Advertisement

Human Genetics

, Volume 137, Issue 6–7, pp 543–552 | Cite as

Phenotypic and genotypic overlap between mosaic NF2 and schwannomatosis in patients with multiple non-intradermal schwannomas

  • Hildegard Kehrer-Sawatzki
  • Lan Kluwe
  • Reinhard E. Friedrich
  • Anna Summerer
  • Eleonora Schäfer
  • Ute Wahlländer
  • Cordula Matthies
  • Isabel Gugel
  • Said Farschtschi
  • Christian Hagel
  • David N. Cooper
  • Victor-Felix Mautner
Original Investigation

Abstract

Schwannomatosis and neurofibromatosis type 2 (NF2) are both characterized by the development of multiple schwannomas but represent different genetic entities. Whereas NF2 is caused by mutations of the NF2 gene, schwannomatosis is associated with germline mutations of SMARCB1 or LZTR1. Here, we studied 15 sporadic patients with multiple non-intradermal schwannomas, but lacking vestibular schwannomas and ophthalmological abnormalities, who fulfilled the clinical diagnostic criteria for schwannomatosis. None of them harboured germline NF2 or SMARCB1 mutations as determined by the analysis of blood samples but seven had germline LZTR1 variants predicted to be pathogenic. At least two independent schwannomas from each patient were subjected to NF2 mutation testing. In five of the 15 patients, identical somatic NF2 mutations were identified (33%). If only those patients without germline LZTR1 variants are considered (n = 8), three of them (37.5%) had mosaic NF2 as concluded from identical NF2 mutations identified in independent schwannomas from the same patient. These findings imply that a sizeable proportion of patients who fulfil the diagnostic criteria for schwannomatosis, are actually examples of mosaic NF2. Hence, the molecular characterization of tumours in patients with a clinical diagnosis of schwannomatosis is very important. Remarkably, two of the patients with germline LZTR1 variants also had identical NF2 mutations in independent schwannomas from each patient which renders differential diagnosis of LZTR1-associated schwannomatosis versus mosaic NF2 in these patients very difficult.

Notes

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Supplementary material

439_2018_1909_MOESM1_ESM.pdf (1.1 mb)
Supplementary material 1 (PDF 1127 KB)

References

  1. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249CrossRefPubMedPubMedCentralGoogle Scholar
  2. Asai K, Tani S, Mineharu Y, Tsurusaki Y, Imai Y, Agawa Y, Iwaki K, Matsumoto N, Sakai (2015) Familial schwannomatosis with a germline mutation of SMARCB1 in Japan. Brain Tumor Pathol 32:216–220CrossRefPubMedGoogle Scholar
  3. Baser ME, Contributors to the International NF2 Mutation Database (2006) The distribution of constitutional and somatic mutations in the neurofibromatosis 2 gene. Hum Mutat 27:297–306CrossRefPubMedGoogle Scholar
  4. Bourn D, Carter SA, Mason S, Gareth D, Evans R, Strachan T (1994) Germline mutations in the neurofibromatosis type 2 tumour suppressor gene. Hum Mol Genet 3:813–816CrossRefPubMedGoogle Scholar
  5. 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 74:358–366CrossRefPubMedGoogle Scholar
  6. Castellanos E, Bielsa I, Carrato C, Rosas I, Solanes A, Hostalot C, Amilibia E, Prades J, Roca-Ribas F, Lázaro C, Blanco I, Serra E, NF2 Multidisciplinary Clinics HUGTiP-ICO-IMPPC (2015) Segmental neurofibromatosis type 2: discriminating two hit from four hit in a patient presenting multiple schwannomas confined to one limb. BMC Med Genom 8:2CrossRefGoogle Scholar
  7. Desmet FO, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C (2009) Human splicing finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 37:e67CrossRefPubMedPubMedCentralGoogle Scholar
  8. 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 62:361–366CrossRefPubMedPubMedCentralGoogle Scholar
  9. Evans DG, Wallace AJ, Wu CL, Trueman L, Ramsden RT, Strachan T (1998a) Somatic mosaicism: a common cause of classic disease in tumor-prone syndromes? Lessons from type 2 neurofibromatosis. Am J Hum Genet 63:727–736PubMedPubMedCentralGoogle Scholar
  10. Evans DG, Trueman L, Wallace A, Collins S, Strachan T (1998b) Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations. J Med Genet 35:450–455CrossRefPubMedPubMedCentralGoogle Scholar
  11. Evans DG, Ramsden RT, Shenton A, Gokhale C, Bowers NL, Huson SM, Pichert G, Wallace A (2007) Mosaicism in neurofibromatosis type 2: an update of risk based on uni/bilaterality of vestibular schwannoma at presentation and sensitive mutation analysis including multiple ligation-dependent probe amplification. J Med Genet 44:424–428CrossRefPubMedPubMedCentralGoogle Scholar
  12. Gripp KW, Baker L, Kandula V, Piatt J, Walter A, Chen Z, Messiaen L (2017) Constitutional LZTR1 mutation presenting with a unilateral vestibular schwannoma in a teenager. Clin Genet 92:540–543CrossRefPubMedGoogle Scholar
  13. 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 45:332–339CrossRefPubMedGoogle Scholar
  14. Hadfield KD, Smith MJ, Urquhart JE, Wallace AJ, Bowers NL, King AT, Rutherford SA, Trump D, Newman WG, Evans DG (2010) Rates of loss of heterozygosity and mitotic recombination in NF2 schwannomas, sporadic vestibular schwannomas and schwannomatosis schwannomas. Oncogene 29:6216–6221CrossRefPubMedGoogle Scholar
  15. Halliday D, Emmanouil B, Pretorius P, MacKeith S, Painter S, Tomkins H, Evans DG, Parry A (2017) Genetic severity score predicts clinical phenotype in NF2. J Med Genet 54:657–664CrossRefPubMedPubMedCentralGoogle Scholar
  16. 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 80:805–810CrossRefPubMedPubMedCentralGoogle Scholar
  17. Hutter S, Piro RM, Reuss DE, Hovestadt V, Sahm F, Farschtschi S, Kehrer-Sawatzki H, Wolf S, Lichter P, von Deimling A, Schuhmann MU, Pfister SM, Jones DT, Mautner VF (2014) Whole exome sequencing reveals that the majority of schwannomatosis cases remain unexplained after excluding SMARCB1 and LZTR1 germline variants. Acta Neuropathol 128:449–452CrossRefPubMedGoogle Scholar
  18. Irving RM, Moffat DA, Hardy DG, Barton DE, Xuereb JH, Maher ER (1994) Somatic NF2 gene mutations in familial and non-familial vestibular schwannoma. Hum Mol Genet 3:347–350CrossRefPubMedGoogle Scholar
  19. 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 61:1293–1302CrossRefPubMedPubMedCentralGoogle Scholar
  20. Johnston JJ, van der Smagt JJ, Rosenfeld JA, Pagnamenta AT, Alswaid A, Baker EH, Blair E, Borck G, Brinkmann J, Craigen W, Dung VC, Emrick L, Everman DB, van Gassen KL, Gulsuner S, Harr MH, Jain M, Kuechler A, Leppig KA, McDonald-McGinn DM, Can NTB, Peleg A, Roeder ER, Rogers RC, Sagi-Dain L, Sapp JC, Schäffer AA, Schanze D, Stewart H, Taylor JC, Verbeek NE, Walkiewicz MA, Zackai EH, Zweier C; Members of the Undiagnosed Diseases Network, Zenker M, Lee B, Biesecker LG (2018) Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants. Genet Med.  https://doi.org/10.1038/gim.2017.249 (Epub ahead of print)Google Scholar
  21. Jordan JT, Smith MJ, Walker JA, Erdin S, Talkowski ME, Merker VL, Ramesh V, Cai W, Harris GJ, Bredella MA, Seijo M, Suuberg A, Gusella JF, Plotkin SR (2018) Pain correlates with germline mutation in schwannomatosis. Medicine (Baltimore) 97:e9717CrossRefGoogle Scholar
  22. Kehrer-Sawatzki H, Farschtschi S, Mautner VF, Cooper DN (2017) The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis. Hum Genet 136:129–148CrossRefPubMedGoogle Scholar
  23. Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46:310-315CrossRefPubMedCentralGoogle Scholar
  24. Kluwe L, Mautner VF (1998) Mosaicism in sporadic neurofibromatosis 2 patients. Hum Mol Genet 7:2051–2055CrossRefPubMedGoogle Scholar
  25. Kluwe L, Bayer S, Baser ME, Hazim W, Haase W, Fünsterer C, Mautner VF (1996) Identification of NF2 germ-line mutations and comparison with neurofibromatosis 2 phenotypes. Hum Genet 98:534–548CrossRefPubMedGoogle Scholar
  26. Kluwe L, Mautner V, Heinrich B, Dezube R, Jacoby LB, Friedrich RE, MacCollin M (2003) Molecular study of frequency of mosaicism in neurofibromatosis 2 patients with bilateral vestibular schwannomas. J Med Genet 40:109–114CrossRefPubMedPubMedCentralGoogle Scholar
  27. Lee JD, Kwon TJ, Kim UK, Lee WS (2012) Genetic and epigenetic alterations of the NF2 gene in sporadic vestibular schwannomas. PLoS One 7:e30418CrossRefPubMedPubMedCentralGoogle Scholar
  28. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O’Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper DN, Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki MI, Moonshine AL, Natarajan P, Orozco L, Peloso GM, Poplin R, Rivas MA, Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K, Stenson PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna MT, Weisburd B, Won HH, Yu D, Altshuler DM, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez JC, Gabriel SB, Getz G, Glatt SJ, Hultman CM, Kathiresan S, Laakso M, McCarroll S, McCarthy MI, McGovern D, McPherson R, Neale BM, Palotie A, Purcell SM, Saleheen D, Scharf JM, Sklar P, Sullivan PF, Tuomilehto J, Tsuang MT, Watkins HC, Wilson JG, Daly MJ, MacArthur DG (2016) Analysis of protein-coding genetic variation in 60,706 humans. Exome Aggreg Consort Nat 536:285–291Google Scholar
  29. MacCollin M, Ramesh V, Jacoby LB, Louis DN, Rubio MP, Pulaski K, Trofatter JA, Short MP, Bove C, Eldridge R et al (1994) Mutational analysis of patients with neurofibromatosis 2. Am J Hum Genet 55:314–320PubMedPubMedCentralGoogle Scholar
  30. 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 60:1968–1974CrossRefPubMedGoogle Scholar
  31. Mehta GU, Feldman MJ, Wang H, Ding D, Chittiboina P (2016) Unilateral vestibular schwannoma in a patient with schwannomatosis in the absence of LZTR1 mutation. J Neurosurg 5:1–3Google Scholar
  32. Merker VL, Esparza S, Smith MJ, Stemmer-Rachamimov A, Plotkin SR (2012) Clinical features of schwannomatosis: a retrospective analysis of 87 patients. Oncologist 17:1317–1322CrossRefPubMedPubMedCentralGoogle Scholar
  33. Mohyuddin A, Neary WJ, Wallace A, Wu CL, Purcell S, Reid H, Ramsden RT, Read A, Black G, Evans DG (2002) Molecular genetic analysis of the NF2 gene in young patients with unilateral vestibular schwannomas. J Med Genet 39:315–322CrossRefPubMedPubMedCentralGoogle Scholar
  34. Moyhuddin A, Baser ME, Watson C, Purcell S, Ramsden RT, Heiberg A, Wallace AJ, Evans DG (2003) Somatic mosaicism in neurofibromatosis 2: prevalence and risk of disease transmission to offspring. J Med Genet 40:459–463CrossRefPubMedPubMedCentralGoogle Scholar
  35. Murray AJ, Hughes TA, Neal JW, Howard E, Evans DG, Harper PS (2006) A case of multiple cutaneous schwannomas; schwannomatosis or neurofibromatosis type 2? J Neurol Neurosurg Psychiatry 77:269–271CrossRefPubMedPubMedCentralGoogle Scholar
  36. Ng PC, Henikoff S (2003) SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 31:3812–3814CrossRefPubMedPubMedCentralGoogle Scholar
  37. Paganini I, Mancini I, Baroncelli M, Arena G, Gensini F, Papi L, Sestini R (2014) Application of COLD-PCR for improved detection of NF2 mosaic mutations. J Mol Diagn 16:393–399CrossRefPubMedGoogle Scholar
  38. Paganini I, Chang VY, Capone GL, Vitte J, Benelli M, Barbetti L, Sestini R, Trevisson E, Hulsebos TJ, Giovannini M, Nelson SF, Papi L (2015) Expanding the mutational spectrum of LZTR1 in schwannomatosis. Eur J Hum Genet 23:963–968CrossRefPubMedGoogle Scholar
  39. Parry DM, MacCollin MM, Kaiser-Kupfer MI, Pulaski K, Nicholson HS, Bolesta M, Eldridge R, Gusella JF (1996) Germ-line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities. Am J Hum Genet 59:529–539PubMedPubMedCentralGoogle Scholar
  40. Piotrowski A, Xie J, Liu YF, Poplawski AB, Gomes AR, Madanecki P, Fu C, Crowley MR, Crossman DK, Armstrong L, Babovic-Vuksanovic D, Bergner A, Blakeley JO, Blumenthal AL, Daniels MS, Feit H, Gardner K, Hurst S, Kobelka C, Lee C, Nagy R, Rauen KA, Slopis JM, Suwannarat P, Westman JA, Zanko A, Korf BR, Messiaen LM (2014) Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. Nat Genet 46:182–187CrossRefPubMedGoogle Scholar
  41. Plotkin SR, Blakeley JO, Evans DG, Hanemann CO, Hulsebos TJ, Hunter-Schaedle K, Kalpana GV, Korf B, Messiaen L, Papi L, Ratner N, Sherman LS, Smith MJ, Stemmer-Rachamimov AO, Vitte J, Giovannini M (2013) Update from the 2011 international schwannomatosis workshop: from genetics to diagnostic criteria. Am J Med Genet Part A 161A:405–416CrossRefPubMedGoogle Scholar
  42. Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C, Hoang-Xuan K, Demczuk S, Desmaze C, Plougastel B et al (1993) Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature 363:515–521CrossRefPubMedGoogle Scholar
  43. Rousseau G, Noguchi T, Bourdon V, Sobol H, Olschwang S (2011) SMARCB1/INI1 germline mutations contribute to 10% of sporadic schwannomatosis. BMC Neurol 11:9CrossRefPubMedPubMedCentralGoogle Scholar
  44. Schwarz JM, Cooper DN, Schuelke M, Seelow D (2014) MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 11:361–362CrossRefPubMedGoogle Scholar
  45. 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 29:227–231CrossRefPubMedGoogle Scholar
  46. Smith MJ, Higgs JE, Bowers NL, Halliday D, Paterson J, Gillespie J, Huson SM, Freeman SR, Lloyd S, Rutherford SA, King AT, Wallace AJ, Ramsden RT, Evans DG (2011) Cranial meningiomas in 411 neurofibromatosis type 2 (NF2) patients with proven gene mutations: clear positional effect of mutations, but absence of female severity effect on age at onset. J Med Genet 48:261–265CrossRefPubMedGoogle Scholar
  47. Smith MJ, Wallace AJ, Bowers NL, Rustad CF, Woods CG, Leschziner GD, Ferner RE, Evans DG (2012) Frequency of SMARCB1 mutations in familial and sporadic schwannomatosis. Neurogenetics 13:141–145CrossRefPubMedGoogle Scholar
  48. Smith MJ, Isidor B, Beetz C, Williams SG, Bhaskar SS, Richer W, O’Sullivan J, Anderson B, Daly SB, Urquhart JE, Fryer A, Rustad CF, Mills SJ, Samii A, du Plessis D, Halliday D, Barbarot S, Bourdeaut F, Newman WG, Evans DG (2015) Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis. Neurology 84:141–147CrossRefPubMedPubMedCentralGoogle Scholar
  49. Smith MJ, Bowers NL, Bulman M, Gokhale C, Wallace AJ, King AT, Lloyd SK, Rutherford SA, Hammerbeck-Ward CL, Freeman SR, Evans DG (2017) Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1-related schwannomatosis. Neurology 88:87–92CrossRefPubMedPubMedCentralGoogle Scholar
  50. Spyra M, Otto B, Schön G, Kehrer-Sawatzki H, Mautner VF (2015) Determination of the mutant allele frequency in patients with neurofibromatosis type 2 and somatic mosaicism by means of deep sequencing. Genes Chromosom Cancer 54:482–488CrossRefPubMedGoogle Scholar
  51. Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, Parry DM, Eldridge R, Kley N, Menon AG, Pulaski K et al (1993) A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 75:826CrossRefPubMedGoogle Scholar
  52. Yamamoto GL, Aguena M, Gos M, Hung C, Pilch J, Fahiminiya S, Abramowicz A, Cristian I, Buscarilli M, Naslavsky MS, Malaquias AC, Zatz M, Bodamer O, Majewski J, Jorge AA, Pereira AC, Kim CA, Passos-Bueno MR, Bertola DR (2015) Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J Med Genet 52:413–421CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Hildegard Kehrer-Sawatzki
    • 1
  • Lan Kluwe
    • 2
  • Reinhard E. Friedrich
    • 3
  • Anna Summerer
    • 1
  • Eleonora Schäfer
    • 1
  • Ute Wahlländer
    • 4
  • Cordula Matthies
    • 5
  • Isabel Gugel
    • 6
  • Said Farschtschi
    • 2
  • Christian Hagel
    • 7
  • David N. Cooper
    • 8
  • Victor-Felix Mautner
    • 2
  1. 1.Institute of Human GeneticsUniversity of UlmUlmGermany
  2. 2.Department of NeurologyUniversity Hospital Hamburg EppendorfHamburgGermany
  3. 3.Department of Oral and Maxillofacial SurgeryUniversity Hospital Hamburg EppendorfHamburgGermany
  4. 4.KBO- Children Clinical Center MunichMunichGermany
  5. 5.Department of NeurosurgeryUniversity of WürzburgWürzburgGermany
  6. 6.Department of NeurosurgeryUniversity Hospital TübingenTübingenGermany
  7. 7.Department of NeuropathologyUniversity Hospital Hamburg EppendorfHamburgGermany
  8. 8.Institute of Medical Genetics, School of MedicineCardiff UniversityCardiffUK

Personalised recommendations