Skip to main content
SpringerLink
Log in

Schwannomatosis associated with multiple meningiomas due to a familial SMARCB1 mutation

  • ORIGINAL ARTICLE
  • Published:
neurogenetics Aims and scope Submit manuscript

Abstract

Schwannomatosis (MIM 162091) is a condition predisposing to the development of central and peripheral schwannomas; most cases are sporadic without a clear family history but a few families with a clear autosomal dominant pattern of transmission have been described. Germline mutations in SMARCB1 are associated with schwannomatosis. We report a family with multiple schwannomas and meningiomas. A SMARCB1 germline mutation in exon 1 was identified. The mutation, c.92A>T (p.Glu31Val), occurs in a highly conserved amino acid in the SMARCB1 protein. In addition, in silico analysis demonstrated that the mutation disrupts the donor consensus sequence of exon 1. RNA studies verified the absence of mRNA transcribed by the mutant allele. This is the first report of a SMARCB1 germline mutation in a family with schwannomatosis characterized by the development of multiple meningiomas.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Huang JH, Simon SL, Nagpal S, Nelson PT, Zager EL (2004) Management of patients with schwannomatosis: report of six cases and review of the literature. Surg Neurol 62:353–361. doi:10.1016/j.surneu.2003.11.020

    Article  PubMed  Google Scholar 

  2. Jacoby LB, Jones D, Davis K, Kronn D, Short MP, Gusella J, MacCollin M (1997) Molecular analysis of the NF2 tumor-suppressor gene in schwannomatosis. Am J Hum Genet 61:1293–1302. doi:10.1086/301633

    Article  CAS  PubMed  Google Scholar 

  3. Hulsebos TJ, Plomp AS, Wolterman RA, Robanus-Maandag EC, Baas F, Wesseling P (2007) Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am J Hum Genet 80:805–810. doi:10.1086/513207

    Article  CAS  PubMed  Google Scholar 

  4. Boyd C, Smith MJ, Kluwe L, Balogh A, Maccollin M, Plotkin SR (2008) Alterations in the SMARCB1 (INI1) tumor suppressor gene in familial schwannomatosis. Clin Genet 74:358–366. doi:10.1111/j.1399-0004.2008.01060.x

    Article  CAS  PubMed  Google Scholar 

  5. Hadfield KD, Newman WG, Bowers NL, Wallace A, Bolger C, Colley A, McCann E, Trump D, Prescott T, Evans DG (2008) Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis. J Med Genet 45:332–339. doi:10.1136/jmg.2007.056499

    Article  CAS  PubMed  Google Scholar 

  6. Sestini R, Bacci C, Provenzano A, Genuardi M, Papi L (2008) Evidence of a four-hit mechanism involving SMARCB1 and NF2 in schwannomatosis-associated schwannomas. Hum Mutat 29:227–231. doi:10.1002/humu.20679

    Article  CAS  PubMed  Google Scholar 

  7. Moyhuddin A, Baser ME, Watson C, Purcell S, Ramsden RT, Heiberg A, Wallace AJ, Evans DGR (2003) Somatic mosaicism in neurofibromatosis 2: prevalence and risk of disease transmission to offspring. J Med Genet 40:459–463. doi:10.1136/jmg.40.6.459

    Article  CAS  PubMed  Google Scholar 

  8. Evans DG, Watson C, King A, Wallace AJ, Baser ME (2005) Multiple meningiomas: differential involvement of the NF2 gene in children and adults. J Med Genet 42:45–48. doi:10.1136/jmg.2004.023705

    Article  CAS  PubMed  Google Scholar 

  9. Rongioletti F, Drago F, Rebora A (1989) Multiple cutaneous plexiform schwannomas with tumors of the central nervous system. Arch Dermatol 125:431–432

    Article  CAS  PubMed  Google Scholar 

  10. Evans DG, Mason S, Huson SM, Ponder M, Harding AE, Strachan T (1997) Spinal and cutaneous schwannomatosis is a variant form of type 2 neurofibromatosis: a clinical and molecular study. J Neurol Neurosurg Psychiatry 62:361–366. doi:10.1136/jnnp.62.4.361

    Article  CAS  PubMed  Google Scholar 

  11. Ishida T, Kuroda M, Motoi T, Oka T, Imamura T, Machinami R (1998) Phenotypic diversity of neurofibromatosis 2: association with plexiform schwannoma. Histopathology 32:264–270. doi:10.1046/j.1365-2559.1998.00336.x

    Article  CAS  PubMed  Google Scholar 

  12. MacCollin M, Willett C, Heinrich B, Jacoby LB, Acierno JS Jr, Perry A, Louis DN (2003) Familial schwannomatosis: exclusion of the NF2 locus as the germline event. Neurology 60:1968–1974

    CAS  PubMed  Google Scholar 

  13. Ogihara S, Seichi A, Iwasaki M, Kawaguchi H, Kitagawa T, Tajiri Y, Nakamura K (2003) Concurrent spinal schwannomas and meningiomas. Case illustration. J Neurosurg 98:300

    PubMed  Google Scholar 

  14. Biegel JA, Zhou JY, Rorke LB, Stenstrom C, Wainwright LM, Fogelgren B (1999) Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res 59:74–79

    CAS  PubMed  Google Scholar 

  15. Sevenet N, Sheridan E, Amram D, Schneider P, Handgretinger R, Delattre O (1999) Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am J Hum Genet 65:1342–1348

    Article  CAS  PubMed  Google Scholar 

  16. Sevenet N, Lellouch-Tubiana A, Schofield D, Hoang-Xuan K, Gessler M, Birnbaum D, Jeanpierre C, Jouvet A, Delattre O (1999) Spectrum of hSNF5/INI1 somatic mutations in human cancer and genotype-phenotype correlations. Hum Mol Genet 8:2359–2368

    Article  CAS  PubMed  Google Scholar 

  17. Savla J, Chen TT, Schneider NR, Timmons CF, Delattre O, Tomlinson GE (2000) Mutations of the hSNF5/INI1 gene in renal rhabdoid tumors with second primary brain tumors. J Natl Cancer Inst 92:648–650. doi:10.1093/jnci/92.8.648

    Article  CAS  PubMed  Google Scholar 

  18. Biegel JA, Tan L, Zhang F, Wainwright L, Russo P, Rorke LB (2002) Alterations of the hSNF5/INI1 gene in central nervous system atypical teratoid/rhabdoid tumors and renal and extrarenal rhabdoid tumors. Clin Cancer Res 8:3461–3467

    CAS  PubMed  Google Scholar 

  19. Fernandez C, Bouvier C, Sevenet N, Liprandi A, Coze C, Lena G, Figarella-Branger D (2002) Congenital disseminated malignant rhabdoid tumor and cerebellar tumor mimicking medulloblastoma in monozygotic twins: pathologic and molecular diagnosis. Am J Surg Pathol 26:266–270

    Article  CAS  PubMed  Google Scholar 

  20. Lee HY, Yoon CS, Sevenet N, Rajalingam V, Delattre O, Walford NQ (2002) Rhabdoid tumor of the kidney is a component of the rhabdoid predisposition syndrome. Pediatr Dev Pathol 5:395–599. doi:10.1007/s10024-001-0259-z

    Article  PubMed  Google Scholar 

  21. Fujisawa H, Takabatake Y, Fukusato T, Tachibana O, Tsuchiya Y, Yamashita J (2003) Molecular analysis of the rhabdoid predisposition syndrome in a child: a novel germline hSNF5/INI1 mutation and absence of c-myc amplification. J Neurooncol 63:257–262. doi:10.1023/A:1024345221792

    Article  PubMed  Google Scholar 

  22. Kusafuka T, Miao J, Yoneda A, Kuroda S, Fukuzawa M (2004) Novel germ-line deletion of SNF5/INI1/SMARCB1 gene in neonate presenting with congenital malignant rhabdoid tumor of kidney and brain primitive neuroectodermal tumor. Genes Chromosomes Cancer 40:133–139. doi:10.1002/gcc.20026

    Article  CAS  PubMed  Google Scholar 

  23. Taylor MD, Gokgoz N, Andrulis IL, Mainprize TG, Drake JM, Rutka JT (2000) Familial posterior fossa brain tumors of infancy secondary to germline mutation of the hSNF5 gene. Am J Hum Genet 66:1403–1406

    Article  CAS  PubMed  Google Scholar 

  24. Janson K, Nedzi LA, David O, Schorin M, Walsh JW, Bhattacharjee M, Pridjian G, Tan L, Judkins AR, Biegel JA (2006) Predisposition to atypical teratoid/rhabdoid tumor due to an inherited INI1 mutation. Pediatr Blood Cancer 47:279–284. doi:10.1002/pbc.20622

    Article  PubMed  Google Scholar 

  25. Swensen JJ, Keyser J, Coffin CM, Biegel JA, Viskochil DH, Williams MS (2009) Familial occurrence of schwannomas and malignant rhabdoid tumour associated with a duplication in SMARCB1. J Med Genet 46:68–72. doi:10.1136/jmg.2008.060152

    Article  CAS  PubMed  Google Scholar 

  26. Patil S, Perry A, Maccollin M, Dong S, Betensky RA, Yeh TH, Gutmann DH, Stemmer-Rachamimov AO (2008) Immunohistochemical analysis supports a role for INI1/SMARCB1 in hereditary forms of schwannomas, but not in solitary, sporadic schwannomas. Brain Pathol 18:517–519. doi:10.1111/j.1750-3639.2008.00155.x

    CAS  PubMed  Google Scholar 

  27. Sestini R, Vivarelli R, Balestri P, Ammannati F, Montali E, Papi L (2000) Neurofibromatosis type 2 attributable to gonosomal mosaicism in a clinically normal mother, and identification of seven novel mutations in the NF2 gene. Hum Genet 107:366–371. doi:10.1007/s004390000378

    Article  CAS  PubMed  Google Scholar 

  28. Rogan PK, Faux B, Schneider TD (1998) Information analysis of human splice site mutations. Hum Mutat 12:153–171. doi:10.1002/(SICI)1098-1004(1998)12:3<153::AID-HUMU3>3.0.CO;2-I

    Article  CAS  PubMed  Google Scholar 

  29. Nalla VK, Rogan PK (2005) Automated splicing mutation analysis by information theory. Hum Mutat 25:334–342. doi:10.1002/humu.20151

    Article  CAS  PubMed  Google Scholar 

  30. Thamburaj K, Radhakrishnan VV, Thomas B, Nair S, Menon G (2008) Intratumoral microhemorrhages on T2*-weighted gradient-echo imaging helps differentiate vestibular schwannoma from meningioma. Am J Neuroradiol. 29:552–557. doi:10.3174/ajnr.A0887

    Article  CAS  PubMed  Google Scholar 

  31. Evans DG, Huson SM, Donnai D, Neary W, Blair V, Newton V, Harris R (1992) A clinical study of type 2 neurofibromatosis. Q J Med 84:603–618

    CAS  PubMed  Google Scholar 

  32. Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A, Viskochil D (1997) The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 278:51–57

    Article  CAS  PubMed  Google Scholar 

  33. Schmitz U, Mueller W, Weber M, Sévenet N, Delattre O, von Deimling A (2001) INI1 mutations in meningiomas at a potential hotspot in exon 9. Br J Cancer 84:199–201. doi:10.1054/bjoc.2000.1583

    Article  CAS  PubMed  Google Scholar 

  34. Rieske P, Zakrzewska M, Piaskowski S, Jaskólski D, Sikorska B, Papierz W, Zakrzewski K, Liberski PP (2003) Molecular heterogeneity of meningioma with INI1 mutation. Mol Pathol 56:299–301. doi:10.1136/mp.56.5.299

    Article  CAS  PubMed  Google Scholar 

  35. Purcell SM, Dixon SL (1989) Schwannomatosis. An unusual variant of neurofibromatosis or a distinct clinical entity? Arch Dermatol 125:390–393

    Article  CAS  PubMed  Google Scholar 

  36. Maquat LE (2001) The power of point mutations. Nat Genet 27:5–6. doi:10.1038/83759

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medical Genetics Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy

    Costanza Bacci, Roberta Sestini, Aldesia Provenzano, Irene Paganini, Irene Mancini, Berardino Porfirio, Maurizio Genuardi & Laura Papi

  2. Dipartimento di Pediatria, Ostetricia e Medicina della Riproduzione, Sezione di Pediatria, University of Siena, Siena, Italy

    Rossella Vivarelli

  3. Fiorgen Foundation for Pharmacogenomics, Sesto Fiorentino, Italy

    Maurizio Genuardi

  4. Sezione di Genetica Medica, Dipartimento di Fisiopatologia Clinica, Viale Pieraccini 6, 50139, Firenze, Italy

    Roberta Sestini

Authors
  1. Costanza Bacci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roberta Sestini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aldesia Provenzano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Irene Paganini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Irene Mancini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Berardino Porfirio
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rossella Vivarelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Maurizio Genuardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Laura Papi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roberta Sestini.

Additional information

Costanza Bacci and Roberta Sestini equally contributed to this work.

Funding: This work was supported by Children’s Tumor Foundation (contract grant number: 2007-02-003).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bacci, C., Sestini, R., Provenzano, A. et al. Schwannomatosis associated with multiple meningiomas due to a familial SMARCB1 mutation. Neurogenetics 11, 73–80 (2010). https://doi.org/10.1007/s10048-009-0204-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10048-009-0204-2

Keywords

Search

Navigation