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Neurofibromatosis type 1 (NF1): Management and prognosis

Author
Bruce R Korf, MD, PhD
Section Editors
Marc C Patterson, MD, FRACP
Helen V Firth, DM, FRCP, DCH
Deputy Editor
Elizabeth TePas, MD, MS

INTRODUCTION

There are three major clinically and genetically distinct forms of neurofibromatosis. Neurofibromatosis type 1 (NF1), previously known as von Recklinghausen disease, is the most common type. The hallmarks of NF1 are the multiple café-au-lait macules and associated cutaneous neurofibromas. The condition is called segmental NF1 when clinical features are limited to one area of the body.

The management and prognosis of NF1 are reviewed here. The pathogenesis, clinical features, and diagnosis are discussed separately (see "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis"). The other two forms of neurofibromatosis, neurofibromatosis type 2 (NF2) and schwannomatosis, are also discussed in detail separately. (See "Neurofibromatosis type 2" and "Schwannomatosis".)

SURVEILLANCE AND SCREENING

Longitudinal care for individuals with NF1 aims at the early detection and symptomatic treatment of complications as they occur. The decision to obtain testing such as imaging studies depends upon the history and physical findings. Clinical evaluation appears to be more useful to detect complications than are screening investigations in asymptomatic patients [1,2]. Thus, for example, guidelines of the Children's Tumor Foundation do not recommend neuroimaging as a screening modality for optic pathway gliomas (OPGs), although not all clinicians agree. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Optic pathway gliomas' and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Bone abnormalities'.)

Both an expert panel [1] and the Genetics Committee of the American Academy of Pediatrics have published diagnostic and health supervision guidelines for children with NF1 [3]. Regular visits at yearly intervals should include:

Physical examination:

                                  

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Literature review current through: Nov 2016. | This topic last updated: Mon Dec 05 00:00:00 GMT+00:00 2016.
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References
Top
  1. Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 1997; 278:51.
  2. Wolkenstein P, Frèche B, Zeller J, Revuz J. Usefulness of screening investigations in neurofibromatosis type 1. A study of 152 patients. Arch Dermatol 1996; 132:1333.
  3. Hersh JH, American Academy of Pediatrics Committee on Genetics. Health supervision for children with neurofibromatosis. Pediatrics 2008; 121:633.
  4. Lama G, Graziano L, Calabrese E, et al. Blood pressure and cardiovascular involvement in children with neurofibromatosis type1. Pediatr Nephrol 2004; 19:413.
  5. Szudek J, Birch P, Friedman JM. Growth in North American white children with neurofibromatosis 1 (NF1). J Med Genet 2000; 37:933.
  6. Clementi M, Milani S, Mammi I, et al. Neurofibromatosis type 1 growth charts. Am J Med Genet 1999; 87:317.
  7. Listernick R, Ferner RE, Liu GT, Gutmann DH. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol 2007; 61:189.
  8. Weiss B, Bollag G, Shannon K. Hyperactive Ras as a therapeutic target in neurofibromatosis type 1. Am J Med Genet 1999; 89:14.
  9. Prada CE, Hufnagel RB, Hummel TR, et al. The Use of Magnetic Resonance Imaging Screening for Optic Pathway Gliomas in Children with Neurofibromatosis Type 1. J Pediatr 2015; 167:851.
  10. Blazo MA, Lewis RA, Chintagumpala MM, et al. Outcomes of systematic screening for optic pathway tumors in children with Neurofibromatosis Type 1. Am J Med Genet A 2004; 127A:224.
  11. Listernick R, Charrow J. Knowledge without truth: screening for complications of neurofibromatosis type 1 in childhood. Am J Med Genet A 2004; 127A:221.
  12. Thiagalingam S, Flaherty M, Billson F, North K. Neurofibromatosis type 1 and optic pathway gliomas: follow-up of 54 patients. Ophthalmology 2004; 111:568.
  13. 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.
  14. Balcer LJ, Liu GT, Heller G, et al. Visual loss in children with neurofibromatosis type 1 and optic pathway gliomas: relation to tumor location by magnetic resonance imaging. Am J Ophthalmol 2001; 131:442.
  15. Liu GT. Optic gliomas of the anterior visual pathway. Curr Opin Ophthalmol 2006; 17:427.
  16. Avery RA, Liu GT, Fisher MJ, et al. Retinal nerve fiber layer thickness in children with optic pathway gliomas. Am J Ophthalmol 2011; 151:542.
  17. Porter DE, Prasad V, Foster L, et al. Survival in Malignant Peripheral Nerve Sheath Tumours: A Comparison between Sporadic and Neurofibromatosis Type 1-Associated Tumours. Sarcoma 2009; 2009:756395.
  18. Matsumine A, Kusuzaki K, Nakamura T, et al. Differentiation between neurofibromas and malignant peripheral nerve sheath tumors in neurofibromatosis 1 evaluated by MRI. J Cancer Res Clin Oncol 2009; 135:891.
  19. Ferner RE, Gutmann DH. International consensus statement on malignant peripheral nerve sheath tumors in neurofibromatosis. Cancer Res 2002; 62:1573.
  20. Ferner RE, Golding JF, Smith M, et al. [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) as a diagnostic tool for neurofibromatosis 1 (NF1) associated malignant peripheral nerve sheath tumours (MPNSTs): a long-term clinical study. Ann Oncol 2008; 19:390.
  21. Warbey VS, Ferner RE, Dunn JT, et al. [18F]FDG PET/CT in the diagnosis of malignant peripheral nerve sheath tumours in neurofibromatosis type-1. Eur J Nucl Med Mol Imaging 2009; 36:751.
  22. Benz MR, Czernin J, Dry SM, et al. Quantitative F18-fluorodeoxyglucose positron emission tomography accurately characterizes peripheral nerve sheath tumors as malignant or benign. Cancer 2010; 116:451.
  23. Vlenterie M, Flucke U, Hofbauer LC, et al. Pheochromocytoma and gastrointestinal stromal tumors in patients with neurofibromatosis type I. Am J Med 2013; 126:174.
  24. North KN, Riccardi V, Samango-Sprouse C, et al. Cognitive function and academic performance in neurofibromatosis. 1: consensus statement from the NF1 Cognitive Disorders Task Force. Neurology 1997; 48:1121.
  25. Fossali E, Signorini E, Intermite RC, et al. Renovascular disease and hypertension in children with neurofibromatosis. Pediatr Nephrol 2000; 14:806.
  26. Chetty SP, Shaffer BL, Norton ME. Management of pregnancy in women with genetic disorders: Part 2: Inborn errors of metabolism, cystic fibrosis, neurofibromatosis type 1, and Turner syndrome in pregnancy. Obstet Gynecol Surv 2011; 66:765.
  27. Terry AR, Barker FG 2nd, Leffert L, et al. Neurofibromatosis type 1 and pregnancy complications: a population-based study. Am J Obstet Gynecol 2013; 209:46.e1.
  28. Gutmann DH, Blakeley JO, Korf BR, Packer RJ. Optimizing biologically targeted clinical trials for neurofibromatosis. Expert Opin Investig Drugs 2013; 22:443.
  29. Gutmann DH. Recent insights into neurofibromatosis type 1: clear genetic progress. Arch Neurol 1998; 55:778.
  30. Canavese F, Krajbich JI. Resection of plexiform neurofibromas in children with neurofibromatosis type 1. J Pediatr Orthop 2011; 31:303.
  31. Dunn GP, Spiliopoulos K, Plotkin SR, et al. Role of resection of malignant peripheral nerve sheath tumors in patients with neurofibromatosis type 1. J Neurosurg 2013; 118:142.
  32. Hummel T, Anyane-Yeboa A, Mo J, et al. Response of NF1-related plexiform neurofibroma to high-dose carboplatin. Pediatr Blood Cancer 2011; 56:488.
  33. 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.
  34. Widemann BC, Dombi E, Gillespie A, et al. Phase 2 randomized, flexible crossover, double-blinded, placebo-controlled trial of the farnesyltransferase inhibitor tipifarnib in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas. Neuro Oncol 2014; 16:707.
  35. Staser K, Yang FC, Clapp DW. Mast cells and the neurofibroma microenvironment. Blood 2010; 116:157.
  36. Robertson KA, Nalepa G, Yang FC, et al. Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial. Lancet Oncol 2012; 13:1218.
  37. Jakacki RI, Dombi E, Potter DM, et al. Phase I trial of pegylated interferon-alpha-2b in young patients with plexiform neurofibromas. Neurology 2011; 76:265.
  38. Jakacki RI, Dombi E, Steinberg SM, et al. Phase II trial of pegylated interferon alfa-2b in young patients with neurofibromatosis type 1 and unresectable plexiform neurofibromas. Neuro Oncol 2016.
  39. Weiss B, Widemann BC, Wolters P, et al. Sirolimus for non-progressive NF1-associated plexiform neurofibromas: an NF clinical trials consortium phase II study. Pediatr Blood Cancer 2014; 61:982.
  40. Weiss B, Widemann BC, Wolters P, et al. Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas: a neurofibromatosis Clinical Trials Consortium phase II study. Neuro Oncol 2015; 17:596.
  41. Widemann BC, Babovic-Vuksanovic D, Dombi E, et al. Phase II trial of pirfenidone in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas. Pediatr Blood Cancer 2014; 61:1598.
  42. Jessen WJ, Miller SJ, Jousma E, et al. MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors. J Clin Invest 2013; 123:340.
  43. Fisher MJ, Loguidice M, Gutmann DH, et al. Visual outcomes in children with neurofibromatosis type 1-associated optic pathway glioma following chemotherapy: a multicenter retrospective analysis. Neuro Oncol 2012; 14:790.
  44. LaFemina J, Qin LX, Moraco NH, et al. Oncologic outcomes of sporadic, neurofibromatosis-associated, and radiation-induced malignant peripheral nerve sheath tumors. Ann Surg Oncol 2013; 20:66.
  45. Reuss DE, Mucha J, Hagenlocher C, et al. Sensitivity of malignant peripheral nerve sheath tumor cells to TRAIL is augmented by loss of NF1 through modulation of MYC/MAD and is potentiated by curcumin through induction of ROS. PLoS One 2013; 8:e57152.
  46. Mohan P, Castellsague J, Jiang J, et al. Genomic imbalance of HMMR/RHAMM regulates the sensitivity and response of malignant peripheral nerve sheath tumour cells to aurora kinase inhibition. Oncotarget 2013; 4:80.
  47. Miettinen M, Fetsch JF, Sobin LH, Lasota J. Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases. Am J Surg Pathol 2006; 30:90.
  48. Mussi C, Schildhaus HU, Gronchi A, et al. Therapeutic consequences from molecular biology for gastrointestinal stromal tumor patients affected by neurofibromatosis type 1. Clin Cancer Res 2008; 14:4550.
  49. Izquierdo ME, Bonastre MT. Patient with high-risk GIST not associated with c-KIT mutations: same benefit from adjuvant therapy? Anticancer Drugs 2012; 23 Suppl:S7.
  50. Li W, Cui Y, Kushner SA, et al. The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1. Curr Biol 2005; 15:1961.
  51. Krab LC, de Goede-Bolder A, Aarsen FK, et al. Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: a randomized controlled trial. JAMA 2008; 300:287.
  52. van der Vaart T, Plasschaert E, Rietman AB, et al. Simvastatin for cognitive deficits and behavioural problems in patients with neurofibromatosis type 1 (NF1-SIMCODA): a randomised, placebo-controlled trial. Lancet Neurol 2013; 12:1076.
  53. Acosta MT, Kardel PG, Walsh KS, et al. Lovastatin as treatment for neurocognitive deficits in neurofibromatosis type 1: phase I study. Pediatr Neurol 2011; 45:241.
  54. Stevenson DA, Birch PH, Friedman JM, et al. Descriptive analysis of tibial pseudarthrosis in patients with neurofibromatosis 1. Am J Med Genet 1999; 84:413.
  55. Stevenson DA, Little D, Armstrong L, et al. Approaches to treating NF1 tibial pseudarthrosis: consensus from the Children's Tumor Foundation NF1 Bone Abnormalities Consortium. J Pediatr Orthop 2013; 33:269.
  56. Greggi T, Martikos K. Surgical treatment of early onset scoliosis in neurofibromatosis. Stud Health Technol Inform 2012; 176:330.
  57. Brunetti-Pierri N, Doty SB, Hicks J, et al. Generalized metabolic bone disease in Neurofibromatosis type I. Mol Genet Metab 2008; 94:105.
  58. Reviron-Rabec L, Girerd B, Seferian A, et al. Pulmonary complications of type 1 neurofibromatosis. Rev Mal Respir 2016; 33:460.
  59. Lázaro C, Ravella A, Gaona A, et al. Neurofibromatosis type 1 due to germ-line mosaicism in a clinically normal father. N Engl J Med 1994; 331:1403.
  60. Riccardi VM, Lewis RA. Penetrance of von Recklinghausen neurofibromatosis: a distinction between predecessors and descendants. Am J Hum Genet 1988; 42:284.
  61. Zlotogora J. Germ line mosaicism. Hum Genet 1998; 102:381.
  62. Ruggieri M, Huson SM. The clinical and diagnostic implications of mosaicism in the neurofibromatoses. Neurology 2001; 56:1433.
  63. Riccardi VM. Neurofibromatosis: Phenotype, natural history, and pathogenesis, Johns Hopkins University Press, Baltimore 1992.
  64. Rasmussen SA, Yang Q, Friedman JM. Mortality in neurofibromatosis 1: an analysis using U.S. death certificates. Am J Hum Genet 2001; 68:1110.
  65. Zöller M, Rembeck B, Akesson HO, Angervall L. Life expectancy, mortality and prognostic factors in neurofibromatosis type 1. A twelve-year follow-up of an epidemiological study in Göteborg, Sweden. Acta Derm Venereol 1995; 75:136.
  66. Guillamo JS, Créange A, Kalifa C, et al. Prognostic factors of CNS tumours in Neurofibromatosis 1 (NF1): a retrospective study of 104 patients. Brain 2003; 126:152.
  67. Sharif S, Ferner R, Birch JM, et al. Second primary tumors in neurofibromatosis 1 patients treated for optic glioma: substantial risks after radiotherapy. J Clin Oncol 2006; 24:2570.
  68. Friedman JM, Birch P. An association between optic glioma and other tumours of the central nervous system in neurofibromatosis type 1. Neuropediatrics 1997; 28:131.
  69. Ferrari A, Bisogno G, Macaluso A, et al. Soft-tissue sarcomas in children and adolescents with neurofibromatosis type 1. Cancer 2007; 109:1406.
  70. Ingham S, Huson SM, Moran A, et al. Malignant peripheral nerve sheath tumours in NF1: improved survival in women and in recent years. Eur J Cancer 2011; 47:2723.
  71. Kolberg M, Høland M, Agesen TH, et al. Survival meta-analyses for >1800 malignant peripheral nerve sheath tumor patients with and without neurofibromatosis type 1. Neuro Oncol 2013; 15:135.