Basal Cell Nevus Syndrome (Gorlin syndrome, Gorlin-Goltz syndrome, nevoid basal cell carcinoma syndrome [NBCCS])

Are You Confident of the Diagnosis?

A diagnosis of basal cell nevus syndrome (BCNS) is based on the presence of at least two major criteria or at least one major and two minor criteria.

Major criteria:

basal cell carcinoma (BCC; multiple and/or early onset, ie, before 20 years of age)
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odontogenic keratocysts of the jaw
palmar/plantar pitting
bilamellar calcification of the falx cerebri
rib anomalies
a first-degree relative with a diagnosis of BCNS

Minor criteria:

macrocephaly
congenital craniofacial malformation skeletal anomalies
radiologic anomalies
other tumor types

Major criteria

Of the major criteria, development of odontogenic keratocysts of the jaw is commonly (up to nearly 80% of cases) the initial presenting feature of BCNS. Jaw cysts tend to manifest initially in the teenage years, and BCNS patients typically develop multiple lesions. A history of multiple jaw cysts with onset early in life should prompt suspicion of BCNS.

Development of multiple and/or early onset BCCs is perhaps the most recognizable feature of BCNS among dermatologists (Figure 1). The age of onset, location, and number of BCCs may vary considerably among BCNS patients. While up to 97% of Caucasian BCNS patients older than 40 years of age have had at least one BCC, approximately 50% have had at least one BCC by the age of 20 years. The average age of development of the first BCC is approximately 20 to 21 years, although BCCs may occur in very young patients.

Cluster of BCCs and scarring at the scalp of a BCNS patient.

BCCs may occur at any site of the skin, warranting thorough examination of all body regions, including sun-protected areas. BCNS patients may develop literally hundreds of BCCs over their lifetime. All typical clinical and histologic variants of BCC (eg, nodular, superficial, infiltrative) may occur in BCNS patients. In addition, BCCs may resemble milia on the face, nevoid papules, or pedunculated acrochordon-like lesions in BCNS patients.

Pitting of the palms and soles is a common feature of BCNS and is readily identifiable among dermatologists (Figure 2). Pitting has been reported to occur in up to 87% of BCNS patients.

Pitting at the sole of the foot of a BCNS patient.

Other major criteria, including bilamellar calcification of the falx cerebri and rib anomalies (bifid, splayed, or fused ribs), may be identified by radiologic studies (skull and rib X-rays, respectively). Suspicion of a diagnosis of BCNS should prompt obtaining such studies, particularly if a diagnosis cannot be firmly established based on other criteria.

A detailed family history, focusing on major and minor criteria for BCNS in first-degree relatives, should be obtained for patients suspected of having BCNS.

Minor criteria

Of the minor criteria, macrocephaly, congenital craniofacial malformation (cleft lip/palate, frontal bossing, coarse facies, hypertelorism) and skeletal anomalies (Sprengel deformity [high hypoplastic scapula], pectus deformity, syndactyly/polydactyly) may be identified on clinical grounds. Radiologic anomalies (vertebral abnormalities, hand/foot modeling defects or flame-shaped lucencies, bridging of the sella turcica) may be assessed by obtaining appropriate X-rays.

Medulloblastoma is a childhood tumor of the brain that has been reported to occur in up to 5% of BCNS patients. Ovarian fibromas may develop in up to 24% of female patients with BCNS. These tumors tend to develop in the teenage years.

Genetic testing for inactivating mutations in the PTCH gene may be helpful for establishing a diagnosis of BCNS, particularly if a diagnosis cannot be firmly established based on other criteria.

Diagnosis confirmation

Differential diagnoses to be considered in patients that present with numerous BCCs include the following:

-Non-syndromic hereditary multiple BCC: Patients manifest a remarkable susceptibility to developing numerous BCCs, in the absence of other features of BCNS, with an autosomal dominant pattern of inheritance.

-Bazex-Dupre-Christol syndrome: Features include follicular atrophoderma, hypotrichosis, and development of multiple BCCs starting at a young age, with an X-linked dominant pattern of inheritance.

-Rombo syndrome: Features include multiple BCCs, trichoepitheliomas, vermiculate atrophoderma, milia, hypotrichosis, and peripheral vasodilation with cyanosis, with an autosomal dominant pattern of inheritance.

-Multiple hereditary infundibulocystic BCC: Features include development of multiple BCCs of this histologic variant at various body sites including the face, scalp, neck, back, trunk, and extremities.

-Linear unilateral basal cell nevus: Features include multiple BCCs, basaloid follicular hamartomas, and comedonal and cystic lesions in a limited, unilateral distribution.

Who is at Risk for Developing this Disease?

BCNS is a hereditary disorder that follows an autosomal dominant inheritance pattern and shows complete penetrance with variable expressivity. Offspring of a parent with BCNS have a 50% chance of inheriting a causative mutation and manifesting features of the syndrome. However, approximately 40% of BCNS cases arise from new mutations and are associated with no family history of the disorder. The prevalence of BCNS has been estimated to be as high as 1 in 57,000 individuals.

What is the Cause of the Disease?

Etiology
Pathophysiology

BCNS is caused by inactivating mutations in the Patched (PTCH) gene, which functions in the Sonic Hedgehog (SHH) signalling pathway. The PTCH protein is membrane-bound and normally functions by suppressing the activity of another membrane-bound protein, encoded by the Smoothened (SMO) gene, which drives activity of the SHH pathway and cell proliferation.

BCNS is a classic example of a tumor suppressor gene syndrome. BCNS patients carry a germline mutation in one allele of the PTCH gene, which alone may account for some clinical features of BCNS. However, deletion or acquisition of an inactivating mutation in the second, otherwise normal copy of the PTCH gene (loss of heterozygosity) in a given precursor cell gives rise to complete loss of PTCH function, constitutive activation of SMO, and unregulated cell proliferation leading to tumor formation. Evidence for loss of heterozygosity of the PTCH gene has been demonstrated in BCCs, medulloblastomas and even odontogenic keratocysts of the jaw in patients with BCNS.

BCNS patients are sensitive to ultraviolet light and ionizing radiation, as these agents can induce DNA damage and subsequent inactivation of the PTCH gene in cells. Consequently, BCNS patients are susceptible to development of numerous BCCs over the course of their lifetime, particularly if subjected to chronic sun exposure or significant ionizing radiation.

Systemic Implications and Complications

Odontogenic keratocysts of the jaw are commonly the initial presenting feature of BCNS and tend to first manifest in the teenage years. Therefore, they may occur and prompt suspicion of a diagnosis of BCNS even before presentation to a dermatologist. Nonetheless, jaw cysts may continue to develop later in life. Jaw cysts are typically asymptomatic, yet may present with facial swelling or pain. Jaw cysts may be identified and monitored by X-ray or Panorex films, and their presence should prompt referral to an oral-maxillofacial surgeon.

Medulloblastoma, a childhood brain tumor, is typically the presenting feature in those BCNS patients in whom they occur. Medulloblastoma tends to occur at a younger age in BCNS patients (approximately 2 years) compared with patients with sporadic medulloblastoma (6 years). The desmoplastic variant of medulloblastoma is typically seen in BCNS patients.

Although medulloblastoma usually develops well before a dermatologist may become involved in the care of a BCNS patient, it is important for dermatologists to be aware of those patients with a history of medulloblastoma. Radiation therapy may be used to treat medulloblastoma, typically before a diagnosis of BCNS is considered, and may lead to development of numerous BCCs within the field of radiation.

Ovarian fibromas are typically asymptomatic but can cause chronic gastrointestinal or genitourinary tract symptoms. Occasionally torsion of a fibroma may lead to infarction of an ovary. Ovarian fibromas do not compromise fertility and rarely undergo malignant transformation.

Skeletal anomalies (e.g., Sprengel deformity) and congenital craniofacial malformations (e.g., cleft lip/palate) should be referred for evaluation and management by appropriate orthopedic, plastic, or oral-maxillofacial surgical specialists.

Treatment Options

Approaches for Prevention of BCC in BCNS:

Medical options

Topical: High-SPF sunscreen; tazarotene

Systemic: Retinoids

Approaches for Treatment of BCC in BCNS:

Medical options

Topical:

-Imiquimod

-Tazarotene

-5-Fluorouracil (5-FU)

Systemic:

-Vismodegib

-Retinoids

-Paclitaxel

Surgical options

-Mohs micrographic surgery

-Surgical excision

-Electrodessication and curettage (ED & C)

-Cryosurgery

Physical modalities

-Photodynamic therapy (PDT)

-Laser therapy

(Radiation therapy is contraindicated.)

Optimal Therapeutic Approach for this Disease

Approaches for Prevention of BCC in BCNS:

Paramount for any approach to management of BCNS patients is aggressive and religious photoprotection. Routine use of high SPF sunscreen, wearing protective clothing including a wide-brimmed hat, and avoidance of sun exposure altogether are essential components of a photoprotection plan for any BCNS patient.

In 2012 vismodegib, an oral hedgehog pathway inhibitor, was approved for metastatic or otherwise inoperable BCC. Subsequent studies have shown this medication is effective in treating BCC as well as odontogenic cysts in BCNS patients. Although this medication is effective, its use is limited by the adverse events. The majority of patients on daily vismodegib (150 mg daily) experience at least one side effect while on therapy including loss of taste, muscle cramps, hair loss, and weight loss. Studies are ongoing to investigate the efficacy of intermittent dosing schedules to help manage the otherwise difficult to tolerate side effects. The risk of cutaneous squamous cell carcinoma is increased by vismodegib.

Systemic retinoids (isotretinoin or acitretin*) have been reported to suppress development of new BCCs in BCNS patients at doses ranging from 0.25 to1.0 mg/kg daily. However, new BCCs developed in patients after discontinuing systemic retinoid therapy. Consequently, risks of retinoid-related side effects and the need for continuous, chronic treatment may limit utility of this approach.

(*The original studies were performed using etretinate, which is no longer available. We are assuming that acitretin would have a similar effect with a similar dosing regimen, despite the lack of documented evidence for this assumption.)

Approaches for Treatment of BCC in BCNS:

Despite the availability of multiple options, no single form of therapy is universally ideal for treating BCCs in BCNS patients. Instead, the optimal approach should entail use of a combination of therapeutic modalities that can be tailored to any given patient’s needs, with the ultimate goals of adequately treating their BCCs while maximizing preservation of unaffected skin and limiting morbidity.

When selecting an approach to treating BCCs in BCNS patients, several factors should be taken into account including anatomic location, clinical/histologic subtype of BCC, size and number of lesions within a region to be treated, and the patient’s ability to tolerate and comply with a given treatment option.

Surgical treatment of BCC represents the “gold standard,” with Mohs micrographic surgery boasting the highest cure rates and lowest recurrence rates. In particular, Mohs surgery is the treatment of choice for high-risk BCCs (e.g., infiltrative BCCs) and BCCs in critical anatomic locations (e.g., face) to preserve adjacent unaffected tissue. Standard surgical excision and ED&C may be sufficient for treating BCCs at other body sites. Cryosurgery, particularly in combination with ED&C, may be effective in treating smaller, well-defined nodular or superficial BCCs. Nonetheless, numerous surgeries over the course of a lifetime may lead to significant scarring, morbidity and disfigurement; thus alternative approaches should be considered when possible.

Physical modalities, including PDT and laser therapy, show promise for treatment of BCCs in BCNS patients. Use of PDT, with either topical aminolevulinic acid (ALA) or methyl-ALA (MAL) and a blue or red light source, in BCNS patients has been reported to be highly effective in clearing superficial BCCs, although somewhat less effective for treating nodular BCCs. Relatively low recurrence rates of cleared BCCs have been observed. Moreover, reduced incidence of new BCCs in regions treated with PDT suggests a preventive effect for PDT in BCNS patients.

A protocol for treating broad areas of skin at regular intervals was reported to treat existing BCCs effectively, with no recurrences and limited development of new BCCs within treated regions after several years of follow-up. Similarly, ablative CO2 laser therapy has been shown to be effective in the treatment of superficial BCCs with low rates of recurrence in BCNS patients. Advantages to these approaches include the potential for treating numerous lesions over a wide area of body surface in a single session, overall tolerability, and excellent cosmetic results.

In contrast to other physical modalities, radiation therapy for treatment of BCCs is contraindicated, given the risk of inducing development of numerous additional BCCs within the field of irradiation.

Several topical approaches for treating BCCs in BCNS patients have been described. Imiquimod 5% cream is indicated for treatment of superficial BCC, using 5 applications per week for 6 weeks. In randomized controlled trials for sporadic BCC, excellent clearance rates were observed and were higher for superficial BCC than for nodular BCC. Good clearance rates for BCCs at the face and trunk have been reported in BCNS patients.

Topical tazarotene 0.1% gel applied daily over 24 weeks led to clearance of nearly one third of sporadic BCCs in one study, while a slightly higher proportion showed more than 50% regression. Mixed results for treating BCC with topical 5-FU have been reported, although improved results may be achieved when used in combination with cryosurgery or topical tretinoin. Overall, topical therapy offers the advantages of a non-surgical modality. However, topical therapy is generally less effective than surgery, and places a greater burden on patients for managing treatment of their BCCs.

Systemic therapy with vismodegib is a recommended treatment modality for patients with large inoperable tumors or widespread numbers of tumors where surgical management would be challenging. Patients need to be warned about the likely side effects including loss of taste, muscle cramps, hair loss, and weight loss. Intermittent vismodegib dosing is a promising alternative. Other systemic therapies for treating BCCs have had a limited role in the management of BCNS patients to date. Response rates of BCCs to systemic retinoids (isotretinoin or acitretin*) have been highly variable, and high doses are generally required to induce regression of lesions. Consequently, retinoid-induced toxicities (e.g., mucocutaneous effects, arthralgias, myalgias, liver function test abnormalities, hypertriglyceridemia) limit use of this approach.

Patient Management

Patients with BCNS should be monitored by a dermatologist at regular intervals, dictated by the frequency and pattern of development of BCCs. Some patients may need follow-up as frequently as every 2 to 3 months, while others as infrequently as every 6 to 12 months. A thorough cutaneous examination of all body sites, including the scalp and otherwise sun-protected regions, is critical at each visit.

Emphasis should be placed on preventive, protective measures and early detection of new BCCs to minimize potential scarring and morbidities associated with treatment and to maximize preservation of unaffected skin. A combination of therapies should be employed and tailored to each patient’s specific situation.

A detailed review of systems should be obtained at each visit, focusing on signs and symptoms that may be associated with other features of BCNS, including jaw cysts (eg, jaw pain and swelling) and ovarian fibromas (e.g., gastrointestinal/genitourinary tract signs and symptoms) in female patients.

BCNS patients should be referred to a medical geneticist and/or genetic counselor to educate on the risks of having affected children and overall familial implications. Genetic testing to identify a PTCH gene mutation may be considered to confirm a diagnosis in a patient suspected of having BCNS. Genetic testing in an established BCNS patient may be of value to facilitate screening other at-risk family members or performing pre-implantation/prenatal testing.

Unusual Clinical Scenarios to Consider in Patient Management

A number of challenging clinical situations may present in patients with BCNS.

Presentation of BCCs can vary significantly and mimic other skin lesions, particularly in the pediatric population of BCNS patients. Thus clinical recognition of BCC lesions can be challenging in some BCNS patients.

Some BCNS patients may present with numerous BCCs, posing challenges for treatment. Approaches that may be used to treat multiple lesions in large areas in a single or few sessions (e.g., PDT, laser therapy) are attractive options and may limit morbidity. Vismodegib, the oral hedgehog inhibitor is emerging as a first line treatment, however, side effects such as loss of taste, muscle cramps, hair loss, and weight loss may limit the use of this therapy.

Some patients may have a history of or require radiation therapy for treatment of a noncutaneous malignancy, or other exposures that may predispose to development of numerous BCCs. Knowledge of this may permit enhanced vigilance for BCCs in the region of exposure and support use of targeted preventive measures or therapeutic modalities with potential protective effects (e.g., PDT).

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