Axenfeld-Rieger syndrome is primarily an eye disorder, although it can also affect other parts of the body. This condition is characterized by abnormalities of the front part of the eye, an area known as the anterior segment. For example, the colored part of the eye (the iris), may be thin or poorly developed. The iris normally has a single central hole, called the pupil, through which light enters the eye. People with Axenfeld-Rieger syndrome often have a pupil that is off-center (corectopia) or extra holes in the iris that can look like multiple pupils (polycoria). This condition can also cause abnormalities of the cornea, which is the clear front covering of the eye.

About half of affected individuals develop glaucoma, a serious condition that increases pressure inside the eye. When glaucoma occurs with Axenfeld-Rieger syndrome, it most often develops in late childhood or adolescence, although it can occur as early as infancy. Glaucoma can cause vision loss or blindness.

The signs and symptoms of Axenfeld-Rieger syndrome can also affect other parts of the body. Many affected individuals have distinctive facial features such as widely spaced eyes (hypertelorism); a flattened mid-face with a broad, flat nasal bridge; and a prominent forehead. The condition is also associated with dental abnormalities including unusually small teeth (microdontia) or fewer than normal teeth (oligodontia). Some people with Axenfeld-Rieger syndrome have extra folds of skin around their belly button (redundant periumbilical skin). Other, less common features can include heart defects, the opening of the urethra on the underside of the penis (hypospadias), narrowing of the anus (anal stenosis), and abnormalities of the pituitary gland that can result in slow growth.

Researchers have described at least three types of Axenfeld-Rieger syndrome. The types, which are numbered 1 through 3, are distinguished by their genetic cause.

Axenfeld-Rieger syndrome results from mutations in at least two known genes, PITX2 and FOXC1. PITX2 gene mutations cause type 1, and FOXC1 gene mutations cause type 3. The gene associated with type 2 is likely located on chromosome 13, but it has not been identified. The proteins produced from the PITX2 and FOXC1 genes are transcription factors, which means they attach (bind) to DNA and help control the activity of other genes. These transcription factors are active before birth in the developing eye and in other parts of the body. They appear to play important roles in embryonic development, particularly in the formation of structures in the anterior segment of the eye.

Mutations in either the PITX2 or FOXC1 gene disrupt the activity of other genes that are needed for normal development. Impaired regulation of these genes leads to problems in the formation of the anterior segment of the eye and other parts of the body. These developmental abnormalities underlie the characteristic features of Axenfeld-Rieger syndrome. Affected individuals with PITX2 gene mutations are more likely than those with FOXC1 gene mutations to have abnormalities affecting parts of the body other than the eye.

Some people with Axenfeld-Rieger syndrome do not have identified mutations in the PITX2 or FOXC1 genes. In these individuals, the cause of the condition is unknown. Other as-yet-unidentified genes may also cause Axenfeld-Rieger syndrome.

Normal Function

The FOXC1 gene provides instructions for making a protein that attaches (binds) to specific regions of DNA and regulates the activity of other genes. On the basis of this action, the FOXC1 protein is called a transcription factor.

The FOXC1 protein plays a critical role in early development, particularly in the formation of structures in the front part of the eye (the anterior segment). These structures include the colored part of the eye (the iris), the lens of the eye, and the clear front covering of the eye (the cornea). Studies suggest that the FOXC1 protein may also have functions in the adult eye, such as helping cells respond to oxidative stress. Oxidative stress occurs when unstable molecules called free radicals accumulate to levels that can damage or kill cells.

The FOXC1 protein is also involved in the normal development of other parts of the body, including the heart, kidneys, and brain.

Health Conditions Related to Genetic Changes

Axenfeld-Rieger syndrome

More than 50 mutations in the FOXC1 gene have been found to cause Axenfeld-Rieger syndrome type 3, a condition that primarily affects the development of the anterior segment of the eye but can also affect other parts of the body. Many FOXC1 gene mutations reduce the amount of functional FOXC1 protein that is produced or result in a defective protein that cannot regulate the activity of other genes. Other genetic changes (such as a duplication of the FOXC1 gene) likely increase the amount or function of the FOXC1 protein. Having either too little or too much activity of this protein disrupts the regulation of other genes needed for normal development.

Changes in the amount or function of the FOXC1 protein impairs the development of the anterior segment of the eye, leading to the eye abnormalities characteristic of Axenfeld-Rieger syndrome. In some cases, changes involving the FOXC1 protein also cause problems with development of other parts of the body.

Peters anomaly

At least two mutations in the FOXC1 gene have been found to cause Peters anomaly. This condition is characterized by abnormal development of the anterior segment and clouding of the cornea. The mutations that cause Peters anomaly likely disrupt the protein's ability to regulate the expression of developmental genes, especially affecting the eye. Abnormal formation of the iris, cornea, and other structures of the anterior segment leads to the features of Peters anomaly. The FOXC1 gene mutations that cause Peters anomaly can cause other related eye disorders, such as Axenfeld-Rieger syndrome (described above), in members of the same family.

Dandy-Walker malformation

MedlinePlus Genetics provides information about Dandy-Walker malformation

Other disorders

Mutations in the FOXC1 gene have also been identified in another eye disorder called iridogoniodysgenesis type 1. Like Axenfeld-Rieger syndrome and Peters anomaly, this condition primarily involves the anterior segment of the eye. Iridogoniodysgenesis type 1 is associated with underdevelopment of the iris and an elevated risk of increased pressure in the eye (glaucoma).

FOXC1 gene mutations have been reported in a few people with abnormalities of brain development. Mutations that change single protein building blocks (amino acids) in the FOXC1 protein have been associated with defects of the cerebellum, which is the part of the brain that is involved in coordinating movement. Additionally, deletions of genetic material from a region of chromosome 6 that includes the FOXC1 gene and several neighboring genes have been associated with a structural abnormality of the cerebellum known as Dandy-Walker malformation.

Other Names for This Gene

• FKHL7
• forkhead box protein C1
• forkhead, drosophila, homolog-like 7
• forkhead-related activator 3
• forkhead-related protein FKHL7
• forkhead-related transcription factor 3
• forkhead/winged helix-like transcription factor 7
• FOXC1_HUMAN
• FREAC-3
• FREAC3
• myeloid factor-delta

Genomic Location

Normal Function

The PITX2 gene provides instructions for making a protein that attaches (binds) to specific regions of DNA and regulates the activity of other genes. On the basis of this action, the PITX2 protein is called a transcription factor. The PITX2 gene is part of a family of homeobox genes, which act during early embryonic development to control the formation of many parts of the body.

The PITX2 protein plays a critical role in early development, particularly in the formation of structures in the front part of the eye (the anterior segment). These structures include the colored part of the eye (the iris), the lens of the eye, and the clear front covering of the eye (the cornea). Studies suggest that the PITX2 protein also has functions in the adult eye, such as helping cells respond to oxidative stress. Oxidative stress occurs when unstable molecules called free radicals accumulate to levels that can damage or kill cells.

The PITX2 protein is also involved in the normal development of other parts of the body, including the teeth, heart, and abdominal organs.

Health Conditions Related to Genetic Changes

Axenfeld-Rieger syndrome

More than 45 mutations in the PITX2 gene have been found to cause Axenfeld-Rieger syndrome type 1, a condition that affects the development of the anterior segment of the eye and other parts of the body. Most PITX2 gene mutations reduce the amount of functional PITX2 protein that is produced in cells. However, some genetic changes (such as a duplication of the PITX2 gene) increase the amount or function of the PITX2 protein. Having either too little or too much of this protein disrupts the regulation of other genes needed for normal development.

Eye development appears to be the most sensitive to changes in PITX2 protein activity, and abnormalities of the anterior segment of the eye are the predominant features of Axenfeld-Rieger syndrome. However, changes in the amount of PITX2 protein can also lead to distinctive facial features, tooth abnormalities, and problems with development of other parts of the body in people with this condition.

Peters anomaly

At least one mutation in the PITX2 gene has been found to cause Peters anomaly. This condition is characterized by abnormal development of the anterior segment of the eye and clouding of the cornea. This mutation (written IVS3AS,A>T,-2) alters the way the PITX2 protein is pieced together. It is thought that this altered protein disrupts the regulation of movement of cells to their proper location in the developing anterior segment, leading to abnormal formation of the structures in this area of the eye and other features of Peters anomaly.

Other disorders

Mutations in the PITX2 gene have also been identified in other eye disorders. Like Axenfeld-Rieger syndrome and Peters anomaly (described above), these conditions primarily involve the anterior segment of the eye. Mutations in the PITX2 gene can cause ring dermoid of the cornea, a condition associated with tumor-like growths on the cornea. Additionally, conditions that cause underdevelopment of the iris can occur, including iris hypoplasia or iridogoniodysgenesis type 2. Iridogoniodysgenesis type 2 is also associated with an elevated risk of increased pressure in the eye (glaucoma).

Other Names for This Gene

• all1-responsive gene 1
• ARP1
• Brx1
• IDG2
• IGDS
• IGDS2
• IHG2
• IRID2
• Otlx2
• paired-like homeodomain 2
• paired-like homeodomain transcription factor 2
• pituitary homeobox 2
• PITX2_HUMAN
• PTX2
• RGS
• RIEG
• rieg bicoid-related homeobox transcription factor 1
• RIEG1
• RS
• solurshin

Genomic Location

Axenfeld-Rieger syndrome has an estimated prevalence of 1 in 200,000 people.