Skip to main content

Advertisement

SpringerLink
Log in

Familial spinal neurofibromatosis due to a multiexonic NF1 gene deletion

  • SHORT COMMUNICATION
  • Published:
neurogenetics Aims and scope Submit manuscript

Abstract

We report the detailed clinical presentation and molecular features of a spinal neurofibromatosis familial case where a 40-year-old woman, presenting with multiple bilateral spinal neurofibromas and no other clinical feature of neurofibromatosis type 1 (NF1), inherited a paternal large multiexonic deletion (c.5944−?_7126+?del) which resulted in NF1 gene haploinsufficiency at the RNA level. In the clinically unaffected 73-year-old father, spinal cord MRI disclosed bilateral and symmetrical hypertrophy of spinal lumbosacral roots. Our study widens the phenotypic and mutational spectrum of NF1 and illustrates the difficulties of counseling patients with border-line or atypical presentation of this disorder.

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

References

  1. Danglot G, Regnier V, Fauvet D, Vassal G, Kujas M, Bernheim A (1995) Neurofibromatosis 1 (NF1) mRNAs expressed in the central nervous system are differentially spliced in the 5′ part of the gene. Hum Mol Genet 4(5):915–920

    Article  PubMed  CAS  Google Scholar 

  2. Li Y, O’Connell P, Breidenbach HH, Cawthon R, Stevens J, Xu G, Neil S, Robertson M, White R, Viskochil D (1995) Genomic organization of the neurofibromatosis 1 gene (NF1). Genomics 25(1):9–18

    Article  PubMed  CAS  Google Scholar 

  3. Ballester R, Marchuk D, Boguski M, Saulino A, Letcher R, Wigler M, Collins F (1990) The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63(4):851–859

    Article  PubMed  CAS  Google Scholar 

  4. Martin GA, Viskochil D, Bollag G, McCabe PC, Crosier WJ, Haubruck H, Conroy L, Clark R, O’Connell P, Cawthon RM et al (1990) The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 63(4):843–849

    Article  PubMed  CAS  Google Scholar 

  5. Xu GF, Lin B, Tanaka K, Dunn D, Wood D, Gesteland R, White R, Weiss R, Tamanoi F (1990) The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell 63(4):835–841

    Article  PubMed  CAS  Google Scholar 

  6. Xu GF, O’Connell P, Viskochil D, Cawthon R, Robertson M, Culver M, Dunn D, Stevens J, Gesteland R, White R et al (1990) The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62(3):599–608

    Article  PubMed  CAS  Google Scholar 

  7. Melean G, Sestini R, Ammannati F, Papi L (2004) Genetic insights into familial tumors of the nervous system. Am J Med Genet C Semin Med Genet 129C(1):74–84

    Article  PubMed  Google Scholar 

  8. Huson SMHR (1994) The neurofibromatoses: pathogenetic and clinical overview. Chapman and Hall, London

    Google Scholar 

  9. Egelhoff JC, Bates DJ, Ross JS, Rothner AD, Cohen BH (1992) Spinal MR findings in neurofibromatosis types 1 and 2. AJNR Am J Neuroradiol 13(4):1071–1077

    PubMed  CAS  Google Scholar 

  10. Poyhonen M, Leisti EL, Kytola S, Leisti J (1997) Hereditary spinal neurofibromatosis: a rare form of NF1? J Med Genet 34(3):184–187

    Article  PubMed  CAS  Google Scholar 

  11. Thakkar SD, Feigen U, Mautner VF (1999) Spinal tumours in neurofibromatosis type 1: an MRI study of frequency, multiplicity and variety. Neuroradiology 41(9):625–629

    Article  PubMed  CAS  Google Scholar 

  12. Carey JC, Viskochil DH (1999) Neurofibromatosis type 1: a model condition for the study of the molecular basis of variable expressivity in human disorders. Am J Med Genet 89(1):7–13

    Article  PubMed  CAS  Google Scholar 

  13. Riccardi VM (1982) Neurofibromatosis: clinical heterogeneity. Curr Probl Cancer 7(2):1–34

    Article  PubMed  CAS  Google Scholar 

  14. Messiaen L, Riccardi V, Peltonen J, Maertens O, Callens T, Karvonen SL, Leisti EL, Koivunen J, Vandenbroucke I, Stephens K, Poyhonen M (2003) Independent NF1 mutations in two large families with spinal neurofibromatosis. J Med Genet 40(2):122–126

    Article  PubMed  CAS  Google Scholar 

  15. Pascual-Castroviejo I, Pascual-Pascual SI, Viano J, Martinez V (2000) Generalized nerve sheath tumors in neurofibromatosis type 1 (NF1). A case report. Neuropediatrics 31(4):211–213

    Article  PubMed  CAS  Google Scholar 

  16. Pulst SM, Riccardi VM, Fain P, Korenberg JR (1991) Familial spinal neurofibromatosis: clinical and DNA linkage analysis. Neurology 41(12):1923–1927

    PubMed  CAS  Google Scholar 

  17. Ars E, Kruyer H, Gaona A, Casquero P, Rosell J, Volpini V, Serra E, Lazaro C, Estivill X (1998) A clinical variant of neurofibromatosis type 1: familial spinal neurofibromatosis with a frameshift mutation in the NF1 gene. Am J Hum Genet 62(4):834–841

    Article  PubMed  CAS  Google Scholar 

  18. Bacci C, Sestini R, Ammannati F, Bianchini E, Palladino T, Carella M, Melchionda S, Zelante L, Papi L (2010) Multiple spinal ganglioneuromas in a patient harboring a pathogenic NF1 mutation. Clin Genet 77(3):293–297

    Article  PubMed  CAS  Google Scholar 

  19. Kaufmann D, Muller R, Bartelt B, Wolf M, Kunzi-Rapp K, Hanemann CO, Fahsold R, Hein C, Vogel W, Assum G (2001) Spinal neurofibromatosis without cafe-au-lait macules in two families with null mutations of the NF1 gene. Am J Hum Genet 69(6):1395–1400

    Article  PubMed  CAS  Google Scholar 

  20. Kluwe L, Tatagiba M, Funsterer C, Mautner VF (2003) NF1 mutations and clinical spectrum in patients with spinal neurofibromas. J Med Genet 40(5):368–371

    Article  PubMed  CAS  Google Scholar 

  21. Pascual-Castroviejo I, Pascual-Pascual SI, Velazquez-Fragua R, Botella P, Viano J (2007) Familial spinal neurofibromatosis. Neuropediatrics 38(2):105–108

    Article  PubMed  CAS  Google Scholar 

  22. Upadhyaya M, Spurlock G, Kluwe L, Chuzhanova N, Bennett E, Thomas N, Guha A, Mautner V (2009) The spectrum of somatic and germline NF1 mutations in NF1 patients with spinal neurofibromas. Neurogenetics 10(3):251–263

    Article  PubMed  CAS  Google Scholar 

  23. Wimmer K, Muhlbauer M, Eckart M, Callens T, Rehder H, Birkner T, Leroy JG, Fonatsch C, Messiaen L (2002) A patient severely affected by spinal neurofibromas carries a recurrent splice site mutation in the NF1 gene. Eur J Hum Genet 10(5):334–338

    Article  PubMed  Google Scholar 

  24. Messiaen C, Williams, Babovic-Vuksanovic, Huson, Legius, Mac Gardner, Pascual-Castroviejo, Plotkin, Schaefer, Wilson, Korf (2007) Genotype-phenotype correlations in spinal NF. Am Soc Hum Genet. San Diego, California, Utah

  25. Willems AJ, Dawson SJ, Samaratunga H, De Luca A, Antill YC, Hopper JL, Thorne HJ (2008) Loss of heterozygosity at the BRCA2 locus detected by multiplex ligation-dependent probe amplification is common in prostate cancers from men with a germline BRCA2 mutation. Clin Cancer Res 14(10):2953–2961

    Article  PubMed  CAS  Google Scholar 

  26. Bottillo I, Ahlquist T, Brekke H, Danielsen SA, van den Berg E, Mertens F, Lothe RA, Dallapiccola B (2009) Germline and somatic NF1 mutations in sporadic and NF1-associated malignant peripheral nerve sheath tumours. J Pathol 217(5):693–701

    Article  PubMed  CAS  Google Scholar 

  27. Cawthon RM, Weiss R, Xu GF, Viskochil D, Culver M, Stevens J, Robertson M, Dunn D, Gesteland R, O’Connell P et al (1990) A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell 62(1):193–201

    Article  PubMed  CAS  Google Scholar 

  28. De Luca A, Bottillo I, Dasdia MC, Morella A, Lanari V, Bernardini L, Divona L, Giustini S, Sinibaldi L, Novelli A, Torrente I, Schirinzi A, Dallapiccola B (2007) Deletions of NF1 gene and exons detected by multiplex ligation-dependent probe amplification. J Med Genet 44(12):800–808

    Article  PubMed  Google Scholar 

  29. De Luca A, Bottillo I, Sarkozy A, Carta C, Neri C, Bellacchio E, Schirinzi A, Conti E, Zampino G, Battaglia A, Majore S, Rinaldi MM, Carella M, Marino B, Pizzuti A, Digilio MC, Tartaglia M, Dallapiccola B (2005) NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome. Am J Hum Genet 77(6):1092–1101

    Article  PubMed  Google Scholar 

  30. Mautner VF, Asuagbor FA, Dombi E, Funsterer C, Kluwe L, Wenzel R, Widemann BC, Friedman JM (2008) Assessment of benign tumor burden by whole-body MRI in patients with neurofibromatosis 1. Neuro Oncol 10(4):593–598

    Article  PubMed  Google Scholar 

  31. Tonsgard JH, Kwak SM, Short MP, Dachman AH (1998) CT imaging in adults with neurofibromatosis-1: frequent asymptomatic plexiform lesions. Neurology 50(6):1755–1760

    PubMed  CAS  Google Scholar 

  32. Fahsold R, Hoffmeyer S, Mischung C, Gille C, Ehlers C, Kucukceylan N, Abdel-Nour M, Gewies A, Peters H, Kaufmann D, Buske A, Tinschert S, Nurnberg P (2000) Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet 66(3):790–818

    Article  PubMed  CAS  Google Scholar 

  33. Pros E, Larriba S, Lopez E, Ravella A, Gili ML, Kruyer H, Valls J, Serra E, Lazaro C (2006) NF1 mutation rather than individual genetic variability is the main determinant of the NF1-transcriptional profile of mutations affecting splicing. Hum Mutat 27(11):1104–1114

    Article  PubMed  CAS  Google Scholar 

  34. Colman SD, Williams CA, Wallace MR (1995) Benign neurofibromas in type 1 neurofibromatosis (NF1) show somatic deletions of the NF1 gene. Nat Genet 11(1):90–92

    Article  PubMed  CAS  Google Scholar 

  35. Upadhyaya M, Han S, Consoli C, Majounie E, Horan M, Thomas NS, Potts C, Griffiths S, Ruggieri M, von Deimling A, Cooper DN (2004) Characterization of the somatic mutational spectrum of the neurofibromatosis type 1 (NF1) gene in neurofibromatosis patients with benign and malignant tumors. Hum Mutat 23(2):134–146

    Article  PubMed  CAS  Google Scholar 

  36. Thomas PK, King RH, Chiang TR, Scaravilli F, Sharma AK, Downie AW (1990) Neurofibromatous neuropathy. Muscle Nerve 13(2):93–101

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Italian Ministry of Health, Ricerca Corrente 2010. All authors have read and approved the manuscript, and they have disclosed any financial conflict of interest that may be used for influencing the results.

Author information

Authors and Affiliations

  1. Department of Experimental Medicine, “Sapienza” University, Rome, Italy

    Antonio Pizzuti

  2. IRCCS Casa Sollievo della Sofferenza, Mendel Laboratory, San Giovanni Rotondo, Italy

    Irene Bottillo, Francesca Inzana, Valentina Lanari, Isabella Torrente & Alessandro De Luca

  3. Department of Neurology and Psychiatry, “Sapienza” University, Rome, Italy

    Francesca Buttarelli

  4. Department of Neurological Sciences, University of Rome “Sapienza”, Rome, Italy

    Anna Teresa Giallonardo

  5. Bambino Gesù Children Hospital, IRCCS, Rome, Italy

    Bruno Dallapiccola

  6. Ospedale Bambino Gesù, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy

    Bruno Dallapiccola

Authors
  1. Antonio Pizzuti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Irene Bottillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesca Inzana
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Valentina Lanari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Francesca Buttarelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Isabella Torrente
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anna Teresa Giallonardo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alessandro De Luca
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bruno Dallapiccola
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bruno Dallapiccola.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pizzuti, A., Bottillo, I., Inzana, F. et al. Familial spinal neurofibromatosis due to a multiexonic NF1 gene deletion. Neurogenetics 12, 233–240 (2011). https://doi.org/10.1007/s10048-011-0278-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10048-011-0278-5

Keywords

Search

Navigation