Overview
Definition:
Retinoblastoma is a malignant intraocular tumor originating from the primitive neuroectodermal cells of the retina
It is the most common primary intraocular malignancy of childhood
Hereditary retinoblastoma, accounting for about 40% of cases, is caused by germline mutations in the RB1 gene and is associated with an increased risk of bilateral disease and other cancers.
Epidemiology:
Retinoblastoma occurs in approximately 1 in 15,000 to 20,000 live births worldwide
About 60% of cases are sporadic (non-hereditary), and 40% are hereditary
The hereditary form is typically bilateral or multifocal, while sporadic cases are usually unilateral
Peak incidence is between 12 and 24 months of age.
Clinical Significance:
Early diagnosis and appropriate management are crucial for preserving vision and saving the child's life
Understanding the genetic basis is paramount for identifying at-risk individuals, providing accurate genetic counseling, and implementing timely screening protocols for affected families, particularly siblings, to prevent delayed diagnosis and improve outcomes.
Hereditary Retinoblastoma
Genetic Basis:
Hereditary retinoblastoma is an autosomal dominant disorder caused by germline mutations in the RB1 tumor suppressor gene, located on chromosome 13q14
The two-hit hypothesis suggests that both alleles of the RB1 gene must be inactivated for tumor development
one mutated allele is inherited, and the second somatic mutation occurs in the retina.
Inheritance Pattern:
Autosomal dominant inheritance with incomplete penetrance
Offspring of affected individuals have a 50% risk of inheriting the mutated RB1 gene
However, not all individuals who inherit the mutation develop retinoblastoma (reduced penetrance).
Clinical Features Hereditary:
Typically presents with bilateral tumors (approx
70-80% of hereditary cases) or multifocal unilateral tumors
Associated with an increased risk of secondary non-ocular cancers (e.g., osteosarcoma, soft tissue sarcomas) in adulthood, forming part of the Li-Fraumeni-like syndrome spectrum if other germline mutations are present.
Genetic Counseling Process
Initial Assessment:
Detailed family history of retinoblastoma, other cancers, and ophthalmologic conditions
Assessment of the proband's tumor characteristics (unilateral vs
bilateral, multifocal).
Risk Assessment:
Quantifying the risk for other family members, especially siblings, based on the proband's diagnosis and family history
Discussing the likelihood of germline RB1 mutation.
Genetic Testing Options:
Discussing germline RB1 gene mutation analysis (e.g., sequencing, MLPA) for the proband and at-risk family members
Interpretation of genetic test results and their implications.
Implications For Family:
Explaining the implications of a positive or negative genetic test result for the individual and their family, including reproductive options and potential for future cancer risk screening.
Screening Siblings And Family
Indications For Screening:
All siblings of a child diagnosed with retinoblastoma, especially if the proband has a confirmed or suspected germline RB1 mutation, or if the proband has bilateral disease or multifocal unilateral disease
First-degree relatives of individuals with known RB1 mutations.
Screening Protocol:
Annual ophthalmologic examinations under sedation, typically starting from birth or within the first few weeks of life, continuing until age 3-4 years
For families with a known RB1 mutation, screening may be initiated earlier or tailored based on specific mutation and family history.
Examination Technique:
Dilated fundus examination performed by an experienced pediatric ophthalmologist
Techniques like indirect ophthalmoscopy and scleral indentation are essential
Ultrasound or MRI may be used if visualization is poor
Routine use of mydriatics and cycloplegics.
Timing Of Screening:
Begin screening from birth or the first month of life for siblings of affected children, as retinoblastoma is most common in the first year
Continue annually until age 3-4 years, as the risk significantly decreases after this age, though rare late-onset cases can occur.
Management Of Identified Carriers
Early Detection Benefits:
Prompt detection of intraocular tumors allows for less aggressive and more vision-sparing treatment options, significantly improving the prognosis for both vision and overall survival.
Surveillance For Secondary Cancers:
Individuals with germline RB1 mutations have a lifelong increased risk of secondary malignancies
Periodic surveillance for common secondary cancers (e.g., bone and soft tissue sarcomas, brain tumors) is recommended according to established guidelines.
Reproductive Options:
Discussing options such as preimplantation genetic diagnosis (PGD) or prenatal diagnosis for families with a known RB1 mutation who wish to assess the risk for future pregnancies.
Psychosocial Support:
Providing emotional and psychological support for families dealing with a cancer diagnosis and the implications of a hereditary condition
Connecting families with support groups and resources.
Key Points
Exam Focus:
Hereditary retinoblastoma is autosomal dominant, caused by RB1 mutations, and has a 50% risk of transmission
Siblings of affected children require annual ophthalmologic screening from birth to age 4
Early detection is key for vision preservation and survival.
Clinical Pearls:
Always consider retinoblastoma in any child presenting with leukocoria (white pupillary reflex), strabismus, or significant vision loss
Familial clustering is a strong indicator for hereditary retinoblastoma and necessitates thorough genetic counseling and screening of at-risk relatives.
Common Mistakes:
Delaying screening of siblings based on a unilateral presentation of the proband
Underestimating the importance of genetic counseling for families
Not performing adequate follow-up examinations for individuals with known RB1 mutations due to risks of secondary cancers.