First Article

            Retinoblastoma (RB) is a genetic disease because it is caused by an error, called a mutation, in the retinoblastoma gene.  Normally each person should have two copies of the retinoblastoma gene, one gene inherited from their mother and the second retinoblastoma gene inherited from their father.  Normal retinoblastoma genes make a protein that can stop cells from dividing to make more cells.  Each of our body cells needs at least one of the two copies of the retinoblastoma gene to be working in order to function as a normal cell.  When both copies of the retinoblastoma gene in each cell are damaged (mutated) then that cell keeps dividing and making more copies of itself.  The resulting ball of cells is the retinoblastoma tumor. 

            Usually the first child affected in the family is also the member of the family to have a mutation in the retinoblastoma gene, but some children affected with retinoblastoma inherit the mutation from one of their parents.  This is the reason why when a child is found to have retinoblastoma, it is recommended that brothers and sisters and first cousins be examined by an ophthalmologist at birth and every few months after birth for several years.  Tiny tumors found this way are usually easy to treat thus saving the eye and vision.  Periodically, relatives who are under 7 years of age should be examined under anaesthetic (EUA).

            Retinoblastoma tumors rarely stop growing without treatment, however, some do and they leave a scar in the eye.  Because of this, the parents of children with retinoblastoma as well as their brothers and sisters should be carefully examined to search for such scars, which would indicate which person carries the mutant retinoblastoma gene.

A) THE RETINOBLASTOMA GENE

            Fifty percent of children with retinoblastoma carry a damaged piece of DNA (the retinoblastoma gene) in every cell of their bodies.  All children with retinoblastoma in both eyes (bilateral retinoblastoma) and 15% of children with only one eye affected (unilateral retinoblastoma) have this abnormal retinoblastoma gene.  When they have their own children, there will be a 50% chance that each of his children will also have retinoblastoma.  Individuals with an abnormal retinoblastoma gene in every cell of their body are very likely to develop retinoblastoma tumors as little children, and have a higher risk than the general population to develop other types of tumors later in life.

            Sometimes both RB genes in one retinal cell of one eye both become mutant and develop into a tumor.  Such children have two normal retinoblastoma genes in the rest of their body cells including their cells that will become egg or sperm in the future.  This type of retinoblastoma is not inherited and can not be passed on to the next generation.  These children have unilateral retinoblastoma.  Further, these children are not at an increased risk genetically for other types of tumors later in life.

B) RISK FOR RETINOBLASTOMA

            Each family situation is different and individual counseling is essential.  The risk for other members of the family to be affected is high when the affected child has retinoblastoma in both eyes.  If only one eye has retinoblastoma but there are other family members affected with retinoblastoma, the risks remain high for other relatives.  When the affected child has tumors in one eye and is the only affected individual in the family the risk for relatives to have retinoblastoma is lower.

            Hereditary unilateral retinoblastoma can only be distinguished from non-hereditary unilateral retinoblastoma by identification of the mutations in both copies if the retinoblastoma gene of tumor cells.  A blood sample must then be examined for the same mutations.  Identification of the same retinoblastoma mutation in blood indicates heritable retinoblastoma, while its absence in blood suggests non-heritable retinoblastoma. 

The following charts illustrate the relative risk for each family member of a child affected with either bilateral or unilateral retinoblastoma and the proposed screening schedule.  The following charts should be followed until molecular has determined exactly which relatives carry the mutation and are at risk for developing retinoblastoma.

•Bilateral retinoblastoma:

Unilateral retinoblastoma:

 C) IDENTIFICATION OF THE MUTATION OF THE AFFECTED CHILD

            Most of the relatives of an isolated case of RB will not carry the RB gene mutation, but unless we can identify who in the family has the mutant retinoblastoma gene, all infants must be repeatedly examined for tumor activity.

            To determine which relatives are at risk, a DNA test using blood has been developed to identify the retinoblastoma gene mutation in the person who developed retinoblastoma.  For bilaterally affected persons, blood alone can be used; for unilaterally affected persons, both tumor and blood must be available.  Thirty percent of mutations are easy to find and the results will be available after a few months of study.  Others are harder to find and the test result may not be available for a year.  A few mutations may escape detection no matter how hard we work.

            Once the mutation has been identified in the member of the family who had retinoblastoma, any relatives can be checked to see whether or not they carry the same mutation.  Only children whose test results show the mutation require the intensive clinical examinations to find early tumors.

D)  PRENATAL & NEWBORN MONITORING FOR RETINOBLASTOMA

            For couples in which one individual carries a known heritable retinoblastoma gene mutation, prenatal diagnosis can be done at 10 weeks by CVS or by amniocentesis 16 weeks from the first day of the last menstrual period.  A less risky alternative is to have amniocentesis 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 anaesthetic (EUAs) are not necessary, however, a baby with a 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 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.