Thompson & Thompson Genetics in Medicine, 8th Edition

Case 39. Retinoblastoma (RB1 Mutation, MIM 180200)

Autosomal Dominant


• Tumor suppressor gene

• Two-hit hypothesis

• Somatic mutation

• Tumor predisposition

• Cell-cycle regulation

• Variable expressivity

Major Phenotypic Features

• Age at onset: Childhood

• Leukocoria

• Strabismus

• Visual deterioration

• Conjunctivitis

History and Physical Findings

J.V., a 1-year-old girl, was referred by her pediatrician for evaluation of right strabismus and leukocoria, a reflection from a white mass within the eye giving the appearance of a white pupil (see Fig. 15-7). Her mother reported that she had developed progressive right esotropia in the month before seeing her pediatrician. She had not complained of pain, swelling, or redness of her right eye. She was otherwise healthy. She had healthy parents and a 4-year-old sister; no other family members had had ocular disease. Except for the leukocoria and strabismus, the findings from her physical examination were normal. Her ophthalmological examination defined a solitary retinal tumor of 8 disc diameters arising near the macula. Magnetic resonance imaging of the head did not show extension of the tumor outside the globe and no evidence for an independent primary tumor involving the pineal gland, which is referred to as trilateral disease. She received chemotherapy combined with focal irradiation. DNA analysis showed that she had a germline nonsense mutation (C to T transition) in one allele of her retinoblastoma (RB1) gene.


Disease Etiology and Incidence

Retinoblastoma (MIM 180200) is a rare embryonic neoplasm of retinal origin (Fig. C-39) that results from germline and/or somatic mutations in both alleles of the RB1 gene. It occurs worldwide with an incidence of 1 in 18,000 to 30,000.


FIGURE C-39 Midline cross section of an enucleated eye from a patient with retinoblastoma. Note the large primary tumor in the posterior third of the globe and a few white vitreous seeds. (The brown discoloration of the vitreous is a fixation artifact.) See Sources & Acknowledgments.


The retinoblastoma protein (Rb) is a tumor suppressor that plays an important role in regulating the progression of proliferating cells through the cell cycle and the exit of differentiating cells from the cell cycle. Rb affects these two functions by sequestration of other transcription factors and by promoting deacetylation of histones, a chromatin modification associated with gene silencing.

Retinoblastoma-associated RB1 mutations occur throughout the coding region and promoter of the gene. Mutations within the coding region of the gene either destabilize Rb or compromise its association with enzymes necessary for histone deacetylation. Mutations within the promoter reduce expression of normal Rb. Both types of mutations result in a loss of functional Rb.

An RB1 germline mutation is found in 40% of patients with retinoblastoma, but only 10% to 15% of all patients have a history of other affected family members. RB1 mutations include cytogenetic abnormalities of chromosome 13q14, single-base substitutions, and small insertions or deletions. Some evidence suggests that the majority of new germline mutations arise on the paternal allele, whereas somatic mutations arise with equal frequency on the maternal and paternal alleles. Nearly half of the mutations occur at CpG dinucleotides. After either the inheritance of a mutated allele or the generation of a somatic mutation on one allele, the other RB1 allele must also lose function (the second “hit” of the two-hit hypothesis; see Chapter 15) for a cell to proliferate unchecked and develop into a retinoblastoma. Loss of a functional second allele occurs by a novel mutation, loss of heterozygosity, or promoter CpG island hypermethylation; deletion or the development of isodisomy occurs most frequently, and promoter hypermethylation occurs least frequently.

Retinoblastoma usually segregates as an autosomal dominant disorder with full penetrance although a few families have been described with reduced penetrance. The RB1 mutations identified in these families include missense mutations, in-frame deletions, and promoter mutations. In contrast to the more common null RB1 alleles, these mutations are believed to represent alleles with some residual function.

Phenotype and Natural History

Patients with bilateral retinoblastoma generally present during the first year of life, whereas those with unilateral disease present somewhat later with a peak between 24 and 30 months. Approximately 70% of patients have unilateral retinoblastoma and 30% bilateral retinoblastoma. All patients with bilateral disease have germline RB1 mutations, but not all patients with germline mutations develop bilateral disease. The disease is diagnosed before 5 years of age in 80% to 95% of patients. Retinoblastoma is uniformly fatal if untreated; with appropriate therapy, however, more than 80% to 90% of patients are free of disease 5 years after diagnosis.

As might be expected with mutation of a key cell-cycle regulator, patients with germline RB1 mutations have a markedly increased risk for secondary neoplasms; this risk is increased by environmental factors, such as treatment of the initial retinoblastoma with radiotherapy. The most common secondary neoplasms are osteosarcomas, soft tissue sarcomas, and melanomas. There is no increase in second malignant neoplasms in patients with nonhereditary retinoblastoma.


Early detection and treatment are essential for optimal outcome. The goals of therapy are to cure the disease and to preserve as much vision as possible. Treatment is tailored to the tumor size and involvement of adjacent tissues. Treatment options for intraocular retinoblastoma include enucleation, various modes of radiotherapy, cryotherapy, light coagulation, and chemotherapy, including direct arterial infusion.

If the disease is unilateral at the time of the patient's presentation, the patient needs frequent examinations to detect any new retinoblastomas in the unaffected eye because 30% of apparently sporadic cases are caused by the inheritance of a new germline mutation. Such frequent examinations are usually continued until at least 7 years of age.

To direct follow-up more efficiently, patients should have molecular testing to identify the mutations in the RB1 gene. Ideally, a tumor sample is examined first, and then another tissue, such as blood, is analyzed to determine whether one of those mutations is a germline mutation. If neither mutation is a germline mutation, the patient does not require such frequent follow-up.

Inheritance Risk

If a parent had bilateral retinoblastoma and thus probably carries a germline mutation, the empirical risk for an affected child is 45%; this risk reflects the high likelihood of a second, somatic mutation (or “hit”) in the second RB1 allele of the child. On the other hand, if the parent had unilateral disease, the empirical risk for an affected child is 7% to 15%; this reflects the relative proportion of germline mutations versus somatic mutations in patients with unilateral disease. Nearly 90% of children who develop retinoblastoma are the first individuals affected within the family. Interestingly, 1% of unaffected parents of an affected child have evidence of a spontaneously resolved retinoblastoma on retinal examination; for these families, therefore, the risk for an affected child is 45%. Except for the rare situation in which one parent is a nonpenetrant carrier of an RB1 mutation, families in which neither parent had retinoblastoma have a risk for recurrence equivalent to that of the general population.

Questions for Small Group Discussion

1. What other diseases develop as a result of a high frequency of mutations in CpG dinucleotides? What is the mechanism of mutation at CpG dinucleotides? What could explain the increased frequency of CpG dinucleotide mutations with increasing paternal age?

2. Compare and contrast the type and frequency of tumors observed in Li-Fraumeni syndrome with those observed in retinoblastoma. Both Rb and p53 are tumor suppressors; why are TP53 mutations associated with a different phenotype than RB1 mutations?

3. Discuss four diseases that arise as a result of somatic mutations. Examples should illustrate chromosomal recombination, loss of heterozygosity, gene amplification, and accumulation of point mutations.

4. Both SRY (see Chapter 6) and Rb regulate development by modulating gene expression through the modification of chromatin structure. Compare and contrast the two different mechanisms that each uses to modify chromatin structure.


Lohmann DR, Gallie BL. Retinoblastoma. [Available from]

Villegas VM, Hess DJ, Wildner A, et al. Retinoblastoma. Curr Opin Ophthalmol. 2013;24:581–588.