Retinoblastoma (hereditary predisposition)

2019-06-01   Francesca Ariani , Anna Maria Pinto , Alessandra Renieri 

Medical Genetics, University of Siena, Siena, Italy ; Genetica Medica,Azienda Ospedaliera Universitaria Senese, Siena, Italy; email: (AF); GeneticaMedica, Azienda Ospedaliera Universitaria Senese, Siena, Italy ; (AMP); Medical Genetics, University of Siena, Siena, Italy ; Genetica Medica,Azienda Ospedaliera Universitaria Senese, Siena, Italy; email: (AR)



Retinoblastoma (hereditary predisposition)


Predisposition to retinoblastoma is transmitted as an autosomal dominant trait trait with incomplete penetrance (Vogel F, 1979; Eloy P et al., 2016; Imperatore V et al., 2018);; it is caused by mutations in the RB1 gene; there is also a non-hereditary form of retinoblastoma (mostly in children with isolated unilateral retinoblastoma) that is caused by RB1-mutations confined to somatic cells
Atlas Image
Figure 1. In the non-hereditary form of retinoblastoma, the two RB1 mutations occur in somatic retinal cells. Only one eye is affected. Hereditary retinoblastoma arises when the first mutation is inherited via germinal cells. Tumor foci are initiated by the second mutation in somatic retinal cells. Many children with hereditable RB have new germinal mutations, and both parents are normal. Tumors may be unilateral or bilateral.






790 Retinoblastoma




Phenotype and clinics

  • Retinoblastoma in early childhood: white pupillary reflexes (leukocoria) in one or both eyes or strabismus usually are the first signs indicating this malignant eye tumour; other signs include glaucoma, inflammation and poor visual tracking (Abramson DH et al., 1998); in most children with the hereditary retinoblastoma, both eyes are affected by multiple tumour foci (bilateral multifocal retinoblastoma)
  • Adults (most often relatives of patients with retinoblastoma) may show retinal scars indicating indicative of a benign lesion called (non-progressive tumours).
  • In addition to retinoblastoma, children with cytogenetic deletions involving 13q14 may show developmental delay and dysmorphic signs.
  • Coats disease
  • Persistent hyperplastic primary vitreous (PHPV)
  • Ocular toxocariasis
  • Other retinal tumors such as astrocytic hamartoma or medulloepithelioma
  • Hereditary disorders including tuberous sclerosis complex, Norrie disease, incontinentia pigmenti, familial exudative vitreoretinopathy, and  von Hippel-Lindau syndrome
  • Atlas Image
    Figure 2. Ophtalmoscopic evaluation of 15X15 mm macular retinoblastoma (stage B).
    Atlas Image
    Figure 3. Ophthalmoscopic examination of cystic retinoma on the right fundus oculi overwhelming the optic nerve head.

    Neoplastic risk

    Early childhood: formation of retinoblastomas NEOPLASTIC_RISK Adolescence and adulthood: tumors outside the eye (second primary neoplasms):
  • osteosarcoma,
  • melanoma,
  • brain tumours (pinealoma in particular some patients also show multiple benign tumours of adipose tissue (lipoma).
  • Treatment

    Tumor stage, localization\/size of the tumor, number of foci, presence of vitreous seeding and the age of the child can influence the treatment of RB. On the basis of these factors, therapeutic approaches can include focal cryotherapy, laser surgery, radiotherapy or chemotherapy. More recently, intra-arterial selective infusion of chemotherapy in the ophthalmic artery has been introduced (Peterson EC et al., 2011; Venturi C et al., 2013). However, enucleation (removal of the entire eye) is still the standard treatment for advanced intraocular RB, since it is effective in preventing progression to clinical metastatic disease in 95% of cases (Balmer A et al., 2006).
    Surveillance: following the diagnosis of retinoblastoma, repeated examinations under general anesthesia are required for early diagnosis of new tumour foci; up to now, no screening for second primary neoplasms.


    Most often, treatment of retinoblastoma is very effective and, therefore, death from retinoblastoma is rare; however, life span in patients that develop second primary neoplasms is reduced (cumulative mortality at age 40: 6.4% in bilateral patients without radiotherapy, 1.5% in patients with unilateral retinoblastoma).


    Inborn condition

    Large-sized molecular deletions including RB1 have been found in 10% of cases causing a contiguous gene deletion syndrome characterized by retinoblastoma, developmental abnormalities and peculiar facial dysmorphisms such as cranial anomalies, frontal bossing, deeply grooved and long philtrum, depressed and broad nasal bridge, bulbous tip of the nose, thin upper lip, broad cheeks, and large ears and lobules (Kloss et al., 1991; Bojinova RI et al., 2001; Lohmann and Gallie 2004; Albrecht P et al., 2005; Caselli R et al., 2007). Few cases of complex translocations resulting in retinoblastoma are reported, and chromosomes involved of balanced reciprocal translocations with 13q14 include 1, 2, 18, 20, and X (Cross HE et al., 1977; Kajii T et al., 1985; Keith CG et al., 1985; Blanquet V et al., 1987; Trivino E et al., 1997; Laquis SJ et al., 2002; Dries D et al., 2003; Huddleston S et al., 2013).

    Genes involved and Proteins


    Atlas Image
    RB1 at 13q14 in normal cells: PAC 825K21 - Courtesy Mariano Rocchi


    180 kb genomic DNA containing 27 exons


    4.7 kb mRNA with 2.7 kb open reading frame


    928 amino acids nuclear phosphoprotein.


    In most tissues.




    Involved in cell cycle regulation, heterochromatin formation, maintenance of genome stability, regulation of cell differentiation and apoptosis (Dimaras H et al., 2015; Dyson NJ et al., 2016).
    Atlas Image
    Figure 4. Schematic representation of the pRB protein with the sixteen recurrent mutations. RBN, amino-terminal domain; pocket domains (A and B); RBC, RB carboxy-terminal domain.


    More than 1,700 different mutations, ranging from single nucleotide changes to large deletions, have been listed in the RB1 Gene Mutation Database (http:\/\/ A large fraction (~40%) of mutations are recurrent and consist in sixteen hot spots, including twelve nonsense, one missense and three splicing mutations (Valverde JR et al., 2005). Remaining mutations are scattered along the 27 exons, the promoter and intronic regions (splice site and deep intronic mutations). Complete inactivation of the protein is the result of the majority of RB1 mutations (complete loss of function, amorphic mutations). These mutations, mostly represented by nonsense and frameshift changes resulting in premature termination codons (PTC), are generally associated with full penetrance (Valverde JR et al., 2005). RB1 amorphic mutations can be associated to reduced penetrance in association with somatic mosaicism (Imperatore V et al., 2018). Hypomorphic mutations partially inactivating protein function or reducing gene expression combined with a parent-of-origin effect can also be associated to incomplete penetrance or variable expressivity (Kanber D et al., 2009; Eloy P et al., 2016; Imperatore V et al., 2018). Another important class of RB1 oncogenic events is represented by large rearrangements (~15%; Taylor M et al., 2007). They can include only the RB1 gene (entire or a portion) or be a part of a larger contiguous deletion involving other genes. Whole gene deletions are associated to the development of fewer tumors (Albrecht P, et al. 2005; Taylor M et al., 2007). A minimal genomic region associated with low penetrance has been defined and MED4 has been identified as a gene fundamental for the survival of RB1-\/- tumor cells (Dehainault C et al., 2014).


    In the majority of retinoblastoma tissues, the mutations that result in biallelic inactivation of the RB1 gene are accompanied by loss of constitutional heterozygosity (LOH), originating from deletions and several chromosomal mechanisms such as mitotic recombination and nondisjunction (Cavenee WK et al., 1983; Zhu X et al., 1992; Hagstrom SA and Dryja TP, 1999; Lohmann DR et al., 1997). RB1 promoter hypermethylation is observed in about 13% of retinoblastomas (Greger V et al., 1994; Ohtani-Fujita N et al., 1997; Klutz M et al., 1999).


  • In 2009 a 1.2 kb CpG island inside intron 2 (CpG 85) of RB1 was found to show parent-of-origin specific methylation (Kanber D et al., 2009). It is methylated on the maternal chromosome 13 and acts as a weak promoter for an alternative RB1 transcript on the paternal chromosome 13. Paternal mRNA levels are reduced as the result of transcriptional interference of the regular promoter resulting in a ~3 fold excess of the RB1 maternal canonical transcript. As a consequence, RB1 maternally inherited pathogenic variants with hypomorphic effect can retain sufficient suppressor activity to prevent tumor development.
  • In retinoblastoma tissues methylation of a CpG island (CpG106) encompassing the promoter region of RB1 is a quite frequent mechanism inactivating one copy of the gene (Greger et al., 1994). The same predisposing event in patients non tumor cells has been rarely described (Jones et al., 1997; Gelli E et al. 2019).
  • To be noted




    http:\/\/\/home\/dr.lohmann\/index.htm Database of RB1-gene mutations


    Pubmed IDLast YearTitleAuthors
    95449091998Presenting signs of retinoblastoma.Abramson DH et al
    161276852005Spectrum of gross deletions and insertions in the RB1 gene in patients with retinoblastoma and association with phenotypic expression.Albrecht P et al
    35026931987De novo t(2;13)(p24.3;q14.2) and retinoblastoma. Mapping of two 13q14 probes by in situ hybridization.Blanquet V et al
    186217942009Incidence of retinoblastoma in the USA: 1975-2004.Broaddus E et al
    175029912007Retinoblastoma and mental retardation microdeletion syndrome: clinical characterization and molecular dissection using array CGH.Caselli R et al
    66336491983Expression of recessive alleles by chromosomal mechanisms in retinoblastoma.Cavenee WK et al
    9108601977Retinoblastoma in a patient with a 13qXp translocation.Cross HE et al
    248589102014The survival gene MED4 explains low penetrance retinoblastoma in patients with large RB1 deletion.Dehainault C et al
    271894212015Retinoblastoma.Dimaras H et al
    128680362003Interstitial deletion of 13q and a 13;X chromosome translocation results in partial trisomy 13 and bilateral retinoblastoma.Dries D et al
    274015522016RB1: a prototype tumor suppressor and an enigma.Dyson NJ et al
    269259702016A Parent-of-Origin Effect Impacts the Phenotype in Low Penetrance Retinoblastoma Families Segregating the c.1981C>T/p.Arg661Trp Mutation of RB1.Eloy P et al
    28773981986A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma.Friend SH et al
    79596821994Frequency and parental origin of hypermethylated RB1 alleles in retinoblastoma.Greger V et al
    100776181999Mitotic recombination map of 13cen-13q14 derived from an investigation of loss of heterozygosity in retinoblastomas.Hagstrom SA et al
    229248202013A novel translocation t(11;13) (q21;q14.2) in a child with suprasellar primitive neuroectodermal tumor and retinoblastoma.Huddleston S et al
    296621542018Parent-of-origin effect of hypomorphic pathogenic variants and somatic mosaicism impact on phenotypic expression of retinoblastoma.Imperatore V et al
    38794321985Translocation (X;13)(p11.21;q12.3) in a girl with incontinentia pigmenti and bilateral retinoblastoma.Kajii T et al
    40154851985Retinoblastoma and retinoma occurring in a child with a translocation and deletion of the long arm of chromosome 13.Keith CG et al
    20639241991Characterization of deletions at the retinoblastoma locus in patients with bilateral retinoblastoma.Kloss K et al
    99733071999RB1 gene mutations in peripheral blood DNA of patients with isolated unilateral retinoblastoma.Klutz M et al
    52795231971Mutation and cancer: statistical study of retinoblastoma.Knudson AG Jr et al
    118124452002Retinoblastoma in a patient with an X;13 translocation and facial abnormalities consistent with 13q-syndrome.Laquis SJ et al
    93117321997Constitutional RB1-gene mutations in patients with isolated unilateral retinoblastoma.Lohmann DR et al
    93091171997Hypermethylation in the retinoblastoma gene is associated with unilateral, sporadic retinoblastoma.Ohtani-Fujita N et al
    212946212011Selective ophthalmic artery infusion of chemotherapy for advanced intraocular retinoblastoma: initial experience with 17 tumors.Peterson EC et al
    92094651997Characterization by FISH of a t(5;13) in a patient with bilateral retinoblastoma.Triviño E et al
    222689932013Superselective ophthalmic artery infusion of melphalan for intraocular retinoblastoma: preliminary results from 140 treatments.Venturi C et al
    3936141979Genetics of retinoblastoma.Vogel F et al
    15443171992Mechanisms of loss of heterozygosity in retinoblastoma.Zhu X et al