Approach to the child with leukocoria

INTRODUCTION — Leukocoria describes the clinical finding of a white pupillary reflex (picture 1). There are many causes of leukocoria in children (table 1); the differential diagnosis can be narrowed through a complete clinical and family history and thorough ophthalmic examination.

An overview of the causes of leukocoria in children and an approach to the diagnostic evaluation are presented here. Retinoblastoma is discussed in detail separately. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis" and "Retinoblastoma: Treatment and outcome".)

TERMINOLOGY

●Leukocoria – The term leukocoria means "white pupil" (from the Greek "leukos" meaning white and "kore" meaning pupil) and is the name given to the clinical finding of a white pupillary reflex (picture 1). Leukocoria can be caused by abnormalities in the lens (eg, cataract), vitreous (eg, hemorrhage), or retina (eg, retinoblastoma) (table 1) [1,2]. It can be the initial manifestation of a wide spectrum of intraocular and systemic disease processes [3-7].

●Pseudoleukocoria – Pseudoleukocoria refers to transient leukocoria that is caused by reflection of a normal optic disc. Pseudoleukocoria may also be observed in children with anisometropia (asymmetric refractive error) and anisometropic amblyopia, in which the pupil of the eye that is well focused may appear darker than the pupil of the eye that is less well focused. (See "Amblyopia in children: Classification, screening, and evaluation".)

Though pseudoleukocoria may represent a benign finding in some children, a complete ophthalmologic evaluation is required to exclude more serious pathology. Thus, all children with newly discovered leukocoria should be referred urgently (ie, within one week) to an ophthalmologist to exclude retinoblastoma and other life- or sight-threatening conditions [8]. (See 'Referral' below.)

CAUSES OF LEUKOCORIA — Common causes of leukocoria in children include (table 1):

●Retinoblastoma – Approximately 20 to 60 percent of cases [9-12]

●Cataract – One of the most common causes, 60 percent in one series [11]

●Coats disease – Approximately 30 to 40 percent of those referred for suspected retinoblastoma [10,12]

●Persistent fetal vasculature (PFV) – Approximately 30 percent of those referred for suspected retinoblastoma [10,12]

●Vitreous hemorrhage – 5 percent of those referred for suspected retinoblastoma [12]

●Ocular toxocariasis – 4 percent of those referred for suspected retinoblastoma [12]

●Hereditary retinal dysplasia (eg, familial exudative vitreoretinopathy, incontinentia pigmenti) – 3 percent of those referred for suspected retinoblastoma [12]

●Retinal detachment (eg, due to trauma, severe retinopathy of prematurity [ROP], or retinal dysplasia) – 3 percent of those referred for suspected retinoblastoma [12]

●Coloboma (fissure or cleft) of the optic disc – 3 percent of those referred for suspected retinoblastoma [12]

●Astrocytic hamartoma – 2 percent of those referred for suspected retinoblastoma [12]

Retinoblastoma — Retinoblastoma (picture 2) is the most common intraocular tumor of childhood. Nearly all cases are diagnosed before five years of age; most present before three years of age. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Epidemiology'.)

Leukocoria is the most common presenting finding. Other common presenting symptoms include strabismus (picture 3), nystagmus, and red eye. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Clinical features'.)

Retinoblastoma occurs in heritable forms (ie, due to germline RB1 gene mutations, which account for approximately 40 percent of cases) and nonheritable forms (ie, due to somatic RB1 gene mutations in the tumor only, which account for approximately 60 percent of cases) (figure 1). Most cases of heritable retinoblastoma result from de novo germline mutations, and only approximately 10 percent of patients have a positive family history. Heritable retinoblastoma tends to present at an early age; most cases are bilateral and/or multifocal. In contrast, children with the nonheritable form typically have unilateral and unifocal disease, have a negative family history, and usually present at a later age. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Genetic predisposition' and "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Family history'.)

The diagnosis of retinoblastoma can usually be made based on the dilated indirect ophthalmoscopic examination and imaging studies, including ocular ultrasound (image 1), optical coherence tomography (OCT), and magnetic resonance imaging (MRI) (image 2). The characteristic findings on MRI are an enhancing tumor mass with low T2 signal and restricted diffusion-weighted imaging. Rarely, necrotic tumors in eyes harboring retinoblastoma may not demonstrate these classic MRI findings. Use of computed tomography (CT) for diagnosis should be avoided, given the risk of radiation exposure in a child with a possible RB1 gene mutation. The characteristic finding on dilated indirect ophthalmoscopic examination is a chalky, off-white retinal mass with a soft, friable consistency. Pathology is not necessary to confirm the diagnosis, and biopsy is contraindicated because of the risk of tumor seeding. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Evaluation'.)

The clinical features, diagnosis, treatment, and prognosis of retinoblastoma are reviewed in greater detail separately. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis" and "Retinoblastoma: Treatment and outcome".)

Cataract — A cataract is an opacity of the lens of the eye that can cause partial or total blindness if not diagnosed and treated promptly (picture 4). Approximately one-third of cataracts in children are inherited, one-third are associated with other disease (table 2), and one-third are idiopathic or sporadic. Acquired cataracts may be caused by ocular trauma, exposure to glucocorticoids, and ionizing radiation. The lenticular opacity is generally visible during office examination once the child's pupils are dilated. In addition, ocular ultrasonography of the posterior segment in congenital cataracts is normal, unlike the previous causes of leukocoria.

Cataracts are discussed in greater detail separately. (See "Cataract in children".)

Coats disease — Coats disease is an exudative retinal vascular disorder characterized by retinal telangiectasias and subretinal exudation leading to serous retinal detachment (image 3) [13]. Presenting complaints include decreased visual acuity, strabismus, or leukocoria. The leukocoria in Coats disease is generally more yellow than white due to the presence of subretinal lipid.

Coats disease is almost always unilateral, and the vast majority of cases occur in boys. It has a bimodal distribution, primarily affecting males less than 18 years of age and middle-aged men, in whom it may be a secondary response to another vascular event [14,15]. The majority of cases presenting with leukocoria are diagnosed between five and nine years of age, which is older than the majority of retinoblastoma patients. However, clinicians should be aware that Coats disease can present in younger children, rarely before one year of age.

Clinical examination reveals subretinal lipid and abnormal telangiectatic vessels. In advanced cases, ocular ultrasonography demonstrates complete retinal detachment with massive subretinal lipid. Intraocular calcification is almost never present in Coats disease, another feature that helps to distinguish it from retinoblastoma. Ultrasound examination can usually demonstrate intraocular calcification, but, if there is any uncertainty, an orbital CT can be done to confirm the presence of calcification, which would then raise suspicion for retinoblastoma.

A postulated cause of Coats disease is a somatic mutation in the NDP gene, resulting in a deficiency of norrin (the protein product of the NDP gene) within the developing retina [16]. This is distinct from Norrie disease, which is a rare X-linked disorder caused by mutation in the NDP gene. (See 'Retinal dysplasia' below.)

Persistent fetal vasculature — PFV (formerly called persistent hyperplastic primary vitreous [PHPV]) results from an idiopathic failure of the embryonic primary vitreous and hyaloid vascular system to involute during gestation. The posterior form is characterized by a rudimentary vascular stalk in the vitreous that usually extends to the optic nerve and is associated with a plaque-like opacity in the posterior lens.

PFV is generally diagnosed shortly after birth. It is almost always unilateral; bilateral lesions may be associated with trisomy 13 [17]. The involved eye is usually smaller (microphthalmia), with a shallow anterior chamber, prominent vessels on the iris, and vascularized white retrolental tissue (picture 5). When visible, elongated and rotated ciliary processes (drawn into the retrolental tissue) are pathognomonic of PFV (picture 6) [9]. Children with PFV may go on to develop glaucoma, cataract, intraocular hemorrhage, or retinal detachment, and the visual prognosis is generally poor [14,18].

PFV is one of the most common mimics of retinoblastoma (pseudoretinoblastoma), especially when noted in infancy. A fibrovascular stalk between the optic nerve and lens seen on ultrasonography, a microphthalmic eye, and rotated ciliary processes are helpful in differentiating PFV from retinoblastoma.

Vitreous hemorrhage — Vitreous hemorrhage causes leukocoria when there is extensive organization of the blood into a clot before degradation [14]. Over time, the reddish hue of the blood is lost and the hemorrhage transforms into whitish debris (picture 7). Vitreous hemorrhage can occur in a number of conditions, including [14,19]:

●Vitamin K-deficient bleeding of the newborn

●Advanced ROP

●PFV

●Trauma

●Leukemia or other blood dyscrasias

Trauma, including abusive head trauma, is the most common cause of vitreous hemorrhage in young children. Ocular ultrasonography is helpful in distinguishing vitreous hemorrhage from retinoblastoma; the absence of a retinal-based mass and/or calcifications exclude retinoblastoma. When the diagnosis is uncertain based on ultrasound imaging alone, CT may be necessary to better evaluate for calcifications. Though CT is usually avoided in children with suspected retinoblastoma because of the risk of radiation-induced secondary malignancies in children germline RB1 gene mutations, the concern is less in these cases since the presentation is usually unilateral (and thus more likely to be due to a somatic RB1 gene mutation). In addition, the risks of CT imaging are felt to be justified in this setting because the need to definitively rule out retinoblastoma before surgical intervention is critical. (See "Child abuse: Eye findings in children with abusive head trauma (AHT)", section on 'Vitreous hemorrhage'.)

Ocular toxocariasis — Ocular toxocariasis (also called ocular larva migrans) is an infection caused by the dog ascarid Toxocara canis or, less commonly, the cat ascarid Toxocara catis. It occurs most commonly in children and adolescents. Common presenting signs of ocular toxocariasis are strabismus and poor vision. Ocular involvement may be the sole manifestation of toxocariasis or it may occur in association with signs and symptoms of visceral larva migrans (eg, hepatitis, pneumonitis, and/or pruritic skin lesions, with eosinophilia). (See "Toxocariasis: Visceral and ocular larva migrans".)

The ocular lesion is caused by the inflammatory response to the second-stage larva, which may localize in the eye. Two characteristic lesions may result:

●A whitish subretinal granuloma measuring one to two disc diameters and located anywhere in the retina; this lesion is often associated with vitreoretinal traction and can cause leukocoria even in the absence of significant uveitis (picture 8)

●A large inflammatory mass (nematode endophthalmitis) with prominent vitreous inflammation (picture 8)

Either of these lesions may be confused with retinoblastoma, particularly if there is associated calcification. However, untreated retinoblastoma does not present with retinal traction, which is almost always present with toxocariasis (table 3). Serology tests can also help distinguish toxocariasis from retinoblastoma; however, the sensitivity is considerably lower for ocular larva migrans compared with visceral larva migrans. (See "Toxocariasis: Visceral and ocular larva migrans", section on 'Diagnosis'.)

Retinal dysplasia — Retinal dysplasia refers to the abnormal development of retinal tissue or cells with retention of some features resembling normal structures. It implies aberrant differentiation in any of the cellular layers and is often associated with the formation of rosettes of circular or oval groupings of dysplastic retinal cells on pathologic examination. The rosettes are highly variable in shape and size (unlike those in retinoblastoma, which are uniform in size). In many cases, retinal dysplasia is associated with retinal detachment [9].

Retinal dysplasia may be genetic or caused by intrauterine infection.

●Inherited retinal dysplasia – Genetic syndromes such as trisomy 13, trisomy 18, familial exudative vitreoretinopathy, Norrie disease, and incontinentia pigmenti are well-known causes of bilateral retinal dysplasia. Affected children may present with bilateral leukocoria and complete bilateral retinal detachments.

•Familial exudative vitreoretinopathy presents with fundus findings similar to ROP but with often highly asymmetric presentation and no history of prematurity. There are no non-ocular findings, and the mode of inheritance is autosomal dominant.

•Norrie disease is an X-linked disorder presenting in males with systemic findings such as microcephaly, congenital blindness, deafness, and progressive neuropsychiatric illness [20,21]. Ocular findings include bilateral retinal dysplasia, occasionally with anterior segment abnormalities such as cataract, iris degeneration, and microphthalmia [9].

•Incontinentia pigmenti is an X-linked dominant disorder that is present only in females and lethal in males. Hyperpigmented skin macules are commonly seen (picture 9A-D). Peripheral retinal avascularity, which, if advanced, can lead to tractional retinal detachment [22]. (See "Incontinentia pigmenti".)

●Retinal dysplasia caused by congenital infection – Congenital infections (eg, cytomegalovirus, toxoplasmosis, Zika virus) may rarely cause leukocoria if there is diffuse retinal involvement or retinal detachment. (See "Overview of TORCH infections".)

Retinopathy of prematurity — ROP is a developmental vascular proliferative disorder that occurs in the incompletely vascularized retina of preterm infants and can lead to retinal detachment and permanent blindness. The most important risk factor for developing ROP is prematurity. However, >50 separate risk factors have been identified. ROP causes leukocoria only when ROP is severe and results in tractional retinal detachment (stage 4, 5). Bilateral and symmetric presentation, history of prematurity, and tractional retinal detachment are usually sufficient to make the diagnosis.

ROP is discussed in greater detail separately. (See "Retinopathy of prematurity (ROP): Risk factors, classification, and screening".)

Optic disc abnormalities — Congenital and acquired abnormalities of the optic disc, such as optic disc coloboma (picture 10), morning glory disc (image 4), myelinated nerve fibers (picture 11), and malignant infiltration (picture 12), also can produce leukocoria. These disorders are diagnosed based on dilated fundus examination. The main distinguishing feature of optic disc abnormalities from retinoblastoma is the absence of an intraocular mass. Congenital and acquired abnormalities of the optic disc are discussed separately. (See "Congenital and acquired abnormalities of the optic nerve".)

Astrocytic hamartoma — Astrocytic hamartomas are a rare cause of leukocoria. Children are found to have gray-white tumors, often near the optic nerve (picture 13). Astrocytic hamartomas can be diagnosed at any age and are most commonly associated with tuberous sclerosis complex and, less commonly, with neurofibromatosis type 1 (NF-1). (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Clinical manifestations' and "Tuberous sclerosis complex: Clinical features".)

If a retinal tumor with features of an astrocytic hamartoma is noted in a young child without underlying tuberous sclerosis or NF-1, the possibility of early retinoblastoma should be considered since these tumors can appear similar. OCT can usually distinguish between them (astrocytic hamartomas appear as hyperreflective elevations confined to the retinal nerve fiber layer, whereas retinoblastoma appears as a smooth, round, homogenous outer retinal mass). Even when this distinction is made, retinal astrocytic hamartoma in the absence of underlying tuberous sclerosis or NF-1 is a provisional diagnosis requiring close follow-up to ensure that the tumor does not enlarge rapidly. Astrocytic hamartomas are slow growing. By contrast, a rapidly enlarging tumor suggests retinoblastoma, which has a doubling time of approximately 14 days. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis".)

CLINICAL EVALUATION

Detection of leukocoria — Evaluation for leukocoria (picture 1) is part of the routine visual examination performed by the primary care practitioner at routine visits (table 4). (See "The pediatric physical examination: HEENT", section on 'Eyes'.)

The method of detection of leukocoria depends upon the age of onset. Asymmetry of the red reflex during examination with a direct ophthalmoscope or other focused light source is the typical finding when leukocoria is present at birth or during the first year of life (figure 2) [23]. In older children, as well as infants, the asymmetry may be noticed in photographs in which the child has one red and one white pupil (picture 1). Because of the optics of the eye, even small retinal lesions or the optic disc itself can produce an abnormal pupillary reflection when the image of the light source falls exactly on that location. Leukocoria may therefore be intermittent and gaze dependent if it is caused by a localized retinal lesion (such as retinoblastoma), particularly if located in the peripheral fundus.

History — A complete medical and family history and review of systems are necessary in the evaluation of a child with leukocoria.

The following information should be obtained:

●Prenatal and birth history – The prenatal and birth history focuses on exposures and/or complications that may be associated with a particular cause of leukocoria (eg, exposure to corticosteroids which can cause cataracts; congenital infections such as cytomegalovirus, toxoplasmosis, or rubella, which can cause chorioretinitis and/or cataracts; and preterm birth, which is associated with retinopathy of prematurity [ROP]).

●Postnatal course – This should include information regarding history of prematurity, neonatal infection, and need for neonatal intensive care. For preterm infants, information regarding ROP screening and, if applicable, ROP treatment should be reviewed.

●Detailed history of medical illnesses and medications, particularly corticosteroids, which may cause cataracts.

●The time course for leukocoria should be assessed (eg, present from birth, developed later, noted only in photographs), as well as any other associated ocular signs such as microphthalmia or strabismus.

●Exposure to puppies or kittens, as well as history of pica or geophagia (eating dirt), because these may predispose to toxocariasis or toxoplasmosis.

●Detailed family history – Questions should address history of retinoblastoma or other eye conditions such as retinal detachment, eye loss, or cancer (particularly osteogenic sarcoma, which has a strong association with retinoblastoma) [24,25]. In addition, a history of previous miscarriages or fetal loss should be noted since these may suggest an underlying genetic or metabolic condition.

●Growth pattern, including history of weight loss or failure to thrive (weight loss or failure to thrive may be indications of metabolic or systemic illness, including retinoblastoma) [26,27].

●Developmental history – Abnormal development is a feature of some genetic conditions that can cause leukocoria. For example, children with 13q minus syndrome have developmental delay and are predisposed to retinoblastoma. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '13q14 deletion syndrome (Retinoblastoma syndrome)'.)

●Review of systems – History of hearing loss and/or cardiac conditions may indicate congenital rubella infection; endocrine problems are sometimes associated with optic disc coloboma.

Physical examination — The physical examination of the child with leukocoria should include evaluation for additional signs of the various conditions associated with leukocoria. As an example, an infant who has a cataract caused by galactosemia may have jaundice, failure to thrive, and hepatosplenomegaly. (See "Galactosemia: Clinical features and diagnosis".)

Areas that require particular attention include:

●Assessment for dysmorphic features

●Growth parameters, including head circumference (microcephaly is associated with certain genetic conditions and congenital infections)

●Evaluation of the skin for signs of coagulopathy, trauma, or neurocutaneous disorders (eg, incontinentia pigmenti (picture 9A-D), neurofibromatosis type 1 [NF-1] (picture 14A-C), tuberous sclerosis complex (picture 15A-E))

The primary care provider typically performs age-appropriate vision assessment, external ophthalmologic examination, evaluation of extraocular muscle movement and ocular alignment, and evaluation of the pupils before referral to an ophthalmologist. (See "The pediatric physical examination: HEENT", section on 'Eyes'.)

These aspects of the examination will be repeated by the ophthalmologist, who will also perform a dilated funduscopic examination (under anesthesia if necessary) and arrange additional evaluation (eg, radiologic imaging) as indicated.

Referral — Because retinoblastoma is among the most common causes of leukocoria in children, and because of the grave consequences to the child's life and vision if retinoblastoma goes undiagnosed, urgent referral to an ophthalmologist specializing in retinoblastoma is essential for all children with leukocoria at the time leukocoria is first detected. Patients with unequivocal leukocoria clinically or in multiple flash photographs in the same eye should be examined by an ophthalmologist within one week of detection and sooner when practical. (See "Retinoblastoma: Treatment and outcome", section on 'Outcome'.)

OPHTHALMOLOGIC EXAMINATION — The ophthalmologist performs a comprehensive ophthalmologic examination as described in the following sections. Anterior segment and dilated funduscopic examination are performed in the office along with ocular ultrasonography. Many children referred with leukocoria will require radiologic testing and/or examination under anesthesia (EUA) to establish a definitive diagnosis or for staging and treatment planning.

External examination and vision assessment — The evaluation begins with age-appropriate vision assessment and external examination. Vision assessment in children is discussed in detail separately. (See "Vision screening and assessment in infants and children".)

The external examination includes assessment for the presence or absence of proptosis, eyelid edema (a sign of trauma, inflammation, or infection), orbital masses, resistance of the globe to retropulsion, lymphadenopathy (preauricular, submandibular, anterior cervical, supraclavicular), and signs of trauma.

The pupils are examined for reactivity and relative afferent defect. The eye movements are observed for any abnormalities (eg, tropias or phorias). Strabismus is a common finding in children with retinoblastoma. Abnormal eye movements may also be seen in orbital trauma. (See "Evaluation and management of strabismus in children".)

Slit lamp examination — Slit lamp examination can be used to detect cataract, rotated ciliary body processes, or anterior chamber inflammation. Inflammatory cells and debris in the anterior chamber and/or vitreous may indicate uveitis, leukemic infiltration, or even pseudohypopyon associated with retinoblastoma. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Ophthalmologic findings'.)

Dilated fundus examination — A dilated funduscopic examination using the indirect ophthalmoscope is essential in the evaluation of children with leukocoria. The examination should assess:

●Status of the retina (eg, retinal detachment, dystrophy)

●Retinal vascular abnormalities and/or exudate (as may occur in Coats disease)

●Tumors, if present

Examination under anesthesia — EUA is required in children suspected of having retinoblastoma. In addition to examination of the ocular adnexa and anterior segment, both fundi must be visualized for 360° to detect tumors or other pathology that may be located in the peripheral retina. EUA is often required and may facilitate the performance of ocular ultrasonography, fundus photography, and, if necessary, laboratory and serologic testing, radiologic scans, and lumbar puncture.

IMAGING STUDIES — If the cause of leukocoria is uncertain, imaging studies may provide useful information.

●Ocular ultrasonography – In a cooperative child, ocular ultrasonography (B-scan, which is two-dimensional), can help to narrow the differential diagnosis before the examination under anesthesia (EUA). B-scan can also be done during EUA. Retinoblastoma is likely if calcification is present within an intraocular mass (image 1) [28-31]. Calcifications are not associated with Coats disease or persistent fetal vasculature (PFV). Rarely, calcification may be seen in association with granulomas in ocular larva migrans (toxocariasis). Calcification also may occur in astrocytic hamartomas, though there is usually more focal calcification in this setting compared with retinoblastoma.

Globe size is often normal in retinoblastoma, although advanced disease can present with buphthalmos. The presence of microphthalmia is suggestive of PFV [28,32]. Retinal detachment may be seen on ultrasound in patients with PFV or Coats disease [13].

●Optical coherence tomography (OCT) – In children with suspected retinoblastoma, OCT is commonly performed during the EUA using a handheld device. OCT produces a high-resolution two-dimensional image, using a technique that is analogous to pulse-echo ultrasound imaging, but infrared light is used rather than sound to create the image.

●Magnetic resonance imaging (MRI) – MRI of the head and orbits should be performed in all children with suspected retinoblastoma. MRI is required both for diagnostic confirmation and to exclude concomitant tumor the pineal gland (ie, "trilateral" retinoblastoma). As previously discussed, computed tomography (CT) should be avoided. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Evaluation'.)

LABORATORY EVALUATION — Laboratory evaluation of the child with leukocoria is guided by the history and physical examination findings and may include:

●Serology or other testing for congenital infections (eg, TORCH infection [toxoplasmosis, other (syphilis), rubella, cytomegalovirus, herpes simplex virus]) or infections for cataracts or Toxocara antibodies. (See "Overview of TORCH infections", section on 'Initial evaluation' and "Toxocariasis: Visceral and ocular larva migrans", section on 'Diagnosis'.)

●Metabolic studies (eg, for galactosemia) if the history is suggestive. (See "Galactosemia: Clinical features and diagnosis".)

●Genetic testing may be warranted if the history and clinical findings suggest a specific genetic disorder (eg, incontinentia pigmenti). Genetic testing is also warranted in the evaluation of retinoblastoma. (See "Incontinentia pigmenti", section on 'Diagnosis' and "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Genetic testing'.)

SUMMARY AND RECOMMENDATIONS

●Terminology and importance – The term leukocoria means "white pupil" and is the name given to the clinical finding of a white pupillary reflex (picture 1). Evaluation for leukocoria is part of the routine visual examination performed by the primary care practitioner at routine visits (table 4). (See 'Terminology' above and 'Detection of leukocoria' above.)

●Referral – All children with newly discovered leukocoria should urgently be referred to an ophthalmologist to exclude retinoblastoma and other life- or sight-threatening conditions. When possible, this consultation should occur within one week of suspected diagnosis. (See 'Referral' above.)

●Causes – The causes of leukocoria in children are summarized in the table (table 1). While occasionally the reflection of a normal optic disc may appear white (pseudoleukocoria), true leukocoria is caused by abnormalities in the lens, vitreous, or retina. It can be the initial manifestation of a wide spectrum of intraocular and systemic disease processes and may be the presenting sign of abusive head trauma. (See 'Causes of leukocoria' above.)

●Evaluation

•History – The history for the child with leukocoria should include prenatal exposures (infection, medications) and complications, birth history, postnatal course (infection, oxygen exposure, medications), medical history, recent exposures (puppies, kittens, pica, geophagia, medications), family history (particularly for retinoblastoma or other eye diseases, eye loss, osteogenic sarcoma, and fetal loss or miscarriage), growth pattern, development, and review of systems. (See 'History' above.)

•Physical examination – The physical examination of the child with leukocoria should include evaluation for additional signs of the various conditions associated with leukocoria (table 1). Areas that require particular attention include dysmorphic features; growth parameters; and evaluation of the skin for signs of coagulopathy, trauma, or neurocutaneous disorders (eg, incontinentia pigmenti (picture 9A-D), neurofibromatosis type 1 [NF-1] (picture 14A-C), tuberous sclerosis complex (picture 15A-E)). (See 'Physical examination' above.)

•Ophthalmologic examination – The ophthalmologist performs a comprehensive ophthalmologic examination, beginning with age-appropriate vision assessment and external examination. Anterior segment and dilated funduscopic examination are performed in the office along with ocular ultrasonography. Many children referred with leukocoria will require radiologic testing and/or examination under anesthesia (EUA) to establish a definitive diagnosis or for staging and treatment planning. (See 'Ophthalmologic examination' above.)

•Ocular ultrasonography and other imaging studies – Ocular ultrasonography can help narrow the differential diagnosis before the EUA. A calcified intraocular mass in a young child is diagnostic of retinoblastoma until definitively proven otherwise (image 1). Calcification is not associated with Coats disease or persistent fetal vasculature (PFV); it is rarely associated with granulomas (which can be seen with toxocariasis) and may occur in astrocytic hamartomas (though usually in a more focal manner than in retinoblastoma). Patients with suspected retinoblastoma require further evaluation with magnetic resonance imaging (MRI). (See 'Imaging studies' above and "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Evaluation'.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Richard Saunders, MD, who contributed to an earlier version of this topic review.