The WT1-related Wilms' tumor (WT) syndromes are a group of hereditary disorders caused by alterations in a gene known as WT1. This group of disorders includes:
In addition to the WT1-related Wilms' tumor syndromes, there are a number of other genetic conditions associated with the development of WT. Some of these conditions include:
To learn more about these conditions, please visit the National Institutes of Health's Gene Tests site.
Patients with these conditions have a greater risk of developing a malignant tumor of the kidney known as nephroblastoma, or Wilms' tumor (WT). Wilms' tumor is the most common type of kidney cancer affecting children. Very rarely, WT can occur in adults.
The average age of diagnosis of Wilms' tumor in children depends upon whether one or both kidneys are affected:
Individuals with the WAGR syndrome are missing one working copy of the WT1 gene. They also may be missing one copy of several other genes that lie next to the WT1 gene on chromosome 11 at position p13. As a result, patients with the WAGR syndrome often have a variety of issues, including:
People with Denys-Drash syndrome may develop the following clinical features:
People with Frasier syndrome may develop the following clinical features:
Individuals with GU anomalies syndrome may develop the following clinical features:
These conditions are caused by alterations, or “mutations," at a specific area in an individual’s genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as “genes.” Genes provide the instructions the cells of the body need to perform their different functions. There is a specific gene known as WT1, located on chromosome 11 at position p13, which is altered in patients with the WT1-related WT syndromes. The WT1 gene produces a protein known as a “transcription factor." The WT1 transcription factor turns “on” and “off” other genes that regulate how cells making up the genitourinary system grow and develop. The specific WT1-related condition that a person may develop is related to the type of alteration that he or she carries in one copy of the WT1 gene:
With the exception of egg and sperm cells, each cell of the body normally has two working copies of the WT1 gene. In patients with WT1-related Wilms' tumor syndromes, however, each cell contains only one normal WT1 gene copy. While the second copy is present, it is altered so that it does not function properly. A person carrying an alteration or deletion in one copy of the WT1 gene has a 50 percent (or 1 in 2) chance of passing this same alteration on to each of his or her future children. Children who inherit the altered gene copy are at risk to develop the features of a WT1-related Wilms' tumor syndrome over the course of their lives. Interestingly, most patients with WT1-related syndromes are the first in their family to have the condition. In these individuals, it is believed that the condition results from the occurrence of a “new” mutation in one copy of the WT1 gene in one of the father’s sperm, one of the mother’s eggs, or in a cell of the developing fetus.
Because gene alterations in WT1 may cause abnormal formation of the reproductive organs in individuals with either DDS or FS, these individuals may be infertile. If an individual is infertile, there should be no chance of passing on the WT1 mutation to future offspring.
When a child is suspected of having a Wilms' tumor, it is necessary to perform diagnostic imaging studies such as:
Although imaging studies are suggested, a definitive diagnosis of Wilms' tumor can only be made after pathological examination of a biopsy (small sample) of a suspected mass or following removal of the involved kidney.
A detailed review of an individual’s medical and family history is important when diagnosing a WT1-related WT syndrome. Specifically, the presence of any of the clinical features noted above in a child that is diagnosed with WT, such as aniridia, hypospadias or undescended testicles, should prompt further investigation of the WT1 gene in that individual. A doctor or genetic counselor may also construct a pedigree, or a multi-generation family tree, that indicates which members of the family, if any, have developed certain clinical findings such as Wilms' tumor, kidney abnormalities, GU anomalies, and/or early onset renal failure. If the pattern of clinical features and/or cancers is suggestive of a WT1-related Wilms' tumor syndrome, the physician or counselor may recommend that genetic testing be performed.
The process of genetic testing can be performed to assess whether an affected individual has an alteration in the WT1 gene:
Note: WAGR syndrome is typically diagnosed by observing a large deletion of genetic material through chromosome studies or specific deletion testing.
WT1 genetic test results can also provide important information for other family members. Knowing the specific alteration that is present in an individual with a WT1-related Wilms' tumor syndrome allows for other family members to undergo testing to determine whether they also carry the alteration and could therefore develop WT or the other features associated with these conditions.
Reproductive options exist for an individual with an alteration in the WT1 gene who does not wish to pass this alteration on to future children:
The most serious cancer risk for patients with the WT1-related WT syndromes is the development of one or more Wilms' tumors, which generally occur during the first 3 years of life. The estimated risks for developing Wilms' tumor depend upon the type of WT1 mutation that is present.
The majority of children with WT1-related Wilms' tumor syndromes have nephroblastomatosis, or pre-malignant lesions of the kidneys. These lesions are Wilms' tumor precursors. Sometimes they develop into Wilms' tumor and other times they regress during early childhood. They are often closely watched for tumor development, or they may be treated surgically or with chemotherapy to prevent tumor formation.
Wilms' tumor can be cured with proper treatment. The probability of cure depends in part upon the cancer's stage, or extent of spread, at diagnosis. We recommend patients with the WT1-related WT syndromes have regular screenings in order to detect potential Wilms' tumor as early as possible. Research shows early detection leads to improved outcomes, because cancers are often smaller and easier to remove surgically. An earlier diagnosis may also reduce the need for chemotherapy and lower the dose of, or eliminate the need for, radiation treatment.
All cancer screening should be performed in consultation with a pediatric oncologist, and radiology studies should be reviewed by a radiologist with pediatric expertise. Whenever possible, cancer screening should be done at the same center for consistency of results. In the event that screening results in a suspected or confirmed tumor, we recommend a prompt referral to a pediatric oncologist.
We recommend the following cancer screening protocol for patients suspected of having, or proven to have, a WT1-related Wilms' tumor susceptibility syndrome:
To screen for Wilms' tumor, an ultrasound examination focusing on the kidneys should be performed every three months until the patient is 5-7 years of age. Abdominal ultrasounds are safe and painless, and they do not involve the use of radiation. If a lesion is suspected, more detailed imaging should be performed using a CT or MRI scan and the patient should be promptly referred to a pediatric oncologist for further management.
To prevent the development of gonadoblastoma in patients with Frasier syndrome or Denys-Drash syndrome who have specific abnormalities of the developing sex organs known as “streak” gonads, it is recommended that the abnormal gonads be surgically removed early during childhood.
In addition to cancer surveillance, patients with WT1-related Wilms' tumor syndromes may require multidisciplinary care provided by pediatric subspecialists:
Children should also continue to have regular check-ups by their physicians.
As general cancer prevention measures, children should be encouraged to lead as healthy a lifestyle as possible. They should eat a balanced diet, avoid excess sun exposure and always wear sun block and a hat when outdoors in the sunlight. As adolescents, they should be discouraged from smoking cigarettes or cigars and should not be exposed to second hand smoke. Parents should watch for symptoms of illness and have their children evaluated promptly if these occur.
Reviewed by: Kim Nichols, MD, Kristin Zelley, MS
Date: September 2012