Gorlin Syndrome

Gorlin syndrome (basal cell naevus syndrome) is an autosomal dominant disorder caused by variants in PTCH1 (and rarely SUFU or PTCH2), with multiple basal cell carcinomas, jaw keratocysts, palmar pits, skeletal anomalies and a risk of medulloblastoma. Basal cell carcinomas appear from the teens and can be numerous.

Pathophysiology. PTCH1 inhibits the hedgehog signalling receptor smoothened. Loss of PTCH1 function leaves hedgehog signalling active and causes skin tumours, jaw cysts and developmental anomalies.

SUFU variants carry a higher risk of early desmoplastic medulloblastoma, while PTCH1 disease carries a lower risk.

Ultraviolet exposure and ionising radiation sharply increase basal cell cancer burden.

• Multiple basal cell carcinomas, often from adolescence
• Odontogenic keratocysts of the jaw
• Palmar and plantar pits
• Macrocephaly, frontal bossing, coarse facies
• Calcification of the falx cerebri
• Bifid, splayed or fused ribs, vertebral anomalies
• Ovarian fibromas and cardiac fibromas
• Medulloblastoma in early childhood
• Ocular anomalies and cleft lip or palate

• Clinical diagnosis: multiple basal cell carcinomas, or one before age 20, jaw keratocysts, and palmar pits.
• Genetic testing of PTCH1 and SUFU (and PTCH2) with deletion and duplication analysis.
• Skin examination with dermoscopy and biopsy of suspicious lesions.
• Dental imaging: orthopantomogram from about 8 years.
• Brain imaging: MRI for medulloblastoma in young children with SUFU disease, and CT or MRI for falx calcification.
• Echocardiography in infancy for cardiac fibroma and pelvic ultrasound for ovarian fibroma.
• Skeletal imaging of chest and spine.

Differential diagnosis.

• Sporadic basal cell carcinoma
• Bazex-Dupré-Christol syndrome and Rombo syndrome
• Odontogenic keratocysts of other cause
• Cowden syndrome and other cancer predisposition syndromes
• Brooke-Spiegler syndrome
• Familial atypical multiple mole melanoma syndrome

• Sun and radiation avoidance: strict sun protection with sun protection factor 50 or more, clothing and shade. Avoid radiotherapy and unnecessary CT, because it provokes hundreds of new basal cell carcinomas in the field.
• Skin surveillance: full skin examination every 6 months from adolescence, adjusted to disease burden.
• Treatment of basal cell carcinomas: surgical excision or Mohs surgery for high risk and facial lesions, curettage and cautery, cryotherapy, photodynamic therapy, topical fluorouracil 5% cream twice daily for 3 to 6 weeks, or imiquimod 5% cream once daily 5 days each week for 6 weeks for superficial lesions.
• Hedgehog inhibitors for multiple or advanced tumours (adults): vismodegib 150 mg orally once daily or sonidegib 200 mg orally once daily. Adverse effects are muscle spasms, taste loss, alopecia and weight loss. They are teratogenic, so contraception is needed, and they are not used in growing children because of premature epiphyseal closure. Intermittent courses can limit toxicity.
• Oral nicotinamide 500 mg twice daily may reduce new keratinocyte cancers.
• Jaw keratocysts: enucleation or marsupialisation, with annual radiographic follow up because of recurrence.
• Medulloblastoma surveillance in SUFU disease: brain MRI every 3 to 4 months until about age 3, then every 6 months until about age 5. Treatment of tumours avoids radiotherapy when possible.
• Other care: surgery for ovarian or cardiac fibroma, dental care, and orthopaedic care.
• Genetic counselling: 50% chance for each child of a carrier.

Special groups.

• Women of childbearing potential on hedgehog inhibitors need contraception during treatment and for 24 months (vismodegib) or 20 months (sonidegib) after.

Monitoring. Skin every 6 months. Dental radiographs yearly from 8 years. Neurological review and brain MRI every 3 to 6 months to about age 5 in SUFU disease.

Referral and escalation. Refer to dermatology, clinical genetics, oral surgery and paediatric neuro oncology. Urgent for a rapidly growing or ulcerated skin lesion, headache with vomiting, or ataxia in a child.