Neurosurgery notes/Tumours/Tumour syndrome/Rhabdoid tumour predisposition syndrome

Rhabdoid tumour predisposition syndrome

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Tumour syndrome

General

  • Aka:
    • Rhabdoid predisposition syndrome
    • Familial posterior fossa brain tumour syndrome of infancy.

Definition

  • A disorder characterized by a markedly increased risk of developing malignant rhabdoid tumours (MRTs) (CNS version of atypical teratoid/ rhabdoid tumours (AT/RTs))
  • Due to constitutional loss or inactivation of one allele of the
    • SMARCB1 gene - rhabdoid tumour predisposition syndrome 1 (RTPS1) - or
    • SMARCA4 gene - rhabdoid tumour predisposition syndrome 2 (RTPS2) (extremely rarely)

Numbers

  • 1/3 of pt with atypical teratoid/ rhabdoid tumours (AT/RTs)
    • Hence all AT/RT need to be investigated for this syndrome
  • Germline mutation more likely to present by <1 yrs old

Diagnostic criteria

  • Demonstration of a germline SMARCB1 or SMARCA4 mutation in a patient with MRT is sufficient for the diagnosis of RTPS1 or RTPS2, respectively

Sites of involvement

  • CNS
    • AT/RT
      • Other CNS tumours with composite rhabdoid features still have functioning SMARCB1
        • Meningiomas
        • Gliomas
        • Melanomas
        • Carcinomas
    • Other less common
      • Choroid plexus carcinoma
      • Medulloblastoma,
      • And supratentorial
      • Primitive neuroectodermal tumour
    • Schwannomatosis
      • SMARCB1 mutation involved in
        • 50% of familial cases
        • <10% of sporadic cases
    • Multiple meningiomas
      • Caused by SMARCB1 germline mutations
      • Preferential location of the cranial meningiomas at the falx cerebri
  • Extra Neural
    • Kidney
      • Most frequent extra-CNS location of MRT
      • SMARCB1
    • Small cell carcinoma of the ovary of hypercalcaemic type
      • Mutated SMARCA4

Genetic

SMARCB1

  • 22q11.23
  • Also Identified as a predisposing gene in familial schwannomatosis
  • Method of mutation
    • Single base deletions
    • Monosomy 22
  • A subunit of SWI/SNF complex (chromatin remodelling complexes)
    • 20% of all human cancer have mutation in the SWI/SNF complex
  • Function
    • Regulate the expression of many genes by using ATP for sliding the nucleosomes along the DNA helix, facilitating or repressing transcription
      • Repression of CCND1 gene expression,
      • Induction of the CDKN2A gene,
      • Hypophosphorylation of retinoblastoma protein,
        • All resulting in G0/G1 cell cycle arrest

SMARCA4 gene

  • 19p.13.2
  • Catalytic subunit of SWI/SNF complex

Coffin-Siris syndrome

  • Germline mutations in both SMARCB1 and SMARCA4
  • A rare congenital malformation syndrome
  • Characterized by
    • Developmental delay or intellectual disability,
    • Coarse facial appearance,
    • Feeding difficulties,
    • Frequent infections, and
    • Hypoplasia/aplasia of the fifth fingernails and fifth distal phalanges