What Causes Retinoblastoma?

Retinoblastomas are malignant tumors that occur mostly in children below 5 years of age. One of three tumors is bilateral. About 250-350 new cases are diagnosed each year in the US. Thus they make up about 4% of all tumors in childhood. Children with bilateral retinoblastoma (as occurs in 40% of cases) are diagnosed at a mean age of 15 months, while those who have unilateral retinoblastoma are diagnosed at 24 months on average.

The Genetic Basis

Most of these tumors are caused by mutations in the RB1 gene, a tumor suppressor gene on chromosome 13. This gene is responsible for regulating the cell cycle so that cell proliferation proceeds in a planned and controlled fashion. Hundreds of mutations have been found to occur in this gene, most of which inhibit its expression and so prevent the synthesis of the cell cycle regulatory protein called pRB.

This translational product inhibits DNA replication under specific conditions, and so prevents malignant proliferation of a cell clone. It also helps to control cell survival, programmed cell death and cell differentiation. Abnormalities in all these processes are characteristic of cancerous cells, which refuse to undergo apoptosis or maturation. Differentiation usually limits a cell’s ability to proliferate, and thus to become cancerous.  

RB1 mutations lead to the wild and erratic division of a single cell in the retina, which becomes a retinoblastoma. This may be influenced by other genetic changes which facilitate the persistence of this cancerous change.

In another small group of tumors, the mutation responsible is a deletion of genetic material in chromosome 13 which contains other genes as well as the RB1 region. In these children, the presence of the retinoblastoma is accompanied by other distinctive features such as mental retardation, physical growth restriction, and certain characteristic facial appearances including a prominent brow, prominent nasal bridge and ear abnormalities.

Are Retinoblastomas Hereditary?

Retinoblastomas are due to either germinal (inheritable) or non-germinal (nonheritable) mutations in RB1. Germinal mutations are those which occur in every cell of the body, and are hereditary or transmissible. These cells lack one normal RB1 gene already, having been derived from a parent with one abnormal copy of the gene. This is called autosomal dominant inheritance. For the condition to develop, however, the second (normal) copy is mutated early in childhood. This leads to the formation of a retinoblastoma, usually in both eyes. These subjects are prone to develop other tumors. These are chiefly of the pineal gland (in which case the child is said to have trilateral retinoblastoma), the bone, and the muscle, as well as cancers of the pigment-producing cells of the skin, the melanocytes, which produce melanomas. Heritable retinoblastomas account for about 40% of these tumors.

Even so, only 25% of children with heritable mutations have a positive family history. The rest are due to a de novo germline mutation, or to the inheritance of a defective copy of the RB1 gene from a parent who did not develop the disease. This carrier state is seen in approximately ten of every hundred individuals with the mutation.

Non-germinal mutations are found in 60% of retinoblastomas, and occur only in the cancerous cells.  They are therefore not passed on to succeeding generations. There is no family history of the disease. In these individuals as well, the cells are initially normal. Early in life, both normal copies of the RB1 gene undergo mutation within the retinal cells, rendering the genes useless. The tumor usually develops in one eye.

Genetic counseling is necessary to help families decide on whether to undergo screening so that the tumors can be detected early if they do occur, while they are easily treatable. Signs that a retinoblastoma is of the heritable variety include:

  • Bilateral tumors or multiple tumors in one eye
  • Tumors in one eye with a child below one year of age
  • Family history of retinoblastoma

Children with heritable forms of the disease need to be carefully monitored every 2-4 months for at least 28 months to detect new lesions. Pinealomas should be looked for using MRI rather than CT scanning, which exposes the child to ionizing radiation. This screening should be continued for at least 5 years.  


  • https://ghr.nlm.nih.gov/condition/retinoblastoma#inheritance
  • http://kellogg.umich.edu/patientcare/conditions/retinoblastoma.html
  • http://www.cancer.gov/types/retinoblastoma/patient/retinoblastoma-treatment-pdq
  • http://www.djo.harvard.edu/site.php?url=/patients/pi/436

Further Reading

  • All Retinoblastoma Content
  • Retinoblastoma – Malignant Tumor of the Retina
  • Signs and Symptoms of Retinoblastoma
  • Retinoblastoma Screening
  • Diagnosing and Treating Retinoblastoma

Last Updated: Feb 27, 2019

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

Source: Read Full Article