Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

Retinoblastoma (hereditary predisposition)

Written2019-06Francesca 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)
This article is an update of :
1998-10Dietmar R Lohmann
Institut fuer Humangenetik, Hufelandstr. 55, D-45122 Essen, Germany
Abstract Review on Retinoblastoma, with data on clinics, and the gene involved.

Keyword Retinoblastoma, RB1, pRB, tumor suppressor, cell cycle regulation, leukokoria, retinoma, sarcoma, melanoma, brain tumors, reduced penetrance.

(Note : for Links provided by Atlas : click)


Atlas_Id 10031
Genes implicated inRB1  
Inheritance 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
  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.


Note Retinoblastoma (RB) is the most common intraocular tumor in children, affecting about 1 in 15,000 to 20,000 live births (Broaddus E et al., 2009). It is caused by biallelic inactivation of RB1 gene located at 13q14.2 (Knudson AG Jr, 1971; Friend SH et al., 1986). The most frequent form is the non hereditary one (60%), with both inactivating events occurring in retinal cells. In this form, the tumor is unilateral with onset after the first year of life in the majority of cases. The hereditary form (40%) is due to a RB1 germline predisposing mutation and subsequent somatic inactivation of the other allele. This form is generally multifocal and/or bilateral with an anticipation of the mean age of diagnosis (within the first year of life). Hereditary RB is transmitted according to an autosomal dominant pattern with incomplete penetrance, generally reported as equal to 90%. A significant fraction of mutation carriers remain unaffected or develop only benign lesions called retinomas (Harbour JW, 2001).
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
      Figure 2. Ophtalmoscopic evaluation of 15X15 mm macular retinoblastoma (stage B). 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.
    Prognosis 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 conditions 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

    Gene NameRB1 (retinoblastoma)
    Alias p105-Rb
    Location 13q14.2
    Description 180 kb genomic DNA containing 27 exons
    Transcription 4.7 kb mRNA with 2.7 kb open reading frame
    Description 928 amino acids nuclear phosphoprotein.
    Expression In most tissues.
    Localisation nucleus
    Function 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).
    Germinal More than 1,700 different mutations, ranging from single nucleotide changes to large deletions, have been listed in the RB1 Gene Mutation Database ( 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).
    Somatic 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).


    Presenting signs of retinoblastoma
    Abramson DH, Frank CM, Susman M, Whalen MP, Dunkel IJ, Boyd NW 3rd
    J Pediatr 1998 Mar;132(3 Pt 1):505-8
    PMID 9544909
    Spectrum of gross deletions and insertions in the RB1 gene in patients with retinoblastoma and association with phenotypic expression
    Albrecht P, Ansperger-Rescher B, Schüler A, Zeschnigk M, Gallie B, Lohmann DR
    Hum Mutat 2005 Nov;26(5):437-45
    PMID 16127685
    De novo t(2;13)(p24
    Blanquet V, Turleau C, Créau-Goldberg N, Cochet C, de Grouchy J
    3;q14 2) and retinoblastoma
    PMID 3502693
    Incidence of retinoblastoma in the USA: 1975-2004
    Broaddus E, Topham A, Singh AD
    Br J Ophthalmol 2009 Jan;93(1):21-3
    PMID 18621794
    Retinoblastoma and mental retardation microdeletion syndrome: clinical characterization and molecular dissection using array CGH
    Caselli R, Speciale C, Pescucci C, Uliana V, Sampieri K, Bruttini M, Longo I, De Francesco S, Pramparo T, Zuffardi O, Frezzotti R, Acquaviva A, Hadjistilianou T, Renieri A, Mari F
    J Hum Genet 2007;52(6):535-42
    PMID 17502991
    Expression of recessive alleles by chromosomal mechanisms in retinoblastoma
    Cavenee WK, Dryja TP, Phillips RA, Benedict WF, Godbout R, Gallie BL, Murphree AL, Strong LC, White RL
    Nature 1983 Oct 27-Nov 2;305(5937):779-84
    PMID 6633649
    Retinoblastoma in a patient with a 13qXp translocation
    Cross HE, Hansen RC, Morrow G 3rd, Davis JR
    Am J Ophthalmol 1977 Oct;84(4):548-54
    PMID 910860
    The survival gene MED4 explains low penetrance retinoblastoma in patients with large RB1 deletion
    Dehainault C, Garancher A, Castéra L, Cassoux N, Aerts I, Doz F, Desjardins L, Lumbroso L, Montes de Oca R, Almouzni G, Stoppa-Lyonnet D, Pouponnot C, Gauthier-Villars M, Houdayer C
    Hum Mol Genet 2014 Oct 1;23(19):5243-50
    PMID 24858910
    Dimaras H, Corson TW, Cobrinik D, White A, Zhao J, Munier FL, Abramson DH, Shields CL, Chantada GL, Njuguna F, Gallie BL
    Nat Rev Dis Primers 2015 Aug 27;1:15021
    PMID 27189421
    Interstitial deletion of 13q and a 13;X chromosome translocation results in partial trisomy 13 and bilateral retinoblastoma
    Dries D, Baca K, Truss L, Dobin S
    Ophthalmic Genet 2003 Sep;24(3):175-80
    PMID 12868036
    RB1: a prototype tumor suppressor and an enigma
    Dyson NJ
    Genes Dev 2016 Jul 1;30(13):1492-502
    PMID 27401552
    A Parent-of-Origin Effect Impacts the Phenotype in Low Penetrance Retinoblastoma Families Segregating the c
    Eloy P, Dehainault C, Sefta M, Aerts I, Doz F, Cassoux N, Lumbroso le Rouic L, Stoppa-Lyonnet D, Radvanyi F, Millot GA, Gauthier-Villars M, Houdayer C
    1981C>T/p Arg661Trp Mutation of RB1
    PMID 26925970
    A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma
    Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TP
    Nature 1986 Oct 16-22;323(6089):643-6
    PMID 2877398
    Frequency and parental origin of hypermethylated RB1 alleles in retinoblastoma
    Greger V, Debus N, Lohmann D, Höpping W, Passarge E, Horsthemke B
    Hum Genet 1994 Nov;94(5):491-6
    PMID 7959682
    Mitotic recombination map of 13cen-13q14 derived from an investigation of loss of heterozygosity in retinoblastomas
    Hagstrom SA, Dryja TP
    Proc Natl Acad Sci U S A 1999 Mar 16;96(6):2952-7
    PMID 10077618
    A novel translocation t(11;13) (q21;q14
    Huddleston S, McNall-Knapp RY, Siatkowski M, Odom C, Brennan R, Wilson MW
    2) in a child with suprasellar primitive neuroectodermal tumor and retinoblastoma Ophthalmic Genet
    PMID 22924820
    Parent-of-origin effect of hypomorphic pathogenic variants and somatic mosaicism impact on phenotypic expression of retinoblastoma
    Imperatore V, Pinto AM, Gelli E, Trevisson E, Morbidoni V, Frullanti E, Hadjistilianou T, De Francesco S, Toti P, Gusson E, Roversi G, Accogli A, Capra V, Mencarelli MA, Renieri A, Ariani F
    Eur J Hum Genet 2018 Jul;26(7):1026-1037
    PMID 29662154
    Translocation (X;13)(p11
    Kajii T, Tsukahara M, Fukushima Y, Hata A, Matsuo K, Kuroki Y
    21;q12 3) in a girl with incontinentia pigmenti and bilateral retinoblastoma
    PMID 3879432
    Retinoblastoma and retinoma occurring in a child with a translocation and deletion of the long arm of chromosome 13
    Keith CG, Webb GC
    Arch Ophthalmol 1985 Jul;103(7):941-4
    PMID 4015485
    Characterization of deletions at the retinoblastoma locus in patients with bilateral retinoblastoma
    Kloss K, Währisch P, Greger V, Messmer E, Fritze H, Höpping W, Passarge E, Horsthemke B
    Am J Med Genet 1991 May 1;39(2):196-200
    PMID 2063924
    RB1 gene mutations in peripheral blood DNA of patients with isolated unilateral retinoblastoma
    Klutz M, Horsthemke B, Lohmann DR
    Am J Hum Genet 1999 Feb;64(2):667-8
    PMID 9973307
    Mutation and cancer: statistical study of retinoblastoma
    Knudson AG Jr
    Proc Natl Acad Sci U S A 1971 Apr;68(4):820-3
    PMID 5279523
    Retinoblastoma in a patient with an X;13 translocation and facial abnormalities consistent with 13q-syndrome
    Laquis SJ, Rodriguez-Galindo C, Wilson MW, Fleming JC, Haik BG
    Am J Ophthalmol 2002 Feb;133(2):285-7
    PMID 11812445
    Constitutional RB1-gene mutations in patients with isolated unilateral retinoblastoma
    Lohmann DR, Gerick M, Brandt B, Oelschläger U, Lorenz B, Passarge E, Horsthemke B
    Am J Hum Genet 1997 Aug;61(2):282-94
    PMID 9311732
    Hypermethylation in the retinoblastoma gene is associated with unilateral, sporadic retinoblastoma
    Ohtani-Fujita N, Dryja TP, Rapaport JM, Fujita T, Matsumura S, Ozasa K, Watanabe Y, Hayashi K, Maeda K, Kinoshita S, Matsumura T, Ohnishi Y, Hotta Y, Takahashi R, Kato MV, Ishizaki K, Sasaki MS, Horsthemke B, Minoda K, Sakai T
    Cancer Genet Cytogenet 1997 Oct 1;98(1):43-9
    PMID 9309117
    Selective ophthalmic artery infusion of chemotherapy for advanced intraocular retinoblastoma: initial experience with 17 tumors
    Peterson EC, Elhammady MS, Quintero-Wolfe S, Murray TG, Aziz-Sultan MA
    J Neurosurg 2011 Jun;114(6):1603-8
    PMID 21294621
    Characterization by FISH of a t(5;13) in a patient with bilateral retinoblastoma
    Triviño E, Guitart M, Egozcue J, Coll MD
    Cancer Genet Cytogenet 1997 Jul 1;96(1):23-5
    PMID 9209465
    Superselective ophthalmic artery infusion of melphalan for intraocular retinoblastoma: preliminary results from 140 treatments
    Venturi C, Bracco S, Cerase A, Cioni S, Galluzzi P, Gennari P, Vallone IM, Tinturini R, Vittori C, De Francesco S, Caini M, D'Ambrosio A, Toti P, Renieri A, Hadjistilianou T
    Acta Ophthalmol 2013 Jun;91(4):335-42
    PMID 22268993
    Genetics of retinoblastoma
    Vogel F
    Hum Genet 1979 Nov 1;52(1):1-54
    PMID 393614
    Mechanisms of loss of heterozygosity in retinoblastoma
    Zhu X, Dunn JM, Goddard AD, Squire JA, Becker A, Phillips RA, Gallie BL
    Cytogenet Cell Genet 1992;59(4):248-52
    PMID 1544317


    This paper should be referenced as such :
    Francesca Ariani, Anna Maria Pinto, Alessandra Renieri
    Retinoblastoma (hereditary predisposition)
    Atlas Genet Cytogenet Oncol Haematol. 2020;24(2):97-101.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :
    History of this paper:
    Lohmann, DR. Retinoblastoma. Atlas Genet Cytogenet Oncol Haematol. 1999;3(1):48-49.

    Other genes implicated (Data extracted from papers in the Atlas) [ 2 ]

    Genes RB1 RB1

    External links

    Other databaseRetinoblastoma (GARD)
    Other databaseDatabase of RB1-gene mutations
    Genes implicated inRB1   [ Atlas ]   [ Entrez ]  [ LOVD ]  [ GeneReviews ]  

    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Fri Oct 1 16:52:47 CEST 2021

    Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

    For comments and suggestions or contributions, please contact us