What are the WT1-related Wilms tumor (WT) syndromes?

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:

• WAGR (Wilms tumor-Aniridia-Genitourinary malformation-Retardation) syndrome
• Denys-Drash syndrome (DDS)
• Frasier syndrome (FS)
• Genitourinary anomalies (abnormalities of the reproductive and urinary systems) syndrome

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:

• Beckwith-Wiedemann syndrome
• Li-Fraumeni syndrome
• Neurofibromatosis type 1
• Sotos syndrome
• Fanconi anemia syndrome
• Bloom’s syndrome
• Simpson-Golabi-Behmel syndrome
• Perlman syndrome
• Trisomy 18

Patients with these conditions have a greater risk of developing a malignant tumor of the kidney known as Wilms tumor (WT), or nephroblastoma. Wilms tumor is the most common type of kidney cancer affecting children. Very rarely, WT can occur in adults.

A look at each syndrome

WAGR syndrome

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:

• Higher risk of developing Wilms tumor: The risk of developing Wilms tumor is about 50 percent.
• Aniridia (complete or partial absence of the iris, the colored part the eye): All people with WAGR syndrome have this; it is due to the loss of one copy of a gene known as PAX6.
• Genitourinary abnormalities: These defects are mostly seen in boys and commonly include undescended testes. The reproductive organs in girls are usually normal.
• Intellectual disabilities and behavioral abnormalities: These features vary but most patients show some degree of cognitive delay. Behavior problems include:
  • Attention deficit hyperactivity disorder (ADHD)
  • Autism spectrum disorders
  • Anxiety
  • Depression
  • Obsessive-compulsive disorder (OCD)
  • Some individuals can have normal intellect and no behavior problems
• Neurologic issues: Nervous center issues include seizures, brain malformations, or muscle weakness/tightness.
• End-stage renal (kidney) disease: Renal failure may develop in patients over time. This feature is generally worse in patients who have been treated for a Wilms tumor.

Denys-Drash (DDS) syndrome

People with Denys-Drash syndrome may develop the following clinical features:

• Higher risk of developing Wilms tumor (the risk is estimated to be more than 90 percent)
• Abnormal or undermasculinized reproductive organs in boys
• Normal or abnormal female reproductive organs
• Higher risk of developing gonadoblastoma (a tumor of the developing reproductive organs, including the ovaries and testes)
• End-stage renal (kidney) disease: Patients may develop renal failure, often in association with a condition known as diffuse mesangial sclerosis

Frasier syndrome (FS)

People with Frasier syndrome may develop the following clinical features:

• Wilms tumor is not usually seen in Frasier syndrome but several cases have been reported
• Abnormal or undermasculinized reproductive organs in boys
• Typically normal reproductive organs in girls
• Higher risk of developing gonadoblastoma
• End-stage renal (kidney) disease: Patients may develop renal failure, often in association with a condition known as focal segmental glomerulosclerosis.

Genitourinary (GU) anomalies syndrome

Individuals with GU anomalies syndrome may develop the following clinical features:

• Higher risk of developing Wilms tumor: The risk of developing Wilms tumor varies, depending upon the WT1 gene alteration that is present.
• Abnormal external genitals: These features are often seen in boys, and may include undescended testicles, inguinal hernias or hypospadias (a birth defect characterized by abnormal placement of the urinary opening).

Causes

WT1-related Wilms tumor syndromes 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 cells of the body need to perform 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 mutation on one copy of the WT1 gene:

• Large deletions that include WT1: A deletion of genetic material on one copy of chromosome 11 that includes WT1 and other nearby genes is responsible for the clinical features associated with WAGR. As a result of this type of deletion, an individual with WAGR has only one working copy of WT1 and one working copy of the neighboring genes present in the deleted segment of DNA.
• Alterations within the WT1 gene: Alterations in different areas of one copy of the WT1 gene can cause Denys-Drash syndrome, Frasier syndrome or the genitourinary anomalies syndrome.
  • DDS: These individuals carry specific alterations known as missense mutations, mostly in exons 8 or 9 of one working copy of the WT1 gene.
  • FS: These individuals carry specific alterations that affect splicing, or processing, of one working copy of the WT1 gene.
  • GU anomalies syndrome: These individuals usually carry changes known as nonsense or frameshift mutations that affect one working copy of the WT1 gene. Less often, patients may have a complete or partial deletion of one copy of WT1.

How are WT syndromes are inherited?

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 a mutation or deletion in one copy of the WT1 gene has a 50 percent chance of passing this same alteration onto 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 children.

Diagnosis

Imaging studies

When a child is suspected of having a Wilms tumor, it is necessary to perform diagnostic imaging studies such as:

• Abdominal ultrasound — This allows for a full view of the abdomen, specifically the kidneys.
• Computed tomography (CT) scan or magnetic resonance imaging (MRI) — This allows for a more detailed visualization of the kidneys, as well as adjacent organs, lymph nodes and blood vessels leading to and from the kidneys.

Biopsy

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.

Family history

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 Wilms tumor, 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 genetic testing be performed.

Genetic testing

The process of genetic testing can be performed to assess whether an affected individual has an alteration in the WT1 gene:

• First, a blood or saliva sample is obtained from an affected individual.
• DNA is isolated from the sample and the two copies of the WT1 gene are evaluated using a variety of methods and compared to the normal reference sequence for WT1.
• If an alteration in one WT1 gene copy is identified, the genetic counselor can next examine whether the alteration has been previously reported in other people with WT1-related conditions.

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 Wilms tumor or the other features associated with these conditions.

Reproductive options

Reproductive options exist for an individual with an alteration in the WT1 gene who does not wish to pass this alteration onto future children:

• Prenatal diagnosis — DNA is isolated from the cells of the developing baby though one of two procedures (chorionic villus sampling [CVS] or amniocentesis) and analyzed for alterations in the WT1 gene. With appropriate counseling, a parent can then decide whether to carry the pregnancy to term or end the pregnancy.
• Preimplantation genetic diagnosis (PGD) — For couples using in vitro fertilization to become pregnant, embryos can be tested for genetic disorders before transferring them into the uterus. Only healthy embryos carrying two working copies of the WT1 gene would be implanted.

Before one can proceed with prenatal testing or PGD, a WT1 mutation must be identified in a parent.

Cancer risks

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.

• WAGR: Risk is probably as high as 50 percent
• DDS: Risk is higher than 90 percent
• Frasier syndrome: This is not usually seen in these patients but several cases have been reported.
• GU anomalies: Some people will develop Wilms tumor

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, and may be treated surgically or with chemotherapy to prevent tumor formation.

Cancer screening recommendations

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 Wilms tumor 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:

Abdominal ultrasound examinations

To screen for Wilms tumor, an ultrasound examination focusing on the kidneys should be performed every 3 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.

Preventive surgery when needed

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.

Care by a team of specialists

In addition to cancer surveillance, patients with WT1-related Wilms tumor syndromes may require multidisciplinary care provided by pediatric subspecialists:

• Pediatric nephrologist: Manages kidney complications, ESRD, increased blood pressure, and medical aspects of kidney transplantation
• Pediatric oncologist: Diagnoses and treats Wilms tumor and gonadoblastoma (tumor of the developing sex organs)
• Pediatric surgeon and/or urologist:
  • Manages Wilms tumor
  • Offers access to renal replacement therapy and kidney transplantation
  • Evaluates and provides surgical removal of abnormal gonads (as a result of gonadoblastoma)
  • Corrects GU anomalies and abnormal genitals (individuals with WAGR, DDS, FS and GU anomalies)
• Pediatric endocrinologist: Evaluates and manages ambiguous sex disorders (individuals with DDS and FS)
• Geneticist: Provides chromosomal analysis, molecular diagnosis, and genetic counseling (individuals with WAGR, DDS, FS and GU anomalies)
• Neurologist and/or developmental pediatrician: Evaluates cognitive delay and behavior abnormalities (individuals with WAGR)
• Ophthalmologist: Manages aniridia (individuals with WAGR)

Regular check-ups

Children should also continue to have regular check-ups by their physicians.

Healthy lifestyle

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.