • Contact lenses can improve appearance by mimicking the missing iris, and also reduce glare and improve vision.
    • Artificial tears and other lubricants can help with dry eye and maintain corneal health.
    • Surgically implanting an artificial iris may be a treatment for some patients.
    • Advanced disease of the cornea may require surgery to replace some of the missing developmental cells.
    • Treatment for glaucoma can involve surgery and medications.
    • Cataracts may require surgery to remove them.

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    References

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    2. Nelson LB, Spaeth GL, Nowinski TS, Margo CE & Jackson L: Aniridia. A review. Surv Ophthalmol. 1984; 28: 621–642.
    3. Lee H, Khan R, O’Keefe M: Aniridia: current pathology and management. Acta Ophthalmol. 2008; 86: 708–715.
    4. Calvao-Pires P, Santos-Silva R, Falcao-Reis F, Rocha-Sousa A. Congenital Aniridia: Clinic,Genetics,Therapeutics, and Prognosis. Int Schol Res Not. 2014; 10: 1-10.
    5. McCulley TJ, Mayer K, Dahr SS, Simpson J, Holland EJ. Aniridia and optic nerve hypoplasia. Eye. 2005; 19: 762–764.
    6. Simpson TI, Price DJ. Pax6; a pleiotropic player in development. Bioessays.2002; 24: 1041–1051.
    7. van Heyningen V, Williamson KA. PAX6 in sensory development. Hum Mol Genet. 2002; 11: 1161–1167.
    8. Lim HT, Seo EJ, Kin GH, et al. Comparison between Aniridia with and without PAX 6 mutations, clinical and molecular analysis of 14 Korean patients. Ophthalmology. 2012; 119:1258-1264.
    9. Gronskov K, Olsen JH, S and A et al. Population-based risk estimates of Wilms tumor in sporadic aniridia. A comprehensive mutation screening procedure of PAX6 identifies 80% of mutations in aniridia. Hum Genet. 2001;109: 11–18. 
    10. McCormick K, Ward D, Newkirk K. Aniridia in two related Tennessee walking horses. Case Rep Vet Med. 2013; 1-4.
    11. Cook C. Ocular embryology and congenital malformations.Vet Ophthal. 2007; 12:3–36.
    12. Beauchamp G, Meisler D. An alternative hypothesis for iris maldevelopment (aniridia). J Pediatr Ophthalmol Strabismus. 1986; 23(6):281-3.
    13. Okamoto F, Nakano S, Okamoto C, Hommura S, Oshika T. Ultrasound biomicroscopic findings in aniridia. Am J Ophthalmo.l 2004; 137: 858–862.
    14. Pagon, R.A. Ocular Coloboma.. Surg Ophthalmol. 1981;25:223-36
    15. Lewallen WM. Aniridia and related iris defects. Arch Ophthalmo.l 1958;59:831-39
    16. Layman PR, Anderson DR, Flynn JT. Frequent occurrence of hypoplastic discs in patients with aniridia. Am J Ophthalmol. 1974;77:513-16.
    17. Tseng SC, Li DQ. Comparison of protein kinase C subtype expression between normal and aniridic human ocular surfaces: implications for limbal stem cell dysfunction in aniridia. Cornea. 1996; 15: 168–178.
    18. Hingorani M, Williamson KA, Moore AT, van Heyningen V: Detailed ophthalmologic evaluation of 43 individuals with PAX6 mutations. Invest Ophthalmol Vis Sci. 2009; 50: 2581–2590.
    19. Chen TC , Walton DS. Goniosurgery for prevention of aniridic glaucoma. Arch Ophthalmol. 1999;117(9):1144–1148.
    20. Sisodiya SM, Free SL, Williamson KA et al. PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans. Nat Genet. 2001; 28: 214–216.
    21. Mitchell TN, Free SL, Williamson KA et al. Polymicrogyria and absence of pineal gland due to PAX6 mutation. Ann Neurol. 2003; 53: 658–663. 
    22. Gillespie FD (1965): Aniridia, cerebellar ataxia and oligophrenia in siblings. Arch Ophthalmol. 73: 338–341.
    23. Holland EJ, Djalilian AR,Schwartz GS. Management of aniridic keratopathy with keratolimbal allograft: a limbal stem cell transplantation technique. Ophthalmol. 2003;110(1): 125–130, 2003.
    24. Akpek EK, Harissi-Dagher M, Petrarca R, Butrus SI, Pineda R II, Aquavella JV & Dohlman CH. Outcomes of Boston keratoprosthesis in aniridia: a retrospective multicenter study. Am J Ophthalmol. 2007; 144: 227–231.
    25. Reinhard T, Engelhardt S & Sundmacher R (2000): Black diaphragm aniridia intraocular lens for congenital aniridia: long-term follow-up. J Cataract Refract Surg 26: 375–381.

    • 11p13 deletion and reduced RBC catalase in a patient with aniridia, glaucoma and bilateral Wilms' tumor. - C Barletta, MA Castello, E Ferrante, I Mavelli, A Clerico - Tumori, 1985 - ukpmc.ac.uk


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