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Retinoblastoma

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

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Synonyms of Retinoblastoma

Disorder Subdivisions

General Discussion

Retinoblastoma is an extremely rare malignant tumor that develops in the nerve-rich layers that line the back of the eyes (retina). The retina is a thin layer of nerve cells that sense light and convert it into nerve signals, which are then relayed to brain through the optic nerve. Retinoblastoma occurs most commonly in children under the age of three. The most typical finding associated with retinoblastoma is the reflection of light off a tumor behind the lens of the eye, which causes the pupil to appear white, the so called "cat's eye reflex" (leukokoria). In addition, the eyes may be misaligned so that they appear crossed (strabismus). In some affected children, the eye(s) may become red and/or painful. The presence of a retinoblastoma may cause glaucoma, a condition marked by a rise in the pressure within the eyeball preventing the normal drainage of fluid from the eye and potentially causing characteristic damage to the optic nerve. Retinoblastoma may affect one eye (unilateral) or both eyes (bilateral). Bilateral forms of retinoblastoma are hereditary. In most cases, retinoblastoma occurs spontaneously for no apparent reason (sporadic).

Symptoms

In approximately 60 percent of cases, the presenting sign of retinoblastoma is a reflection of light off a tumor behind the lens of the eye that results in the pupil appearing white (leukokoria). This condition has also been referred to as a glint or gleam in the affected eye.

Additional symptoms may include misalignment of the eyes in which they often appear crossed (strabismus), differences in pupil size (anisocoria), differences in pupil color (heterochromia), decreased vision, and potentially blindness in the affected eye(s). In some cases, multiple tumors may form. In two-thirds of cases only one eye is affected (unilateral). When both eyes are affected, the tumors usually develop simultaneously. In rare cases, some individuals with a tumor in one eye will develop a tumor in the unaffected eye later on. In most cases, retinoblastoma only affects the eye and does not spread to surrounding tissue.

In rare cases, additional symptoms may occur, including bulging eyes (proptosis) and redness or pain in the eye. Pain and redness rarely occur early in the disease. Some affected individuals may exhibit bleeding (hemorrhaging) in front of colored portion of the eye (iris), accumulation of tumor cells in front of the iris (pseudohypopyon), inflammation of the eye cavity (orbit), clouding of the lenses of the eyes (cataract) and elevated fluid pressure within the eye preventing the normal outflow of fluid from the eye and potentially causing damage to the optic nerve (glaucoma).

Some individuals with retinoblastoma, especially those with tumors affecting both eyes, may be at a greater risk than the general population of developing other types of cancer, such as osteogenic sarcoma (a childhood form of bone caner), later during life.

If a retinoblastoma is not detected early, it may spread to affect the tissue surrounding the eye or other parts of the body such as the central nervous system, lymph nodes, skeleton, liver, or kidney. These cases are referred to as extraocular or metastatic retinoblastoma.

In rare cases, individuals with retinoblastoma may exhibit symptoms associated with a rare disorder called partial monosomy 13q. (For more information on this disorder, see the Related Disorders section of this report).

Causes

Approximately 60 percent of cases of retinoblastoma are nonhereditary; and 40 percent are hereditable. Of the nonhereditary cases, approximately 85 percent will only affect one eye (unilateral). Of the heritable cases, approximately 85 will develop multiple tumors affecting both eyes (bilateral).

In addition, of the heritable cases of retinoblastoma, only 25 percent have a positive family history of the disorder. Most cases occur as random (spontaneous) genetic changes (mutations) that may be transmitted as an autosomal dominant trait (i.e., new dominant gene mutations) or are inherited from a parent who carries the retinoblastoma gene but does not have any symptoms (asymptomatic).

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

Investigators have determined that retinoblastoma is caused by disruption or changes (mutations) of the retinoblastoma 1 gene (RB-1) gene located on the long arm (q) of chromosome 13 (13q14.1-14.2). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Chromosomes are further subdivided into bands that are numbered. For example, "chromosome 13q14.1-14.2" refers to bands 14.1-14.2 on the long arm of chromosome 13.

Recently, scientists have determined that the retinoblastoma gene is a recessive oncogene. Experts believe there are two kinds of oncogenes: those that cause cancer by their presence, and those that cause it by their absence. Both types are mutant or incomplete versions of ordinary genes that normally regulate cell growth. One kind is dominant and causes out-of-control growth (cancer). Recessive oncogenes or tumor suppressor genes normally limit or stop the growth of cells. When they are lost, cells can multiply (proliferate) wildly, causing cancer. When the normal gene is present, they appear to prevent cancer from developing. This genetic discovery is potentially very important in the understanding of many types of cancer.

Affected Populations

Retinoblastoma affects males slightly more often than females. It is estimated to occur in 1 in 15,000-23,000 live births. Approximately 250-350 new cases are diagnosed each year in the United States. More than 90 percent of retinoblastomas become apparent before the age of five years, with the majority appearing before the age of three years.

Although retinoblastoma is a rare disorder, it is the most common intraocular tumor of childhood and one of the most common forms of childhood cancer overall.

Related Disorders

Symptoms of the following disorders can be similar to those of retinoblastoma. Comparisons may be useful for a differential diagnosis:

Ocular toxocariasis is an infectious disease caused by the parasite Toxocara, a worm of dogs and cats. Infection occurs when there is purposeful or incidental ingestion of soil from hand to mouth through such activities as biting fingernails or inserting recently contaminated objects such as toys into the mouth. (Consequently, the disorder is found disproportionately among children.) Once ingested, the eggs hatch into larvae and burrow into body tissue of all types. When the larvae affect the eye, the disorder is known as ocular toxocariasis. Symptoms may include a brief redness of the sclera (white of the eye) without pain, a "whitish" appearance of the pupil, visual acuity changes, or blindness of one eye. (For more information on this disorder, choose "Toxocariasis" as your search term in the Rare Disease Database.)

Coats disease is an extremely rare disorder characterized by abnormal enlargement or widening (dilation) of the ends of the blood vessels in the retina that may result in blood leaking from the vessel. In some cases, the retina may become detached from the back of the eye. A white membrane or mass may develop in the pupil area behind the lens of the eyes (leukokoria) that causes the pupil to appear white when light reflects off it. The exact cause of Coats disease is unknown. The disorder may result from mutations of the Norrie disease gene on the X chromosome. (For more information on this disorder, choose "Coats" as your search terms in the Rare Disease Database.)

Persistent hyperplastic primary vitreous (PHPV) is a developmental disorder affecting the eye that is present at birth (congenital). The disorder is characterized by abnormalities of certain eye structures and loss of vision. Specific symptoms include abnormally small eyes (microphthalmia), cataracts, and/or the formation of a white membrane or mass in the pupil area behind the lens of the eyes (leuokokoria) that causes the pupil to appear white when light reflects off it.

Retinopathy of prematurity (ROP) is a multifactorial disorder that occurs in premature infants. The disorder is characterized by abnormalities affecting the retina that may lead to vision loss and, potentially, blindness.

Primary retinal dysplasia is a rare inherited condition characterized by an elevated retinal fold arising from the optic disc covering the macular area inside the eye, and widening toward the temporal fundus, which may cause blindness. This condition is thought to be inherited as an X-linked trait.

There are a variety of tumors that can affect the eye that should be included in a differential diagnosis. These tumors may include retinal astrocytoma, glioneuroma, and retinal hamartoma. (For more information on these disorders, choose the specific tumor name as your search term in the Rare Disease Database.)

The following disorder may occur in association with retinoblastoma:

Chromosome 13, Partial Monosomy 13q is a rare chromosomal disorder in which a portion of the long arm (q) of chromosome 13 is missing (deleted or monosomic). The range and severity of symptoms may vary greatly, depending upon the exact size and location of the deletion on 13q. Chromosome 13, Partial Monosomy 13q is usually apparent at birth and may be characterized by low birth weight, malformations of the head and facial (craniofacial) area, abnormalities of the eyes, defects of the hands and/or feet, genital malformations in affected males, and/or additional physical abnormalities. Affected infants and children may also exhibit delays in the acquisition of skills requiring the coordination of mental and muscular activity (psychomotor retardation) as well as varying degrees of mental retardation. In the majority of cases, Chromosome 13, Partial Monosomy 13q appears to occur randomly, for no apparent reason (sporadic).

Standard Therapies

Diagnosis
The diagnosis of retinoblastoma is made based upon a thorough clinical evaluation, detailed patient history, the identification of characteristic symptoms, and a variety of specialized tests. In most cases, the presenting symptom is leukokoria. A complete examination of the interior of the eye (funduscopic examination) may be performed to locate the presence of a tumor or tumors. Imaging studies such as computed tomography (CT) scans or magnetic resonance imaging (MRIs) may be used to determine the extent of the tumor(s) and see whether it has spread to surrounding structures or tissue. Ultrasonography may be used to rule out other conditions.

Treatment
The treatment retinoblastoma of is directed toward the specific symptoms that are apparent in each individual and preserving vision in the affected eye(s). Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, specialists who asses and treat eye problems (ophthalmologists), pediatric ophthalmologists, specialists who assess and treat cancer (oncologists), pediatric oncologists) and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment.

Specific treatment methods depend upon the size of the tumor(s), whether one or both eyes are affected, whether the tumor has spread, an individual's age, and the associated likelihood of retaining adequate vision.

Individuals with multiple and large tumors may be treated by a combination of certain anticancer drugs (chemotherapy) or surgical removal (excision) of the affected eye (enucleation) and part of the optic nerve. During the last few decades, the rate of enucleation as a treatment for retinoblastoma has dropped considerably and is usually reserved for individuals with disease that recurs after treatment or is resistant to treatment and who have no useful vision left in the affected eye.

Individuals with smaller tumors may be treated with less invasive methods directed at preserving the vision of the affected eye. These methods include a procedure that uses extreme cold to destroy tissue and cancer cells (cryotherapy), a procedure that uses intense, focused light (e.g., laser therapy) to heat and destroy tissue and cancer cells (photocoagulation), or procedures that use radiation to destroy tissue and cancer cells (external beam radiotherapy [EBR] or brachytherapy).

With EBR, a laser beams are delivered by a machine to the retina to destroy cancer cells. A treatment session only takes a few minutes and is usually given five days weeks over three to four weeks. EBR can affect nearby healthy tissue and may increase the risk of developing a second caner later during life.

Brachytherapy is also known as internal radiation therapy. During brachytherapy radioactive material (implant) is placed within the eye socket usually near the base of a tumor. The implant is left there for several days. This procedure is done only for individuals with small tumors.

In individuals in whom only one eye is affected and when the prospects of retaining adequate vision are unlikely, enucleation of the affected eye may be performed. However, if useful vision can be retained in the eye, cryotherapy or radiation therapy may be recommended.

In most cases in which both eyes are affected, the more severely affected eye is treated with enucleation. The other eye is treated with cryotherapy, radiation therapy, or photocoagulation to preserve vision.

In rare cases, where a retinoblastoma has spread outside of the eye (extraocular retinoblastoma), affected individuals are usually treated with chemotherapy either alone or in combination with external beam radiotherapy. For individuals with central nervous system involvement, chemotherapy may be delivered intrathecally directly in to the fluid surrounding the brain and spinal cord.

Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

Genetic probes (synthetic genes) that seek out their natural counterparts in human genetic material can locate individual genes within the 50,000 to 100,000 human genes that control the human body's functions. Currently such probes are being used experimentally on newborn babies who may be genetically predisposed to Retinoblastoma. This procedure may lead to earlier diagnosis, and perhaps help to determine which factors serve to precipitate onset of the disorder in genetically susceptible children.

Researchers are studying the use of gene therapy as a treatment for retinoblastoma. More studies are needed to determine the long-term safety and effectivness of this treatment. For more information, contact:

Richard Louis Hurwitz, M.D.
Pediatrics Hematology and Oncology Department
Texas Children's Clinical Care Center at Baylor College of Medicine
One Baylor Plaza Mail Stop 3-3320
Houston, TX 77030
Tel: (713) 770-4259
E-mail: rhurwitz@bcm.tmc.edu

A Phase II clinical trial is being coordinated to study the effectiveness of sequential therapy with carboplatin, etoposide, cyclophosphamide, doxorubicin, topotecan and radiotherapy followed by autologous bone marrow transplantation in individuals with extrachoroidal or metastatic retinoblastoma. For more information on this study, contact:

Saint Jude Children's Research Hospital
Memphis Tennessee
38105-2794,
Charles Benton Pratt, III 901-495-3442

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Retinoblastoma Resources

Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder (e.g., visual handicaps, etc.)

Organizations:

References

TEXTBOOKS
Rimoin D, Connor JM, Pyeritz RP, Korf BR. Eds. Emory and Rimoin's Principles and Practice of Medical Genetics. 4th ed. Churchill Livingstone. New York, NY; 2002:3604-3634.

Bennett JC, Plum F, eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, PA: W.B. Saunders Co; 1996:2180.

Behrman RE, ed. Nelson Textbook of Pediatrics. 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:1470-1; 1792-93.

Kanski JJ, ed. Clinical Ophthalmology, 4th ed. Woburn, MA: Butterworth-Heinemann; 1999: 337-42.

Raghavan D, ed. Textbook of Uncommon Cancer, 2nd ed. New York, NY: John Wiley & Sons, Ltd; 1999:341-52.

JOURNAL ARTICLES
Chintagumpala M, Chevez-Barrios P, Paysse EA, Plon SE, Hurwitz R. Retinoblastoma: review of current management. Oncologist. 2007;12:1237-1246.

Balmer A, Zografos L, Munier F. Diagnosis and current management of retinoblastoma. Oncogene. 2006;25:5341-5439.

Doz F. Retinoblastoma: a review. Arch Pediatr. 2006;13:1239-1327.

Shields CL, Meadows AT, Leachey AM, Shields JA. Continuing challenges in the management of retinoblastoma with chemotherapy. Retina. 2004;24:849-862.

Nevins JR. The Rb/E2F pathway and cancer. Hum Mol Genet. 2001;10:699-703.

Blanquet V, Turleau C, Gross-Morand MC, et al. Spectrum of germline mutations in the RB1 gene: a study of 232 patients with hereditary and non hereditary retinoblastoma. Hum Mol Genet. 1995;4:383-388.

Liu Z, Song Y, Bia B, Cowell JK. Germline mutations in the RB1 gene in patients with hereditary retinoblastoma. Genes Chromosomes Cancer. 1995;14:277-284.

Naumova A, Sapienza C. The genetics of retinoblastoma, revisited. Am J Hum Genet. 1994;54:264-273.

Cowell JK, Rutland P, Hungerford J, Jay M. Deletion of chromosome region 13q14 is transmissible and does not always predispose to retinoblastoma. Hum Genet. 1988;80:43-45.

FROM THE INTERNET
Lohmann DR, Gallie BL. Updated:05/07/2007. Retinoblastoma. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at http://www.genetests.org.

Mayo Clinic for Medical Education and Research. Retinoblastoma. August 25, 2006. Available at: http://www.mayoclinic.com/health/retinoblastoma/DS00786 Accessed On: March 28, 2008.

Aerts I, Lumbroso-Le Rouic L, Gauthier-Villars M, et al. Retinoblastoma. Orphanet encyclopedia, September 2003. Available at: http://www.ojrd.com/content/pdf/1750-1172-1-31.pdf Accessed on: March 28, 2008.

Report last updated: 2008/04/14 00:00:00 GMT+0