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A novel truncating mutation of PTCH1 in a Chinese family with Gorlin syndrome.

ABSTRACT: Gorlin syndrome, a rare autosomal dominant disease, is characterized by numerous basal cell carcinomas, multiple jaw cysts, palmar and plantar pits and embryological deformities. Mutations in the PTCH1 gene are the most common molecular defects associated with Gorlin syndrome. We detected a duplication of thymine after nucleotide position 2927 in exon 18 of the PTCH1 gene (c.2927 dupT) in a fifty-year-old male proband with peri-anal basal cell carcinoma and his brother. The mutation creates a frameshift and leads to a premature stop codon (p.Tyr977 Leufs* 16) lacking 5 of the 12 transmembrane-spanning domains. However, the functional significance of truncation of the N terminal regions remains currently unknown and to be further investigated. The current findings indicate that genetic testing of PTCH1 gene mutational status may aid in the early diagnosis of Gorlin syndrome in which multiple complex abnormalities are present, hampering prompt diagnosis and treatment.

SUBMITTER: Liu Q

PROVIDER: S-EPMC6965468 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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A novel truncating mutation of PTCH1 in a Chinese family with Gorlin syndrome.

Liu Qin Q Liu Lanting L Wu Xuejingzi X Du Tiankai T Zheng Kaiping K Song Jiquan J

International journal of clinical and experimental pathology 20170801 8

Gorlin syndrome, a rare autosomal dominant disease, is characterized by numerous basal cell carcinomas, multiple jaw cysts, palmar and plantar pits and embryological deformities. Mutations in the <i>PTCH1</i> gene are the most common molecular defects associated with Gorlin syndrome. We detected a duplication of thymine after nucleotide position 2927 in exon 18 of the <i>PTCH1</i> gene (c.2927 dupT) in a fifty-year-old male proband with peri-anal basal cell carcinoma and his brother. The mutatio ...[more]

PMID: 31966778

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Project description:Gorlin syndrome or nevoid basal cell carcinoma syndrome is a rare genetic disease characterized by predisposition to congenital defects, basal cell carcinomas and medulloblastoma. The syndrome results from a heritable mutation in PATCHED1 (PTCH1), causing constitutive activation of the Hedgehog pathway. The present study described a patient with Gorlin syndrome who presented early in life with characteristic basal cell carcinomas and later developed a small cell glioblastoma (GBM), World Health Organization grade IV, associated with a Patched 1 (PTCH1) N97fs*43 mutation. Comprehensive genomic profiling of GBM tissues also revealed multiple co-occurring alterations including cyclin-dependent kinase 4 (CDK4) amplification, receptor tyrosine-protein kinase 3 (ERBB3) amplification, a fibroblast growth factor receptor 1 and transforming acidic coiled-coil containing protein 1 (FGFR1-TACC1) fusion, zinc finger protein (GLI1) amplification, E3 ubiquitin-protein ligase (MDM2) amplification and spectrin α chain, erythrocytic 1 (SPTA1) T1151fs*24. After the biopsy, imaging revealed extensive leptomeningeal enhancement intracranially and around the cervical spinal cord due to leptomeningeal disease. The patient underwent craniospinal radiation followed by 6 months of adjuvant temozolomide (150 mg/m2) with good response. She was then treated with vismodegib for 11 months, first combined with temozolomide and then with bevacizumab, until disease progression was noted on MRI, with no significant toxicities associated with the combination therapy. She received additional therapies but ultimately succumbed to the disease four months later. The current study presents the first documentation in the literature of a primary (non-radiation induced) glioblastoma secondary to Gorlin syndrome. Based on this clinical experience, vismodegib should be considered in combination with standard-of-care therapies for patients with known Gorlin syndrome-associated glioblastomas and sonic hedgehog pathway mutations.

Dataset Information

A novel truncating mutation of PTCH1 in a Chinese family with Gorlin syndrome.

Publications

A novel truncating mutation of PTCH1 in a Chinese family with Gorlin syndrome.

Similar Datasets

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