Gorlin-Goltz syndrome (nevoid basal cell carcinoma syndrome) is a rare autosomal dominant tumor-predisposition disorder characterized by multiple basal cell carcinomas (BCCs), odontogenic keratocysts of the jaws, and variable systemic manifestations. Although pathogenic variants in PTCH1 are a major genetic cause, transcript-level functional evidence for splice-site variants and real-world data on tolerability-oriented dosing of Hedgehog pathway inhibitors remain limited. We report a three-generation family in which a heterozygous canonical PTCH1 splice-donor variant (NM₀00264. 5: c. 3449 + 1G A) segregated with disease. A minigene splicing assay demonstrated exon 20 skipping, supporting a loss-of-function mechanism. Two affected relatives with symptomatic BCC burden received oral sonidegib for 6 months using different schedules (200 mg once daily vs. 200 mg every other day). Both patients showed clinical regression of target BCC lesions. Dysgeusia and alopecia occurred with daily dosing, whereas every-other-day dosing was well tolerated. This case highlights the value of transcript-level functional assays for interpreting PTCH1 splice-site variants and supports individualized, toxicity-guided sonidegib scheduling in selected patients with Gorlin-Goltz syndrome.
L et al. (Tue,) studied this question.