Pathophysiology: NBCCS chromosomal mutation has been mapped to band 9q23.1-q31, where it is thought to act as a tumor suppressor gene. There is a high degree of penetrance, and although extent of expression of features often is variable, severity tends to breed true within families. A mutation exists in the PTC 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 NBCCS patients 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. Studies on chromosome instability and cellular radiation sensitivity in NBCCS have been conflicting and inconclusive.

Frequency:

• Internationally: Prevalence of NBCCS ranges from 1 per 57,000 population in England to 1 per 164,000 in Australia. Between 1-2% of all medulloblastomas and 0.5% (or estimated 4500 in USA) of all basal cell carcinomas may be attributed to this syndrome. BCCs, jaw cysts, palmar pits, and macrocephaly occur at frequencies of 75-80%. Incidence of medulloblastoma in NBCCS is 3-5%, with a male-to-female ratio of 3:1. It is considered rare in black persons, with less than 5% of cases reported in this population. Also, black persons have far fewer basal cell carcinomas (possibly due to increased skin pigmentation) but do exhibit many of the other features of NBCCS.

Mortality/Morbidity: Specific mortality rate for a diagnosis of NBCCS has yet to be determined. Basal cell carcinomas are reported in approximately 76% of cases of NBCCS; face and back are most severely affected, followed by 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 present with pain, swelling, abnormal taste sensation, and visual disturbance or paresthesiae. Development of BCCs can be extensive, with 500 or more BCCs not entirely uncommon in those over age 30 years. Early death is rare but has been reported from brain and lung invasion and even metastases from BCCs.

Race: Medulloblastoma is considered rare in black persons, with less than 5% of cases reported in this population. Also, black persons have far fewer basal cell carcinomas (possibly due to increased skin pigmentation) but do exhibit many of the other features of NBCCS.

Sex: Males and females are equally affected by NBCCS, yet incidence of medulloblastoma in NBCCS has a male-to-female ratio of 3:1.

History: Patients with NBCCS may be asymptomatic, or they may have symptoms of associated conditions. Patients may report a change in number and characteristics of nevi. Often a positive family history exists with approximately one half of first-degree relatives of affected individuals showing signs of this syndrome.

Physical: Along with benign and malignant tumors, patients may present with any of a number of malformations including the following:

• Pits of palms and soles
• Keratocysts of the jaw
• 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), occasionally exhibiting 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 more often present in the second decade of life. The number of pits increases with age and can total into the hundreds.

Diagnosis may be difficult because of the variability of expressivity of this condition and different ages of onset for various traits of this disorder. For instance, whereas a medulloblastoma may show up at age 2 years, jaw cysts and BCCs may develop by ages 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 early as age 2 years, but more commonly appear in patients aged 17-35 years. Basal cell carcinomas 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 it is important to note that BCCs do not appear in all affected persons.

Approximately 10% of Caucasians and 60% of blacks do not develop BCCs as part of the syndrome. Smaller nevoid basal cell carcinomas tend to be flesh colored, whereas larger lesions often are pigmented with frequent ulceration. While presentation of BCCs most often is bilateral, reported cases exist of unilateral or even quadrant distribution. 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 come to medical attention because of their BCCs or jaw cysts.

Jaw cysts often are multiple, with an average incidence of 6 cysts and a range of 1-30 cysts. Roughly 80% of patients with NBCCS older than 20 years develop cysts. Cysts of the jaw often are 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 symptomatology 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.

• NBCC diagnostic criteria: Diagnosis of NBCC relies on the presence of 2 major or 1 major and 2 minor criteria as identified below.

• Major criteria - Multiple basal cell carcinomas or 1 appearing before age 20 years, odontogenic keratocysts proven by histology, palmar or plantar pits (3 or more), bilamellar calcification of the falx cerebri, positive family history of NBCCS

• Minor criteria - Congenital skeletal anomaly (ie, rib, vertebral), macrocephaly (higher than 97th percentile with frontal bossing), cardiac or ovarian fibroma, medulloblastoma, lymphomesenteric cysts, congenital malformations (ie, cleft lip/palate, polydactyly, eye anomaly)

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

Lab Studies:

• No specific laboratory blood tests are required in the workup of 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 identify the mutation prenatally, postnatally, and preimplantationally. Definitive presymptomatic diagnosis can be achieved by molecular genetic linkage currently taking place at Yale University School of Medicine.

Imaging Studies:

• X-ray

• Skull, neck, and chest x-rays are useful in helping diagnose the condition at birth in those at risk. Panoramic radiography of the jaw is used to diagnose jaw cysts. Hand and spinal column x-rays may also be helpful.

• Radiological signs include calcification of the falx cerebri or tentorium cerebelli, bridged sella turcica, bifid ribs, hemivertebrae, fusion of vertebral bodies, 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, as children may not yet manifest the other anomalies of NBCCS.

• CT scan and MRI

• While x-ray often is useful, CT scan can identify earlier the falx and tentorial calcification, cerebral atrophy, and dysgenesis or agenesis of the corpus callosum.

• However, because of radiation involved in CT scanning, annual MRIs of the cerebrum are recommended in detection of medulloblastomas in children aged 8 years and younger.

• Echocardiography: Although rare, cardiac fibromas can be excluded by periodic chest x-rays and echocardiography starting at birth for those at risk for NBCCS and subsequently based on clinical suspicion.

• Ultrasound of the pelvic area can diagnose ovarian fibromas.

Procedures:

• No procedures are specific to this syndrome.

Histologic Findings: Basal cell carcinomas, as 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.

Medical Care: Although radiation often is used to treat BCCs, patients tend to form new BCCs at sites of irradiation soon after exposure. Radiation also is a common treatment for medulloblastomas and results in extensive and invasive BCCs in the radiation field. Thus, where possible, radiation therapy should be minimized or avoided, because more invasive BCCs and other tumors may result following treatment.

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.

Oral isotretinoin has shown some marginal benefit, but it is not FDA approved for NBCCS and carries risk of toxicity.

In adults, photodynamic therapy (PDT) has been beneficial in the treatment of BCCs with an average of 95% complete tumor response; PDT is not recommended in children because of a poorer response and scarring.

Surgical Care:

• Basal cell carcinomas 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.

• Odontogenic keratocysts require an average of 4 operations in one's lifetime, although some individuals have experienced up to 28 surgical procedures. Odontogenic keratocysts must be treated aggressively 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

Medications are used for symptomatic patients, usually as a temporary measure, while awaiting definitive treatment.

Drug Category: Keratolytics -- Management of superficial multicentric 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 NBCCS and carry risk of toxicity.

Further Outpatient Care:

• For children at risk for inheriting the gene for NBCC or already diagnosed with the condition, regular visits to a dermatologist (every 2-3 months) are encouraged, particularly during adolescence. Along with physical examination for pitting and other minor features of NBCC, radiological evaluation with rib, spine, and skull films to look for abnormalities are indicated as well as a panoramic radiograph of the jaws once a year from age 8 years onward, or earlier if the child is compliant.

• Any patient presenting at an unusually young age (<5 years) 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 neurological surveillance every 6 months with annual MRIs of the cerebrum is indicated up to age 8 years.

• Most ovarian fibromas are asymptomatic and almost never become malignant. Initial ultrasound at the preteen stage is advised and should be taken subsequently based on symptoms.

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 from 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.