Hereditary Cancer Predisposition Program at the Cancer Center


What is retinoblastoma?

Retinoblastoma is a rare cancer of the eye that arises from the retina, a thin layer of nerve tissue that enables the eye to see. Most cases involve only one eye (unilateral), but in some patients, both eyes may be involved (bilateral). About 300 children are diagnosed with retinoblastoma in the United States each year and boys and girls are equally affected.

Retinoblastoma tumors are composed of immature cells known as retinoblasts. During gestation and early life, retinoblasts are able to actively divide. This is the process that helps make enough cells to populate the retina. As children grow older, their retinal cells undergo a process of maturation and are no longer able to divide. Since retinoblastoma tumors arise from retinoblasts, they generally develop during the first one to two years of life, and only very rarely after 5 years of age.

How do we diagnose retinoblastoma?

The diagnosis of retinoblastoma is made by examining the eyes. If a newborn has a family history of retinoblastoma, the baby should be examined shortly after birth by an ophthalmologist (medical eye doctor) who specializes in cancers of the eye.

If a white pupil or strabismus (crossed-eyes) is noticed by a parent or pediatrician, the child should be referred to an ophthalmologist familiar with the treatment of retinoblastoma. The doctor will do a thorough examination to check the retina for a tumor. Depending on the age of the child, either a local or general anesthetic is used during the eye examination. The ophthalmologist will make a drawing or take a photograph of the tumors in the eyes to provide a record for future examinations and treatments, and may use additional tests to confirm or detect tumors. These tests may include:

Imaging tests

Additional tests 

What causes retinoblastoma?

Retinoblastoma can occur in one of two forms: hereditary retinoblastoma and nonhereditary (sporadic) retinoblastoma.  

Hereditary retinoblastoma

Hereditary retinoblastoma is caused by alterations, also known as mutations, at specific areas within 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 necessary instructions that our cells require to perform their different functions within our bodies.

In patients with hereditary retinoblastoma, the disorder develops as the result of alterations in a specific gene known as RB1, which is located on chromosome 13 at position q14.1-q14.2. RB1 is the only gene known to be associated with hereditary retinoblastoma. The protein produced by the RB1 gene acts as a “tumor suppressor,” which means that it helps to keep cells from growing and dividing too quickly and it promotes cell death.

With the exception of egg and sperm cells, each cell of the body normally has two working copies of the RB1 gene. Patients with hereditary retinoblastoma generally carry an alteration in one copy of the RB1 gene in all the cells of their body. If the second copy of the gene undergoes a change within a retinoblast, a retinoblastoma tumor can develop. Since every cell of the body already has an alteration in the first copy of RB1, it is relatively easy for more than one retinal cell to undergo a change in the second copy of the gene. Therefore, children with hereditary retinoblastoma may have more than one retinoblastoma tumor, and they usually have both eyes affected. All children who develop bilateral retinoblastoma have the hereditary form.

Children with the hereditary form of retinoblastoma are also at a slightly increased risk to develop tumors in the pineal gland (a small gland located in the brain) and possibly another cancer, such as a bone or muscle cancer, later in life. The risk to develop additional tumors is higher in children who receive radiation therapy. If possible, radiotherapy should be avoided to reduce the lifetime risk of developing these additional tumors.

All children with hereditary retinoblastoma have a 50 percent (or 1 in 2) chance of passing the RB1 genetic alteration on to each of their offspring. 

Nonhereditary (sporadic) retinoblastoma

Most children with retinoblastoma do not have the hereditary form. They are not born with an alteration in the RB1 gene in every cell of the body. They develop a tumor in only one eye because both RB1 gene copies in a single retinoblast have undergone genetic alterations. Children with sporadic retinoblastoma are not at increased risk to develop pineal gland or other tumors. They are also not at increased risk to transmit the trait to develop retinoblastoma to their children.

If neither parent has had retinoblastoma and the child is over 2 years of age at diagnosis, the probability of having the hereditary form is very small. If eye tumor tissue is available for study, there is a genetic test that can be done to determine whether the child is one of the approximately 10-15 percent of children with unilateral tumors who have the hereditary form.

Your child’s oncologist will discuss with you which form of retinoblastoma your child might have, whether genetic testing is warranted, and what this information means for follow-up for the child and for other members of your family. 

How is hereditary retinoblastoma inherited?

In 10 to 20 percent of cases of hereditary retinoblastoma, children inherit an alteration in one RB1 gene copy from an affected parent who carries the same genetic mutation. Interestingly, most children with hereditary retinoblastoma do not have a parent with retinoblastoma. In many of these cases, a child develops hereditary retinoblastoma as the result of a “new” mutation in the RB1 gene in one of the father’s sperm, the mother’s eggs, or in a cell of the developing fetus. If this is the case, the child will carry the RB1 gene alteration in all the cells of the body, although they will be the first person in the family to have hereditary retinoblastoma. Less commonly, one parent may have a condition known as “gonadal mosaicism," meaning that the parent carries a genetic alteration in one copy of the RB1 gene in only certain cells of the body, such as the egg or sperm cells, while other cells of the body (including the cells in the retina) have two working copies of RB1. Therefore, this parent will not develop retinoblastoma, but a proportion of their children can inherit the genetic alteration present in the egg or sperm cells.

All children with hereditary retinoblastoma have a 50 percent (or 1 in 2) chance of passing the RB1 genetic alteration on to each of their offspring.

Genetic testing for hereditary retinoblastoma

All children with bilateral eye involvement and somewhere between 10 and 15 percent of children with unilateral disease have the hereditary form of retinoblastoma. To determine on a molecular level whether a person has the hereditary or nonhereditary form of retinoblastoma, a genetic test may be performed.

Testing when eye tumor tissue is available

If eye tumor tissue from the affected individual is available, DNA is isolated from the tumor sample and the two copies of the RB1 gene are evaluated by direct DNA sequencing. Sequencing is a process by which a person’s genetic code is compared to a “normal” reference code. DNA sequencing is performed on the tumor tissue first in order to identify the two RB1 alterations present in the tumor. DNA from a sample of peripheral blood is then screened for the presence of one of the two RB1 gene alterations that was found in the tumor.

If one of the RB1 alterations identified in the tumor sample is also identified in the affected individual’s blood sample, this would strongly support a diagnosis of hereditary retinoblastoma. The absence of any retinoblastoma gene abnormalities in DNA from the blood sample typically confirms a diagnosis of sporadic (non-hereditary) retinoblastoma.

Testing when eye tumor tissue is not available

Eye tumor tissue may not be available for testing in all cases. DNA sequencing can still be performed on a blood sample from the affected individual to investigate for the presence of an alteration in RB1. However, when no tumor is available for comparative genetic study, the failure to identify an alteration in RB1 alteration in the individual’s blood sample does not rule out the possibility that the individual has hereditary retinoblastoma as it remains possible that this individual carries an RB1 mutation that escaped detection due to technical issues related to the genetic testing process.

RB1 genetic test results can provide important information for other family members. Knowing the specific alteration that is present in a person with cancer allows other family members to have testing to determine whether they also carry this alteration in the RB1 gene. 

Options for people considering pregnancy

There are several options for an individual who is found to have an alteration in RB1 and who does not want to pass this alteration on to his or her future children. To do prenatal testing, the familial RB1 mutation must be identified in the affected parent.

If a parent carrying an RB1 alteration does not wish to undergo prenatal testing for retinoblastoma, genetic testing can be performed at birth to determine whether the child inherited the familial mutation. Children who have inherited the familial mutation are at risk to develop retinoblastoma and should follow the surveillance guidelines listed below. Children who did not inherit the familial mutation do not have hereditary retinoblastoma. These children should have eye exams performed as needed for routine pediatric care; they do not need to undergo additional surveillance for retinoblastoma.

What are the cancer risks in children and adults with hereditary retinoblastoma?

During the first 5 years of life, almost all individuals carrying an alteration in RB1 will develop retinoblastoma. However, in some families, the risk to develop retinoblastoma is much less. In these families, the RB1 gene alterations appear to be less damaging.

Individuals with hereditary retinoblastoma are also at a slightly increased risk to develop tumors of the pineal gland.

Later in life, patients may develop other tumors, most commonly bone or muscle tumors. Individuals with retinoblastoma who receive external beam radiation therapy have an increased risk (30-50 percent or higher) to develop second primary tumors over the course of their lives.

Recommended cancer screening protocol for individuals at risk to develop retinoblastoma

Individuals at risk to develop retinoblastoma who should undergo cancer surveillance include:

For these children, it is recommended that they undergo eye exams by an ophthalmologist knowledgeable about retinoblastoma starting directly after birth, performed every three to four weeks until age 1 year and then less frequently until age 5 years. Young or uncooperative children may need to be examined under anesthesia.

To monitor for the development of pineal gland involvement, patients should undergo MRI examinations of the brain every six months until the age of 5 years.

There is currently no consensus regarding recommendations for surveillance for older children with hereditary retinoblastoma who are at risk to develop second malignancies. These individuals should lead a healthy lifestyle, avoid the use of tobacco products and excess sun exposure, and wear sunscreen and a hat when outdoors. They should also be vigilant for unexplained aches and pains, and seek medical attention should these occur, as they could indicate an underlying malignancy. 

Support and information resources for retinoblastoma

GeneReviews: Retinoblastoma

National Library of Medicine Genetics Home Reference: Retinoblastoma

A Parent’s Guide to Understanding Retinoblastoma

National Cancer Institute: Retinoblastoma Home Page 

Reviewed by: Kim Nichols, MD, Kristin Zelley, MS
Date: September 2012

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