Nevoid basal cell carcinoma

Definition

Nevoid basal cell carcinoma syndrome (NBCCS) is primarily a genetic skin cancer condition. The syndrome derives its name from the cancerous skin lesions that typically begin in the third decade of life. However, the name is not completely satisfactory as there are other manifestations of the syndrome.

Description

A condition that was first described in 1894, nevoid basal cell carcinoma syndrome has been found in mummies dating back to 1000 B.C. However, the condition was brought to medical attention by Dr. Robert Gorlin, and thus also bears the name Gorlin syndrome. Other names include Gorlin-Goltz syndrome and basal cell nevus syndrome.

While NBCSS often leads to cancer, it can also result in various other physical findings and birth defects. The most common cancer is that of the skin, known as basal cell carcinoma. However, medulloblastoma (brain cancer) and ovarian cancer are also possible. Also frequently present are cysts (fluid-filled sacs) of the skin and jaw, palmar and plantar pits (slight depressions on the surface of the skin), a non-cancerous growth on the heart known as a fibroma, macrocephaly, and various skeletal problems.

Genetic profile

NBCCS is caused by mutations in a gene known as "patched" (PTCH). PTCH is located on chromosome 9. It is believed to be a tumor suppressor gene. The normal role of such genes is to prevent the growth of tumors. They do this by controlling cell growth and division. It is the presence of uncontrolled cell growth that can lead to a tumor.

NBCCS is inherited in an autosomal dominant manner, meaning that only one of the two PTCH genes found in every cell of the body must be mutated in order to have NBCCS. If a person has a mutation in just one of their PTCH genes, the disease will be present. This will include some of the signs and symptoms of the condition.

Fifty percent of the time, a mutation in the PTCH gene may be inherited from a parent with NBCCS. In the other 50% of cases, a mutation can also occur by chance, in an individual without a family history of NBCCS. If the mutated gene is inherited from a parent, the symptoms of the disorder may be very different than those present in the parent. Some individuals will be more severely affected than others, even if they are all from the same family.

Once an individual has a PTCH mutation, there is a 50% chance with each pregnancy that the mutated PTCH gene will be passed on. If inherited, that male or female will have NBCCS.

While an individual with NBCCS will have a mutation in one of their two PTCH genes, it is the development over time of a second PTCH mutation in skin cells that actually leads to the development of the basal cell carcinomas. Such a second mutation is believed to occur by chance, with the exact factors leading to a second mutation not yet fully understood. A second mutation in other cells may also lead to the other types of growths that can occur in NBCCS, including cardiac and ovarian fibromas, as well as medulloblastoma.

Demographics

NBCCS occurs in an estimated one out of every 57,000 individuals worldwide. However, this may be an underestimate of the true prevalence. While NBCCS is seen in all ethnic groups, individuals of Caucasian descent tend to exhibit more cases of skin cancer than individuals of African descent. Approximately 0.4% of all cases of basal cell carcinoma are caused by the NBCCS.

Signs and symptoms

The characteristics associated with NBCCS are variable. The most prevalent symptom with this condition is skin cancer. Small growths (1–10 mm [0.04–0.4 in] in diameter) on the skin can occur during as early as two years of age. However, if not removed, these can develop into basal cell carcinomas by as early an age as puberty. The number of growths may vary from just a few to thousands.

Medulloblastoma, a type of brain cancer, occurs in 3–5% of individuals with NBCSS. It typically presents around two years of life and occurs in males more commonly than females. Seizures have occasionally been seen as part of this condition, but are not felt to be related to the presence of medulloblastoma.

An increased risk for other cancers has been proposed to be associated with this syndrome. However, as of the year 2005 this has not been definitely proven.

Jaw cysts are another common sign of NBCCS. They typically first appear around 15 years of age. Although often large, they rarely cause symptoms other than tooth displacement. The number of cysts can vary greatly and they do have a tendency to recur after surgical removal.

Various birth defects are more common in NBCCS. These can include polydactyly , cleft lip, cleft palate, various eye abnormalities, minor kidney anomalies, rib problems, and spinal anomalies (such as unusually shaped bones of the spinal column). Interestingly, overall height in individuals with NBCCS is slightly higher than average.

There are many possible eye abnormalities, such as cataracts found at birth, unusually small eyeballs, cysts in the eye, failure of the eye to fully develop, shaky or jerky eye movements, and problems with the nerve connecting the eye to the brain.

Rib anomalies are found in 45–60% of individuals with NBCCS. They generally do not cause any problems, although can be a clue to the diagnosis. The different rib problems can include partially missing ribs, ribs that split into two (known as bifid ribs), and ribs that fuse together.

The kidney problems are not as common a symptom, occurring in 14% or less of individuals with NBCCS. The most serious condition is when both kidneys are fused together, known as a horseshoe kidney. Unusual shaped kidneys, cysts, a single missing kidney, and duplication of parts of the kidney can also occur. However, as many of these kidney problems do not tend to cause health issues, they are not always detected unless specifically looked for.

A small percentage of males will have undescended testicles, a lack of smell, unusual breast tissue development, as well as sparse facial and body hair. These can all be signs of hormonal or endocrine disturbance.

Other features often include macrocephaly and growths (fibromas) in the heart and ovaries. Finally, pits or lesions in the palms of the hand or soles of the feet are very common, harmless findings.

Diagnosis

To make a diagnosis of NBCCS an individual must have at least two major and one minor characteristics that meet the diagnostic criteria. Alternatively, one major and three minor criteria can be present. Since there are many different symptoms that are considered major and minor, no two individuals with NBCCS will be exactly alike in their manifestations.

Examples of major criteria include:

• More than five basal cell carcinomas, or one before the age of 30 years
• Jaw cysts
• Two or more palmar or plantar pits
• Deposits of calcium or other salts on parts of the brain that can be seen on x rays
• A first-degree relative (sibling, parent, or child) known to have NBCCS

Examples of minor criteria include:

• Macrocephaly
• A cleft lip or palate
• Eye abnormalities of various types
• Polydactyly
• Ovarian or cardiac fibromas
• Childhood medulloblastoma
• Rib or spinal anomalies of various types

There is no exact age by which someone can be assured they do not have NBCCS. This is because each possible symptom can develop at a different time. For example, 90% of affected individuals develop jaw cysts by their second decade, but 10% of affected individuals never develop a single basal cell carcinoma. However, enough symptoms are usually present by the twenties to thirties that a diagnosis may be possible.

Alternatively, using a blood sample to test the PTCH gene for the presence of a mutation can also make a diagnosis of NBCCS. However, only 65–80% of individuals with NBCCS will actually have a detectable mutation using the technology available as of 2005.

Treatment and management

Removal of the multiple skin tumors and jaw cysts is recommended. Failure to do so can lead to both the development of basal cell carcinomas and to social difficulties due to the disfiguring nature of these tumors. Removal of jaw cysts should be undertaken by an oral surgeon and the basal cell carcinomas by a plastic surgeon. Radiation therapy should be avoided as these can cause further development of the basal cell carcinomas.

Ovarian fibromas, if present, can be surgically removed. The same is true for cardiac fibromas, although they do not usually cause symptoms.

Since manifestations of NBCCS can vary, any affected individual should be monitored carefully by the appropriate specialist. These include a dermatologist (skin doctor), dentist or orthodontist, ophthalmologist (eye doctor), pediatrician, and geneticist (specialist in genetics). Special precautions should be taken to avoid radiation, in the form of both radiation treatment and sun exposure, as this increases the risk to form basal cell carcinomas. Typical methods to reduce sun exposure, such as sun block and hats, should be used.

Phototherapies (treatment of disease by means of light rays) and topical treatments (skin creams based on vitamin A) are currently under investigation as possible means of treatment.

Prognosis

The life expectancy of individuals with NBCCS is considered to be essentially average. However, the key to this is diagnosis and proper treatment.

Developmental delay can be associated with the enlarged head size, but intelligence is often normal. Therefore, head circumference should be monitored throughout childhood and any rapid changes evaluated by magnetic resonance imaging (MRI) right away.

Resources

WEBSITES

GeneTests, in association with the National Institutes of Health. 9725 Third Avenue NE, Suite 602, Seattle, WA 98115. (206) 221-2943. <http://www.genetests.org> (March 14, 2005).

ORGANIZATIONS

Basal Cell Carcinoma Nevus Syndrome/Gorlin Syndrome Homepage. 3044 Peoria, Steger, IL 60475. (708) 756-3410. <http://www.hometown.aol.com/budcaruso/skinindex.html> (March 14, 2005).

BCCNS Life Support Network. PO Box 321, Burton, OH 44021. (440) 635-0078. <http://www.bccns.org> (March 14, 2005).

Sajid Merchant, BSc, MS, CGC