Peds Ophtho Case 1: Diagnosis & Conclusions

Diagnosis: Retinoblastoma (RB)

Leukocoria, or a white pupillary reflex, can present in a variety of conditions and at any age. However, findings of leukocoria in children requires urgent ophthalmologic consultation given its association with serious, vision and sometimes life-threatening conditions. The differential diagnosis includes congenital cataract (60% of all leukocoria cases), retinoblastoma (a “can’t miss” diagnosis), Coats disease (abnormal blood vessel development in the retina), retinopathy of prematurity (ROP), persistent fetal vasculature, retinal detachment, familial exudative vitreoretinopathy (FEVR), and ocular toxocariasis (associated with cats/dogs). Leukocoria should be distinguished from pseudoleukocoria, a benign condition resulting from light transiently reflecting off a normal optic disc. Patients with pseudoleukocoria will have a normal eye exam.

Retinoblastoma is the most common primary eye malignancy in children. It develops early in childhood with a median diagnosis of 18-24 months in unilateral disease and 12 months in bilateral disease. Leukocoria is found in 60% of all retinoblastomas and arises from light reflecting off the retinal mass. It is identified by family members who may observe a white pupil, particularly in low lit rooms or on flash photography, or by pediatricians during red reflex testing. Other clinical findings which can be associated with retinoblastoma include strabismus (in 20% of cases), uveitis, and secondary glaucoma.

Retinoblastoma typically arises from mutations in the RB1 gene on chromosome 13. Nearly 40% of cases are caused by germ-line mutations and can be passed down by a disease-free parent. Only 10% of cases have a family history of retinoblastoma while the remaining 90% are nonhereditary. The American Academy of Pediatrics recommends red reflex testing at all neonatal and pediatric health visits for all children. Individuals with a positive family history for retinoblastoma should be routinely screened. 

Trilateral RBRetinoblastoma can hematogenously spread to the bone, liver, central nervous system, and other organs. In rare cases, patients with germline mutations can also have a primitive neuroectodermal tumor (PNET). These patients tend to also have bilateral retinoblastoma and the presence of a PNET tumor along with bilateral RB is referred to as “Trilateral retinoblastoma.” However PNET can still arise in germline mutations that cause unilateral RB. (Left Image Credit)

In addition to metastases, retinoblastoma can be associated with other conditions. Patients with a history of heritable retinoblatoma are at increased risk of developing second bone or soft tissue sarcomas, such as osteosarcomas. This risk is independent of receipt of radiation treatment and is likely due to changes in the RB gene throughout their body.

As discussed above, Coats disease and congential cataract are also on the differential for leukocoria. Coats disease is a disease that causes abnormal development of the vessels in the retina. It predominantly affects boys older than age 5. In contrast to retinoblastoma, the leukocoria is more yellow-white due to the presence of cholesterol and fundoscopy would typically demonstrate retinal hemorrhages. Congenital cataract refers to opacification of the crystalline lens, and would be associated with a normal fundoscopic exam. 


As retinoblastoma is a fatal disease if left untreated, the primary goals of care are to save a patient’s life without decreasing quality of life.  Therefore, “vision-sparing” treatments are attempted first before considering enucleation. With treatment, retinoblastoma has a good prognosis with >95% 5-year survival rate in children. 

All patients are managed with chemotherapy to reduce tumor burden. If the tumors are small and focal, possible treatment modalities include cryotherapy, laser photocoagulation, brachytherapy, thermotherapy, and chemothermotherapy. Use of chemotherapy prior to focal therapies have been shown to be more effective than chemotherapy alone. In a single center case series, tumors that were treated with both chemotherapy and focal therapies had a lower recurrence rate than tumors treated with chemotherapy alone (45% vs 22%, respectively). The Children’s Oncology Group (COG) randomized controlled trials (ARET0331 and ARET0231), are investigating the effectiveness of combination chemotherapy and local therapies for the treatment of retinoblastoma. 

For larger or multiple tumors, or if focal treatments fail, external beam radiotherapy (EBRT) is another vision-sparing modality that can be used (EBRT). However, as EBRT involves use of significant radiation, EBRT may damage other ocular structures or increase risk of developing secondary cancers. 

In cases where the patient’s vision cannot be salvaged (i.e. large tumor burden, extraocular spread, or progression of disease despite vision-sparing treatments), enucleation is the definitive treatment. 

References and Additional Resources:

1. “Retinoblastoma.” Available at: 
2. Syed R, Ramasubramanian A,  Fekrat S, Scott IU. “A Stepwise Approach to Leukocoria.” Eyenet. July 2016. Available at:
3. Melamud A, Palekar R, Singh. “Retinoblastoma.American Family Physician. 2006;73(6):1039-1044.
4. Kaufman PL, Kim J, Berry JL. (2018). Retinoblastoma: Treatment and outcome. Payasse EA, Pappo AS, & Armsby C (Eds), UptoDate. Available at:
5. Balmer A, Munier F. “Differential diagnosis of leukocoria and strabismus,  first presenting signs of retinoblastoma.” Clin Ophthalmol. 2007;1(4):431-439.
6. Correa ZM, Berry JL. “Review of Retinoblastoma.” April 2016. Available at:
7. Shields CL, Mashayekhi A, Cater J, et al. “Chemoreduction for Retinoblastoma: Analysis of Tumor Control and Risks for Recurrence in 457 Tumors.” Trans Am Ophthalmol Soc. 2004;102:35-45.

Case 1 Index

Peds Ophtho Case 1 Index
Peds Ophtho Case 1: Introduction
Peds Ophtho Case 1: Physical Exam
Peds Ophtho Case 1: Ophtho Visit
Peds Ophtho Case 1: Case Continued…