Update on the management of familial central nervous system tumor syndromes



Hereditary central nervous tumor syndromes are a varied group of conditions that include neurofibromatosis type 1 and 2, tuberous sclerosis, Von Hippel-Lindau disease, and Cowden, Turcot, and Gorlin syndromes. The responsible genes have been identified in most of these disorders. These genes typically act as tumor suppressor genes, maintain normal cellular function and homeostasis, and regulate cell growth and differentiation. Familial central nervous system tumors are mostly inherited as autosomal dominant traits and involve germline mutations. Neoplastic development occurs when a somatic mutation inactivates the second allele. These patients also present unique challenges for their management. This review highlights the clinical manifestations, molecular genetics, pathophysiology, and current treatment options of these disorders with a focus on neuro-oncologic manifestations of the diseases.

References and Recommended Reading

  1. 1.
    Gutmann DH: The neurofibromatoses: when less is more. Hum Mol Genet 2001, 10:747–755.PubMedCrossRefGoogle Scholar
  2. 2.
    Friedman JM: Epidemiology of neurofibromatosis type 1. Am J Med Genet 1999, 89:1–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol 1988, 45:575–578.Google Scholar
  4. 4.
    Quigg M, Rust RS, Miller JQ: Clinical findings of the phakomatoses: neurofibromatosis. Neurology 2006, 66:E23–24.PubMedCrossRefGoogle Scholar
  5. 5.
    Hofman KJ, Harris EL, Bryan RN, Denckla MB: Neurofibromatosis type 1: the cognitive phenotype. J Pediatr 1994, 124:S1–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Rosser TL, Vezina G, Packer RJ: Cerebrovascular abnormalities in a population of children with neurofibromatosis type 1. Neurology 2005, 64:553–555.PubMedGoogle Scholar
  7. 7.
    Rawal A, Yin Q, Roebuck M, et al.: Atypical and malignant peripheral nerve-sheath tumors of the brachial plexus: report of three cases and review of the literature. Microsurgery 2006, 26:80–86.PubMedCrossRefGoogle Scholar
  8. 8.
    Bausch B, Borozdin W, Neumann HP: Clinical and genetic characteristics of patients with neurofibromatosis type 1 and pheochromocytoma. N Engl J Med 2006, 354:2729–2731.PubMedCrossRefGoogle Scholar
  9. 9.
    Jahraus CD, Tarbell NJ: Optic pathway gliomas. Pediatr Blood Cancer 2006, 46:586–596.PubMedCrossRefGoogle Scholar
  10. 10.
    Ogura, T, Adachi J, Nishikawa R, et al.: Synchronous optic and pineal pilocytic astrocytomas in a paediatric patient with neurofibromatosis type 1. Pediatr Neurosurg 2004, 40:301–305.PubMedCrossRefGoogle Scholar
  11. 11.
    Deliganis AV, Geyer JR, Berger MS: Prognostic significance of type 1 neurofibromatosis (von Recklinghausen Disease) in childhood optic glioma. Neurosurgery 1996, 38:1114–1148; discussion 1118–1119.PubMedCrossRefGoogle Scholar
  12. 12.
    King A, Listernick R, Charrow J, et al.: Optic pathway gliomas in neurofibromatosis type 1: the effect of presenting symptoms on outcome. Am J Med Genet 2003, 122:95–99.CrossRefGoogle Scholar
  13. 13.
    Opocher E, Kremer LC, Da Dalt L, et al.: Prognostic factors for progression of childhood optic pathway glioma: a systematic review. Eur J Cancer 2006, 42:1807–1816.PubMedCrossRefGoogle Scholar
  14. 14.
    Listernick R, Louis DN, Packer RJ, Gutmann DH: Optic pathway gliomas in children with neurofibromatosis 1: consensus statement from the NF1 Optic Pathway Glioma Task Force. Ann Neurol 1997, 41:143–149.PubMedCrossRefGoogle Scholar
  15. 15.
    Listernick R, Ferner RE, Piersall L, et al.: Late-onset optic pathway tumors in children with neurofibromatosis 1. Neurology 2004, 63:1944–1946.PubMedGoogle Scholar
  16. 16.
    Astrup J: Natural history and clinical management of optic pathway glioma. Br J Neurosurg 2003, 17:327–335.PubMedCrossRefGoogle Scholar
  17. 17.
    Walker D: Recent advances in optic nerve glioma with a focus on the young patient. Curr Opin Neurol 2003, 16:657–664.PubMedCrossRefGoogle Scholar
  18. 18.
    Widemann BC, Salzer WL, Arceci RJ, et al.: Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitor tipifarnib in children with refractory solid tumors or neurofibromatosis type I and plexiform neurofibromas. J Clin Oncol 2006, 24:507–516.PubMedCrossRefGoogle Scholar
  19. 19.
    Perilongo G, Moras P, Carollo C, et al.: Spontaneous partial regression of low-grade glioma in children with neurofibromatosis-1: a real possibility. J Child Neurol 1999, 14:352–356.PubMedGoogle Scholar
  20. 20.
    Broniscer A, Gajjar A, Bhargava R, et al.: Brain stem involvement in children with neurofibromatosis type 1: role of magnetic resonance imaging and spectroscopy in the distinction from diffuse pontine glioma. Neurosurgery 1997, 40:331–337; discussion 337–338.PubMedCrossRefGoogle Scholar
  21. 21.
    Packer RJ, Ater J, Allen J, et al.: Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg 1997, 86:747–754.PubMedCrossRefGoogle Scholar
  22. 22.
    Grill J, Couanet D, Cappelli C, et al.: Radiation-induced cerebral vasculopathy in children with neurofibromatosis and optic pathway glioma. Ann Neurol 1999, 45:393–396.PubMedCrossRefGoogle Scholar
  23. 23.
    Hamaratoglu F, Willecke M, Kango-Singh M, et al.: The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat Cell Biol 2005, 27–36.Google Scholar
  24. 24.
    Hirokawa, Y, Tikoo A, Huynh J, et al.: A clue to the therapy of neurofibromatosis type 2: NF2/merlin is a PAK1 inhibitor. Cancer J 2004, 10:20–26.PubMedGoogle Scholar
  25. 25.
    Baser ME, Friedman JM, Aeschliman D, et al.: Predictors of the risk of mortality in neurofibromatosis 2. Am J Hum Genet 2002, 71:715–723.PubMedCrossRefGoogle Scholar
  26. 26.
    Evans DG, Huson SM, Donnai D, et al.: A clinical study of type 2 neurofibromatosis. Q J Med 1992, 84:603–618.PubMedGoogle Scholar
  27. 27.
    Parry DM, Eldridge R, Kaiser-Kupfer MI, et al.: Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity. Am J Med Genet 1994, 52:450–461.PubMedCrossRefGoogle Scholar
  28. 28.
    Evans DG, Baser ME, O’Reilly B, et al.: Management of the patient and family with neurofibromatosis 2: a consensus conference statement. Br J Neurosurg 2005, 19:5–12.PubMedCrossRefGoogle Scholar
  29. 29.
    Brennan JW, Rowed DW, Nedzelski JM, Chen JM: Cerebrospinal fluid leak after acoustic neuroma surgery: influence of tumor size and surgical approach on incidence and response to treatment. J Neurosurg 2001, 94:217–223.PubMedGoogle Scholar
  30. 30.
    Evans DG, Birch JM, Ramsden RT, et al.: Malignant transformation and new primary tumours after therapeutic radiation for benign disease: substantial risks in certain tumour prone syndromes. J Med Genet 2006, 43:289–294.PubMedCrossRefGoogle Scholar
  31. 31.
    Ho SY, Kveton JF: Rapid growth of acoustic neuromas after stereotactic radiotherapy in type 2 neurofibromatosis. Ear Nose Throat J 2002, 81:831–833.PubMedGoogle Scholar
  32. 32.
    Lenarz T, Lim HH, Reuter G, et al.: The auditory midbrain implant: a new auditory prosthesis for neural deafnessconcept and device description. Otol Neurotol 2006, 27:838–843.PubMedCrossRefGoogle Scholar
  33. 33.
    Mayfrank L, Mohadjer M, Wullich B.: Intracranial calcified deposits in neurofibromatosis type 2. A CT study of 11 cases. Neuroradiology 1990, 32:33–37.PubMedCrossRefGoogle Scholar
  34. 34.
    Crino PB, Nathanson KL, Henske EP: The tuberous sclerosis complex. N Engl J Med 2006, 355:1345–1356.PubMedCrossRefGoogle Scholar
  35. 35.
    Roach ES, Gomez MR, Northrup H: Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 1998, 13:624–628.PubMedGoogle Scholar
  36. 36.
    Thiele EA: Managing epilepsy in tuberous sclerosis complex. J Child Neurol 2004, 19:680–686.PubMedGoogle Scholar
  37. 37.
    Curatolo P, Bombardieri R, Verdecchia M, Seri S: Intractable seizures in tuberous sclerosis complex: from molecular pathogenesis to the rationale for treatment. J Child Neurol 2005, 20:318–325.PubMedCrossRefGoogle Scholar
  38. 38.
    Goh S, Butler W, Thiele EA: Subependymal giant cell tumors in tuberous sclerosis complex. Neurology 2004, 63:1457–1461.PubMedGoogle Scholar
  39. 39.
    Sutton LN: Current management of low-grade astrocytomas of childhood. Pediatr Neurosci 1987, 13:98–107.PubMedCrossRefGoogle Scholar
  40. 40.
    Franz DN, Leonard J, Tudor C, et al.: Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol 2006, 59:490–498.PubMedCrossRefGoogle Scholar
  41. 41.
    Bader RS, Chitayat D, Kelly E, et al.: Fetal rhabdomyoma: prenatal diagnosis, clinical outcome, and incidence of associated tuberous sclerosis complex. J Pediatr 2003, 143:620–624.PubMedCrossRefGoogle Scholar
  42. 42.
    Seizinger BR, Rouleau GA, Ozelius LJ, et al.: Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature 1988, 332:268–269.PubMedCrossRefGoogle Scholar
  43. 43.
    Shuin T, Yamasaki I, Tamura K, et al.: Von Hippel-Lindau disease: molecular pathological basis, clinical criteria, genetic testing, clinical features of tumors and treatment. Jpn J Clin Oncol 2006, 36:337–343.PubMedCrossRefGoogle Scholar
  44. 44.
    Linehan WM, Lerman MI, Zbar B: Identification of the von Hippel-Lindau (VHL) gene. Its role in renal cancer. JAMA 1995, 273:564–570.PubMedCrossRefGoogle Scholar
  45. 45.
    Glasker S: Central nervous system manifestations in VHL: genetics, pathology and clinical phenotypic features. Fam Cancer 2005, 4:37–42.PubMedCrossRefGoogle Scholar
  46. 46.
    Richard S, Campello C, Taillandier L, et al.: Haemangioblastoma of the central nervous system in von Hippel-Lindau disease. French VHL Study Group. J Intern Med 1998, 243:547–553.PubMedCrossRefGoogle Scholar
  47. 47.
    Wanebo JE, Lonser RR, Glenn GM, Oldfield EH: The natural history of hemangioblastom as of the central nervous system in patients with von Hippel-Lindau disease. J Neurosurg 2003, 98:82–94.PubMedCrossRefGoogle Scholar
  48. 48.
    Dwarakanath S, Suri A, Sharma BS, Mehta VS: Intracranial hemangioblastomas: an institutional experience. Neurol India 2006, 54:276–278.PubMedCrossRefGoogle Scholar
  49. 49.
    Conway JE, Chou D, Clatterbuck RE, et al.: Hemangioblastomas of the central nervous system in von Hippel-Lindau syndrome and sporadic disease. Neurosurgery 2001, 48:55–62.PubMedCrossRefGoogle Scholar
  50. 50.
    Weil RJ, Lonser RR, DeVroom HL, et al.: Surgical management of brainstem hemangioblastomas in patients with von Hippel-Lindau disease. J Neurosurg 2003, 98:95–105.PubMedGoogle Scholar
  51. 51.
    Escudier B, Eisen T, Stadler WM, et al.: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007, 356:125–134.PubMedCrossRefGoogle Scholar
  52. 52.
    Motzer RJ, Bukowski RM: Targeted therapy for metastatic renal cell carcinoma. J Clin Oncol 2006, 24:5601–5608.PubMedCrossRefGoogle Scholar
  53. 53.
    Singh AD, Shields CL, Shields JA: von Hippel-Lindau disease. Surv Ophthalmol 2001, 46:117–142.PubMedCrossRefGoogle Scholar
  54. 54.
    Manski TJ, Heffner DK, Glenn GM, et al.: Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel-Lindau disease. JAMA 1997, 277:1461–1466.PubMedCrossRefGoogle Scholar
  55. 55.
    Kleihues, P, Schauble B, Zur Hausen A, et al.: Tumors associated with p53 germline mutations: a synopsis of 91 families. Am J Pathol 1997, 150:1–13.PubMedGoogle Scholar
  56. 56.
    Olivier M, Goldgar De, Sodha N, et al.: Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res 2003, 63:6643–6650.PubMedGoogle Scholar
  57. 57.
    Frebourg T, Abel A, Bonaiti-Pellie C, et al.: Li-Fraumeni syndrome: update, new data and guidelines for clinical management. Bull Cancer 2001, 88:581–587.PubMedGoogle Scholar
  58. 58.
    Taylor MD, Mainprize TG, Rutka JT: Molecular insight into medulloblastoma and central nervous system primitive neuroectodermal tumor biology from hereditary syndromes: a review. Neurosurgery 2000, 47:888–901.PubMedCrossRefGoogle Scholar
  59. 59.
    Gorlin RJ: Nevoid basal-cell carcinoma syndrome. Medicine (Baltimore) 1987, 66:98–113.Google Scholar
  60. 60.
    Vortmeyer AO, Stavrou T, Selby D, et al.: Deletion analysis of the adenomatous polyposis coli and PTCH gene loci in patients with sporadic and nevoid basal cell carcinoma syndrome-associated medulloblastoma. Cancer 1999, 85:2662–2667.PubMedCrossRefGoogle Scholar
  61. 61.
    Raffel C: Medulloblastoma: molecular genetics and animal models. Neoplasia 2004, 6:310–322.PubMedCrossRefGoogle Scholar
  62. 62.
    Albright AL, Wisoff JH, Zeltzer PM, et al.: Effects of medulloblastoma resections on outcome in children: a report from the Children’ Cancer Group. Neurosurgery 1996, 68:265–271.CrossRefGoogle Scholar
  63. 63.
    Hubbard JL, Scheithauer BW, Kispert DB, et al.: Adult cerebellar medulloblastomas: the pathological, radiographic, and clinical disease spectrum. J Neurosurg 1989, 70:536–544.PubMedGoogle Scholar
  64. 64.
    Packer RJ, Sutton LN, Elterman R, et al.: Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg 1994, 81:690–698.PubMedGoogle Scholar
  65. 65.
    Louis DN, von Deimling A: Hereditary tumor syndromes of the nervous system: overview and rare syndromes. Brain Pathol 1995, 5:145–151.PubMedGoogle Scholar
  66. 66.
    Hamilton SR, Liu B, Parsons RE, et al.: The molecular basis of Turcot’ syndrome. N Engl J Med 1995, 332:839–847.PubMedCrossRefGoogle Scholar
  67. 67.
    Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP: PTEN is essential for embryonic development and tumour suppression. Nat Genet 1998, 19:348–355.PubMedCrossRefGoogle Scholar
  68. 68.
    Backman S, Stambolic V, Mak T: PTEN function in mammalian cell size regulation. Curr Opin Neurobiol 2002, 12:516–522.PubMedCrossRefGoogle Scholar
  69. 69.
    Chow LM, Baker SJ: PTEN function in normal and neoplastic growth. Cancer Lett 2006, 241:184–196.PubMedCrossRefGoogle Scholar
  70. 70.
    Lyons CJ, Wilson CB, Horton JC: Association between meningioma and Cowden’ disease. Neurology 1993, 43:1436–1437.PubMedGoogle Scholar
  71. 71.
    Tuli S, Provias JP, Bernstein M: Lhermitte-Duclos disease: literature review and novel treatment strategy. Can J Neurol Sci 1997, 24:155–160.PubMedGoogle Scholar

Copyright information

© Current Medicine Group LLC 2007

Authors and Affiliations

  1. 1.Departments of Neurology and PediatricsMemorial Sloan-Kettering Cancer CenterNew YorkUSA

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