• Glaucoma, Secondary Glaucoma

    Introduction

    Glaucoma may be associated with a variety of predominantly ocular anomalies present at birth. They may or may not be accompanied by systemic features. The risk of glaucoma is lifelong and the assessment of intraocular pressure (IOP) and its effects on the eye must be made throughout that time.

    Aniridia

    Definition

    Aniridia is a bilateral, congenital condition characterized by a variable absence of iris. The iris is not completely absent as the name suggests, but may be present as a rudimentary stump or partially absent. Its incidence ranges from 1:64.000 to 1:100.000. It is often associated with optic nerve and foveal hypoplasia, glaucoma, cataract, ectopia lentis and corneal surface abnormalities due to corneal epithelial limbal stem cell dysfunction (aniridia-associated keratopathy).1 Patients also commonly have nystagmus due to the underlying mentioned variable ocular pathology. The prevalence and severity of the keratopathy increases with the patient's age and can be made worse by intraocular surgery.2 Furthermore, central corneal thickness is increased compared to normal.

    Inheritance and genetics

    Aniridia results from abnormal neural crest cell development secondary to PAX6 gene mutations at chromosome 11p13.3 PAX6 expression level appears to be critical for eye development. Inheritance is usually autosomal dominant with high penetrance and variable expressivity. In 30% of cases, inheritance is sporadic and is then passed on in an autosomal-dominant pattern. Sporadic aniridia is associated with nephroblastoma (Wilms tumor), genitourinary abnormalities, and mental retardation (WAGR) related to large deletions of 11p1, which encompasses PAX6 and the adjacent Wilms tumor locus. Gillespie syndrome is a very rare autosomal recessive condition associated with aniridia, cerebellar ataxia, ptosis, and mental retardation. The typical presentation is the discovery of fixed dilated pupils in a hypotonic infant.

    The aniridia phenotype has been found in individuals with PITX2 and FOXC1 mutations and no PAX 6 abnormality. A distinct phenotype of partial aniridia, ectropion uveae, and central keratopathy with autosomal recessive CYP1B1 mutations has also been reported.4

    Incidence and mechanism of glaucoma

    Glaucoma occurs in around 50-70% of cases, usually presenting in preadolescence or early adulthood. It may be due to progressive angle closure from the iris stump or, more commonly, may be associated with an open angle.

    Management

    Children with aniridia should be regularly monitored for the onset of elevated IOP. Medical therapy should be first-line treatment. Angle surgery (goniotomy) is associated with poor results.5, 6 Modified goniotomy to prevent elevated IOP in cases with a strong family history of glaucoma and documented progression of angle closure has been described, but not widely practiced due to the potential risk of intraocular trauma, especially to the lens.6, 7 Trabeculectomy with antiscarring agents and glaucoma drainage device (GDD) surgery are further options with modifications to minimize the risk of hypotony.8, 9 A limbal-based conjunctival flap high in the fornix should be considered, in theory, to minimize trauma to the limbal stem cells. Transscleral cyclodestruction can be considered in refractory cases. Symptomatic relief of photophobia can be achieved with lubricants and tinted spectacles.

    All sporadic cases must be screened for Wilms tumor by renal ultrasound and urinalysis on a regular basis, or until genetic test results become available.10 The decision to discontinue tumor surveillance should be made by the pediatrician and the clinical geneticist.

    There are no reports of the use of iris prosthetic devices (Morcher aniridia rings) or iris diaphragm lens (Morcher aniridia IOL) in children, but reports in adults suggest a significant risk of elevated IOP or worsening IOP control.11, 12 The management of aniridia-related keratopathy is challenging, with long-term visual outcomes being the same without or with surgery (limbal stem cell transplant and penetrating keratoplasty).13

    Axenfeld-Rieger anomaly (Axenfeld-Rieger syndrome)

    Definition

    Axenfeld-Rieger anomaly covers a spectrum of disease involving neural crest mesenchyme.14 Clinical features involve the peripheral cornea, peripheral iris, and angle, and include posterior embryotoxon (anteriorly displaced, prominent Schwalbe line) with attached peripheral iris strands (threadlike to broad bands) (Figure 1), and iris changes such as corectopia or iris stromal thinning. Peripheral iris changes may not be readily visible but apparent on gonioscopy only, so the diagnosis can only be excluded after gonioscopy. In association with systemic anomalies such as hypertelorism, periumbilical skin tags, and dental (microdontia, hypodontia), genitourinary, and cardiac abnormalities, it is referred to as Axenfeld-Rieger syndrome. It is usually bilateral and asymmetrical. 

     

    Figure 1. Axenfeld-Rieger syndrome, bilateral. 

    Inheritance and genetics

    Axenfeld-Rieger anomaly shows an autosomal dominant inheritance pattern but can be sporadic. Family members must undergo an examination, including gonioscopy, both to determine whether the patient is a sporadic or familial case and to detect undiagnosed cases. The PITX2 gene at chromosome 4q25 and FOXC1 at 6p25 are the major genes identified. Genotype-phenotype correlations exist with systemic findings more likely to be associated with PITX2 than FOXC1 defects. The risk of glaucoma is greatest in decreasing order with FOXC1 duplication, PITX2 mutations and FOXC1 mutations.15

    Incidence and mechanism of glaucoma

    The risk of glaucoma is 50% and usually occurs in childhood or young adulthood, very rarely in infancy.16 It is thought to be due to an underlying trabeculodysgenesis associated with abnormal migration of neural crest cells.3, 14

    Management

    Children with Axenfeld-Rieger anomaly should be regularly monitored for the onset of elevated IOP. Medical therapy is usually first line. Angle surgery (goniotomy) is potentially more complicated due to iris attachments and is less successful than primary congenital glaucoma (PCG) surgery.16 If medical therapy fails, trabeculectomy with antiscarring agents or GDD surgery may be necessary to control the IOP.17 Transscleral cyclodestruction can be considered in refractory cases or if the visual potential is limited.

    It is important to exclude systemic involvement by referring to a pediatrician.17 Ophthalmic examination, including gonioscopy, of family members is necessary.

    Peters anomaly

    Definition

    Peters anomaly is characterized by a congenital central corneal opacity with underlying defects in the stroma, Descemet membrane, and endothelium. The opacity can be variable in size and density and can clear with time. Peters anomaly describes a range of disease severity. It may be an isolated finding or be associated with iris (iridocorneal adhesions) and lens (corneolenticular adhesions, cataract) involvement. It has been subdivided into Peters anomaly type I (central corneal opacity and iridocorneal adhesions), Peters anomaly type II (central corneal opacity and corneolenticular adhesions or cataract), and Peters plus syndrome in association with systemic features (cleft lip/palate, short stature, abnormal ears, and mental retardation).18 It is usually bilateral (80%) and can be asymmetrical.

    Inheritance and genetics

    Peters anomaly is usually sporadic but can be autosomal dominant or recessive. It is genetically heterogeneous and may result from abnormalities of the PITX2, FOXC1, FOXE3, CYP1B1 and PAX6 genes.18 Peters plus syndrome is an autosomal recessive condition associated with B3GALTL mutations in most patients.

    Incidence and mechanism of glaucoma

    The risk of glaucoma is 50% from goniodysgenesis associated with abnormal migration or differentiation of neural crest cells.3 Peters anomaly type II and Peters plus syndrome are associated with a higher risk of glaucoma.

    Management

    Regular monitoring for elevated IOP is necessary but challenging as the central corneal opacity makes it difficult to measure the IOP and it may obscure the visibility of the optic discs. Attempt to measure the IOP in clear cornea if possible and record it consistently from the same location. Monitoring biometric parameters (corneal diameter and axial length) in neonates and infants is useful to detect the development or progression of glaucoma. The management of glaucoma once medical therapy fails is usually challenging in Peters anomaly and associated with poor results.19 It is important to first ascertain the extent of ocular involvement by ultrasound biomicroscopy (UBM), B scan, or anterior segment optical coherence tomography (AS OCT), if it is not obvious clinically. Angle surgery (trabeculotomy) may be considered in selected cases, such as the presence of an open anterior chamber angle and absence of irido/lenticular-corneal adhesions. Trabeculectomy with antiscarring agents may be considered in mild Peters anomaly, and primary GDD surgery may be indicated in the moderate to severe forms.19 Transscleral cyclophotocoagulation is useful in cases of refractory glaucoma and/or those with poor visual potential. Exclude the presence of systemic involvement by referring for medical evaluation.

    Visual rehabilitation is also a challenge. If the lens is clear, with a relatively small or eccentric area of corneal opacification, pupillary dilatation or a broad optical iridectomy should be considered. Lowering IOP medically in the absence of glaucoma may improve corneal clarity, as may successful glaucoma surgery. Penetrating keratoplasty results are disappointing, especially in infants, due to high rates of rejection,20-22 but they may be considered with bilateral dense corneal opacities in at least one eye. A dedicated caregiver is required to deal with the demands of postoperative care. IOP control is essential for corneal graft survival. Young age at surgery (less than 6 months of age), severity of disease, peripheral anterior synechiae (PAS), and preoperative glaucoma are poor prognostic factors for graft survival.21, 22

    Congenital ectropion uveae

    Definition

    Congenital ectropion uveae is a rare, unilateral condition in which there is a congenital hyperplasia of the posterior pigment epithelium onto the anterior iris stroma. It is typically nonprogressive. The ectropion may be sectorial or circumferential. A high iris insertion in the angle may be seen. Systemic associations include neurofibromatosis type I (NF1) and Prader-Willi syndrome.23 It is thought to be a disorder of neural crest origin.23

    Inheritance and genetics

    Congenital ectropion uveae is usually sporadic.

    Incidence and mechanism of glaucoma

    The incidence of glaucoma with congenital ectropion uveae due to goniodysgenesis is unknown but thought to be high, usually presenting between early childhood and puberty.

    Management

    Children with ectropion uveae should be followed regularly for glaucoma onset. Medical therapy is first line. Trabeculectomy with antiscarring agents may be successful.24, 25 Systemic syndromes such as NF1 should be excluded.

    Congenital iris hypoplasia

    Congenital iris hypoplasia is a condition characterized by thin, featureless irides due to distinctive hypoplastic iris stroma.14 There is a characteristic grey/brown iris color due to the pigmented iris epithelium showing through the hypoplastic stroma. The iris collarette may be absent or small. The angle may look normal on gonioscopy.

    Inheritance and genetics

    Autosomal dominant iris hypoplasia is associated with FOXC1 and PITX2 gene mutations.14

    Incidence and mechanism of glaucoma

    Congenital iris hypoplasia is due to maldevelopment of the anterior stromal layer of the iris and is associated with early onset glaucoma (16-43 years). Glaucoma is thought to be due to goniodysgenesis related to abnormal neural crest cell development.14

    Management

    Response to goniotomy is poor.14 Trabeculectomy with antiscarring agents and GDD can be considered.

    Sclerocornea

    Definition

    Sclerocornea is a congenital, nonprogressive, noninflammatory condition in which the cornea is opacified and vascularized. It may affect only the periphery (in mild cases), or the entire cornea. It is usually bilateral and asymmetric. Sclerocornea is commonly associated with corneal flattening (cornea plana) due to limbal involvement. The vision is affected depending on the degree of scleralization and associated corneal flattening. Other ocular and systemic features may occur, such as cataract, facial anomalies, and mental retardation. Syndromes that feature sclerocornea include Dandy-Walker, Hurler, and Hallermann-Streiff syndrome.

    Inheritance and genetics

    Autosomal dominant (less severe) and recessive patterns of inheritance have been reported, but 50% of cases are thought to be sporadic.26

    Incidence and mechanism of glaucoma

    Glaucoma is common and thought to be due to goniodysgenesis related to abnormal neural crest cell development.3

    Management

    The accuracy of IOP measurements is affected by the scleralization. More than one instrument should be used and the eyes balloted to confirm the accuracy of the measurement. Attention should be paid to abnormal ocular growth as a proxy for inadequately controlled IOP in the very young. When the anterior segment cannot be visualized, consider UBM or AS OCT and B scan if optic disc cupping is not visible. These also help confirm the diagnosis, highlight other structural anomalies, and guide decisions regarding surgical management. Glaucoma treatment is challenging, and medications should be first line. The most appropriate intervention (laser or surgery) is determined by the degree of corneal involvement and other ocular findings, in other words the visual potential of both eyes. Optical iridectomy may be indicated if the peripheral cornea is clear. Penetrating keratoplasty for total sclerocornea can be performed, but visual outcomes tend to be compromised by graft rejection and uncontrolled glaucoma.27

    Microcornea

    Definition

    Microcornea is an uncommon condition defined by a cornea less than or equal to 10 mm in diameter, with the rest of the eye being normal. If it is associated with a small eye and contents then it is termed microphthalmos. Microcornea can be unilateral or bilateral and is usually associated with hypermetropia. It may occur as an isolated anomaly or more commonly be associated with other ocular or systemic conditions, such as persistent fetal vasculature, Axenfeld-Rieger anomaly, and fetal alcohol syndrome. Congenital cataract-microcornea syndrome is congenital cataract associated with microcornea in the absence of other systemic features.

    Inheritance and genetics

    Autosomal dominant and autosomal recessive inheritance patterns have been reported, but microcornea can also be sporadic.

    Incidence and mechanism of glaucoma

    Glaucoma is common and can be due to open-angle and angle-closure mechanisms. Microcornea is a significant risk factor for development of glaucoma following congenital cataract surgery and so should be followed closely for the development of glaucoma.28-30 Elevated IOP following surgery in neonates and infants can result in relative buphthalmos and make the eye appear normal in size.

    Management

    If angle closure is present, then iridotomy/iridectomy should be considered. Medical treatment is first line. Angle surgery, especially goniotomy, may be challenging. GDD surgery may be indicated in the presence of aphakia.

    Children with microcornea should have hypermetropia (or other refractive errors) corrected to avoid amblyopia. Genetic screening and evaluation should be considered.

    Microphthalmos

    Definition

    Microphthalmos refers to a small eye and proportionally small eye contents. It may be isolated (simple microphthalmos) or associated with other ocular or systemic anomalies (complex microphthalmos). It is thought to be due to nonspecific failure of growth of the eye from genetic or prenatal causes. The visual potential is determined by whether it is bilateral, the severity of microphthalmos (ie, corneal diameter), and associated other ocular anomalies, including coloboma and cataract and retinal problems. It is bilateral in 10% of cases.

    Inheritance and genetics

    Simple microphthalmos is usually sporadic but can be autosomal dominant. Autosomal recessive and X-linked recessive inheritance has also been reported.

    Incidence and mechanism of glaucoma

    Glaucoma is common and can be due to open-angle and angle-closure mechanisms. Microphthalmos is a significant risk factor for development of glaucoma following congenital cataract surgery and so should be followed closely for the development of glaucoma.28-30 Elevated IOP following surgery in neonates and infants can result in relative buphthalmos and make the eye appear normal in size.

    Management

    If angle closure is present, then iridotomy/iridectomy should be considered. Medical treatment is first line. Angle surgery, especially goniotomy, may be challenging. GDD surgery may be indicated in the presence of aphakia.

    Children with microphthalmos should have hypermetropia (or other refractive errors) corrected to avoid amblyopia. Genetic screening and evaluation should be considered. 

    Nanophthalmos

    Definition

    Nanophthalmos is a rare condition characterized by a small eye and normal eye contents with thick/abnormal sclera and no systemic associations. Axial length is usually less than 20 mm. It is usually bilateral with equal sex distribution. Nanophthalmos is characterized by deeply set small eyes, high hyperopia, shallow anterior chambers with very narrow angles, thick sclerae, and a tendency toward spontaneous and post-laser or postoperative uveal effusions. Uveal effusions are a unique feature, postulated to result from a combination of elevated ocular venous pressure from compression of vortex veins by thickened sclera and reduced scleral protein permeability due to abnormal sclera.31-33 Uveal effusions can be associated with nonrhegmatogenous retinal detachment and are difficult to treat.

    Inheritance and genetics

    Nanophthalmos is typically sporadic but autosomal recessive, and dominant patterns of inheritance have been reported. MFRP mutations on chromosome 11 have been associated with autosomal recessive nanophthalmos.34 MFRP is thought to be necessary for prenatal ocular growth and postnatal emmetropization.

    Incidence and mechanism of glaucoma

    Angle-closure glaucoma is common in young adults and occurs from crowding of the anterior segment due to a high lens-to-eye volume.32

    Management

    Patients with nanophthalmos should be regularly reviewed with gonioscopy for angle closure and elevated IOP. Medical therapy should be first line. Any laser treatment or surgery can be complicated by uveal effusions, which should be taken into consideration when any intervention is planned.35-37 Postoperative complications are common.38 Unsutured, V-shaped, full-thickness sclerostomies anteriorly over the pars plana with intraocular surgery have been reported to reduce the risk of complications.39 Patients should be warned to be cautious of medications that are contraindicated in narrow/closed-angle glaucoma.

    Persistent Fetal Vasculature

    Definition

    Persistent fetal vasculature (PFV) is a congenital anomaly and describes a variable clinical spectrum that includes a retrolental fibrovascular mass, microphthalmos, elongated ciliary processes, a shallow anterior chamber, varying degrees of lenticular opacification (and anterior surface vascularization), elevated vitreous membrane or stalk from optic nerve, retinal fold, retinal traction, or detachment and severe intraocular hemorrhage. It is usually associated with cataract, but the lens may be clear due to posterior segment involvement only or it may become cataractous with time. Cataract surgery is often necessary.40 PFV is often an isolated anomaly but can occur with other ocular conditions, although systemic associations are uncommon. It is classified into anterior and posterior types, although usually both features exist in the same eye (60%). The posterior type is less common and occurs in the posterior segment characterized by a white, dense, opaque membrane or a prominent retinal fold. Optic disc and macular abnormalities have been reported. PFV is usually unilateral (90%). The exact etiology of the failure of primary vitreous and hyaloid vasculatures to regress remains unknown.

    Inheritance and genetics

    PFV is usually sporadic, but may have a genetic basis in light of familial cases and its association with ocular anomalies.

    Incidence and mechanism of glaucoma

    Glaucoma is sometimes present at diagnosis but usually develops from angle closure as a result of lens enlargement from cataract, and from contraction of a retrolental fibrovascular membrane with secondary anterior lens-iris diaphragm movement.41 PFV is a known risk factor for developing glaucoma following lensectomy.42

    Management

    The aim of treatment is to achieve useful vision and prevent or treat secondary complications such as glaucoma. Management is determined by the extent of anterior and posterior segment involvement. In eyes with severe posterior involvement, surgery is not usually indicated. Surgical treatment can be challenging and is recommended before the development of deprivation amblyopia or secondary complications. For patients with a non-visually significant cataract and normal IOP, regular monitoring is required to assess anterior chamber depth and the angle for the risk of angle-closure glaucoma. If there is progressive angle closure, even without elevated IOP, then lensectomy is recommended to avoid acute angle closure.

    Once medical therapy for elevated IOP fails, options are cyclodiode, trabeculectomy, or GDD surgery (especially if aphakic) depending on the visual potential of the eye.43, 44

    Consider referral to a geneticist for evaluation of possible associations with systemic syndromes and for bilateral PFV, such as is seen in Norrie disease.

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