PTCH1-Related Gorlin Syndrome: Expanding the Clinical and Molecular Spectrum in a Cohort of 11 Patients

Gorlin syndrome (GS, MIM #109400) is a cancer predisposition syndrome characterized by macrocephaly, odontogenic keratocysts, calcification of the falx cerebri, basal cell carcinoma, and medulloblastoma. It is caused by pathogenic variants in the PTCH1 and SUFU genes.

We evaluated the clinical and molecular features of 11 patients with GS using single-gene testing, multigene panel analysis, and clinical exome sequencing.

All patients exhibited characteristic craniofacial features. Macrocephaly was observed in 10 patients (90.9%) and odontogenic keratocysts in nine patients (81.8%). Palmar pits and falx cerebri calcification were observed in eight patients (72.7%). Basal cell carcinoma occurred in four patients (36.3%), and medulloblastoma in two (18.2%). GS was clinically suspected based on the observed clinical and radiological findings in all patients. Seven distinct heterozygous pathogenic PTCH1 variants were identified, four of which were novel. One patient had a dual diagnosis of L-2-hydroxyglutaric aciduria.

These findings underscore the marked phenotypic variability of PTCH1-related GS. Due to age-dependent clinical manifestations, patients require regular long-term surveillance and comprehensive clinical assessment.

Molecular confirmation of the diagnosis is important for the provision of genetic counselling, consideration of preimplantation genetic diagnosis, and appropriate patient follow-up and treatment planning.