WAGR syndrome is a disorder that affects many body systems and is named for its main features: Wilms tumor, aniridia, genitourinary anomalies, and a range of developmental delays.

People with WAGR syndrome have a 45 to 60 percent chance of developing Wilms tumor, a rare form of kidney cancer. This type of cancer is most often diagnosed in children but is sometimes seen in adults. Some people with WAGR syndrome develop nephrogenic rests, which are abnormal clumps of cells in the kidneys. These can lead to Wilms tumor, but some people with nephrogenic rests never develop Wilms tumor.

Most people with WAGR syndrome have aniridia, an absence of the colored part of the eye (the iris). This can reduce the sharpness of a person's vision (visual acuity) and increase sensitivity to light (photophobia). Aniridia is typically the first noticeable sign of WAGR syndrome. Other eye problems may also develop, such as clouding of the lens of the eyes (cataracts), increased pressure in the eyes (glaucoma), and involuntary eye movements (nystagmus).

Abnormalities of the genitalia and urinary tract (genitourinary anomalies) are seen more frequently in males with WAGR syndrome than in affected females. The most common genitourinary abnormality in affected males is undescended testes (cryptorchidism). Affected females may not have functional ovaries and may instead have undeveloped clumps of tissue called streak gonads. Females with WAGR syndrome may also have a heart-shaped (bicornate) uterus, which makes it difficult to carry a pregnancy to term.

Intellectual disability and other developmental delays are also common in people with WAGR syndrome. Affected individuals often have difficulty processing, learning, and properly responding to information. Many affected individuals have difficulty speaking or understanding language. Some individuals with WAGR syndrome also have psychiatric or behavioral problems such as depression, anxiety, attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), or a developmental disorder called autism spectrum disorder that affects communication and social interaction.

Other signs and symptoms of WAGR syndrome can include ongoing constipation, inflammation of the pancreas (pancreatitis), kidney failure, breathing problems, and allergies. Some affected children have obesity. When WAGR syndrome includes childhood-onset obesity, it is often referred to as WAGRO syndrome.

WAGR syndrome is a rare genetic condition that can affect both boys and girls. Babies born with WAGR syndrome often have eye problems, and are at high risk for developing certain types of cancer, and mental disability. The term "WAGR" stands for the first letters of the physical and mental problems associated with the condition:

• (W)ilms' Tumor, the most common form of kidney cancer in children.

• (A)niridia, some or complete absence of the colored part of the eye, called the iris (singular), or irises/irides (plural).

• (G)enitourinary problems, such as testicles that are not descended or hypospadias (abnormal location of the opening for urination) in boys, or genital or urinary problems inside the body in girls.

• Mental (R)etardation.

Most people who have WAGR syndrome have two or more of these conditions. Also, people can have WAGR syndrome, but not have all of the above conditions.

Other names for WAGR syndrome that are used are:

• WAGR Complex

• Wilms' Tumor-Aniridia-Genitourinary Anomalies-Mental Disability Syndrome

• Wilms' Tumor-Aniridia-Gonadoblastoma-Mental Disability Syndrome

• Chromosome 11p deletion syndrome

• 11p deletion syndrome

The cause of WAGR syndrome is deletion of a group of genes located on chromosome number 11 (11p13 - the "p13" refers to the specific place on chromosome 11 that is affected). Chromosomes are packages of genetic characteristics. There are 22 pairs of chromosomes that are the same in males and females. The 23rd pair determines a person's sex with males having an X and Y chromosome and females having two X chromosomes.

The prevalence of WAGR syndrome ranges from 1 in 500,000 to 1 million individuals. It is estimated that one-third of people with aniridia actually have WAGR syndrome. Approximately 7 in 1,000 cases of Wilms tumor can be attributed to WAGR syndrome.

WAGR syndrome is caused by a deletion of genetic material on the short (p) arm of chromosome 11. The size of the deletion varies among affected individuals.

The signs and symptoms of WAGR syndrome are related to the loss of multiple genes on the short arm of chromosome 11. WAGR syndrome is often described as a contiguous gene deletion syndrome because it is caused by the loss of several neighboring genes.

The PAX6 and WT1 genes are always deleted in people with the typical signs and symptoms of this disorder. Because changes in the PAX6 gene can affect eye development, researchers think that the loss of the PAX6 gene causes the characteristic eye features of WAGR syndrome. The PAX6 gene may also affect brain development.

Variants (also called mutations) in the WT1 gene can cause Wilms tumor and genitourinary abnormalities, so deletion of the WT1 gene is very likely the cause of these features in people with WAGR syndrome.

In people with WAGRO syndrome, an additional gene is deleted from chromosome 11. The BDNF gene is active (expressed) in the brain and plays a role in the survival of nerve cells (neurons). The protein produced from the BDNF gene is thought to be involved in the management of eating, drinking, and body weight. Loss of the BDNF gene is likely the cause of childhood-onset obesity in people with WAGRO syndrome.

People with WAGRO syndrome may be at greater risk of neurological problems such as intellectual disability and autism than those with WAGR syndrome. It is unclear whether this increased risk is due to the loss of the BDNF gene or other nearby genes.

Researchers are still studying the genes that are deleted in people with WAGR syndrome and determining how the loss of these genes causes features of the disorder.

Normal Function

The BDNF gene provides instructions for making a protein found in the brain and spinal cord called brain-derived neurotrophic factor. This protein promotes the survival of nerve cells (neurons) by playing a role in the growth, maturation (differentiation), and maintenance of these cells. In the brain, the BDNF protein is active at the connections between nerve cells (synapses), where cell-to-cell communication occurs. The synapses can change and adapt over time in response to experience, a characteristic called synaptic plasticity. The BDNF protein helps regulate synaptic plasticity, which is important for learning and memory.

The BDNF protein is found in regions of the brain that control eating, drinking, and body weight; the protein likely contributes to the management of these functions.

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WAGR syndrome

The BDNF gene is located in a region of chromosome 11 that is often deleted in a condition known as WAGRO syndrome. This condition is a variant of WAGR syndrome, which is a disorder that affects many body systems and is named for its main features: a childhood kidney cancer known as Wilms tumor, an eye problem called anirida, genitourinary anomalies, and intellectual disability (formerly referred to as mental retardation). WAGRO syndrome also includes obesity. The deletions that cause WAGRO syndrome remove many genes from one copy of chromosome 11, including part or all of the BDNF gene. The loss of this gene is responsible for weight gain that begins in childhood in people with WAGRO syndrome.

People with WAGRO syndrome may be at greater risk of neurological problems such as intellectual disability and a developmental disorder called autism spectrum disorder that affects communication and social interaction than those with WAGR syndrome. It is unclear whether this increased risk is due to the loss of the BDNF gene or other nearby genes.

Other disorders

Certain common genetic variations (polymorphisms) in the BDNF gene have been associated with an increased risk of developing psychiatric disorders such as bipolar disorder, anxiety, and eating disorders.

Most studies have focused on the effects of a particular polymorphism in the BDNF gene. This variation alters a single protein building block (amino acid) in the protein, replacing the amino acid valine with the amino acid methionine at position 66 (written at Val66Met or V66M). This change impairs the protein's ability to function. Many studies report an association between the Val66Met polymorphism and psychiatric disorders; however, some studies have not supported these findings. It is unclear how changes in the BDNF gene are related to these disorders. A large number of genetic and environmental factors, most of which remain unknown, likely determine the risk of developing these complex conditions.

Other Names for This Gene

• abrineurin
• ANON2
• BDNF_HUMAN
• brain-derived neurotrophic factor
• BULN2
• neurotrophin

Genomic Location

Normal Function

The PAX6 gene belongs to a family of genes that play a critical role in the formation of tissues and organs during embryonic development. The members of the PAX gene family are also important for maintaining the normal function of certain cells after birth. To carry out these roles, the PAX genes provide instructions for making proteins that attach to specific areas of DNA and help control the activity (expression) of particular genes. On the basis of this action, PAX proteins are called transcription factors.

During embryonic development, the PAX6 protein is thought to turn on (activate) genes involved in the formation of the eyes, the brain and spinal cord (central nervous system), and the pancreas. Within the brain, the PAX6 protein is involved in the development of a specialized group of brain cells that process smell (the olfactory bulb). Additionally, researchers believe that the PAX6 protein controls many aspects of eye development before birth. After birth, the PAX6 protein likely regulates the expression of various genes in many structures of the eyes.

Health Conditions Related to Genetic Changes

Aniridia

More than 280 mutations in the PAX6 gene have been found to cause aniridia, which is an absence of the colored part of the eye (the iris). Most of these mutations create a premature stop signal in the instructions for making the PAX6 protein and lead to the production of an abnormally short, nonfunctional protein. As a result, there is less PAX6 protein to regulate the activity of other genes.

The majority of mutations that cause aniridia occur within the PAX6 gene; however, some disease-causing mutations occur in neighboring regions of DNA that normally regulate the expression of the PAX6 gene, known as regulatory regions. Mutations in PAX6 gene regulatory regions reduce the expression of the PAX6 gene. These mutations lead to a shortage of functional PAX6 protein, which disrupts the formation of the eyes during development.

Peters anomaly

At least two mutations in the PAX6 gene have been found to cause Peters anomaly. This condition is characterized by the abnormal development of certain structures at the front of the eye and clouding of the clear front surface of the eye (cornea). The mutations that cause Peters anomaly change single protein building blocks (amino acids) in the PAX6 protein. These mutations reduce but do not eliminate the protein's function and are less severe than mutations that cause aniridia (described above). The mutations that cause Peters anomaly reduce the PAX6 protein's ability to bind to DNA, disrupting its role as a transcription factor. As a result, normal development of the eye is impaired, leading to the features of Peters anomaly. The PAX6 gene mutations that cause Peters anomaly can cause other related eye disorders in members of the same family.

Coloboma

Mutations in the PAX6 gene can cause an eye problem called coloboma, in which there is a gap or split in one of the structures that make up the eye. The mutations that cause this abnormality occur in one copy of the PAX6 gene in each cell. Most of these mutations change single amino acids in the PAX6 protein. These mutations reduce but do not eliminate the protein's normal function, impairing its role as a transcription factor.

Microphthalmia

Mutations in one copy of the PAX6 gene can cause microphthalmia, which describes eyes that are smaller than usual. These genetic changes reduce but do not eliminate PAX6 protein function. As a result, the PAX6 protein is less able to control the activity of certain genes involved in eye development.

WAGR syndrome

The PAX6 gene is located in a region of chromosome 11 that is deleted in people with WAGR syndrome, which is a disorder that affects many body systems and is named for its main features: a childhood kidney cancer known as Wilms tumor, an eye problem called anirida, genitourinary anomalies, and intellectual disability (formerly referred to as mental retardation). As a result of this deletion, affected individuals are missing one copy of the PAX6 gene in each cell. A loss of the PAX6 gene is associated with the characteristic eye features of WAGR syndrome, including aniridia, and may affect brain development.

Other disorders

Mutations in the PAX6 gene can cause a variety of eye problems. Most of these mutations change single amino acids in the PAX6 protein. These mutations reduce but do not eliminate the protein's normal function, impairing its role as a transcription factor.

In addition to microphthalmia or coloboma (described above), individuals with these relatively mild PAX6 gene mutations may be born with pupils that are not centrally positioned in the eye (ectopia papillae) or underdeveloped optic nerves, which are the structures that carry information from the eyes to the brain. Mild PAX6 mutations can also result in underdevelopment of the region at the back of the eye responsible for sharp central vision (the fovea). Additional conditions caused by these PAX6 gene mutations may be present at birth or develop later. These conditions may include a clouding of the lens of the eye (cataracts), involuntary eye movements (nystagmus), and inflammation of the front surface of the eye called the cornea (keratitis).

It is unclear why the effects of some mutations in the PAX6 gene are limited to the eye, while other mutations affect the development of many parts of the body.

Other Names for This Gene

• AN
• AN2
• D11S812E
• MGC17209
• MGDA
• paired box gene 6
• paired box gene 6 isoform a
• paired box gene 6 isoform b
• PAX6_HUMAN

Genomic Location

Normal Function

The WT1 gene provides instructions for making a protein that is necessary for the development of the kidneys and gonads (ovaries in females and testes in males) before birth. After birth, WT1 protein activity is limited to a structure known as the glomerulus, which filters blood through the kidneys. The WT1 protein plays a role in cell growth, the process by which cells mature to perform specific functions (differentiation), and the self-destruction of cells (apoptosis). To carry out these functions, the WT1 protein regulates the activity of other genes by attaching (binding) to specific regions of DNA. On the basis of this action, the WT1 protein is called a transcription factor.

Health Conditions Related to Genetic Changes

Denys-Drash syndrome

Many variants (also known as mutations) in the WT1 gene have been found to cause Denys-Drash syndrome, a condition that affects development of the kidneys and genitalia and most often affects males. These variants are germline, which means they are present in cells throughout the body. The variants that cause Denys-Drash syndrome almost always occur in areas of the gene known as exon 8 and exon 9. Most of these variants result in changes in single protein building blocks (amino acids) in the WT1 protein. The most common variant that causes Denys-Drash syndrome (found in about 40 percent of cases) replaces the amino acid arginine with the amino acid tryptophan at protein position 394 (written Arg394Trp or R394W).

The variants that cause Denys-Drash syndrome lead to the production of an abnormal WT1 protein that cannot bind to DNA. As a result, the activity of certain genes is unregulated, which impairs development of the kidneys and genitalia. Abnormal development of these organs leads to the signs and symptoms of Denys-Drash syndrome.

Rarely, a variant in exon 8 or exon 9 of the WT1 gene causes a related condition called Frasier syndrome (described below). Because these two conditions share a genetic cause and have overlapping features, some researchers have suggested that they are part of a spectrum and not two distinct conditions.

Frasier syndrome

Variants in the WT1 gene have been found to cause Frasier syndrome, a condition that affects development of the kidneys and genitalia and most often affects males. The variants that cause Frasier syndrome are germline and almost always occur in an area of the gene known as intron 9. The most common variant that causes Frasier syndrome (found in over half of affected individuals) changes a single DNA building block (nucleotide) in this area of the gene, written as IVS+4C>T. This variant and others that cause Frasier syndrome alter the way the gene's instructions are pieced together to produce the WT1 protein.

The WT1 gene variants that cause Frasier syndrome lead to the production of a protein with an impaired ability to control gene activity and regulate the development of the kidneys and reproductive organs, resulting in the signs and symptoms of Frasier syndrome.

Rarely, a variant in intron 9 of the WT1 gene causes a related condition called Denys-Drash syndrome (described above). Because these two conditions share a genetic cause and have overlapping features, some researchers have suggested that they are part of a spectrum and not two distinct conditions.

Wilms tumor

Variants in the WT1 gene can cause Wilms tumor, a rare form of kidney cancer that occurs almost exclusively in children. Most of these variants are somatic, which means they are acquired during a person's lifetime and present only in the tumor cells. Other WT1 gene variants are germline.

WT1 gene variants that cause Wilms tumor lead to a WT1 protein with a decreased ability to bind to DNA. As a result, the protein cannot regulate gene activity, leading to uncontrolled growth and division of cells in the kidney and allowing tumor development.

Many conditions caused by germline variants in the WT1 gene, including WAGR syndrome, Denys-Drash syndrome, and Frasier syndrome (described above), are associated with an increased risk of developing Wilms tumor.

WAGR syndrome

The WT1 gene is located in a region of chromosome 11 that is often missing (deleted) in people with WAGR syndrome, which is a disorder that affects many body systems and is named for its main features: a childhood kidney cancer known as Wilms tumor (described below), an eye problem called anirida, genitourinary anomalies, and intellectual disability. This deletion affects one copy of the WT1 gene in each cell. The loss of this gene is responsible for the genitourinary abnormalities and the increased risk of Wilms tumor in affected individuals.

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Other disorders

Germline variants in the WT1 gene have been found to cause Meacham syndrome. This condition is characterized by abnormalities in the development of the male genitalia, heart, and diaphragm. Individuals with this condition have a typical male chromosome pattern (46,XY) but have external genitalia that do not look clearly male or clearly female or have genitalia that appear female-typical. Additionally, the internal reproductive organs are female, but they do not develop normally.

Individuals with Meacham syndrome typically have heart defects of varying severity that are present from birth. They also have a hole in the muscle that separates the abdomen from the chest cavity (the diaphragm), which is called a congenital diaphragmatic hernia. Meacham syndrome is typically fatal in infancy. Approximately a dozen individuals have been diagnosed with Meacham syndrome.

Variants in the WT1 gene can also cause a condition called isolated nephrotic syndrome. This condition is characterized by an inability of the kidneys to filter waste products from the blood, which leads to protein in the urine, swelling (edema) of the abdomen, and ultimately, kidney failure. Isolated nephrotic syndrome includes diffuse glomerulosclerosis, in which scar tissue forms throughout the clusters of tiny blood vessels (glomeruli) in the kidneys, and focal segmental glomerulosclerosis, in which glomeruli in only certain areas of the kidneys experience scarring. Variants in the WT1 gene most often cause diffuse glomerulosclerosis.

Other Names for This Gene

• WIT-2
• WT1_HUMAN
• WT33

Genomic Location

Most cases of WAGR syndrome are not inherited. They are caused by a chromosomal deletion that occurs randomly during the formation of reproductive cells (eggs or sperm) or in early fetal development. Affected people typically have no history of the disorder in their family.

In rare cases, WAGR syndrome is inherited. In these cases, a parent who does not have the signs and symptoms of the condition has a chromosomal rearrangement called a balanced translocation. In this rearrangement, a piece of chromosome 11 is relocated to another chromosome, but no genetic material is gained or lost.

However, the translocation can become unbalanced when genetic material is passed to the next generation. A child may inherit a copy of chromosome 11 this is missing a piece of the short arm, which causes WAGR syndrome.

WAGR is called a genetic syndrome. The symptoms of WAGR syndrome are usually seen after the baby is born. The mother's pregnancy and the baby's birth history are not unusual. Enlargement of the baby's kidneys may be seen on a prenatal ultrasound. The eye problems (aniridia) are usually noticed in the newborn period, and for infant boys, the problems with the genitals and urinary systems are also usually obvious in the newborn period.

Individuals born with WAGR syndrome are at higher risk for developing other problems during infancy, childhood, and adulthood. These problems can affect the kidneys, eyes, testes or ovaries. The specific symptoms that happen in a person who has WAGR syndrome depend on the combination of disorders that are present.

Wilms' tumor: About one half of individuals who have WAGR syndrome develop a type of kidney cancer called Wilms' tumor. In the early stages of Wilms' tumor there are usually no symptoms. The first signs of this cancer may be blood in the urine, a low-grade fever, loss of appetite, weight loss, lack of energy or swelling of the abdomen.

Aniridia: In infants who are born with aniridia that is associated with WAGR syndrome, the irises of the eyes fail to develop normally before birth. This causes partial or complete absence of the round colored part of the eye (iris). Aniridia is almost always present in babies born with WAGR syndrome. Other eye problems are often present or can develop as the child grows older. These include: clouding of the lens of the eye (cataract); rapid, involuntary movements of the eye (nystagmus); and all or partial loss of vision due to high pressure of the fluid in the eye (glaucoma).

Genital and urinary (GU) problems: A range of GU problems may be present in a baby born with WAGR syndrome. For boys, these may involve the urinary tract opening somewhere along the shaft of the penis rather than at the tip (hypospadias) or undescended testes (cryptorchidism). In girls, these problems may include underdeveloped (streak) ovaries, and malformations of the uterus, fallopian tubes or vagina. In some people with WAGR syndrome, problems with the development of the genitals may make their sexual assignment at birth (male or female) uncertain. Individuals with WAGR syndrome may have a higher risk for a type of cancer called gonadoblastoma, a cancer of the cells that form the testes in males and the ovaries in females.

Mental disability: Mental disability and developmental delay are common in children with WAGR syndrome. The severity of mental disability varies from person to person, ranging from severe to mild mental disability. Some children who have WAGR syndrome may have normal intelligence.

Other symptoms of WAGR syndrome may also include:

• Developmental, behavioral, and/or psychiatric disorders including autism, attention deficit disorder, obsessive compulsive disorder, anxiety disorders, and depression.

• Early-onset overweight (obesity) and high blood cholesterol levels.

• Excessive food intake (polyphagia/hyperphagia).

• Chronic kidney failure, most often after age 12 years.

• Breathing problems, asthma and pneumonia and breathing problems during sleep (sleep apnea).

• Frequent infections of the ears, nose, and throat, especially during infancy and early childhood.

• Teeth problems - crowded or uneven teeth.

• Problems with muscle tone and strength, especially during infancy and childhood.

• Seizure disorder (epilepsy).

• Inflammation of the pancreas (pancreatitis).

Symptoms that suggest WAGR syndrome, like aniridia, are usually noted shortly after birth, and genetic testing for the 11p13 deletion is done. A genetic test called a chromosome analysis or karyotype is done to look for the deleted area (11p13) on chromosome number 11. A more specific genetic test called FISH (fluorescent in situ hybridization) is sometimes done to look for the deletion of specific genes on chromosome number 11.

Treatment of WAGR syndrome is aimed at the specific symptoms present in the individual. Monitoring to look for problems is also important to catch problems early so that treatment can be given as soon as possible.

Wilms' tumor: Wilms' tumor happens in about half of children with WAGR syndrome. The tumor usually develops between the ages of 1 and 3 years. Most cases of Wilms' tumor have been detected by age 8 years, but in rare cases may occur later. Babies who are suspected to have WAGR syndrome should have ultrasounds of their abdomen at birth. They then need to have abdominal ultrasounds every 3 months until they reach age 8 years. Feeling the abdomen for signs of swelling and masses can be done by both the baby's doctor and the parents, when they are taught how to do this. After age 8 years, watching for signs of Wilms tumor may be done by ultrasound and/or by watching for symptoms such as a low-grade fever, loss of appetite, weight loss, lack of energy or swelling of the abdomen.

Wilms' tumor can often be treated successfully. The overall survival rate of patients with Wilms tumor is excellent and is related to the features of the tumor, and the stage of the disease. Treatment may include surgery to remove the kidney, radiation therapy and chemotherapy.

Aniridia: The treatment of aniridia is aimed at keeping the person's vision. Drugs or surgery may help when there is glaucoma or cataracts. Contact lenses can harm the cornea and should be avoided.

Genital and urinary problems: Children with WAGR syndrome should have regular evaluations to detect abnormal development of their ovaries or testes. Surgery may be needed to remove abnormal gonads or to prevent cancer of the gonads (gonadoblastoma). When both gonads are removed, the individual is given hormone replacement treatment. Surgery may also be done when a boy with WAGR syndrome has undescended testes. When girls with WAGR syndrome have abnormal ovaries, they have routine pelvic ultrasounds or MRI's (magnetic resonance imaging) to watch for the development of gonadoblastoma.

Mental Disability/developmental delays: Individuals with WAGR syndrome may have mental disability ranging from severe to mild. Some individuals with WAGR syndrome have normal intelligence.

Children with WAGR syndrome should be referred for Early Intervention Services soon after they are born, or when the diagnosis is made. Treatments include: vision therapy, physical, occupational and speech therapies. Special Education services are also used to help children with WAGR syndrome develop to their fullest ability.

Kidney (renal) failure: The renal failure that can happen in WAGR syndrome often causes the person to have high blood pressure, high cholesterol, and leakage of protein from the blood into the urine (called proteinuria). All individuals with WAGR syndrome should be routinely screened for high blood pressure and urinary protein. These problems are treated with medications called "ACE inhibitors" or "ARBs." Some people with WAGR syndrome and renal failure are treated with dialysis or kidney transplant.