Gorlin syndrome

Gorlin syndrome is inherited in an autosomal dominant pattern and affects many areas of the body, increasing a patient’s chance of developing various cancerous and noncancerous tumours. A distinctive facial appearance and skeletal anomalies are often present.

• Jaw cysts (odontogenic keratocysts) from the second decade of life.
• Multiple basal cell carcinomas of the skin from the third decade of life.
• Palmar and plantar pits.
• Distinct facial features, including macrocephaly, frontal and temporoparietal bossing, hypertelorism, mandibular prognathism and, in some, cleft lip and palate.
• Skeletal anomalies: bifid ribs, kyphoscoliosis, early calcification of falx cerebri (diagnosed with AP radiograph), rib and vertebrae anomalies.
• Brachydactyly, thumb anomalies or polydactyly.
• Ovarian or cardiac fibromas.
• Eye anomalies, including cataract, coloboma and microphthalmos.
• Medulloblastoma (typically desmoplastic), which occurs in 33% of individuals with SUFU variants and under 2% of individuals with PTCH1 variants, with peak incidence at 12 to 24 months of age.

Gorlin syndrome is caused by loss-of-function genetic variants (nonsense, frameshift, missense, splicing and deletions) in PTCH1 (9q22.3) or, less commonly, SUFU. Both genes have a tumour suppressor function, with basal cell carcinomas and medulloblastoma arising as a result of a ‘second hit’ inactivating the other copy of the PTCH1 or SUFU gene.

For information about testing, see Presentation: Child with a suspected overgrowth-intellectual disability syndrome and Presentation: Child with macrocephaly.

Gorlin syndrome is an autosomal dominant condition, and affected individuals have a 50% offspring risk.

Around 70%–80% of individuals with Gorlin syndrome will have an affected parent, though the expression (features shown in individuals with the gene change) can vary significantly both within and between families.

Where parents do not carry the pathogenic gene variant identified in the affected child, the recurrence risk will be less than 1%. The risk remains slightly above that of the background population due to the small possibility of constitutional (germline) mosaicism.

The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genomic counselling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Management of children with Gorlin syndrome is principally supportive and suggested approaches, including skin and dental surveillance as well as avoidance of environmental factors that increase the risk of cancers, have been published by several authors.

For clinicians

• Cancer Research UK: Gorlin syndrome
• GeneReviews: Nevoid Basal Cell Carcinoma Syndrome
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• OMIM: 109400 (Basal cell nevus syndrome)
• Orphanet: Gorlin syndrome
• U.S. National Library of Medicine: ClinicalTrials.gov database

For patients

• Gorlin Syndrome Alliance