A case of multiple familial trichoepitheliomas responding to treatment with the Hedgehog signaling pathway inhibitor vismodegib

Virchows Arch. 2018 Aug;473(2):241-246. doi: 10.1007/s00428-018-2397-y. Epub 2018 Jun 22.


Multiple familial trichoepitheliomas (MFT) is an autosomal dominantly inherited disease characterized by multiple skin appendage tumors. We describe a patient showing a continuous spectrum of follicular differentiated neoplasms including classical trichoepitheliomas but also infiltrative growing and finally metastasizing malignant follicular differentiated tumors. Germline mutation analysis revealed a nonsense mutation in the cylindromatosis (CYLD) gene. Gene expression analysis by real-time PCR of tumor tissue showed overexpression of glioma-associated oncogene Gli1 mRNA. Treatment with the Hedgehog pathway inhibitor vismodegib resulted in a significant regression of the highly differentiated trichoepitheliomas. Gli upregulation is indicative of an active Hedgehog signaling pathway. We hypothesize that its upregulation is indirectly caused by CYLD mutation which promotes tumor development. Vismodegib treatment could thus provide a new treatment option for patients with this debilitating disorder.

Keywords: Brooke syndrome; CYLD; Hedgehog pathway; Trichoepithelioma; Vismodegib.

Publication types

  • Case Reports

MeSH terms

  • Anilides / therapeutic use*
  • Antineoplastic Agents / therapeutic use*
  • Codon, Nonsense
  • Deubiquitinating Enzyme CYLD / genetics
  • Genetic Predisposition to Disease
  • Heredity
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Neoplastic Syndromes, Hereditary / drug therapy*
  • Neoplastic Syndromes, Hereditary / genetics
  • Neoplastic Syndromes, Hereditary / metabolism
  • Neoplastic Syndromes, Hereditary / pathology
  • Pedigree
  • Phenotype
  • Pyridines / therapeutic use*
  • Signal Transduction / drug effects
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Tomography, X-Ray Computed
  • Treatment Outcome
  • Up-Regulation
  • Zinc Finger Protein GLI1 / genetics
  • Zinc Finger Protein GLI1 / metabolism


  • Anilides
  • Antineoplastic Agents
  • Codon, Nonsense
  • GLI1 protein, human
  • HhAntag691
  • Pyridines
  • Zinc Finger Protein GLI1
  • CYLD protein, human
  • Deubiquitinating Enzyme CYLD

Supplementary concepts

  • Familial cylindromatosis