Gorlin syndrome, also known as Nevoid Basal Cell Carcinoma Syndrome (NBCCS), is a rare, inherited condition affecting approximately 1 in 56,000 to 164,000 people globally. This complex disorder impacts multiple organ systems, including the skin, nervous system, eyes, and skeletal structure. Individuals with the syndrome have a high predisposition to developing various tumors, both benign and malignant, as well as specific developmental abnormalities.
Genetic Basis and Underlying Mechanism
The root cause of Gorlin syndrome lies in a change to a specific gene known as Patched 1, or PTCH1. This gene is located on chromosome 9 and functions as a tumor suppressor. In healthy cells, the protein produced by PTCH1 helps regulate cell growth and division by acting as a brake on the Sonic Hedgehog signaling pathway.
When one copy of the PTCH1 gene is mutated, this regulatory function is impaired. The loss of this genetic control allows the cell proliferation pathway to become inappropriately activated, leading to uncontrolled cell growth and the eventual formation of tumors and cysts. This mechanism is often described as the “two-hit” hypothesis for tumor development, involving a first inherited change followed by a second spontaneous change in a somatic cell.
Gorlin syndrome follows an autosomal dominant inheritance pattern. This means that a person needs only to inherit one copy of the mutated gene from either parent to develop the condition. While most cases are inherited, approximately 30-40% of individuals with Gorlin syndrome have a spontaneous or de novo mutation, meaning they are the first in their family to have the genetic change.
Diverse Clinical Features
The manifestations of Gorlin syndrome are wide-ranging and affect multiple body systems. Dermatologic features are among the most common and often provide the first indication of the syndrome. Basal Cell Carcinomas (BCCs), the most common type of skin cancer, frequently begin to appear during adolescence or early adulthood, much earlier than in the general population.
These skin cancers can number in the dozens or even hundreds over a lifetime and often develop on non-sun-exposed areas, such as the trunk, in addition to the head and neck. Another distinctive skin feature is the presence of palmar and plantar pits, which are small, shallow indentations found on the palms and soles of the feet. These pits are a highly characteristic finding, occurring in 75% to 90% of patients.
Skeletal and dental features are also prominent in the syndrome. A hallmark feature is the development of Odontogenic Keratocysts (OKCs), which are benign but locally aggressive cysts that form within the jawbones. These typically begin to appear around the age of 13 and can recur even after surgical removal, potentially causing pain and swelling.
Skeletal anomalies can include fusion or splitting of the ribs (bifid ribs) and abnormalities in the shape of the vertebrae in the spine. Many individuals also present with macrocephaly (a larger-than-average head size) and a prominent forehead. A radiological feature frequently observed is the calcification of the falx cerebri, a sheet of tissue separating the two halves of the brain.
Neurologic features include an increased risk for a malignant brain tumor called medulloblastoma, particularly in young children, with most cases occurring before the age of five. This tumor is the second most common malignancy associated with the syndrome. Other potential findings include benign growths in the ovaries (ovarian fibromas) and the heart (cardiac fibromas).
Lifelong Screening and Care
Genetic testing to confirm a mutation in PTCH1 or SUFU establishes the diagnosis, which is helpful when clinical features are inconclusive. This information guides specific screening protocols, as SUFU mutations carry a substantially higher risk for medulloblastoma.
For medulloblastoma screening, children with a SUFU gene change require a brain Magnetic Resonance Imaging (MRI) every three to six months until age five. Regular dermatologic examinations should begin annually around age ten to monitor for and promptly treat any new BCCs. After the first BCC appears, the frequency of these skin checks often increases.
Dental monitoring for jaw cysts involves a specialized X-ray called an orthopantomogram every 12 to 18 months, starting around age eight. Treatment for BCCs often involves surgical removal. However, due to the high number of lesions, minimally invasive alternatives like topical treatments or cryosurgery are also used. Hedgehog pathway inhibitors, a newer class of medications, can treat more severe BCCs by directly targeting the genetic mechanism of the disease.
Patients must strictly minimize sun exposure, as ultraviolet light increases the risk of BCC development. Traditional radiation therapy is generally avoided for all tumors, including medulloblastoma, because it significantly increases the number and aggressiveness of new skin cancers within the radiation field.