Hereditary Neuroblastoma

Cancer risk with hereditary neuroblastoma

People with hereditary neuroblastoma are at increased risk to develop tumors. These tumors include:

• Neuroblastoma
• Ganglioneuroblastoma
• Ganglioneuroma

Hereditary neuroblastoma often varies in how severe it is, even among people in the same family. Some people may have multiple tumors. Others do not develop any tumors. Even within the same person, some tumors might shrink and go away on their own. Other tumors may be aggressive and continue to grow.

The risk of developing a tumor is highest in infancy. This risk decreases by late childhood. People with an ALK mutation have a 50–60% chance of developing a tumor.

Not all mutations in PHOX2B increase a person’s risk for neuroblastoma. Instead, there are specific mutations that increase tumor risk. The exact tumor risk for people with PHOX2B is not known because these mutations are much less common. If a person is diagnosed with a mutation in PHOX2B that increases a section of the gene to 29-33 repeats (known as polyalanine repeat mutations, PARMs) or if a mutation is outside of this gene repeat section (known as a non-polyalanine repeat mutation, NPARM), these people have a higher risk and should be screened for neuroblastoma.

Your geneticist, genetic counselor or other health care provider can help you determine what type of PHOX2B mutation you have.

Hereditary neuroblastoma symptoms

People with hereditary neuroblastoma may have symptoms of their tumor. These people may have:

• Flu-like symptoms (persistent fever, feeling tired, pain, loss of appetite, weight loss, or diarrhea)
• Swelling in the abdomen (belly)
• Trouble breathing
• Horner syndrome: This looks like a drooping eyelid, a small pupil, decreased sweating, and red skin on only 1 side of the face.
• High blood pressure, rapid heartbeat, flushing of the skin, and sweating
• Rapid eye movements and jerky muscle motions caused by opsoclonus myoclonus syndrome, a rare condition

Patients with PHOX2B mutations may have conditions that affect the nervous system. These include:

• Hirschsprung disease: a condition that affects the large intestine (colon) in which some nerves are missing. This results in bowel blockage or trouble with bowel movements (severe constipation).
• Decreased esophageal motility: a condition that affects the esophagus (the tube that connects the mouth and the stomach). In this condition, food does not move from the mouth to the stomach as well as it should.
• Congenital central hypoventilation syndrome: a condition of the central nervous system. This results in breathing control which is absent or does not work right.

These neurological conditions are not seen in people with ALK mutations.

Causes of hereditary neuroblastoma

Hereditary neuroblastoma is caused by changes in 1 of 2 genes: ALK or PHOX2B. The ALK and PHOX2B genes control how and when nerve cells grow, divide, and die. Researchers believe that ALK and PHOX2B mutations lead to neuroblastoma by influencing the growth and development of neural cells, which makes them more likely to become cancerous.

How hereditary neuroblastoma is inherited

Most people without hereditary neuroblastoma carry 2 working copies of the ALK and PHOX2B genes in their cells. One copy comes from each parent.

Cells from people with hereditary neuroblastoma carry 1 working copy of the ALK or PHOX2B gene and 1 copy that is changed. This change (a mutation) causes the gene to not work right. Hereditary neuroblastoma is more commonly caused by ALK mutations than PHOX2B mutations.

Most children with hereditary neuroblastoma caused by a mutation in the ALK gene have inherited the mutation from a parent. Some children with ALK gene mutations are the first people in their families to carry the mutation.

Most children with hereditary neuroblastoma caused by a mutation in the PHOX2B gene did not inherit the mutation from a parent. These children have no history of the condition in their family. In these cases, the gene mutation happened either in:

• An ovum (egg) or sperm cell that formed the child
• 1 of the child’s cells before they were born

No matter how they acquired the mutation, people with hereditary neuroblastoma have a 50% (1 in 2) chance of passing it on to their children.

Hereditary neuroblastoma diagnosis

Health history

A health care provider may suspect that your child has hereditary neuroblastoma after looking at their medical and family cancer history.

This information helps the health care provider and the genetic counselor know if:

• There are more cancers than normal in your family
• These cancers happened at a younger age than expected
• The types of tumors are those that might be seen in those with hereditary neuroblastoma

Your provider or genetic counselor may recommend genetic testing if they suspect hereditary neuroblastoma.

Learn more about types of genetic tests. 

Genetic testing for hereditary neuroblastoma

A blood sample is sent to a genetic testing lab. The lab runs genetic tests that look for changes in the ALK gene, the PHOX2B gene, or both.

If your child has a mutation in the ALK gene or the PHOX2B gene, a genetic counselor will work with your family to:

• Find out if other family members should consider testing for an ALK mutation or a PHOX2B mutation
• Help your family understand the increased cancer risk from hereditary neuroblastoma
• Help with your decisions about prenatal genetic testing

It is important to remember that genetic testing does not always find mutations in the ALK or PHOX2B genes for all people with hereditary neuroblastoma. A person can still have hereditary neuroblastoma even if no mutations are found in these genes. There may be other genes that are related to the condition that doctors do not know about yet.

Genetic testing before or during pregnancy

Parents may choose to do prenatal testing to find out if a pregnancy is affected with a known ALK or PHOX2B mutation. Testing may take place either before pregnancy occurs or during pregnancy.

You should work with a genetic counselor to review the pros and cons of the test. The genetic counselor can also help you prepare for the results.

Testing before pregnancy is called preimplantation genetic testing (PGT). This special type of genetic testing is done along with in vitro fertilization (IVF). PGT tests embryos for a known ALK or PHOX2B mutation before a provider places the embryo into the uterus.

Testing during pregnancy can help providers see if a pregnancy has a known ALK or PHOX2B mutation. A doctor gathers cells from the pregnancy in 1 of 2 ways:

• Chorionic villus sampling (CVS) is done during the first 3 months of pregnancy (1st trimester).
• Amniocentesis is done after the first 3 months of pregnancy (2nd trimester or later).

After tissue collection, the lab checks the sample for the ALK or PHOX2B mutation identified in the family. Both tests carry minor risks. Discuss these risks with an experienced health care provider or genetic counselor.

Special concerns for genetic testing

Take time to think carefully about the benefits and risks of genetic testing. Speak with a genetic counselor before testing. If you decide to get tested, talk with your health care provider or a genetic counselor about your results so you can understand what they mean.

Sometimes, children or adults with hereditary neuroblastoma feel sad, anxious, or angry after getting their test results. Parents may feel guilty if they pass the ALK or PHOX2B mutation to 1 or more of their children. People with the ALK or PHOX2B mutation may also have trouble getting disability or life insurance.

Read more about genetic discrimination. 

Monitoring and follow-up care for hereditary neuroblastoma

Children with hereditary neuroblastoma should have regular screenings to detect tumors as early as possible. The goal of screening is to find and treat tumors early to allow the best outcome for patients.

Neuroblastoma screening is recommended for people who have 1 of the following:

• ALK gene mutation
• PHOX2B gene NPARM
• PHOX2B gene PARM mutation containing 28 to 33 repeats

If possible, people with hereditary neuroblastoma should be managed by a health care provider who knows this condition well and who specializes in treating neuroblastoma.

You and your child’s care provider may consider the following tests:

• Yearly physical exams by a provider who knows hereditary neuroblastoma well.
• Urine testing for the levels of certain kinds of hormones called catecholamines. (These are also called HVA and VMA). The level of catecholamines in the urine is often higher in people with neuroblastoma tumors than in those without neuroblastoma. This testing should be started at diagnosis for patients with an ALK mutation or a PHOX2B NPARM. It should be repeated every 3 months from birth to age 6. It should then be repeated every 6 months. It should be discontinued at age 10.
• Ultrasound of the abdomen and chest x-ray. These should be started at diagnosis and repeated every 3 months from birth to age 6. These tests should then be repeated every 6 months until age 10. Patients with a PHOX2B PARM between 20/28 and 20/33 should have annual abdominal ultrasounds and chest x-rays. If a tumor is suspected, more detailed images should be taken using CT or MRI scans. The child should also be seen by a pediatric cancer specialist (pediatric oncologist).
• Yearly checkups with a pediatrician.

Recommendations may change as we learn more about hereditary neuroblastoma. Parents should discuss all screening options for their child with a health care provider who knows hereditary neuroblastoma well, if possible. Because it is a complex condition, it is important that parents seek out an experienced provider for their child.

Living with hereditary neuroblastoma

People of any age with hereditary neuroblastoma have a higher risk of cancer. They should monitor their health and adopt healthy habits throughout life.

It is important to continue to have regular physical checkups and screenings. That way, any cancer can be found early and at the most treatable stage.

Problems to watch for

People with hereditary neuroblastoma should watch closely for general signs or symptoms that could signal cancer:

• Unexplained weight loss
• Loss of appetite
• Pain in abdomen
• Blood in the stool or changes in bowel habits
• Aches, pains, lumps, or swelling that cannot be explained
• Headaches or changes in vision or nerve function that do not go away

It is important to seek medical help if anything unusual appears.

Maintain a healthy lifestyle

Habits that will help you maintain a healthy lifestyle include:

• Eat a healthy diet with lots of fruit and vegetables.
• Get regular exercise.
• Avoid excess sun exposure. Always wear a hat, protective clothing, and sunscreen (SPF 30 or higher) when out in the sun.
• Avoid unnecessary radiation exposure.
• Avoid smoking or the use of tobacco products.
• Avoid being around secondhand smoke.
• Avoid excessive alcohol use.

Hereditary neuroblastoma care at St. Jude

The St. Jude Cancer Predisposition Program is dedicated to diagnosing and screening children with a genetic predisposition for cancer. Our program offers the best clinical care possible. We engage in cutting-edge research to gain more information about genetic disorders and cancer and to improve the care and treatment for patients who are affected by these conditions. Learn more about the Division of Cancer Predisposition at St. Jude.

Our genetic counselors, clinicians, genetics nurse practitioners, and research assistants work together to provide patients with:

• A complete health history
• A record of cancer that happened over the past 3 generations (family tree or pedigree) to see how diseases were passed down
• Physical exams to check for genetic disease
• Confidential genetic counseling and testing
• Cancer screenings for those with genetic disease to detect and treat cancer as soon as it occurs
• Recommended cancer treatments and ways to reduce cancer risk
• Genetic testing for immediate (1st degree) relatives

Hereditary neuroblastoma increases your child’s risk for cancer. 

Related clinical trials 

St. Jude offers clinical trials and cancer research studies for children, teens, and young adults who have cancers linked to hereditary neuroblastoma . See diseases treated at St. Jude. 
Learn more about clinical research at St. Jude

Resources outside St. Jude