What are the treatment options for a patient with Gorlin syndrome, a rare genetic disorder characterized by multiple basal cell carcinomas?

Gorlin Syndrome (Nevoid Basal Cell Carcinoma Syndrome)

Overview and Genetic Basis

Gorlin syndrome is a rare autosomal dominant disorder caused by germline mutations in PTCH1 (most common) or SUFU genes, with a birth incidence of approximately 1 in 19,000 to 1 in 256,000, characterized by multiple basal cell carcinomas, medulloblastomas, odontogenic keratocysts, and skeletal abnormalities. 1, 2

• The syndrome results from heterozygous germline pathogenic variants predominantly in PTCH1, with SUFU mutations being less common but associated with higher medulloblastoma risk (7-9.2% vs 0.37-1.1%) 1
• PTCH2 has not been shown to be a relevant predisposition gene 1
• Genetic testing is recommended when clinical features suggest the diagnosis, though genetic confirmation is not mandatory for clinical management 3

Clinical Manifestations

Basal Cell Carcinomas

• Patients develop multiple BCCs frequently in early life, with equal incidence between males and females 2
• BCCs increase in prevalence with age and are dramatically accelerated by radiation therapy and excessive ultraviolet light exposure 1
• The mutation type cannot be used to predict disease burden 2

Other Key Features

• Odontogenic keratocysts (jaw cysts): Common in PTCH1 carriers but not described in SUFU carriers, can cause severe discomfort but rarely undergo malignant transformation 1
• Medulloblastomas: Primarily SHH subgroup, most commonly occurring in infants and younger children (up to 40% of SHH-MB cases have cancer predisposition syndromes) 1
• Fibromas: Cardiac and ovarian fibromas can develop 1, 3
• Meningiomas: Increased incidence, both primary and secondary to irradiation, more common with SUFU than PTCH1 mutations 1
• Skeletal abnormalities: Bifid ribs, macrocephaly, pectus excavatum, kyphoscoliosis 1, 3

Treatment of Basal Cell Carcinomas

Surgical Management

For localized BCCs in Gorlin syndrome, surgical excision remains the primary treatment, with Mohs micrographic surgery preferred for high-risk lesions to minimize tissue loss while achieving complete excision. 4, 5

• Standard surgical excision with 2-4 mm margins for low-risk BCCs 4
• Mohs micrographic surgery for high-risk histologic subtypes, recurrent BCCs, and critical anatomical sites, achieving 5-year disease-free rates exceeding 98% 5
• Multiple surgeries are often required throughout the patient's lifetime given the continuous development of new BCCs 6

Systemic Therapy with Hedgehog Pathway Inhibitors

For patients with excessively numerous or aggressive BCCs where surgery is inappropriate, vismodegib or sonidegib (Hedgehog pathway inhibitors) should be considered, with objective response rates of 30-43% for metastatic BCC and 43-67% for locally advanced BCC. 1, 7

• Vismodegib (Erivedge): FDA-approved at 150 mg orally once daily for locally advanced or metastatic BCC 7
• In the pivotal trial, 21% of patients had Gorlin syndrome, with objective response rates of 30.3% in metastatic BCC and 42.9% in locally advanced BCC 7
• Median duration of response was 7.6 months for both cohorts 7
• Sonidegib: Alternative SMO inhibitor with response rates of 44-58% in locally advanced BCC 1
• Patients resistant to one SMO inhibitor may be resistant to another 1

Indications for Hedgehog Inhibitors in Gorlin Syndrome

• Excessively numerous BCCs where surgical management is impractical 1
• Aggressive BCCs where surgery would result in substantial deformity 7
• Locally advanced BCC that has recurred after radiotherapy (when radiotherapy is contraindicated due to Gorlin syndrome) 7
• Unresectable lesions 7

Adverse Effects and Limitations

• Common adverse events: Muscle spasms and arthralgias, alopecia, dysgeusia leading to weight loss 1
• Serious adverse events occurred in 22-26% of patients, with 12-36% discontinuing treatment due to adverse events 1
• Drug resistance can develop over time 1
• The role in treating syndromic odontogenic keratocysts requires further study, though preliminary data suggests size reduction 6

Photodynamic Therapy

Methylaminolaevulinate-photodynamic therapy (MAL-PDT) is an effective and safe alternative for superficial BCCs of all sizes and nodular BCCs <2 mm in thickness in Gorlin syndrome patients. 8

• Treatment schedule should follow labeling, though may be adapted to monthly intervals based on clinical assessment 8
• Multiple lesions and large areas can be treated during the same session with adequate pain management 8
• Particularly useful for patients with numerous lesions where surgical management would be impractical 8

Radiation Therapy

Radiation therapy must be avoided or used with extreme caution in Gorlin syndrome patients due to dramatically increased risk of developing additional BCCs in irradiated fields. 1

• Ionizing radiation should be avoided unless absolutely necessary 1
• For medulloblastoma treatment in Gorlin syndrome infants, radiation is usually omitted in first-line management 1
• In older patients requiring craniospinal radiation, prompt identification of Gorlin syndrome is crucial for informing discussions about radiation dosing 1
• Radiation-induced meningiomas occur more frequently in SUFU carriers 1

Surveillance Recommendations

Dermatologic Surveillance

All Gorlin syndrome patients require lifelong dermatologic surveillance with skin examinations by a dermatologist starting at age 10 years (or earlier if radiotherapy exposure or suspect findings), performed annually. 1

• Pediatricians should perform skin examinations at routine visits 1
• Patients should be counseled on rigorous sun protection and avoidance of ionizing radiation 1
• Monthly self-examination of all skin surfaces is recommended 1
• Annual orthopantomogram for PTCH1 carriers should be replaced with MRI when possible to avoid radiation exposure 1

Cardiac and Ovarian Surveillance

• Echocardiogram for cardiac fibromas: Baseline in infancy, ideally before 6 months of age 1
• Pelvic ultrasound for ovarian fibromas: Starting at age 18 years for PTCH1 carriers, age 5 years for SUFU carriers, performed once (repeat at pregnancy or if symptomatic) 1

Dental Surveillance (PTCH1 Carriers Only)

• Dental examination starting at age 2 years, then annually from age 8 years 1
• Orthopantomogram or MRI to detect odontogenic keratocysts 1

Neurologic Surveillance

For SUFU mutation carriers, brain MRI surveillance for medulloblastoma is required every 3-4 months from infancy until age 3 years, then every 6 months until age 5 years. 1

• For PTCH1 carriers, surveillance is clinical only (neurological examination, head circumference) every 3-4 months until age 5 years 1
• Routine brain imaging is not currently recommended for PTCH1 carriers 1
• Meningioma screening with brain MRI every 3-5 years starting at age 30 years after medulloblastoma treatment, only for SUFU carriers 1

Prevention Strategies

Stringent sun avoidance and protection are mandatory, including routine use of sunscreens, seeking shade, and wearing broad-brimmed head coverings. 1, 4

• Avoid all unnecessary ionizing radiation, including diagnostic imaging when alternatives exist 1
• Oral retinoids (acitretin, isotretinoin) can reduce development of new BCCs but have significant side effects, are teratogenic, and therapeutic effects disappear after cessation 1
• Aggressive treatment of precancerous lesions can prevent development of invasive tumors 1

Critical Pitfalls to Avoid

• Never use routine radiotherapy for BCC treatment in Gorlin syndrome patients—this will induce multiple additional BCCs in the radiation field 1
• Do not rely on family history alone for diagnosis—46% of patients with germline alterations lack family history 1
• Avoid superficial biopsies that may miss infiltrative components at deeper margins 5
• Do not assume mutation type predicts BCC burden—clinical surveillance is essential regardless 2
• Recognize that treatment de-escalation for medulloblastoma is appropriate given excellent prognosis, but monitor for treatment-related second neoplasms (desmoid, thyroid, pilomatrixoma) 1