Anterior Segment Dysgenesis
Erin D. Stahl, MD
’
Introduction
Anterior segment dysgenesis (ASD) includes a spectrum of developmental disorders affecting the cornea, lens, iris, and angle structure. Eyes with such abnormalities in the anterior segment have been labeled into specific diagnostic entities depending on clinical findings. This heterogenous group includes the Peters anomaly, Axenfeld-Rieger syndrome (ARS), and sclerocornea. With the advent of sophisticated anterior segment imaging, murine models, and advancements in genetic testing, the overlap between these conditions has become increasingly evident. The term ASD is an appropriate general term to describe these conditions and the clinical and genetic findings can be used to further classify and determine treatment for these disorders. ’
Embryology
To understand the spectrum of disease seen with ASD, a review of ocular embryology is essential. In the sixth week of gestation the embryonic cup has formed and the lens vesicle has invaginated. Surface ectoderm covers the developing eye and will later become the corneal epithelium. Three waves of neural crest-derived tissues then form beneath the surface ectoderm. The first wave creates the corneal endothelium. Next, the corneal stroma forms between the surface ectoderm and the endothelium. The final wave of neural crest tissue forms the iris stroma. An arrest in development of any of these layers can lead to failure in the development of successive waves leading to the variable forms of ASD. By the fifth month of gestation, the development of the iris and the cornea are advanced and the angle structures and trabecular meshwork have formed. A defect at any point in this development can result in maldevelopment of the anterior segment. INTERNATIONAL OPHTHALMOLOGY CLINICS Volume 54, Number 3, 95–104 r 2014, Lippincott Williams & Wilkins
www.internat-ophthalmology.com | 95
96
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’
Nomenclature and Clinical Findings
Stahl
The Peters anomaly, ARS, and sclerocornea are categorized by the best fit of clinical and anatomic findings. Congenital ocular abnormalities include, alone or in combination, corneal opacity, posterior embryotoxon, iris hypoplasia, corectopia or polycoria, and adhesions between the iris and the lens. A brief overview of these diseases will discuss the historical context of each and the clinical findings. Peters Anomaly
In 1906, Peters1 described a syndrome characterized by a shallow anterior chamber, synechiae between the iris and cornea, central corneal leukoma, and a defect in the Descemets membrane. This syndrome can vary in severity with ocular findings ranging from unilateral mild central corneal opacity to severe bilateral microphthalmia, corneal opacification, cataract, and glaucoma. The Peters anomaly has been further divided into type I and type II. Type I Peters anomaly is categorized by central corneal opacity and iridocorneal adhesions. Type II Peters anomaly has a more severe phenotype with corneal opacity and lens involvement with iridocorneal touch with or without cataract. Eighty percent of the Peters anomaly cases are bilateral. The Peters plus syndrome includes the anterior segment findings with systemic developmental anomalies including cleft lip/palate, short stature, ear abnormalities, and mental retardation (Fig. 1). ARS
This condition was first described in 1920 by Axenfeld2 as patients with posterior embryotoxon and iris strands adherent to the anteriorly displaced the Schwalbe line (Axenfeld anomaly). Rieger3 then reported a series of ‘‘mesodermal dysgenesis of the cornea and iris’’ including patients with iris atrophy, pseudopolycoria, and posterior embryotoxon (Reiger anomaly). Rieger anomaly in addition to systemic findings, such as dental abnormalities, facial bone defects including maxillary hypoplasia, umbilical abnormalities, or pituitary involvement was then classified as Rieger syndrome. With the advancement of molecular genetics it has been found that the clinical findings associated with Axenfeld and Rieger anomalies originate from the same gene loci and the spectrum of disorders has now been termed as ARS. ARS severity can range from subtle gonioscopic findings to severe ocular and systemic deformity. The diagnosis of ARS should also prompt systemic evaluation with attention to the cardiac outflow tract and potential endocrine abnormalities4 (Fig. 2). www.internat-ophthalmology.com
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Figure 1. The Peters anomaly.
Figure 2. Axenfeld-Rieger Syndrome with iris atrophy and pseudopolycoria. www.internat-ophthalmology.com
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Sclerocornea
In another form of ASD, sclerocornea is a peripheral corneal finding wherein the scleral tissue replaces normal corneal tissue. The sclera tissue is vascularized in the typical scleral pattern. This can be a mild finding of the peripheral 1 to 2 mm of cornea or can be total with the whole cornea replaced by sclera tissue. This nonprogressive condition is typically bilateral, although it can be asymmetric. Cornea plana is a common association with sclerocornea, which can lead to high refractive error. ’
Molecular Genetics
Identification of the genetic etiology of ASD has revealed multiple genetic loci. Although the primary phenotype associated with ASD genes is typically distinct, most genes are involved in multiple-related ASD phenotypes with a high degree of familial variability.5 PITX2 and FOXC1
Disruption in either of these genes by mutation or deletion has been strongly associated with ASD phenotypes6 and are thought to account for 40% of cases.7 Typically, PITX2 disruption is associated with ARS with ocular and dental abnormalities and FOXC1 is associated with ARS with hearing or cardiac abnormalities. They can both be seen with only ocular abnormalities. Additional phenotypes found with PITX2 and FOXC1 include the Peters anomaly, isolated iris hypoplasia, iridogoniodysgenesis, ring dermoid of the cornea, primary congenital glaucoma, and aniridia. Table 1 presents genes that have been associated with various phenotypes of ASD. PAX6 is most commonly associated with aniridia but can show clinical findings in the ASD spectrum, including an isolated Peters anomaly case.8 Likewise, CYP1B1 is commonly associated with primary congenital glaucoma but can also have clinical findings within the ASD spectrum. This frequent overlap highlights the phenotypic variability with multiple genetic loci within ASDs. ARS has been found to have an autosomal dominant inheritance pattern in 70% of cases. In Peters anomaly, rare cases have been attributed to PITX2, FOXC1, and PAX6 mutations,9–11 but the majority of cases are sporadic and are diagnosed on clinical features alone. ’
Diagnosis
Most diagnoses of moderate to severe ASD are made at a young age. Full diagnostic work-up often requires slit-lamp corneal examination, gonioscopy, corneal thickness, intraocular pressure, anterior segment www.internat-ophthalmology.com
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’
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Table 1. The Common Genes Found With Anterior Segment Dysgenesis (ASD) and Their Associated Clinical Findings5: Genes Associated With Anterior Segment Dysgenesis Genes
Locus
Inheritance
PITX2
4q25-q26
AD
FOXC1
6p25
FOXC2 PAX6
16p24.3 11p13
PITX3
10q25
JAG1
20p12
FOXE3
1p32
CYP1B1
2p22-p21
B3GALTL
13q12.3
Clinical Findings
Axenfeld-Rieger syndrome, Peters anomaly, iris hypoplasia AD Axenfeld-Rieger syndrome, Peters anomaly, iris hypoplasia, primary congenital glaucoma, aniridia AD ASD, lymphedema-distichiasis syndrome AD Aniridia, Peters anomaly, keratitis, foveal hypoplasia, congenital cataract AD Congenital posterior polar cataract with or without ASD AD Alagille syndrome with posterior embryotoxon, iris hypoplasia, microcornea, iridocorneal adhesions, and corectopia AD or AR Peters anomaly, ASD with cataract, microphthalmia, primary aphakia AR Primary congenital glaucoma, Peters anomaly, ASD aniridia AR Peters plus syndrome
AD indicates autosomal dominant inheritance; AR, autosomal recessive inheritance; ASD, anterior segment dysgenesis.
optical coherence tomography, ultrasound biomicroscopy, corneal diameter, axial length measurement, fundus examination, and refraction. Depending on the age of the patient, this may require examination under anesthesia. Systemic examination should also be arranged with a geneticist or pediatrician to look for other systemic abnormalities. The physician performing this examination should be alerted to pay careful attention for dental, umbilical, cardiac, hearing, and craniofacial abnormalities, as well as mental retardation. When infants present with ASD, timely diagnosis is important to allow for early surgical or conservative treatment to promote visual development and avoid deep amblyopia (Fig. 3). Less severe cases of ASD may present in late childhood or adulthood, commonly with the development of glaucoma. Mild forms of the disease, presenting with isolated posterior embryotoxon and adherent iris strands may only be detected with gonioscopy and should be considered in all patients with newly diagnosed glaucoma. Examination of family members to look for posterior embryotoxon may be helpful in making the diagnosis of ASD (Figs. 4, 5).
’
Medical and Surgical Management
Fifty percent of patients with ASD will develop glaucoma.12 This may present as a severe congenital glaucoma or may slowly develop over time www.internat-ophthalmology.com
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Figure 3. The Peters Anomaly—ultrasound biomicroscopy with iridocorneal adhesions.
and present in late adolescence or adulthood. The severity and presentation of the glaucoma are the primary determinants of management. With congenital and early-onset childhood glaucoma, there is often a severe drainage angle abnormality that requires prompt surgical intervention. Overall surgical success with ASD is lower than when
Figure 4. Posterior embryotoxon. www.internat-ophthalmology.com
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Figure 5. Posterior embryotoxon with iris processes.
treating primary congenital glaucoma. This is thought to be due to the significant histopathologic abnormalities of the angle and the Schlemm canal with ASD.13,14 Although there are reports of success with primary angle surgery (goniotomy or trabeculotomy),15 the majority of these surgeries fail to control the glaucoma. Procedures that provide an alternate drainage route for aqueous including sclerotomy, trabeculectomy, and glaucoma drainage device implantation may be the best surgical options for ASD-related glaucoma.16 For less severe cases wherein the glaucoma develops in late childhood to adulthood, medical management with topical glaucoma medications can control the intraocular pressure. If surgical management is required, then trabeculectomy or glaucoma drainage device placement could be considered. ASD cases with Peters anomaly or sclerocornea and associated congenital corneal opacities present a significant challenge in terms of amblyopia management and surgical planning. Peripheral corneal opacities that spare the central cornea can be managed conservatively with refractive correction, amblyopia treatment, and close observation. Dense central corneal opacities require aggressive surgical management for functional vision to develop. Patients with total sclerocornea wherein the opacity covers the visual axis and requires surgical intervention have a worse prognosis than with the Peters anomaly.17 Penetrating keratoplasty with or without lensectomy is the most common treatment for a central corneal opacity. Many factors must be considered when considering surgical management for a congenital central corneal opacity. Unilateral Versus Bilateral
Laterality of the dysgenesis is a significant factor in counseling parents on the risks and benefits of early surgical intervention for a www.internat-ophthalmology.com
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congenital corneal opacity. Twenty percent of patients with the Peters anomaly have unilateral findings and if the involved eye has very significant dysgenesis, it is appropriate to conservatively manage the involved eye without immediate surgical intervention. If the only involved eye has mild dysgenesis, such as in the case of a Type I Peters anomaly, there is reasonable expectation for a favorable prognosis18 and surgery should be considered. In bilateral cases, surgical intervention is necessary to develop vision and should be strongly considered in one or both eyes. Age
There is no consensus about the optimal age for the surgical removal of congenital corneal opacities. With studies on unilateral congenital cataracts, it is known that there is a critical period around 6 to 8 weeks of age for early visual development.19 Cataract removal in the 6- to 8-week range can improve overall visual function over delayed surgery. With early keratoplasty, the visual benefit of early surgery must be weighed against the potential risks. There is a strong relationship between earlier keratoplasty and rejection risk. The benefit of long-term graft survival must be considered with the visual benefit of early surgery. Multiple studies have seen little correlation between age of surgery and visual acuity outcomes.20–22 Severity
Disease severity is another important factor in considering surgical intervention. In one study, type I Peters anomaly cases with no lens involvement had a rate of clear graft and functional visual acuity in above 85% of eyes.18 In another study reporting severe cases involving vascularized corneas and large grafts, the success rate was poor leading to 75% of eyes with light perception and no light perception vision.23 In mild cases, an optical iridectomy can be performed without penetrating keratoplasty with good visual benefit.24 Glaucoma
Another poor prognostic factor in maintaining a clear corneal graft and developing functional vision is the presence of glaucoma.18,21 Glaucoma is well known to lead to graft failure, which decreases the possibility for functional vision. In addition, optic nerve damage from elevated pressure can be the cause for vision loss even in the presence of a clear graft. After corneal surgery, suspicion for the development of glaucoma should be very high at every postoperative visit. Glaucoma should be aggressively managed with medication and/or surgery in these patients. www.internat-ophthalmology.com
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Risks
Retinal detachment, phthisis, cataract formation, poor vision, pain, and repeated sessions of general anesthesia are all risks that accompany the decision to operate on a child with a corneal opacity from ASD.25 It is imperative that the parents understand the significance of these risks and the requirement of frequent office visits, demanding medication schedules, and the need for multiple trips to the operating room. Proceeding with surgical rehabilitation of an eye with ASD requires that the parents understand and accept these risks and inconveniences. ’
Conclusions
ASD is a heterogenous spectrum of disorders that describe congenital abnormalities of the cornea, lens, iris, and anterior chamber drainage angle. The findings associated with ASD can range from very severe forms with corneal opacity and glaucoma, to mild forms that are only identified later in life. Once distinct entities including the Peters anomaly, ARS, sclerocornea, molecular genetics, a more thorough understanding of ocular development has revealed that there is significant overlap in these conditions that fit under the classification of ASD. Early intervention of these disorders is important in promoting visual development. Management may include glaucoma surgery, corneal surgery, lensectomy, medications, and, most importantly, refractive and amblyopia therapy. This is a rare condition that typically requires the expertise of a glaucoma specialist, a pediatric cornea specialist, and a pediatric ophthalmologist working in close coordination.
The author declares that there are no conflicts of interest to disclose.
’
References
1. Peters A. On a congenital defect of Descemet’s membrane. Klin Mbl Augenheik. 1906;44:27. 2. Axenfeld T. Embryotoxon corneae posterious. Ber Deutsch Ophthalmol Ges. 1920;42: 301–302. 3. Rieger H. Contributions to the knowledge of rare malformations of the iris II: hypoplasia of the iris stroma with dislocation and irregularity of the pupil. Albrecht von grafes arch klin exp ophthalmol. 1935;133:602–635. 4. Chang TC, Summers CG, Schimmenti LA. Axenfeld-Rieger syndrome: new perspectives. Br J Ophthalmol. 2012;96:318–322. 5. Reis LM, Semina EV. Genetics of anterior segment dysgenesis disorders. Curr Opin Ophthalmol. 2011;22:(no. 5):314–324. www.internat-ophthalmology.com
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6. Lines MA, Kozlowski K, Walter MA. Molecular genetics of Axenfeld-Rieger malformations. Hum Mol Genet. 2002;11:1177–1184. 7. D’haene B, Meie F, Claerhout I. Expanding the spectrum of FOXC1 and PITX2 mutations and copy number changes in patients with anterior segment malformations. Invest Ophthalmol Vis Sci. 2011;52:324–333. 8. Sowden J. Molecular and developmental mechanisms of anterior segment dysgenesis. Eye. 2007;21:1310–1318. 9. Dahl E, Koseki H, Balling R. Pax genes and organogenesis. Ophthalmic Surg Lasers. 1997;28:311–312. 10. Doward W, Perveen R, Lloyd JC. A mutation in REIG1 gene associated with Peters anomaly. J Med Genet. 1999;36:152–155. 11. Iseru SU, Osbourne RJ, Farrall M. Seeing clearly: the dominant amd recessive nature of FOXE3 in eye development abnormalities. Hum Mutat. 2009;10:1378–1386. 12. Alward W. Axenfeld-Rieger syndrome in the age of molecular genetics. Am J Ophthal. 2000;130:107–115. 13. Gould DB, John SW. Anterior segment dysgenesis and the developmental glaucomas are complex traits. Hum Mol Genet. 2002;11:1185–1193. 14. Shields M, Buckley E, Klintworth GK. Axenfeld-Rieger syndrome: a spectrum of developmental disorders. Ophthalmol. 1985;29:387–409. 15. Luntz M. Congenital, infantile and juvenile glaucoma. Ophthalmology. 1979;86: 793–802. 16. Wallace D, Plager DA, Snyder SK. Surgical results of secondary glaucomas in childhood. Ophthalmology. 1998;105:101–111. 17. Kim YW, Choi HJ, Kim MK. Clinical outcome of penetrating keratoplasty in patients 5 years or younger: Peters anomaly versus sclerocornea. Cornea. 2013;32:1432–1435. 18. Zaidman G, Flanagan JK, Furey CC. Long-term visual prognosis in children after corneal transplant surgery for Peters anomaly type I. Am J Ophthalmol. 2007;144: 104–108. 19. Birch E, Stager DR. The critical peroid for surgical treatment of dense congenital unilateral cataract. Invest Ophthalmol Sci. 1996;37:1532–1538. 20. Rao K, Fernandes M, Gangopadhyay N. Outcome of penetrating keratoplasty for Peters anomaly. Cornea. 2008;27:749–753. 21. Gollamudi SR, Traboulsi EI, Chamon W. Visual outcome after surgery for Peters anomaly. Ophthalcim Genet. 1994;15:31–35. 22. Chang J, Kim MK, Kim JH. Long-term visual outsomes of penetrating keratoplasty for Peters anomaly. Graefes Arch Clin Exp Ophthalmol. 2013;251:953–958. 23. Yang L, Lambert SR, Drews-Botsch C. Long-term visual outcome of penetrating keratoplasty in infants and children with Peters anomaly. J AAPOS. 2009;13:175–180. 24. Dana M, Schaumberg DA, Moyes AL. Corneal transplantation in children with Peters anomaly and mesenchymal dysgenesis. Ophthalmology. 1997;104:1580–1586. 25. Yang L, Lambert SR, Lynn MJ. Long-term results of corneal graft susvisal in infants and children with Peters anomaly. Ophthalmology. 1999;106:833–848.
www.internat-ophthalmology.com
Erin D. Stahl, MD
’
Introduction
Anterior segment dysgenesis (ASD) includes a spectrum of developmental disorders affecting the cornea, lens, iris, and angle structure. Eyes with such abnormalities in the anterior segment have been labeled into specific diagnostic entities depending on clinical findings. This heterogenous group includes the Peters anomaly, Axenfeld-Rieger syndrome (ARS), and sclerocornea. With the advent of sophisticated anterior segment imaging, murine models, and advancements in genetic testing, the overlap between these conditions has become increasingly evident. The term ASD is an appropriate general term to describe these conditions and the clinical and genetic findings can be used to further classify and determine treatment for these disorders. ’
Embryology
To understand the spectrum of disease seen with ASD, a review of ocular embryology is essential. In the sixth week of gestation the embryonic cup has formed and the lens vesicle has invaginated. Surface ectoderm covers the developing eye and will later become the corneal epithelium. Three waves of neural crest-derived tissues then form beneath the surface ectoderm. The first wave creates the corneal endothelium. Next, the corneal stroma forms between the surface ectoderm and the endothelium. The final wave of neural crest tissue forms the iris stroma. An arrest in development of any of these layers can lead to failure in the development of successive waves leading to the variable forms of ASD. By the fifth month of gestation, the development of the iris and the cornea are advanced and the angle structures and trabecular meshwork have formed. A defect at any point in this development can result in maldevelopment of the anterior segment. INTERNATIONAL OPHTHALMOLOGY CLINICS Volume 54, Number 3, 95–104 r 2014, Lippincott Williams & Wilkins
www.internat-ophthalmology.com | 95
96
’
’
Nomenclature and Clinical Findings
Stahl
The Peters anomaly, ARS, and sclerocornea are categorized by the best fit of clinical and anatomic findings. Congenital ocular abnormalities include, alone or in combination, corneal opacity, posterior embryotoxon, iris hypoplasia, corectopia or polycoria, and adhesions between the iris and the lens. A brief overview of these diseases will discuss the historical context of each and the clinical findings. Peters Anomaly
In 1906, Peters1 described a syndrome characterized by a shallow anterior chamber, synechiae between the iris and cornea, central corneal leukoma, and a defect in the Descemets membrane. This syndrome can vary in severity with ocular findings ranging from unilateral mild central corneal opacity to severe bilateral microphthalmia, corneal opacification, cataract, and glaucoma. The Peters anomaly has been further divided into type I and type II. Type I Peters anomaly is categorized by central corneal opacity and iridocorneal adhesions. Type II Peters anomaly has a more severe phenotype with corneal opacity and lens involvement with iridocorneal touch with or without cataract. Eighty percent of the Peters anomaly cases are bilateral. The Peters plus syndrome includes the anterior segment findings with systemic developmental anomalies including cleft lip/palate, short stature, ear abnormalities, and mental retardation (Fig. 1). ARS
This condition was first described in 1920 by Axenfeld2 as patients with posterior embryotoxon and iris strands adherent to the anteriorly displaced the Schwalbe line (Axenfeld anomaly). Rieger3 then reported a series of ‘‘mesodermal dysgenesis of the cornea and iris’’ including patients with iris atrophy, pseudopolycoria, and posterior embryotoxon (Reiger anomaly). Rieger anomaly in addition to systemic findings, such as dental abnormalities, facial bone defects including maxillary hypoplasia, umbilical abnormalities, or pituitary involvement was then classified as Rieger syndrome. With the advancement of molecular genetics it has been found that the clinical findings associated with Axenfeld and Rieger anomalies originate from the same gene loci and the spectrum of disorders has now been termed as ARS. ARS severity can range from subtle gonioscopic findings to severe ocular and systemic deformity. The diagnosis of ARS should also prompt systemic evaluation with attention to the cardiac outflow tract and potential endocrine abnormalities4 (Fig. 2). www.internat-ophthalmology.com
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Figure 1. The Peters anomaly.
Figure 2. Axenfeld-Rieger Syndrome with iris atrophy and pseudopolycoria. www.internat-ophthalmology.com
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Sclerocornea
In another form of ASD, sclerocornea is a peripheral corneal finding wherein the scleral tissue replaces normal corneal tissue. The sclera tissue is vascularized in the typical scleral pattern. This can be a mild finding of the peripheral 1 to 2 mm of cornea or can be total with the whole cornea replaced by sclera tissue. This nonprogressive condition is typically bilateral, although it can be asymmetric. Cornea plana is a common association with sclerocornea, which can lead to high refractive error. ’
Molecular Genetics
Identification of the genetic etiology of ASD has revealed multiple genetic loci. Although the primary phenotype associated with ASD genes is typically distinct, most genes are involved in multiple-related ASD phenotypes with a high degree of familial variability.5 PITX2 and FOXC1
Disruption in either of these genes by mutation or deletion has been strongly associated with ASD phenotypes6 and are thought to account for 40% of cases.7 Typically, PITX2 disruption is associated with ARS with ocular and dental abnormalities and FOXC1 is associated with ARS with hearing or cardiac abnormalities. They can both be seen with only ocular abnormalities. Additional phenotypes found with PITX2 and FOXC1 include the Peters anomaly, isolated iris hypoplasia, iridogoniodysgenesis, ring dermoid of the cornea, primary congenital glaucoma, and aniridia. Table 1 presents genes that have been associated with various phenotypes of ASD. PAX6 is most commonly associated with aniridia but can show clinical findings in the ASD spectrum, including an isolated Peters anomaly case.8 Likewise, CYP1B1 is commonly associated with primary congenital glaucoma but can also have clinical findings within the ASD spectrum. This frequent overlap highlights the phenotypic variability with multiple genetic loci within ASDs. ARS has been found to have an autosomal dominant inheritance pattern in 70% of cases. In Peters anomaly, rare cases have been attributed to PITX2, FOXC1, and PAX6 mutations,9–11 but the majority of cases are sporadic and are diagnosed on clinical features alone. ’
Diagnosis
Most diagnoses of moderate to severe ASD are made at a young age. Full diagnostic work-up often requires slit-lamp corneal examination, gonioscopy, corneal thickness, intraocular pressure, anterior segment www.internat-ophthalmology.com
Anterior Segment Dysgenesis
’
99
Table 1. The Common Genes Found With Anterior Segment Dysgenesis (ASD) and Their Associated Clinical Findings5: Genes Associated With Anterior Segment Dysgenesis Genes
Locus
Inheritance
PITX2
4q25-q26
AD
FOXC1
6p25
FOXC2 PAX6
16p24.3 11p13
PITX3
10q25
JAG1
20p12
FOXE3
1p32
CYP1B1
2p22-p21
B3GALTL
13q12.3
Clinical Findings
Axenfeld-Rieger syndrome, Peters anomaly, iris hypoplasia AD Axenfeld-Rieger syndrome, Peters anomaly, iris hypoplasia, primary congenital glaucoma, aniridia AD ASD, lymphedema-distichiasis syndrome AD Aniridia, Peters anomaly, keratitis, foveal hypoplasia, congenital cataract AD Congenital posterior polar cataract with or without ASD AD Alagille syndrome with posterior embryotoxon, iris hypoplasia, microcornea, iridocorneal adhesions, and corectopia AD or AR Peters anomaly, ASD with cataract, microphthalmia, primary aphakia AR Primary congenital glaucoma, Peters anomaly, ASD aniridia AR Peters plus syndrome
AD indicates autosomal dominant inheritance; AR, autosomal recessive inheritance; ASD, anterior segment dysgenesis.
optical coherence tomography, ultrasound biomicroscopy, corneal diameter, axial length measurement, fundus examination, and refraction. Depending on the age of the patient, this may require examination under anesthesia. Systemic examination should also be arranged with a geneticist or pediatrician to look for other systemic abnormalities. The physician performing this examination should be alerted to pay careful attention for dental, umbilical, cardiac, hearing, and craniofacial abnormalities, as well as mental retardation. When infants present with ASD, timely diagnosis is important to allow for early surgical or conservative treatment to promote visual development and avoid deep amblyopia (Fig. 3). Less severe cases of ASD may present in late childhood or adulthood, commonly with the development of glaucoma. Mild forms of the disease, presenting with isolated posterior embryotoxon and adherent iris strands may only be detected with gonioscopy and should be considered in all patients with newly diagnosed glaucoma. Examination of family members to look for posterior embryotoxon may be helpful in making the diagnosis of ASD (Figs. 4, 5).
’
Medical and Surgical Management
Fifty percent of patients with ASD will develop glaucoma.12 This may present as a severe congenital glaucoma or may slowly develop over time www.internat-ophthalmology.com
100
’
Stahl
Figure 3. The Peters Anomaly—ultrasound biomicroscopy with iridocorneal adhesions.
and present in late adolescence or adulthood. The severity and presentation of the glaucoma are the primary determinants of management. With congenital and early-onset childhood glaucoma, there is often a severe drainage angle abnormality that requires prompt surgical intervention. Overall surgical success with ASD is lower than when
Figure 4. Posterior embryotoxon. www.internat-ophthalmology.com
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Figure 5. Posterior embryotoxon with iris processes.
treating primary congenital glaucoma. This is thought to be due to the significant histopathologic abnormalities of the angle and the Schlemm canal with ASD.13,14 Although there are reports of success with primary angle surgery (goniotomy or trabeculotomy),15 the majority of these surgeries fail to control the glaucoma. Procedures that provide an alternate drainage route for aqueous including sclerotomy, trabeculectomy, and glaucoma drainage device implantation may be the best surgical options for ASD-related glaucoma.16 For less severe cases wherein the glaucoma develops in late childhood to adulthood, medical management with topical glaucoma medications can control the intraocular pressure. If surgical management is required, then trabeculectomy or glaucoma drainage device placement could be considered. ASD cases with Peters anomaly or sclerocornea and associated congenital corneal opacities present a significant challenge in terms of amblyopia management and surgical planning. Peripheral corneal opacities that spare the central cornea can be managed conservatively with refractive correction, amblyopia treatment, and close observation. Dense central corneal opacities require aggressive surgical management for functional vision to develop. Patients with total sclerocornea wherein the opacity covers the visual axis and requires surgical intervention have a worse prognosis than with the Peters anomaly.17 Penetrating keratoplasty with or without lensectomy is the most common treatment for a central corneal opacity. Many factors must be considered when considering surgical management for a congenital central corneal opacity. Unilateral Versus Bilateral
Laterality of the dysgenesis is a significant factor in counseling parents on the risks and benefits of early surgical intervention for a www.internat-ophthalmology.com
102
’
Stahl
congenital corneal opacity. Twenty percent of patients with the Peters anomaly have unilateral findings and if the involved eye has very significant dysgenesis, it is appropriate to conservatively manage the involved eye without immediate surgical intervention. If the only involved eye has mild dysgenesis, such as in the case of a Type I Peters anomaly, there is reasonable expectation for a favorable prognosis18 and surgery should be considered. In bilateral cases, surgical intervention is necessary to develop vision and should be strongly considered in one or both eyes. Age
There is no consensus about the optimal age for the surgical removal of congenital corneal opacities. With studies on unilateral congenital cataracts, it is known that there is a critical period around 6 to 8 weeks of age for early visual development.19 Cataract removal in the 6- to 8-week range can improve overall visual function over delayed surgery. With early keratoplasty, the visual benefit of early surgery must be weighed against the potential risks. There is a strong relationship between earlier keratoplasty and rejection risk. The benefit of long-term graft survival must be considered with the visual benefit of early surgery. Multiple studies have seen little correlation between age of surgery and visual acuity outcomes.20–22 Severity
Disease severity is another important factor in considering surgical intervention. In one study, type I Peters anomaly cases with no lens involvement had a rate of clear graft and functional visual acuity in above 85% of eyes.18 In another study reporting severe cases involving vascularized corneas and large grafts, the success rate was poor leading to 75% of eyes with light perception and no light perception vision.23 In mild cases, an optical iridectomy can be performed without penetrating keratoplasty with good visual benefit.24 Glaucoma
Another poor prognostic factor in maintaining a clear corneal graft and developing functional vision is the presence of glaucoma.18,21 Glaucoma is well known to lead to graft failure, which decreases the possibility for functional vision. In addition, optic nerve damage from elevated pressure can be the cause for vision loss even in the presence of a clear graft. After corneal surgery, suspicion for the development of glaucoma should be very high at every postoperative visit. Glaucoma should be aggressively managed with medication and/or surgery in these patients. www.internat-ophthalmology.com
Anterior Segment Dysgenesis
’
103
Risks
Retinal detachment, phthisis, cataract formation, poor vision, pain, and repeated sessions of general anesthesia are all risks that accompany the decision to operate on a child with a corneal opacity from ASD.25 It is imperative that the parents understand the significance of these risks and the requirement of frequent office visits, demanding medication schedules, and the need for multiple trips to the operating room. Proceeding with surgical rehabilitation of an eye with ASD requires that the parents understand and accept these risks and inconveniences. ’
Conclusions
ASD is a heterogenous spectrum of disorders that describe congenital abnormalities of the cornea, lens, iris, and anterior chamber drainage angle. The findings associated with ASD can range from very severe forms with corneal opacity and glaucoma, to mild forms that are only identified later in life. Once distinct entities including the Peters anomaly, ARS, sclerocornea, molecular genetics, a more thorough understanding of ocular development has revealed that there is significant overlap in these conditions that fit under the classification of ASD. Early intervention of these disorders is important in promoting visual development. Management may include glaucoma surgery, corneal surgery, lensectomy, medications, and, most importantly, refractive and amblyopia therapy. This is a rare condition that typically requires the expertise of a glaucoma specialist, a pediatric cornea specialist, and a pediatric ophthalmologist working in close coordination.
The author declares that there are no conflicts of interest to disclose.
’
References
1. Peters A. On a congenital defect of Descemet’s membrane. Klin Mbl Augenheik. 1906;44:27. 2. Axenfeld T. Embryotoxon corneae posterious. Ber Deutsch Ophthalmol Ges. 1920;42: 301–302. 3. Rieger H. Contributions to the knowledge of rare malformations of the iris II: hypoplasia of the iris stroma with dislocation and irregularity of the pupil. Albrecht von grafes arch klin exp ophthalmol. 1935;133:602–635. 4. Chang TC, Summers CG, Schimmenti LA. Axenfeld-Rieger syndrome: new perspectives. Br J Ophthalmol. 2012;96:318–322. 5. Reis LM, Semina EV. Genetics of anterior segment dysgenesis disorders. Curr Opin Ophthalmol. 2011;22:(no. 5):314–324. www.internat-ophthalmology.com
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