Retinoblastoma Predisposition – Definition
Retinoblastoma (OMIM #180200) is a malignant tumor of the immature retina that is based on mutations in both alleles of the RB1 gene and usually occurs before the age of 5. The tumor can occur unilaterally or bilaterally. The hereditary form of retinoblastoma also predisposes to primitive neuroectodermal tumors, the most common of which is pineoblastoma. There is also an increased risk of developing secondary tumors such as osteosarcomas and other soft tissue sarcomas, tumors of the nasal cavity, eye and orbit, melanomas, and brain tumors.
Synonym:
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)
Pattern of inheritance:
Autosomal dominant
40% of retinoblastomas are hereditary.
80% of hereditary retinoblastomas are de novo mutations.
Prevalence:
Incidence about 1:15,000-1:20,000 live births;
Incidence rate 3-5 per 1 million
Genotype-phenotype correlation:
Nonsense and frameshift mutations in exons 2 to 25 (the most common mutations with familial occurrence) almost always lead to bilateral retinoblastomas with high penetrance.
Lower penetrance with variable expressivity is present in missense, promoter, and splice mutations.
Patients with mutations of lower penetrance also show a lower risk of developing secondary tumors.
Patients with complete 13q deletion have the same outcome for retinoblastoma, and pineoblastomas also occur. In addition, these patients exhibit facial dysmorphia (anteverted ears, broad forehead, long philtrum) and varying degrees of neurological impairment.
Penetrance:
90-95% for most mutations
Retinoblastoma Predisposition – Diagnosis
Clinical Diagnostics
A retinoblastoma is suspected if the following findings are present:
- Leukocoria
- Strabismus
- Changed appearance of the eye
- Reduced vision
The diagnosis of “retinoblastoma” can be clinically confirmed by an ophthalmological examination.
Genetic Diagnostics
Hereditary retinoblastoma is suspected in the following cases:
- Any patient with a diagnosis of “retinoblastoma,” including unilateral and bilateral involvement
- Patient with retinoma
- Person with a positive family history of retinoblastoma
The diagnosis of “hereditary retinoblastoma” is confirmed by genetic diagnostics. If there are no pathological findings after sequence analysis and deletion/duplication analysis of RB1, a methylation analysis of the RB1 promoter CpG island can be performed. If there is no hypermethylation of the promoter, a test for MYCN amplification can be performed, which occurs in about 1.5% of cases with isolated unilateral retinoblastoma.
Differential Diagnoses
The following diseases with ocular involvement may be clinically similar to retinoblastoma:
- Persistent hyperplastic primary vitreous
- Coats’ disease
- Hereditary diseases, including tuberous sclerosis, Norrie syndrome, Bloch-Sulzberger syndrome (incontinentia pigmenti), familial exudative vitreoretinopathy, and von Hippel-Lindau syndrome
Ocular infestation of Toxocara canis (canine roundworm)
Clinical Presentation
Clinically, a distinction is made between unilateral, bilateral, and trilateral retinoblastoma.
Unilateral Retinoblastom
In this form, only one eye is affected. Around 60% of all retinoblastoma patients have unilateral retinoblastoma, while only 10-15% of patients with hereditary retinoblastoma have unilateral retinoblastoma. The average age at diagnosis is 24 months. As a rule, unilateral retinoblastomas are also unifocal.
Bilateral Retinoblastoma
In this form, both eyes are affected. Overall, around 40% of all retinoblastoma patients have bilateral retinoblastoma, while most patients with hereditary retinoblastoma have bilateral retinoblastoma. The average age at diagnosis is 15 months. At the time of diagnosis, both eyes are usually already affected.
Trilateral Retinoblastoma
In this form, a primitive neuroectodermal tumor (PNET) occurs in addition to the bilateral (or rarely unilateral) retinoblastoma. This is usually a pineoblastoma, but supra- or parasellar region tumors have also been described.
Other Tumors
Patients with retinoblastoma have an increased risk of developing further extraocular tumors, so-called secondary tumors. These are
- Osteosarcomas
- Soft tissue sarcomas (mostly leiomyosarcomas or rhabdomyosarcomas)
- Melanomas
These usually develop in adolescence or adulthood. The incidence of secondary tumors is increased to over 50% in retinoblastoma patients who have previously received percutaneous radiotherapy.
Special Features of Treatment
The treatment of retinoblastoma depends on many factors and should be planned and carried out on an interdisciplinary basis. The initial aim is to remove the tumor to ensure survival while preserving vision, if possible, and to prevent secondary tumors. The choice of therapy varies depending on the tumor stage, location, and size of the tumor, number of foci, occurrence and type of extraocular tumors, and available resources. Treatment options include enucleation, cryotherapy, local and systemic chemotherapy, laser coagulation, brachytherapy, and, as a last resort, percutaneous radiotherapy.
If possible, any form of ionizing radiation, including X-ray, CT, and percutaneous radiation, should be avoided to minimize the risk of secondary tumors.
Diagnosis of Retinoblastoma Predisposition- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Diagnosis of Retinoblastoma Predisposition- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Recommendations for Early Detection in Your Patients
Genetic Counseling
This plays a major role in patients with hereditary retinoblastoma, particularly in early detection examinations and the risk of developing secondary tumors, as well as in the care of siblings. Furthermore, genetic counseling should be carried out again when survivors of retinoblastoma reach childbearing age.
Examinations for Early Detection
The following screening tests are suggested for patients with hereditary retinoblastoma or a positive family history:
Intraocular Retinoblastomas
| Age | Frequency |
|---|---|
| Birth to 8 weeks | Examinations without sedation every 2 to 4 weeks |
| 8 weeks to 12 months | Examinations under sedation monthly |
| 12 to 24 months | Examinations under sedation every 2 months |
| 24 to 36 months | Examinations under sedation every 3 months |
| 36 to 48 months | Examinations under sedation every 4 months |
| 48 to 60 months | Examinations under sedation every 6 months |
| 5 to 7 years | Examinations without sedation every 6 months |
Trilateral Retinoblastoma
- Cranial MRI at the time of diagnosis
- Some centers recommend cranial MRI every 6 months until the age of 5 years.
Secondary Tumors
- Education regarding the risk of secondary tumors and attentiveness to any new signs or symptoms
- Skin examinations are part of regular preventive examinations in childhood. The family doctor, pediatrician, or dermatologist should continue these annually.
- Some centers recommend annual whole-body MRI examinations from the age of 8.
Prenatal Diagnostics
Due to a lack of data, no standardized recommendation is yet available.
According to current knowledge, a more favorable outcome in terms of therapy-related consequences is not to be expected for patients in whom the tumor disposition has already been determined prenatally. Prenatal diagnostics motivated in this regard are therefore not recommended in Germany.
When examining the eyes as part of the U1 examination, attention should be paid to signs of retinoblastoma that may already be recognizable (leukocoria, strabismus). The first ophthalmological examination for the early detection of retinoblastoma should be carried out in an ophthalmology center specializing in retinoblastoma within 14 days of birth.
Ophthalmologic examinations for early detection are not recognizably required if predictive diagnostics immediately after birth have ruled out the possibility that the child has inherited the known disease-causing change in the family (targeted examination). For this purpose, the parents’ declaration of consent should be obtained prenatally so that umbilical cord vein blood can be taken at birth for genetic diagnostics. A report of the findings is available within 1 week in the case of most pathogenic changes and, therefore, before the date of the otherwise necessary first ophthalmological examination in a center specializing in retinoblastomas.
