What are the other Names for this Condition? (Also known as/Symptoms)

• 11p Deletion Syndrome
• WAGR Contiguous Gene Syndrome
• Wilms’ Tumor, Aniridia, Genitourinary Anomalies, and Mental Retardation Syndrome

What is WAGR Syndrome? (Definition/Background Information)

• WAGR Syndrome is a rare genetic disorder in which different conditions co-exist within a single individual. The 4 main features of this syndrome are Wilms’ tumor, Aniridia, Genitourinary abnormalities, and Retardation (or intellectual disability); hence the acronym WAGR
• The signs and symptoms of WAGR Syndrome generally involve the kidneys (Wilms’ tumor), reduction or lack of colored part of the eyes (aniridia), malformation of the urinary tract, problems with the genitalia (genitourinary abnormalities), and diminished mental acuity (intellectual disability)
• Kidney failure and conditions, such as diabetes and hyperlipidemia (in obese individuals), are complications that are commonly observed in children with WAGR Syndrome
• WAGR Syndrome is caused by genetic mutational abnormalities. Specific gene mutations have been identified. The common gene mutations include the ‘deletion of a portion of the short arm (p) of chromosome 11’. This deletion leads to the loss of specific genes called PAX6 and WT1. Both PAX6 and WT1 genes are important to the development of the eyes, brain, genitalia, kidneys, and the urinary tract
• Additionally, deletion of the BDNF gene can cause WAGRO Syndrome. The BDNF gene regulates eating, drinking, and body weight in individuals. The loss of the BDNF gene on chromosome 11 leads to obesity, the “O” in WAGRO Syndrome (in addition to other characteristic signs and symptoms of WAGR Syndrome)
• A very small proportion of those with WAGR Syndrome have a family history of the condition, which may be a risk factor for development of this disorder
• The diagnosis for WAGR Syndrome can involve a physical examination, assessment of symptoms, genetic analysis of the chromosome for large deletions, and the use of specific genetic techniques. Genetic analysis of the parents prior to pregnancy, as well as prenatal analysis of the fetus, can potentially yield important information regarding WAGR Syndrome
• Treatment options for WAGR Syndrome are dictated by the symptoms that are observed. Children affected by WAGR Syndrome may require coordinated and long-term medical care. Those with Wilms’ tumor due to WAGR Syndrome may require chemotherapy, radiotherapy, and/or surgery
• Periodic and life-long health monitoring is a requisite for those with WAGR Syndrome. Supportive care from the family is also an important aspect of managing symptoms of the disorder. Specifically, children may need special education and therapy in order to aid normal development
• Individuals with WAGR Syndrome are reported to have generally good prognosis (long-term survival), if provided with periodic health check-ups, which is followed by prompt symptomatic treatment. Likewise, the prognosis for Wilms’ tumor is also reported to be excellent with adequate treatment
• Due to the fact that WAGR Syndrome is caused by the loss of genetic material; there are currently no standard means of prevention. If a family history of the condition is known, genetic testing of the parents prior to pregnancy may help identify the specific risks. If prenatal testing reveals that the child likely has WAGR Syndrome, counselling may help the parents understand the disease better

Who gets WAGR Syndrome? (Age and Sex Distribution)

• WAGR Syndrome is a rare genetic disorder that affects one in about 500,000-1,000,000 individuals
• The syndrome is seen to affect both males and females
• Within the United States, the prevalence of WAGR Syndrome in children is 8 per million fair-skinned individuals. However, the occurrence of this condition is reported to be marginally higher in African-American children

What are the Risk Factors for WAGR Syndrome? (Predisposing Factors)

The risk factors for WAGR Syndrome include:

• A family history of WAGR Syndrome: Only a very small percentage of those affected have inherited forms of the condition
• Being of African descent may slightly increase the risk

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of WAGR Syndrome? (Etiology)

WAGR Syndrome is caused by the loss of genetic material from the short arm (p) of chromosome 11 due to a spontaneous (de-novo) deletion. The size of the deletion may vary among individuals.

• The deletion can occur either during the formation of gametes (egg and sperm) or in the early fetal developmental stages. The deletion frequently results in the loss of PAX6 and WT1 genes. The deletion of PAX6 gene is reported to affect eye and brain development. The WT1 gene deletion is believed to cause Wilms’ tumor and genitourinary abnormalities
• When obesity is observed in individuals with WAGR Syndrome, it is termed WAGRO Syndrome. In such individuals, an additional deletion of BDNF gene is reported. BDNF gene regulates eating, drinking, and body weight
• It is not clear whether the increased susceptibility to neurological and intellectual conditions observed in individuals with WAGRO Syndrome is a result of BDNF gene deletion alone, or if it is due to the additional deletion of nearby genes
• Scientific research is currently being conducted in order to better understand additional gene deletions that might contribute to WAGR and WAGRO Syndromes

The syndrome can also occur due to alteration in the structure of chromosome 11, owing to a phenomenon called “balanced translocation”. This is often the case with the inherited form of WAGR Syndrome. In the inherited form of WAGR Syndrome, there is often loss of genetic material from the short arm of chromosome 11

• A parent carries gamete cells (egg or sperm) which have a chromosomal re-arrangement. There is exchange of parts between chromosome 11 and another chromosome, as a result of which there is no net loss of genetic material
• In a balanced translocation, since there is no genetic material lost, the child does not have any signs and symptoms. However, the region of chromosome with the balanced translocation may get lost in subsequent generations, during chromosomal exchanges that occur as part of sperm and ovum formation. This loss of genetic material results in WAGR Syndrome
• Unfortunately, the unbalanced translocation in normal individuals often goes undetected, because of which, the increased risk of WAGR Syndrome in their children is unrecognized
• Hence, children inheriting unbalanced translocation may have extra or missing genetic material.

What are the Signs and Symptoms of WAGR Syndrome?

The signs and symptoms of WAGR Syndrome depend on the amount of genetic material lost from the short arm of chromosome 11. The classic signs and symptoms of WAGR Syndrome may include:

Wilms’ tumor: Cancer of the kidneys, predominantly seen in children and occurs infrequently in adults. Due to this, the following symptoms may be observed:

• Pain in abdomen
• Blood in urine
• Nausea
• Constipation
• High blood pressure

Aniridia or the absence of iris, which is the colored part of the eye, is the earliest manifested symptom of WAGR Syndrome. It may be accompanied by the following symptoms:

• A partial or complete absence of colored part of the eye, usually in both eyes
• Reduced sharpness of vision (loss of visual acuity)
• Sensitivity to light (photophobia)
• Cataracts
• Involuntary movements of the eyes (nystagmus)
• Squinting
• Pressure build-up in eyes (glaucoma)
• Growth of blood vessels on the cornea (corneal pannus)
• Underdeveloped optic nerve leading to optic nerve hypoplasia

Genitourinary abnormalities: These are defects observed in the genitals and urinary tract. It is more common in males than females.

• In males, the following symptoms may be observed:
  • Undescended testes (cryptorchidism)
  • Opening of urethra on the underside of penis (hypospadias)
  • Abnormalities in structures of kidneys and ureter
  • Inflammation of pancreas
• In females, the following symptoms may be observed:
  • Development of streak gonads  (presence of clump of tissue in place of functional ovaries)
  • Heart-shaped uterus, with a resultant inability to carry a baby full term
  • Inflammation of pancreas
  • Abnormalities in structures of kidneys and ureter

Intellectual disability: It was previously termed “mental retardation” and it may be accompanied by the following symptoms:

• Learning disabilities
• Lack of proper processing and response to information feed
• Short attention spans
• Attention deficit hyperactivity disorder (ADHD)
• Obsessive compulsive disorder (OCD)
• Depression
• Signs of autism, such as problems in social interactions and difficulties communicating with others

Obesity: In an individual affected by WAGRO Syndrome, the symptoms start appearing in childhood (childhood onset of obesity) and these include:

• Uncontrolled eating and drinking
• Fatigue
• Snoring

How is WAGR Syndrome Diagnosed?

It is estimated that about 30% of the individuals with aniridia also have WAGR Syndrome. Likewise, a percentage of those diagnosed with Wilms’ tumor (7 in 1,000 cases) have WAGR Syndrome as well. Hence, the presence of aniridia and/or Wilms’ tumor should prompt the healthcare provider to look for other features of WAGR Syndrome. Since WAGR Syndrome is a collection of 4 different conditions, independent diagnosis of each condition could actually be indicative of WAGR Syndrome.

The following tests and methods are typically employed for the diagnosis of WAGR Syndrome:

• A thorough physical examination
• An evaluation of family history (although in most cases, a family medical history may not be very helpful)
• An assessment of symptoms: The earliest manifested symptom is aniridia. However, not all individuals with aniridia are diagnosed with WAGR Syndrome
• Molecular analysis to check for genetic chromosomal abnormalities pertaining to WAGR Syndrome
  • Chromosome analysis for detection of large deletions in the short arm of chromosome 11
  • For small deletions, the diagnostic methods employed could include: Fluorescence in-situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and array comparative genomic hybridization analyses (array CGH analyses)
• If a family history of WAGR Syndrome is present, then the following may be considered:
  • Pre-implantation genetic diagnosis (PGD) in case the parents are opting for in vitro fertilization (or IVF)
  • Genetic tests on either parent to understand whether they are carriers of the disorder
  • Prenatal genetic analysis (of the fetus)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of WAGR Syndrome?

The following complications may develop in individuals with WAGR Syndrome:

• Wilms’ tumor complications that include
  • Metastasis of the tumor to other locations such as the bones, brain, liver, and lungs
  • Recurrence of the tumor after its surgical removal
  • Serious impairment of kidney (failure) necessitating removal of the kidney
• Diabetes and hyperlipidemia, in case of WAGRO Syndrome
• Severe emotional stress for both the child and parents

How is WAGR Syndrome Treated?

At the present time, treatment for WAGR Syndrome is tailored towards offering relief from various symptoms. A team of medical professionals is generally involved to treat the condition. The following are some symptom-specific treatment measures employed:

Eye-related abnormalities:

• Corrective lenses
• Protective glasses for photophobia
• For squinting, training the affected eye with an eye patch on the normal eye
• Medication and/or surgery for glaucoma
• Surgery for cataracts

Conditions affecting the kidneys and genitals:

• Regular kidney examinations, through X-rays, ultrasonograms and blood tests, owing to the high risk of Wilms’ tumors in affected individuals
• Both children and adults need monitoring, with the frequency of monitoring dictated by how healthy the kidneys are. If Wilms’ tumor is evident, chemotherapy, radiation therapy and/or surgery, with routine follow-up care is essential
• Dialysis for kidney failure
• Kidney transplant, when all treatments to restore kidney functions fail
• Surgery for undescended testes
• Surgery to correct hypospadias

Obesity: 

• Consultation with a dietician to formulate a diet plan for the affected individual
• Adherence to the diet plan
• Family support and care

Rehabilitation: Both children and adults may require rehabilitation treatment and care that include:

• Children
  • Special education
  • Psychological counseling
  • Support of family, educators, medical professionals
• Adults
  • Counseling
  • Psychotherapy
  • Support of family and friends

How can WAGR Syndrome be Prevented?

• Currently, there are no specific methods of prevention for WAGR Syndrome, since it is a genetic condition
• If there is a family history of the disease, genetic testing of the expecting parents (and related family members), as well as prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess the risks prior to child rearing
• Active research is currently being performed in order to explore treatment possibilities and methods of prevention for acquired genetic diseases like WAGR Syndrome

Periodic monitoring with tests and physical examinations are strongly recommended for those diagnosed with WAGR and WAGRO syndromes. This will allow an individual’s medical team to diagnose and treat evolving symptoms promptly.

What is the Prognosis of WAGR Syndrome? (Outcomes/Resolutions)

• The prognosis of WAGR Syndrome is dependent upon the severity of the signs and symptoms. Individuals usually survive long-term, although for a better outcome, periodic and long-term monitoring of the affected individuals is required
• Many affected individuals may develop life-long disabilities including vision impairment and diminished intellectual acuity. Also, the presence of advanced stage Wilms’ tumor can result in a poor outcome
• With periodic monitoring for Wilms’ tumor, prompt treatment in case an individual does develop the kidney tumor, and long-term follow-up, the prognosis is reported to be excellent
• Late stage renal failure may contribute to increased mortality rates, more so than due to Wilms’ tumor

Additional and Relevant Useful Information for WAGR Syndrome:

Gene deletions characteristic of WAGR Syndrome can occur either in the gametes of either parent during cell division, or during early fetal development. Gene deletions can also be inherited as unstable translocations. This is where the deletion occurs in the parent as an asymptomatic balanced translocation and becomes unbalanced in subsequent generations.