Leukocoria: Differential Diagnosis

Leukocoria is an abnormal white or whitish reflection from the pupil, replacing the normal red reflex, most easily appreciated on red reflex testing or in flash photographs. It is a critical pediatric ophthalmic finding because it is the most common presenting sign of retinoblastoma, the most common primary intraocular malignancy of childhood, making prompt evaluation essential regardless of how benign the underlying cause ultimately proves to be.

Retinoblastoma typically presents under age 2-3, can be unilateral or bilateral, and is associated with germline or somatic RB1 mutations; family history substantially raises risk. Other causes have distinct risk profiles: persistent fetal vasculature is typically sporadic and unilateral, Coats disease shows male predominance, and ROP is specific to preterm, low-birth-weight infants. Mechanistically, leukocoria results whenever a white or reflective structure lies in the visual axis behind the pupil: a calcified tumor mass in retinoblastoma, lens opacification in cataract, a retrolental fibrovascular membrane in persistent fetal vasculature, lipid-rich subretinal exudation in Coats disease, or a detached retinal surface in advanced ROP.

Leukocoria is often first noticed by a parent, sometimes in a flash photograph, or incidentally during red reflex screening. Strabismus is another common presenting sign, particularly in retinoblastoma, sometimes preceding overt leukocoria.

Key differentials: retinoblastoma (leukocoria/strabismus under age 2-3, often a calcified mass), cataract (lens opacification, no mass), persistent fetal vasculature (unilateral, microphthalmia, retrolental stalk), Coats disease (telangiectatic vessels and exudation, male predominance, no discrete mass), and ROP-related retinal detachment (preterm infant with appropriate screening history). Rare mimickers include intraocular medulloepithelioma, which can present with strabismus, leukocoria, and a large mass closely resembling retinoblastoma, distinguishable definitively only by histopathology¹; and neoplastic uveitis masquerade syndromes (diffuse infiltrating retinoblastoma, intraocular leukemia), which can mimic inflammatory uveitis with pseudohypopyon, iris infiltration, or vitreous seeding rather than a classic calcified mass.²

Absent or asymmetric red reflex is assessed with direct ophthalmoscopy or the Bruckner test. Dilated fundus exam, and examination under anesthesia with indirect ophthalmoscopy and scleral depression where retinoblastoma is suspected, characterizes any mass, its extent, and associated findings. Ocular ultrasound detects calcification, a characteristic though not universal retinoblastoma feature. MRI of the orbits and brain characterizes intraocular findings further and excludes trilateral retinoblastoma and extraocular extension. Multimodal imaging — ultrasound, enhanced-depth OCT, fluorescein angiography, and cross-sectional imaging — combined with history and laboratory evaluation helps distinguish retinoblastoma and its mimickers from inflammatory and benign causes.²

Any child with leukocoria requires prompt referral to a pediatric ophthalmologist or ocular oncology service given the possibility of retinoblastoma. Confirmed retinoblastoma is managed by a multidisciplinary ocular oncology team, ranging from focal therapy (laser, cryotherapy) and intra-arterial or intravitreal chemotherapy for localized disease to systemic chemotherapy or enucleation for advanced disease. Other causes of leukocoria are managed according to their specific underlying pathology. Bilateral retinoblastoma warrants surveillance neuroimaging to exclude trilateral retinoblastoma.

• Leukocoria should always be treated as a pediatric ophthalmic emergency until retinoblastoma has been definitively excluded
• The Bruckner test is a fast, accessible screening tool any pediatrician or family physician can use to detect asymmetric or absent red reflexes
• Diffuse infiltrating retinoblastoma often lacks a discrete calcified mass and can closely mimic inflammatory uveitis, a classic diagnostic pitfall²
• Intraocular medulloepithelioma should be kept in mind as a rare retinoblastoma mimicker, especially with atypical histopathology after enucleation¹
• Common pitfall: attributing pseudohypopyon or vitreous seeding in a child to infectious/inflammatory uveitis without considering a neoplastic masquerade syndrome²
• Common pitfall: failing to screen for trilateral retinoblastoma with neuroimaging in bilateral disease