Congenital cataract: for professionals

• Overview
• Clinical phenotype
• Genetics
• Key investigations
• Diagnosis
• Management
• Current research
• Further information and support
• References
• Congenital cataract: for patients

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Overview

Incidence	2.5-3.5 per 10,000[1]
Inheritance	Autosomal dominant for most causative genes Autosomal recessive X-linked recessive X-linked dominant
Genes involved (OMIM No.)	115 genes identified to date with the most common being: CRYAA (#123580) CRYGD (#123690) GJA3 (#121015) GJA8 (#600897) MIP (#154050) NHS (#300457) PITX3 (#602669) HSF4 (#602438)
Symptoms	Visual impairment in the first year of life (if visually significant cataract) or a more gradually progressive disease course
Signs	Nystagmus Impaired red reflex Leukocoria Other associated ocular abnormalities may be present
Systemic features	Congenital cataract can be associated with various recognized syndromes, examples include: Lowe syndrome (OCRL-1) Intellectual disability Proximal tubular dysfunction (Fanconi syndrome) Glaucoma Pathological fractures Cutaneous cysts Cryptorchidism Patau syndrome (Trisomy 13) Microphthalmia, anophthalmia, coloboma (MAC) spectrum Cleft lip/palate Hypertelorism Microcephaly Lifespan of a few days to weeks
Key investigations	B-scan USS to detect microphthalmia and any posterior segment abnormalities Electrophysiology TORCH screen Systemic assessment with a pediatrician and other relevant specialists if suspicious of extraocular involvement or directed by molecular diagnosis
Molecular diagnosis	Next generation sequencing Targeted gene panels (cataract) Whole exome sequencing Whole genome sequencing
Management	Ocular Cataract removal +/- implantation of intraocular lens if causing deprivation amblyopia Regular monitoring of vision with supportive management Correction of residual refractive errors Amblyopia treatment Low vision aids Systemic Multidisciplinary approach Monitor global development to identify any coexisting features that may suggest syndromic cataract Early involvement of practitioners familiar with developmental surveillance and intervention for children with visual impairment (VI) is crucial to optimise development
Therapies under research	Current research focuses on establishing genotype-phenotype relationships and integrating genetic testing to the clinical management of congenital cataract

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Clinical phenotype

Congenital cataract is a highly heterogenous disease with a broad aetiology. In bilateral cataract, a genetic cause can be identified in up to 90% of the cases.^[2,3] Other important causes include:

• TORCH infections (Toxoplasma, Syphilis, Varicella Zoster, Parvovirus B19, Coxsackievirus, Rubella, Cytomegalovirus, Herpes simplex virus I and II); rubella is the most common infective cause worldwide^[4]
• Anterior uveitis secondary to juvenile idiopathic arthritis (JIA)
• Physical trauma
• Iatrogenic (e.g. steroids or radiation therapy) are important considerations but are relatively rare in this age group unless there is prolonged steroid use in atopy/JIA management^[5,6]

Presenting features

Congenital cataract is defined as cataract present at birth or which occurs during the first year of life. It is also possible for children to develop cataract during childhood which has been classified in various ways (e.g. developmental, infantile or juvenile).  However, such classification can be challenging as babies are usually asymptomatic at birth which may cause a delay in presentation. In the UK, cataracts are normally detected during newborn screening. The following features may be identified:

• Nystagmus
• Leukocoria (“white reflex”)
• Reduced or absent red reflex

Related links

• Different types of congenital cataracts

Other associated ocular features

Majority of patients present with isolated cataract. However, it can be associated with other ocular abnormalities (complex ocular cataract).^[7] This is because environmental influences, or genes involved in the development or maintenance of the lens are also involved in other parts of the eye. At least 20 genes are associated with complex ocular cataract.^[3] The associated features include:

• Anterior segment dysgenesis (ASD)
• Corneal abnormalities (dystrophy or opacity)
• Iris hypoplasia
• Microphthalmia, anophthalmia, coloboma (MAC) spectrum
• Strabismus
• Glaucoma
• Vitreoretinal dysplasia

Associated extraocular features

Various types of genetic mutations such as chromosomal abnormalities, loss-of-heterozygosity (loss of one of the two alleles in a loci/multiple locus), mitochondrial disorders and triplet repeats (a mutation with increasing number of trinucleotide repeats making the affected DNA segment unstable) can cause syndromic cataract.^[3]

The presence of cataract can be variable in syndromic cases. In some, it may not always be present or is only a part of a complex disease with multiple ocular and systemic pathologies such as Downs Syndrome (Trisomy 21).

In other diseases, it may be an initial or central feature such as:

• Lowe syndrome (OCRL-1) (cataract, intellectual disability and proximal tubular dysfunction)
• Zellweger spectrum disorder (a form of metabolic disorder caused by pathogenic mutations in 14 genes encoding proteins crucial to the formation and normal functioning of peroxisomes)
• Galactokinase disorder (GALK1)  
• Cerebrotendinous Xanthomatosis (CYP27A1) 

The identification of cataract is crucial in galactokinase disorder and cerebrotendinous xanthomatosis as disease halting/altering interventions are available.^[8,9]

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Genetics

Pathogenic mutations in 115 genes have been identified so far causing congenital cataracts. All the identified causative genes encode proteins that play an important role in the development, structure or function of the lens. The main groups include crystallins, connexins, cytoskeletal structural proteins and transcription factors. ^[10] About 50% of non-syndromic cataracts are due to variants in genes encoding crystallin proteins. ^[11]

Lens proteins/role	Genes/Locus
Crystallins	CRYAA, CRYAB, CRYBA1, CRYBA2, CRYBA4, CRYBB1, CRYBB2, CRYBB3, CRYGB, CRYGC, CRYGD, CRYGS
Connexins/proteins involved at the membrane	AQP0, CHMP4B, DNMBP, EPHA2, GJA3, GJA8, JAM3, LEMD2, LIM2, MIP, NF2, SLC2A1, SLC33A1, WFS1
Cytoskeletal structural proteins	BFSP1, BFSP2, NHS, VIM
Transcription factors	ERCC2, ERCC3, ERCC6, ERCC8, HMX1, HSF4, GTF2H5, MAF, FOXE3, PITX3, PAX6, FYCO1, TDRD7, VSX2, BCOR, NDP
Intracellular enzymes and associated proteins	AGK, CYP27A1, CYP51A1, LSS, PXDN, ADAMTS10, AGPS, ALDH18A1, B3GLCT, DCR, DHCR7, DMPK, EED, GALK1, GALT, GCNT2, HTRA2, INPP5K, LONP1, MAN2B1, MSMO1, OCRL, POMT1, RAB18, RAB3GAP1, RAB3GAP2, RECQL4, SC5D, SEC23A, SIL1, SRD5A3, TFAP2A, WRN, XYLT2
Protein synthesis	EIF2B2, FBN1, GEMIN4, MYH9, P3H2, COL2A1, COL4A1, COL4A5, COL11A1, COL8A1
Lipid (myelin)/phospholipid synthesis	FAM126A, GNPAT
Peroxisomal biogenesis	PEX1, PEX2, PEX3, PEX5, PEX6, PEX7, PEX10, PEX11B, PEX12, PEX13, PEX14, PEX16, PEX19, PEX26
Myosin specific chaperone	UNC45B
Genetic locus	DCR
Unknown protein/ role	OPA3

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

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Key investigations

Ocular

1) Examination of other family members

Performing dilated fundal examination in parents and sibling(s) may reveal mild cataracts (in autosomal dominant cases with reduced penetrance) or X-linked female carrier phenotypes which can direct further clinical and genetic investigations. For example, female carriers of Nance Horan syndrome usually display characteristic posterior Y-suture-centred lens opacities and variable degree of facial dysmorphism similar to affected males.^[12]

2) Ultrasound B-scan

To measure axial length, document microphthalmia and detect any posterior segment abnormalities. 

3) Electrophysiology

Visual evoked potentials and full-field and pattern electroretinograms (ERG) can be considered to establish level of vision and exclude any retinal or optic disc dysfunction. Dense bilateral cataracts may make this examination challenging.

Systemic

Due to the high likelihood of a genetic aetiology, children with bilateral congenital cataracts (or those with dysmorphic features and/or extraocular symptoms) should be referred to a paediatrician for a general assessment to exclude metabolic disorders, congenital infections, syndromic features or other potentially life-threatening causes. Some patients with no overt systemic features may require paediatric screening later on if a gene known to be associated with syndromic cataract is identified through genetic testing.

The assessment usually includes but not limited to:

• General physical examination including assessment of weight, height/length, head circumference and plotting of growth chart
• TORCH screen may be more appropriate in places where the prevalence of congenital infection is high*
• Blood tests to exclude metabolic disorders
• MRI brain and orbit imaging  
• Echocardiogram/ electrocardiogram
• Renal ultrasound

*Note: The prevalence of congenital infections in the UK is low. Bilateral cataracts in a child born in the UK are more likely to have a genetic aetiology than an infectious one.^[13,14] A targeted testing of components of the TORCH screen may be more appropriate after careful evaluation of the maternal antenatal history, the child’s co-morbidities and vaccination status. 

Related links

• Review of how to use the neonatal TORCH screen

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Diagnosis

Genetic testing is key so that a molecular diagnosis can be obtained to direct future management. This can be achieved through a variety of next generation sequencing (NGS) methods:

• Targeted gene panels (cataracts)
• Whole exome sequencing
• Whole genome sequencing

The diagnostic rate for bilateral cataracts using targeted gene panels have a diagnostic rate between 50-90%.^[2,15] However, diagnostic rates can increase by a further 40% with whole genome sequencing.^[16]

Related links

• Genomics England PanelApp for cataracts
• Clinical genetic testing: for professionals

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Management

Ocular

1) Paediatric cataract surgery

The management of congenital cataract varies significantly from adult cataracts as many factors need to be taken into consideration, which include:

• Age of the child
• Unilateral/bilateral involvement
• Level of vision
• Timing of surgery
• Associated ocular abnormalities
• Adherence to the visual rehabilitation process (contact lens/glasses wear, amblyopia therapy, regular follow-ups)
• General health of the child

If the cataract is compromising visual development/visually significant, then removal of the opacified lens should be performed as soon as possible to avoid the risk of deprivation amblyopia. Surgery is usually delayed till after 6 weeks corrected age (even if the cataract is detected from birth) due to the higher risk of complications if operated earlier.^[17,18] For children whom surgery may not be indicated (i.e. non-visually significant cataract), they should be closely monitored for the development of deprivation amblyopia.

Surgery usually involves lensectomy with/without anterior capsulotomy, posterior capsulotomy and anterior vitrectomy.^[19] Primary intraocular lens (IOL) implantation may be considered, or children may be left aphakic and the residual refractive error corrected with contact lenses/glasses. The main complications of surgery include:

• Visual axis opacification due to re-proliferation of lens material, pupillary membranes and/or visually significant corectopia requiring further surgery
• Development of secondary glaucoma
• Strabismus
• Loss of accommodation
• Retinal detachment
• Inflammation
• Infection

Comparison of visual outcome and associated complications between primary IOL implantation and conventional treatment (aphakic correction with contact lenses/glasses) for both unilateral and bilateral cataracts have been studied in three large studies:

• Infant Aphakia Treatment Study (IATS) — A multicentre randomised clinical trial involving infants aged less than 7 months old with a unilateral congenital cataract
• IOLunder2 study — A multicentre prospective observational cohort study in children aged 2 years or younger with unilateral/bilateral congenital cataract
• The Toddler Aphakia and Pseudophakia study (TAPS) — A retrospective review of children aged 2 years or younger with unilateral/bilateral congenital cataract operated by IATS surgeons during the IATS enrolment period

The main findings of the studies were:

• Children under 2 years of age with bilateral cataracts that were operated on tend to have better visual outcome than those with treated unilateral cataract (5-year follow-up)^[17,20]
• Medium (5 year) and long-term (10 year) visual outcomes were similar between both treatment options for unilateral (data up to 10 years) and bilateral cases (data up to 5 years) in children under 2 years of age (only up to a quarter of children achieved BCVA 6/12 or better in the IATS study)^[17,20-22]
• Cataract removal (with/without primary IOL implantation) in children aged 1-6 months at time of surgery was associated with a higher risk of developing secondary glaucoma and visual axis opacification^[17,22-24]
• Visual axis opacification was the most common adverse event associated with primary IOL implantation in children under 2 years of age with unilateral/bilateral cataracts (majority required additional surgery within the first year)^[17,23]
• The TAPS study however suggested that primary IOL implantation in infants aged 7-24 months with unilateral cataract was safe with lower rates of complications and re-operations compared to the IATS study
• Primary IOL implantation did not protect against development of secondary glaucoma for unilateral (<7 months old) or bilateral (<2 years old) cases^[17,20,24]

2) Post-operative visual rehabilitation/supportive management

• Regular monitoring of visual function
• Commencement of amblyopia treatment
• Correction of residual refractive errors
• Ensuring adherence to contact lens/glasses wear and amblyopia treatment
• Some may require referral to low vision services for extra support
• Monitoring for associated complications such as glaucoma and visual axis opacification which may require urgent intervention

Systemic

Multidisciplinary management is required for children with systemic involvement and/or those who need extra support due to visual impairment. Paediatricians can help co-ordinate the various specialities involved and establish appropriate care pathways including support in the community.

Visual impairment at a young age can also 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

Congenital cataract can be inherited via all Mendelian traits:

• Autosomal dominant (44% of families)^[2]
• Autosomal recessive
• X-linked recessive
• X-linked dominant

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

Emotional and social support

Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients in clinic. They provide emotional and practical support to help patients deal with their 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 congenital cataract

Current research is mainly focused on strengthening the genotype-phenotype correlations to help better understand the disease and related conditions. Other research aims to demonstrate the clinical utility of genetic testing in congenital cataract by facilitating the integration of genomic medicine into clinical practice and expanding testing services in the UK.^[25] This will invariably aid in the identification of novel genes and further contribute to genotype-phenotype studies.

Related links

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

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Further information and support

• NHS
• Royal National Institute of Blind People (RNIB)
• Guide Dogs for the Blind Association
• Look UK

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References

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