Aniridia in the Newborn

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					Aniridia in the Newborn
Article Last Updated: Aug 4, 2008

AUTHOR AND EDITOR INFORMATION
Author: Sophie Bakri, MD, Assistant Professor of Ophthalmology, Vitreoretinal
Diseases and Surgery, Mayo Clinic of Rochester

Sophie Bakri is a member of the following medical societies: American Academy
of Ophthalmology

Coauthor(s): John W Simon, MD, Chair, Department of Ophthalmology,
Professor, Departments of Ophthalmology and Pediatrics, Albany Medical
College

Editors: Gerhard W Cibis, MD, Clinical Professor, Director of Pediatric
Ophthalmology Service, Department of Ophthalmology, University of Kansas,
Kansas City; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor,
eMedicine; J James Rowsey, MD, Former Director of Corneal Services, St
Luke's Cataract and Laser Institute, Florida; Lance L Brown, OD, MD,
Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital,
Regional Eye Center, Joplin, Missouri; Hampton Roy Sr, MD, Associate Clinical
Professor, Department of Ophthalmology, University of Arkansas for Medical
Sciences

Author and Editor Disclosure

Synonyms and related keywords: aniridia, congenital aniridia, aniridia in
newborn, iris hypoplasia, absence of iris, iris absence, Wilms tumor, Wilm's
tumor, nephroblastoma, WAGR complex, Miller syndrome, pediatric glaucoma,
panophthalmic disorder




INTRODUCTION
Background

In 1818, Barratta first described aniridia (Greek for absence of the iris). Aniridia is
a rare, bilateral, panophthalmic disorder, of which iris hypoplasia is the most
striking feature. Aniridia also has corneal, lens, optic nerve, and retinal
manifestations. Foveal and optic nerve hypoplasia are often present, causing a
reduction in visual acuity and congenital sensory nystagmus. Progressive
worsening of vision may occur later in life as a result of cataracts, glaucoma, and
corneal opacification.

Pathophysiology

Aniridia may be familial or sporadic. It is caused by a mutation in the PAX6 gene
on chromosome 11.

Approximately 85% of cases are familial (designated AN1) with autosomal
dominant inheritance with complete penetrance but variable expressivity. These
familial cases usually have isolated ocular involvement.

The 15% of cases that are sporadic have a deletion or mutation on the short arm
of chromosome 11. The same deletion is responsible for the development of
Wilms tumor (nephroblastoma).

The exact pathogenesis of aniridia is unknown. After early reports of ocular
colobomas in patients with aniridia, some authors proposed that it is a
colobomatous disorder. Others attributed it to a failure of mesodermal
development with involvement of the rim of the optic cup, causing iris hypoplasia.
Still others advocated the neuroectodermal theory, which links the presence of
retinal anomalies and iris muscular hypoplasia to a developmental failure of
neuroectoderm.

Frequency

United States

Aniridia is a very rare disorder. According to a population-based study in
Michigan, it has been estimated to affect approximately 1 per 61,000 newborns.

International

A more recent study from Denmark reported the incidence as 1 per 96,000 live
births.

Mortality/Morbidity

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. A homozygous mutation of the aniridia gene may possibly be lethal. The
morbidity of aniridia is significant because of the decreased vision and
nystagmus.
Race

No racial predilection has been described.

Sex

The incidence of aniridia is equal in males and females.

Age

Aniridia is a congenital disorder apparent at birth. It is never acquired.




CLINICAL
History

An infant may come to medical attention with nystagmus or photophobia.
Patients may present with strabismus and amblyopia. The family may notice an
abnormal pupil, or they may describe a fixed, dilated pupil.

Physical

Visual acuity is reduced, usually to around the 20/100 level. Pendular nystagmus,
strabismus, and amblyopia may be present. Nystagmus occurs in 85-92% of
patients. Ocular examination reveals absence of the irides or dilated
unresponsive pupils. Other findings may include small anterior polar cataracts,
pupillary membrane remnants, ectopia lentis (in 18-35%), corneal pannus,
progressive keratopathy, and optic nerve or foveal hypoplasia.

Poor vision in infancy often is due to foveal or optic nerve hypoplasia and
secondary nystagmus. Acquired vision loss may be due to cataract (present in
85% of cases), glaucoma (present in 70%), keratopathy, or amblyopia.

Some have considered aniridia a misnomer because a rudimentary stump of
tissue usually can be found behind the limbal sclera by gonioscopy. The
diagnosis can be very difficult to make in patients with a substantial amount of iris
tissue. However, characteristic absence of the pupillary rim, iris sphincter muscle,
and central iris tissue is noted.

      Syndromes associated with aniridia
          
          o   Miller syndrome (WAGR complex, 11p- syndrome)
                  o
          Approximately 30% of patients with sporadic aniridia develop
           Wilms tumor, usually before age 5 years. The association
           between aniridia and Wilms tumor is referred to as Miller
           syndrome, after his 1964 report of 6 cases of aniridia among
           440 cases of Wilms tumor. It was reported that 1.4% of
           patients with Wilms tumor have aniridia compared to 1 in
           64,000 to 1 in 100,000 of the general population.
         Affected children have other genitourinary abnormalities,
           craniofacial dysmorphism, hemihypertrophy, and severe
           mental retardation. They also may have poorly lobulated
           low-set ears, prominent noses, and long narrow facies. 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 workup by a family
           practitioner or pediatrician.
o   Gillespie syndrome
       o
         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 patients have anatomical defects in the cerebellum
          and other 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.
o   Glaucoma
       o
          Glaucoma is one of the major causes of visual loss in
           patients with aniridia, with a reported incidence of 6-75%.
           This variation is explained by the referral patterns of the
           various institutions, the variable phenotypic expression of
           aniridia, and the definitions of glaucoma. Glaucoma in
           aniridia is rare in infants and newborns and typically is
           acquired in early adulthood. As a result of its delayed onset,
           the clinical findings of megalocornea, buphthalmos, and
           Haab striae typically are not found.
          Progressive apposition of the rudimentary stump of iris to the
           trabecular meshwork is believed to occur during the first 2
           decades of life. In patients without glaucoma, the structures
           of the anterior chamber angle appear normal by gonioscopy.
           In older patients with aniridic glaucoma, the severity of the
           glaucoma is related to the proportion of the filtration angle
          covered by the iris stump. The periphery of the hypoplastic
          stump of iris may insert anteriorly, and even where it is more
          open, the scleral spur and ciliary body band may be defined
          poorly. In the rare cases of infants with aniridic glaucoma,
          filtration-angle defects are present at birth. In these cases,
          the angle usually is covered by vascularized sheets
          extending from the iris, rather than being blocked by the iris
          stump.
o   Cataracts
       o
          Cataracts occur in 50-85% of patients with aniridia, usually
           acquired during the first 2 decades of life. At birth, small lens
           opacities may be noted, but these typically are not visually
           significant. Types of cataracts described include anterior
           polar, pyramidal, nuclear, lamellar, and cortical.
         Visually significant cataracts in neonates require prompt
           surgical extraction to prevent amblyopia. However, in
           patients whose cataracts develop later, the factor most
           strongly limiting visual acuity is the presence of foveal
           hypoplasia, not the cataract. Areas of clear space may be
           present in the cataractous lens, which allows for relatively
           good vision. In these patients, surgery is best delayed, since
           the risks of glaucoma developing or progressing in aniridic
           eyes outweighs the small potential for visual improvement.
o   Ectopia lentis: Some investigators have reported lens subluxations
    in as many as 56% of eyes with aniridia, while others have reported
    none. This finding may be due to failure to detect mild cases. The
    zonules are believed to be histologically normal, but their molecular
    structure is not understood clearly.
o   Corneal defects
       o
          Progressive corneal opacification and pannus occur in most
           patients, developing as early as age 2 years. Initially, fine
           radial vessels invade the superficial layers of the peripheral
           cornea at the 6- and 12-o'clock positions and, then, involve
           the whole circumference. This process may progress to
           involve the entire cornea, requiring corneal transplantation.
          Pathologically, the pannus seen in aniridic keratopathy is
           quite unusual; the corneal epithelium may harbor ectopic
           conjunctival goblet cells, and inflammatory cells are usually
           present. The pathogenesis is uncertain, but many theories
           have been proposed. It has been attributed to a total
           absence of the limbal girdles of Vogt and corneal epithelial
           limbal stem cells. PAX6 has been found in corneal and
           conjunctival epithelia, and it is believed that this gene may
           play a role in the activity of corneal stem cells.
                    Microcornea also has been found in most cases of aniridia.
          o   Optic nerve and foveal hypoplasia
                 o
                    Posterior segment abnormalities include both macular and
                     optic nerve hypoplasia. Approximately 75% of patients with
                     aniridia have some degree of optic nerve hypoplasia. The
                     macula and optic nerve are usually normal in patients with
                     Gillespie syndrome. Mild cases may be difficult to detect
                     because of nystagmus and corneal or lens opacities. Poor
                     macular or retinal development may be responsible for the
                     optic nerve hypoplasia. Because the retina is derived from
                     neuroectoderm, as are the iris epithelium and musculature,
                     foveal hypoplasia often is associated with aniridia.
                   Decreased vision and nystagmus in patients with aniridia
                     result from faulty development of the macula, not the iris.
                     There appears to be no correlation between the degree of
                     iris hypoplasia and foveal hypoplasia. In some patients,
                     foveal hypoplasia may be so subtle that fluorescein
                     angiography may be necessary to demonstrate lack of the
                     foveal avascular zone.
          o Strabismus: This is a common finding in patients with aniridia, and
              esotropia most frequently is found. A full cycloplegic refraction is
              warranted because amblyopia may occur from anisometropia or
              strabismus.
          o Nystagmus: This is commonly pendular secondary to poor vision
              from foveal hypoplasia. It may improve with visual maturation.
      Other findings
          
          o  Peripheral retinal lipoidal deposits have been reported in at least 3
             patients.
         o Electroretinogram (ERG) amplitudes are low in patients with worse
             than 20/60 vision, while patients with better vision may have high
             a:b wave ratios.
      See related CME at Neuro-ophthalmology and Pediatric Ophthalmology.

Causes

Aniridia may be familial or sporadic. It is caused by a mutation in the PAX6 gene
on chromosome 11.




DIFFERENTIALS
Aniridia
Cataract, Congenital
Ectopia Lentis
Glaucoma, Complications and Management of Glaucoma Filtering
Glaucoma, Juvenile
Nystagmus, Congenital

WORKUP
Histologic Findings

Histopathologic examination of advanced cases of aniridia reveals only stubs of
iris tissue that lack dilator and sphincter muscles, both neuroectodermal
derivatives.




TREATMENT
Medical Care

      Medical management of glaucoma associated with aniridia
          
          o  Medical therapy of the glaucoma is the initial treatment of choice. It
             initially may be efficacious in reducing intraocular pressure, but
             most patients with aniridia who have glaucoma eventually require
             surgical therapy.
          o Miotics often are tried first; they improve aqueous outflow by
             contracting the ciliary muscle. However, the induced myopia may
             not be well tolerated by young patients. Adrenergic agonists, beta-
             blockers, and carbonic anhydrase inhibitors also may be tried, but
             they often are ineffective long term as the patient becomes
             refractory to them. Whenever a new medication is to be instituted, a
             trial should be performed, adding and removing only one
             medication at a time.
      Optical correction
          
          o    Patients with aniridia may be emmetropic, myopic, or hyperopic.
               Spectacle or contact lens correction of significant refractive errors
               should begin in the newborn. In cases of lens subluxation, the
               refractive error should be corrected through the aphakic portion of
               the pupil.
           o To lessen photophobia, patients may be fitted with tinted or iris
               contact lenses or with tinted spectacle lenses at any age.
      Treatment of amblyopia and strabismus: In cases of strabismus, patching
       of the favored eye is indicated to treat amblyopia. Cycloplegic refraction
       should be performed, and appropriate correction should be given.
       Strabismus surgery may be indicated at an early age to enhance
       binocularity.

Surgical Care

No convincing opinion exists as to which surgical procedure is the treatment of
choice for aniridic glaucoma; none has been considered reliable and predictable
in efficacy. Surgical procedures for the treatment of aniridic glaucoma include the
following:

      Goniotomy
          
          o     Although goniotomy has been suggested early in the management
                of aniridic glaucoma, reported series have shown disappointing
                results. The procedure is hazardous in these eyes, since the
                Barkan goniotomy knife is passed over the vulnerable lens and
                zonules in the anterior chamber. However, results of prophylactic
                goniotomy have been encouraging.
            o Two separate surgeries on each eye may be performed to strip the
                tissue extending over the trabecular meshwork, working on 180° of
                the angle each time. The benefit of this prophylactic procedure is
                not yet proven, and it should be delayed until after the first year of
                life. Because of the shallow anterior chamber angle, patients with
                aniridia should have gonioscopy performed yearly. If the iris
                processes are becoming more prominent, strong consideration
                should be given to performing a prophylactic goniotomy.
      Trabeculotomy: This procedure is considered safer than goniotomy, since
       it relies on the posterior approach (ab externo), which avoids the lens and
       zonules. However, it is not without risk and has been associated with the
       need for repeat surgery.
      Trabeculectomy: Most surgeons opt for trabeculectomy after a few
       attempts at goniotomy or trabeculotomy. However, the risk of vitreous loss
       is increased in aniridia, and cataract formation or progression may occur
       with inadvertent damage to the lens during surgery. Nelson et al reported
       that 5 of 14 patients needed reoperation or had failure with
       trabeculectomy1; others have reported initial success rates from 0-9%.
      Setons: The success rate of the Molteno implant has been reported as
       83% of 6 eyes. This device cannot be recommended as the initial
       operation of choice because of the higher risk of complications.
      Cyclophotocoagulation and cyclocryotherapy: Both these modalities are
       designed to destroy part of the ciliary body. Cyclophotocoagulation is
       performed with the yttrium-aluminum-garnet (YAG) laser. Both methods
       must be split into multiple treatment sessions to avoid complications, such
       as uveitis, phthisis bulbi, uveal effusion, vitreous hemorrhage, and
       prolonged hypotony. Cryotherapy may accelerate peripheral corneal
       opacification or cataract progression. Therefore, these procedures must
       be approached with extreme caution, and they have been associated with
       hypotony and vitreous hemorrhage.
      Cataract extraction: When the cataract is dense, removal may result in
       some improvement in visual acuity. Lensectomy performed with an
       aspiration-cutting instrument has been recommended. Capsule-supported
       intraocular lenses are not appropriate for patients with ectopia lentis.
      Penetrating keratoplasty: This may be indicated for corneas that have
       opacified from pannus. However, the prognosis is guarded because of
       rejection and underlying amblyopia or other structural defects.

Consultations

      Genetic counseling
          
          o   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.
          o   A full physical examination should be performed concentrating on
              the genitourinary system. Imaging of the abdomen and brain,
              preferably MRI, is indicated.
          o   Chromosome analysis of the patient and family members and
              genetic analysis of the PAX6 gene should be performed.
          o   Parents and close relatives should have a careful ocular
              examination performed.
          o   Fluorescein angiography of the iris and fundus may reveal subtle
              abnormalities not found clinically, for example, abnormalities of the
              iris collarette and foveal avascular zone.

MEDICATION
Currently, no medications are approved by the US Food and Drug Administration
(FDA) for the treatment of pediatric glaucoma. Medications, such as miotics,
topical beta-blockers, and topical carbonic anhydrase inhibitors, have been tried;
however, these medications must be prescribed only after a full discussion of
their risks and benefits with the parents. The doses are not discussed here since
the medications are not approved by the FDA.

Further Outpatient Care

      Patients should be observed by the ophthalmologist as indicated,
       depending on the complications and their severity.
In/Out Patient Meds

     Available medications are discussed in Medical Care and Medication.

Complications

     The complications of aniridia are discussed throughout this article.

Prognosis

     The prognosis and visual acuity level varies depending on the
      complications of aniridia. Generalizations cannot be made.

Patient Education

     The parents of the patient should be educated about the disease.
      Education should be geared toward maintaining careful follow-up care of
      the specific ocular complications of aniridia being experienced by the
      patient.

Medical/Legal Pitfalls

     Medical/legal pitfalls relate to mismanagement of the specific
      complications of aniridia.

				
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