Gorlin综合征或痣样基底细胞癌综合征是一种罕见的遗传性疾病,以先天性缺陷为特征,基底细胞癌和髓母细胞瘤。该综合征是由PATCHED1(PTCH1)的可遗传突变引起的,导致Hedgehog途径的组成型激活。本研究描述了一名Gorlin综合征患者,该患者在生命早期出现特征性基底细胞癌,后来发展为小细胞胶质母细胞瘤(GBM)。世界卫生组织四级,与补丁1(PTCH1)N97fs*43突变相关。GBM组织的综合基因组分析也揭示了多种共同发生的改变,包括细胞周期蛋白依赖性激酶4(CDK4)扩增,受体酪氨酸蛋白激酶3(ERBB3)扩增,成纤维细胞生长因子受体1和转化酸性卷曲螺旋含蛋白1(FGFR1-TACC1)融合,锌指蛋白(GLI1)扩增,E3泛素蛋白连接酶(MDM2)扩增和血影蛋白α链,红细胞1(SPTA1)T1151fs*24。活检后,影像学显示,由于软脑膜疾病,颅内和颈脊髓周围广泛的软脑膜增强。患者接受头颅脊髓放疗,随后接受替莫唑胺(150mg/m2)辅助治疗6个月,反应良好。然后她用vismodegib治疗了11个月,首先联合替莫唑胺,然后联合贝伐单抗,直到MRI发现疾病进展,没有与联合治疗相关的显著毒性。她接受了额外的治疗,但最终在四个月后死于这种疾病。本研究提供了Gorlin综合征继发的原发性(非辐射诱导的)胶质母细胞瘤的文献中的第一份文献。根据这些临床经验,对于已知与Gorlin综合征相关的胶质母细胞瘤和Sonichedgehog通路突变的患者,应考虑将vismodegib与标准护理疗法联合治疗.
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.