Leukocoria, or “white pupil,” is an abnormal clinical finding of a white pupillary reflex (Figure 40.1). It is often the initial manifestation of a wide range of serious intraocular disorders involving the retina (eg, retinoblastoma), lens (eg, cataract), or vitreous (eg, hemorrhage).¹ The mean age of children at presentation with the chief complaint of “abnormal red reflex” or “leukocoria” is 22.0 + 32.5 months.² In a study by Lin et al., almost 40% of children referred to pediatric ophthalmology for leukocoria had a visually significant diagnosis (retinoblastoma; refractive error requiring glasses; amblyopia; cataracts; strabismus; or a cornea, retina, or iris condition).²

Despite recommended routine pediatric screening with the red reflex test, most children with retinoblastomas initially present with leukocoria detected by a family member.³ Abramson et al.⁴ reported 80% of children with retinoblastoma had their presenting sign of leukocoria initially detected by a parent or a friend, compared with 8% by a pediatrician. As most conditions of leukocoria are vision threatening, the discovery of leukocoria necessitates rigorous etiologic workup and urgent ophthalmology evaluation to assess for life-threatening conditions, in particular retinoblastoma, to avoid serious morbidity and mortality.

Although the differential diagnosis of leukocoria is broad, it can be further narrowed down based on patient history (including history of present illness, birth history with prematurity or trauma), full family history, additional clinical examination findings, and a good ophthalmic examination (including indirect ophthalmoscopy and fundus photography). Whereas older children are often incidentally diagnosed with leukocoria from photographs, infants are mostly diagnosed by fundoscopic examination with finding of asymmetry of the red reflex.¹

Whereas a detailed history is paramount to provide diagnostic clues, a thorough clinical examination is pivotal to the diagnosis of leukocoria. The method of detection of leukocoria depends on the age of onset, certain positions or conditions (eg, dark environment, dilated pupil) to allow for better visualization.^1,3 In addition, the more peripheral a lesion is within the retina, the more important positioning and lighting become.²

The evaluation begins with age-appropriate vision assessment and external examination for the presence or absence of proptosis, orbital mass, signs of ocular trauma, infection, or inflammation (including regional lymphadenopathy).¹ Any child presenting with leukocoria should be evaluated for visual acuity, pupillary reflexes, indirect ophthalmoscopy, and slit lamp examination of both anterior segment and fundus.⁵

The pupils are examined for reactivity and relative afferent defect. A markedly diminished pupillary reflex, a white reflex, dark spots in the reflex, or asymmetry (ie, Brückner reflex) are all considered to be abnormal findings.^5,6 The color of the pupillary reflex also gives a hint of the diagnosis. As an example, white pupillary reflex is typical for retinoblastoma, whereas a yellow reflex (or xanthocoria) could be indicative of Coats disease, and a blue-gray pupil is commonly seen in congenital cataracts.⁷

Extraocular muscle abnormalities can be evaluated by observing gross eye movements, assessing for alignment by observing the corneal light reflex of a single point light source (eg, from a pen light or an otoscope), and the cover/uncover test. Signs of misalignment can be a common finding seen in retinoblastoma. The slit lamp examination can be used to detect cataract, cornea opacity, or anterior chamber inflammation. Lastly, a dilated funduscopic examination can assess the status of the retina (eg, retinal detachment), detect retinal vascular abnormalities or exudates, or the presence of mass lesions.^1,3 Ophthalmology follow-up or urgent consultation is appropriate for this examination.

Ocular point-of-care ultrasound (POCUS) can give accurate and clinically relevant information on intraocular disease in a leukocoria patient. Ultrasound is readily available in the emergency department (ED) without the use of potentially harmful ionizing radiation.⁸ Guidelines no longer recommend computed tomography (CT) imaging for leukocoria owing to the concern for possible retinoblastoma.⁹

The differential diagnosis of leukocoria is extensive. Primary diagnostic considerations and clinical findings associated with the commonly diagnosed conditions of leukocoria are summarized as follows.

Retinoblastoma (Figure 40.2) affects both sexes equally without significant racial or ethnic predilection.^5,7 Nearly all cases are diagnosed before 5 years of age; median age at diagnosis is younger for the bilateral form (<12 months) than for the unilateral unifocal form (24 months).^7,10 Approximately 90% of diagnosed cases of retinoblastoma are sporadic. Overall, retinoblastoma is unilateral in 70% and bilateral in 30% of cases.⁷

Retinoblastoma results from malignant transformation of the primitive retinal cells, caused by a mutation in the RB1 tumor suppressor gene. Heritable retinoblastoma is associated with germline mutations in the RB1 gene. Patients present at an early age and have bilateral and/or multifocal disease, and approximately 10% have a positive family history.⁷ In contrast, children presenting
with nonheritable retinoblastoma typically have unilateral and unifocal disease, have a negative family history, and usually present at a later age. The nonheritable form results from somatic RB1 mutations in the tumor only.¹

Any child presenting with unequivocal leukocoria should prompt urgent referral to an ophthalmologist within 1 week of detection, and sooner when practical, because patient survival in retinoblastoma is highly dependent on early detection and the degree of tumor extension at the time of initial diagnosis.^1,4

Cataract (Figure 40.3) is opacification of the lens, which can cause partial or total blindness if not diagnosed and treated promptly. The most common etiology is idiopathic, but an autosomal-dominant inheritance is also possible.¹¹ Infants and children with cataracts may present with an asymmetric red reflex, leukocoria, strabismus, nystagmus in one or both eyes.^2,11 Cataract in children may be congenital or acquired, unilateral or bilateral.

Cataracts may also be associated with congenital infections such as rubella, toxoplasmosis, herpes simplex virus, and cytomegalovirus (CMV).¹¹ Unilateral cataracts are usually sporadic, whereas bilateral cataracts are associated with other systemic diseases like intrauterine infections (eg, TORCH infection), metabolic disorders (eg, galactosemia), and chromosomal anomalies.⁵ Acquired cataracts may be caused by ocular trauma, uveitis, associated with long-term systemic corticosteroid therapy, and ionizing radiation.^1,11