On this page
Coloboma (PAX2-associated)
This condition occurs when the eye does not fully close during early development, resulting in a gap or 'coloboma'. It is caused by changes in the PAX2 gene and typically presents with vision problems, sometimes alongside kidney abnormalities.
Overview
Coloboma (PAX2-associated) is a rare genetic disorder characterised by the incomplete closure of structures within the eye during foetal development [PMID:11590487]. This results in a gap or 'coloboma' in one or more parts of the eye, such as the iris (the coloured part), retina (the light-sensitive tissue), choroid (blood vessel layer), or optic nerve. This can affect one eye (unilateral) or both eyes (bilateral) and can vary in severity between individuals.
The condition is caused by specific alterations in the PAX2 gene. While primarily known for its eye manifestations, PAX2-associated coloboma can sometimes be associated with extracardiac clinical characteristics including kidney abnormalities. The clinical features can be wide-ranging, from mild visual difficulties to significant visual impairment, and may include kidney dysfunction in some cases [PMID:10099407].
Symptoms & clinical features
The primary symptoms of coloboma (PAX2-associated) relate to vision. Individuals may experience reduced vision, sensitivity to light (photophobia), or an abnormal eye reflex (leukocoria). The visual impact depends on the size and location of the coloboma within the eye. For example, a coloboma affecting the iris might make the pupil appear keyhole-shaped, but may have less impact on vision than one affecting the retina or optic nerve.
Beyond eye symptoms, some individuals with PAX2-associated coloboma may develop kidney problems. These can range from mild abnormalities, such as the kidney not developing to its full size (hypoplasia), to more severe issues like abnormal kidney structure (dysplasia) or even complete absence of a kidney (agenesis). In rare instances, severe kidney dysfunction may lead to chronic kidney disease [PMID:10099407]. Regular screening for kidney involvement is therefore important for individuals diagnosed with this condition.
Video: Genetics 101
Affected organs
The primary organ affected in coloboma is the eye. The condition can impact various parts of the eye, including the iris, lens, retina, choroid, and optic nerve. These structures are crucial for vision, and their incomplete formation can lead to a variety of visual impairments.
The kidneys are the other significant organs that can be affected in PAX2-associated coloboma. Kidney involvement can vary from subtle anatomical differences to significant functional impairments. Early identification of kidney issues allows for appropriate monitoring and management.
Risks & severity
The severity of coloboma (PAX2-associated) is highly variable. Some individuals may have a small coloboma with minimal impact on vision, while others might experience significant visual impairment, including blindness, particularly if the retina or optic nerve is severely affected. The degree of vision loss can also depend on whether one or both eyes are affected and the presence of other eye conditions like nystagmus (involuntary eye movements) or strabismus (misalignment of the eyes).
The risk of kidney involvement also varies. While not every individual with PAX2-associated coloboma will have kidney problems, it is a recognised association, and kidney function should be regularly assessed. In some cases, kidney problems may be present at birth, while in others, they may develop or become more noticeable later in life. There is currently no clear correlation between the severity of eye involvement and the severity of kidney involvement.
Genetic causes
Coloboma (PAX2-associated) is caused by pathogenic variants in the PAX2 gene. The PAX2 gene provides instructions for making a protein that is vital for the normal development of several organs, particularly the eyes and kidneys [PMID:11590487]. It acts as a transcription factor, meaning it helps control the activity of other genes, playing a critical role in shaping these structures during early foetal development.
Pathogenic variants in PAX2 can lead to a PAX2 protein that is either non-functional or has reduced function. This disruption interferes with the normal developmental processes, leading to the characteristic coloboma in the eye and, in some cases, abnormalities in kidney development [PMID:10099407]. It is understood that around 10-15% of individuals presenting with coloboma also have kidney abnormalities, and a significant proportion of these cases are due to PAX2 variants.
- PAX2 paired box 2
Inheritance pattern
Coloboma (PAX2-associated) is inherited in an autosomal dominant pattern. This means that only one copy of the altered PAX2 gene in each cell is sufficient to cause the condition. An affected individual has a 50% chance of passing on the altered gene to each of their children, regardless of the child's sex.
In some cases, a pathogenic variant in PAX2 can occur spontaneously in an individual with no family history of the condition. This is known as a de novo variant. If a de novo variant is identified, the risk to future children of the affected individual remains 50%, but the risk to siblings of the affected individual is generally low, though genetic counselling is recommended to discuss specific circumstances.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosing coloboma (PAX2-associated) typically begins with a thorough ophthalmological examination to identify the characteristic eye malformations. If kidney involvement is suspected or identified, further investigations such as renal ultrasounds and kidney function tests may be performed. Given the genetic nature of the condition, a definitive diagnosis relies on genetic testing.
Genetic testing for pathogenic variants in the PAX2 gene can confirm the diagnosis. This testing is usually performed on a blood sample and involves analysing the DNA sequence of the PAX2 gene. Referral for genetic testing is typically made by an ophthalmologist, nephrologist, or a clinical geneticist. In the UK, genetic testing for coloboma with kidney anomalies is available through the NHS Genomic Medicine Service, often utilising an R-code, such as R241 Coloboma +/- congenital anomalies of the kidney and urinary tract (CAKUT).
Management & lifestyle
Management for coloboma (PAX2-associated) focuses on addressing the specific symptoms and potential complications. For ocular coloboma, treatment aims to optimise vision and may involve corrective lenses, low vision aids, or strategies to manage light sensitivity like tinted glasses. Regular follow-up with an ophthalmologist is crucial to monitor vision changes and address any developing eye conditions.
For individuals with kidney involvement, management includes regular monitoring of kidney function, blood pressure control, and appropriate medical intervention for any kidney issues that arise. This will typically involve specialist paediatric or adult nephrology care. Genetic counselling is an important part of overall management, providing information about the condition, inheritance patterns, and support for families. Current NHS care pathways guide individuals towards relevant specialist teams for comprehensive, multidisciplinary care.
UK care pathway
In the UK, individuals suspected of having coloboma (PAX2-associated) are typically referred through general practitioners to specialist services. This often involves an ophthalmologist for eye assessments and potentially a nephrologist for kidney evaluation. If a genetic cause is suspected, individuals may be referred to a Clinical Genetics service. These services offer genetic counselling and access to appropriate genetic testing, such as through the NHS Genomic Medicine Service, using relevant R-codes (e.g., R241, Coloboma +/- CAKUT). Genetic counsellors play a key role in explaining the condition, inheritance patterns, and available support.
Frequently asked questions
What is the difference between coloboma and PAX2-associated coloboma?
Coloboma is a general term for a gap in the eye structure. PAX2-associated coloboma specifically refers to this eye malformation when it is caused by genetic changes in the PAX2 gene. Knowing the specific genetic cause helps to understand potential associated health issues, particularly kidney involvement.
Can coloboma (PAX2-associated) affect my child's learning?
The primary impact of coloboma (PAX2-associated) on learning typically relates to visual impairment. Depending on the severity of vision loss, children may require additional support at school, such as larger print materials or assistive technologies. The condition itself does not usually directly affect cognitive abilities.
If I have PAX2-associated coloboma, will my children definitely inherit it?
As PAX2-associated coloboma is inherited in an autosomal dominant pattern, there is a 50% chance for each child you have to inherit the altered gene. This applies to each pregnancy, regardless of the child's sex. Genetic counselling can provide more personalised information and support.
Are there any treatments to close the gap in the eye caused by a coloboma?
Currently, there is no surgical procedure that can 'close' the coloboma itself in a way that restores the missing eye tissue. Management focuses on optimising existing vision, which may include corrective lenses, low vision aids, or specialised therapies to help with visual function. Surgical interventions may be considered for associated conditions, such as cataracts.
What kind of kidney problems might be expected with PAX2-associated coloboma?
Kidney issues can vary from mild underdevelopment (hypoplasia), abnormal structure (dysplasia), or even absence of a kidney (agenesis). In some cases, these can lead to reduced kidney function over time, potentially requiring ongoing medical management or, in rare severe cases, kidney replacement therapies. Regular monitoring by a kidney specialist is important.