**2. Genetic considerations**

Rb can be inherited by an affected parent or developed *de novo* in a child with no known family history of Rb (i.e., sporadic). The neoplasm can involve one or both eyes and may present in an asymmetrical manner, with different grades in each eye at presentation or even initially appearing as unilateral and becoming bilateral in the course of the disease. The disorder, which is believed to originate from an immature cone photoreceptor cell early in childhood, is initiated in most cases by a mutation in the *RB1* gene. *RB1* loss initially produces a retinoma, the benign precursor of Rb, and causes genomic instability that subsequently leads to the cancerous tumor, Rb.

In hereditary Rb cases, a single *RB1* allele is mutated in most or every cell of a child's body. An additional "hit" in the second allele in the retina will result in clinical Rb. These cases usually present with bilateral and multifocal disease at a median age of 15 months, but can present also in unilateral disease, albeit less frequently. Between 30 and 37% of Rb cases are bilateral [2], and all bilateral cases are hereditary. However, it is estimated that up to 18% of unilateral cases are also hereditary [3]. This emphasizes the importance of genetic testing in addition to clinical examination, as it has direct impact on the recommended screening frequency of the fellow eye and occasionally on management decisions.

Non-hereditary cases (i.e., somatic) usually present at a later age (median: 24 months) with unilateral unifocal disease. In order for the disease to develop in this scenario, two consecutive "hits" occur in a retinal cell, resulting in both *RB1* alleles mutated and the development of clinical Rb.

All familial cases are hereditary, but not necessarily vice versa. A mutation can occur at or after conception in an individual with no family history of Rb, and depending on the stage at which it occurs, some of the fetus' cells will have a mutated *RB1* allele, resulting in mosaicism. Children with mosaicism are at increased risk of developing Rb. The disease in this scenario is not inherited, hence siblings of the proband are not at risk, but offspring potentially are, and therefore should be screened soon after birth.

Hereditary Rb has been associated with an increased risk of developing secondary non-Rb malignancies [4, 5], including sarcomas, carcinomas, malignant melanoma, and neuroectodermal cancers. Secondary tumors were reported to occur in up to 20% of cases in 10 years and the incidence was reported to directly correlate with the time lag from initial diagnosis. It is also well established that treatment by radiotherapy increases the risk of developing secondary tumors, both in and outside the field of radiation [6]. Draper et al. showed in a series of nearly 400 hereditary cases that close to 10% developed secondary malignancies, mainly osteosarcomas, most of which were in the field of radiation [6].

Trilateral Rb is a syndrome consisting of unilateral or bilateral hereditary Rb associated with an intracranial neuroblastic tumor that develops most often in the pineal gland (i.e., Pinealblastoma). On a meta-analysis by Kivelä [7], 2% of trilateral Rb cases had a brain tumor but no intraocular Rb, 12% had unilateral Rb and the remaining had bilateral disease.
