AUTHOR AND EDITOR INFORMATION

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

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• Introduction
• Clinical
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Background

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by a predisposition to cancer and multiple developmental defects. First reported in 1894 by Jarisch and White, it was first delineated in the 1950s and 1960s by Gorlin and Goltz. Individuals with NBCCS 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. NBCCS is unique to most hereditary disorders associated with cancer in that it features developmental defects.

Pathophysiology

NBCCS chromosomal mutation has been mapped to bands 9q22.3, 9q31, and 1p32, where it acts as a tumor suppressor gene. The degree of penetrance is high (approximately 97%), and, although the extent of expression of features is often variable, 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 NBCCS 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 NBCCS have been conflicting and inconclusive.

Frequency

International

The prevalence of NBCCS ranges from 1 case per 57,000 population in England to 1 case per 164,000 population in Australia. 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 NBCCS 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 NBCCS.

Mortality/Morbidity

The specific mortality rate for a diagnosis of NBCCS has yet to be determined. BCCs are reported in approximately 76% of NBCCS cases ; the face and back are most severely affected, followed by the chest and upper limbs. Jaw cysts are reported in 75% of cases, with operations necessary for symptomatic or cosmetic reasons. While often asymptomatic, jaw cysts occasionally cause pain, swelling, abnormal taste sensation, and oral discharge. 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.

Race

Medulloblastoma is considered rare in black persons; fewer than 5% of cases are 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 NBCCS.

Sex

Males and females are affected with equal frequency by NBCCS, but prevalence of medulloblastoma in NBCCS has a male-to-female ratio of 3:1.

Age

The average age for diagnosis of NBCCS is 13 years. The average age for presentation of BCC is 20 years.

CLINICAL

Section 3 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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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 often exists, 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 any of a number of malformations, including the following:

• Pits in the palms of the hands and the soles of the feet (60%)
• 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 NBCCS, and, therefore, examination is useful and 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 NBCCS.

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 show up 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 show up 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. While 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 NBCCS 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 NBCCS 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 is dependent 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 1 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 NBCCS
• 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 NBCCS. No clear evidence exists for chromosome instability or cellular radiation sensitivity.

DIFFERENTIALS

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Other Problems to be Considered

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

WORKUP

Section 5 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Lab Studies

• No specific laboratory blood tests are required in the workup of nevoid basal cell carcinoma syndrome (NBCCS).
• Genetic testing is not widely available at this time. However, in research settings, genotyping is informative in identifying additional family members once the proband's genotype has been determined. Molecular genetic studies can be used to identify the mutation prenatally, postnatally, and preimplantationally. Definitive presymptomatic diagnosis can be achieved by molecular genetic linkage studies currently taking place at the Yale University School of Medicine.

Imaging Studies

• Radiography
• • Skull, neck, and chest radiography are useful in diagnosing the condition at birth in individuals at risk. Panoramic radiography of the jaw is used to diagnose jaw cysts. Hand and spinal column radiography may also be helpful.
  • Radiologic signs include calcification of the falx cerebri or tentorium cerebelli, bridged sella turcica, large paranasal sinuses, increased mandibular length, rib anomalies (eg, bifid, fused, missing, splayed), vertebral anomalies (eg, kyphoscoliosis, abnormal segmentation), short fourth metacarpal, sclerotic bone lesions (rare), and flame-shaped lucencies of the bones of the hand.
  • Because skeletal anomalies are a common and early presentation of the syndrome, occurrence of multiple lesions should raise suspicion of this syndrome because children may not yet manifest the other anomalies of NBCCS.
• CT scanning and MRI
• • Although radiography is often useful, CT scanning can be performed for earlier identification of the falx and tentorial calcification, cerebral atrophy, and dysgenesis or agenesis of the corpus callosum.
  • However, because of the radiation involved in CT scanning, annual MRI of the cerebrum is recommended in detection of medulloblastomas in children aged 8 years and younger.
• Echocardiography: Although rare, cardiac fibromas can be excluded in those at risk for NBCCS by obtaining periodic chest radiographs and echocardiograms starting at birth and subsequently obtained on the basis of clinical suspicion.
• Ultrasonography: Ultrasonography of the pelvic area can aid in the diagnosis of ovarian fibromas.

Procedures

• No procedures are specific to this syndrome.

Histologic Findings

Basal cell carcinomas (BCCs) that are part of NBCCS cannot be differentiated from BCCs observed in patients without the syndrome. The solid and superficial types of BCCs are most common in this syndrome, with all other types of BCC observed less frequently.

Odontogenic keratocysts should be proven by histology. They are lined by thin, corrugated, stratified squamous epithelium with varying degrees of keratinization and surrounded by a thick fibrous capsule.

TREATMENT

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Medical Care

• Although radiation is often used to treat basal cell carcinomas (BCCs), patients tend to form new BCCs at sites of irradiation soon after exposure. Radiation is also a common treatment for medulloblastomas and results in extensive and invasive BCCs in the radiation field. Thus, when possible, radiation therapy should be minimized or avoided because more invasive BCCs and other tumors may result following treatment (Choudry, 2006).
• Management of superficial multicentric BCCs without follicular involvement can be achieved through total body application of topical 0.1% tretinoin cream and 5% 5-fluorouracil (5-FU) twice daily. Lesions around the eyes are treated with 5-fluorouracil only. Patients should be examined every 3 months, and lesions that are growing or invading should be excised or curetted.
• Recently, evidence has accumulated to support the use of topical imiquimod on superficial BCCs. One recent study in patients with nevoid basal cell carcinoma syndrome (NBCCS) showed clearance of BCCs after treatment for 6-8 weeks. Other types of BCC do not appear to respond as well. Occlusion does not appear to affect the response rate.
• Oral isotretinoin has shown some benefit (Campbell, 2006). However, it is not approved by the US Food and Drug Administration (FDA) for use in NBCCS and carries risk of toxicity.
• In adults, photodynamic therapy (PDT) has been beneficial in the treatment of BCCs (topical and systemic), with an average of a 95% complete tumor response rate; PDT is not recommended in children because of a poorer response rate and scarring.

Surgical Care

• BCCs are treated with curettage/electrodesiccation, simple excision, or Mohs surgery, but, because of the frequency of lesions, patients are left with extensive scarring from surgical procedures.
• Recently, ultrapulse carbon dioxide laser has been demonstrated to be effective in the treatment of small BCCs in low-risk areas in patients with NBCCS.
• Odontogenic keratocysts require an average of 4 operations throughout a lifetime, although some individuals have experienced up to 28 surgical procedures. Odontogenic keratocysts must be aggressively treated to prevent a high recurrence rate of 6-60% and should be removed by experienced oral-maxillofacial surgeons or otolaryngologists.
• Medulloblastomas require surgery, radiation, and chemotherapy.

Consultations

• Geneticist
• Dermatologist
• Plastic surgeon
• Oral surgeon
• Neurosurgeon
• Ophthalmologist
• Radiation oncologist
• Dentist

MEDICATION

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Medications are used for symptomatic patients, usually as a temporary measure, while patients await definitive treatment. New medical options, such as topical imiquimod and 5-aminolevulinic acid (ALA) photodynamic therapy, have recently increased and improved the armamentarium.

Drug Category: Keratolytics

Management of superficial multicentric basal cell carcinomas (BCCs) without follicular involvement can be achieved through total body application of topical 0.1% tretinoin cream and 5% fluorouracil once daily. Lesions around the eyes are treated with 5-fluorouracil only. Oral isotretinoin and etretinate have shown some marginal benefit, but they are not FDA approved for treatment of nevoid basal cell carcinoma syndrome (NBCCS) and carry risk of toxicity. More recently, topical imiquimod has shown benefit, as has photodynamic therapy.

Drug Category: Immune response modifiers

These agents regulate, adjust, or potentiate immune function.

Drug Category: Photosensitizing Agent, Topical

These agents are used with photodynamic therapy.

FOLLOW-UP

Section 8 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• For children at risk for inheriting the gene for nevoid basal cell carcinoma syndrome (NBCCS) or those in whom the condition is already diagnosed, regular visits to a dermatologist (every 2-3 mo) are encouraged, particularly during adolescence. Along with physical examination for pitting and other minor features of NBCCS, radiologic evaluation with rib, spine, and skull radiographs to look for abnormalities are indicated, as well as a panoramic radiograph of the jaws once a year in patients aged 8 years and older (or earlier if the child is compliant).
• Any patient presenting at an unusually young age (<5 y) with a medulloblastoma should be screened for NBCCS. Conversely, patients diagnosed with NBCCS at a young age should be screened for the presence of a medulloblastoma. Regular neurologic surveillance every 6 months with annual MRI of the cerebrum is indicated until children are aged 8 years.
• Most ovarian fibromas are asymptomatic and almost never become malignant. Initial ultrasonography performed at the preteen stage is advised, and ultrasonographic evaluation should be subsequently undertaken based on symptoms.
• Along with periocular basal cell carcinomas (BCCs), other ophthalmic manifestations include multiple eyelid cysts, strabismus, myopia, hyperopia, cataracts, and amblyopia. Thus, periodic ophthalmologic examination is warranted (Taylor, 2006).

Deterrence/Prevention

• Minimizing or avoiding ultraviolet radiation may lessen the risk of developing BCCs.

Complications

• Brain and lung invasion and even metastases from BCCs

Prognosis

• Early death from BCCs is rare but has been reported due to brain and lung invasion and even from metastases.
• In many cases of metastatic BCCs, early detection can identify solitary lesions that may be amenable to surgical removal. In situations where surgery is not feasible, radiotherapy offers a reasonable palliative option.

Patient Education

• Education on the importance of minimizing or avoiding ultraviolet radiation may lessen the risk of developing BCCs.
• For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education articles Skin Cancer and Skin Biopsy.

MISCELLANEOUS

Section 9 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to refer patients with odontogenic keratocysts to experienced oral-maxillofacial surgeons or otolaryngologists for aggressive treatment
• Failure to refer patients to a dermatologist when children are at risk for inheriting the gene for nevoid basal cell carcinoma syndrome (NBCCS) or for patients in whom the condition is already diagnosed
• Failure to educate the patient and/or parents on preventive measures (eg, avoiding ultraviolet radiation)
• Failure to use MRI instead of CT scanning in detection of medulloblastomas in children younger than 8 years because of the radiation involved in CT scanning
• Failure to minimize or avoid radiation therapy because more invasive basal cell carcinomas (BCCs) and other tumors result following treatment

Special Concerns

• In one series conducted by Shanley et al in 1994, more than 80% of patients with NBCCS could have been diagnosed within the first 2 decades of life without radiologic imaging.

MULTIMEDIA

Section 10 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Palmar pits in an adult.
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Media file 2:  Syndactyly is noted in some affected persons such as this 8 year-old boy.
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
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• Bale AE. The nevoid basal cell carcinoma syndrome: genetics and mechanism of carcinogenesis. Cancer Invest. 1997;15(2):180-6. [Medline].
• Caccialanza M, Percivalle S, Piccinno R. Possibility of treating basal cell carcinomas of nevoid basal cell carcinoma syndrome with superficial x-ray therapy. Dermatology. 2004;208(1):60-3. [Medline].
• Campbell RM, Digiovanna JJ. Skin cancer chemoprevention with systemic retinoids: an adjunct in the management of selected high-risk patients. Dermatol Ther. 2006;Sep-Oct;19(5):306-14. [Medline].
• Chiritescu E, Maloney ME. Acrochordons as a presenting sign of nevoid basal cell carcinoma syndrome. J Am Acad Dermatol. May 2001;44(5):789-94. [Medline].
• Choudry Q, Patel HC, Gurusinghe NT, Evans DG. Radiation-induced brain tumours in nevoid basal cell carcinoma syndrome: implications for treatment and surveillance. Childs Nerv Syst. Sep 15 2006;[Medline].
• Gorlin RJ. Nevoid basal cell carcinoma (Gorlin) syndrome. Genet Med. Nov-Dec 2004;6(6):530-9. [Medline].
• Hall J, Johnston KA, McPhillips JP, et al. Nevoid basal cell carcinoma syndrome in a black child. J Am Acad Dermatol. Feb 1998;38(2 Pt 2):363-5. [Medline].
• Kimonis VE, Goldstein AM, Pastakia B, et al. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet. Mar 31 1997;69(3):299-308. [Medline].
• Korczak JF, Brahim JS, DiGiovanna JJ, et al. Nevoid basal cell carcinoma syndrome with medulloblastoma in an African-American boy: a rare case illustrating gene-environment interaction. Am J Med Genet. Mar 31 1997;69(3):309-14. [Medline].
• Manfredi M, Vescovi P, Bonanini M, Porter S. Nevoid basal cell carcinoma syndrome: a review of the literature. Int J Oral Maxillofac Surg. Mar 2004;33(2):117-24. [Medline].
• Pastorino L, Cusano R, Baldo C, et al. Nevoid Basal Cell Carcinoma Syndrome in infants: improving diagnosis. Child Care Health Dev. May 2005;31(3):351-4. [Medline].
• Shanley S, Ratcliffe J, Hockey A, et al. Nevoid basal cell carcinoma syndrome: review of 118 affected individuals. Am J Med Genet. Apr 15 1994;50(3):282-90. [Medline].
• Sterry W, Ruzicka T, Herrera E, et al. Imiquimod 5% cream for the treatment of superficial and nodular basal cell carcinoma: randomized studies comparing low-frequency dosing with and without occlusion. Br J Dermatol. Dec 2002;147(6):1227-36. [Medline].
• 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(6):569-72. [Medline].
• Taylor SF, Cook AE, Leatherbarrow B. Review of patients with basal cell nevus syndrome. Ophthal Plast Reconstr Surg. Jul-Aug 2006;22(4):259-65. [Medline].

Article Last Updated: Nov 1, 2006