Bharat R Agarwal
Retinoblastoma - Introduction
Retinoblastoma is the most common primary tumor of the eye that arises from the nuclear layer of the retina and accounts for about 3% of the cancers occurring in children younger than 15 years of age.

Retinoblastoma can occur in both hereditary (40%) and sporadic (60%) forms. Hereditary disease includes those patients with a positive family history and those patients who have inherited a germline mutation from an unaffected parent. It has been found associated with deletions or mutations of the "Retinoblastoma" gene on the q14band of chromosome 13. The germline form can manifest both as unilateral or bilateral disease. However, most unilateral disease are sporadic where as all bilateral diseases are hereditary. But, unilateral disease in an infant is more likely to be a hereditary condition. 95% of the diagnosed cases of Retinoblastoma occur before the age of 5 years.

The genetic basis of retinoblastoma has been well established. Loss of tumour suppressor function of RB1 gene located on chromosome 13q14, by mutation or deletion leads to RB formation. Apart from this many other mutations may cause uncontrolled growth of immature retinal cells (retinoblastsor retinal progenitor cells) giving rise to this tumor. Recently, lower dietary intake of fresh fruits and vegetables in pregnant mothers has been linked with increased incidence of unilateral ,sporadic cases.

For a normal cell, to convert into an abnormal cell of retinoblastoma, two steps are involved. This is called the "Knudson's two hit hypothesis ". The First hit causes one allele to become abnormal. This alone will not cause retinoblastoma. The second "hit" would "knock off"the only remaining normal allele and hence would give rise to the tumor.
As with most other genetic conditions; based on when and where the mutation occurs, the presentation of the disease differs.

Sporadic non heritable(60%): If the genetic mutation is sporadic, where in both "hits " affect a single somatic cell, it gets mutated, giving rise to a single, unilateral tumor, which is not hereditary. Hence, this type would occur without a family history and without any risk of passing the disease on to the future generations..

Sporadic heritable(30%). A sporadic mutation in RB1 gene occurring in the sperm or the ovum forming the proband, or in in the early embryogenesis and involve his germ cells, so that one hit has already occurred and all cells of the body carry that mutation. Once the second hit occurs, the child develops retinoblastoma. The second hit may occur in many such predisposed cells, hence, these patients are more likely to develop multi focal, and bilateral disease. This type would not have family history, but there would be a risk of passing it on to the future generations, since it is a germ line mutation.

Familial inherited(10%). A familal mutation has been inherited from the parent. All cells in the body carry this mutation. Hence, these patients are also likely to develop multi focal, and bilateral disease. Family history would be positive, as is the risk of passing on the disease to the future generations. Often screening of parents may not show a typical malignant tumor, but a benign retinal tumor or 'retinocytoma' . Sibling screening is important. Prenatal genetic testing is recommended, and in positive cases prenatal diagnosis of the disease is possible.
Moreover in bilateral sporadic and familial cases RB1 gene mutation may produce other tumors like osteo sarcoma, malignant melanoma, Ewing's sarcoma etc.

The name retinoblastoma was coined by Verhoff in 1926. As the name suggests, it is comprised of uncontrolled proliferation of immature cells (retinoblasts) , of the inner layer of the eye; the retina. The possible hereditary nature of this disease was known since early 1900s. Historically, the great physicist Newton had siblings (10 out of 16) lost to this diseases. However, times have changed and currently there is greater than 90%survival of this once deadly disease.

Retinoblastoma has a global incidence of 1 in 15,000 live births. It is the commonest intraocular malignancy in our country. An estimated 2000 new cases are diagnosed in India every year. Almost 90% cases present before the age of 3 years. The mean age of diagnosis is 18 months. In about 1/3rd of cases, the disease could be bilateral . Bilateral cases tend to present earlier (mean age of diagnosis s 14 months) versus unilateral (24months) Sometimes, the tumor may start developing in utero as well.

Retinoblastoma Retinoblastoma 01/03/2001
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