Retinoblastoma (OMIM #180200) is a malignant tumor of the immature retina that is caused by mutations in both alleles of the RB1 gene and generally occurs before the age of 5. The occurrence of the tumor may be either unilateral or bilateral. In addition, the hereditary form of retinoblastoma leads to a predisposition to primitive neuroectodermal tumors, most of which are instances of pineoblastoma. In addition, there is an increased risk of developing secondary tumors such as osteosarcomas and other soft tissue sarcomas, tumors of the nasal cavity, the eye, and the orbita, melanomas, and brain tumors.

Key Data

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Gene RB1
In 1.5% of cases with isolated unilateral retinoblastoma: MYCN amplification
Gene product RB1
Function Ubiquitous nuclear phosphoprotein involved in cell cycle regulation (transition from G1 to S phase)
Heredity Autosomal dominant
40% of retinoblastomas are hereditary.
80% of hereditary retinoblastomas are de novo mutations.
Prevalence Incidence of around 1:15.000-1:20.000 live births;
incidence rate of 3-5 per 1 million
Genotype-phenotype correlation Nonsense and frameshift mutations in exons 2 to 25 (the most frequent mutations with familial occurrence) nearly always result in bilateral retinoblastomas with a high level of penetrance.
Missense, promoter, and splice variant mutations have a low level of penetrance and variable expression levels.
Patients with mutations that have a low level of penetrance also exhibit a low risk of developing secondary tumors.
Patients with complete deletion of 13q have the same outcome for retinoblastomas, with pineoblastomas also occurring. In addition, these patients exhibit facial dysmorphia (anteverted ears, a broad forehead, a long philtrum) and neurological impairments of varying degrees.
Penetrance 90-95% for most mutations
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Clinical Diagnostics

Retinoblastoma is suspected when the following findings apply:

  • Leukocoria

  • Strabismus

  • Altered appearance of the eye

  • Reduced vision

The diagnosis of “retinoblastoma” can be confirmed clinically by an ophthalmological examination.

Genetic Diagnostics

Hereditary retinoblastoma is suspected when the following findings apply:

  • Every patient with the diagnosis of “retinoblastoma,” including unilateral and bilateral involvement

  • Patient with retinoma

  • Person with a concomitant family history of retinoblastoma

The diagnosis of “hereditary retinoblastoma” is confirmed by genetic diagnostics. If the sequence analysis or the deletion/duplication analysis fail to detect any pathological findings, a methylation analysis of the RB1 promoter CpG island should be conducted. If no hypermethylation of the promoter is found, MYCN amplification can be tested. This occurs in approximately 1.5% of isolated unilateral retinoblastoma cases.

Differential Diagnoses

The clinical symptoms of the following diseases with ocular involvement may be similar to those of retinoblastoma:

  • Persistent hyperplastic primary vitreous body

  • Coats disease

  • Hereditary diseases, including tuberous sclerosis, Norrie syndrome, Bloch-Sulzberger syndrome (incontinentia pigmenti), familial exudative vitreoretinopathy, and von-Hippel-Lindau syndrome

  • Ocular Toxocara canis infestation (dog roundworm)

Clinical Presentation

A clinical distinction is made between unilateral, bilateral, and trilateral retinoblastoma.

Unilateral Retinoblastoma

Only one eye is affected with this form. Overall, unilateral retinoblastoma is found in approximately 60% of all retinoblastoma patients, with the unilateral form occurring in only 10-15% of patients with hereditary retinoblastoma. The average age at diagnosis is 24 months. Unilateral retinoblastomas are generally unifocal as well.

Bilateral Retinoblastoma

Both eyes are affected with this form. Overall, bilateral retinoblastoma is found in approximately 40% of all retinoblastoma patients, with the bilateral form occurring in the majority of patients with hereditary retinoblastoma. The average age at diagnosis is 15 months. Both eyes are usually already affected by the time the diagnosis is made.

Trilateral Retinoblastoma

In this form, a primitive neuroectodermal tumor (PNET) occurs in addition to the bilateral (or rarely unilateral) retinoblastoma. While it is usually a pineoblastoma, tumors of the suprasellar or parasellar regions have also been described.

Other Tumors

In patients with retinoblastoma, there is an increased risk of other extraocular tumors occurring, called secondary tumors, namely the following:

  • Osteosarcomas

  • Soft tissue sarcomas (usually leiomyosarcomas or rhabdomyosarcomas)

  • Melanomas

They usually develop during adolescence or adulthood. The incidence of secondary tumors is more than 50% higher in retinoblastoma patients who have already undergone percutaneous radiation therapy.

Therapeutic Considerations

The treatment of retinoblastoma depends on a large number of factors and should be planned and carried out by an interdisciplinary team. Removing the tumor to ensure survival is of primary importance, making every effort to preserve the patient’s visual capacity and avoid secondary tumors while doing so. The treatment chosen varies depending on the stage, location, and size of the tumor, the number of foci, the occurrence and type of extraocular tumors, and the resources that are available. Other treatment options include enucleation, cryotherapy, local and systematic chemotherapy, laser coagulation, brachytherapy, and – as a last resort – percutaneous radiation therapy.

If possible, every kind of ionizing radiation should be avoided, including X-rays, CT, and percutaneous radiation, in order to keep the risk of secondary tumors to a minimum.

Surveillance Recommendations

Genetic Counseling

This plays an important role for patients with a hereditary retinoblastoma, especially with regard to screening examinations and the risk of developing secondary tumors, and also when providing care to siblings. Moreover, genetic counseling should be offered again when retinoblastoma patients in complete remission reach childbearing age.

Surveillance Recommendations

The following surveillance examinations are suggested for patients with hereditary retinoblastoma or a concomitant family history:

Intraocular Retinoblastoma

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Age Frequency
Birth to 8 weeks Examinations without sedation every 2 to 4 weeks
8 weeks to 12 months Examinations with sedation once a month
12 to 24 months Examinations with sedation every 2 months
24 to 36 months Examinations with sedation every 3 months
36 to 48 months Examinations with sedation every 4 months
48 to 60 months Examinations with sedation every 6 months
5 to 7 years Examinations without sedation every 6 months
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Trilateral Retinoblastomas

  • Cranial MRI at the time of diagnosis

  • A few centers recommend a cranial MRI every 6 months until the age of 5.

Secondary Tumors

  • Clarification concerning the risk of secondary tumors and being aware of any new signs or symptoms

  • Examinations of the skin as part of regular preventive examinations during childhood. They should be conducted every year by the family doctor, the pediatrician, or a dermatologist.

  • A few centers recommend annual whole-body MRI examinations starting at 8 years of age.

Prenatal Diagnostics

Due to the limited data available, there are currently no standardized recommendations.

Based on current evidence, patients in whom a tumor predisposition was already diagnosed prenatally are not expected to have improved therapeutic outcomes. For this reason, prenatal diagnostics are not recommended in Germany.

When examining the eyes as part of the first neonatal examination, it is important to look for any signs of retinoblastoma (leukocoria, strabismus) that may already be evident. The initial ophthalmological examination for the specific early detection of retinoblastomas should be conducted at an ophthalmology center specialized in retinoblastomas within 14 days after birth.

There is no evidence that ophthalmological examinations for early detection are necessary if it is possible using predictive diagnostics directly after birth to rule out the chance that the child has inherited the known disease-causing change in the family (specific examination). To this end, the consent of the parents should already be obtained before birth so that umbilical cord blood can be collected at birth for the genetic diagnostics. This report can then be consulted to check for a wide range of disease-causing alterations within 1 week and therefore prior to the date of the initial required ophthalmological examination at a center specialized in retinoblastomas.