Tumor suppressor genes act on the cellular level to suppress aberrant growth and limit the emergence of malignant clones. Loss or inactivation of such a gene can lead to an increased risk for malignancies and/or overgrowth syndromes. The mechanism of oncogenesis mediated by ionizing irradiation in patients with Gorlin syndrome is unknown. White blood cells from patients with Gorlin syndrome are not exquisitely sensitive to irradiation as is observed in cells from patients with another sun-sensitive disorder, xeroderma pigmentosum.

An interesting aspect of Gorlin syndrome is that some of the developmental defects (such as jaw cysts) also appear to have undergone 2 genetic hits but without developing into a malignancy. In some patients, the lining of the jaw cysts has lost the normal Gorlin syndrome gene while retaining the mutant allele, paralleling the pathway to malignant transformation. This may explain the behavior of the jaw cysts, which may be more like low-grade neoplasms than congenital malformations.

Study of the genetics of Gorlin syndrome has led to important basic discoveries in developmental biology. DNA analysis from patients with Gorlin syndrome has shown that the gene is homologous to a sequence in the fruit fly Drosophila called the segment polarity gene or patched gene. The patched gene is known to be important in developmental abnormalities, growth regulation, and segmentation in Drosophila.

The patched gene analogue in humans codes for a transmembrane protein, which represses transcription (in certain cells) of genes encoding members of the transforming growth factor (TGF)–beta and Wnt families of signaling proteins. Basal cell carcinomas from patients with Gorlin syndrome have abnormalities of the patched sequence, reinforcing the importance of the Gorlin mutation in oncogenesis and suggesting a potential role of this gene as a tumor suppressor gene. DNA from sporadic basal cell carcinomas (from tumors in patients who were otherwise healthy and did not have Gorlin syndrome) also had allelic loss in the nevoid basal cell carcinoma syndrome (NBCCS) region with inactivating mutations of the remaining allele, suggesting that the gene may play a role in a final common pathway to oncogenesis in basal cell carcinomas.

Gailani et al (1992) showed that inactivation of patched gene is probably a necessary step in basal cell carcinoma development, even in patients without Gorlin syndrome. Up to one third of patients with medulloblastoma and Gorlin syndrome have lost the wild type allele on chromosome arm 9q, implying that this site may code for tumor suppressor activity. Multiple defects in the Gorlin syndrome gene have been reported. Wicking et al (1994) concluded that the preponderance of truncation mutations in the germ line of patients with Gorlin syndrome suggested that the developmental defects are likely a result of haploinsufficiency.

Frequency:

• Internationally: Incidence of Gorlin syndrome is estimated to be 1 in 50,000-150,000 in the general population. The perceived incidence may vary by region; for example, the apparent incidence may be higher in Australia. This may be a result of demographics because a large percentage of the Australian population is made up of fair-skinned peoples transplanted from Europe to the intense solar climate in parts of Australia. Subtle cases that may be undetected in the cooler north may be more likely to present to medical attention in sunnier climates.

Mortality/Morbidity:

• Early death from Gorlin syndrome is rare. An important potential cause for early death includes effects of medulloblastoma, a malignant brain tumor of the posterior fossa that develops in 10% of patients with Gorlin syndrome.

History: Patients most commonly present in the third or fourth decade of life with either dental cysts or basal cell carcinomas. Rarely, patients present in childhood with medulloblastoma. In a significant percentage of patients, the syndrome is probably never diagnosed.

Consider a diagnosis of Gorlin syndrome in any patient who presents with basal cell carcinomas at an early age (eg, <30 y), especially if the tumors occur in skin with minimal sun exposure (in contradistinction from more typical sites, such as the tip of the nose or ear). Obviously, suspicion for Gorlin syndrome should be high if basal cell carcinomas are detected in the pediatric age range. A significant fraction of patients with Gorlin syndrome may never be diagnosed. Many different physical findings have been described in patients with Gorlin syndrome. One of the most sensitive and specific findings is the presence of palmar and plantar pits. These tiny dermal defects are readily observed with a magnifier with a tangential light source and are highly specific for Gorlin syndrome. Unfortunately, the pits are not always present in young children, and they become apparent in most patients as they get older.

• Kimonis (1997) has proposed that the diagnosis of Gorlin syndrome can be made in the presence of two major or one major and two minor criteria.

• Major criteria
  • Two or more basal cell carcinomas in persons younger than 20 years
  • Odontogenic keratocysts of the jaw
  • Three or more palmar or plantar pits
  • Bilamellar calcification of the falx cerebri
  • Bifid, fused, or markedly splayed ribs
  • First-degree relative with Gorlin syndrome

• Minor criteria
  • Macrocephaly
  • Congenital malformations (eg, cleft lip or palate, frontal bossing, "coarse face," hypertelorism)
  • Other skeletal abnormalities, such as Sprengel deformity, marked pectus deformity, or syndactyly of the digits
  • Radiological abnormalities such as bridging of the sella turcica, vertebral anomalies such as hemivertebrae or fusion or elongation of the vertebral bodies, modeling defects of the hands and feet, or flame-shaped lucencies of the hands or feet
  • Ovarian fibroma
  • Medulloblastoma

• Diagnostic criteria are not uniformly present at an early age. For example, in one series of patients with Gorlin syndrome described by Shanley (1994), the mean age of onset of basal cell carcinomas was 20 years. In this same series, jaw cysts were first noted at a mean age of 15 years. Similarly, palmar pits are not uniformly present at an early age. Therefore, these 3 major criteria (ie, basal cell carcinomas, jaw cysts, palmar pits) are only variably present at a young age, making definitive diagnosis difficult in many young patients.

• The keratoses of the jaw, although benign abnormalities, require surgical intervention. Interestingly, they can recur after surgery, mimicking low-grade neoplasm more than resembling a congenital anomaly.

• Patients with Gorlin syndrome are extremely sensitive to ionizing radiation. Excessive sun exposure is a risk factor for skin cancers of many types, including basal cell carcinomas, even in the general population. However, the risk is even higher in patients with Gorlin syndrome. Virtually every patient with Gorlin syndrome eventually develops basal cell carcinomas, regardless of sun exposure. Nevertheless, counsel patients to avoid sun exposure.

Lab Studies:

• No specific laboratory studies are indicated. The genetic test for Gorlin syndrome is not commercially available and is usually unnecessary for diagnosis.

Imaging Studies:

• Depending on the situation, imaging studies may include MRI of the brain, echocardiography, abdominal ultrasonography, dental radiography, and skeletal survey. Because patients with Gorlin syndrome are especially sensitive to ionizing radiation, minimize the use of irradiation.

Procedures:

• Patients suspected of having Gorlin syndrome should have biopsies obtained from several suspicious skin lesions. Obviously, if an infratentorial mass is detected by brain MRI, it should be biopsied as well.

Histologic Findings: The histologic features of the basal cell carcinomas in Gorlin syndrome are usually identical to those observed in sporadic basal cell carcinomas. Medulloblastomas in Gorlin syndrome have been reported to usually have the desmoplastic phenotype, which has been linked, in some studies, with a better prognosis.

Staging: Basal cell carcinomas are not typically staged in Gorlin syndrome, although they tend to be nonaggressive lesions. Some reports state that basal cell carcinomas of the scalp are more aggressive than those in other locations. The Chang staging system is used for the staging of medulloblastoma in Gorlin syndrome.

Medical Care: Patients with Gorlin syndrome can have multiple medical problems related to their congenital anomalies. They may need to be treated by a wide range of specialists, including dermatologists, dentists, cardiologists, oncologists, and orthopedic surgeons. The most common medical presentation is to a dermatologist because of skin nodules.

• Treating some patients with Gorlin syndrome can be difficult because of multiple and widespread basal cell carcinomas. This is especially the case in patients whose carcinomas are the result of prior therapy with ionizing irradiation.

• Surgical excision is the typical approach to a patient with a basal cell carcinoma if the number of lesions is limited. However, in patients who present with numerous lesions, other modalities may be needed.
• Other treatments that may be effective and more efficient than surgical excision in patients with multiple lesions include laser ablation, photodynamic therapy, and topical chemotherapy.
  • Laser ablation is quick and efficient but can lead to scarring. In addition, no surgical margins exist to allow determination of whether a total resection is achieved.
  • Photodynamic therapy is effective in treating large numbers of basal cell carcinomas. Patients are treated with a prodrug administered orally, intravenously, or topically. Some prodrugs are preferentially taken up by tumor cells. The drug is then photoactivated by laser or UV light, resulting in formation of an active moiety. This therapy can be used to treat hundreds of lesions simultaneously. However, it can be associated with pain, scarring, and skin burning.
  • Widespread basal cell carcinomas can also be treated with chemotherapy, including 5-flourouracil and/or topical tretinoin, although significant local reactions can be observed with these as well. Of note, the basal cell carcinomas in Gorlin syndrome only rarely become invasive. Most patients are able to achieve good disease control without aggressive therapy.

• Odontogenic keratosis in the jaw may require intervention. These lesions typically are surgically removed. However, they can recur and require multiple interventions, reflecting their neoplastic nature.
• Finally, patients with Gorlin syndrome can present with medulloblastoma, a malignant tumor of the posterior fossa. The median age at diagnosis for a child with medulloblastoma is about 5 years; the median age at presentation is about 2 years in the subgroup with medulloblastoma and Gorlin syndrome. Approximately 10% of patients with medulloblastoma who are younger than 2 years have Gorlin syndrome.
• Treatment for medulloblastoma typically requires intensive multimodality therapy. The best outcomes have been obtained in patients who have been treated with aggressive resection, chemotherapy, and radiation therapy. Patients with Gorlin syndrome are very sensitive to ionizing radiation, and the use of therapeutic irradiation is known to cause multiple basal cell carcinomas in patients with Gorlin syndrome. In some patients, iatrogenic lesions can number in the thousands. For this reason, patients with Gorlin syndrome and medulloblastoma are best treated without standard radiation therapy.

• One approach is to use a skin-sparing technique. Patients may benefit from a skin-sparing approach to radiation using nonconformal techniques. If possible, treat patients without radiation therapy or with irradiation only of the posterior fossa.
• The limited field approach may be justified because anecdotal evidence indicates that medulloblastoma in Gorlin syndrome is a less aggressive subtype. Many medulloblastomas are desmoplastic, but this is not linked to the low-grade nature. The important part of the treatment of children with medulloblastoma and Gorlin syndrome is the avoidance of widespread high-dose radiation therapy.

• Chemoprevention may also be used in patients with Gorlin syndrome.

• The retinoids, including isotretinoin, are vitamin A analogues that may have an important role in preventing or slowing the development of cancers. Isotretinoin has been shown to be effective in preventing the emergence of new basal cell carcinomas in patients with Gorlin syndrome and xeroderma pigmentosum. This property is especially important in patients at very high risk for developing multiple basal cell carcinomas, for example, following the use of radiation therapy. Unfortunately, isotretinoin does not appear to be useful in preventing skin cancers in healthy adults.
• Oral chemoprevention is most relevant for patients with numerous tumors that cannot be treated with local measures. Some toxicity is associated with these drugs, and they are effective only for as long as they are taken; once stopped, the cancers grow again. Whether the use of retinoids can lead to tumor regression in patients with Gorlin syndrome is unclear.

Surgical Care:

• Surgical excision is the typical approach to a patient with a basal cell carcinoma. This is certainly feasible in patients with limited numbers of lesions. However, in patients that present with numerous lesions, other modalities may be needed.

• Keratoses of the jaw, although benign abnormalities, require surgical intervention. They can recur after surgery, acting more like a low-grade neoplasm than a congenital anomaly.

Consultations: Patients with Gorlin syndrome can have multiple medical problems related to their congenital anomalies. They may require consultation with a wide range of specialists including dermatologists, dentists, cardiologists, oncologists, and orthopedic surgeons. Advise patients with Gorlin syndrome to consult a geneticist for discussions related to transmission of the disease and identification of other afflicted family members.

Basal cell carcinomas are usually not treated medically. In Gorlin syndrome, large numbers of lesions may limit the utility of surgery alone. While a scattered few cutaneous carcinomas can be excised, patients with hundreds or thousands of lesions need alternate therapy. Topical 5-flourouracil with or without topical tretinoin is probably the best topical option.

The use of oral isotretinoin alone is a good option for patients with a limited number of lesions but who are at high risk for developing numerous future lesions (eg, secondary to radiation therapy). In patients with numerous lesions who are at risk for developing many additional lesions, a combination of these 2 approaches can be used.

Use of retinoids in this fashion represents a novel form of chemoprevention. Additionally, retinoids may act in part by inducing differentiation of tissue.
Drug Category: Retinoids -- Important in the therapy of skin diseases. Retinoids have been shown to affect the keratinization process. Their use as antineoplastic agents is based on the ability to maintain epithelial cell differentiation and modify cell growth and differentiation. Proposed mechanisms of action of the retinoids include the following:

• Stimulate mitotic activity and increase follicular cell turnover
• Corticosteroidlike mechanism (eg, anti-inflammatory)
• Affect posttranslational glycosylation
• Disrupt cell membrane
• Liposomal enzyme release
• Suppress ornithine decarboxylase (ie, DNA synthesis inhibition)
• Immunostimulation of T-killer cells
• Inhibit polymorphonuclear (PMN) leukocyte function

Drug Category: Antineoplastic agents -- Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect this growth. After cells divide, they enter a period of growth (ie, phase G1), followed by DNA synthesis (ie, phase S). The next phase is a premitotic phase (ie, G2), then finally a mitotic cell division (ie, phase M).
Cell division rate varies for different tumors. The majority of common cancers increase very slowly in size compared to normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover more quickly than malignant ones from chemotherapy, and is the rationale behind current cyclic dosage schedules.
Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle specific, while others (eg, alkylating agents, anthracyclines, cisplatin) are not phase-specific. Cellular apoptosis (ie, programmed cell death) is also a potential mechanism of many antineoplastic agents.

Deterrence/Prevention:

• Patients with Gorlin syndrome are extremely sensitive to ionizing radiation. Excessive sun exposure is a risk factor for skin cancers of many types, including basal cell carcinomas, even in the general population. However, the risk is higher in patients with Gorlin syndrome. Virtually every patient with Gorlin syndrome eventually develops basal cell carcinomas, regardless of sun exposure. Nevertheless, counsel patients to avoid sun exposure.

• Minimize the use of radiographic irradiation and irradiation to treat cancer as well.