Continuing Education Activity

Peters anomaly is a rare congenital disorder characterized by central corneal opacity with a relatively clear peripheral cornea. It can have associated systemic abnormalities like cleft lip, cleft palate, short stature, abnormal ears, and intellectual disability. The definitive treatment for the Peters anomaly is penetrating keratoplasty, but there are high chances of graft failure. A significant number of patients develop glaucoma and amblyopia. This activity highlights the role of the interprofessional team in the diagnosis and management of patients with a Peters anomaly.

Objectives:

• Describe the epidemiology of the Peters anomaly.
• Explain how to manage the Peters anomaly appropriately.
• Outline the differential diagnosis and staging of the Peters anomaly.
• Summarize the role of interprofessional collaboration in ensuring optimal outcomes in the Peters anomaly.

Introduction

Peters anomaly is a rare congenital disorder of the anterior segment of the eye.[1] It is named after Dr. Alfred Peters, a German ophthalmologist.[2] It is characterized by central corneal opacity of variable size with a corresponding defect in the posterior stroma, Descemet membrane, and endothelium.[3] The peripheral cornea is relatively clear, but a variable degree of haze may be associated with central opacity. In the Peters anomaly, the iridocorneal adhesions typically arise from the collarette and get attached to the margin of the corneal opacity.[4] 

This iridocorneal adhesion can present as thin filaments, thick bands, or arcuate sheets. In 1974, Townsend et al. classified the Peters anomaly into three types. Type I involves the cornea alone and presents as a central corneal opacity. Type II presents with corneo-lenticular touch and corneal opacity. Type III has central corneal opacity with Rieger mesodermal dysgenesis.[5] Presently Peters anomaly is classified into two types.[3] 

Type I has iridocorneal adhesion with corneal opacity. Type I predominantly involves one eye. Corneal opacity density varies from mild to severe with a clear peripheral cornea.[5] Sometimes peripheral corneal edema or scleralization may also be present.[6] Type I has fewer vitreoretinal and systemic abnormalities as compared to type II.[7] It has a good visual prognosis.[8] Type II has corneo-lenticular touch or corneal opacity with lens abnormalities.[9] 

Type II most commonly presents bilaterally. In type II, the lens is directly adherent to the posterior corneal opacity. The lens is cataractous in type II, but it is in the center. The systemic association is more in type II patients. The term Peters-Plus syndrome was first proposed by VanSchooneveld et al. in 1984.[10] 

If the Peters anomaly presents with systemic manifestations like cleft lip/palate, short stature, abnormal ears, and intellectual disability, it is called a Peters plus syndrome.[11] Krause-Kivlin syndrome is an autosomal recessive disorder, which has features of Peters anomaly, along with facial abnormalities, disproportionate short stature, and underdeveloped skeletal maturation.[12]

Etiology

Peters anomaly commonly occurs as a sporadic disorder, but few inheritances patterns (autosomal dominant and autosomal recessive) have been noticed. Alteration in genes like the PAX6, PITX2, PITX3, COL4A1, FOXC1, and COL6A3 is responsible for the Peters anomaly.[13][14][15] PAX6 and FOXC1 are the most common gene mutations in the Peters anomaly. A study conducted by Vincent et al. in 2006 showed that 20% of cases of the Peters anomaly are due to mutation in CYP1B1.[16] Exposure to teratogens during the intrauterine growth period, intrauterine infection, and maternal alcoholism can also be causative factors in the Peters anomaly.[17]

PAX6

It is situated on chromosome 11p13. It has 14 exons, and it encodes a 422-amino acid protein.[18][19] PAX6 is a transcriptional factor that helps in the development of ocular tissue and the central nervous system. Mutations of the PAX6 gene lead to multiple ocular anomalies.[20] Ocular abnormalities due to mutation of the PAX6 gene include aniridia, Peters anomaly, congenital cataract, foveal hypoplasia, microphthalmia, morning glory disc anomaly, and optic nerve hypoplasia.[21][22][23][24]

FOXC1

It is a transcription factor situated at chromosome 6p25.[25] The missense mutation, nonsense mutation, frameshift mutation, and whole gene deletion of the FOXC1 gene lead to ocular, heart, and hearing defects. It has been implicated in the causation of anterior segment dysgenesis three and the type 3 Axenfeld-Rieger syndrome.

PITX2

It is situated on chromosome 4q25.[26] it is a homeodomain-containing transcription factor. PITX2 mutations and deletions lead to ocular, cardiac, and hearing defects.[27][28] PITX2 is estimated to be responsible for 40 % of Axenfeld-Rieger syndrome.[29][30] Diseases associated with a mutation in PITX2 include Axenfeld-Rieger syndrome, type 1; anterior segment dysgenesis 4; and ring dermoid of the cornea.

CYP1B1

The location of the gene is chromosome 2p22.2. Around 20% of cases of Peters anomaly are caused by the mutation of CYP1B1.

TFAP2A 

It is a transcription factor situated at chromosome 6p24.3. Its response to retinoic acid is required for the normal development of the lens, optic cup, and craniofacial region. Mutation of this gene leads to branchiooculofacial syndrome.[31]

COL6A3 

It is situated at the 2q37.3 chromosome and has 44 exons. This gene encodes the longest alpha three chains, which is needed for the firmness of collagen IV molecules. Collagen IV is amply expressed in the cornea.[32] The mutation of this gene leads to the retention of mutant protein in the endoplasmic reticulum (ER), and it further increases ER stress response. This leads to a decline in the resistance and cell variability to oxidative stress. The mutation of this gene may be noted in cases with isolated Peters anomaly.

CHD2 (chromodomain helicase DNA binding protein 2)

It is situated at chromosome 15q26.1. This gene encodes transmembrane protein N-cadherin. It is responsible for cell to cell adhesion. N cadherin protein is present in developing lens stalk and future corneal endothelium.[33]

DOP1B (DOP1 leucine zipper-like protein B)

It is situated at the 21q22 chromosome. This gene helps in protein-protein interaction. This gene may be responsible for autosomal recessive Peters anomaly in a consanguineous family.[34]

B3GLCT (β1,3-glucosyltransferase) 

B3GLCT gene located on 13q12.3. This gene prompts the transfer of glucose to O-linked fucose on thrombospondin type-1 repeats (TSRs). Mutation of this gene leads to Peters plus syndrome (autosomal recessive).[35]

Other genes implicated in the Peters anomaly include PITX3, FOXE3, FLNA, HCCS, NDP, SLC4A11, and COL4A1.[14]

Epidemiology

Approximately 3.3 to 6.0 per 10,000 births have ocular malformation, of which the Peters anomaly forms a majority of the anterior segment malformation.[36] In the United States, 44 to 60 cases of Peters anomaly are reported annually.[37] In 80% of cases, it is bilateral but asymmetrical.[7] Around 50% of Peters Anomaly patients have ocular defects, and nearly 60% have systemic abnormalities.[38]

Pathophysiology

Neural crest cells (NCC) are multipotent cells and are extremely important for embryonic development.[39] Around the optic cup, these neural crest cells are termed periocular mesenchyme (POM).[40] NCCs cells migrate in three waves:

First Wave

In the first wave, neural crest cells pass between the anterior surface of the lens and the surface ectoderm. the first wave cells further differentiate into trabecular meshwork and corneal endothelium; this corneal endothelium will lead to form the Descemet membrane.[41]

Second Wave

Second wave neural crest cells are present between the corneal epithelium and endothelium. These cells further form corneal keratocytes of the corneal stroma.[41] 

Third Wave

Neural crest cells in the third wave migrate to the angle between the corneal endothelium and the anterior edge of the optic cup. Third-wave cells differentiate into the iris stroma and ciliary body.[40]

The neural crest is responsible for developing an anterior segment of the eye, including the cornea, iris, sclera, ciliary body, trabecular meshwork, and aqueous outflow tracts. Any defect in the neural crest leads to anterior segment anomalies such as Axenfeld–Rieger syndrome and Peters anomaly. Peters anomaly occurs due to abnormal separation of lens vesicles from the surface ectoderm.[39]

Anterior Chamber Cleavage Syndrome

It is also called mesodermal dysgenesis of the iris and cornea. This syndrome includes three groups: 

1. Central 
2. Peripheral
3. Central and peripheral components

Peripheral abnormalities include prominent Schwalbe line, attachment of iris strand to Schwalbe line, and anterior iris stromal hypoplasia. Central abnormalities include a central posterior corneal defect, central iridocorneal adhesion, and corneo-lenticular adhesion. Peters anomaly has also been called anterior chamber cleavage syndrome as it is associated with mesodermal dysgenesis of iris and posterior embryotoxon.[42]

Posterior Corneal Ulcer (Von Hippel’s Internal Corneal Ulcer)

It has corneal opacity associated with adherent iris and/or lens, along with signs of inflammation. Signs of inflammation differentiate it from Peters anomaly.[43]

Histopathology

Under a light microscope, the histological section shows the complete absence of endothelium and the Descemet membrane in the area of corneal opacity. The Bowman membrane may be thin or absent.[37] The cornea has proteoglycans, including Decorin, Keratan, and Lumican, which play essential roles in corneal development and transparency.[44] 

Lumican is responsible for the posterior stromal collagen fibril arrangement and diameter. On lumican immunolabelling in Peters anomaly patients, there is a significant decrease in lumican level in the posterior corneal stroma.[45] This lumican deficiency seems to be responsible for larger and irregular development of the collagen bundle.[46] 

The deficiency of decorin proteoglycan leads to corneal scarring.[47] Decorin staining intensity is significantly less in Peters anomaly cases than in normal corneal tissue. The major proteoglycan of the cornea is keratan sulfate. Keratan sulfate is responsible for maintaining the transparency and normal development of the cornea.[48] The immunolabelling intensity of keratan sulfate is less in Peters anomaly and congenital glaucoma.

History and Physical

It is important to discuss with the patient's family the duration of onset, nature of the progression of reduced vision, to take thorough maternal history regarding exposure to teratogens, alcohol intake, or any history of infection, and examine the eyes of parents and siblings for central corneal opacity. 

Systemic and Ocular Examination

Generally, pediatricians first notice a central corneal opacity with abnormal red reflex. The central corneal opacity can vary in density and size with a relatively clear periphery and iridocorneal adhesion. In Peters anomaly type II, central corneal opacity and iridocorneal adhesion, lens abnormalities like cataracts are also present. In the bilateral cases of the Peters anomaly, the incidence of strabismus is higher.[49] 

Peters anomaly may have nystagmus, microcornea, cornea plana, and glaucoma due to dysgenesis of the angle. Iris abnormalities, chorioretinal coloboma, retinal dysplasia, persistent hyperplastic primary vitreous, optic nerve hypoplasia, coloboma, and ptosis have also been associated.[50] 

In the Peters anomaly, congenital glaucoma is present in 50 to 70% of cases. Raised intraocular pressure in peters anomaly is due to maldevelopment of trabecular meshwork and Schlemm's canal.[51] Congenital glaucoma usually presents within one year of birth but can be evident in childhood or even later.[52]

Screening for systemic abnormalities is also important. Systemic anomalies such as developmental delay, seizures disorder, central nervous system abnormalities, craniofacial abnormalities like cleft lip, cardiac malformation, and skeletal deformities may also be associated. Wilms tumor and linear skin defect are rare systemic associations that can present with the Peters anomaly.[53] 

An abnormal corpus callosum and malformation of cortical development are common findings in brain imaging in patients with the Peters anomaly. In some cases, hypoplasia of the cerebellar vermis, cerebral calcification, and malformation of the hippocampus can be associated with the Peters anomaly.[54] Bilateral cases of Peters anomaly may have a higher rate (71.8%) of systemic abnormalities than unilateral cases of Peters anomaly.

Evaluation

Peters anomaly is diagnosed clinically, and investigations are done to characterize other abnormalities and document ocular abnormalities.

Ocular Investigations

Anterior Segment Photo

Anterior segment photo is useful for clinical, academic, and research purposes. The clinical picture helps with the following:

• Evaluating the accurate size, shape, and location of the lesion
• Comparing the condition of both eyes
• Explaining to the patients and their relatives about the condition
• Comparing preoperative and postoperative photos
• Teleconsultations[55]

Ultrasonography Brightness (USG B) SCAN

It helps in the evaluation of severity and diagnosis of the Peters anomaly.[54] B scan gives an idea about posterior segment abnormalities like retinal detachment or mass.

Ultrasound Biomicroscopy (UBM)

UBM is a noninvasive and diagnostic investigation for the Peters anomaly.[56] It uses a high frequency (50MHz), which provides a resolution axially up to 20 micrometers and 50 micrometers laterally, and the depth of tissue penetration is 4-5mm.[57] 

At high resolution, it shows a shallow anterior chamber, iridocorneal adhesion, corneo-lenticular touch, hyperreflectivity at the posterior surface of the cornea, hyperechoic lens, and lens luxation.[56] It also detects early corneal edema and the absence of the Descemet membrane.[58] The 35 MHz probe has higher penetration and can visualize the ciliary body vividly.

Intraoperative OCT [iOCT, Spectral-domain OCT (SD-OCT)]

It is performed under anesthesia before corneal transplantation or during evaluation under anesthesia in a dark room. A total of 31 images of the limbal area were taken and analyzed in a study. It scans the central 6 mm cornea with an axial resolution of 5 micrometers.[59]

It helps in:

• Evaluation of anatomical features and severity
• Making the surgical decisions

The Peters anomaly was classified into three groups based on SD-OCT: mild, moderate, and severe.

Mild disease: It has irregular corneal thickness with defects in the Descemet membrane and the corneal endothelial layer with no iridocorneal adhesion. The anterior chamber angle is open.

Moderate disease: SD-OCT shows the irregular corneal thickness and iridocorneal adhesion. Iridocorneal adhesion can be present in one to three quadrants. A variable extent of anterior chamber angle closure is present.

Severe Disease: In this group, SD-OCT shows lenticulo-corneal adhesion with complete closure of all quadrants of the angle of the anterior chamber.[59] 

Histological Investigation 

It is useful in case of severe corneal opacity. It shows changes in every layer of the cornea. On histological examination, there is an absence of the Descemet membrane and endothelium at the site of corneal opacity. It shows disorderly arranged corneal stromal lamellae and iridocorneal adhesion.[60] 

Radiological Investigation 

A neurological investigation like MRI (magnetic resonance imaging) of the brain and orbit helps in detecting associated intracranial involvement and involvement of optic nerve. MRI orbit also helps differentiate long axial length due to coloboma, glaucoma, and axial myopia.[54]

Systemic Evaluation

• Echocardiography to rule out congenital abnormal development of the heart
• An abdominal ultrasound evaluation for renal malformation
• MRI and CT (computed tomography) scan of the brain and orbit to rule out cerebral and ocular involvement

Treatment / Management

In Peters anomaly patients, the main goal of management is to improve vision and prevent amblyopia. The management options include medical therapy or surgery.

Medical Management 

Medical management includes occlusion therapy with or without mydriasis. Occlusion therapy is effective in mild cases only to prevent amblyopia.[49]

Indications of occlusion therapy include:

• Corneal opacity that is not too dense and with visible fundus
• Unilateral corneal opacity in Peters anomaly
• Asymmetric bilateral corneal opacity

Medical management is also required to control intraocular pressure before and after glaucoma surgery.[61] However, medical management is not the definitive management of the Peters anomaly.

Surgical Management 

Definitive treatment of the Peters anomaly is surgical, but the decision to perform surgery at a young age depends on multiple factors. The surgical intervention relies on the density of corneal opacity, the status of cornea, lens, and other ocular abnormalities.[61] 

Surgical options include:

• A) Peripheral iridectomy: This can be done in cases where corneal opacity was limited with a clear periphery and a transparent lens.[62] Peripheral iridectomy is a safer technique and requires less postoperative care.[63]

• B) Penetrating keratoplasty with cataract extraction (if the lens is also involved).

Indications of penetrating keratoplasty include:

• Pupil occluding the corneal opacity even after dilation with a dilating agent
• Corneal opacity that is too dense with no view of the fundus
• Bilateral dense corneal opacity

Pediatric Keratoplasty Association conducted a survey and noticed that in infants, 65% of corneal grafts are done for Peters anomaly patients.[64] However, the success rate of grafts decreased to approximately 30 % after 5 to 10 years of surgery.[65]

The risk of Graft Failure increases in these cases:

• Larger and smaller grafts
• Anterior synechiae
• Central nervous system abnormality- Uncooperative patients may have poor postoperative care and compliance.[66]
• Young age
• An increased postoperative inflammatory response
• Other associated congenital ocular defects[67]

Keratoprostheses are indicated after multiple failed penetrating keratoplasties and in patients with severe corneal disease. The outcome of this intervention is very poor due to glaucoma, endophthalmitis, and retinal detachment.[65] 

Glaucoma surgery, including trabeculectomy, diode laser cyclophotocoagulation, trabeculectomy with mitomycin C, and glaucoma drainage device, is generally performed. Primarily, the intraocular pressure can be controlled surgically, but adjunctive medical management may be required.

Differential Diagnosis

Differential diagnosis of congenital corneal opacity includes Sclerocornea, Trauma, Ulcer, Mucopolysaccharides, Peters anomaly, the Congenital Hereditary Endothelial Dystrophy, and corneal Dermoid. This can be remembered by the STUMPED acronym.[62]

Sclerocornea 

It is not a very common disorder of anterior segment dysgenesis. Sclerocornea clinically presents as peripheral or complete corneal scleralization with loss of an identifiable limbus. If the entire cornea is involved, the central cornea is relatively clearer than the periphery. A 1 to 2 mm of the peripheral cornea is vascularized.[68] Other ocular abnormalities include shallow anterior chamber, iris deformities, and microphthalmos. Systemic abnormalities include limb abnormalities; and craniofacial and/or genitourinary malformation.

Tear in Descemet Membrane

Forceps-assisted delivery leads to birth trauma and causes clouding of the cornea due to rupture of the Descemet membrane. Rupture in the Descemet membrane due to forceps causes vertical Descemet tears, whereas, in congenital glaucoma, Horizontal or circumferential Haab's striae are present.[69] Other signs like peri-orbital ecchymosis and lid edema may be present.[70] Even after corneal haze is resolved, anisometropic astigmatism can develop and lead to severe amblyopia. Refractive error correction and patching may be required.[71]

Amniocentesis injury: This is an extremely rare condition that presents as unilateral angular or linear corneal opacity due to perforation by the needle. Along with corneal opacity, newborns may present with hyphema, corneal blood staining, raised intraocular pressure, iris and pupil deformity, and cataracts.[70]

Keratitis

Infectious cause like herpes simplex keratitis and bacterial keratitis is responsible for corneal opacity in newborns. Viral keratitis often presents within two weeks of birth. It is evident as cloudy cornea with the corneal epithelial defect.[70] 

Corneal opacity is extremely rarely caused by congenital rubella. This infection is acquired in the first trimester of gestation. In rubella infection, corneal opacity occurs due to endotheliitis, raised intraocular pressure, or corneo-lenticular adhesion.[72]

Mucopolysaccharidosis

It is a lysosomal storage disorder inherited in an autosomal recessive manner. Clouding of the cornea occurs in the first year of life due to the accumulation of glycosaminoglycans.[73] Diffuse corneal opacity presents as bilaterally.[74] Other signs and symptoms include hypermetropia and astigmatism, keratoconjunctivitis sicca, glaucoma, retinopathy, and optic nerve head swelling. Corneal clouding is noted in MPS-IS (Schie). MPS-IH (Hurler), MPS-IV (Morquio), and MPS-VI (Maroteaux Lamy).

Other metabolic disorders like cystinosis and mucolipidosis IV are also responsible for corneal opacity in newborns.

Mucolipidosis IV: This condition is an extremely rare metabolic disorder that presents within a few weeks of birth. Corneal opacity and squint may be the first signs noted. Hospitalization is required due to severe psychomotor delay.[70]

Cystinosis: In cystinosis patients, elongated cystine crystals are deposited in the cornea due to a high cystine level. Crystals first deposit in the peripheral part of the cornea and the anterior stroma. Crystals deposits can be seen on the iris and ciliary body. Glaucoma can occur due to the deposition of crystals in the ciliary body. Other ophthalmic findings included astigmatism and bilateral hypopigmented retinopathy.[75]

Congenital Hereditary Endothelial Dystrophy (CHED)

CHED presents as diffuse corneal edema due to dysfunction of the corneal endothelium.CHED has a symmetrical thickening of the Descemet membrane in both eyes. CHED is autosomal recessive. In the 'IC3D Classification of Corneal Dystrophies—Edition 2', the so-called autosomal dominant CHED (previously called CHED1) has been reclassified under posterior polymorphous corneal dystrophy.[76] Corneal opacity differs in density from a blue-gray to complete corneal opacity. It is typically a bilateral process.[70]

Dermoid

It is a choristoma, mainly present in the epibulbar part, but sometimes it may involve the cornea and cover the visual axis.[77] Its size may vary. A large dermoid requires surgical intervention.[78]

Congenital Glaucoma 

It can present as corneal haziness with raised intraocular pressure. Differentiating features of congenital glaucoma are buphthalmos, curvilinear Haab's striae, megalocornea, and optic disc cupping.[79]

Posterior polymorphous corneal dystrophy (PPCD)

It is an autosomal dominant disorder, usually reported in the second or third decade of life. In this disease, endothelium behaves like epithelial cells.[80] Its presentation ranges from linear, band-like, and grouped lesions. Epithelial cells may invade the angle of the anterior chamber and iris, causing raised intraocular pressure and irregular iris. It's a progressive disease, unlike CHED.[81] PPCD patients are at high risk of open and closed-angle glaucoma.[82]

Posterior Keratoconus  

It is a rare corneal abnormality presenting as a local anterior bulging of posterior corneal curvature associated with stromal thinning.[83] Corneal haze in the posterior keratoconus is present in the center.[84] It is most frequently present unilaterally but can also be bilateral.[85]

Staging

Peters anomaly is divided into three grades based on the ocular structure involvement:

• Mild: Only cornea is involved, rest of iris and lens is normal.
• Moderate: There are iridocorneal adhesions or iris abnormalities like coloboma and iris atrophy.
• Severe: This is characterized by corneo-lenticular adhesion or corneal staphyloma with or without corneo-lenticular adhesion.[50]

Prognosis

Prognosis depends upon multiple factors like age of presentation, the severity of disease, and associated systemic abnormalities. Early surgical intervention like penetrating keratoplasty may prevent amblyopia, but it is associated with a high risk of graft failure. A study conducted by Rao et al. in 2005 suggested that only 22 % maintain clear grafts after two years of surgery.[67] Type I has a better visual prognosis than type II.[60]

Complications

The majority of complications in the Peters anomaly are present after penetrating keratoplasty. Postsurgical complication includes graft failure, glaucoma, cataract, retinal detachment, and phthisis.[86][87] Glaucoma is the most common complication present after surgery. Risk factors for complications include large donor grafts, multiple surgeries like lensectomy and vitrectomy, along with penetrating keratoplasty.[88] Non-surgical complications include amblyopia, nystagmus, and squint.

Deterrence and Patient Education

Genetic counseling and evaluation should be done in patients with Peters anomaly. The prognosis should be appropriately conveyed to the parents. The need for regular follow-up is paramount. The patients should receive education about the importance of compliance to therapy as the chances of amblyopia, glaucoma, squint, and other complications are high in these children.

Enhancing Healthcare Team Outcomes

The approach toward a child suffering from the Peters anomaly has to be extensive and collaborative. Early identification of this condition first by the treating pediatrician followed by prompt treatment by an ophthalmologist is required. Other associated systemic conditions such as developmental delay, seizure disorder, central nervous system malformations, craniofacial abnormalities like cleft lip, cardiac malformation, and skeletal deformities need interprofessional coordination among the various specialists, including an endocrinologist, cardiologists, pediatric surgeons, plastic surgeons, orthopedic surgeons, and a neurologist.

An interprofessional team approach is warranted to manage this condition, starting from early detection by the pediatrician and motivation for seeking advice from an ophthalmologist to prevent visual morbidity. It also involves validation of proper medication dosage and screening for drug interactions by the pharmacist, along with monitoring of vital signs, and parental education by the nurses. Visual evaluation by the optometrist is needed.

Subsequent counseling and education of the parents about various treatment options available for treating this condition by the ophthalmologist is crucial. Genetic counseling and evaluation play a vital role in managing patients with the Peters anomaly. Hence, this interprofessional teamwork plays a crucial role in the successful treatment of such newborns to improve the final outcome.