Irem Karaer

Leukocoria, defined as a white pupillary reflex, represents one of the most urgent clinical signs in paediatric ophthalmology and should always be regarded as pathological until proven otherwise (1). Leukocoria has a broad differential diagnosis collectively including both malignant and non‑malignant entities, but the immediate clinical priority is to exclude retinoblastoma  without delay (2). Large cohorts have shown that retinoblastoma accounts for a substantial proportion of children referred with leukocoria, while Coats disease, persistent fetal vasculature and other pseudoretinoblastoma conditions constitute most of the remaining cases, and diagnostic delay is associated with advanced disease and poorer visual and survival outcomes (2,3). Consequently, leukocoria must be approached with a high index of suspicion, and retinoblastoma should be considered the default diagnosis until adequately excluded.

Leukocoria has a wide spectrum of differential diagnosis including retinoblastoma, Coats disease, persistent foetal vasculature (PFV), retinopathy of prematurity (ROP), familial exudative vitreoretinopathy (FEVR), cataract, uveitis, toxocariasis, astrocytic hamartoma, coloboma, endophthalmitis, retinal detachment, TORCH syndrome and medulloepithelioma.

Clinical assessment

Evaluation should begin with a focused but thorough history and examination aimed at rapidly stratifying the likelihood of retinoblastoma. Key historical points include the age at onset, duration, past ocular and medical history, whether leukocoria was present at birth indicating PFV, a history of prematurity leading us to ROP, and whether the abnormal reflex was first noticed on photographs or direct observation. Associated features such as strabismus, reduced visual behaviour, prior ocular trauma or infection, and any family history of retinoblastoma, FEVR or inherited eye disease should also be explored (1,4).  

Initial examination in any clinical setting should assess visual acuity, intraocular pressure, fixation and following, ocular alignment, the presence of strabismus or nystagmus, and laterality-comparison of the red reflex between the two eyes using a direct ophthalmoscope or torch (1,5).

Definitive assessment requires specialist examination with dilation and indirect ophthalmoscopy and imaging. This allows careful evaluation of the vitreous, retina, and optic nerve, with particular attention to intraocular masses, subretinal exudation, telangiectatic vessels, retinal detachment, or fibrovascular stalks (1,5).

Any child with leukocoria, especially when accompanied by strabismus, reduced visual responses, or suspicion of an intraocular mass, should be referred urgently to a paediatric ophthalmology or retinoblastoma centre. Prolonged observation or repeated non-specialist reviews risk avoidable diagnostic delay.  

Pseudoleukocoria and Red Reflex Asymmetry

Pseudoleukocoria describes an apparent abnormal red reflex that mimics leukocoria but arises from non-pathological factors such as off-axis fixation, strabismus, or anisometropia. In strabismus, the fixing eye may show a darker reflex while the non-fixing eye appears brighter due to  a reflex from optic disc, creating misleading asymmetry. Similarly, anisometropia can alter reflex brightness due to differences in axial length, with the more myopic eye typically demonstrating a reduced red reflex. These optical variations can be subtle and difficult to interpret, particularly for non-specialist clinicians, highlighting the need for careful assessment and prompt referral when uncertainty exists (5).

Anatomical framework of leukocoria

A practical way to approach leukocoria is to consider the anatomical level at which light scatter or reflection is occurring.

Pathology of the lens and anterior segment, such as congenital or developmental cataract, anterior PFV, or dense corneal opacities, may obstruct the red reflex and produce a white or grey pupillary appearance (5).

Conditions affecting the vitreous or retrolenticular space, including PFV and persistent hyaloid canal, endophthalmitis, or vitritis seen in infections such as toxocariasis, may simulate a mass behind the lens (4,5).

The retina and choroid account for the most clinically significant causes of leukocoria. Retinoblastoma remains the most critical diagnosis to exclude, but other posterior segment conditions, including Coats disease, FEVR, ROP, retinal detachment, coloboma, astrocytic hamartomas and ocular toxoplasmosis, also feature prominently in the differential diagnosis (5).

Age at Presentation

The spectrum of pseudoretinoblastoma conditions presenting with leukocoria varies significantly according to age at presentation. The mean age at diagnosis of retinoblastoma is approximately 18 months, which is the most concerning cause of leukocoria (4). In infants aged 1 year or younger, PFV represents the most common differential diagnosis, with other congenital and early-onset conditions, such as vitreous haemorrhage, coloboma, congenital cataract, and retinal detachment, also occurring predominantly in this age group. In contrast, among children older than 2 years, Coats disease emerges as the most frequent alternative diagnosis. In those older than 5 years, the differential diagnosis shifts further towards acquired or later-presenting conditions, including ocular toxocariasis, FEVR, astrocytic hamartoma, endogenous endophthalmitis, and myelinated retinal nerve fibres. These age-related patterns highlight the importance of considering patient age as a key determinant when prioritising differential diagnoses in the evaluation of leukocoria (3).

Role of imaging

Imaging plays a central role when the posterior segment view is limited or retinoblastoma is suspected. B-scan ultrasonography is an essential first-line investigation. It can identify intraocular masses, detect calcification characterised by high-amplitude echoes with acoustic shadowing, and distinguish between retinal detachment, vitreous pathology, and PFV, even in the presence of dense media opacity (6). Magnetic resonance imaging (MRI) of the orbits and brain is preferred when retinoblastoma is likely, as it allows assessment of optic nerve involvement, extraocular extension, and associated intracranial tumours such as trilateral retinoblastoma. The use of CT scans should be limited due to the increased risk of secondary malignancies associated with radiation exposure in patients with heritable retinoblastoma (6). Optical coherence tomography (OCT), particularly handheld OCT, may provide useful adjunctive information regarding macular involvement or subtle exudation in selected cases, often under anaesthesia (4). Particularly, handheld OCT is gaining more validation on diagnosing, treatment decision and follow-ups for retinoblastoma (7).

Retinoblastoma within the leukocoria spectrum

Retinoblastoma is the most common primary intraocular malignancy of childhood, and in the majority of cases leukocoria is the first clinical sign while the tumour is still confined to the eye, representing a critical window for curative, eye‑salvaging treatment. When diagnosis and treatment follow within roughly 3-6 months of the first appearance of leukocoria, survival is high; in contrast, delays, especially in low‑ and middle‑income settings, lead to presentations with proptosis and orbital extension and are associated with markedly increased mortality (2).​

Within the leukocoria spectrum, retinoblastoma occupies the life‑threatening malignant end of a range. Retinoblastoma arises from biallelic loss of the RB1 tumour suppressor gene on chromosome 13q14, leading to loss of cell-cycle regulation (6). Earlier presentation is associated with bilateral disease. Bilateral retinoblastoma is uniformly heritable and typically presents within the first year of life, whereas most unilateral cases are non-heritable and present later, usually in the second to third year. The typical funduscopic appearance is a yellow‑white retinal mass with dilated feeder vessels, often with calcification, subretinal fluid, and vitreous or subretinal seeds; on B‑scan ultrasonography, a heterogeneous echogenic intraocular mass with high‑reflective foci and acoustic shadowing strongly supports the diagnosis by indicating intralesional calcification (6).​

In clinical practice, any infant or young child presenting with leukocoria should be managed as having retinoblastoma until proven otherwise, with prompt, dilated fundus examination under anaesthesia, ocular ultrasonography, and preferably MRI to distinguish intraocular tumour from retinoblastoma mimickers (2,6).

Distinguishing Pseudoretinoblastoma

For a trainee confronting leukocoria, the differential diagnosis can seem broad, but prevalence data provides a roadmap. In a general paediatric setting, congenital cataract is often the most frequent cause of an abnormal red reflex (1). However, when a patient is referred to a tertiary ocular oncology centre with suspected retinoblastoma, the landscape shifts. In this specialised setting, while retinoblastoma is confirmed in the majority of cases, the remaining are simulating lesions. Among these mimics, Coats disease and PFV are by far the most common entities a trainee will encounter (3).

Congenital cataract

Congenital cataract is a common cause of leukocoria and may present as an isolated finding or in association with systemic disease. It produces a central white or grey pupillary reflex originating from the lens and accounts for a common cause of leukocoria, including unilateral and bilateral presentations. Unilateral cataracts are usually sporadic, whereas bilateral cataracts are frequently associated with underlying conditions, including chromosomal abnormalities (trisomy 13, 18, and 21), systemic syndromes (Alport syndrome, Lowe syndrome, Stickler syndrome, and myotonic dystrophy), metabolic disorders (galactosaemia, Fabry disease, diabetes mellitus, Wilson disease), and intrauterine infections (rubella, cytomegalovirus, toxoplasmosis, syphilis, herpes simplex virus, and varicella). Trauma and radiation exposure may also contribute. Timely diagnosis is essential, as surgery performed before 6 weeks of age in unilateral cataracts and before 8 weeks in bilateral cases is associated with optimal visual outcomes. (1,5).

Coats Disease

Coats disease is an important differential diagnosis in children presenting with leukocoria and typically affects young males, with a later average age at presentation compared to retinoblastoma (3). Clinically, it is characterised by xanthocoria, a yellow pupillary reflex caused by extensive lipid exudation, distinguishing it from the classically white leukocoria seen in retinoblastoma (4,5).

The hallmark feature is retinal telangiectasia with irregular dilatations, often described as a “lightbulb” appearance on fluorescein angiography, accompanied by significant subretinal exudation. A distinguishing sign on fundoscopy is that retinal vessels course over the exudative detachment in Coats disease, whereas they typically dip into the detachment in retinoblastoma. In contrast to retinoblastoma, the vitreous usually remains clear without seeding, and ultrasonography demonstrates subretinal fluid without a solid mass or (4). Although generally sporadic, genetic alterations involving genes such as NDP, CRB1, and PANK2 have been described (1). Advanced complications include anterior chamber cholesterolosis and neovascular glaucoma, which may necessitate enucleation but is preventable with early intervention for retinal detachment (1,4).

Persistent fetal vasculature

PFV is a congenital developmental anomaly caused by failure of regression of the fetal hyaloid vascular system and typically presents in infancy as a unilateral condition. PFV is classically divided into anterior and posterior forms. Anterior PFV primarily affects the anterior segment, presenting with a shallow anterior chamber, lens opacity, and a retrolental fibrovascular membrane or stalk, producing a white pupillary reflex unrelated to neoplastic intraocular masses. Whereas, posterior PFV predominantly involves the vitreoretinal structures and is characterised by vitreous membranes with a persistent stalk, tractional retinal detachment, optic nerve and macular hypoplasia, a typically clear lens, and associated strabismus (1,4). PFV most commonly presents as the combined variant, in which both the anterior and posterior segments are involved, comprising approximately 60% of reported cases (5). Ultrasonography usually demonstrates persistent hyaloid remnants, aiding differentiation from retinoblastoma (4).

Clinical implications

From a trainees perspective, leukocoria is an alarming sign that highlights the value of routine red reflex testing for the early detection of potentially sight- and life-threatening ocular disease, warranting urgent ophthalmological referral when abnormal (5). Early detection, through vigilant clinical examination, parental awareness, and appropriate imaging, remains the cornerstone of reducing preventable vision loss and mortality in children presenting with a white pupillary reflex (2,5). Even when leukocoria is ultimately attributed to non‑tumorous pathology, delayed assessment can result in irreversible visual loss, so educating parents and primary‑care providers that leukocoria is an ophthalmic “red flag” requiring urgent specialist referral is a key component of differential diagnosis within the leukocoria spectrum (5). Structured retinoblastoma screening programs aim to increase early intraocular diagnoses and reduce extraocular disease/mortality, emphasizing leukocoria and screening awareness (8). 

Conclusion

Leukocoria is a critical clinical sign that should always prompt urgent evaluation, with retinoblastoma considered the default diagnosis until safely excluded. Although a range of benign and malignant conditions may underlie a white pupillary reflex, delayed recognition and referral carry significant risks for vision loss and mortality. A structured clinical approach, supported by timely specialist examination and appropriate imaging, is essential to distinguish retinoblastoma from pseudoretinoblastoma conditions while prioritising patient safety. Early detection-through vigilant clinical assessment, red reflex screening, and parental awareness-remains the cornerstone for improving visual and survival outcomes in children presenting with leukocoria.

References

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