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Nevoid Basal Cell Carcinoma Syndrome (Gorlin's Syndrome)
Thad Labbe, MD · Mark Levine, MD
Gorlin's syndrome, also known as nevoid basal cell carcinoma syndrome, is an inherited condition that affects many organ systems. Late in the course of this disease, a patient may present with multiple, aggressive basal cell carcinomas that are predominantly found on the face and neck. Early diagnosis is crucial so that early monitoring can begin for the disfiguring and life-threatening manifestations of this disease. Although multiple basal cell carcinomas in a young patient demands a work up for Gorlin's syndrome, patients who present with iris colobomas, optic nerve colobomas, congenital cataracts, or nystagmus may also need a work up for Gorlin's syndrome if the clinical suspicion is high.1 These ophthalmologic conditions have been associated with Gorlin's syndrome and form minor criteria, which are helpful in diagnosing this syndrome when other major criteria are present.2 Once a diagnosis is made, it is important that physicians are prepared to teach patients the precautions to use to reduce the number of cancers they will develop.
Depending on the population studied, the prevalence of Gorlin's syndrome has been estimated to be as high as 1 in 56,000. Men and women are affected with the same frequency. A parent affected with this syndrome has a 50% chance of having a child with this syndrome since this is an autosomal dominant condition with complete penetrance. However, the affected child may have any of the many manifestations of this disease because the responsible gene's expression is variable.3
The cause of Gorlin's syndrome can be traced to a transmembrane protein encoded by 4.5 kilobases of DNA on chromosome 9q22.3-q31. This protein is involved in embryonic development of multiple organ systems, which explains how one gene can produce so many abnormalities. This gene also acts as a tumor suppressor gene. Therefore, patients who inherit the disease have one defective gene and one normal gene. Any damage to the normal gene can lead to the development of a cancer.4 Patients with no family history can also get Gorlin's syndrome if they have a new germ-line mutation. It is estimated that 8% of patients with Gorlin's syndrome have new germ-line mutations.3
Patients with Gorlin's syndrome have several external features that are suggestive of the syndrome. An external examination of these patients may reveal heavy, confluent eyebrows, broad nasal bridges giving the appearance of hypertelorism in 60% of patients, true hypertelorism in 5% of patients, and prominent brows. These patients are also taller than normal patients.5
Although a gene for Gorlin's syndrome has been identified, it is important to clinically diagnose this syndrome in a suspected patient. Diagnosis requires the identification of two major criteria or the diagnosis of one major criterion and two minor criteria.2
The discovery of multiple basal cell carcinomas, or a basal cell carcinoma diagnosed before the age of 20, is a major criterion for diagnosing Gorlin's syndrome.2 However, only about 15% of patients manifest with skin lesions before puberty. Patients may have few to thousands of nevoid basal cell carcinomas arising in any region of the skin, especially on the face, neck, and upper trunk. The periorbital areas, eyelids, nose, malar region, and upper lip are the facial sites most often affected. Slide 1 shows an example of a patient with Gorlin's syndrome with multiple basal cell carcinomas. The nevoid lesions may range from pearly to flesh-colored to reddish brown, and may vary in size from 1 mm to 10 mm in diameter. The tumors may be papular, pedunculated, pigmented, nodular, erythematous, or ulcerative. An example of pigmented and nonpigmented basal cell carcinomas on the neck of a patient with Gorlin's syndrome is shown in Slide 2. Some tumors may even appear clinically similar to milia. However, the pathology is characteristic of basal cell carcinoma from their initial appearance.6 A full spectrum of basal cell carcinoma may develop from the nodular type to morpheaform. Before puberty, the lesions are harmless, but after puberty into adolescence, the lesions may enlarge, ulcerate, and deeply infiltrate, which may lead to loss of one or both eyes and portions of the nose. Treatment at that time is critically important.
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The presence of a unilocular odontogenic keratocyst is a major criterion in Gorlin syndrome diagnosis that can occur as early as age 8. The odontogenic keratocyst is a keratinizing epithelial-lined cyst found in either the maxillae or the mandible.7 A radiographic example of this lesion is shown in Slide 3, adjacent to the roots of the tooth. Approximately 5% of odontogenic keratocysts that are associated with Gorlin's syndrome have been found to overexpress cyclin D1 and p53 proteins. It is suggested that the loss of control cellular proliferation in this syndrome may lead to a more aggressive clinical behavior of the keratocysts.8
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Radiographic changes are important in Gorlin's syndrome because they are some of the earliest manifestations of the disease. Calcification of the falx occurs in approximately 85% of Gorlin syndrome patients and is a major diagnostic criterion (Slide 4). However, calcification of the tentorium cerebelli and the choroid plexus also occurs.1
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Finding three or more palmar or plantar pits is another major criterion. Approximately 65% of patients with Gorlin's syndrome present with 1-mm to 2-mm pits on their palms or on the bottoms of their feet; although hands are more commonly involved. Slide 5 demonstrates the typical clinical appearance of the lesion. Although uncommon in children, these pits become more common as patients age. In addition, cases of the development of basal cell carcinomas in the base of these pits have been reported.1
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Because of the autosomal dominant nature of this syndrome, family history of Gorlin's syndrome is another major criterion. Children with a family history of Gorlin's syndrome should have a work up soon after birth looking for the earliest manifestations of this syndrome.2
A patient with a single major criterion should then be examined for at least two minor criteria that will help make the diagnosis of Gorlin's syndrome. A young patient can be x-rayed to look for abnormal rib development (bifid, fused, or missing), or abnormal vertebral development (bifid or fused). These radiographic changes are important because they are often seen at birth.6 Slide 6 shows the typical appearance of the bifid rib in Gorlin's syndrome. Frontal bossing in a child with greater than 97th percentile head circumference can help make the diagnosis. A patient with a cleft lip or polydactyly should raise the suspicion of the possibility of Gorlin's syndrome and major criteria should be investigated. Ophthalmologists should look for congenital cataracts, microphthalmos, or iris colobomas because any two of these diagnoses along with a major criteria will make the clinical diagnosis.2
Gorlin's syndrome should also be considered in a patient with meduloblastoma because 1% of patients with meduloblastoma have Gorlin's syndrome.10 The radiographic appearance of a meduloblastoma is demonstrated in Slide 7. Meduloblastomas, ovarian fibroid cysts, cardiac fibromas, or abdominal cysts known as lymphomesenteric cysts more commonly occur in patients with Gorlin's syndrome.1
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Genetic testing to look for defects in the tumor suppressor gene implicated in Gorlin's syndrome is now available. This testing helps reinforce clinical and radiographic evidence.2
Early diagnosis is crucial to catch the life-threatening manifestations of Gorlin's syndrome at an early stage. Certain precautions in patients are potentially life saving if begun early. Even though complete avoidance of sunlight will not prevent all tumors, protection from sun exposure can drastically reduce the number of skin cancers patients can get.11
Once Gorlin's syndrome is diagnosed, patients need regular surveillance for skin tumors. It is recommended that patients visit the dermatologist every 2 to 3 months. Beginning at age 8, patients should have a panoramic radiograph of the jaws to look for odontogenic keratocysts. Five percent of patients with Gorlin's syndrome develop a meduloblastoma before age 2. Therefore, if an infant is at risk, he or she should have magnetic resonance imaging every year until 8 years old to rule out meduloblastoma.5
Gorlin's syndrome patients respond differently from unaffected patients to standard treatments. For example, when a meduloblastoma is associated with Gorlin's syndrome, treatment with radiation therapy can increase the number of tumors that develop in the irradiated area.12 Additionally, basal cell carcinomas can act differently. Understanding the natural history of basal cell carcinomas in Gorlin's syndrome is important in understanding the appropriate treatment of patients with basal cell carcinomas. Before puberty, basal cell carcinomas are non-aggressive. These tumors usually do not infiltrate and do not display destructive behavior before patients reach 10 years old; however, it is recommended that these tumors not be treated at this age. Basal cell carcinomas become more aggressive in adolescence. The tumors enlarge and ulcerate, and it is recommended that these tumors be treated at this time.6 An example of the clinical appearance of a patient's disfigurement from the multiple basal cell carcinomas seen with Gorlin's syndrome is shown in Slide 8.
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Several treatments are available for basal cell carcinoma. The gold standard for basal cell carcinoma removal is surgery. If Mohs' micrographic surgery is performed, a recurrence rate as low as 1% can be achieved. Other surgical techniques, such as curettage and electrodessication, have recurrence rates above 7.7% and 10%. Although cryotherapy is easy to use, it causes discomfort to patients and has a 16% recurrence rate. Other treatment options are sometimes needed when the tumor is unable to be resected. Imiquimod cream has shown remarkable success and has had recurrence rates of only 8%. Although 5-fluorouracil has occasionally been recommended for treatment of basal cell cancers, patients find it uncomfortable and it is associated with a high recurrence rate. Photodynamic therapy is a new technology that has also had some success in treating basal cell carcinoma.11 Oseroff and colleagues at Roswell Park Center Institute showed that 5-amino levulinic acid photodynamic therapy was not only safe and well-tolerated, but it also had an 85% to 98% success rate in removing basal cell carcinomas.13
