Nevoid Basal Cell Carcinoma Syndrome (NBCCS), also known as Gorlin Syndrome, is a rare, inherited disorder. It is characterized by the development of various cancerous and noncancerous tumors, alongside developmental abnormalities affecting multiple areas of the body. The condition creates a predisposition for these growths, which can appear from early childhood through adulthood. While its manifestations vary, the syndrome follows a predictable genetic pattern and is estimated to affect between 1 in 57,000 and 1 in 256,000 people.
Key Signs and Features
A defining characteristic of Nevoid Basal Cell Carcinoma Syndrome is the development of multiple basal cell carcinomas (BCCs), a form of skin cancer. These cancers appear during adolescence or early adulthood, significantly earlier than in the general population. The BCCs can range from flesh-colored bumps to ulcerating plaques and are most commonly found on the face, back, and chest. The number of BCCs an individual develops can vary from a few to several thousand.
Another common feature is the formation of non-cancerous jaw cysts, known as keratocystic odontogenic tumors (KCOTs). These cysts are diagnosed in children and young adults and can continue to form until around age 30. While benign, KCOTs can be destructive, leading to painful facial swelling and tooth displacement if untreated. Their recurrent nature often requires repeated interventions.
Distinctive pits in the skin of the palms and soles are also a hallmark of the syndrome. These small, shallow depressions, referred to as palmar and plantar pits, are a frequent finding. They become noticeable during a person’s twenties and are permanent. The presence of these pits is a strong indicator of the syndrome.
Skeletal abnormalities are prevalent among individuals with NBCCS. An unusually large head size, or macrocephaly, with a prominent forehead is a common physical trait apparent from early childhood. Other skeletal issues include ribs that are split at the end (bifid ribs) and malformations of the spinal column vertebrae. These differences are often identified through X-ray imaging.
Other features can also be associated with the condition. Calcification of the falx cerebri, a membrane that separates the two hemispheres of the brain, is a frequent finding on brain scans. There is also an increased risk for a childhood brain tumor called medulloblastoma, which affects about 5-10% of individuals with NBCCS. Benign fibrous tumors, or fibromas, may also develop in the heart or ovaries.
Genetic Basis
NBCCS is a genetic disorder caused by a mutation in a tumor suppressor gene. In most cases, the syndrome is linked to an alteration in the Patched-1 (PTCH1) gene on chromosome 9. Tumor suppressor genes like PTCH1 provide instructions for proteins that control cell growth and division. When a mutation occurs in one copy of the PTCH1 gene, this regulatory function is impaired.
The loss of proper function in the PTCH1 gene disrupts a cellular signaling pathway for embryonic development. This allows cells to grow and divide uncontrollably, leading to the formation of the characteristic tumors and developmental abnormalities. While most cases are tied to PTCH1, mutations in other tumor suppressor genes like PTCH2 or SUFU can also cause the syndrome, though this is less common.
NBCCS is inherited in an autosomal dominant pattern, meaning inheriting one copy of the mutated gene from a parent is sufficient to cause the condition. An affected individual has a 50% chance of passing the mutation on to each of their children. The syndrome can also arise from a new (de novo) mutation in an individual with no family history, which accounts for approximately 30% to 50% of cases.
Diagnostic Process
The diagnosis of NBCCS is made based on a combination of clinical findings, imaging, and genetic testing. Healthcare providers use an established set of major and minor criteria to evaluate a patient, and a definitive diagnosis requires meeting a specific combination of these features.
A formal diagnosis can be made when a person meets a combination of these criteria, such as having two major and one minor, or one major and three minor criteria. Major diagnostic criteria include:
- More than two basal cell carcinomas or one before the age of 20
- Keratocystic odontogenic tumors of the jaw confirmed by a pathologist
- Three or more palmar or plantar pits
- Calcification of the falx cerebri
Minor criteria can include skeletal abnormalities like bifid ribs, macrocephaly, and other related tumors like ovarian fibromas.
Imaging studies are an important part of the diagnostic workup. A panoramic dental X-ray is used to detect jaw cysts that may not be otherwise visible. Brain imaging, such as an MRI or CT scan, can reveal calcification of the falx cerebri and is also used to screen for medulloblastoma in young children. A biopsy of a suspicious skin lesion is performed to confirm basal cell carcinoma.
Genetic testing can provide a definitive confirmation of the diagnosis. A blood test can analyze the PTCH1 gene for a disease-causing mutation. This testing is useful when clinical signs are not entirely clear or to confirm the diagnosis in individuals with a family history. Identifying a specific mutation is also valuable for genetic counseling and for testing other family members.
Multidisciplinary Management and Surveillance
Managing NBCCS requires a coordinated, lifelong approach involving a team of specialists. Because the syndrome affects multiple body systems, care is provided by a multidisciplinary team. This team often includes a dermatologist, an oral and maxillofacial surgeon, a dentist, a medical oncologist, a neurologist, and a genetic counselor.
Regular and proactive surveillance is a central component of managing NBCCS to detect and address problems early. This includes frequent skin examinations to identify and treat BCCs before they become large. Routine dental X-rays, done annually, are necessary to monitor for the development or recurrence of keratocystic odontogenic tumors.
Periodic imaging may be recommended based on the individual’s age and specific risks. For example, young children with the syndrome may undergo regular brain MRIs to screen for medulloblastoma. This proactive monitoring allows for early intervention. The specific surveillance schedule is tailored to each person by their healthcare team.
Treatment is focused on managing the specific manifestations as they arise. Surgical removal is a common treatment for both BCCs and jaw cysts. Other treatments for BCCs may include laser ablation, especially when lesions are numerous. A primary consideration is the avoidance of radiation therapy, as individuals with NBCCS have a heightened sensitivity to radiation, which can trigger the development of hundreds of new basal cell carcinomas within the treatment field.