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Congenital Aniridia

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1,2,3

Dewang Angmo, 2Bhaskar Jha, 3Anita Panda

Department of ophthalmology, Dr Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi, India

Correspondence: ............................................................................................................................. .............................................. ...................................................................................................................................................................................................


ABSTRACT Aniridia is a rare bilateral ccondition that may have life threatening associations. It occurs as a result of abnormal neuroectodermal development secondary to a mutation in the PAX6 gene linked to 11p13. This gene controls the development of a number of structures, hence the broad nature of ocular and systemic associations.This article presents a review of congenital aniridia including epidemiology, genetics, clinical features, ocular & systemic associations and management modalities. Keywords: A n i r i d i a , s u b l u x a t i o n , g l a u c o m a f i l t e r i n g s u r g e r y , P A X 6 g e n e .

INTRODUCTION Aniridia (Greek; absence of iris) is an uncommon hereditary bilateral congenital, panocular disorder affecting not only the iris but also the cornea, anterior chamber angle, lens, retina, and optic nerve as well with life-threatening associations. Its first description was given by Barrata in 1818. 1 It is characterized by profound hypoplasia of the iris (Figs 1A and B) in frequent association with multiple ocular anomalies, such as peripheral corneal pannus and keratopathy, foveal hypoplasia, diffuse retinal dysfunction as seen on electroretinography6,7, impaired acuity with nystagmus, cataract and ectopia lentis and optic nerve hypoplasia20. These defects, in combination, usually cause a formidable barrier to normal visual function. Often, the iris is vestigial (little more than a margin is present) and the eye appears to have colorless (only a larger than normal) pupil. It may be associated with systemic defects consisting of mental retardation, genital anomalies and Wilms tumor.1 Epidemiology: Incidence reported from studies are 1:64,000 to 1:96,000.1,2 Pedigree analyses have shown that two-thirds of children with aniridia have an affected parent.1,3 Mortality/Morbidity: All patients with aniridia are visually handicapped for their whole life. Complications like cataract

and glaucoma reduce the vision furthermore. The patients with Wilms tumor have a reduced span of life. Aniridia itself is not a lethal disorder. However, miscarriages and a stillborn child have been the only results of a consanguineous mating between individuals with aniridia. It is possible that a homozygous mutation of the aniridia gene may be lethal. The morbidity of aniridia is significant because of the decreased vision and nystagmus. Genetics: Aniridia can occur as the following: Autosomal disorder: Dominant and recessive Deletion of the short arm of chromosome 11, including band p13 Sporadic case. In the majority of cases with familial inheritance, an autosomal dominant inheritance pattern with almost complete penetrance has been demonstrated.1 However, variations in expression have also been seen to occur. Rarely it may be transmitted in an autosomal recessive manner.4,5 Consanguineous marriages have also been implicated in some studies.30 Of the sporadic cases of aniridia, two-thirds represent a new autosomal dominant condition. Regarding racial predisposition it has been seen that it does not exist.

Figs 1A and B: (A) Showing the peripheral iris rim and a clear view of the lens equator, (B) total aniridia with inferiorly subluxated lens

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Table 1: Classification of aniridia AN-1 is autosomal dominant, accounts for 66% of cases and has no systemic implications. Penetrance is complete, but expressivity variable. AN-2 ( Miller syndrome) is sporadic and accounts for 33%. It carries 30% risk of Wilms tumor developing before the age of 5 years. AN-3 ( Gillespie syndrome) is autosomal recessive and accounts for the remainder. It is associated with mental handicap and cerebellar ataxia.

formation or excessive regression of various layers of the anterior segment caused by cellular or biochemical aberrations. This explains the combined anterior and posterior segment, neural ectodermal and mesenchymal defects. The iris stroma is hypoplastic, indicating an altered third neural crest wave of mesenchyme. Clinical Presentations (Table 2) The age at presentations is generally infancy when the parents notice abnormally large pupil. Sometimes they may also complain poor vision and photophobia in early childhood along with nystagmus. Congenital glaucoma and aniridia usually are not associated at birth. The glaucoma develops at either the preteen or the teenage level. Significant cataracts may occur before puberty. The risk for cataract increases with age with lens opacities observed in 50 to 85% of patients during the first two decades of life. The clinical presentations/features are discussed one by one: Decreased Vision It is the most common symptom of the aniridia. Many series report that as many as 86% of affected individuals have 20/ 100 vision or worse in the better eye. The causes of poor vision are: Foveal hypoplasia Cataract Glaucoma Corneal dystrophy Nystagmus Aberrations of light have also been indicated as a cause of early poor vision in aniridia Strabismus Ectopia lentis Optic nerve hypoplasia. Photophobia It is often present in affected patients and considered secondary to excessive light stimulation because of poor pupillary
Table 2: Clinical features 1. Aniridia alone 2. Aniridia with other systemic abnormalities Wilms tumor (20% cases) Genitourinary abnormalities Mental retardation 3. Aniridia with other ocular disorders Albinism Ectopia lentis (50%) Spontaneous lens dislocation Arcus juvenilis Keratoconus Cataract (50-85%) Glaucoma (30-50%) Nystagmus Strabismus Optic nerve hypoplasia (75%) Pupillary membrane remnants.

As an isolated ocular malformation, aniridia is an autosomal dominant disorder, which is caused by a mutation in the PAX6 (paired box gene family) gene. Patients with aniridia who have a positive family history are not at an increased risk for Wilms tumor. Two genetic loci for aniridia have been identified: one (AN1) on chromosome arm 2p and one (AN2) on chromosome 11 (Table 1). Miller Syndrome (WAGR Complex, 11p Syndrome) The association between aniridia and Wilms tumor is referred to as Miller syndrome. Approximately 30% of patients with sporadic aniridia develop Wilms tumor, usually before age 5 years. It is reported that 1.4% of patients with Wilms tumor have aniridia compared to one in 64,000 to one in 100,000 of the general population. Other associated features are genitourinary abnormalities, craniofacial dysmorphism, hemihypertrophy and severe mental retardation. These patients also have poorly lobulated low-set ears, prominent noses, and long narrow faces. The acronym WAGR (Wilms tumor, aniridia, genitourinary anomalies and mental retardation) describes some of the features of Miller syndrome. Miller syndrome has been attributed to a deletion of band 11p13. Patients with sporadic aniridia should undergo a thorough physical examination and work-up by a family practitioner or pediatrician. Gillespie Syndrome Gillespie syndrome is the association of aniridia, cerebellar ataxia and mental retardation. It is autosomal recessive, occurring in approximately 2% of patients with aniridia. These parts of the brain, and they are not predisposed to developing Wilms tumor. A study of the PAX6 gene in Gillespie syndrome failed to find a mutation, suggesting that abnormalities in the PAX6 gene are not responsible for this syndrome. Pathophysiology Primary developmental arrest of the neuroectoderm and a secondary alteration of all three neural crest waves of the mesenchyme have been implicated in the pathogenesis of aniridia. The exact defect in iris morphogenesis giving rise to aniridia is unknown. Because the iris pigment epithelium, the iris musculature, the retina, and the optic nerve are derived from neuroectoderm, there may be a common embryologic origin

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constriction. A characteristic facial expression in many children consists of narrowing of the palpebral fissure and furrowing of the brow.1 Iris Abnormalities Aniridia is still considered by some to be one of the colobomatous disorders.10 The abnormalities can be: Complete absence; as seen on oblique illumination Hypoplasia with irregular pupillary margins (atypical coloboma of pupil) Only root of the iris; visible on gonioscopy. Iris abnormalities from almost total absence to mild hypoplasia of the iris may occur in affected individuals. Since a small portion of iris tissue can almost always be found on gonioscopic examination, the term irideremia better describes the condition than does aniridia.8,9 In addition, ocular colobomas and aniridia have been reported among individuals in the same family in the patients with aniridia. It is now known that iris thinning with a round; normal-appearing pupil may be found in family members of aniridics who, on further examination, show evidence of characteristic corneal or lenticular involvement of aniridia.9 Glaucoma Congenital glaucoma with or without buphthalmos is rare in infants with aniridia, but the reported incidence of glaucoma later in childhood is 6 to 75%.11-16 Although some infants have congenital angle anomalies (trabeculodysgenic anomaly) and early glaucoma, most glaucomas occur later in childhood or early adulthood with closure of the iridocorneal angle. As a result of its delayed onset, the clinical findings of megalocornea, buphthalmos and Haabs striae are not found. Routine gonioscopic examination is important to detect anatomical changes in the angle structures that may progress to angle-closure. During the first few years of life, the trabecular meshwork appears open and is not covered by iris tissue. Grant and Walton believe that a progressive change in the angle structures occurs during the first two decades of life in those patients who will develop glaucoma.14 These changes consist of extensions of iris stroma, somewhat resembling anterior synechia, that reach across and attach anterior to the filtration area of the trabecular meshwork. These iris extensions may eventually form a sheet that covers most of the filtration area in patients who will develop glaucoma. The lOP elevation is presumed to occur at a later developmental stage, usually after the age of 5, or often in adolescence. The severity of glaucoma is directly correlated with the extent of progressive synechial angle closure by the pulled-up residual iris stump. Glaucoma secondary to intumescent lens changes or ectopia lentis (Fig. 1B) has been reported in aniridia. Cataract

Cataracts (Fig. 2) occur frequently and at a young age in aniridics.17 Lens opacities develop in 50 to 85% of patients,

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Congenital Aniridia

Fig. 2: Total aniridia with superiorly subluxated cataractous lens (oblique illumination)

usually during the first two decades of life. Subtle changes may be present in the lens at birth, and these can progress to significant opacities by middle age. Types of cataracts are as following: Anterior polar Pyramidal Nuclear Lamellar Cortical. Anterior and posterior lens opacities noted after birth do not usually cause significant visual difficulty. Cortical, subcapsular, and lamellar opacities often develop by the teenage years and may require lens extraction. Areas of clear space may be present in the cataractous lens, which allows for relatively good vision. In these patients, cataract surgery is best delayed, since the risks of glaucoma, developing or progressing, and foveal hypoplasia in aniridic eyes outweighs the small potential for visual improvement. Ectopia Lentis Ectopia lentis (Figs 1B to 3) has been reported in up to 56% of patients with aniridia. Segmental absence of zonules is a possibility but zonules are morphologically normal. The high incidence of ectopia lentis in aniridia may eventually be attributed to defects in their molecular structure.18,19 Corneal Defects These can be seen in the following forms: Pannus (Fig. 3) Epithelial ulcers Arcus juvenilis Microcornea. Progressive corneal opacification and pannus occur in most patients, developing as early as age of 2 years. In majority of individuals aniridic keratopathy manifests in the first decade of life as thickened irregular epithelium of the peripheral cornea.

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inferior retinal arteriole prior to its bifurcation with the disk size. While the normal disk/arteriole ratio in an adult eye is 14.6 2.4, in hypoplastic disks the range is from 6.1 to less than 14.6.21 True aplasia of the optic nerve is although rare in the general population, but can be found in these patients. The association between poor retinal development and aniridia is not surprising, since the iris epithelium and musculature, and the retina, are derived from neuroectoderm. Foveal Hypoplasia Foveal hypoplasia is a devastating feature of some cases of aniridia , with patients having nystagmus from an early age, and a visual acuity potential of only about 20/200. This should Fig. 3: Total aniridia with inferiorly subluxated lens with pannus and make the physician cautious about the visual results from 360 limbal stem cell deficiency cataract extraction or penetrating keratoplasty. In some patients, foveal hypoplasia may be so subtle that fluorescein angiography The epitheliopathy is typically accompanied by fine superficial may be necessary to demonstrate lack of the foveal avascular neovascularization (Fig. 3). Initially, fine radial vessels invade zone. Approximately, 75% of patients with aniridia have some the superficial layers of the peripheral cornea at the 6- and degree of optic nerve hypoplasia. The macula and optic nerve 12-Oclock positions, and then involve the whole circumference. are usually normal in patients with Gillespie syndrome. This process may initially involve epithelial and subepithelial layers, and later on may progress to involve the entire thickness Strabismus and Refractive Errors of cornea. Overtime subepithelial fibrosis and stromal scarring predisposes aniridic patients to recurrent erosions, corneal Strabismus is common in aniridic patients and mostly it is ulceration and chronic pain. This corneal dystrophy associated esotropia.1,15 Asymmetric visual loss in aniridic children may with aniridia may progress in a variable manner to completely occur from amblyopia secondary to strabismus or cover the cornea, further compromise vision requiring corneal anisometropia. High refractive errors are not uncommon and a transplantation. Since, the corneal abnormality is vascularized careful cycloplegic refraction is necessary in affected children. and inflamed, it cannot be included among the group of diseases This can be either myopia or hypermetropia. Visual acuity may known as dystrophies. improve if clinical suspicion is high for amblyopia and Microcornea has been reported in association with appropriate optical correction and occlusion therapy begins aniridia.19 early in the childs visual development. The cause for the keratopathy is still not clear. It is thought to be resulting from dysfunction of limbal stem cells which Nystagmus originates from following observations: 1. The clinical morphology of the limbus in aniridic patients Pendular nystagmus is present in the majority of aniridics. Most has been shown to be abnormal. These patients lack the investigators believe that nystagmus is secondary to macular 13,17 The presence of nystagmus should alert the phypalisades of Vogt. These palisades serve as a marker for hypoplasia. corneal stem cell differentiation. The absence of this sician to the likelihood of foveal hypoplasia. The other causes important limbal structure suggests localization of the of nystagmus and poor vision in infancy are the characteristic iris defect and lack of foveal reflex in aniridia. Mild cases may epithelial abnormalities in aniridic patients to the limbus. 2. Healthy corneal epithelium is a stratified squamous be difficult to detect because of nystagmus, and corneal or lens epithelium that contains no goblet cells or other conjunctival opacities. specific elements. In aniridic patients, goblet cells are present in significant numbers in the peripheral corneal Differential Diagnosis epithelium. Rieger syndrome with iridocorneal dysgenesis Posterior Segment Disorder It consists of optic nerve hypoplasia and foveal hypoplasia 20 ; optic nerve hypoplasia has rarely been reported in aniridic patients. True aplasia to even mild anomalies can be seen in the patients with aniridia. Mild cases can be noted if careful comparisons are made between the widths of the superior or Congenital coloboma of the iris Surgical iris coloboma Hereditary iris hypoplasia Traumatic iris injury Bilateral congenital mydriasis AGR triadsporadic (bilateral or unilateral) aniridia, genitourinary abnormalities and mental retardation

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Corectopia ICE syndromes Anterior cleavage syndromes Colobomatous microphthalmia.

Schirmers test: To find out associated dry eye. Ultrasound biomicroscopy26:


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This is helpful in imaging,

Investigations Gonioscopy Grant and Walton studied detailed angles assessement in aniridic children.25 They noted that the angles of aniridic patients without glaucoma are free from iris attachments to the trabecular meshwork and that the iris remnant is in the normal iris plane, which is perpendicular to the axis of the eye. The angles of aniridic patients developing glaucoma show increased confluence of irregular attachments from the iris stroma to the angle wall. They found that in most of the eyes the peripheral stump of iris gradually extended anteriorly to cover the filtration portion of the trabecular meshwork (Figs 4A and B) eventually leading to synechial angle closure. Typically, later in childhood the filtration area of the trabecular meshwork is covered by extension of abnormal iris tissue forward on to the trabecular meshwork, and therefore rising the intraocular pressures.25 Therefore, gonioscopy is must to find out the progression of angle closure glaucoma. If the iris stump is enlarging it is an indication of prophylactic goniotomy.

Figs 4A and B: Gonioscopy of superior (A) and inferior (B) angle in aniridia showing peripheral stump of iris gradually extended anteriorly to cover the filtration portion of the trabecular meshwork

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especially in cases of opaque cornea. Ultrasound biomicroscopy imaging demonstrates shallow anterior chamber, irregular corneal thickness, hyperechoic lesion of the corneal stroma and short, thin ciliary body (ciliary body hypoplasia)26. It also shows peripheral residual iris stump. Ultrasound biomicroscopic imaging demonstrated that not only iris hypoplasia but also ciliary body hypoplasia exist in aniridia. Anterior inclination of the ciliary process was also found, which was thought to be at least partly responsible for the shallow anterior chamber. Impression cytology : To find out abnormal cells in the epithelium. The presence of caliciform cells in corneal impression cytology defines the instability of the lacrimal film and an epithelial defect. FFA Intravenous fluorescein angiography shows an early vascular loop in the remaining iris and late leakage from the pupillary margin; this may be a helpful finding in those cases where the diagnosis of aniridia is not apparent because of a round, more normal-appearing pupil. The posterior pole of aniridic patients shows persistence of vessels in the normally avascular zone of the macula. Electrophysiological Tests The electroretinographic (ERG) signal amplitudes in patients with visual acuity of 20/60 or worse are abnormally low, while some patients with better acuities may have abnormally high a:b wave ratios. Prolonged latencies of the b wave peaks (implicit times) were also demonstrated in some patents; no ERG findings have been consistent enough to be useful diagnostically. The electrooculogram (EOG) has usually been normal7. Lab Studies Chromosomal deletion is detected by cytogenetic testing with the use of high-resolution banding. Submicroscopic deletions of the Wilms tumor gene are recognized with a fluorescent in situ hybridization (FISH) technique. High-resolution chromosome studies are obtained in sporadic cases to determine if there is a deletion of band 11p13. Serial renal ultrasound examinations are indicated in patients through age 7 years, especially for those with a deletion of band 11p13 or those with a negative family history of aniridia and normal chromosomes. Histologic Findings Histologically, small portions of the iris are always present; the ciliary body is usually hypoplastic; and the anterior chamber

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angle may be normal, immature (i.e. incompletely developed), or malformed. Histopathologic examination of advanced cases of aniridia reveals only stubs of iris tissue that lack dilator and sphincter muscles, both neuroectodermal derivatives. In eyes enucleated from older patients, extensive peripheral anterior synechia that cause the iris stump to adhere to the posterior corneal surface have been observed. Retinal lipoidal deposits in the peripheral retina have been reported in three patients suggests that the underlying defect may be in the metabolic pathway of fats, which results in storage of an abnormal lipid compound in the tissues.

procedures for the treatment of aniridic glaucoma include the following: 1. Goniotomy is useful if performed before the development of irreversible synechial closure. This early surgical therapy has some risk to the crystalline lens and zonules because the surgery is performed from the anterior approach. It was reported by Barkan11 in the 1950s to control IOP in one patient with aniridia followed for 9 months. Since that time, however, multiple authors have reported disappointing outcomes with IOP control from goniotomy.25,27 2. Trabeculotomy may be safer than goniotomy since it relies on the posterior approach (ab externo). The tissues can be Systemic Investigations defined more clearly, and accurate surgery can be performed. However, failures are common. Adachi et al41 Abdominal ultrasound: To rule out associated Wilms tumor found that in 12 eyes, which initially underwent Genitourinary referral: To find out associated anomaly trabeculotomy, 10 eyes (83%) obtained good IOP control (defined as an IOP of 21 mm Hg or lower) after the first or IQ evaluation: For mental retardation. second trabeculotomy with a mean follow-up of 9.5 years. In eyes that underwent other procedures first (i.e. goniotomy, TREATMENT trabeculectomy, trabeculectomy with trabeculotomy and Glaucoma Molteno implant), only three of 17 eyes (18%) obtained This is difficult and the prognosis guarded. Prophylaxis is good IOP control. They concluded that in eyes with aniridia directed toward the prevention of glaucoma, which includes and uncontrolled glaucoma, trabeculotomy is the preferred the following: initial surgical intervention. Their patient population, Medical treatment with miotics however, developed glaucoma and underwent surgery at Surgical separation of the iris from the trabecular meshwork an earlier age than most patients with aniridia. Of the 29 in selected cases. eyes that had glaucoma surgery, 14 eyes had glaucoma surgery in the first year of life. This is inconsistent with the Medical treatment is frequently the initial approach, although general belief that many patients with aniridia develop it is usually eventually inadequate. The medical treatment is glaucoma later in childhood (i.e. between ages 5 and 15) directed toward control of intraocular pressure, which includes because of progressive angle closure, and that glaucoma in the topical use of the following: infancy is rare in aniridic patients. The success rate reported Miotics: Miotics often are tried first; they improve aqueous by Adachi et al includes patients who had an IOP of 21 or outflow by contracting the ciliary muscle. However, the induced lower, with or without medications. In fact, only three of myopia may not be well-tolerated by young patients. Adrenergic 12 eyes (25%) treated with initial trabeculotomy achieved agonists, beta-blockers, and carbonic anhydrase inhibitors also IOP control without medications. Wiggins and Tomey27 did may be tried, but they often are ineffective long-term as the not have as much success with trabeculotomy in treating patient becomes refractory to them. Whenever a new medication aniridic glaucoma as the two eyes that underwent this is to be instituted, a trial should be performed, adding and procedure in their large series did not achieve successful IOP control. removing only one medication at a time. 3. Filtering procedures : Most surgeons operate for Beta-blockers trabeculectomy after a few attempts at goniotomy or trabeculotomy. There is a greater danger of injury to the Sympathomimetics crystalline lens and to disturbance of the vitreous along with Carbonic anhydrase inhibitors. vitreous loss in trabeculectomy because of the absence of Argon laser trabeculoplasty: It has been described in the patients iris. The surgical complications of direct lens injury, lens with aniridia. Nelson performed the procedure in four of his or vitreous incarceration in filtration sites can be patients and all had good control of IOP.1 Poor results have considerably reduced with the use of intracameral been obtained with laser trabeculoplasty.1 viscoelastic perioperatively. Several other studies, however, have reported poor IOP control after trabeculectomy in eyes Surgical Procedures with glaucoma associated with aniridia. Grant and Walton reported poor IOP control (defined as pressure > 22 mm No convincing opinion exists as to which surgical procedure is Hg or the need for further surgery) in nine eyes of seven the treatment of choice for aniridic glaucoma; none has been patients treated with filtering surgery for glaucoma considered reliable and predictable in efficacy. Surgical

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Congenital Aniridia

associated with aniridia. Nelson and Spaeth1 noted that in five of 14 patients with glaucoma associated with aniridia, IOP remained uncontrolled after trabeculectomy. Okada and associates28 reported successful IOP control in young aniridic patients after filtering surgery. In their study, 17 trabeculectomies and three trabeculectomies with mitomycin C were performed on 10 eyes of six patients younger than 40 years, followed up for a mean of 14.6 months (range, 2-54 months). The mean duration of successful IOP control (defined as pressure lower than 20 mm Hg with or without glaucoma medications) after filtering surgery was 14.6 months. 4. Glaucoma drainage devices: The choice of the techniques and the order, in which they are used, depends upon the peculiarities of the case and the perception of the surgeon. Use of luminal occlusive suture, which can be removed later, has greatly improved the success of this procedure and enhanced the safety. Arroyave et al22 studied five patients with aniridia (8 eyes) who underwent placement of glaucoma drainage devices (7 eyes had Baerveldt implants and 1 a double plate Molteno implant) at an average age of 92 months and who were followed up for an average of 19 months. Insertion of the glaucoma drainage implant was the initial glaucoma surgery in six of the eight eyes in this study. They reported a success rate of 100% at 6 months and 88% at 1 year, with success defined as IOP < 21 mm Hg, with or without medications, with no visually devastating complications or need for reoperation for glaucoma. The patients experienced a decrease in average IOP from 35 mm Hg preoperatively on an average of one glaucoma medication to 14.9 mm Hg postoperatively with no eye drops. Vision remained stable in 25% of eyes, improved in 63% of eyes, and decreased in the one eye that experienced a complication, retinal detachment.22 Wiggins and Tomey also reported a high rate of success with glaucoma drainage implants in advanced cases of aniridic glaucoma, in that 83% of the eyes that underwent this procedure had a postoperative IOP < 21 mm Hg with no visually devastating complications. Many of these eyes had multiple prior IOP lowering procedures including trabeculectomy, trabeculotomy, laser trabeculoplasty, and cyclocryotherapy.27 Thus, glaucoma drainage implants have a role in aniridic glaucoma and can be used as an initial surgical approach or in advanced cases with extensive prior surgical attempts at IOP lowering. 5. Cyclodestructive procedures have also been reported in the treatment of aniridic glaucoma, with limited success and frequent complications. Wagle et al 37 described the combined experience of two institutions in treating eight eyes with aniridia with cyclocryotherapy. Two of eight eyes (25%) were in the success group, defined as an IOP of 21 mm Hg or less without devastating complications or the need for further glaucoma surgery. However, 50% of the
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eyes with aniridia treated with cyclocryotherapy developed

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devastating complications, in that three eyes went on to develop phthisis and one eye had a retinal detachment followed by phthisis.37 Wallace et al38 reported good IOP control in six of nine aniridic eyes treated with one or more sessions of cyclocryotherapy, but over half of the eyes treated experienced a decline in vision. Wiggins and Tomey27 reported a success rate of 25% in eyes with aniridic glaucoma undergoing cyclocryotherapy, but they also observed complications of cataract and phthisis. Kirwan et al39 studied the use of diode laser cyclophotocoagulation in 77 eyes with uncontrolled pediatric glaucoma, including five eyes with aniridia. They found that cyclodiode therapy could provide effective IOP control with repeat treatments in the pediatric glaucoma population, but the results are not broken down to detail the aniridic patients in particular. They do comment that the aniridic patients did not have a higher rate of adverse events from cyclophotocoagulation compared with the other patients in their study, in contrast to the findings of Wagle et al.37 In 1992, Wiggins and Tomey27 reported the outcomes of glaucoma surgery in 17 eyes of 10 patients with aniridia. Forty-five procedures were performed, and 11 eyes achieved IOP control with a mean of 2.8 surgeries. They observed that trabeculectomy and cyclocryotherapy controlled the IOP in 9% (one of 11 eyes) and 25% (five of 20 eyes). 6. Goniosurgery: Chen and Walton24,40 described a different approach to aniridic glaucoma, using goniosurgery to prevent the development of glaucoma in selected young patients with aniridia. They reported the use of a modified goniosurgery in 55 eyes of 33 patients with aniridia, all of whom met inclusion criteria (i.e. age greater than 1 year of life and the presence of particular gonioscopic findings). Eyes that were felt to be good candidates for prophylactic goniosurgery included aniridic eyes with greater than half the circumference of the posterior trabecular meshwork covered by extensions of tissue from the peripheral iris, or eyes with progressive covering of the trabecular meshwork by iris tissue. Eyes with aniridia and IOP mm Hg, or eyes with less severe gonioscopic changes were not considered good candidates for prophylactic goniosurgery. These selected eyes that were felt to be at high-risk for the development of glaucoma because of progressive iris changes then underwent a modified goniosurgery. In this modified goniosurgery, a goniotomy knife was used to remove the abnormal tissue spanning between the iris and the trabecular meshwork. Care was taken to avoid injury to the trabecular meshwork. Similar to goniosynechialysis surgery, this iris tissue is peeled away from the wall of the angle. Unlike goniotomy surgery, no incision through the trabecular meshwork or into Schlemm canal is made. Chen and Walton reported successful prevention of glaucoma in 89% of patients treated with this prophylactic goniosurgery (i.e. IOPs were < 22 mm Hg without medications at last follow-up). Additionally, the remaining 11% of patients who

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underwent the procedure subsequently developed glaucoma with elevations of IOP that could be controlled with two glaucoma medications or less. These results were based on an average follow-up of 9.5 years, and there were no complications of surgery.40 This is in contrast to the literature, which reports the incidence of glaucoma in aniridia to be about 50%. Glaucoma occurs in about half of all cases of aniridia and is difficult to control with medications and surgery. Different surgical approaches have been attempted with only limited success. The most successful approach may be to prevent aniridic glaucoma by performing goniosurgery in selected eyes with progressive angle changes. For aniridic glaucoma, glaucoma drainage devices may be more successful in lowering IOP and may have fewer complications than trabeculectomy and cyclodestructive procedures.

Cataract Lens opacification may require cataract extraction. Before operating, however, the ophthalmologist should attempt refraction through the aphakic portion of the pupil if the lens is subluxated. Either extracapsular or phacoemulsification surgery may be used, depending on the stability of the zonules. Management of Cataract

In-the-bag lens implantation in cases without lens dislocation In-the-bag IOL placement with intracapsular ring, when there is slight lens displacement Lens extraction followed by contact lens correction, if the lens is grossly out of place. Cataract extraction can be difficult and is often accompanied by vitreous loss or further deterioration of the cornea. Dense cataract removal may result in some improvement in visual acuity. Lensectomy performed with an aspiration-cutting Corneal Problems instrument has been recommended. Capsule-supported 1. Penetrating keratoplasty may be indicated for corneas that intraocular lenses are not appropriate for patients with ectopia have opacified from pannus or in the cornea that becomes lentis. The use of intraocular lens implants in children is an sufficiently opaque. Surgical results from penetrating evolving field, and their use in patients with aniridia is still not keratoplasty are quite poor because of the abnormal stem very clear. cells and highly vascular host. Therefore, visual results are A combined approach for both glaucoma and cataractous marginal (one to two lines improvement in Snellen acuity) subluxated lens: In the bag limbal lensectomy with Ahmed and the prognosis is guarded because of rejection and glaucoma valve implantation. underlying amblyopia or other structural defects. Kremer et al reported recurrence of ocular surface abnormalities in Surgical Technique 91% of treated eyes and rejection of corneal grafts in 64% In the Bag Limbal Lensectomy42-44 of patients.30 Gomes documented graft failure in 100% of patients requiring repeat penetrating keratoplasty for The surgery is done through limbal ports, which are made using recurrent aniridic epithelial disease.31 20 G microvitreoretinal (MVR) blade, at 9 and 2o clock 2. Keratolimbal allograft: These have been tried to address position for superiorly subluxated lens (Fig. 5). A third port is the problem of limbal stem cell deficiency. Results have made at 4 and 5o clock position for the anterior chamber been found encouraging.32 maintainer. 3. Amniotic membrane transplantation is a very effective MVR blade is used to make an opening in the anterior lens procedure, although its effect is transitory, for restoring the capsule followed by hydrodissection with hydrodissection ocular surface integrity in patients with congenital aniridia cannula. Vitrectomy cutter of phacoemulsification system is and moderate limbal deficiency.23 used in I/A-Cut mode (in which irrigation and aspiration comes 4. Stem cell transplantation: Ocular surface stem cell before cutting). Vitrectomy probe is inserted into the anterior transplantation is a new therapy aimed at correcting stem chamber and then through the opening in anterior capsule into cell deficiency and has been highly successful in treating the lens (Fig. 6). the corneal disease associated with aniridia. The goal of Second port is used for irrigation cannula to maintain the surgery is to transplant normal stem cells from donor chamber. All the cortical matter is aspirated and then capsular eyes to the stem cell deficient aniridic eye. bag is taken with the help of vitrectomy cutter in the same mode. 5. A recent analysis of patients treated demonstrates the Now a thorough anterior vitrectomy is done in Cut-I/A mode establishment of a stable ocular surface in 90.5% of aniridic (Fig. 7). patients treated with appropriate immunosuppression. Of these patients, approximately one-third were spared the need Ahmed Glaucoma Valve Implantation for subsequent corneal transplantation. In those patient in which significant scarring had already occurred prior to stem Adequate surgical exposure is dependent on proper placement cell transplantation, corneal transplantation was performed of a traction suture. A 6-0 polyglactin (Vicryl) or silk traction and was successful in 85% of patients on appropriate suture on a spatulated needle is placed through superficial cornea immunosuppression. near the superior limbus and attached to the drape beneath the 6. Autologous serum has also been proved in these patients. eye.45
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Fig. 5: Showing superiorly subluxated lens

Fig. 7: Viscoelastic is injected in the anterior chamber after a thorough anterior vitrectomy has been done

Fig. 6: MVR blade is used to make an opening in the anterior lens capsule with anterior chamber maintainer in situ

Fig. 8: Colored photograph showing creation of subconjunctival space in the superotemporal quadrant

A fornix-based conjunctivalTenon capsule flap is created, usually in the superotemporal quadrant, to expose the sclera bed (Figs 8 and 9A). The flap is slightly elevated to allow for blunt dissection between Tenon and episclera with blunt Westcott scissors. Radial relaxing incisions on one or both sides of the conjunctival flap can improve surgical exposure. Whenever possible, the superonasal quadrant should be avoided to reduce the risk for strabismus/motility problems. The Ahmed drainage device, when placed in the superonasal quadrant, has also been shown to come within 1 mm of the optic nerve.46

With Ahmed valved implants, balanced salt solution must be irrigated through the tube using 27 gauge cannula (Fig. 10), before the insertion into the anterior chamber, to ensure that the valve opens properly. The external plate is then tucked posteriorly into the subTenon space (Fig. 9C) and is sutured to sclera with nonabsorbable 9-0 Prolene or nylon sutures through the anterior positional holes of the plate, with the anterior border at 8 to 10 mm posterior to the limbus. The tube is then cut, bevel up, to permit its extension 2 to 3 mm into the anterior chamber (Fig. 9C). It is best to maintain

Figs 9A to C: (A) Creation of subconjunctival space in the superotemporal quadrant, (B) insertion of plate into subconjunctival space and (C) cutting the tube to the appropriate length

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Fig. 10: Priming of AGVbalanced salt solution in 27G cannula is used and it is injected through the end of the tube, a jet of BSS comes out of the valve which indicates it is primed

Figs 12A and B: (A) Colored photograph, (B) sketch: showing tube insertion into the anterior chamber via the needle track, using nontoothed or specially designed tube-insertion forceps

through this needle track, is positioned between cornea and iris, without touching the cornea. The tube is then inserted into the anterior chamber via the needle track using nontoothed or specially designed tubeinsertion forceps, but these generally are not necessary (Fig. 12). The tube can be secured to the sclera by using a nonabsorbable suture, such as 9-0 prolene or nylon. The anterior chamber may need to be deepened with balanced salt solution, or viscoelastic, via the paracentesis, and Figs 11A and B: (A) Colored photograph and (B) sketch: showing anterior chamber entry through the limbal area with a 23 gauge or a 22 the tube is checked for proper position in the anterior chamber. To avoid the potential complications related to tube erosion, a gauge needle to the iris plane rectanglular patch of preserved sclera 57 mm is sutured over the anterior chamber at a normal depth achieved by the anterior the tube at the limbus (Figs 13A and B).49 Processed pericardium chamber maintainer. (Tutoplast), donor sclera, dura and fascia lata are also available The anterior chamber is then entered with a 23 gauge or a commercially for this purpose. It is also possible to use 22 gauge needle, parallel to the iris plane/stump (Figs 11A and B). The needle creates a watertight seal, preventing leakage autologous sclera or to place the tube under a partial-thickness around the tube, and thus reducing the risk for postoperative scleral flap similar to a trabeculectomy procedure. The conjunctiva is then sutured back to its original position hypotony.47 The angle at which the needle enters the anterior chamber using 8-0 Vicryl sutures (Fig. 14). Once again vitrectomy status is critical, because it is important that the tube, which will pass is checked, triamcinolone acetate can be used for this purpose.
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Figs 13A and B: (A) Colored photograph, (B) sketch: a rectanglular patch of preserved sclera 5 7 mm is sutured over the tube at the limbus

Type 96G is used in the capsular bag in cases of sector iris defects up to 90. Iris defects between 90 and 180 could be managed by inserting two such devices. One version consists of an artificial black iris attached to a standard polymethylmethacrylate intraocular lens. This type of iris is best used when suturing of the lens is required to secure the lens in place. An advantage of this implant is that it is very stable. Treatment of Photophobia, Nystagmus and Strabismus Patients should be given following things: Tinted or iris contact lenses Tinted spectacle lenses Tinted intraocular lenses (IOLs). By the above measures, reducing the amplitude and Fig. 14: Conjunctiva is sutured back to its original position using 8-0 Vicryl sutures and the anterior chamber is formed after hydrating the frequency of nystagmus is possible. ports In cases of strabismus, patching of the favored eye is indicated to treat amblyopia. Cycloplegic refraction should be Anterior chamber is formed after hydrating the ports. performed, and appropriate correction should be given. Subconjunctival steroids and antibiotics are injected at the Strabismus surgery may be indicated at an early age to enhance completion of the procedure in a quadrant away from the surgical binocularity. site. Treatment of Refractive Errors, Strabismus and Amblyopia Iris Abnormalities Various methods have been used to overcome the disabling effects of iris deficiency, including eyelid surgery, colored contact lenses,34 corneal tattooing35 and implantation of artificial irides.36 The most commonly used prosthetic iris devices are the Morcher aniridia IOL types 67F and 67G, the aniridia ring type 50C, and the coloboma diaphragm type 96G.33 Types 67F and 67G are used in traumatic or congenital aniridia either in the ciliary sulcus, if there is adequate capsular support, or transsclerally sutured in the absence of capsular support. Morcher 67G aniridia IOL and type 50C is designed for endocapsular implantation in cases of traumatic or congenital aniridia. For a total reconstruction of the missing iris, two rings have to be implanted and turned against each other to form a complete ring, and then an additional foldable lens is inserted.33 Careful refraction and complete correction must be done to decrease the risk of amblyopia. Usually, the potential visual acuity in both eyes should be symmetrical. When the vision is unequal without structural difference, vigorous amblyopia exercises should be performed in the worst eye. Binocularity can be achieved if macular hypoplasia is not severe. Strabismus surgery is indicated at an early age. Consultations Banded chromosome analysis on the patient and both parents Linkage analysis when large families are available.
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Genetic Counseling All patients with aniridia should be referred for genetic counseling. A full family history should be sought, with specific attention to ocular abnormalities, low vision, genitourinary abnormalities, Wilms tumor and mental retardation A full physical examination should be performed concentrating on the genitourinary system. Imaging of the abdomen and brain, preferably MRI, is indicated Chromosome analysis of the patient and family and genetic analysis of the PAX6 gene should be performed Parents and close relatives should have a careful ocular examination performed Fluorescein angiography of the iris and fundus may reveal subtle abnormalities not found clinically, e.g. abnormalities of the iris collarette and foveal avascular zone.

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1. Nelson Lb, Spaeth Gl, Nowinski Ts, Margo Ce, Jackson L. Aniridia: A review. Surv Ophthalmol 1984;28:621-42. 2. Shaw MW, Falls HF, Neel JV. Congenital aniridia. Am J Hum Genet 1960;12:389-415. 3. Duke-Elder S. Normal and abnormal development: Congenital deformities. System of Ophthalmology. St Louis: CV Mosby 1963;3:566. 4. Gillespie FD. Aniridia, cerebellar ataxia, and oligophrenia. Arch Ophthalmol 1965;13:338-41. 5. Falls HF. A gene producing various defects of the anterior segment of the eye with a pedigree of a family. Am J Ophthalmol 1949;32:41-52. 6. Noel W, Walker U, Kang B, et al. Retinal damage by light in rats. Invest Ophthalmol 1966;5:450. 7. Reeser F, Weinstein G, Feiock K, et al. Electro-oculography as a test of retinal function. Am J Ophthalmol 1970;70:505-14. 8. Collins T. Aniridia and glaucoma. Ophthalmol Res 1891;10: 101-06. 9. Hittner HM, Riccardi VM, Ferrell RE, et al. Variable expressivity in autosomal dominant aniridia by clinical electrophysiologlcal and angiographic criteria. Am J Ophthalmol 1980;89:531-39. 10. Pagon RA. Ocular coloboma. Surg Ophthalmol 1981;25: 223-36. 11. Barkan O. Goniotomy for glaucoma associated with aniridia. Arch Ophthalmol 1953;49:l-5. 12. Callahan A. Aniridia with ectopia lentis and secondary glaucoma: Genetic, pathologic and surgical considerations. Am J Ophthalmol 1949;32:28-39. 13. Elsas FJ, Maumenee IH, Kenyon KR, et al. Familial aniridia with preserved ocular function. Am J Ophthalmol 1977;83: 718-24. 14. Grant WM. Walton DS. Progressive changes in the angle in congenital aniridia with development of glaucoma. Am J Ophthalmol 1974;18:842-47. 15. Lewallen WM. Aniridia and related iris defects. Arch Ophthalmol 1958;59:831-39. 16. Shaffer RN, Cohen JS. Visual reduction in aniridia. J Ped Ophthalmol 1975;12:220-22. 17. Layman PR, Anderson DR, Flynn JT. Frequent occurrence of hypoplastic optic discs in patients with aniridia. Am J Ophthalmol 1974;77:513-16.

18. Callahan A. Aniridia with ectopia lentis and secondary glaucoma: Genetic, pathologic and surgical considerations. Am J Ophthalmol 1949;32:28-39. 19. David R, MacBeath L, Jenkins T. Aniridia associated with microcornea and subluxated lenses. Br J Ophthalmol 1978;62:118-21. 20. Ginsbwg J Buvc KE Cuesta MC. Aplasia of the optic nerve with aniridia. Ann Ophthalmol 1980;12:433-39. 21. Blue JB. Bilateral aniridia. Am J Ophthalmol 5t 1922;483. 22. Arroyave CP, Scott IU, Gedde SJ, Parrish RK 2nd, Feuer WJ. Use of glaucoma drainage devices in the management of glaucoma associated with aniridia. Am J Ophthalmol Feb 2003;135(2):155-59. 23. Lopez-Garcia JS, Rivas L, Garcia-Lozano I. Moderate limbal deficiency in patients with congenital aniridia treated with amniotic membrane transplantation. Arch Soc Esp Oftalmol. Sep 2005;80(9):517-23. 24. Walton DS. Aniridic glaucoma: The results of gonio-surgery to prevent and treat this problem. Tr Am Ophth Soc 1986;50-70. 25. Grant WM, Walton DS. Progressive changes in the angle in congenital aniridia, with development of glaucoma. Tr Am Ophth Soc 1974;LXXII:207-29. 26. Okamoto F, Nakano S, Okamoto C, Hommura S, Oshika T. Ultrasound biomicroscopic findings in aniridia. Am J Ophthalmol 2004;137:858-62. 27. Wiggins RE, Tomey KF. The results of glaucoma surgery in aniridia. Arch Ophthalmol 1992;110:503-05. 28. Mandal AK, Prasad K, Naduvilath TJ. Surgical results and complications of mitomycin-Caugmented trabeculectomy in refractory developmental glaucoma. Ophthalmic Surg Laser 1999;30:473-80. 29. Chen CT, Walton DS. Goniosurgery for prevention of aniridic glaucoma. Arch Ophthalmol 1999;117:1144-48. 30. Kremer I, Rajpal RK, Rapuano CJ, et al. Results of penetrating keratoplasty in aniridia. Am J Ophthalmol Mar 15, 1993; 115(3):317-20. 31. Gomes JA, Eagle RC Jr, Gomes AK, Rapuanao CJ, Cohen EJ, Laibson PR. Recurrent keratopathy after penetrating keratoplasty for aniridia. Cornea 1996;15:457-62. 32. Holland EJ, Djalilian AR, Schwartz GS. Management of aniridic keratopathy with keratolimbal allograft: A limbal stem cell transplantation technique. Ophthalmology Jan 2003; 110(1): 125-30. 33. Mavrikakis I, Mavrikakis E, Syam PP, Bell J, Casey JH, Casswell AG, Brittain GP, Liu C. Surgical management of iris defects with prosthetic iris devices. Eye 2005;19:205-09. 34. Burger DS, London R. Soft opaque contact lenses in binocular vision problems. J Am Optom Assoc 1993;64:176-80. 35. Burris TE, Holmes-Higgin DK, Silvestrini TA. Lamellar intrastromal corneal tattoo for treating iris defects (artificial iris). Cornea 1998;17:169-73. 36. Thompson CG, Fawzy K, Bryce IG, Noble BA. Implantation of a black diaphragm intraocular lens for traumatic aniridia. J Cataract Refract Surg 1999;25:808-13. 37. Wagle NS, Freedman SF, Buckley EG, et al. Long-term outcome of cyclocryotherapy for refractory pediatric glaucoma. Ophthalmology 1998;105:1921-27. 38. Wallace DK, Plager DA, Snyder SK, et al. Surgical results of secondary glaucomas in childhood. Ophthalmology 1998;105:101-11. 39. Kirwan JF, Shah P, Khaw PT. Diode laser cyclophotocoagulation: Role in the management of refractory pediatric glaucomas. Ophthalmology 2002;109:316-23.

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Dewang Angmo et al 40. Chen TC, Walton DS. Goniosurgery for prevention of aniridic glaucoma. Arch Ophthalmol 1999;117:1144-48. 41. Adachi M, Dickens CJ, Hetherington J Jr, et al. Clinical experience of trabeculectomy for the surgical treatment of aniridic glaucoma. Ophthalmology 1997;104:2121-25. 42. Harpel M, BenEzra D. Surgery of hereditary subluxated lens in children. April 1996:681-86. 43. Behki R, Noel LP, Clarke WN. Limbal lensectomy in the management of ectopia lentis in children. Arch Ophthalmol 1990;108:809-11. 44. Yu YS, Kang YH, Lim KH. Improvement in visual acuity following limbal lensectomy for subluxated lenses in children. Ophthalmic Surg Lasers 1997;28(12):1006-10. 45. Englert JA, Freedman SF, Cox TA. The Ahmed glaucoma valve in refractory pediatric glaucoma. Am J Ophthalmol 1999;127: 34-42 46. Leen MM, Witkop GS, George DP. Anatomic considerations in the implantation of Ahmed glaucoma valve. Arch Ophthalmol 1996;114:223-24. 47. Nguyen QH, Budenz DL, Parrish RK II. Complications of Baerveldt glaucoma drainage implants. Arch Ophthal 1998;116(5):571-75. 48. Krebs DB, Liebmann JM, Ritch R, et al. Late infectious endophthalmitis from exposed glaucoma setons. Arch Ophthal 1992;110(2):174-75.

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