What is nevoid basal cell carcinoma syndrome (NBCCS)?

Nevoid basal cell carcinoma syndrome, also known as “Gorlin syndrome," is a hereditary cancer syndrome characterized by:

• A type of skin cancer known as basal cell carcinoma
• Specific growths within the jaw bones known as keratocysts
• Distinctive small pits within the palms of the hands and soles of the feet
• Skeletal abnormalities, such as differences in the shape of the ribs and vertebrae
• Characteristic facial features, which can include:
  • Hypertelorism (wide-set eyes)
  • Macrocephaly (larger-than-average head size) with or without hydrocephalus (build up of fluid inside the brain)
  • Milia (tiny white cysts embedded in the skin, commonly appearing on the cheeks and around the eyes and lips)

In addition to developing one or more basal cell carcinomas, individuals with nevoid basal cell carcinoma syndrome are also at increased risk to develop other tumor types including:

• Fibromas (benign connective tissue tumors) of the heart and ovaries
• Medulloblastoma, a type of childhood brain tumor

Because nevoid basal cell carcinoma syndrome is hereditary, the risk of developing features associated with it can be passed from generation to generation in a family. The clinical findings of nevoid basal cell carcinoma syndrome can vary greatly within a family, with some affected individuals having only palmar or plantar pits, while others develop keratocysts, basal cell carcinomas, or more extensive manifestations.

Causes

Nevoid basal cell carcinoma syndrome is caused by alterations, also known as mutations, at specific areas within an individual’s genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as “genes.” Genes provide the necessary instructions that our cells require to perform their different functions within our bodies.

In 50-90 percent of patients with nevoid basal cell carcinoma syndrome, the disorder develops as the result of alterations in a specific gene known as PTCH1, located on chromosome 9 at position q22.3. The PTCH1 gene has the ability to produce an essential protein involved in a series of reactions within cells that gives them the information they need to ensure that an embryo develops properly.

The protein produced by PTCH1 acts as a “tumor suppressor," which means that it helps to keep cells from growing and dividing too quickly and it promotes cell death. It has a fundamental role in controlling the growth and development of normal tissues, specifically the skin, brain and jaw.

With the exception of egg and sperm cells, each cell of the body normally has two working copies of the PTCH1 gene. Patients with nevoid basal cell carcinoma syndrome carry an alteration in one copy of the PTCH1 gene in all the cells of their body. Patients are born and develop normally, but are at an increased risk to develop non-cancerous and cancerous growths. These growths are believed to develop because, over time, the second working copy of the PTCH1 gene may become altered within one or more cells. This can lead to abnormal growth of the affected cells, increasing their chance to become cancerous.

How is nevoid basal cell carcinoma syndrome inherited?

A person carrying an alteration in one copy of the PTCH1 gene has a 50 percent — or one in two — chance of passing this same alteration on to each of his or her children. Children who inherit the altered gene copy will have nevoid basal cell carcinoma syndrome and will therefore be at increased risk to develop cancer and other features associated with this condition.

Approximately 70-80 percent of patients with nevoid basal cell carcinoma syndrome inherit an altered copy of the PTCH1 gene from a parent who also has the syndrome. In the remaining 20-30 percent of patients, there is no family history of nevoid basal cell carcinoma syndrome. In these individuals, nevoid basal cell carcinoma syndrome likely results from presence of a “new mutation” in one copy of PTCH1. Although these individuals will be the first ones in their family to carry the genetic change, each of their future children will now have a 50 percent chance to inherit the same genetic change.

Diagnosis

The diagnosis of nevoid basal cell carcinoma syndrome relies primarily on the presence of certain clinical symptoms, which are grouped into major and minor diagnostic criteria. A diagnosis of nevoid basal cell carcinoma syndrome can be made based on the presence of two major and one minor diagnostic criteria or one major and three minor criteria (Evans et al., 1993):

Criteria for diagnosis

Major criteria

• More than five basal cell carcinomas in any individual over his lifetime or one basal cell carcinoma developing by age 30
• Odontogenic keratocysts of the jaw, proven by histopathology
• Palmar or plantar pits (two or more)
• Calcification of a part of the brain known as the falx cerebri
• First-degree relative with nevoid basal cell carcinoma syndrome

Minor criteria

• Macrocephaly (larger-than-average head size)
• Lympho-mesenteric or pleural cysts
• Cleft lip or cleft palate
• Vertebral or rib anomalies observed on chest X-ray and/or spinal X-ray
• Polydactyly (congenital abnormality that produces more than five fingers on a hand or more than five toes on a foot)
• Ovarian or cardiac fibromas (benign tumors of the ovary or heart)
• Medulloblastoma (a type of brain cancer)
• Eye anomalies (cataract, developmental defects, and pigmentary changes of the retinal epithelium)

Basal cell carcinomas (BCCs)

Basal cell carcinomas can appear in early childhood, but more often appear between puberty and 35 years of age, with the mean age of onset at age 25. Basal cell carcinomas include the following features:

• They can be pink, brown or orange in appearance and can resemble moles, skin tags, an ordinary nevus (birth mark), or hemangiomas.
• They can also vary in number (from a few to thousands) and size (1 to 10 mm).
• They are most commonly located on the face, back and chest. Sebaceous and dermoid cysts are also common.
• There are rare cases where basal cell carcinomas have metastasized, and if left untreated, they can also lead to disfigurement, especially on the face.

Basal cell carcinomas are typically treated by surgical removal when the number of lesions is limited. Other therapies may be utilized, but radiation therapy should always be avoided in individuals with nevoid basal cell carcinoma syndrome as new tumors can arise in the radiation fields even after many years.  

Keratocysts

Jaw cysts, known as keratocysts, are a representative sign of nevoid basal cell carcinoma syndrome, and are found in 90 percent of affected individuals. They typically occur in the first and second decades of life (by age 20). Jaw cysts rarely occur after age 30. Keratocysts should be surgically removed because if left untreated, they can lead to disruption of the teeth and fracture of the jaw.

Other clinical features

Skeletal abnormalities

Nevoid basal cell carcinoma syndrome is characterized by skeletal abnormalities, such as bifid ribs (ribs that are split into two pieces) and wedge-shaped vertebrae. Skeletal defects are typically only seen with the use of X-ray films and may be helpful in making the diagnosis.

Approximately 5 percent of individuals with nevoid basal cell carcinomas are found to have other malformations, including cleft lip/palate, polydactyly, or other eye abnormalities.

Other tumors

Other tumors, such as cardiac and ovarian fibromas, have been reported in 2-20 percent of patients with nevoid basal cell carcinoma syndrome, respectively. Cardiac fibromas are usually present at birth or soon after and can be asymptomatic or cause complications. Ovarian fibromas are usually diagnosed during pregnancy or delivery and may cause torsion (twisting) of the ovary but they are not thought to affect fertility. They can become very large and calcified but rarely transform to a malignant tumor.

A detailed review of an individual’s medical and family history becomes important in diagnosing nevoid basal cell carcinoma syndrome. A doctor or genetic counselor may construct a pedigree, or a multi-generation family tree, that indicates which members of the family have developed cancer, the types of cancer and the ages of onset, as well as the presence of any clinical manifestations. If the pattern of clinical features and/or cancers is suggestive of nevoid basal cell carcinoma syndrome, the physician or counselor may recommend that genetic testing be performed.

Testing for nevoid basal cell carcinoma syndrome

In order to confirm on a molecular level that an individual has nevoid basal cell carcinoma syndrome, he or she can undergo the process of genetic testing:

• DNA is isolated from the sample and the two copies of the PTCH1 gene are evaluated using a variety of methods and compared to the normal reference sequence for PTCH1.
• If an alteration in one PTCH1 gene copy is identified, the genetic counselor can next examine whether the alteration has been previously reported in other individuals with nevoid basal cell carcinoma syndrome.

How test results are used

In patients carrying a diagnosis of nevoid basal cell carcinoma syndrome, approximately 50-90 percent of individuals will have a mutation or deletion involving PTCH1. However, it is important to remember that not all patients with nevoid basal cell carcinoma syndrome carry a detectable alteration in PTCH1. There are likely to be additional, undiscovered genes that play a role in the development of the remaining 10-50 percent of patients with the syndrome. Therefore, the failure to identify an alteration in the PTCH1 gene does not exclude the diagnosis of nevoid basal cell carcinoma syndrome.

PTCH1 genetic test results can also provide important information for other family members. Knowing the specific alteration that is present in an individual with nevoid basal cell carcinoma syndrome allows for other family members to undergo testing to determine whether they also carry the alteration and could therefore develop the features of nevoid basal cell carcinoma syndrome.

Reproductive options

Reproductive options exist for an individual with an alteration in the PTCH1 gene who does not wish to pass the alteration onto future children:

• Prenatal diagnosis — DNA is isolated from the cells of the developing baby though one of two procedures, chorionic villus sampling (CVS) or amniocentesis, and is analyzed for alterations in the PTCH1 gene. With appropriate counseling, a parent can then decide whether to carry the pregnancy to term or to end the pregnancy.
• Preimplantation genetic diagnosis (PGD) — For couples using in vitro fertilization to become pregnant, embryos can be tested for genetic disorders before transferring them into the uterus. Only healthy embryos carrying two working copies of the PTCH1 gene would be implanted. Before one can proceed with prenatal testing or PGD, a PTCH1 mutation must be identified in a parent with nevoid basal cell carcinoma syndrome.

Cancer screening protocol

Whether or not one is tested for PTCH1 mutations, it is strongly recommended that an individual with nevoid  basal cell carcinoma syndrome consider the following evaluation and surveillance recommendations, which are included in the Consensus Statement from the First International Colloquium on Basal Cell Nevus Syndrome (Bree & Shah, 2011).

These are only recommendations and should be discussed and performed in consultation with a healthcare provider familiar with nevoid basal cell carcinoma syndrome. The most common lesions accounting for the syndrome are usually not life-threatening, but surveillance and evaluation is still warranted:

• Echocardiography in the first year of life to evaluate for cardiac fibromas. Repeat if symptomatic.
• Baseline brain MRI to screen for medulloblastoma. Repeat yearly until 8 years old, then discontinue. Repeat sooner if symptomatic.
• Head circumference should be followed throughout childhood and plotted on appropriate growth charts. Rapid enlargement should prompt evaluation for hydrocephalus (increased build-up of fluid in the brain).
• Baseline panorex of jaw (digital if possible) as soon as tolerated. Repeat yearly until first jaw cyst. After first jaw cyst, repeat every 6 months until there are no jaw cysts for 2 years, or until age 21. Repeat more regularly if needed for symptoms or occurrence.
• Baseline spine film at 1-year-old or at the time of diagnosis (digital if possible). Repeat if symptomatic. If abnormal, repeat per scoliosis protocol every 6 months.
• Additional radiologic studies if warranted, including chest X-ray for bifid ribs, PA and lateral skull for calcification of the falx, imaging of the long bones for bone cysts, and hand film.
• Annual dermatologic examination until first basal cell carcinoma. After first BCC, repeat every 6 months or more frequently as needed.
• Routine developmental screening with well child visits. If the child fails screening or is not meeting milestones, further developmental assessment and testing is warranted. If the child has difficulty learning in school, cognitive evaluation and testing is warranted.
• For females, ultrasound examination of the ovaries to evaluate for ovarian fibromas prior to pregnancy.
• Ophthalmologic evaluation for evidence of cataract, developmental defects, and pigmentary changes of the retinal epithelium. Repeat if symptomatic.

In addition to the recommended cancer surveillance guidelines, children and adults with nevoid basal cell carcinoma syndrome should be encouraged to lead as healthy a lifestyle as possible with avoidance of exposure to the sun and ionizing radiation, which increase the likelihood of developing basal cell carcinomas. Patients and parents should be alert to signs and symptoms of basal cell carcinomas and pursue medical attention promptly should these occur.

Early treatment of basal cell carcinomas is essential to prevent cosmetic problems. The priorities of treatment are to ensure complete eradication of aggressive basal cell carcinomas, and to preserve normal tissue to prevent disfigurement. Surgical excision can be supplemented by a number of other possible treatments including cryotherapy and laser treatment for early lesions as well as photodynamic therapy.

References

Evans DG, Ladusans EJ, Rimmer S, Burnell LD, Thakker N, Farndon PA. Complications of the nevoid basal cell carcinoma syndrome: results of a population based study. J Med Genet. 1993 Jun;30(6):460-4. Cited in PubMed; PMID 8326488. Read the article.

Bree AF, Shah MR. Consensus statement from the first international colloquium on basal cell nevus syndrome (BCNS). Am J Med Genet Part A. 2011 Sep;155A(9):2091-7. doi: 10.1002/ajmg.a.34128. Epub 2011 Aug 10. Read the abstract.