Clinical vs. molecular diagnosis of Gorlin syndrome: relevance of diagnostic criteria depends on the age of the patients.

Background: Gorlin syndrome (GS) is an autosomal dominant disorder characterized by a predisposition to basal cell carcinoma and developmental defects. It is caused by pathogenic variants in the PTCH1 or SUFU genes.

Objectives: To ascertain the effectiveness of molecular screening in a cohort of patients with a suspicion of GS and to describe the patients' clinical and genetic characteristics.

Methods: In total, 110 patients with a suspicion of GS were studied. The patients were seen at the genetic department of Bichat University Hospital for molecular screening. The patients' clinical and paraclinical data were collected and analysed according to Evans' diagnostic criteria and were compared with molecular information.

Results: Among 110 probands, only 56% fulfilled Evans' diagnostic criteria. Overall, 75% of the patients who fulfilled those criteria carried a pathogenic variation in PTCH1 or SUFU. We compared the clinical and paraclinical data of 54 probands carrying a PTCH1 or SUFU mutation with 56 probands without identified mutations. Among patients carrying a pathogenic variation in the PTCH1 or SUFU genes, 30 years appears to be the cut-off age after which all patients have clear clinical GS. Indeed, after age 30 years, all patients carrying a PTCH1 or SUFU mutation fulfilled the diagnostic criteria of Evans (82% met the clinical criteria, reaching 100% with complementary examinations such as X-rays and ultrasound). Before 30 years of age, only 37% of patients with mutated genes fulfilled the clinical diagnostic criteria, reaching only 62% with simple complementary exams. We also report 22 new mutations in PTCH1.

Conclusions: Molecular screening of patients with GS who do not fulfil Evans' diagnostic criteria should only be offered in the first instance to patients under 30 years of age. After age 30 years, careful clinical examination and complementary radiological exams should be enough to eliminate the diagnosis of GS among patients who do not fulfil the diagnostic criteria.