Gorlin syndrome, also known as nevoid basal cell carcinoma syndrome, is a condition that affects many areas of the body and increases the risk of developing various cancerous and noncancerous tumors.

In people with Gorlin syndrome, the type of cancer diagnosed most often is basal cell carcinoma, which is the most common form of skin cancer. Individuals with Gorlin syndrome typically begin to develop basal cell carcinomas during adolescence or early adulthood. These cancers occur most often on the face, chest, and back. The number of basal cell carcinomas that develop during a person's lifetime varies among affected individuals. Some people with Gorlin syndrome never develop any basal cell carcinomas, while others may develop thousands of these cancers. Individuals with lighter skin are more likely to develop basal cell carcinomas than are people with darker skin. The number of carcinomas may be reduced with ongoing treatment.

Most people with Gorlin syndrome also develop noncancerous (benign) tumors of the jaw, called keratocystic odontogenic tumors. These tumors usually first appear during adolescence, and new tumors form until about age 30. Keratocystic odontogenic tumors rarely develop later in adulthood. If untreated, these tumors may cause painful facial swelling and tooth displacement.

Individuals with Gorlin syndrome have a higher risk than the general population of developing other tumors. A small proportion of affected individuals develop a brain tumor called medulloblastoma during childhood. A type of benign tumor called a fibroma can occur in the heart or in a woman's ovaries. Heart (cardiac) fibromas often do not cause any symptoms, but they may obstruct blood flow or cause irregular heartbeats (arrhythmia). Ovarian fibromas are not thought to affect a woman's ability to have children (fertility).

Other features of Gorlin syndrome include small depressions (pits) in the skin of the palms of the hands and soles of the feet; an unusually large head size (macrocephaly) with a prominent forehead; and skeletal abnormalities involving the spine, ribs, or skull. These signs and symptoms are typically apparent from birth or become evident in early childhood.

Mutations in the PTCH1 gene are the main cause Gorlin syndrome. This gene provides instructions for making a protein called patched-1, which functions as a receptor. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. Together, ligands and their receptors trigger signals that affect cell development and function. A protein called Sonic Hedgehog is the ligand for the patched-1 receptor. Patched-1 blocks cell growth and division (proliferation) until Sonic Hedgehog is attached.

The PTCH1 gene is a tumor suppressor gene, which means it stops cells from proliferating too rapidly or in an uncontrolled way. Mutations in this gene prevent the production of patched-1 or lead to the production of an abnormal version of the receptor. An altered or missing patched-1 receptor cannot effectively suppress cell growth and division. As a result, cells proliferate uncontrollably to form the tumors that are characteristic of Gorlin syndrome. It is less clear how PTCH1 gene mutations cause the other signs and symptoms related to this condition.

The characteristic features of Gorlin syndrome can also be associated with a chromosomal change called a 9q22.3 microdeletion, in which a small piece of chromosome 9 is deleted in each cell. This deletion includes the segment of chromosome 9 that contains the PTCH1 gene, and as a result, people with a 9q22.3 microdeletion are missing one copy of this gene. Loss of this gene underlies the signs and symptoms of Gorlin syndrome in people with 9q22.3 microdeletions. Affected individuals also have features that are not typically associated with Gorlin syndrome, including delayed development, intellectual disability, overgrowth of the body (macrosomia), and other physical abnormalities. Researchers believe that these other signs and symptoms may result from the loss of additional genes in the deleted region of chromosome 9.

Mutations in the PTCH1 gene account for 50 to 85 percent of cases of Gorlin syndrome, while mutations in other genes, some known and some unidentified, are responsible for the remaining cases.

Normal Function

The PTCH1 gene provides instructions for producing the patched-1 protein, which functions as a receptor. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. A protein called Sonic Hedgehog is the ligand for the patched-1 receptor. Together, ligands and their receptors trigger signals that affect cell development and function.

Patched-1 and Sonic Hedgehog function in a pathway that is essential for early development. This pathway plays a role in cell growth, cell specialization, and determining the shape (patterning) of many different parts of the developing body. When Sonic Hedgehog is not present, patched-1 prevents cells from growing and dividing (proliferating). When Sonic Hedgehog is attached, patched-1 stops suppressing cell proliferation. Based on its role in preventing cells from proliferating in an uncontrolled way, PTCH1 is called a tumor suppressor gene.

Health Conditions Related to Genetic Changes

Gorlin syndrome

More than 225 mutations in the PTCH1 gene have been found to cause Gorlin syndrome (also known as nevoid basal cell carcinoma syndrome), a condition that affects many areas of the body and increases the risk of developing various cancerous and noncancerous tumors. Mutations in this gene prevent the production of patched-1 or lead to the production of an abnormal version of the receptor. An altered or missing patched-1 receptor cannot effectively suppress cell growth and division. As a result, cells proliferate uncontrollably to form the tumors that are characteristic of Gorlin syndrome. It is less clear how PTCH1 gene mutations cause the other signs and symptoms related to this condition, including small depressions (pits) in the skin of the palms of the hands and soles of the feet, an unusually large head size (macrocephaly), and skeletal abnormalities.

9q22.3 microdeletion

The PTCH1 gene is located in a region of chromosome 9 that is deleted in people with a 9q22.3 microdeletion. As a result of this deletion, affected individuals are missing one copy of the PTCH1 gene in each cell. Researchers believe that many of the features associated with 9q22.3 microdeletions, particularly the signs and symptoms of Gorlin syndrome (described above), result from a loss of the PTCH1 gene. When this gene is missing, patched-1 is not available to suppress cell proliferation. As a result, cells divide uncontrollably to form the tumors that are characteristic of Gorlin syndrome. Other signs and symptoms related to 9q22.3 microdeletions (such as delayed development, intellectual disability, overgrowth of the body, and other physical abnormalities) may result from the loss of additional genes in the deleted region of chromosome 9.

Nonsyndromic holoprosencephaly

At least seven mutations in the PTCH1 gene have been found to cause nonsyndromic holoprosencephaly. This condition occurs when the brain fails to divide into two halves during early development. PTCH1 gene mutations are a rare cause of this condition. These mutations prevent the signaling that is necessary for normal brain cell patterning. The signs and symptoms of nonsyndromic holoprosencephaly are caused by abnormal development of the brain and face.

Coloboma

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Other disorders

At least seven mutations in the PTCH1 gene have been found to cause nonsyndromic holoprosencephaly. This condition occurs when the brain fails to divide into two halves during early development. PTCH1 gene mutations are a rare cause of nonsyndromic holoprosencephaly. These mutations prevent the signaling that is necessary for normal brain cell patterning. The signs and symptoms of nonsyndromic holoprosencephaly are caused by abnormal development of the brain and face.

Cancers

Some mutations are acquired during a person's lifetime and are present only in certain cells. These genetic changes, called somatic mutations, are not inherited. Somatic mutations in both copies of the PTCH1 gene are associated with a non-hereditary (sporadic) type of skin cancer called basal cell carcinoma. Other sporadic types of cancer may be associated with somatic mutations in the PTCH1 gene, including some forms of skin cancer, a childhood brain tumor called medulloblastoma, breast cancer, and colon cancer. A noncancerous (benign) jaw tumor called a keratocystic odontogenic tumor can also be associated with somatic PTCH1 gene mutations.

Other Names for This Gene

• BCNS
• FLJ26746
• FLJ42602
• HPE7
• NBCCS
• patched
• patched homolog 1 (Drosophila)
• PTC
• PTC1
• PTC1_HUMAN
• PTCH

Genomic Location

Gorlin syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the condition. In most cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

Having one mutated copy of the PTCH1 gene in each cell is enough to cause the features of Gorlin syndrome that are present early in life, including macrocephaly and skeletal abnormalities. For basal cell carcinomas and other tumors to develop, a mutation in the second copy of the PTCH1 gene must also occur in certain cells during the person's lifetime. Most people who are born with one PTCH1 gene mutation eventually acquire a second mutation in some cells and consequently develop various types of tumors.

• Abnormal deposits of calcium in the brain (cerebral calcification)
• Skeletal abnormalities (bifid ribs, wedge-shaped vertebrae)
• Skin pits on the hands and feet (palmar and plantar pits)
• Large head size (macrocephaly)
• Medulloblastoma (childhood brain tumor)
• Multiple jaw cysts (odontogenic keratocysts)
• Basal cell carcinoma
• Abnormal or excessive tissue growth
• Noncancerous tumors of the heart
• Noncancerous tumors of the ovary

• Cardiologist
• Dermatologist
• Medical geneticist
• Ophthalmologist
• Oncologist

There are screening recommendations for people who are known or suspected to have nevoid basal cell carcinoma syndrome (NBCCS). Screening can help with early diagnosis and treatment of many of the features of NBCCS. The recommendations include:

• A neurologic evaluation every six months from birth to age three, then every year to age seven to look for signs of medulloblastoma
• Measurement of head size regularly throughout childhood
• Yearly dental x-rays, beginning at age eight, to look for jaw cysts
• At least yearly skin exams (beginning in the teenage years) to watch for basal cell skin cancer. Some physicians recommend a skin examination every three to four months. The frequency of exams will vary based on how many basal cell cancers or other skin problems a person has experienced. Early treatment of small basal cell skin cancer reduces the amount of surgery and scarring.

Screening recommendations may change over time as new technologies are developed and more is learned about NBCCS. Due to the high risk for multiple skin cancers, people with NBCCS should avoid sun exposure and protect their skin when outside. People with NBCCS should not receive radiation therapy because it increases the risk of basal cell skin cancers. No other tumors occur at a frequency that warrants more surveillance than is offered to people without NBCCS.

Gorlin syndrome affects an estimated 1 in 31,000 people. While more than 1 million new cases of basal cell carcinoma are diagnosed each year in the United States, fewer than 1 percent of these skin cancers are related to Gorlin syndrome.