Heritable retinoblastoma
Heritable retinoblastoma (ORPHA:790, OMIM:180200) is the hereditary form of retinoblastoma, a malignant tumour of the developing retina that is the most common malignant intraocular neoplasm in childhood. The incidence of retinoblastoma is estimated between 1 in 15,000 and 1 in 20,000, of which about 50% are associated with the heritable form. In heritable retinoblastoma, the tumours are often multifocal and bilateral, and rarely there may be a family history of retinoblastoma. People with heritable retinoblastoma have an increased risk of developing other types of tumours, including retinoma (the benign precursor of retinoblastoma), pinealoblastoma, osteosarcoma, soft tissue sarcomas and melanoma. The risk is particularly increased after radiation therapy.
Heritable retinoblastoma is caused by a germline heterozygous pathogenic variant in the RB1 gene, encoding a nuclear protein that is involved in cell cycle regulation. In patients with this predisposition, retinoblastoma begins to develop when the second copy of the RB1 gene is also altered or lost in a developing retinal cell.
Heritable retinoblastoma is inherited in an autosomal dominant manner. Each affected individual has a 50% chance of passing on the familial pathogenic variant in the RB1 gene to their children, who are expected to develop retinoblastoma.
However, only a minority of individuals with heritable retinoblastoma inherited an RB1 pathogenic variant from an affected parent, and the majority of pathogenic variants newly occurred within an individual (de novo origin), so that the person with retinoblastoma is the only affected person in the family.
Notably, in the majority of carriers of RB1 pathogenic variants the penetrance (that is, the risk of developing retinoblastoma) is nearly 100%. However, a few specific variants may be associated with a significantly lower risk (<25%) of developing retinoblastomas. Further, in some cases risk may also be dependent on the parental (maternal vs paternal) origin of the variant.
Preimplantation and prenatal genetic testing are possible if the pathogenic variant of the RB1 gene has been identified.
Carriers of germline heterozygous RB1 pathogenic/likely pathogenic variants should have regular eye examinations from birth (initially every 3-4 weeks) and throughout childhood, and prompt clinical evaluation for any signs/symptoms of non-ocular malignancies. Routine dermatological surveillance is recommended given the increased risk of melanoma. Annual history and exam can be considered and signs and symptoms possibly related to a secondary malignancy should be promptly evaluated.
In order to minimize the lifetime risk of developing subsequent malignancies, individuals with heritable retinoblastoma should avoid unnecessary radiation (e.g., X-rays, CT scans, etc.) and DNA-damaging agents such as tobacco and UV light. Chemotherapy should also be considered carefully.
More information regarding heritable retinoblastoma:
https://www.orpha.net/en/disease/detail/357027
https://www.ncbi.nlm.nih.gov/books/NBK1452/
https://pmc.ncbi.nlm.nih.gov/articles/PMC5744255/pdf/nihms928879.pdf
https://pmc.ncbi.nlm.nih.gov/articles/PMC7606265/pdf/nihms-1596662.pdf
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A list of healthcare providers with expertise in Thematic Group 4: Other rare - predominantly malignant - genturis can be found here.
A non-exhaustive list of patient associations for genetic tumour risk syndromes in EU member states can be found here.