Second Article

Bilateral Retinoblastoma

Joanne Sutherland, MSc and Brenda Gallie, MD

Eye Genetics Team

The Hospital for Sick Children in Toronto, Ontario CANADA

Retinoblastoma (RB) is the most common eye cancer in children and it can be inherited. The hereditary material is passed on to the next generation as structures called chromosomes and we have 23 pairs of chromosomes in each cell of our body. Chromosomes are very long strings of DNA and genes are small
sections of that DNA. Genes make proteins which are required for the normal development and function of our body. In each body cell there are two genes for every feature that we inherit, one gene we inherit from our mother and one gene we inherit from our father.

The RB gene is located on chromosome 13. The RB gene makes a protein to stop cells from dividing to make more cells. Each of our body cells needs at leas one working copy of the RB gene to function as a normal cell. Different mistakes (mutations) can occur in the RB gene. Some children inherit a normal RB gene from one parent and an RB gene with an error in it from the other parent. Inheriting a mutation in one RB gene predisposes the individual to the development of retinal tumours.

Heritable RB-- all bilateral cases

Children who develop RB tumors in both eyes (bilateral RB) or at more than one site in one eye (multifocal, unilateral RB) have heritable RB, that is, the predisposition to development of RB tumors can be passed on to the next generation of children.

Since only 10% of children with RB have a family history of the disorder, we know that most new cases of heritable RB occur as a new mutation in the mother's egg or the father's sperm or shortly after the egg and sperm combined to start forming the child. This error, in one of the two RB genes, was present right at the beginning of the child's life and is present in every cell of the child's body. The RB mutation would al so be present in the cells which will later form the sperm or egg cells and that is why adults who were treated for RB as a child have a risk of having a child with RB.

For a couple, both unaffected, who have a child with bilateral RB, what is the chance that they will have a second child affected with RB?

There is a 1 in 20 (5%) chance for their next child to have RB. If the parent has a new partner, the new baby is half, 1 in 40 (2.5%). While this is a low risk, it is higher than for couples who do not have a family member affected with retinoblastoma (1 in 20,000).

What is the chance that an individual with bilateral RB will have children with RB?

Children who are affected bilaterally have heritable RB, that is, the predisposition to development of RB tumors can be passed on to the next generation of children. Adults, who have had both eyes treated for RB as a child, have a 50% risk of passing on the RB gene mutation to each child. This mutation, in one of the two RB genes, is present right at the beginning of the child's life and is present in every cell of the child's body. The RB mutation would also be present in the cells which will later form the sperm or egg cells.

Is it possible to have the RB mutation but never have tumors develop?

Yes, usually an individual carrying an RB gene mutation has a risk of around 90% of having tumors develop. There are families in which RB seems to skip generations in which the risk of tumors developing may be much lower (around 30%) but many of the individuals have only one affected eye.

Information for sibs and relatives of an individual diagnosed with RB.

When a child is found to have RB, it is recommended that brothers, sisters and first cousins be offered ophthamological exams and periodic examinations under anaesthetic (EUAs) from birth to age 7. Some ophthalmologists suggest EUAs every three months in the first year, every four months in the second year and every 6 months in the third year. Office eye examinations are recommended twice a year from ages 3 to 5 and once a year until age 7. Most of the relatives of an isolated RB will not carry the RB gene mutation.

For isolated cases of unilateral RB, the risks for relatives of inheriting the RB gene are as follows:


1/20,000 (<<1%) any child born, that is, children with NO aff relatives (pop'n risk)

1/2,000 (<1%) a first cousin of a bilateral RB patient

1/20 (5%) a brother or sister of a bilateral RB patient

1/2 (50%) a child of a bilateral RB patient

1/10 (10%) a parent of a bilateral RB patient is an unaffected carrier (5% each)

1/1 (100%) an identical twin of a bilateral RB patient


The consequences of missing the diagnosis and therefore not providing treatment are so detrimental that the risks of anesthetic for eye examinations is justified. Small tumors can be treated successfully with laser and/or chemotherapy therefore early detection is extremely important to reduce the risk of vision loss and the possibility of the tumors spreading outside the eye via the optic nerve to the rest of the body.

If an individual is the only family member to have bilateral RB, is there a way to find out whether the brothers, sisters and cousins are at risk for developing RB tumors?

Yes, a blood sample can be sent to Dr. Brenda Gallie's laboratory for the "Mutation analysis of the Retinoblastoma gene". This is also called "Molecular Testing". Once the mutation has been identified in the patient, any relative at risk can be screened by one blood test to determine whether or not they carry the same mutation. analysis is complete within 2 weeks. Those who do not carry the mutation can stop having EUAs and those with the mutation should continue. In fact, over 90% of the at-risk relatives will require no further eye examinations. Absence of the family's mutation in an individual strongly predicts that RB will occur at only the risk of the general population for that individual.

What are the possible results of testing and what would the implications be?

First, the lab has to identify the RB gene mutation in the affected individual's blood sample. Then the parents and sibs should be tested for that same error. If the RB mutation is not found in either parents' blood sample, then none of their nieces and nephews are at increased risk for RB tumor development or other types of cancer. If the RB mutation is found in one of the parents' blood samples then only that parent's nieces and nephews are at increased risk for RB. These individuals should have molecular testing to determine whether they have the mutation or not. Individuals found to carry the RB mutation should continue being monitored for RB tumor development by office visits and examinations under anesthetic (EUAs) as appropriate. The extended family members of the other parent are not at risk. EUAs are not necessary for relatives in whom
molecular testing has indicated the absence of the family's RB mutation. When ready to have a family, the individual affected with RB should have genetic counselling and any future child should have molecular testing either prenatally or postnatally so that treatment options can be discussed (50% will be found to require screening for tumors and 50% will not).

What options are available when there is a pregnancy at risk?

For couples in which one individual carries a known heritable RB gene mutation, prenatal diagnosis can be done at 10 (CVS) or 16 (amniocentesis) weeks from the first day of the last menstrual period. A less risky alternative is to test the baby at 36 weeks gestation. DNA analysis is used to determine whether the fetus has inherited the RB gene mutation. A baby without the family's RB mutation can be carried to term and examinations under anesthetic (EUAs) are not necessary. However, a baby with the mutation can be delivered a few weeks early for an ophthalmological examination and/or an early EUA and treatment. Most  small tumors can be treated successfully with laser and/or chemotherapy therefore early detection is extremely important. If the mutation is unknown, a baby can either be delivered early to check for tumors or specialized ultrasound examinations by an experienced operator can be offered starting at 33 weeks gestation to monitor the eyes for indications of tumor development. If there are suspicious findings, a baby may be delivered early. High risk pregnancies (50%) should not be allowed to continue past the due date.