Information on the following diseases can be found in the Related Disorders section of this report:

• Bazex syndrome
• Linear unilateral basal cell nevus with comedones
• Rasmussen syndrome
• Rombo syndrome

Some clinicians suggest that the symptoms of NBCCS fit into five major categories. These are: multiple localized skin cancers (basal cell carcinomas); multiple cysts in the bones of the jaw; skeletal abnormalities such as prominences on the forehead (frontal bossing) and a forward-thrusting jaw (prognathism); bone-like growths in unlikely and unusual positions on the body (ectopic calcifications); and pits on the soles of the feet (plantar) and/or the palms of the hand (palmar).

The localized skin cancers (lesions) are found most often on the neck, face, back and chest. This disorder usually first becomes obvious after puberty, and the number of lesions increases with age. After age 30, there may be as many as 500 of the lesions. The incidence of other cancers, such as medullo-blastomas, ovarian and cardiac fibromas, and meningiomas, may also be abnormally high. With this disorder, there may be swelling of the jaw due to multiple cysts, or a projection of the jaw beyond the forehead. Late eruption of the teeth in children, abnormal contraction of the toes upon irritation of the soles of the feet (plantar reflexes), and mental retardation may also occur.

Vision problems, such as cataracts, and defects in the pigmented vascular coat of the eye as well as the optic nerve are also symptomatic of this disorder. Other characteristics may be irregularities of the vertebrae, bifid (split) ribs, scoliosis (curvature of the spine) and a hardening of some areas of the brain (calcification of falx cerebri).

Nevoid basal cell carcinoma syndrome is an autosomal dominant disorder. It has been linked to a gene on the long arm of chromosome 9 (9q22.3-q31). PTCH is the only gene associated with NBCCS.

Human traits, including the classic genetic diseases, are a product of the interaction of two genes for that condition, one received from the father and one from the mother.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 9q22.3-q31" refers to a region on the long arm of chromosome 9 between bands 22.3 and 31. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

It is believed that, in between 70% and 80% of new cases of NBCCS, the disorder is inherited from a parent. In about 20% to 30% of cases, the disorder is thought to have occurred as a result of a sporadic mutation without the involvement of parental genes.

Studies in England suggest that the prevalence of NBCCS is about 1 in 57,000. Similar studies in Australia found the prevalence to be about 1 in 164,000 people. NBCCS affects males and females in about equal numbers.

The incidence of medulloblastoma in patients with NBCCS is about 3-5% with a male-to-female ratio of about 3 to 1. Among African-American patients with NBCCS, the occurrence of medulloblastoma is substantially lower and the number of lesions is usually lower as well.

Symptoms of the following disorders can be similar to those of Nevoid Basal Cell Carcinoma. Comparisons may be useful for a differential diagnosis:

Basex syndrome is a distinct syndrome that seems to combine the characteristics of NBCCS with atrophied skin, many tiny, usually colored, cysts on the skin (milia), loss of hair (hypotrichosis, and localized absence of sweat glands (hypohidrosis). Not infrequently, patients who have, in addition to Basex syndrome, carcinomas of the respiratory tract or digestive tract will show eruptions of reddish blisters (erythematous) that are distributed symmetrically about the body. The skin lesions begin by involving the hands, feet, ears, and nose, spreading later to the cheeks, elbows, knees and, lastly, the trunk.

Linear unilateral basal-cell nevus syndrome with comedones is an extremely rare disorder characterized by the unilateral distribution over the body of basal-cell carcinomas and epidermal cysts. In addition, scar-like lesions (stria-like atrophy) over the stomach, breasts, buttocks, and thighs are almost invariably present. These lesions may be bluish-purple at first but fade to white over time. The hair follicles and the cysts are characteristically plugged by protein (keratin) and wax (sebum) in which substrate bacteria flourish, leading to blackheads and acne-like eruptions.

Rasmussen syndrome is a rare form of brain malfunction that may occur at any time during childhood. The brain cells in one half of the brain (hemisphere) become inflamed and trigger an electrical discharge in the form of an epileptic seizure. In the vast majority of cases, there is no evidence of viral infection. The cause of the disorder remains unknown.

Rombo syndrome is characterized by benign skin tumors that are focused in the hair matrix and appear most often on the face. More women are affected than are men. In many instances, many tiny, usually colored, cysts on the skin (milia) appear as well. The blood vessels of the head, arms and legs (peripheral vasodilation) may open, interfering with blood flow. Consequently, the lips and skin of the patient may become bluish (cyanotic) suggesting oxygen deprivation.

Diagnosis
The diagnosis of NBCCS is made using sets of clinical diagnostic criteria. Studies suggest that of those who fulfill the clinical criteria, about 60%-85% will also test positively for a mutated gene (labeled PTCH) at chromosomal locus 9q22.3.

The following major and minor criteria may be considered when a diagnosis is made.

Major criteria:
Hardening of a sickle-shaped fold (falx calcification) of some of the material covering the brain (dura mater). The fold penetrates the space separating the cerebral hemispheres and is obvious on X-rays after age 20.

One or more cysts in the jaw that interfere with the development of teeth and the bones of the jaw

Pitting of the soles of the feet and/or palms of the hand (plantar/palmar pits)

Multiple basal cell carcinomas (BCC): more than five (5) in a lifetime, or a basal cell carcinoma identified before age 30

Close kin (first degree relative) with NBCCS

Minor criteria:
Identification of a medulloblastoma during childhood

Cysts developing in the lymph glands, the tissues lining organs (mesentery) or bronchial passages (pleural cysts)

Unusually large head (macrocephaly)

Cleft lip or cleft palate

Split (bifid) ribs and/or vertebrae

Odd numbers and structure of fingers and/or toes (polydactyly)

Fibrous growths (fibromas) about the ovary and/or heart

Abnormalities of the eye such as cataracts, color changes in the retina

The use of X-rays on patients with NBCCS may promote the appearance of basal cell carcinomas, so physicians tend to limit the use of X-rays when NBCCS is suspected.

It is possible, through genetic analysis of individual family members, to determine who is carrying the defective gene. Genetic analysis may also be performed prenatally.

Treatment
Larger numbers of lesions and/or tumors than usual may make the treatment of NBCCS more difficult. Treatment, at least until recently, is primarily surgical. Mohs micrographic surgery, a specialized surgical technique, and the use of extreme cold (cryosurgery) may be employed to treat the basal cell carcinomas. Scraping and burning off of skin growths (electrodesiccation and curettage), as well as photodynamic therapy, in which a drug is combined with a specific type of light, are other possible treatments.

The U.S. Food and Drug Administration (FDA) has approved the use of imiquimod (Aldara) topical cream as a treatment for superficial basal cell carcinoma. Aldara is made by the 3-M Company of Minneapolis, MN.

Other treatment is symptomatic and supportive. Genetic counseling may be of benefit for patients and their families.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

A study of photodynamic therapy in treating patients with skin cancer is being sponsored by the Roswell Park Cancer Institute in Buffalo, New York. The principal investigator is:

Allen Oseroff, MD, PhD
Tel: (716) 845-8816
e-mail: allen.oseroff@roswellpark.org

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Basal Cell Nevus Syndrome; BCNS. Entry No: 109400; Last Update: 6/30/2004.

TEXTBOOKS
MacKie RM. Epidermal Skin Tumors: Naevoid Basal Cell Carcinoma Syndrome. In: Champion RH, Burton JL, Ebling FJG, eds. Textbook of Dermatology. 5th ed. Blackwell Scientific Publications. London, UK; 1992:1495-96.

Conti CM, Crollick JS. Malignant Tumors of the Skin and Subcutaneous Tissue in Children: Basal Cell Nevus Syndrome. In: Raghaven D, Brecher ML, Johnson DH. Textbook of Uncommon Cancer. 2nd ed. John Wiley & Sons. New York, NY; 1999:636.

REVIEW ARTICLES
Manfredi M, Vescovi P, Bonanini M, et al. Nevoid basal cell carcinoma syndrome: a review of the literature. Int J Oral Maxillofac Surg. 2004;33:117-24.

Cohen MM Jr. The hedgehog signaling network. Am J Med Genet. 2003;123A:5-28.

Kulkarni P, Brashear R, Chuang TY. Nevoid basal cell carcinoma syndrome in a person with dark skin. J Am Acad Dermatol. 2003;49:332-35.

Amlashi SF, Riffaud L, Brassier G, et al. Nevoid basal cell carcinoma syndrome: relation with desmoplastic medulloblastoma in infancy. A population-based study and review of the literature. Cancer. 2003;98:618:24.

High AS, Robinson PA. Novel approached to the diagnosis basal cell nevous syndrome. Expert Rev Mol Diagn. 2002;2:321-28.

JOURNAL ARTICLES
Itkin A, Gilchrest BA. Delta-aminolevulinic acid and blue light photodynamic therapy for treatment of multiple basal cell carcinomas in two patients with Nevoid Basal Cell Carcinoma Syndrome. Dermatol Surg. 2004;30:1054-61.

Ahn DG, Lim YS, Kim DK, et al. Nevoid basal cell carcinoma syndrome: a retrospective analysis of 33 affected Korean individuals. Int J Oral Maxillofac Surg. 2004;33:458-62.

Haylett AK, Ward TH, Moore JV. DNA damage and repair in Gorlin syndrome and normal fibroblasts after aminolevulinic acid photodynamic therapy: a comet assay study. Photochem Photobiol. 2003;78:337-41.

Micali G, Lacarruba F, Nasca MR, et al. The use of imiquimod 5% cream for the treatment of basal cell carcinoma as observed in Gorlin's syndrome. Clin Exp Dermatol. 2003; 28 Suppl 1:19-23.

Mark JC. Implant prosthodontic rehabilitation of a patient with nevoid basal cell carcinoma syndrome: a clinical report. J Prosthet Dent. 2003;89:436-42.

Stockfleth E, Ulrich C, Hauschild A, et al. Successful treatment of basal cell carcinomas in a nevoid basal cell carcinoma syndrome with topical 5% imiquimod. Eur J Dermatol. 2002;12:569-72.

FROM THE INTERNET
Basal cell nevus syndrome. Medical Encyclopedia, MedlinePlus. Update date: 7/24/2002. 3pp.
www.nlm.nih.gov/medlineplus/ency/article/001452.htm

Evans DG, Farndon PA. Nevoid Basal Cell Carcinoma Syndrome. GENEReviews. Posted: 20 June 2002. 15pp.
www.genetests.org

Barankin B, Searles GE. Nevoid Basal Cell Carcinoma Syndrome. emedicine. Last Updated; April 7, 2004. 15pp.
www.emedicine.com/ped/topic1592.htm

Berg D. Nevoid Basal Cell Carcinoma Syndrome. emedicine. Last Updated; January 27, 2004. 10pp
www.emedicine.com/derm/topic291.htm

Gorlin Syndrome. Orphanet. January 2002. 1p
www.orpha.net/consor/cgi-bin/OC_exp.php?Lng=GB&Expert=377

Lo Muzio L. Gorlin syndrome. Orphanet encyclopedia, January 2002. 10pp.
www.orpha.net/data/patho/GB/uk-gorlin.pdf

Nevoid BCC Syndrome. The Doctor's Doctor. Last Updated 4/25/2001.
www.thedoctorsdoctor.com/diseases/nevoidbcc_ca.htm

Bitar GJ, Herman CK, Dahman MI, et al. Basal Cell Nevus Syndrome: Guidelines for Early Detection. American family Physician. June 15, 2002. 6pp.
www.aafp.org/afp/20020615/2501.html