Gorlin syndrome is a rare, inherited disorder that significantly increases the risk of developing various tumors, both cancerous and noncancerous, across multiple body systems. It is also known as Nevoid Basal Cell Carcinoma Syndrome (NBCCS) because its most common manifestation is the development of numerous basal cell carcinomas (BCCs) on the skin. This condition is categorized as a familial cancer syndrome, predisposing affected individuals to a higher lifetime risk of certain tumors and developmental abnormalities.
Genetic Basis and Inheritance
The underlying cause of Gorlin syndrome is typically a mutation in the PTCH1 gene, a tumor suppressor gene located on chromosome 9. This gene produces the Patched-1 protein, which acts as a receptor in the Hedgehog signaling pathway, controlling cell growth and division. Normally, Patched-1 blocks uncontrolled cell proliferation until a signaling molecule called Sonic Hedgehog binds to it.
A faulty PTCH1 gene results in a non-functional or missing Patched-1 receptor, effectively removing the “brake” on cell growth. This disruption leads to the uncontrolled cell proliferation that forms the characteristic tumors and cysts of the syndrome. Gorlin syndrome follows an Autosomal Dominant inheritance pattern, meaning a child needs to inherit only one copy of the mutated gene from either parent to have the condition.
This inheritance pattern gives a 50% chance of transmission to any offspring of an affected individual. While most cases are inherited, approximately 20% to 30% of diagnoses result from a de novo, or spontaneous, mutation in the gene. In a small number of cases, mutations in the SUFU gene, another tumor suppressor in the same pathway, can also cause the syndrome.
Primary Clinical Manifestations
The clinical presentation of Gorlin syndrome is highly variable, affecting the skin, skeleton, nervous system, and endocrine system. Dermatologic features are the most common and often lead to initial diagnosis. Individuals frequently develop multiple basal cell carcinomas (BCCs), the most common form of skin cancer, often starting in adolescence or early adulthood.
These BCCs are typically found on sun-exposed areas like the face, chest, and back, and their number can range from a few to hundreds over a lifetime. Another distinctive skin finding is the presence of palmar and plantar pits, which are small depressions found on the palms and soles of the feet. These pits affect a large percentage of patients and usually become apparent in the teenage years.
Skeletal and dental abnormalities are also hallmark features of the syndrome. A frequent finding is the development of odontogenic keratocysts (OKCs), which are benign, yet locally aggressive, cysts that form within the jawbone. These jaw cysts can appear as early as age seven and may cause painful swelling and displacement of teeth. Skeletal anomalies include fused or bifid ribs, vertebral defects, and an unusually large head size, known as macrocephaly.
Neurological and ocular complications, while less common, can be serious. A small proportion of children, particularly those with SUFU gene mutations, have an increased risk of developing medulloblastoma, a type of malignant brain tumor. Other neurological findings include the calcification of the falx cerebri, a fold of the brain’s covering, which is often visible on imaging. Noncancerous tumors, called fibromas, may also occur in the heart or ovaries.
Diagnosis and Screening Protocols
Diagnosis of Gorlin syndrome is established through a combination of clinical findings, often grouped into major and minor criteria, and genetic confirmation. The clinical criteria, sometimes called the Gorlin criteria, require the presence of either two major features or one major and two minor features. Major criteria include:
- Multiple BCCs or a single BCC before age 20.
- The presence of odontogenic keratocysts.
- Palmar or plantar pitting.
- Calcification of the falx cerebri.
Genetic testing confirms the diagnosis, especially in individuals who do not fully meet the clinical criteria. This testing analyzes blood or saliva samples to identify a pathogenic variant in the PTCH1 gene or, less commonly, the SUFU gene. Identifying the specific gene mutation is important for understanding the individual’s risk profile, such as the heightened risk of medulloblastoma associated with SUFU mutations.
Proactive screening is fundamental for managing the condition and ensuring early detection of complications. Children at risk typically undergo regular neurological evaluations and may receive annual brain magnetic resonance imaging (MRI) scans, particularly up to age five, to screen for medulloblastoma. Regular dental panoramic X-rays (panorex) should begin around age eight to monitor for the development of jaw cysts. Dermatologic examinations by a specialist are recommended every few months for adults and at least annually for children to detect and treat new BCCs.
Management and Long-Term Outlook
Management of Gorlin syndrome is a continuous, multidisciplinary effort focusing on surveillance, prevention, and targeted treatment of specific manifestations. Individuals are highly sensitive to radiation, so both diagnostic and therapeutic radiation are generally avoided unless absolutely necessary, as radiation can hasten the development of new BCCs. Prevention centers on rigorous sun protection, including wearing sun-protective clothing and using broad-spectrum sunscreen, to reduce the cumulative damage that triggers new skin cancers.
Basal cell carcinomas are managed through various techniques designed to minimize tissue damage and preserve cosmetic appearance. Treatment options include surgical methods like excision or Mohs surgery, as well as non-surgical approaches. Topical treatments, such as 5-fluorouracil or imiquimod cream, can be used for superficial lesions. Systemic medications, such as Hedgehog pathway inhibitors, are a newer class of oral drugs that can shrink or prevent the formation of new BCCs, though they are often reserved for severe cases due to potential side effects.
Odontogenic keratocysts require surgical removal to prevent bone destruction and tooth displacement. Due to the high rate of recurrence, frequent dental surveillance with panoramic X-rays is necessary even after successful removal. Females are also advised to undergo pelvic ultrasounds around the time of menarche or early adulthood to screen for ovarian fibromas.
The long-term outlook for individuals with Gorlin syndrome is generally positive, provided they adhere to a rigorous, lifelong surveillance and management plan. While the condition is chronic and requires ongoing intervention, life expectancy is comparable to that of the general population. The goal of the multidisciplinary team is to detect and treat complications, such as tumors and cysts, at their earliest and most manageable stages, thereby maintaining the individual’s quality of life.