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Germline SMARCB1 mutation and somatic NF2 mutations in familial multiple meningiomas
  1. I Christiaans1,
  2. S B Kenter2,
  3. H C Brink1,
  4. T A M van Os1,
  5. F Baas2,
  6. P van den Munckhof3,
  7. A M J Kidd4,
  8. T J M Hulsebos2
  1. 1Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands
  2. 2Department of Neurogenetics, Academic Medical Center, Amsterdam, The Netherlands
  3. 3Department of Neurosurgery, Academic Medical Center, Amsterdam, The Netherlands
  4. 4Canterbury Health Laboratories, Christchurch, New Zealand
  1. Correspondence to Dr Theo J M Hulsebos, Department of Neurogenetics, Academic Medical Center, Room K2-216, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands; t.j.hulsebos{at}


Background Multiple meningiomas occur in <10% of meningioma patients. Their development may be caused by the presence of a predisposing germline mutation in the neurofibromatosis type 2 (NF2) gene. The predisposing gene in patients with non-NF2 associated multiple meningiomas remains to be identified. Recently, SMARCB1 was reported to be a potential predisposing gene for multiple meningiomas in a family with schwannomatosis and multiple meningiomas. However, involvement of this gene in the development of the meningiomas was not demonstrated.

Results Five affected members of a large family with multiple meningiomas were investigated for the presence of mutations in SMARCB1 and NF2. A missense mutation was identified in exon 2 of SMARCB1 as the causative germline mutation predisposing to multiple meningiomas; furthermore, it was demonstrated that, in accordance with the two-hit hypothesis for tumourigenesis, the mutant allele was retained and the wild-type allele lost in all four investigated meningiomas. In addition, independent somatically acquired NF2 mutations were identified in two meningiomas of one patient with concomitant losses of the wild-type NF2 allele.

Conclusion It is concluded that, analogous to the genetic events in a subset of schwannomatosis associated schwannomas, a four-hit mechanism of tumour suppressor gene inactivation, involving SMARCB1 and NF2, might be operative in familial multiple meningiomas associated meningiomas.

  • Molecular genetics
  • neuro oncology

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  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.