Neurosurgery notes/Tumours/Tumour syndrome/Naevoid basal cell carcinoma syndrome

Naevoid basal cell carcinoma syndrome

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Tumour syndrome

Nomenclature

  • Gorlin-Goltz syndrome
  • Basal cell naevus syndrome
  • Fifth phacomatosis.

Definition

  • An autosomal dominant disease associated with developmental disorders and predisposition to benign and malignant tumours, including
    • Basal cell carcinomas of the skin
      • Starts at 20 yrs and >90% present at 40 yrs
    • Odontogenic keratocysts
    • Palmar and plantar dyskeratotic pits,
    • Intracranial calcifications,
    • Macrocephaly
    • Medulloblastomas of the desmoplastic/ nodular subtypes;
      • Developed by 3 yrs. old

Numbers

  • Prevalence: 1/57k
  • Medulloblastoma and gorlin
    • 1-2% with medulloblastoma have PTCH1 germline mutation
    • 6% with medulloblastoma had SUFU mutation
    • 2% of Gorlin syndrome with germline PTCH1 mutation will develop medulloblastoma
    • 20% of Gorlin syndrome with germline SUFU mutation will develop medulloblastoma
  • Gorlin due to PTCH2 mutation is rare (only 2 family has been reported)

Genetic

  • Caused by germline mutations of genes encoding members of the hedgehog signalling pathway, including
    • The PTCH1 gene on 9q22,
    • Its homologue PTCH2 on 1p34, and
    • The SUFU gene on 10q24
  • PTCH1
    • 9q22
    • Normally suppresses SMO, but suppression releases when is bound to sonic hedgehog
    • Desmoplastic variant of medulloblastoma
  • PTCH2
    • 1p34
    • Homolog of PTCH1
    • Desmoplastic variant of medulloblastoma
    • Frame shift mutation and missense mutation
  • SUFU
    • 10q
    • Suppresses GLI transcription factor
    • Desmoplastic variant of medulloblastoma
    • Missense mutations, splice site mutations, or deletions
  • Normal mech of SHH pathway
      • Hedgehog signaling is activated by interaction of a secreted hedgehog ligand (Hh) with the multipass transmembrane receptor PTCH.
      • Ligand binding relieves the repressive effects of PTCH on SMO and permits the activation and nuclear translocation of GLI transcription factors.
      • GLI activation is also promoted by FU, and suppressed by SU(FU).
      • COS2 proteins are thought to serve as a scaffold for these interactions.
      • Once in the nucleus, GLI factors induce the transcription of various pathway targets, including feedback loops involving PTCH1 and GUI.
      notion image

Diagnostic criteria

  • 2 major OR 1 major and 2 minor
  • Major criteria
    • Multiple basal cell carcinomas,
    • Odontogenic keratocytes of the jaw
    • Calcification of the falx cerebri,
    • Palmar and plantar pits,
    • Bifid or fused ribs,
    • First-degree relatives with the syndrome
  • Minor criteria
    • Medulloblastoma (mainly of the desmoplastic/nodular subtypes),
    • Ovarian fibroma,
    • Macrocephaly,
    • Congenital facial abnormalities (e.g. cleft lip or palate, frontal bossing, and hypertelorism),
    • Skeletal abnormalities (e.g. digit syndactyly),
    • Radiological bone abnormalities (e.g. bridging of the sella turcica)