eMedicine Specialties > Pediatrics: General Medicine > Dermatology
Nevoid Basal Cell Carcinoma Syndrome
Updated: Mar 13, 2009
Introduction
Background
Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by a predisposition to cancer and multiple developmental defects.1 First reported in 1894 by Jarisch and White, it was first delineated in the 1950s and 1960s by Gorlin and Goltz. Individuals with nevoid basal cell carcinoma syndrome are predisposed to basal cell carcinomas (BCCs) of the skin, medulloblastomas, and ovarian fibromas; frequency of fibrosarcomas, meningiomas, rhabdomyosarcomas, and cardiac fibromas may also be increased. Nevoid basal cell carcinoma syndrome is unique to most hereditary disorders associated with cancer in that it features developmental defects.
Pathophysiology
Nevoid basal cell carcinoma syndrome chromosomal mutation has been mapped to bands 9q22.3, 9q31, and 1p32, where it acts as a tumor suppressor gene.2 The degree of penetrance is high (approximately 97%), and, although the extent of expression of features often varies, severity tends to breed true within families. A mutation is present in the PTCH gene, the human homologue of the Drosophila patched gene. Inactivation of this gene is associated with development of BCCs and other tumors, as well as developmental errors.
Approximately 35-50% of cases represent new mutations. A 2-hit hypothesis is postulated, wherein an initial mutation in the germline of patients with nevoid basal cell carcinoma syndrome occurs, followed by a separate hit to the second allele, which is required to develop tumors in particular tissues. Additional genetic and environmental events may be required for full expression of the syndrome. Study results on chromosome instability and cellular radiation sensitivity in nevoid basal cell carcinoma syndrome have been conflicting and inconclusive.
Frequency
International
The prevalence of nevoid basal cell carcinoma syndrome ranges from 1 case per 57,000 population in England to 1 case per 164,000 population in Australia.3 Approximately 1-2% of all medulloblastomas and 0.5% (or estimated 4500 in the United States) of all BCCs may be attributed to this syndrome. BCCs, jaw cysts, palmar pits, and macrocephaly occur at frequencies of 75-80%. Prevalence of medulloblastoma in nevoid basal cell carcinoma syndrome is 3-5%, with a male-to-female ratio of 3:1. It is considered rare in black persons, with fewer than 5% of cases reported in this population. Also, black persons have far fewer BCCs (possibly because of increased skin pigmentation) but do exhibit many of the other features of nevoid basal cell carcinoma syndrome.
Mortality/Morbidity
The specific mortality rate for nevoid basal cell carcinoma syndrome has yet to be determined.
BCCs are reported in approximately 76% of nevoid basal cell carcinoma syndrome cases; the face and back are most severely affected, followed by the chest and upper limbs. Development of BCCs can be extensive; the presence of 500 or more BCCs is not entirely uncommon in patients older than 30 years. Early death is rare but has been reported due to brain and lung invasion and even metastases from BCCs.
Jaw cysts are reported in 75% of cases, with operations necessary for symptomatic or cosmetic reasons. Although often asymptomatic, jaw cysts occasionally cause pain, swelling, abnormal taste sensation, and oral discharge.
Race
Medulloblastoma is considered rare in black persons; fewer than 5% of cases are reported in this population.4 Also, black persons have far fewer BCCs (possibly because of increased skin pigmentation) but do exhibit many of the other features of nevoid basal cell carcinoma syndrome.
Sex
Males and females are affected with equal frequency by nevoid basal cell carcinoma syndrome, but prevalence of medulloblastoma in nevoid basal cell carcinoma syndrome has a male-to-female ratio of 3:1.
Age
The average age for diagnosis of nevoid basal cell carcinoma syndrome is 13 years. The average age for presentation of BCC is 20 years.
Clinical
History
Patients with nevoid basal cell carcinoma syndrome (NBCCS) may be asymptomatic or may have symptoms of associated conditions. Patients may report a change in number and characteristics of nevi. A positive family history is often noted, with approximately one half of first-degree relatives of affected individuals showing signs of this syndrome.
Jaw cysts are often asymptomatic but may occasionally cause jaw swelling, pain, abnormal taste, or an oral discharge.
Physical
Along with benign and malignant tumors, patients may present with numerous malformations, including the following:
- Pits in the palms of the hands and the soles of the feet (60%)
Palmar pits in an adult.
- Keratocysts of the jaw (80%, with a 30-60% recurrence rate)
- Cleft palate
- Coarse characteristic facies with milia, frontal bossing, widened nasal bridge, and mandibular prognathia
- Strabismus, dystrophic canthorum, ocular hypertelorism, and congenital blindness
- Dysgenesis of the corpus callosum
- Calcification of the falx cerebri
- Spina bifida occulta, pectus deformity, and other spine abnormalities
- Bifid ribs and other rib abnormalities
- Ectopic calcification, mesenteric cysts
- High arched eyebrows and palates
- Narrow sloping shoulders
- Immobile thumbs
- Low-pitched voice in females
- Kidney anomalies
- Hypogonadism in males
- Macrocephaly and generalized overgrowth
Patients often are taller (proportionately) and occasionally exhibit features similar to acromegaly.
Pitting of the palms or soles is very specific for nevoid basal cell carcinoma syndrome, and, therefore, examination is useful and is often aided by soaking the hands in warm water for 10 minutes to increase visibility of pits. Pits are permanent, not palpable, and asymptomatic. They appear as shallow depressions, 1-3 mm in depth and 2-3 mm in diameter, caused by a partial or complete absence of stratum corneum. Occasionally present in childhood, they develop more often in the second decade of life. The number of pits increases with age and can total into the hundreds.
Performing a biopsy on skin tags in children is a recent suggestion because they may be early presenting signs of nevoid basal cell carcinoma syndrome.
Diagnosis may be difficult because of the variability this condition's expressivity and different ages of onset for various traits of this disorder. For instance, a medulloblastoma may develop in a patient aged 2 years, but jaw cysts and basal cell carcinomas (BCCs) may not develop until the patient is aged 15 years and 20 years, respectively.
BCCs occur in both sun-exposed skin and nonexposed skin. BCCs have been reported to develop in patients as young as 2 years old but appear more commonly in patients aged 17-35 years. BCCs vary in size from 1-10 mm in diameter and commonly involve the face, back, and chest. The number of BCCs can vary from a few to more than a thousand, but BCCs do not appear in all affected persons.
Approximately 10% of whites and 60% of blacks do not develop BCCs as part of the syndrome. Smaller nevoid BCCs tend to be flesh colored, whereas larger lesions are often pigmented with frequent ulceration. Although the presentation of BCCs is most often bilateral, cases of unilateral or even quadrant distribution have been reported. Most lesions remain static in growth, although after puberty, a small fraction of BCCs become aggressive, with local invasion. An increase in size, ulceration, bleeding, and crusting indicate an invasive process.
Most patients with nevoid basal cell carcinoma syndrome seek medical attention because of their BCCs or jaw cysts.
Jaw cysts are often multiple, with an average prevalence of 6 cysts and a range of 1-30 cysts. Roughly 80% of patients with nevoid basal cell carcinoma syndrome who are older than 20 years develop cysts. Cysts of the jaw are often located in the premolar area and may displace the child's teeth. They can be unilocular or multilocular with a preference for the mandible. Often multiple and bilateral, they can cause considerable symptoms, including pain, swelling, intraoral drainage, and unusual taste. One third of jaw cysts do not cause any symptoms. Jaw cysts may displace teeth, with resulting malocclusion, and they may cause pathologic fractures of the mandible or facial distortion.
The diagnosis of NBCCS depends on the presence of one of the following: 2 major features, 1 major feature and an affected first-degree relative, 2 minor features and an affected first-degree relative, or multiple BCCs in childhood. The major and minor features are as follows:
- Major features - Multiple BCCs or one appearing before age 20 years, odontogenic keratocysts confirmed by histology, palmar or plantar pits (>3), bilamellar calcification of the falx cerebri, positive family history of nevoid basal cell carcinoma syndrome
- Minor features - Congenital skeletal anomaly (ie, bifid ribs, vertebral anomalies), macrocephaly (>97th percentile with frontal bossing), cardiac or ovarian fibroma, medulloblastoma, lymphomesenteric cysts, congenital malformations (ie, cleft lip/palate, polydactyly, eye anomaly)
Causes
A defect in a tumor suppressor gene on chromosome band 9q23.1-q31 causes nevoid basal cell carcinoma syndrome. No clear evidence suggests chromosome instability or cellular radiation sensitivity.
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References
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Further Reading
Keywords
nevoid basal cell carcinoma syndrome, NBCCS, Gorlin syndrome, basal cell nevus syndrome, BCNS, Gorlin-Goltz syndrome, multiple basal cell nevi, PTCH gene, basal cell carcinoma, BCC, medulloblastomas, ovarian fibromas, fibrosarcomas, rhabdomyosarcomas, meningiomas, cardiac fibromas, jaw cysts, palmar pits, macrocephaly, jaw swelling, keratocysts, cleft palate, spina bifida occulta, pectus deformity, spinal abnormalities, hypogonadism, kidney anomalies, acromegaly, malocclusion
