Genetics of Eye Color

Genetics and pathogenesis of retinoblastoma

The development of retinoblastoma is directly linked to genetic alterations. Two main pathways of mutation origin are distinguished:

• Familial cases: the mutation is inherited from one of the parents.
• Sporadic genetic cases: a de novo mutation occurs directly in germ cells.

If a patient already carries a mutation in one copy of the gene, the loss or mutation of the second copy occurs much faster. This is precisely why tumors in such cases develop at an earlier age. The second mutation is always localized directly in the retinal tissues.

In 1971, Alfred Knudson proposed the "two-hit" hypothesis (double mutation). According to this concept, two consecutive mutations of the Rb gene must occur in a cell to trigger tumor growth.

• In the hereditary form, the first mutation is established in germline cells, while the "second hit" affects somatic cells.
• In the sporadic (non-hereditary) form, both mutations occur within a single somatic cell. Due to the low rate of somatic mutations, the probability of such an event is low; therefore, sporadic retinoblastoma is less common, develops at a later age, and typically presents as a single lesion site.

The Rb gene functions as a tumor suppressor. Its inactivation is encountered not only in retinoblastoma but also in small-cell lung cancer, bladder cancer, breast cancer, and prostate cancer. Patients with the familial form of retinoblastoma have a genetically determined predisposition to other malignant neoplasms, specifically an elevated risk of developing osteosarcomas and soft tissue tumors.

Modern perspective: Today, Knudson's hypothesis is considered outdated. It has been proven that tumor formation is a multifactorial process. It cannot be explained solely by the loss of a single gene and requires the mandatory combined participation of both suppressor genes and proto-oncogenes.

Histological picture and tumor growth characteristics

Regarding its histogenesis, retinoblastoma develops from cells of neuroepithelial origin.

Macroscopically, the tumor is localized in the posterior chamber of the eye and appears as a single or multiple pinkish-white formation. The presence of necrosis and calcification foci is extremely characteristic of it.

Microscopically, the picture is represented by small round cells with scant cytoplasm and hyperchromatic nuclei. Sometimes tumor cells arrange into ribbon-like structures. For more differentiated forms of retinoblastoma, the formation of "true rosettes"—structures where cubic or low columnar cells are arranged like a palisade around a small central cavity—is specific.

Dynamics of process propagation:

1. Initially, the tumor grows strictly within the retina.
2. As its mass increases, it destroys the glass membrane (membrana vitrea).
3. The process extends to the choroid and vitreous body.
4. The tumor can completely fill the posterior chamber and invade the walls of the eyeball.
5. In late stages, it is capable of destroying the bony walls of the orbit.
6. Extension into the cranial cavity along the course of the optic nerve is possible.

Congenital optic atrophy

Genetically determined (congenital) optic atrophy is subdivided into two types depending on the inheritance mechanism:

• Autosomal dominant type: characterized by asymmetric visual acuity reduction ranging from 0.8 to 0.1.
• Autosomal recessive type: distinguished by an extremely severe course, leading to a sharp drop in visual acuity down to complete blindness as early as early childhood.

Classification and diagnosis of optic atrophy

The degree of optic nerve fiber damage and the severity of optic disc (OD) pallor determine the type of atrophy:

• Initial: against the background of a preserved pink color of the optic disc, pallor appears, the intensity of which increases over time.
• Partial: pallor captures only the temporal half of the optic disc, arteries are narrowed. Kestenbaum's sign (reduction of the number of capillaries on the disc to 7 or fewer) is detected.
• Incomplete: the optic disc pales evenly, arteries are narrowed, Kestenbaum's sign is moderately expressed.
• Complete: total pallor of the optic disc. Vessels are sharply narrowed (arteries to a greater extent than veins), Kestenbaum's sign is sharply expressed.

A distinction is made for secondary (post-edematous) atrophy, which develops against the background of prior optic disc edema. Its distinctive feature is the persistence of blurred borders and disc pattern even after complete resolution of edema, while the retinal arteries remain narrowed.

The timing of the appearance of ophthalmoscopic signs depends on the cause:

• In inflammations or traumas, changes are visible after a few days or weeks.
• In space-occupying lesions in the cranial cavity, clinical visual disorders appear first, while fundus atrophy forms many weeks or months later.

When any signs of atrophy are detected, the mandatory examination plan includes:

1. Determination of visual acuity.
2. Assessment of visual field boundaries (for white, red, and green colors).
3. Measurement of intraocular pressure.

Class and exam questions

What else to study on this topic

• Histogenesis and cellular composition of retinoblastoma (formation of "true rosettes").
• Dynamics of retinoblastoma extension beyond the retina.
• Ophthalmoscopic signs of various stages of optic atrophy.
• Timing of atrophy manifestation in trauma and space-occupying lesions.
• Secondary (post-edematous) optic atrophy.

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.