Paeds · ophthalmology

Leukocoria and retinoblastoma

Also known as White pupillary reflex · Cat-eye reflex · Retinoblastoma · RB1 tumour suppressor gene · Two-hit hypothesis · International Intraocular Retinoblastoma Classification · Trilateral retinoblastoma · Ophthalmic artery chemosurgery

Fellowship guide to leukocoria and retinoblastoma in children. Covers the white pupillary reflex as the red-flag sign, the differential diagnosis of leukocoria from the retinoblastoma through the congenital cataract, the Coats disease, the retinopathy of prematurity and the toxocariasis, the RB1 tumour suppressor gene on chromosome thirteen and the Knudson two-hit hypothesis, the heritable and the non-heritable forms, the International Intraocular Retinoblastoma Classification of groups A through E, the imaging with ultrasound and magnetic resonance imaging, the urgent referral to the ocular oncology centre, the risk-adapted treatment from the focal laser and cryotherapy through the ophthalmic artery chemosurgery and the systemic chemotherapy to the enucleation, the trilateral retinoblastoma and its poor prognosis, and the survivorship surveillance for the second malignancy and the late effects.

high10 referencesUpdated 16 July 202632 min readVerification in progress

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Red flags

Any white pupillary reflex or an abnormal red reflex in a child is retinoblastoma until proven otherwise, and it demands a same-day referral to the ophthalmology service, because the leukocoria is the single most important sign of childhood eye cancerA child under two years with a new strabismus, a turn in the eye, has retinoblastoma until the fundus is examined, because the tumour may sit behind the fovea and present with the squint before the leukocoriaA bilateral retinoblastoma is a heritable germline RB1 disease, and it carries the risk of the second primary malignancy, the pineal trilateral retinoblastoma and the transmission to the offspringThe child with retinoblastoma who presents with the proptosis, the orbital cellulitis or the intracranial spread has the advanced extraocular disease that defines the poor-prognosis presentation of the low-resource settingA family history of retinoblastoma in a parent or a sibling demands the genetic testing and the early surveillance of the at-risk infant, because the heritable form is passed with the near-complete penetrance

Life stages

fetalneonateinfanttoddlerpreschool

Care settings

preventive-medical-homecommunity-schooloutpatientwarded-acuterural-remotetelehealth

Clinical exam formats

written-only

Board mappings

Recognises leukocoria, the white pupillary reflex, as the red-flag sign that demands the exclusion of retinoblastoma in any childNames retinoblastoma as the commonest primary intraocular malignancy of childhood, arising from the developing retinal cells and driven by the RB1 tumour suppressor gene on chromosome thirteenPerforms the red reflex test correctly with the direct ophthalmoscope in a dim room and refers any abnormality for the same-day ophthalmology assessmentExplains the Knudson two-hit hypothesis, the heritable germline and the non-heritable somatic forms, and the implication of the bilateral disease for the genetic counselling and the offspring riskApplies the International Intraocular Retinoblastoma Classification of groups A through E and integrates it with the imaging into the risk-adapted treatment planCoordinates the multidisciplinary pathway from the focal laser and cryotherapy through the ophthalmic artery chemosurgery and the systemic chemotherapy to the enucleation, and the survivorship surveillanceA white pupillary reflex or an abnormal red reflex in a child is retinoblastoma until proven otherwise, and it is referred the same day to the ophthalmology service, because the delay costs the eye and the lifeA child with the bilateral retinoblastoma has the heritable germline RB1 disease, and the pineal trilateral retinoblastoma and the second primary malignancy are the risks that define the surveillanceThe prognosis of retinoblastoma is determined by the income of the country, because the high-resource setting presents with the leukocoria and the cure, while the low-resource setting presents with the proptosis and the deathExamines the child with the suspected leukocoria systematically, performing the red reflex test in the dim room and mapping the strabismus and the systemic featuresCounsels the family of a child newly diagnosed with the heritable retinoblastoma about the genetic risk, the offspring risk and the lifelong surveillance for the second malignancySynthesises the multidisciplinary plan that balances the globe salvage, the vision, the systemic control and the late effects across the treatment and the survivorshipLevel 1: Recognition of the leukocoria and the strabismus as the red-flag presentations of retinoblastoma, and performance of the red reflex testLevel 2: Application of the ophthalmology referral, the imaging, the RB1 testing and the International Intraocular Retinoblastoma Classification to the diagnosis and the stagingLevel 3: Coordination of the risk-adapted treatment and the survivorship surveillance across the heritable and the non-heritable formsThe RB1 tumour suppressor gene on chromosome thirteen and the Knudson two-hit hypothesis that explains the heritable and the non-heritable retinoblastomaThe International Intraocular Retinoblastoma Classification of groups A through E and the differential diagnosis of leukocoriaThe trilateral retinoblastoma and the second primary malignancy as the risks of the heritable disease, and the global disparity in the presentation and the outcomeCorrect performance of the red reflex test with the direct ophthalmoscope in the dim room, and the recognition of the leukocoriaCommunication of the diagnosis of the heritable retinoblastoma to the family, balancing the cure of the intraocular disease against the lifelong surveillanceStructured examination that distinguishes the retinoblastoma from the cataract, the Coats disease and the retinopathy of prematurity on the red reflex and the associated featuresRetinoblastoma as the commonest primary intraocular malignancy of childhood, presenting with the leukocoria, the strabismus and the less common red eye or the orbital inflammationThe diagnostic pathway from the red reflex test and the ophthalmology referral to the examination under anaesthesia, the ultrasound and the magnetic resonance imagingThe risk-adapted treatment and the survivorship surveillance, including the RB1 genetic testing and the screening for the trilateral retinoblastomaRecognition of the leukocoria as the red-flag sign that mandates the urgent ophthalmology referralApplication of the red reflex test at the newborn and the well-child examination and the correct interpretation of the abnormal reflexCoordination of the multidisciplinary pathway with the ocular oncology, the genetics and the paediatric oncology servicesCanadian approach to the urgent evaluation and the referral of the child with the leukocoria or the abnormal red reflex suspected to be retinoblastomaThe International Intraocular Retinoblastoma Classification and the RB1 testing as the guides to the treatment intensity and the genetic counsellingThe risk-adapted treatment and the survivorship surveillance for the heritable and the non-heritable retinoblastoma

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Target exams

RACP DWERACP DCEMRCPCH TheoryMRCPCH ClinicalABP General Pediatrics

Red flags

Life stages

fetalneonateinfanttoddlerpreschool

Care settings

preventive-medical-homecommunity-schooloutpatientwarded-acuterural-remotetelehealth

Clinical exam formats

written-only

Board mappings

Overview & Definition

A parent sees a white glow in the pupil of their infant in the flash of a photograph, and the family is unsettled by something they cannot name. A general practitioner performs the red reflex at the six-week check and finds a yellow-white reflex where there should be a warm orange-red. Both have met leukocoria, the white pupillary reflex, and the most important single sign in paediatric ophthalmology, because behind it may sit retinoblastoma, the commonest primary intraocular malignancy of childhood. The clinician who sees the white pupil and moves to the urgent referral without delay is the clinician who saves the eye and the life, because the early retinoblastoma is one of the most curable of all childhood cancers and the late retinoblastoma is one of the most lethal. [1][2]

Retinoblastoma is a tumour of the developing retina that arises from the immature cone-precursor cell, and it is driven by the loss of both copies of the RB1 tumour suppressor gene on the long arm of chromosome thirteen. The disease sits at the intersection of the paediatrics, ophthalmology, oncology and the clinical genetics, because it is at once a cancer, a genetic disease and a model of the tumour suppressor gene. The Knudson two-hit hypothesis, proposed by Alfred Knudson in nineteen-seventy-one to explain the age and the laterality of retinoblastoma, gave the world the concept of the tumour suppressor gene, and it is one of the most consequential ideas in all of oncology. The candidate who can hold the biology, classification, staging and the treatment in one frame holds the whole topic. [1][5][6]

The clinical gravity of the disease is concentrated in the speed of the referral and in the resource of the country. In the high-income setting, where the red reflex is checked at the newborn examination and the well-child visits, the retinoblastoma presents with the leukocoria or the strabismus, the disease is confined to the eye, and the survival is above ninety-five percent. In the low-income setting, where the red reflex is not checked and the specialist is far, the retinoblastoma presents with the proptosis, the orbital cellulitis or the intracranial spread, and the survival is below forty percent. The Global Retinoblastoma Study of the JAMA Oncology, which analysed over four thousand children across the world, showed that the single greatest determinant of the outcome of retinoblastoma is the national income, and it is the fact that the boards reward the candidate who can name. [2][3]

One-sentence answer for the exam

A child with leukocoria, the white pupillary reflex, has retinoblastoma until proven otherwise, and the abnormal red reflex demands a same-day referral to the ophthalmology service. Retinoblastoma is the commonest primary intraocular malignancy of childhood, arising from the developing retina and driven by the loss of both copies of the RB1 tumour suppressor gene on chromosome thirteen, explained by the Knudson two-hit hypothesis as the heritable germline and the non-heritable somatic forms. The disease is classified by the International Intraocular Retinoblastoma Classification of groups A through E, staged by the ultrasound and the magnetic resonance imaging, and treated in a risk-adapted pathway from the focal laser and cryotherapy through the ophthalmic artery chemosurgery and the systemic chemotherapy to the enucleation of the unsalvageable eye. The heritable bilateral disease carries the risk of the trilateral retinoblastoma and the second primary malignancy, and the survival is above ninety-five percent in the high-income setting and below forty percent in the low-income setting.

[1][2][5][6]

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References10Show ledger

[1]Dimaras H, Corson TW, Cobrinik D, et al. Retinoblastoma. Nat Rev Dis Primers, 2015.PMID 27189421
[2]Fabian ID, Abdallah E, Abdullahi SU, et al. Global Retinoblastoma Presentation and Analysis by National Income Level. JAMA Oncol, 2020.PMID 32105305
[3]Dimaras H, Corson TW Retinoblastoma, the visible CNS tumor: A review. J Neurosci Res, 2019.PMID 29314142
[4]Thériault BL, Dimaras H, Gallie BL, et al. The genomic landscape of retinoblastoma: a review. Clin Exp Ophthalmol, 2014.PMID 24433356
[5]Chernoff J The two-hit theory hits 50. Mol Biol Cell, 2021.PMID 34735271
[6]Mastrangelo D, De Francesco S, Di Leonardo A, et al. The retinoblastoma paradigm revisited. Med Sci Monit, 2008.PMID 19043380
[7]Sábado Alvarez C Molecular biology of retinoblastoma. Clin Transl Oncol, 2008.PMID 18628066
[8]Rodjan F, de Graaf P, Brisse HJ, et al. Trilateral retinoblastoma: neuroimaging characteristics and value of routine brain screening on admission. J Neurooncol, 2012.PMID 22802019
[9]Mouratova T Trilateral retinoblastoma: a literature review, 1971-2004. Bull Soc Belge Ophtalmol, 2005.PMID 16281731
[10]Taich P, Requejo F, Asprea M, et al. Topotecan Delivery to the Optic Nerve after Ophthalmic Artery Chemosurgery. PLoS One, 2016.PMID 26959658

Leukocoria and retinoblastoma

high10 referencesUpdated 16 July 202632 min readVerification in progress

Practise this topic

Overview & Definition

Paediatrics Fellowship Pro

You have read the opening of this topic. The complete unit — every section and its primary-source references — is part of the Paediatrics Fellowship fellowship atlas.

References10Show ledger

[1]Dimaras H, Corson TW, Cobrinik D, et al. Retinoblastoma. Nat Rev Dis Primers, 2015.PMID 27189421
[2]Fabian ID, Abdallah E, Abdullahi SU, et al. Global Retinoblastoma Presentation and Analysis by National Income Level. JAMA Oncol, 2020.PMID 32105305
[3]Dimaras H, Corson TW Retinoblastoma, the visible CNS tumor: A review. J Neurosci Res, 2019.PMID 29314142
[4]Thériault BL, Dimaras H, Gallie BL, et al. The genomic landscape of retinoblastoma: a review. Clin Exp Ophthalmol, 2014.PMID 24433356
[5]Chernoff J The two-hit theory hits 50. Mol Biol Cell, 2021.PMID 34735271
[6]Mastrangelo D, De Francesco S, Di Leonardo A, et al. The retinoblastoma paradigm revisited. Med Sci Monit, 2008.PMID 19043380
[7]Sábado Alvarez C Molecular biology of retinoblastoma. Clin Transl Oncol, 2008.PMID 18628066
[8]Rodjan F, de Graaf P, Brisse HJ, et al. Trilateral retinoblastoma: neuroimaging characteristics and value of routine brain screening on admission. J Neurooncol, 2012.PMID 22802019
[9]Mouratova T Trilateral retinoblastoma: a literature review, 1971-2004. Bull Soc Belge Ophtalmol, 2005.PMID 16281731
[10]Taich P, Requejo F, Asprea M, et al. Topotecan Delivery to the Optic Nerve after Ophthalmic Artery Chemosurgery. PLoS One, 2016.PMID 26959658