Wilms' tumor or nephroblastoma is cancer of the kidneys that typically occurs in children, rarely in adults.

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Its common name is aneponym, referring to Dr. Max Wilms, the German surgeon (18671918)
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who first described this kind of tumor.

Approximately 500 cases are diagnosed in the U.S. annually. The majority (75%) occurs in otherwise normal children; a minority (25%) is associated with other developmental abnormalities. It is highly responsive to treatment, with about 90% of patients surviving at least five years. Wilms' tumor is a rare type of kidney cancer that affects children. It causes a tumor on one or both kidneys. Having certain genetic conditions or birth defects can increase the risk of developing Wilms' tumor. Children who are at risk should be screened for Wilms' tumor every three months until they turn eight. Possible signs of a kidney tumor include a lump in the abdomen and blood in the urine. The tumor is usually diagnosed and removed in surgery. Other treatments include chemotherapy, radiation, biologic therapy or a combination. Biologic therapy, or immunotherapy, boosts your body's own ability to fight cancer. Most children with Wilms' tumor can be cured.

Prognosis
Tumor-specific loss-of-heterozygosity (LOH) for chromosomes 1p and 16q identifies a subset of Wilms' tumor patients who have a significantly increased risk of relapse and death. LOH for these chromosomal regions can now be used as an independent prognostic factor together with disease stage to target intensity of treatment to risk of treatment failure.[4][5] Genome-wide copy number and LOH status can be assessed with virtual karyotyping of tumor cells (fresh or paraffin-embedded). The overall prognosis with surgical removal is positive. Early removal tends to promote positive outcomes.

taging and treatment Staging is determined by combination of imaging studies and pathology findings if the tumor is operable (adapted from www.cancer.gov). Treatment strategy is determined by the stage:
[edit]Stage

I (43% of patients)

For stage I Wilms' tumor, 1 or more of the following criteria must be met:
  

Tumor is limited to the kidney and is completely excised. The surface of the renal capsule is intact. The tumor is not ruptured or biopsied (open or needle) prior to removal.

  

No involvement of extrarenal or renal sinus lymph-vascular spaces No residual tumor apparent beyond the margins of excision. Metastasis of tumor to lymph nodes not identified.

Treatment: Nephrectomy +/- 18 weeks of chemotherapy depending on age of patient and weight of tumor. EG: less than 2 years old and less than 550g only requires Nephrectomy with observation Outcome: 98% 4-year survival; 85% 4-year survival if anaplastic
[edit]Stage

II (23% of patients)

For Stage II Wilms' tumor, 1 or more of the following criteria must be met:
  

Tumor extends beyond the kidney but is completely excised. No residual tumor apparent at or beyond the margins of excision. Any of the following conditions may also exist:  Tumor involvement of the blood vessels of the renal sinus and/or outside the renal parenchyma.  The tumor has been biopsied prior to removal or there is local spillage of tumor during surgery, confined to the flank.  Extensive tumor involvement of renal sinus soft tissue.

Treatment: Nephrectomy + abdominal radiation + 24 weeks of chemotherapy Outcome: 96% 4-year survival; 70% 4-year survival if anaplastic
[edit]Stage

III (23% of patients)

For Stage III Wilms' tumor, 1 or more of the following criteria must be met:
   

Unresectable primary tumor. Lymph node metastasis. Tumor is present at surgical margins. Tumor spillage involving peritoneal surfaces either before or during surgery, or transected tumor thrombus.

Treatment: Abdominal radiation + 24 weeks of chemotherapy + nephrectomy after tumor shrinkage

Outcome: 95% 4-year survival; 56% 4-year survival if anaplastic

[edit]Stage

IV (10% of patients)

Stage IV Wilms' tumor is defined as the presence of hematogenous metastases (lung, liver, bone, or brain), or lymph node metastases outside the abdomenopelvic region. Treatment: Nephrectomy + abdominal radiation + 24 weeks of chemotherapy + radiation of metastatic site as appropriate Outcome: 90% 4-year survival; 17% 4-year survival if anaplastic
[edit]Stage

V (5% of patients)

Stage V Wilms tumor is defined as bilateral renal involvement at the time of initial diagnosis. Note: For patients with bilateral involvement, an attempt should be made to stage each side according to the above criteria (stage I to III) on the basis of extent of disease prior to biopsy. The 4-year survival was 94% for those patients whose most advanced lesion was stage I or stage II; 76% for those whose most advanced lesion was stage III. Treatment: Individualized therapy based on tumor burden
[edit]Stage

I-IV Anaplasia

Children with stage I anaplastic tumors have an excellent prognosis (8090% five-year survival). They can be managed with the same regimen given to stage I favorable histology patients. Children with stage II through stage IV diffuse anaplasia, however, represent a higher-risk group. These tumors are more resistant to the chemotherapy traditionally used in children with Wilms tumor (favorable histology), and require more aggressive regimens.
[edit]Treatment

Once a kidney tumor is found, a surgical biopsy is done. A sample of tissue from the tumor is sent to a pathologist, who looks at it under a microscope to check for signs of cancer. If the tumor is only in the kidney (typical), it can be removed along with the whole kidney (a nephrectomy). If there are tumors in both kidneys or if the tumor has spread outside the kidney, a piece of the tumor will be removed.

Children 16 years old or older have higher mortality rates within their stages. This is due to them being treated less aggressively and consistently.[citation needed] Adjuvant chemotherapy is sometimes used.[11]
[edit]Risk

Factors

People of African descent have the highest rates of Wilms' tumor. Females are also more likely than males to develop the tumors. Most instances of cancer occur among children under the age of 5.[citation needed]
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Wilms Tumor Signs and Symptoms

Unfortunately, Wilms Tumor might go undetected until the tumor reaches a large size and becomes noticeable or can be felt. The symptoms can vary between patients. Some of the common Wilms' tumor signs and symptoms are:
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Abdominal pain Abdominal swelling Abdominal mass Blood in urine (this symptom occur in less than of the children) Nausea Vomiting Loss of appetite Fever High blood pressure General discomfort. Constipation Erythrocytosis (a medical condition where there are too many red cells in the blood)

How are Wilms tumors diagnosed?

Wilms tumors are usually brought to a doctor's attention because of signs or symptoms a child is having. But even if the doctor thinks a child has Wilms tumor because of the results of a physical exam or imaging tests, the diagnosis needs to be confirmed by looking at a sample of the tumor under a microscope.

Signs and symptoms of Wilms tumor

Wilms tumors can be hard to find early because they can grow quite large without causing any symptoms. Children may look healthy and play normally. The first sign is usually swelling or a hard mass in the abdomen (belly), which parents may notice while bathing or dressing the child. It feels firm and is often large enough to be felt on both sides of the belly. It is usually not painful, but it may cause belly pain in some cases. Some children with Wilms tumor may also have fever, nausea, loss of appetite, constipation, or blood in the urine.

Many of these signs and symptoms are more likely to be caused by something other than a kidney tumor. Still, if symptoms suggest that a tumor may be present, check with your child's doctor so that the cause can be evaluated and treated, if needed.

Medical history and physical exam

If your child has signs or symptoms that suggest a tumor may be present, the doctor will want to get a complete medical history to learn more about the symptoms and how long they have been there. The doctor may also ask if there's a family history of cancer or birth defects, especially in the genitals or urinary system. The doctor will examine your child to look for possible signs of Wilms tumor or other health problems. The main focus will likely be on the abdomen and on any increase in blood pressure, which is another possible sign of this cancer.

Imaging tests
If the doctor thinks your child might have a kidney tumor, he or she will probably order imaging tests. These tests use sound waves, x-rays, magnetic fields, or radioactive substances to create pictures of the inside of the body. Imaging tests are done for a number of reasons, including:

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To help find out if there is a tumor in the kidney(s), and if so, if it is likely to be a Wilms tumor To learn how far the tumor may have spread, both within the kidney and to other parts of the body To help guide surgery or radiation therapy To look at the area after treatment to help determine if it has been effective

Ultrasound (ultrasonography)
Ultrasound uses sound waves to create images of internal organs. For this test, a small, microphone-like instrument called a transducer is placed on the skin (which is first lubricated with a gel). It is moved across the skin over the kidney so that it can be viewed from different angles. The transducer gives off sound waves and picks up the echoes as they bounce off the tissues in the kidney. The echoes are converted by a computer into a black and white image on a screen. The echo patterns made by most kidney tumors look different from those of normal kidney tissue. Different echo patterns also can distinguish some types of cancerous and non-cancerous kidney tumors from one another. In addition, ultrasound is very useful when looking for tumor thrombus (tumor growing into the main veins around the kidney). This helps in planning the surgery. This is often the first imaging test done if the doctor suspects your child has a Wilms tumor because it is easy to have, does not involve radiation, and lets the doctor see the entire abdomen.

Computed tomography (CT, CAT) scan

The CT scan is an x-ray test that produces detailed cross-sectional images of parts of your child's body. Instead of taking one picture, like a regular x-ray, a CT scanner takes many pictures as it rotates around your child while he or she lies on a table. A computer then combines these pictures into images of slices of the part of the body being studied. Unlike a regular x-ray, a CT scan creates detailed images of the soft tissues in the body. Before the scan, your child may be asked to drink a contrast solution and/or get an intravenous (IV) injection of a contrast dye that better outlines abnormal areas in the body. Your child may need an IV line for the dye. The contrast may cause some flushing (a feeling of warmth, especially in the face). Some people are allergic and get hives. Rarely, more serious reactions like trouble breathing or low blood pressure can occur. Be sure to tell the doctor if your child has any allergies or has ever had a reaction to any contrast material used for x-rays.

CT scans take longer than regular x-rays. Your child will need to lie still on a table while they are being done. During the test, the table slides in and out of the scanner, a ring-shaped machine that completely surrounds the table. Some people feel a bit confined by the ring they have to lie in while the pictures are being taken. Some doctors may give younger children medicine to help keep them calm or even asleep during the test. Spiral CT (also known as helical CT) is now used in many medical centers. This type of CT scan uses a faster machine. The scanner part of the machine rotates around the body continuously, allowing doctors to collect the images much quicker than with standard CT. This lowers the chance of images blurring as a result of body movement. It also lowers the dose of radiation received during the test. The slices it images are thinner, which gives more detailed pictures. CT scanning is one of the most useful tests to look for a mass inside the kidney. It is also helpful in checking whether a cancer has spread to organs and tissues beyond the kidney, such as the lungs.

Magnetic resonance imaging (MRI) scan

Like CT scans, MRI scans provide detailed images of soft tissues in the body. But MRI scans use radio waves and strong magnets instead of x-rays (and therefore don't expose your child to radiation). The energy from the radio waves is absorbed and then released in a pattern formed by the type of body tissue and by certain diseases. A computer translates the pattern into a very detailed image of parts of the body. A contrast material called gadolinium may be injected into a vein before the scan to better see details. The contrast material usually does not cause allergic reactions. MRI scans take longer than CT scans often up to an hour. Your child may have to lie inside a narrow tube, which is confining and can be distressing, so sedation is sometimes needed. Newer, more open MRI machines may be another option for some children. The MRI machine makes loud buzzing and clicking noises that your child may find disturbing. Some places provide headphones or earplugs to help block this out. MRI scans show more detailed images than CT and ultrasound. They may be done if there's a chance that the cancer is in a major vein (the inferior vena cava) in the abdomen. They may also be used to look for possible spread of cancer to the brain or spinal cord if doctors are concerned the cancer may have spread there.

Chest x-ray
In most cases, a chest x-ray will be done to look for any spread of Wilms tumor to the lungs, as well as to have a baseline view of the lungs to compare with other x-rays that might be done in the future.

Bone scan
For this test, a small amount of low-level radioactive material is injected into a vein (intravenously, or IV). The substance settles in areas of damaged bone throughout the entire skeleton over the course of a couple of hours. Your child then lies on a table for about 30 minutes while a special camera detects the radioactivity and creates a picture of the skeleton. Younger children may be given medicine to help keep them calm or even asleep during the test. Areas of active bone changes appear as "hot spots" on the skeleton that is, they attract the radioactivity. These areas may suggest the presence of cancer, but other bone diseases can also cause the same pattern. To distinguish between these conditions, other imaging tests such as plain x-rays or MRI scans, or even a bone biopsy might be needed. Bone scans can help find cancer that has spread to bones. Doctors don't usually order this test unless they think your child has a type of Wilms tumor that is likely to spread.

Lab tests
A urine sample may be tested (urinalysis) to look for blood and other substances in the urine. The urine may also be tested for substances called catecholamines. This is done to make sure your child doesn't have another kind of tumor called neuroblastoma. (Neuroblastomas often start in the adrenal gland, which lies just above the kidney.)

Blood tests are not used to find Wilms tumors, but they may be done to check a child's general health (especially before surgery) and to look for side effects during treatment such as chemotherapy. These may include tests to count the number of white blood cells, red blood cells, and blood platelets, and tests to measure certain chemicals and salts in the blood that give clues about how well the liver and kidneys are working.

Kidney biopsy/surgery
In most cases, imaging tests can give doctors enough information to decide if a child probably has a Wilms tumor, and therefore surgery should be done. But the actual diagnosis of Wilms tumor is made when a sample of the tumor is removed and looked at under a microscope. The cells in Wilms tumors have a characteristic appearance when looked at this way. This is also when doctors determine the histology of the Wilms tumor (favorable or unfavorable), as was described in the section "What is Wilms tumor?" In most cases, the sample is obtained during surgery to treat the tumor (see the Surgery section in "How is Wilms tumor treated?"). Less often, the sample to confirm the diagnosis is obtained during a biopsy as a separate procedure before surgery to treat the tumor. The biopsy may be done either surgically or with a long, hollow needle.

Causes and Risk Factors

The exact causes why certain children develop Wilms tumor are not known yet, but medical researchers have made progress in understanding some of the mechanisms that lead to Wilms' tumor (nephroblastoma). Wilms tumors form when undifferentiated kidney cells do not correctly mature and remain as fetal kidney cells. These cells can collect in clusters, grow and divide abnormally causing tumors to form. In some cases, the impaired maturation process of the kidney cells, that lead to Wilms tumors, is caused by a mutation that occurs in two genes called WT1 and WT2. These mutations cause an overgrowth in certain tissues. However, these mutations can either be inherited, or are acquired early in the children's life or even before birth. In other cases (11 to 17 percent), the Wilms tumors display an abnormality in the chromosome 1 or chromosome 16. Unfortunately, these tumors are more likely to spread or to relapse after treatment. Some of the risk factors that are associated with Wilms' tumor include: Age: Children between the age of 3 and 5 are at higher risk to develop Wilms' tumor. Gender: The risk of developing Wilms' tumor is slightly higher in girls than in boys. Sex: For the US population, the risk for developing Wilms' tumor is slightly higher among African Americans that Caucasians, and is lower among Asian Americans. family history of Wilms' tumor: Between 1 to 3 percent of the children that suffer from Wilms tumor have one or more relatives with this type of kidney cancer. In these cases, researchers believe that the children inherited a mutated gene from one of the parents, a mutation which has increased the risk for cancer. Displaying certain birth defects: There is a high connection between Wilms tumor and birth defects specific to certain syndromes, such as:
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WAGR - This acronym stands for (1)Wilms tumor, (2) aniridia (complete or partial missing of the iris -the colored portion - of the eyes) (3) genitourinary abnormalities (such as kidneys, urinary tract, penis, scrotum, testicles, clitoris, or ovaries defects), and (4) mental retardation.

Children that suffer from this syndrome have a 3 percent chance for developing Wilms' tumor. Beckwith-Wiedemann syndrome - This is a congenital growth disorder (present at birth) that causes larger body size, large organs, and impaired body functions. Children with this symptom have larger internal organs (larger than normal), a larger tongue, an oversized arm or leg, or other parts of the body (condition called hemibinhypertrophy). Children with Beckwith-Wiedemann syndrome are at higher risk for developing Wilms' tumor. Denys-Drash syndrome -This syndrome is characterized by the absence of the penis, testicles, and scrotum. Children that suffer from this syndrome develop kidney problems and the kidney may fail to function.

Abnormalities of the genitals or urinary system:

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Cryptorchidism is a medical condition where one or both testicles do not descend from the scrotum. Hypospadias is a medical condition where the urethral (the urinary opening) is not in its normal position at the tip of the penis, but underneath.

Medical Tests and Diagnosis

Wilms' tumor symptoms can be signs of other medical conditions and only a doctor can establish a correct diagnosis. The diagnosis procedure involves a certain number of steps: Anamnesis (detailed medical review of past health state): One of the first steps in establishing a Wilms tumor diagnosis is a detailed and complex medical review of a patient's past health problems and general health state, family medical history, risk factors, and symptoms. Physical examination: During the physical examination, the doctor looks for abdominal masses that can be felt by touch and also measure the blood pressure. Laboratory Tests:
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Blood tests: In patients that might suffer from Wilms' tumor, a complete blood count (CBC) is performed. This set of tests measures: (1) the number of red and white blood cells, (2) the total amount of hemoglobin in the blood, (3) the size of red blood cells, and (4) the fraction of the blood composed of red blood cells. Another blood test performed is called serum creatinine, and it measures the level of creatinine in the blood. Urine tests: There are two urine tests performed in patients with Wilms tumor: (1)blood urea nitrogen (BUN) - this test measures the amount of nitrogen in the blood that comes from urea (a substance produced by the liver, which is removed from the blood by the kidneys), and (2) urinalysis or routine urine test- is a physical and chemical examination of the urine. Creatinine clearance. This is a test that compares the level of creatinine from the urine with the one from the blood.

maging Tests
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Abdominal Ultrasound is an easy, noninvasive, fast, and painless imaging technique that uses high-frequency sound waves to create an interior image of the body on a special

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computer screen. This image is formed from the echoes of the sound waves on the surface of the organs. Abnormal tissue masses and organs reflect sound waves differently. This test involves a device called a transducer, that is placed on the upper part of the abdomen, and a computer that translates this sound into an image. An abdominal ultrasound is one of the first imaging tests that is performed for children suspected of having Wilms' tumor. Abdominal X-ray is an imaging test that uses high energy electromagnetic radiation to penetrate the body and create the interior image on film. An abdominal x-ray can reveal the presence of kidney tumor(s) and provides useful information regarding the size, location and the extent of the tumor. Chest X-ray is a test similar with the abdominal x-ray performed in order to reveal if the cancer has spread to other organs within the chest cavity. Intravenous Pyelogram is an x-ray type technique designed to study the kidneys, bladder, and ureters. During this test, the patient receives a special contrast agent which is picked up by the kidney from the blood and collected in the urine. This x-ray reveals if the kidneys and ureters suffered modifications or if the contrast agent is distributed differently within the kidneys. Computed Tomography (CT) is an imaging test which is similar with an x-ray test, and creates a detailed cross-sectional image of the body. A CT scan is usually performed in two steps for a better diagnosis: 1). First, the targeted area is scanned without a contrast agent. 2). Second, the targeted area is scanned after a contrast agent was administrated. Computed tomography is another effective imaging test that helps finding abnormal masses within the kidney, and provides useful information regarding the extend of the cancer. Magnetic Resonance Imaging is an imaging technique which uses radio waves and strong magnets to reveal a complete image of the liver. The energy from the radio waves is absorbed by the tissues and then revealed into a recognizable pattern on a special monitor. This imaging study can reveal if the cancer has spread to other structures or organs within the body. Bone scan is an imaging technique used to detect whether or not the cancer has affected the bones. During this test, the patient receives, through an injection, a radioactive agent that travels throughout the body and collects in areas where cancerous cells have been collected. Biopsy is a medical procedures which confirms if the tumor or abnormal growth is a malignant tissue or not. A biopsy is a medical procedure where a sample of tissue is removed from the kidney tumor.

reatment Options
Wilms' tumor is best treated when diagnosed in the early stages, before the cancer has spread in the body. Nearly half of all Wilms tumor cases are diagnosed in the first stage, when the treatment outcome is good. The prognosis for most cases is good and statistics show that 92 percent of the children diagnosed with Wilms' tumor are treated effectively. The treatment approach is based on two factors: (1) the cancer stage, and (2) the tumor histology (favorable or unfavorable tumors), and its main goal is to remove the primary tumor (the one located in the kidney) even if the cancer has spread to other areas of the body. The treatment options for Wilms' tumor include: surgery, chemotherapy, and radiation therapy. Surgery Surgery is the main treatment approach used in patients with Wilms' tumor in the USA. In Europe, the patient undergoes surgery after they receive chemotherapy.

Surgical removal of the kidney tissue is called nepherectomy. There are four types of nepherectomy performed in patients with Wilms tumor: 1. Simple nepherectomy. During this surgery, the doctor removes the entire kidney where the tumor is present. 2. Partial nepherectomy. During this surgery, the doctor removes the tumor together with the surrounding kidney tissue. 3. Radical nephetectomy. During this surgery, the doctor removes the tumor together with the entire kidney, the ureters (thin tube that carries the urine from the kidney to the urine bladder), the adrenal gland, the fat tissue that capsules the kidney, and sometimes with the adjacent lymph nodes. 4. Nephron-sparing surgery. During this surgery, the doctor tries to remove only the tumor with as little damage to the kidney tissue as possible . uring the surgery, the doctor will examine the nearby structures and organs to determine whether or not the cancer has spread. This step is essential in establishing a further treatment approach. In some cases, especially when the patient needs further chemotherapy, during surgery the doctor inserts a thin tube (called venous access device) into a large blood vessel (usually under the collar bone) while the other end is placed beneath the skin. Through this tube, the doctor can later remove blood samples and administrates drugs or transfusions. Chemotherapy Chemotherapy is a systemic treatment (affects cells throughout the entire body) that uses drugs either to stop the abnormal growth and dividing process of the cancer cells, or to kill the cancer cells. This treatment can be administrated as pills, through injections, or through a catheter placed in a blood vessel. The most common drugs used in patients with Wilms tumor are: - For early stages: actinomycin D, vincristine. - For advanced stages and unfavorable tumors: doxorubicin (Adriamycin), cyclophosphamide, and/or etoposide. In Europe, chemotherapy is used as a primary treatment approach in treating patients with Wilms' tumor. The doctors prescribe chemotherapy before and after the surgery. In US, chemotherapy is used as a secondary treatment option. Like every medicated treatment, chemotherapy can cause side effects. The complexity and extent of the side effects depend on the drug used and its dosage. The most common chemotherapy side effects include:
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Severe nausea with or without vomiting. Temporary hair loss Fatigue Mouth and lip sores Diarrhea Loss of appetite Tiredness Weakness Constipation High vulnerability to infections Easily bruising and bleeding after minor cuts or injuries. Heart damage (if the drug used is Adriamycin)

Bone marrow damage (this side effect can occur in those patients that receive a high dose of chemotherapy; the doctor will remove bone marrow and freeze it until the treatment is over, when the marrow will be returned intravenously) A slight risk of developing a secondary type of cancer (such leukemia) within few years after the Wilms tumor was cured.

Radiation Therapy This is a treatment approach which uses high-energy rays or particles to destroy cancerous cells. The most common type of radiation therapy used in patients with Wilms' tumor is external beam therapy, which uses an external device (linear accelerator) to generate high-energy rays that focus on the tumor. In some cases, if the child is too small, he/she will be sedated during the treatment to remain still. The doctors will try to limit the area of radiation to avoid growth problems, because this treatment interferes with the normal growth of the tissue. This type of treatment is often use along with surgery in advanced stages of Wilms' tumor patients (stage III, V, and VI) or in early stages (stage I and II) if the tumor has an unfavorable histology. The radiation therapy side effects include:
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Feeling tired as the treatment continues Skin irritation (the skin becomes red, dry, or tender in the area where the body is irradiated). Loss of appetite Diarrhea

Pathophysiology
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Wilms' tumor is a type of malignant tumor. This means that it is made up of cells that ares i g n i f i c a n t l y i m m a t u r e a n d a b n o r m a l . T h e s e c e l l s a r e a l s o c a p a b l e o f i n v a d i n g n e a r b y structures within the kidney and traveling out of the kidney into other structures. Malignantcells can even travel through the body to invade other organ systems, most commonly thelungs and brain. These features of Wilms' tumor make it a type of cancer that, withouttreatment, would eventually cause death. However, advances in medicine during the last 20years have made Wilms' tumor a very treatable form of cancer. (Pathophysiology TumorWilms, Tumor De Wilms)Wilms' tumor occurs almost exclusively in young children. The average patient is aboutthree years old. Females are only slightly more likely than males to develop Wilms' tumors.In the United States, Wilms' tumor occurs in 8.3 individuals per million in white childrenunder the age of 15 years. The rate is higher among African-Americans and lower amongAsian-Americans. Wilms' tumors are found more commonly in patients with other types of birth defects. These defects include: absence of the colored part (the iris) of the eye (aniridia)

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enlargement of one arm, one leg, or half of the face (hemihypertrophy) certain birth defects of the urinary system or genitals certain genetic syndromes (WAGR syndrome, Denys-Drash syndrome, and Beckwith-Wiedemann syndrome)