Gorlin Syndrome

Etiology

Basal cell nevus syndrome is caused by mutations in the patched (PTCH) gene that encodes a transmembrane receptor which recognizes sonic hedgehog signaling proteins. There is near complete penetrance with variable expressivity. De novo mutations represent approximately 20% to 30% of cases of BCNS.

Epidemiology

Prevalence of Gorlin syndrome is estimated at 1 per 40,000-60,000. The disease affects men and women in rather equal distribution (1:1.3). Although the disease affects all races, African American and Asians represent only 5% of cases and more often are incidentally diagnosed with extracutaneous findings, such as odontogenic keratocysts, as compared to BCCs.

Pathophysiology

Gorlin syndrome is caused by a mutation in patched 1 (PTCH1), a tumor suppressor gene located on chromosome 9q.  PTCH encodes a transmembrane receptor protein that recognizes signaling proteins of the sonic hedgehog family. Homozygous inactivation of the PTCH gene leads to tumorigenecity and the formation of multiple BCCs and other neoplasms. Patients with Gorlin syndrome inherit one defective copy of the tumor suppressor gene and acquire a "second hit" mutation, such as from ultraviolet light or ionizing radiation. Recently, mutations in suppressor of fused gene (SUFU) on chromosome 10q and PTCH2 on chromosome 1p have been found in patients meeting criteria for Gorlin's syndrome. Of note, patients with SUFU mutations have a reported 20-fold increased risk of developing medulloblastoma as compared to PTCH1 mutations in Gorlin syndrome.[5][6][7]

Patients with one mutated copy of the PTCH1 gene in each cell can have the features of Gorlin syndrome early in life. This includes skeletal abnormalities and macrocephaly. A mutation in the second copy of the PTCH1gene must also occur in certain cells during the person's lifetime for basal cell carcinomas and other tumors to develop. Patients with one PTCH1 gene mutation eventually develop a second mutation in some cells and consequently develop various types of tumors.

History and Physical

Patients with Gorlin syndrome can present as early as infancy with BCCs; however, the median age of developing BCCs is 20 years. Multiple BCCs are the hallmark feature of Gorlin syndrome and BCCs may present as classic translucent papules with telangiectasias or may resemble acrochordons (skin tags). Superficial pits on the palms and soles occur in 75% to 90% of patients. Epidermal inclusion cysts and milia are reported in approximately 50% of cases.

Pain, swelling, and drainage of jaw cysts (odontogenic keratocysts) may be the initial reason for presentation and occur at an average age of 13 years. Rare reports of malignant transformation of jaw cysts have been reported. Medulloblastoma is the second most common malignancy in BCNS with a frequency of approximately 5% and occurs at an average age of two years.  Patients may experience seizures, mental retardation, and other neurologic abnormalities. Musculoskeletal anomalies are very common occurring in 60% to 75% of patients and often are congenital. Bifid or splayed ribs, frontal bossing, cleft lip/palate, vertebral fusion, pectus excavatum, syndactyly, and hypoplastic thumbs are some potential musculoskeletal anomalies. Ophthalmologic abnormalities such as hypertelorism, congenital blindness, cataracts, strabismus, and colobomas of the retina or iris may occur. Profound bradycardia from cardiac fibromas can occur during general anesthesia.

Evaluation

Diagnosis of BCNS requires the presence of two major or one major and two minor clinical criteria.

Major criteria include: multiple (>2) BCCs or 1 BCC by ≤20 years of age, odontogenic keratocysts of the jaw proven by histology, palmar or plantar pitting, bilamellar calcification of the falx cerebri, bifid/fused/splayed ribs, first-degree relative with BCNS.

Minor criteria include:  medulloblastoma, increased circumference of the head, congenital malformations (frontal bossing, coarse facies, cleft lip/palate, moderate or severe hypertelorism), other skeletal abnormalities (Sprengel deformity, marked pectus deformity, marked syndactyly of the digits), radiologic abnormalities (bridging of the sella turcica, hemivertebrae, fusion or elongation of the vertebral bodies, modeling defects of the hands and feet, or flame-shaped lucencies of the hands or feet), ovarian and cardiac fibromas. 

Genetic testing for PTCH1 is suggested for the following situations: (1) diagnosis confirmation in patients lacking sufficient clinical diagnostic criteria; (2) predictive testing for patients at risk with an affected family member but not meeting clinical criteria; (3) prenatal testing if there is a known familial mutation. 

Treatment / Management

A multidisciplinary approach is required to manage patients with Gorlin syndrome.  Close surveillance by a dermatologist or dermatologic surgeon is required to diagnose and treat BCCs as rarely metastasis has occurred in these patients. Pediatric patients should have an annual skin screening by a dermatologist until the first BCC, then undergo screening at least every six months. Adults should have a complete skin check at least every four months.[8][9][10][11](B3)

Numerous baseline examinations are recommended in pediatric patients. Given the risk of medulloblastoma in pediatric patients, a baseline MRI scan of the brain (repeated yearly until eight years of age then discontinue) is recommended. Baseline jaw X-rays as soon as tolerated and repeated annually until first jaw cyst then every six months until no jaw cysts for two years or until the patient is 21 years of age. Baseline spine X-rays at one year of age and repeat if symptomatic or per scoliosis protocol every six months if abnormal. Baseline cardiac ultrasound is recommended in pediatric patients to evaluate for cardiac fibromas. Girls should have a pelvic ultrasound at menarche or age 18 to evaluate for ovarian fibromas. Annual speech, vision, and hearing screening along with routine developmental screening should be performed in pediatric patients with Gorlin syndrome.

Patients with Gorlin syndrome not diagnosed in childhood should have a baseline MRI scan of the brain, genetic counseling, and possibly a psychological evaluation if needed. Jaw X-rays should be repeated as needed for symptoms and an annual neurology evaluation should occur in patients with a history of medulloblastoma. Pregnant patients should undergo a maternal fetal medical evaluation given risk for hydrocephalus, microcephaly, and cardiac fibromas.

Treatment of BCCs in Gorlin syndrome is challenging given the number of neoplasms. Electrodessication and curettage, cryosurgery, surgical excision, Mohs micrographic surgery (MMS), and MMS in combination with CO2 laser treatment have all be reported. Topical treatment options include 5% 5-fluorouracil, 5% imiquimod, or photodynamic therapy. Vismodegib, an antagonist of the smoothened receptor and a hedgehog pathway inhibitor, can be used to treat BCCs in BCNS; however, side effects can be limiting, and regrowth of BCCs occurs after cessation of vismodegib.

Differential Diagnosis

• Bazex syndrome

• Fibrous papule of the face

• Melanocytic nevi

• Milia

• Pseudohypoparathyroidism

• Rombo syndrome

• Seborrheic keratosis

• Unilateral nevoid BCC with comedones