Peters anomaly is a congenital disorder in which the corneal endothelium, Descemet’s membrane, and part of the corneal stroma are absent, resulting in a disc-shaped opacity in the central cornea. Approximately 80% of cases are bilateral, and it is caused by abnormal migration of neural crest cells after the 6th to 7th week of gestation. It is often accompanied by iridocorneal adhesions or lens-corneal adhesions, and glaucoma is complicated in 50–70% of cases.
It was first reported in 1906 by the German ophthalmologist Peters 1). The original description included pediatric cases presenting with shallow anterior chamber, iridocorneal adhesions, central corneal leukoma, and Descemet’s membrane defects 1).
Peters anomaly is classified into the following three types.
Type 1: Defect of the posterior corneal surface and corneal opacity only. No structural abnormalities of the iris or lens. The density of opacity varies by case, but it is usually unilateral, and the peripheral cornea remains clear. Visual prognosis is relatively good, and systemic abnormalities are rare.
Type 2: Posterior corneal defect combined with iridocorneal adhesions. Characteristic strand-like adhesions from the iris to the posterior cornea are present, often with angle abnormalities. The risk of glaucoma is higher than in type 1.
Type 3: Accompanied by lens opacity, anterior displacement, and adhesion to the posterior cornea. This is the most severe type, complicated by anterior polar cataract or microphakia. The rate of systemic abnormalities is high, and visual prognosis is the poorest.
Another classification divides into type I (no lens abnormality) and type II (with cataract or lens position abnormality). Type I roughly corresponds to type 1 above, and type II corresponds to the severe group of types 2 and 3. Peters anomaly accounts for approximately 40–65% of congenital corneal opacities and is the most common disease among them 2).
Within the spectrum of anterior segment dysgenesis, Peters anomaly is positioned as an abnormality of corneal endothelial formation (first wave of neural crest cell migration), and differs in the developmental stage from Axenfeld-Rieger anomaly (angle and iris formation abnormality) and posterior embryotoxon (anterior displacement of Schwalbe’s line).
Incidence: Estimated at approximately 1.5 per 100,000 births 1). Peters anomaly accounts for 40.3–65% of congenital corneal opacities 2).
Bilaterality: Approximately 80% of cases are bilateral. Bilateral cases have a higher rate of systemic malformations compared to unilateral cases (71.8% vs. 36.8%) 2).
Inheritance pattern: Most cases are sporadic. Rare cases of autosomal dominant or autosomal recessive inheritance have been reported.
Glaucoma association: 50–70% develop glaucoma by age 6. The mechanism is thought to be impaired aqueous humor outflow due to high insertion of the iris root in the angle. Glaucoma is the most important complication of Peters anomaly and significantly affects visual prognosis. Types 2 and 3 have a higher rate of glaucoma and tend to be more refractory.
Age at onset: 60% are diagnosed by 6 months of age, and 80% by 1 year. Early detection and intervention are essential for improving visual prognosis.
In the Glaucoma Clinical Practice Guidelines (5th edition), glaucoma associated with Peters anomaly is classified as “glaucoma related to congenital ocular developmental anomalies” among secondary childhood glaucomas 3). The diagnostic criteria are the presence of ocular developmental anomalies from birth without clear systemic association, and meeting the diagnostic criteria for childhood glaucoma3).
QHow often does glaucoma occur with Peters anomaly?
A
Glaucoma occurs in 50–70% of cases. The rate is higher in type II (type 3). Glaucoma develops due to impaired aqueous outflow from high iris root insertion in the angle and often appears as an early-onset type by age 6. Regular intraocular pressure measurement and optic nerve evaluation are essential. For details on treatment, see the section on “Standard Treatment.”
Because Peters anomaly develops early in life, patients cannot report symptoms themselves. Caregivers often notice the following signs and seek medical attention.
Corneal opacity: The central cornea is white and opaque from birth. This is the most typical complaint.
Photophobia (sensitivity to light): Irritation from corneal epithelial edema due to elevated intraocular pressure causes aversion to light.
Central corneal opacity: Presents with a distinct disc-shaped opacity from birth. The density and extent of the opacity vary among cases. The peripheral cornea is usually clear.
Posterior corneal defect: Defects in Descemet’s membrane and corneal endothelium are present corresponding to the opacity.
Iridocorneal adhesions: Observed in type 2 and above. Characteristic strand-like adhesions from the iris to the posterior corneal surface.
Lens abnormalities: In type 3, the lens is displaced anteriorly and contacts the posterior cornea. May be accompanied by cataract.
Natural course of corneal opacity: In mild cases, if intraocular pressure is normal, it often gradually decreases. Severe cases present with anterior staphyloma where the entire cornea protrudes forward.
Associated ocular abnormalities: May be associated with Axenfeld-Rieger anomaly, aniridia, and persistent fetal vasculature (formerly known as persistent hyperplastic primary vitreous).
Elevated intraocular pressure: Often shows clear high intraocular pressure, but in younger children, the increase in intraocular pressure is compensated by an increase in corneal diameter. Therefore, even if intraocular pressure is 20 mmHg or less, glaucoma should be suspected if there is a tendency for globe enlargement. In neonates and infants under sedation, intraocular pressure is evaluated with 15 mmHg as the upper normal limit.
Increased corneal diameter (buphthalmos): Cases that develop before 3-4 years of age with corneal enlargement are called early-onset type (buphthalmos). Suspect globe enlargement if the horizontal corneal diameter is 12 mm or more in neonates and 13 mm or more in infants. Haab striae (rupture lines of Descemet’s membrane on the posterior cornea) are often difficult to evaluate in corneal opacities of Peters anomaly.
UBM findings: Ultrasound biomicroscopy (UBM) shows high iris insertion, iris processes, and angle closure. On gonioscopy, poor formation of the angle recess and inability to visualize the ciliary body band or extremely narrow findings are indicators of angle dysgenesis.
Optic disc evaluation: When corneal opacity is severe, fundus examination becomes difficult. Ultrasound B-scan and confirmation of optic disc cupping enlargement after reduction of corneal opacity are important. A progressive increase in the cup-to-disc ratio (C/D ratio) is an indicator of glaucoma progression.
Systemic abnormalities are found in about one-third of cases. When examining Peters anomaly, systemic evaluation is recommended.
Organ System
Main Complications
Central nervous system
Brain malformation, developmental delay
Face
Cleft lip and palate
Cardiovascular system
Congenital heart malformation
Respiratory system
Pulmonary hypoplasia
Urogenital system
Renal and genital malformations
Skeletal system
Short stature, spina bifida, sacral hypoplasia
Chromosomes
Trisomy 13, trisomy 15
Peters-Plus syndrome is a specific syndrome characterized by Peters anomaly accompanied by limb shortening (brachydactyly), short stature, cleft lip and palate, and intellectual disability, and is caused by biallelic mutations in the B3GALTL (B3GLCT) gene1).
QWhat symptoms should be noticed in infants with Peters anomaly?
A
The most typical finding is a white opacity in the central cornea present from birth. Additionally, if photophobia, persistent tearing, or blepharospasm are observed, it may indicate elevated intraocular pressure, and prompt consultation with a pediatric ophthalmologist is necessary.
The fundamental etiology of Peters anomaly is an abnormality in the migration and differentiation of neural crest cells during embryonic development.
Around the 5th week of gestation, the lens vesicle separates from the surface ectoderm. Around the 6th to 7th week, neural crest cells invade the space, forming the corneal endothelium and stroma, separating the lens. Depending on the timing and extent of abnormalities in this process, anterior segment dysgenesis such as Peters anomaly, Axenfeld-Rieger anomaly, and posterior embryotoxon can occur.
Neural crest cells migrate in three waves 1).
First wave: Forms the corneal endothelium. Peters anomaly is considered an abnormality of this first wave.
Second wave: Forms the keratocytes of the corneal stroma.
Third wave: Forms the angle, ciliary body, and iris stroma.
The molecular diagnostic rate in large registries is reported to be 56.5% for glaucoma associated with anterior segment dysgenesis overall 4). The most frequent gene mutations were FOXC1 (20.3%), PITX2 (17.4%), and PAX6 (10.1%) 4).
PAX6 and FOXC1 are involved in neural crest cell migration. PITX3 and FOXE3 are important for lens vesicle formation, and mutations in these genes have been associated with a severe type (type 3) involving corneal-lenticular adhesion 1).
Sporadic cases are the majority: Most cases are sporadic without a family history. Penetrance and expressivity vary by gene, and even within the same family, clinical features can vary greatly among individuals.
Consanguineous marriage: Reported cases of autosomal recessive inheritance are found in consanguineous marriages 1). This includes recessive inheritance patterns due to biallelic mutations in CYP1B1 or FOXE3.
Drug exposure: There are reports that oral isotretinoin during the first trimester of pregnancy caused anterior segment abnormalities similar to Peters anomaly1). Prenatal exposure to teratogenic substances should be noted as a risk factor for anterior segment dysgenesis.
Chromosomal abnormalities: Abnormalities of chromosomes 4, 11, 13, and 20 have been reported in association with Peters anomaly1). Trisomy 13 and trisomy 15 may also be complicated by Peters anomaly.
The diagnosis of Peters anomaly is based on the following triad:
Central corneal opacity
Corresponding defect of Descemet’s membrane and corneal endothelium
Iridocorneal adhesions (type 2 or higher)
According to the diagnostic criteria of the guidelines, congenital ocular malformation must be present from birth and meet the diagnostic criteria for childhood glaucoma (usually with ocular enlargement) 3).
Perkins applanation tonometer: Portable but often difficult to measure due to body movement.
Tono-pen® / iCare: Can be measured even in young children or eyes with corneal deformation, and is convenient.
Measurement under sedation: Performed under sedation in neonates and infants. 15 mmHg is used as the upper limit of normal.
Congenital corneal opacity is frequently associated with angle developmental abnormalities, and intraocular pressure measurement is essential from the first visit.
Based on UBM findings, a classification has been proposed: type I (corneal DM/endothelial defect only: good PKP prognosis), type II (+ iridocorneal adhesion: variable PKP prognosis), and type III (+ corneal-lenticular adhesion: poor PKP prognosis) 1).
From around 5–6 years of age, anterior segment OCT (optical coherence tomography) can non-invasively observe corneal thickness, corneal shape, anterior chamber, angle, and iris. It has been reported that it can be used even in newborns 1). Intraoperative OCT has been reported to change the surgical plan in 21% of pediatric corneal transplant cases 1).
When severe corneal opacity prevents observation of the posterior pole, it is used for posterior segment evaluation as a screening for retinal detachment and posterior pole abnormalities 1).
Differentiation from Axenfeld-Rieger syndrome or congenital aniridia is often difficult. History of trauma can be distinguished by interview, and metabolic diseases (e.g., mucopolysaccharidosis, cystinosis) should be referred to pediatrics for definitive diagnosis. Genetic testing is particularly useful for differentiating atypical cases and is recommended to accurately classify overlapping phenotypes of anterior segment dysgenesis4).
QWhat tests are used for Peters anomaly?
A
UBM (ultrasound biomicroscopy) is an essential examination that allows detailed evaluation of anterior segment structures when conventional observation is difficult due to corneal opacity. Anterior segment OCT noninvasively assesses corneal thickness and angle, and iCare can easily measure intraocular pressure even in infants. In cases of severe opacity, ultrasound B-scan is also needed to evaluate the posterior segment.
Management of glaucoma associated with Peters anomaly consists of two main pillars: control of intraocular pressure (IOP) and management of corneal opacity.
Surgery is the first-line treatment 3). This is based on the empirical fact that the cause is developmental abnormality of the angle, which can be surgically addressed, and that in infants, drug therapy is difficult to implement and its efficacy is hard to confirm 3).
In Peters anomaly, good postoperative IOP control is achieved in only about one-third of surgical cases 5). Because of corneal abnormalities, achieving useful vision is often difficult 3).
Angle Surgery
Trabeculotomy: The principle of initial surgery. It has the advantage of being feasible even when corneal transparency is poor 3).
360° trabeculotomy: Full-circumference incision using a suture or microcatheter is increasingly being attempted 3).
Goniotomy: Indicated for eyes with clear cornea. An incision of 90–120° can be made in one session. In Peters anomaly, it is often difficult due to corneal opacity 3).
Trabeculectomy: Indicated when angle surgery is ineffective. The sclera in children is thin, making scleral flap creation difficult 3). Even with antimetabolites, bleb formation may be difficult. One-year success rate 50–87% 3).
Tube shunt surgery: Considered when filtration surgery also fails. In a pediatric GDD meta-analysis (1,221 eyes), success rates were 87% at 12 months, 77% at 24 months, and 37% at 120 months 6).
In a meta-analysis of Ahmed/Baerveldt GDD for pediatric glaucoma (32 studies, 1,221 eyes), mean preoperative IOP was 31.8±3.4 mmHg, decreasing to 16.5 mmHg (95% CI: 15.5–17.6) at 12 months and 17.6 mmHg (95% CI: 16.4–18.7) at 24 months. Complications included shallow anterior chamber (13.6%), hypotony (11.7%), and serous choroidal detachment (8.3%) 6).
Drug therapy is used as an adjunct during the perioperative period or after surgical treatment 3).
Beta-blockers (timolol, carteolol, etc.): Start with low concentrations.
Carbonic anhydrase inhibitors (dorzolamide 1%, brinzolamide 1%): Can be used in combination with beta-blockers.
Prostanoid FP receptor agonists (latanoprost, travoprost, etc.): Effects in children are weaker than in adults 3).
Sympathetic alpha-2 receptor agonists (brimonidine): Contraindicated in children under 2 years due to neuropsychiatric symptoms (apnea, bradycardia, hypotension, muscle hypotonia, central nervous system depression) 3).
In infants, the dose of eye drops relative to body weight and body surface area is relatively high. Use the lowest possible concentration and be vigilant for systemic side effects 3).
Observation: If intraocular pressure is normal, corneal opacity often gradually resolves spontaneously. In a study of 4 eyes, opacity regressed with observation alone 1). Generally, a policy of monitoring while prioritizing intraocular pressure control is recommended; active corneal surgery should be avoided unless the opacity is severe enough to cause amblyopia.
Penetrating keratoplasty (PKP): Definitive treatment for severe corneal opacity requiring visual improvement, but prognosis is poor in children. Reported clear graft survival rates vary widely from 39% to 90% 2). Few cases achieve visual acuity of 20/100 or better 7). Rejection is frequent in children, almost inevitable under 5-6 years. Steroid-induced glaucoma is also a significant concern. Management algorithms based on the extent, depth, and presence of lens adhesion have been proposed 11).
Optical iridectomy: Performed as an alternative to corneal transplantation to secure a visual axis through clear cornea remaining around central corneal opacity. Reported effective in mild to moderate cases of type 1 1).
SEPA (selective endothelial removal): A minimally invasive procedure for type 1 with preserved peripheral healthy endothelium, removing abnormal central endothelium to promote corneal clearing via endothelial cell migration from the periphery. In a study of 34 eyes, partial to complete clearing of the central visual axis was reported in 85% 10).
Hard contact lenses: Attempted to correct irregular astigmatism after reduction of corneal opacity.
If corneal opacity occurs in infancy, even if mild, it can lead to amblyopia. Observe until around age 3 when visual acuity can be measured, and if amblyopia is suspected, perform occlusion of the healthy eye. Prescribe glasses or hard contact lenses as needed. Strabismus is found in 72% of cases, with esotropia (54%) being the most common 1).
QWhat is the success rate of glaucoma surgery for Peters anomaly?
A
Even with treatment according to PCG, good postoperative intraocular pressure is achieved in only about one-third of surgical cases 5). A meta-analysis of tube shunt surgery (GDD) shows a 12-month success rate of 87%, but it drops to 37% at 120 months 6). Multiple surgeries are often required, and long-term intraocular pressure management is essential.
In normal anterior segment development, neural crest cells migrate in three waves to form each structure 1).
First wave (6-7 weeks gestation): Neural crest cells migrate between the lens and surface ectoderm to form the corneal endothelium. Peters anomaly is associated with abnormalities at this stage.
Second wave: Cells migrate between the corneal epithelium and endothelium to form keratocytes of the corneal stroma.
Third wave: Cells migrate to the angle between the endothelium and the anterior rim of the optic cup to form the ciliary body and iris stroma.
Defective formation of the corneal endothelium leads to absence of Descemet’s membrane and corneal endothelium, resulting in corneal opacity. If separation of the lens vesicle is incomplete, the lens adheres to the posterior cornea, resulting in type 3. Depending on the timing and extent of neural crest cell invasion impairment, anterior segment dysgenesis such as Peters anomaly, Axenfeld-Rieger anomaly, and posterior embryotoxon occur as a continuous spectrum 9).
Glaucoma associated with Peters anomaly is thought to be mainly due to aqueous humor outflow obstruction caused by high insertion of the iris root in the angle.
Histologically, the trabecular meshwork shows a thick compact tissue beneath Schlemm’s canal (composed of trabecular cells with short cell processes, collagen and elastin-like fibers, and basement membrane-like amorphous material), and the normal lamellar structure is lost. This immaturity of the trabecular meshwork increases resistance to aqueous outflow, leading to elevated intraocular pressure.
If onset occurs before age 3-4, it presents as an early-onset type (buphthalmos) with enlargement of corneal diameter. Since the sclera in infants is more flexible than in adults, elevated intraocular pressure tends to manifest as physical expansion of the eyeball, and increases in corneal diameter and axial length are often the only signs of high intraocular pressure. Gonioscopy reveals poor formation of the angle recess, inability to visualize the ciliary body band, or extreme narrowing, which are indicators of angle dysgenesis.
Factors that determine the prognosis of glaucoma associated with Peters anomaly include the degree of angle underdevelopment and the extent of damage to the angle structures due to excessive expansion of the anterior segment 3). These two factors are risk factors for failure; the more severe the iris adhesion, the more advanced the physical obstruction of the aqueous outflow pathway, making glaucoma control difficult.
The following histological features have been reported in the cornea of Peters anomaly1)8).
Descemet membrane and corneal endothelium: Absent or thinned in the opaque area. Completely absent at the site of iris adhesion.
Posterior corneal stroma: Disorganized lamellar structure and edematous changes.
Bowman layer: May be replaced by pannus (fibrovascular tissue).
Peripheral cornea: Normal structure preserved throughout the full thickness.
Self-repair of endothelial cells: It has been suggested that endothelial cells from the healthy peripheral area may migrate to the central area, leading to partial repair over time 1).
This migration and repair mechanism from the peripheral endothelium provides the theoretical basis for SEPA (selective endothelial removal) 10).
7. Latest Research and Future Perspectives (Investigational Reports)
First reported in 2012, SEPA is attracting attention as a minimally invasive treatment for type I Peters anomaly10). It selectively removes abnormal endothelium, allowing healthy peripheral endothelium to migrate to the central area, promoting corneal clarity. In a study of 34 eyes of 28 patients, partial to complete clarity of the central visual axis was achieved in 85% of eyes 10). A major advantage is the avoidance of corneal transplantation, but the indication is limited to mild to moderate cases with an opacity diameter of less than 7 mm 1).
With the widespread use of next-generation sequencing (NGS) and whole-genome sequencing (WGS), the molecular diagnostic rate for anterior segment dysgenesis including Peters anomaly has improved. A large registry reported a diagnostic rate of 56.5% 4), and the correlation between genotype and clinical phenotype is being elucidated. Previously unknown related genes such as CPAMD8 and TMEM98 are also being identified 4).
Genetic testing contributes to definitive diagnosis, genetic counseling, and prognosis prediction. Molecular diagnosis is clinically important especially in atypical cases or those difficult to differentiate from Axenfeld-Rieger syndrome.
Application of keratoprosthesis has been reported in cases of severe bilateral Peters anomaly with multiple corneal graft failures 2). Long-term outcomes of the Boston type keratoprosthesis in children are still limited, but its role as a final vision restoration option in severe cases with no other alternatives is being explored 2).
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