Leukocoria means “white pupil” and is derived from the Greek words leukos (white) and kore (pupil). It refers to a condition in which a white light reflection is observed instead of the normal red reflex when illuminating the fundus through the pupil.
When there is opacity or an abnormal structure anywhere along the optical path from the cornea to the posterior pole, the red reflex from the choroidal vessels is blocked, resulting in a white pupillary reflex. The causative diseases include tumors, congenital anomalies, vascular diseases, inflammatory diseases, and opacities of the ocular media.
The most important disease in the differential diagnosis of leukocoria is retinoblastoma. Retinoblastoma is the most common intraocular malignant tumor in children, with an estimated incidence of 1 in 15,000–18,000 births2). Leukocoria and strabismus are the main initial signs2), and early detection is directly linked to life prognosis and visual prognosis.
In addition, myelinated retinal nerve fiber layer (MRNFL) is a congenital anomaly found in approximately 1% of the population and may be discovered as leukocoria 1)3).
Retinoblastoma. It is the most common intraocular malignant tumor in children and is directly linked to life prognosis, so when leukocoria is observed, it must be ruled out as a top priority. For details, see the section “Diagnosis and Examination Methods”.
Leukocoria is usually discovered in infants, so there are no subjective complaints. It is often noticed by parents in the following situations.
The normal red reflex is replaced by a white or gray-white reflex. Asymmetry of the reflex between the two eyes (positive Bruckner reflex) is also an important finding.
Depending on the underlying disease, the following may be observed.
Findings specific to the underlying disease are observed.
Asymmetry of the red reflex is an indication for an eye examination. The American Academy of Pediatrics (AAP) recommends red reflex testing for all newborns, infants, and children. A white reflex or asymmetry of the reflex requires prompt referral to an ophthalmologist.
The causes of leukocoria are diverse. Major causative diseases are listed by category.
Tumors
Retinoblastoma: Most important. Caused by RB1 gene mutation (13q14). 95% occur before age 5.
Medulloepithelioma: A rare tumor originating from the ciliary body.
Retinal pigment epithelium (RPE) adenoma/hamartoma: A hamartomatous lesion of the retina and retinal pigment epithelium.
Retinal astrocytic hamartoma: May be associated with tuberous sclerosis.
Congenital Anomalies
Persistent fetal vasculature (PFV): Associated with microphthalmos and a fibrous membrane behind the lens.
Coloboma: Due to incomplete closure of the optic fissure. May involve the optic nerve and choroid.
Myelinated retinal nerve fiber layer (MRNFL): Present in about 1% of the population. May be associated with high myopia and amblyopia.
Others: Norrie disease, incontinentia pigmenti, retinal dysplasia, morning glory syndrome.
Vascular Diseases
Retinopathy of prematurity (ROP): Occurs in preterm and low birth weight infants. Bilateral.
Coats disease: Retinal telangiectasia with exudation. Incidence about 0.09 per 100,000. 85% are young males 6).
Familial exudative vitreoretinopathy (FEVR): Often autosomal dominant inheritance.
Inflammatory and Other Conditions
Ocular toxocariasis: Granulomatous lesion caused by infection with dog roundworm. Unilateral.
Congenital toxoplasmosis: Chorioretinitis due to intrauterine infection.
Cataract: Opacity of the ocular media due to congenital cataract.
Others: Cytomegalovirus retinitis, corneal opacity, and organized vitreous hemorrhage may also be causes. Silicone oil emulsification may also appear as leukocoria5).
According to the 2008 American Academy of Pediatrics (AAP) recommendation, all newborns, infants, and children should undergo red reflex testing before discharge and during routine checkups.
All of the above abnormalities are indications for referral to an ophthalmologist. The transillumination method is useful for diagnosing cataracts and is also important for determining the surgical indication for infantile cataracts.
The differential points of major diseases causing leukocoria are shown below.
| Disease | Laterality | Typical Age of Onset | Ultrasound Features |
|---|---|---|---|
| Retinoblastoma | Unilateral ~70% | 95% by age 5 | Tumor + Calcification |
| Persistent fetal vasculature | Unilateral predominance | Congenital | Cord-like shadow to the optic disc |
| Retinopathy of prematurity | Both eyes | Immediately after birth | Peripheral vascular immaturity |
| Coats disease | Mainly unilateral | School age | Retinal detachment, no calcification |
| Ocular toxocariasis | Unilateral | Variable | Mass without calcification |
Ultrasound is excellent for detecting calcifications and is suitable as an initial screening tool that can be performed quickly in an outpatient setting. MRI is best for differentiating retinoblastoma from Coats disease and persistent fetal vasculature, and can also evaluate optic nerve invasion and choroidal invasion.
Treatment for leukocoria varies greatly depending on the underlying cause. Treatment for each major cause is described below.
Retinoblastoma
Systemic chemotherapy: The standard regimen is a combination of three drugs: vincristine 1.5 mg/m², etoposide 150 mg/m², and carboplatin 560 mg/m²2).
Local therapy: Transpupillary thermotherapy (TTT), laser photocoagulation, and cryocoagulation are used as local treatments2).
Enucleation: Enucleation is performed for unilateral Group E disease with no prospect of visual function, extraocular extension, or failure to respond to eye-preserving treatment10). Biopsy of an intraocular tumor is generally not performed because of the risk of extraocular dissemination of tumor cells.
Coats Disease
Early stage (Stage 1-2): Laser photocoagulation is used to occlude dilated blood vessels6).
Intermediate stage (with significant exudation): Cryotherapy is used to destroy abnormal blood vessels6).
Advanced stage (with retinal detachment): Vitreous surgery or other retinal detachment surgery is performed. If untreated, secondary glaucoma may lead to enucleation6).
MRNFL and Amblyopia
MRNFL itself: This is a benign congenital anomaly and does not require treatment3).
Associated amblyopia: Refractive correction (glasses or contact lenses) and patching (occlusion of the healthy eye) are the basics. Early intervention during the critical period of visual development (up to about 10 years of age) is important1)3).
Concomitant strabismus: If exotropia or other strabismus has a large angle, extraocular muscle surgery is performed3).
For other causative diseases, laser photocoagulation or intravitreal injection of anti-VEGF agents12) is performed for retinopathy of prematurity (ROP), cataract surgery for congenital cataracts, and lensectomy/vitrectomy for persistent fetal vasculature (PFV).
Myelinated retinal nerve fibers (MRNFL) themselves are a benign congenital anomaly and do not require treatment. However, because they are frequently associated with high myopia and amblyopia, early amblyopia treatment with refractive correction and patching affects visual prognosis. For details, see the section “Standard treatment”.
Light from the ophthalmoscope passes through the cornea, anterior chamber, lens, and vitreous to reach the retina. The abundant blood vessels in the choroid beneath the retina reflect light, observed as a red reflex. If there is opacity, tumor, or abnormal structure anywhere in this optical pathway, the red reflex is blocked, resulting in leukocoria.
Biallelic inactivation of the tumor suppressor gene RB1 (located on chromosome 13q14) leads to uncontrolled proliferation of retinal cells2)4).
A white retinal tumor directly blocks the red reflex, presenting as leukocoria.
It is a non-hereditary, sporadic disease, and two pathogenic pathways have been proposed6).
Advanced exudative retinal detachment causes leukocoria.
Normally, myelination of nerve fibers occurs only posterior to the lamina cribrosa, and nerve fibers within the retina are unmyelinated. In MRNFL, immaturity or defect of the lamina cribrosa allows oligodendrocyte-like cells to invade the retina and form myelin sheaths around axons of retinal ganglion cells3). Myelin sheaths impede light transmission, so extensive MRNFL is recognized as leukocoria.
Badalova et al. (2025) reported in a retrospective cohort study using the Dutch National Retinoblastoma Registry (1991–2019) that all 28 cases of familial retinoblastoma who were fully screened from birth were diagnosed before 1 year of age (median age at diagnosis 18 days, range 3–352 days). In 57.1%, the diagnosis was made at the first examination within the first month of life, and 82.1% were diagnosed within 6 months. In the incomplete screening group (10 cases), the median age at diagnosis was 420 days. Based on these results, the protocol was revised to shorten screening for the low-risk group (estimated risk <3%) to up to 2 years of age 7).
Lomi et al. (2025) reported a case of bilateral retinoblastoma in an infant with Dandy-Walker syndrome (DWS). Both DWS and retinoblastoma have been suggested to be associated with chromosome 13q abnormalities, but the coexistence of both diseases is extremely rare. In an MRI study of 168 children with retinoblastoma by Rodjan et al., only one case had a Dandy-Walker variant. This suggests the importance of screening for intraocular malignancy in children with congenital brain malformations8).
It has been discussed that in vitro fertilization (IVF) may increase the risk of developing retinoblastoma through epigenetic abnormalities. A Dutch study suggested an increased incidence of retinoblastoma after IVF, but multiple large-scale epidemiological studies have not found a significant association, and the conclusion remains inconclusive 4).
The triad of myelinated retinal nerve fibers (MRNFL), myopia, and amblyopia is called Straatsma syndrome. Factors associated with visual prognosis include the type of MRNFL (type 1: only the superior arcade, type 2: both the superior and inferior arcades, type 3: not continuous with the optic disc), the degree of anisometropia, and the foveal shape and macular ellipsoid zone structure on OCT. Type 2 had the poorest visual prognosis, whereas poor response to amblyopia treatment was associated with macular findings such as abnormal foveal shape or ellipsoid zone disruption 1).
