# Case Report: PTCH1 splice-site mutation and sonidegib treatment in Gorlin-Goltz syndrome: clinical insights from a family case study

## TL;DR

This case study explores a PTCH1 gene mutation in a family with Gorlin-Goltz syndrome and evaluates sonidegib treatment effectiveness and side effects.

## Contribution

The study provides transcript-level evidence for a PTCH1 splice-site variant and real-world dosing insights for sonidegib in Gorlin-Goltz syndrome.

## Key findings

- A PTCH1 splice-donor variant caused exon 20 skipping, supporting a loss-of-function mechanism.
- Sonidegib treatment led to clinical regression of BCC lesions in two patients.
- Every-other-day sonidegib dosing was better tolerated compared to daily dosing.

## Abstract

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 (NM_000264.5: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.