Peters anomaly

Peters anomaly is a type of anterior segment dysgenesis (ASD), characterized by congenital corneal opacity due to defects in the central Descemet membrane, corneal endothelium, and deep corneal stroma.
It accounts for about three-quarters of ASD cases with corneal opacity, and the overall frequency of ASD is 1 in 12,000 to 15,000 births ¹⁾.
Approximately 80% of cases are bilateral, and 50-70% are complicated by glaucoma.
It is classified into type I (iris-corneal adhesion only) and type II (with anterior lens displacement and cataract), with type II having a poorer prognosis ²⁾.
About 60% of cases have systemic complications (cleft lip/palate, growth retardation, cardiac malformations, etc.), known as Peters plus syndrome.
Visual prognosis is poor, with over 60% having corrected visual acuity less than 0.1; corneal transplant outcomes are also poor, and low vision care is the mainstay of management ¹⁾.
It was designated as an intractable disease in 2017, and patients with severity grade III or higher are eligible for medical expense subsidies.

1. What is Peters anomaly?

Peters anomaly is a congenital disorder characterized by a congenital defect of the corneal endothelium, Descemet membrane, and part of the corneal stroma, resulting in a disc-shaped opacity in the central cornea. The incidence is reported to be approximately 1.5 per 100,000 births ³⁾. It is the most common cause of congenital corneal opacity (CCO), accounting for 40.3-65% of all CCO cases ³⁾.

Peters anomaly is a congenital disease primarily involving central corneal Descemet membrane defect, posterior corneal defect, and corneal opacity with thinning, often accompanied by iris-corneal adhesion, lens abnormalities, and iris abnormalities. It is frequently associated with glaucoma and is often bilateral.

This disease is classified as a representative type of anterior segment dysgenesis (ASD). ASD is a collective term for posterior embryotoxon, Axenfeld-Rieger syndrome, posterior keratoconus, Peters anomaly, sclerocornea, and anterior staphyloma ¹⁾. Among cases with corneal opacity, Peters anomaly is the most common type, accounting for about three-quarters of all ASD cases ¹⁾.

It is thought to result from an abnormality of the mesenchymal layer during embryonic development, leading to impaired separation of the iris and cornea. Approximately 80% of cases are bilateral, and about 60% of cases have systemic complications such as dwarfism, central nervous system abnormalities, cleft palate, cleft lip, cardiac malformations, intellectual disability, endocrine abnormalities, genitourinary abnormalities, and spinal abnormalities (Peters plus syndrome). The more systemic complications present, the higher the risk of glaucoma.

It was designated as a specified intractable disease under the Intractable Disease Act in 2017, and patients can receive medical expense subsidies according to severity.

2. Classification

Type I and Type II classification

Peters anomaly is classified into two types based on the extent of intraocular involvement and lens involvement ²⁾.

Type I

Features: In addition to a central posterior corneal defect and corneal opacity, iris strands (iris-corneal adhesions) are present. No lens abnormalities.

Prognosis: Relatively better than Type II.

Type II

Features: In addition to Type I findings, anterior displacement of the lens or cataract is present. The lens and posterior cornea are in contact or adherent.

Prognosis: Worse than Type I. Glaucoma and poor outcomes after corneal transplantation are more common.

Peters plus syndrome

Peters anomaly with systemic complications is called Peters plus syndrome. Examples of complications include cleft lip/palate, growth retardation, developmental delay, congenital heart disease, and central nervous system abnormalities. Overall, 20–30% of ASD cases have systemic complications ¹⁾, and in reports of isolated Peters anomaly, about 60% have some systemic complication.

Severity classification

The severity classification for intractable disease designation is defined in the following four stages ¹⁾.

Severity	Definition
Grade I	One eye affected, the other eye normal.
Grade II	Both eyes affected, corrected visual acuity in the better eye 0.3 or better
Grade III	Both eyes affected, corrected visual acuity in the better eye 0.1 or better but less than 0.3
Grade IV	Both eyes affected, corrected visual acuity in the better eye less than 0.1

Even for grades I to III, if accompanied by visual field narrowing due to secondary glaucoma (central residual visual field within 20 degrees with Goldmann I/4 target), the grade is shifted up one level ¹⁾. Grade III or higher is eligible for medical expense subsidies ¹⁾.

3. Epidemiology

The overall frequency of ASD is estimated at 1 in 12,000 to 15,000 births, with approximately 70 to 90 new cases per year ¹⁾. Peters anomaly is the most common type, accounting for about three-quarters of ASD corneal opacity cases.

Bilateral involvement accounts for about three-quarters, unilateral for about one-quarter
Clinical features often differ between the right and left eyes
No sex difference
Most cases are sporadic, but families with autosomal recessive or autosomal dominant inheritance have also been reported ¹⁾
Corneal opacity accounts for 10 to 14% of all visually impaired children, making it a socially important disease group ¹⁾

Severity Stage Classification (Khasnavis Classification)

Khasnavis et al. proposed a 5-stage classification based on severity ³⁾. Severity increases stepwise from Stage 1 (opacity less than 3 mm centrally) to Stage 5 (total corneal opacity with iris adhesion). Severe cases present with anterior staphyloma, where the entire cornea protrudes forward.

4. Symptoms and Findings

Major Ocular Findings

Central corneal opacity: Present from the neonatal/infant period, with thinning and absence of Descemet’s membrane, corneal endothelium, and deep corneal stroma. The opacity may improve over time.
Iris strands: The iris adheres to the area of endothelial defect, observed as gray-white strands.
Lens abnormalities (Type II): Anterior lens displacement or cataract may occur ²⁾. The anterior lens capsule may adhere to the posterior corneal surface.
Glaucoma: Complication rate 50–70%. Causes include trabecular meshwork and Schlemm’s canal dysgenesis, and progression of anterior iris synechiae.
Photophobia: Severe photophobia due to corneal opacity.

Visual Prognosis

In Peters anomaly, more than 60% of cases have corrected visual acuity less than 0.1, and more than 40% have less than 0.01, resulting in severe visual impairment ¹⁾. It is often accompanied by form deprivation amblyopia, and appropriate intervention from infancy affects the prognosis.

Systemic Complications (Peters Plus Syndrome)

Approximately 60% of cases have systemic complications. Major complications are listed below.

Short stature, growth retardation
Central nervous system abnormalities
Cleft palate / cleft lip
Congenital heart disease
Intellectual disability
Endocrine abnormalities
Genitourinary abnormalities
Spinal abnormalities

The more systemic complications present, the higher the risk of glaucoma, necessitating multidisciplinary collaboration with pediatrics, cardiac surgery, plastic surgery, and other specialties.

Q What is Peters plus syndrome?

Peters anomaly accompanied by systemic complications (such as cleft lip/palate, growth retardation, developmental delay, congenital heart disease) is called Peters plus syndrome. Systemic complications are seen in about 60% of cases, and the more systemic complications, the higher the risk of glaucoma. Multidisciplinary collaboration with pediatrics, cardiology, plastic surgery, etc., is necessary.

5. Diagnosis

Diagnostic criteria

Based on the diagnostic criteria for anterior segment dysgenesis (2020), the diagnosis is confirmed by the following criteria ¹⁾.

A. Symptoms (one or more of the following)

Corneal opacity present from the neonatal or infant period
Visual impairment
Photophobia

B. Laboratory Findings

Bilateral or unilateral total or partial corneal opacity from the neonatal period to infancy
Strands continuous from the posterior corneal surface to the iris, or posterior corneal defect

Diagnostic Categories¹⁾:

Definite (1): At least one A + B1 + B2 present, and differential diagnoses excluded
Definite (2): At least one A + B1 present, and differential diagnoses can be excluded
Probable: At least one A + B1 present, but differential diagnoses cannot be excluded

Useful Tests

Slit-lamp microscopy: Basic anterior segment evaluation
Ultrasound biomicroscopy (UBM): Allows detailed assessment of the anterior chamber, angle, and iris even when posterior view is poor due to corneal opacity. Guidelines suggest performing this test for disease type diagnosis (weak recommendation, evidence C)²⁾. In young children, local or general anesthesia may be required²⁾.
Anterior segment OCT: Non-contact method to confirm posterior corneal defects and iris strands. Also useful for differentiating type I and type II²⁾.

Differential Diagnosis

Differentiation from the following diseases is necessary¹⁾.

Corneal opacity due to intrauterine infection (rubella, CMV, etc.)
Corneal edema/opacity due to birth trauma (forceps delivery)
Corneal opacity due to postnatal trauma or infection
Systemic congenital metabolic disorders (e.g., mucopolysaccharidosis)
Congenital corneal dystrophy
Congenital glaucoma
Aniridia
Corneal limbal dermoid
Axenfeld-Rieger syndrome (some cases are difficult to differentiate)

Q What are the signs suggesting glaucoma in Peters anomaly?

In infants, an enlarged corneal diameter (greater than 11 mm in newborns, greater than 12 mm in children under 1 year, and greater than 13 mm at any age) is an important sign of glaucoma ²⁾. In children, a cup-to-disc ratio (CD ratio) exceeding 0.3 raises suspicion of glaucoma. Note that this differs from the adult criterion (greater than 0.7). If intraocular pressure measured on two or more occasions exceeds 21 mmHg, the possibility of glaucoma should also be considered ²⁾.

6. Treatment

There is no curative treatment for Peters anomaly. Comprehensive management combining individual management of each complication and utilization of residual visual function is the basic approach.

Management of corneal opacity

According to guidelines, surgical treatment (corneal transplantation) for corneal opacity is “suggested not to be performed” (weak recommendation, evidence C) ²⁾.

Corneal opacity often partially improves with growth if intraocular pressure is normal, and the standard policy is usually not to perform corneal transplantation in early childhood. Key data on the outcomes of penetrating keratoplasty (PKP) are shown below ²⁾.

Corneal clarity survival rate at 10 years postoperatively: approximately 35%
In Peters anomaly type I, corneal transparency is relatively well maintained, but in type II it is poor.
Visual prognosis is significantly worse in cases with glaucoma.
Simultaneous cataract surgery or vitrectomy significantly increases the rate of graft opacification.

Selective Endothelial Removal (SEPA)

This is a minimally invasive procedure that selectively removes the Descemet membrane and corneal endothelium in the opaque area, expecting re-coverage by surrounding healthy endothelial cells ³⁾. It has been reported that corneal clarity was achieved in 85% of 34 eyes, with the advantage of no need for donor cornea and no risk of rejection. Candidates are cases with sufficient healthy endothelium remaining in the periphery.

Treatment of Glaucoma

Glaucoma often resists medical treatment with eye drops and frequently requires surgical therapy.

Medical therapy: Intraocular pressure control with eye drops is basic, but many cases are resistant.
Outflow reconstruction (trabeculotomy): Often insufficient to achieve adequate intraocular pressure reduction.
Filtration surgery (trabeculectomy): Even when indicated, outcomes tend to be poor.
Tube shunt surgery: Selected for cases resistant to medication and filtration surgery. It may be the option that offers the best intraocular pressure control.

In general, glaucoma associated with Peters anomaly responds poorly to surgery and requires long-term management.

Monitoring of Glaucoma

According to the guidelines, for infants and toddlers, it is recommended to measure corneal diameter and perform intraocular pressure testing when not crying, and for school-age children and older, to perform intraocular pressure testing and visual field testing (weak recommendation, evidence C) ²⁾.

Intraocular pressure: >21 mmHg on two or more measurements suggests glaucoma
Corneal diameter: >11 mm in newborns, >12 mm in infants under 1 year, >13 mm at all ages
Cup-to-disc ratio (CD ratio): >0.3 suggests glaucoma
Rebound tonometer (iCare) allows intraocular pressure measurement in infants without general anesthesia
Continue regular examinations with glaucoma in mind even into adulthood ²⁾

Amblyopia treatment and low vision care

Prevention and treatment of form deprivation amblyopia due to corneal opacity are important. Early intervention from infancy can maximize the development of residual visual function.

Appropriate refractive correction (glasses, contact lenses)
In unilateral cases, early occlusion therapy of the healthy eye ²⁾
Optical and non-optical visual aids (magnifiers, enlarged textbooks, tablet devices, etc.)
Lighting adjustments for decreased contrast sensitivity and photophobia associated with corneal opacity ²⁾
Coordination with education and employment support according to life stage

7. Pathophysiology

Peters anomaly is a congenital disease resulting from abnormal migration of neural crest cells ¹⁾. It has been clarified that the mesenchymal tissue involved in the development of the anterior segment (cornea, iris, angle) is derived from the neural crest, not the mesoderm ²⁾, and disruption of this developmental process leads to anterior segment dysgenesis.

The core pathology is an abnormality of the embryonic mesenchyme layer, leading to failed separation of the iris and cornea, resulting in adhesions between the iris and the posterior corneal surface.

Genes reported to be involved ¹⁾:

PAX6: A transcription factor involved in the development of the anterior segment, retina, and lens.
PITX2: Involved in the development of the angle, iris, and cornea.
CYP1B1: Involved in the development of the anterior segment including the trabecular meshwork. It is also a major causative gene for primary congenital glaucoma ⁴⁾.
FOXC1: Involved in the development of anterior segment tissues derived from neural crest cells. It is the most frequently mutated gene (20.3%) in genetic analysis of ASD overall ⁵⁾.
FOXE3: Causes abnormal lens separation and is associated with the pathology of Peters anomaly type II ⁴⁾.
B3GLCT: The causative gene for Peters Plus syndrome. Autosomal recessive mutations cause dysfunction of a glycosyltransferase ⁴⁾.

The inheritance pattern is most often sporadic, but families with autosomal recessive or autosomal dominant inheritance also exist ¹⁾.

Q Should corneal opacity in Peters anomaly be treated with surgery?

The guidelines do not actively recommend penetrating keratoplasty (PKP) (weak recommendation: “suggest not performing”) ²⁾. Corneal opacity in Peters anomaly often improves with growth if intraocular pressure is normal. The 10-year clear graft survival rate after PKP is only about 35%, and the prognosis is particularly poor in type II and cases with glaucoma. The indication for surgery should be determined after comprehensive evaluation of the specific disease type, presence of glaucoma, and impact on visual function.

8. Future Perspectives

With the spread of genetic diagnostic technology, identification of gene mutations involved in Peters anomaly, such as PAX6, PITX2, CYP1B1, and FOXC1, is progressing. This is expected to contribute to future genetic counseling and early detection of familial cases.

Regarding corneal transplantation in infancy, reports of improved success rates due to advances in surgical techniques and postoperative management are accumulating. Standardization of multidisciplinary care protocols for Peters plus syndrome is also an issue, and guidelines for systematic evaluation and management of systemic complications are needed.

Understanding the actual situation through large-scale patient registries is considered to play an important role in future guideline revisions.

9. References

重安千花, 山田昌和, 大家義則, ほか. 前眼部形成異常の診断基準および重症度分類. 日眼会誌. 2020;124:89-95.
厚生労働科学研究費補助金難治性疾患政策研究事業「角膜難病の標準的診断法および治療法の確立を目指した調査研究」研究班. 前眼部形成異常の診療ガイドライン. 日眼会誌. 2021;125:605-629.
Khasnavis T, Fernandes M. Peters anomaly: An overview. Taiwan J Ophthalmol. 2023;13(4):379-393.
Paredes ME, Ong Tone S, Bhatt P, et al. Genetics of the anterior segment dysgenesis. Taiwan J Ophthalmol. 2023;13(4):394-413.
Reis LM, Sorokina E, Bell S, et al. Comprehensive Genetic Assessment of the Anterior Segment Dysgenesis Phenotypic Spectrum. Ophthalmology. 2021;128(11):1545-1558.

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