Peters anomaly and Peters Plus syndrome (PPS): for professionals

• Overview
• Clinical phenotype
• Genetics
• Key investigations
• Diagnosis
• Management
• Current research
• Further information and support
• References

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Overview

Prevalence	Peters anomaly: 1:24,000-70,000[1,2] Peters Plus Syndrome (PPS): unknown
Inheritance	Peters anomaly: De novo sporadic Autosomal dominant Autosomal recessive PPS: Autosomal recessive
Genes involved (OMIM No.)	Multiple genes have been implicated for Peters anomaly including: PAX6 (#607108) PITX2 (#601542) PITX3 (#602669) CYP1B1 (#601771) FOXC1 (#601090) FOXE3 (#601094) COL4A1 (#120130) Peters Plus Syndrome (PPS) B3GLCT (#610308)
Symptoms	Visual impairment of variable severity Visual field loss due to glaucoma (50% risk)
Ocular features	Unilateral or bilateral: Type I – central corneal opacity with iridocorneal adhesions Type II – central corneal opacity with cataracts and/or karatolenticular adhesions Peters anomaly most common ocular feature in PPS but other ASD features may be present instead
Systemic features	Peters anomaly Neurological anomalies Cardiovascular anomalies Respiratory anomalies Gastrointestinal anomalies Genitourinary anomalies Facial and airway anomalies Developmental and mental delay PPS Cleft lip (45%) Cleft palate (33%) Developmental delay (80%) Short limbs with broad distal extremities
Key investigations	Ultrasound biomicroscopy/AS-OCT to help identify anterior segment features in the presence of corneal opacity B-scan ultrasound to measure axial length and exclude microphthalmia Glaucoma assessment and monitoring with tonometry, gonioscopy and perimetry Assessment with a paediatrician to screen for any associated extraocular features
Molecular diagnosis	Next generation sequencing Targeted gene panels (ASD) Whole genome sequencing
Management	Ocular Dependent on severity and availability at treatment centres (Pharmacological dilation of the pupil, surgical optical iridectomy, corneal transplant, keratoprosthesis) Correct refractive errors Monitor for amblyopia and treat if detected Glaucoma monitoring and treatment Systemic Symptomatic management of the various systemic manifestations in a multidisciplinary setting Early referral to practitioners familiar with developmental surveillance and intervention in young children with visual impairment to optimise development
Therapies under research	None at present

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Clinical phenotype

Presenting features

Peters anomaly is typified by congenital central corneal opacity with surrounding clear cornea, iridocorneal and/or keratolenticular adhesions. It is important to note that there are several other conditions which can present with congenital corneal opacity, and these must be considered on the list of differentials (i.e. congenital glaucoma, corneal dystrophies, corneal ulcers, sclerocornea, and metabolic disorders such as mucopolysaccharidoses/mucolipidoses and limbal dermoid).^[3]

Clinically, Peters anomaly can be divided into: 

• Type I–Central corneal opacity with iridocorneal adhesions
• Type II–Central cornea opacity with cataracts and/or corneolenticular adhesions (a more severe phenotype)

Although Peters anomaly refers to an ocular sign, it can however be associated with extraocular features, or feature as part of a syndrome such as Peters Plus syndrome (PPS). PPS is characterised by^[4-7] :

• Anterior segment dysgenesis (ASD) —most commonly Peters anomaly (85%); Other ASD features such as Axenfeld-Reiger anomaly, posterior embryotoxon, sclerocornea, mild mesenchymal dysgenesis and iris coloboma may be observed instead of Peters anomaly^[5,6]
• Cleft lip (45%)
• Cleft palate (33%)
• Developmental delay (80%)
• Short limbs with broad distal extremities

Peters anomaly may present unilaterally or bilaterally, however bilateral ocular involvement (71.8%) are more likely to be associated with extraocular manifestations compared to unilateral involvement (36.8%).^[4,8]

Ocular features

1) Corneal opacity

Corneal opacity is observed from birth in Peters anomaly and is the primary cause for reduced visual acuity (VA). The corneal opacity may obstruct the central visual axis, causing sensory deprivation amblyopia. The size and density of the corneal opacity is considered the most important factor contributable to final visual outcome. If less than half of the cornea is affected, it is considered mild while a severe case has more than 50% involvement.^[9] Spontaneous improvement may occasionally occur in mild cases.

The opacification is mainly due to corneal oedema as a result of localised loss of endothelial pump function in the presence of anomalous endothelial and Descemet membrane cell loss.^[10]

2) Other associated features

Apart from corneal opacity, some patients may have additional ocular features as well, which include:  

• Glaucoma –High risk of development (50-70%) due to abnormal trabecular meshwork anatomy^[1,11]
• Microphthalmia
• Persistent hyperplastic primary vitreous (PHPV)
• Aniridia

Associated extraocular features

Extraocular features have been reported more often in bilateral (71.8%) compared to unilateral Peters anomaly (36.8%).^[4,8] These include^[12-14] :

• Central nervous system anomalies (microcephaly, hydrocephalus, cerebral atrophy, and seizures)
• Cardiovascular anomalies (Ventricular and/or atrial septal defect, patent ductus arteriosus, pulmonary stenosis, tetralogy of Fallot, and dextrocardia)
• Facial and airway anomalies (Cleft lip/palate, macroglossia, laryngomalacia, anterior larynx, depressed nasal bridge, low set ears, obstructive sleep apnoea)
• Pulmonary anomalies (Pulmonary hypoplasia, pectus excavatum, kyphoscoliosis)
• Gastrointestinal anomalies (Intestinal volvulus, gastroesophageal reflux disease, jaundice)
• Genitourinary anomalies (micropenis, pyelonephritis, hydronephrosis, double ureters)
• Developmental delays in various aspects (learning difficulties, motor delay, growth retardation)
• Endocrinal anomalies (pituitary dysfunction)

Peters Plus Syndrome describes a specific disorder with characteristic presentation of ASD (most commonly Peter’s anomaly), cleft lip, cleft palate, developmental delay and short limbs with broad distal extremities. In addition, other systemic features associated with Peters anomaly may be present as well, along with higher rates of miscarriage and still births (37%), and utero non-viability.^[5]

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Genetics

Ocular development is a complex process comprised of a sequence of specific events that are tightly regulated by multiple interacting genes, namely FOXC1, PITX2, and PAX6. Consequently, mutations in these genes may result in Peters anomaly as well as other ASD conditions.

The majority of patients with Peters anomaly lack a genetic diagnosis, although mutations in CYP1B1 is believed to be responsible for up to 20% of cases.^[4]  Comparatively, autosomal recessive mutations in B3GLCT is causative for PPS and has been identified in all cases.^[7]

Phenotype	Gene
Peters anomaly	PAX6, PITX2, PITX3, CYP1B1, FOXC1, FOXE3, COL4A1, TFAP2A, FLNA, HCCS, NDP, SLC4A11
Peters Plus Syndrome	B3GLCT (formerly B3GALTL)

Further information about each gene can be found on OMIM and Medline Plus.

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Key investigations

Ocular

1) Orthoptic assessment and refraction

To assess current level of vision and determine if amblyopia therapy and/or refractive correction are required to optimise vision.

2) Intraocular pressure (IOP) and gonioscopy

IOP should be assessed regularly and lifelong, as patients with Peters anomaly are at increased risk of developing glaucoma. Gonioscopy should be performed if tolerated to assess for any angle abnormalities.

3) Ultrasound biomicroscopy and B-scan ultrasound

In the presence of dense corneal opacification, it may be difficult to examine the anterior and posterior chambers of the eye. Ultrasonography can be utilised to look for the presence of cataracts, iridocorneal and/or keratolenticular adhesions, and vitreous abnormalities. Axial length measurements should be undertaken to exclude microphthalmia.

4) Anterior segment optical coherence tomography (AS-OCT)

AS-OCT can be used to document and visualise anterior segment structures and help with characterisation of Peters anomaly. Corneal thickness measurement can also be achieved with AS-OCT.

5) Electrophysiology

Visual evoked potentials, full-field and pattern electroretinogram (ERG) should be done to assess the child’s level of vision, and to assess visual function in non-verbal patients or those experiencing developmental delays. It can help predict potential for visual improvement if surgical management of the cornea is being considered.

Systemic

Where Peters anomaly is diagnosed, it is important to consider if there is any extraocular involvement including PPS, especially in bilateral cases. Patients should be referred to a paediatrician for an assessment which may include:

• General physical examination including assessment of height, weight (BMI), head circumference and plotting of growth chart
• MRI brain imaging  
• Echocardiogram
• Ultrasound abdomen and renal
• Thyroid function test
• Growth hormone stimulation test

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Diagnosis

Peters anomaly or PPS can be diagnosed clinically. Genetic testing should be undertaken to obtain a molecular diagnosis which can help in directing further clinical management, facilitating genetic counselling and providing accurate advice on prognosis and future family planning.

This can be achieved through a variety of next generation sequencing (NGS) methods:

• Targeted gene panels (ASD)
• Whole genome sequencing

It is important to be aware that a causative gene may not be found despite testing with NGS techniques.

Related links

• Genomics England PanelApp for corneal abnormalities
• Genomics England PanelApp for glaucoma
• Clinical genetic testing: for doctors

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Management

Ocular

1) Conservative management

• Mild corneal opacity (<50%) can be observed as it may spontaneously improve without surgical intervention
• Pharmacological pupil dilation to increase incoming light through clear cornea (non-surgical option/adjunct whilst awaiting surgery)
• Medically lowering IOP may improve corneal clarity even when there is no glaucoma

2) Surgery

Special considerations may need to be taken prior to surgery, particularly if the patient has any associated systemic anomalies or a difficult airway.^[12]

(a) Surgical iridectomy

This can be utilised in milder cases, and where advance corneal surgery may not be a suitable option or available. The iridectomy should be ideally situated where the cornea is clearest and not obstructed by the lid.

(b) Corneal grafts and Boston keratoprosthesis

Penetrating keratoplasty (PK) is an option in more severe cases of Peters anomaly, where it is the most common indication for full-thickness grafts in infants.^[9] It is important to explain the long-term implications which include:

• Frequent follow-ups
• Long-term drop use (particularly steroids and its potential side effects)
• Potential surgical complications
• Risks of graft infection, rejection, and failure
• Post-surgery visual rehabilitation (regular monitoring of visual function and amblyopia treatment)

The survival rate of PK grafts in Peters anomaly is generally worse compared to other indications due to multiple factors such as early age of surgery, greater inflammatory responses, poor co-operation with post-operative care and the presence of other ocular anomalies.^[1,15] Peters anomaly type I tends to have a better success rate (87.5%) and 10-year survival rate (54%) compared to type II, which represents a more severe form (14.2% and 0% respectively).^[4,10]

An autorotational graft may be suitable in cases with a small focal corneal opacity that can be surgically rotated away from the central visual axis. This procedure has less risk of rejection but still carries other risks and considerations associated with PK. Lensectomy can be performed together with the corneal graft if the lens is attached to the cornea.

Boston keratoprosthesis may be considered in children with multiple failed PKs. However, it is not often recommended in children due to poor visual outcomes and complications such as endophthalmitis, retinal detachment, glaucoma and retroprosthetic membranes.^[16]

(c) Other procedures

Cataracts and glaucoma may arise secondary to surgical intervention or secondary to ASD itself. Precautions need to be taken when operating on patients with Peters anomaly, as corneal opacity makes it harder to visualise ocular structures, and surgery may be more complex in the presence of abnormal anatomy. IOP management in Peters anomaly is also difficult to achieve and may require multiple surgical interventions to achieve control.^[1,5] Glaucoma can be treated medically initially but glaucoma drainage devices are usually the surgery of choice to control IOP (53% success at 10 years), or alternatively trabeculectomy with anti-scarring agents (25% success at 10 years). Cyclodiode laser is a useful procedure to consider for refractory cases with limited visual potential (80% success at 10 years).^[17]

3) Supportive management

• Correcting any refractive errors
• Monitor and treat amblyopia treatment if present
• Referral to low vision services
• Directing patients and families to supporting organisations  
• Monitoring for associated complications such as glaucoma and cataracts
• Encourage the use of assistive technology that may improve quality of life

Systemic

A multidisciplinary approach is usually required due to the various systemic manifestations associated with Peters anomaly and Peters Plus Syndrome. New patients should be under joint care with a paediatrician to screen for any systemic associations and managing them symptomatically.

In addition, early-onset visual impairment can have a negative impact on a child’s early general development. Therefore, timely referral to practitioners familiar with developmental surveillance and intervention for children with visual impairment (VI), such as developmental paediatricians as well as a Qualified Teacher of children and young people with Visual Impairment (QTVI) is crucial to optimise their developmental potential.

The Developmental Journal for babies and young children with visual impairment (DJVI) is a structured early intervention programme designed to track developmental and vision progress from birth to three years of age. It is mainly used by qualified healthcare professionals working in services providing support to babies and young children with VI in conjunction with the child’s parents. Children with VI may be referred to specialist services such as the developmental vision clinic in the Great Ormond Street Hospital for Children or other specialist developmental services for further management.

Family management and counselling

Majority of patients with Peters anomaly lack a genetic diagnosis. However, the following inheritance patterns have been reported for the identified mutations in the literature:

• De novo sporadic (50-70%)
• Autosomal dominant
• Autosomal recessive

PPS is inherited in an autosomal recessive manner where pathogenic mutations in the B3GLCT gene is causative in all reported cases.^[7]

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Due to the extensive range of disease-causing genes, variable expressivity, large number of de novo variants and mosaicism associated with Peters Anomaly, counselling might be challenging but it should not be an obstacle to support families in making informed medical and personal decisions.

Emotional and social support

Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

• Coping with sight loss
• Education and learning
• Family support service

Referral to a specialist centre

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.

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Current research in Peters anomaly

Much of the current research is mainly focused on understanding the causes and disease mechanisms of ASD. As ocular development involves such a complex interplay between a multitude of genes, the primary goal now is to identify the full repertoire of genes involved in this process. With increasing availability of genetic testing, it is hoped that more novel genes can be identified through its implementation in routine ophthalmological management.^[18] A rare disease patient registry (NCT 01793168) is also available for patients to enrol and researchers to access.

Although PK remains an important treatment modality for Peters anomaly, a recent technique has been described in a case report where endothelial cells were selectively removed without corneal transplant in a patient with Type 1 Peters anomaly.^[10]

Related links

• Research Opportunities at Moorfields Eye Hospital UK
• Searching for current clinical research or trials

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Further information and support

• Glaucoma UK
• Glaucoma Research Foundation
• Royal National Institute of Blind People (RNIB)
• Guide Dogs for the Blind Association
• Look UK
• Scottish Sensory Centre 

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References

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