Basal cell nevus syndrome

Related Terms

Basal cell carcinoma, basal cell naevus syndrome, BCC, BCNS, bifid rib, broad nose, crossed eyes, cysts, fifth phacomatosis, genetic disorder, Gorlin syndrome, Gorlin's syndrome, Gorlin-Goltz syndrome, hedgehog, hydrocephalus costovertebral dysplasia and Sprengel anomaly, kyphosis, medulloblastoma, multiple basal cell nevi odontogenic keratocysts and skeletal anomalies, NBCCS, naevoid basal cell carcinoma syndrome, nevoid basal cell carcinoma syndrome, palmar and plantar pits, Patched-1, photodynamic therapy, PTCH1 gene, scoliosis, smoothened, Sonic hedgehog, underbite.

Background

First reported in 1894 by Jarisch and White and first described in 1960 by Gorlin, basal cell nevus syndrome (BCNS) is a rare genetic disorder that affects many systems in the body, including the integumentary (skin), skeletal, reproductive, urinary, endocrine, and nervous systems. Basal cells are located in the outer layer of the skin. BCNS may result in the development of more than two types of basal cell carcinoma, a cancer of the outer layer of the skin that usually occurs prior to the age of 30; cysts in the jaw; eye or facial abnormalities; abnormalities in the rib cage and vertebrae (the spinal column); increased risk of cardiac and uterine fibromas (noncancerous tumors); increased incidence of medulloblastoma, the most common childhood central nervous system tumor; and pits in the palms of the hands and soles of the feet. Symptoms of BCNS may be apparent at birth or may develop in the second or third decade of life.
BCNS is caused by a mutation or defect in the PTCH1 gene. Mutations in this gene have also been identified in individuals with basal cell carcinomas and medulloblastoma, which is the most common childhood central nervous system tumor. Medulloblastomas form between the brain stem and the cerebellum. BCNS is inherited or passed down among family members as an autosomal dominant trait.
This gene was first identified in fruit flies, an organism popularly used by biologists to study development. The PTCH1 gene was determined to be important in the growth and development of many parts of the body. For example, correct functioning of the PTCH1 gene is needed for the proper development of the arms, legs, and spinal cord. The PTCH1 gene produces the Patched-1 protein, which interacts with a protein called Sonic Hedgehog to transmit signals in the body that allow its proper functioning. Specifically, the interaction is important in early development and plays a role in cell growth, cell specialization, and determining the shape of many different parts of the developing body.
BCNS is estimated to occur in one out of every 56,000-164,000 people. The prevalence is likely to be higher among young people with basal cell carcinomas. BCNS appears to affect males and females of all races and ethnicities equally. While exact death rates are not available, patients with BCNS tend to die of skin cancer or complications of cancer.
There is no cure for BCNS. Treatment aims to reduce symptoms and prevent or treat complications.

Signs and symptoms

General: Basal cell nevus syndrome (BCNS) is a rare genetic disorder that affects many systems in the body, including the integumentary (skin), skeletal, reproductive, urinary, endocrine, and nervous systems. Basal cells are located in the outer layer of the skin. BCNS may result in the development of more than two types of basal cell carcinoma, a cancer of the outer layer of the skin that usually occurs prior to the age of 30; cysts in the jaw; eye or facial abnormalities; abnormalities in the ribcage and vertebrae (the spinal column); increased risk of cardiac and uterine fibromas (noncancerous tumors); increased incidence of medulloblastoma, the most common childhood central nervous system tumor; and pits in the palms of the hands and soles of the feet. Symptoms of BCNS may be apparent at birth or may develop in the second or third decade of life.
Brain: A rare symptom of BCNS is a type of brain cancer called medulloblastoma, the most common childhood central nervous system tumor. Medulloblastomas form between the brain stem and the cerebellum. Common symptoms include balance problems, headaches, and vomiting caused by hydrocephalus (fluid on the brain) from blockage of cerebrospinal fluid flow. Medulloblastoma has the tendency to spread to other sites in the nervous system and occasionally to other organs.
Dental: Dental problems are common in BCNS. These often include an underbite, in which the bottom teeth overlap the top set of teeth when the mouth is closed, and cysts in the jaw.
Eyes: There are several eye symptoms that may be observed in patients with BCNS, including crossed eyes, widely spaced eyes, cysts in the conjunctiva (linings of the eyes), holes in the iris, glaucoma (increased pressure in the eye), and abnormalities of the corners of the eyes. Blindness may also be present from birth, and individuals with BCNS may also have cataracts, a clouding of the lens of the eye, which may lead to blindness.
Face: Distinctive facial characteristics include a broad face, prominent forehead, and broad bridge of the nose. In addition, patients may have a cleft palate, which is an incomplete closure of the roof of the mouth, a cleft lip, which is an abnormal groove in the upper lip beneath the nose, or both.
Reproductive organs: Females with BCNS may develop fibrous noncancerous ovarian cysts and ovarian cancer. Ovarian cancer may not produce any obvious symptoms, but as the tumor grows, it may result in pressure or pain in the abdomen, back, pelvis, or legs, a swollen or bloated abdomen, nausea, indigestion, diarrhea, gas, or constipation, and fatigue. Ovarian cancer may spread to other organs, including the liver, lungs, and abdomen, if left untreated.
Skeleton: Common skeletal symptoms observed in BCNS include calcification or hardening of the back of the skull; rib abnormalities such as a bifid rib, a congenital abnormality that results in the rib being split into two; scoliosis (sideways curvature of the spine); kyphosis (forward curvature of the spine); unspecified problems with vertebrae; and short fingers.
Skin: Skin symptoms of BCNS include pits on the palms of the hands and soles of the feet.
Basal cell carcinomas may occur in individuals with BCNS. Although pain may occur at the local site of the carcinoma, it is very rare for this type of cancer to spread to another site within the skin or to other organs. Basal cell carcinomas are most common on the face, the neck, and the upper part of the trunk, that is, in sun-exposed areas, but in BCNS they are also found in relatively sun-protected areas.
Other: Noncancerous cysts may also develop in the lungs, heart, and abdomen. In addition, a type of noncancerous polyp may develop in the stomach. Additional reported symptoms include cerebral gigantism (an abnormally enlarged head), long fingers, extra fingers, and cysts on the eyelids.

Diagnosis

General: Diagnosis of basal cell nevus syndrome (BCNS) is generally made if a patient has two major criteria or one major criterion and two minor criteria. Major criteria include more than two basal cell carcinomas in a patient of any age or one in a patient younger than 20 years of age; characteristic cysts in the jaw; three or more pits on the palms of the hands or soles of the feet; calcification or hardening of the back of the skull; characteristic abnormalities of the ribs; and a first-degree relative with BCNS. Minor criteria include an enlarged head; distinctive features of the head or face, including a broadened nasal bridge, increased distance between the eyes, and exaggerated jaw length; skeletal abnormalities other than those described in the major criteria; characteristic ovarian cysts; and medulloblastoma.
Biopsy: In a biopsy, a small sample of tissue is taken for analysis in a lab. To diagnose BCNS, a skin biopsy may be taken to evaluate certain suspected cancers, including basal cell nevi and basal cell carcinomas. A biopsy may also be done on tissue from the jaw to evaluate the presence of characteristic jaw cysts.
Echocardiography: An echocardiogram produces an ultrasound, or two- or three-dimensional picture, of the heart to allow for the assessment of cardiac valve areas and function, any abnormal communications between the left and right side of the heart, and any valvular regurgitation (leaking of blood through the valves), as well as calculation of cardiac blood flow. An echocardiogram may be used to evaluate the presence of cardiac fibroma, a fibrous cyst that may develop in the heart. This test may be done early in life to establish a baseline and repeated several times throughout the patient's life to evaluate any changes. Echocardiograms may be performed two ways. The first is a transthoracic echocardiogram, in which the echocardiography probe is placed on the chest wall of the patient, and images are taken through the chest wall. The second is a transesophageal echocardiogram, in which a specialized probe containing an ultrasound transducer at its tip is passed into the patient's esophagus. A benefit to performing a transesophageal echocardiogram is that images are clearer than those from the transthoracic test.
Eye exam: A thorough eye exam should be performed to evaluate common symptoms associated with BCNS, including crossed eyes, cysts in the conjunctiva (linings of the eyes), holes in the iris, glaucoma (increased pressure in the eye), cataract (clouding of the lens of the eye), and abnormalities of the corners of the eyes.
Genetic testing: If BCNS is suspected, deoxyribonucleic acid (DNA) sequencing may be performed to confirm a diagnosis. A sample of the patient's blood is taken and analyzed in a laboratory for the defect in the PTCH1 gene. If this defect is detected, a positive diagnosis is made.
Imaging: X-rays may reveal skeletal abnormalities of the ribs, vertebrae, spine, skull, hands, and feet. X-rays may also identify dental abnormalities or cysts in the jaw that may be displacing teeth. Magnetic resonance imaging (MRI) of the head may be done to evaluate the calcification or hardening of the back of the skull and the presence of medulloblastoma, a tumor that forms between the brain stem and the cerebellum. MRI uses magnetic fields to visualize organs within the body. An ultrasound, or two- or three-dimensional picture, of the pelvis may be done in females to evaluate the presence of fibrous ovarian cysts.
Physical exam: In a thorough physical exam, a physician should look for distinctive facial, eye, and dental symptoms characteristic of BCNS. These include an underbite, in which the bottom teeth overlap the top set of teeth when the mouth is closed; crossed eyes, widely spaced eyes, cysts in the conjunctiva (linings of the eyes), holes in the iris, and abnormalities of the corners of the eyes; scoliosis (sideways curvature of the spine); kyphosis (forward curvature of the spine); short fingers; and pits on the palms of the hands and soles of the feet.

Complications

Cancer: Basal cell nevi and basal cell carcinomas are the most common complications of basal cell nevus syndrome (BCNS). Aggressive basal cell carcinomas may cause pain. Only a small percentage of basal cell nevi develop into problematic lesions. About 15% of patients with BCNS do not develop any basal cell carcinomas. The spread of this type of cancer to other parts of the body is very rare. Basal cell carcinomas are much more common on areas of the skin exposed to the sun. In addition, this type of cancer tends to be more common among Caucasians with BCNS. (However, this may be because fewer patients of different races were included in the analyses.) Medulloblastoma, a tumor that occurs in the brain, is a rare complication that tends to occur only in very young patients with BCNS. Medulloblastoma is a very aggressive type of cancer that may spread throughout the central nervous system if left untreated.
Dental problems: Odontogenic keratocysts (jaw cysts) may not cause any symptoms, or they may cause pain and displacement of teeth, with unclear severity.
Neurological problems: If a child develops medulloblastoma, a type of brain tumor, he or she may experience neurological problems. Increased pressure within the skull as a result of the tumor may cause headaches, vision problems, and vomiting, commonly first thing in the morning. Children often appear tired, weak, and irritable. Changes in personality and behavior may also be noticed. Because the cerebellum controls muscle coordination, a tumor in this area may cause problems with walking. A person may appear to stumble or walk in an awkward or uncoordinated way. Speech may also be affected, and words may be slurred or muddled.
Reproductive problems: Fibrous ovarian cysts may not cause any problems in patients with BCNS, or they may cause pain, which may range from mild to severe. Females with BCNS may also develop ovarian cancer. Ovarian cancer may not produce any obvious symptoms, but as the tumor grows, it may result in pressure or pain in the abdomen, back, pelvis, or legs; a swollen or bloated abdomen; nausea, indigestion, diarrhea, gas, or constipation; and fatigue. Ovarian cancer may spread to other organs, including the liver, lungs, and abdomen if left untreated. Treatment of ovarian cancer, such as chemotherapy, may lead to infertility.

Treatment

General: There is no cure for basal cell nevus syndrome (BCNS). Instead, treatment aims to reduce symptoms and prevent or treat complications.
Drugs: Some drugs that are applied to the skin may help treat basal cell carcinomas. 5-Fluorouracil (5-FU) cream is a chemotherapy agent that acts to inhibit the cells from replicating their DNA, preventing the cancer from growing. 5-FU may be applied to affected areas twice daily for at least three weeks. This agent should be avoided in people who are hypersensitive to the drug or its constituents and should not be used during pregnancy or lactation. Adverse effects may include inflammation or swelling.
Imiquimod (Aldara?) is a cream that works to stimulate the immune system to release a number of chemicals called chemokines, which are important in destroying cancer cells. Imiquimod should be applied to the affected area five nights per week at bedtime for six weeks. The cream should be left on the skin for eight hours and then washed off. This agent should not be used in people who are hypersensitive to the drug or its constituents and should not be used during pregnancy or lactation. Adverse effects may include redness, swelling, itching, burning, and soreness in the areas of application.
Photodynamic therapy (PDT): Basal cell carcinomas may be treated with photodynamic therapy, which delivers a phototoxic (light-activated) drug and light treatment. In live cells, this process causes the selective death of the cells that express a certain fluorescent molecule. Aminolevulinic acid (Levulan?) and methyl-aminolevulinic acid (Metvixia?) applied to the skin, combined with light therapy, for example, have been used to treat basal cell carcinomas. This form of treatment may be ideal for multiple small lesions as opposed to large, recurrent, or particularly aggressive ones. Potential adverse effects include redness, swelling, and photosensitivity (sensitivity to light).
Surgery: Some complications of BCNS may be treated with surgery. Jaw cysts may be removed surgically, but recurrence rates are high. Radiation therapy should be avoided in patients with BCNS, because it is not typical for basal cell carcinomas to spread to other parts of the body. Alternative means should be used to remove basal cell carcinomas.
Electrodesiccation and curettage (ED&C) is a procedure in which the tumor is cut from the skin and a needle-shaped electrode stops the bleeding and destroys any remaining cancer cells near the edges of the wound. This process may need to be repeated several times until no cancer cells are present.
Surgical excision of basal cell carcinomas may be done in an outpatient setting. This procedure may be disfiguring and may not be appropriate in patients who develop multiple tumors, especially on the face.
Large, recurrent, or aggressive tumors may be removed using Mohs micrographic surgery, in which the tumor is cut from the skin in thin layers. Each layer is examined for cancer cells and layers of skin continue to be removed until no cancer cells are detected. Tumors in the heart or ovaries may need to be surgically removed to alleviate or prevent symptoms.

Integrative therapies

Currently there is a lack of scientific evidence on the use of integrative therapies for the treatment or prevention of basal cell nevus syndrome (BCNS).

Prevention

General: Basal cell nevus syndrome (BCNS) occurs as the result of inheritance or spontaneous mutation. Therefore, there are no known means of prevention. Patients with BCNS should be regularly seen by a dermatologist, physician, ophthalmologist, and dentist to prevent complications. In addition, patients with BCNS should avoid exposure to ultraviolet rays and radiation therapy, because these may increase the likelihood of developing basal cell carcinomas, and they should also be instructed on how to screen skin lesions for potential problems. Patients should also be instructed on proper sunscreen use during exposure to the sun.
Genetic testing and counseling: Individuals who have BCNS may meet with a genetic counselor to discuss the risks of having children with the disease. Genetic counselors may explain the options and the associated risks of various tests, including preimplantation genetic diagnosis (PGD), amniocentesis, and chorionic villus sampling (CVS).
Preimplantation genetic diagnosis (PGD) may be used with in vitro (artificial) fertilization. In PGD, embryos are tested for the defective PTCH1 gene, and only the embryos that are not affected may be selected for implantation. The defective gene may also be detected in a fetus, so parents may choose whether to continue the pregnancy. Genetic counselors may assist parents with these difficult decisions.

Author information

This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography

Bale AE, Gailani MR, Leffell DJ. The Gorlin syndrome gene: a tumor suppressor active in basal cell carcinogenesis and embryonic development. Proc Assoc Am Phys. 1995;107: 253-7.
BCCNS life support network. .
Evans DGR, Ladusans EJ, Rimmer S, et al. Complications of the naevoid basal cell carcinoma syndrome: results of a population based study. J Med Genet. 1993; 30: 460-4.
Gorlin RJ. From oral pathology to craniofacial genetics. Am J Med Genet. 1993;46: 317-34.
High A, Zedan W. Basal cell nevus syndrome. Curr Opin Oncol. 2005;17(2):160-6.
Honavar SG, Shields JA, Shields CL, et al. Basal cell carcinoma of the eyelid associated with Gorlin-Goltz syndrome. Ophthalmology 2001;108: 1115-23.
Kimonis VE, Goldstein AM, Pastakia B, et al. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet. 1997;69: 299-308.
Kimonis VE, Mehta SG, Digiovanna JJ, et al. Radiological features in 82 patients with nevoid basal cell carcinoma (NBCC or Gorlin) syndrome. Genet Med. 2004;6(6):495-502.
Natural Standard: The Authority on Integrative Medicine. .
Oseroff AR, Shieh S, Frawley NP, et al. Treatment of diffuse basal cell carcinomas and basaloid follicular hamartomas in nevoid basal cell carcinoma syndrome by wide-area 5-aminolevulinic acid photodynamic therapy. Arch Dermatol. 2005;141(1):60-7.
Shanley S, Ratcliffe J, Hockey A, et al. Nevoid basal cell carcinoma syndrome: review of 118 affected individuals. Am J Med Genet. 1994;50: 282-90.
Veenstra-Knol HE, Scheewe JH, van der Vlist GJ, et al. Early recognition of basal cell naevus syndrome. Eur J Pediatr. 2005;164(3):126-30.

Causes

Basal cell nevus syndrome (BCNS) is an inherited disorder caused by mutations or defects in the PTCH1 gene. The PTCH1 gene produces the Patched-1 protein, which interacts with a protein called Sonic Hedgehog to transmit signals in the body that allow its proper functioning. Specifically, the interaction between this receptor and ligand is important in early development and plays a role in cell growth, cell specialization, and determining the shape of many different parts of the developing body. About two-thirds of cases of BCNS are inherited, or passed down among family members. The remaining cases result from a spontaneous mutation.
Inheritance: When inherited, BCNS follows an autosomal dominant pattern of inheritance. Individuals receive two copies of most genes, one from the mother and one from the father. For a dominant disorder to occur, only one defective copy of the defective PTCH1 gene is necessary. If one parent has the disorder, there is a 50% chance that his or her child will have the disorder. If both parents have the disorder, there is a 75% chance that their child will have the disorder.
Random occurrence: Some people with no family history of BCNS develop the disorder. This occurs as the result of a genetic mutation in the sperm or egg cells or in the developing embryo. These spontaneous mutations may be caused by advanced age of the father. The exact effect of the father's age on the development of BCNS is unclear.

Risk factors

Basal cell nevus syndrome (BCNS) is primarily an inherited disorder. Therefore, the only known risk factor is a family history of the disorder. BCNS is estimated to occur in one out of every 56,000-164,000 people. The prevalence is likely to be higher among young people with basal cell carcinomas. BCNS appears to affect males and females of all races and ethnicities equally.
Some studies have found that 40% of cases occur as a result of spontaneous mutations, meaning that the disease was not inherited from the parents. It has also been reported that paternal age may increase the chance of this type of mutation.