Pathophysiology of Neurofibromatosis Type 1
Authors: Amy Theos, Bruce R. Korf
Journal: Annals of Internal Medicine (2006)

Reviews6 June 2006Pathophysiology of Neurofibromatosis Type 1Amy Theos, MD and Bruce R. Korf, MD, PhDAmy Theos, MDFrom the University of Alabama at Birmingham, Birmingham, Alabama. and Bruce R. Korf, MD, PhDFrom the University of Alabama at Birmingham, Birmingham, Alabama.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-144-11-200606060-00010 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Clinical PrinciplesNeurofibromatosis type 1 (NF1) was formerly known as von Recklinghausen disease.It has autosomal dominant inheritance with complete penetrance, variable expression, and a high rate of new mutation.It affects approximately 1 in 3500 individuals worldwide.Diagnostic clinical signs include neurofibromas, café-au-lait macules, skinfold freckling, skeletal dysplasia, Lisch nodules, and optic gliomas.Persons with NF1 are at increased risk for malignant conditions, especially malignant peripheral nerve sheath tumor (MPNST), leukemia, and rhabdomyosarcoma.Other complications include cognitive problems and vascular dysplasias.Molecular genetic testing is available.Clinical trials of potential therapies for plexiform neurofibromas are under way.Pathophysiologic PrinciplesNeurofibromatosis type 1 is a classic single-gene disorder with a ...References1. Korf BR. Neurofibromas and malignant tumors of the peripheral nervous system.. In: Friedman JM, Gutmann DH, MacCollin M, Riccardi VM, eds. Neurofibromatosis: Phenotype, Natural History, and Pathogenesis. 3rd ed. Baltimore: Johns Hopkins Univ Pr; 1999:142-61. Google Scholar2. Korf BR. Plexiform neurofibromas. Am J Med Genet. 1999;89:31-7. [PMID: 10469434] CrossrefMedlineGoogle Scholar3. Evans DG, Baser ME, McGaughran J, Sharif S, Howard E, Moran A. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002;39:311-4. [PMID: 12011145] CrossrefMedlineGoogle Scholar4. 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;41:143-9. [PMID: 9029062] CrossrefMedlineGoogle Scholar5. Molloy PT, Bilaniuk LT, Vaughan SN, Needle MN, Liu GT, Zackai EH, et al. Brainstem tumors in patients with neurofibromatosis type 1: a distinct clinical entity. Neurology. 1995;45:1897-902. [PMID: 7477989] CrossrefMedlineGoogle Scholar6. Korf BR. Malignancy in neurofibromatosis type 1. Oncologist. 2000;5:477-85. [PMID: 11110599] CrossrefMedlineGoogle Scholar7. North KN, Riccardi V, Samango-Sprouse C, Ferner R, Moore B, Legius E, et al. Cognitive function and academic performance in neurofibromatosis 1: consensus statement from the NF1 Cognitive Disorders Task Force. Neurology. 1997;48:1121-7. [PMID: 9109916] CrossrefMedlineGoogle Scholar8. Zöller ME, Rembeck B, Bäckman L. Neuropsychological deficits in adults with neurofibromatosis type 1. Acta Neurol Scand. 1997;95:225-32. [PMID: 9150813] CrossrefMedlineGoogle Scholar9. Zöller ME, Rembeck B. A psychiatric 12-year follow-up of adult patients with neurofibromatosis type 1. J Psychiatr Res. 1999;33:63-8. [PMID: 10094241] CrossrefMedlineGoogle Scholar10. Friedman JM, Arbiser J, Epstein JA, Gutmann DH, Huot SJ, Lin AE, et al. Cardiovascular disease in neurofibromatosis 1: report of the NF1 Cardiovascular Task Force. Genet Med. 2002;4:105-11. [PMID: 12180143] CrossrefMedlineGoogle Scholar11. Huson SM, Harper PS, Compston DA. Von Recklinghausen neurofibromatosis. A clinical and population study in south-east Wales. Brain. 1988;111 Pt 6 1355-81. [PMID: 3145091] CrossrefMedlineGoogle Scholar12. Carey JC, Laub JM, Hall BD. Penetrance and variability in neurofibromatosis: a genetic study of 60 families. Birth Defects Orig Artic Ser. 1979;15:271-81. [PMID: 118780] MedlineGoogle Scholar13. Rasmussen SA, Yang Q, Friedman JM. Mortality in neurofibromatosis 1: an analysis using U.S. death certificates. Am J Hum Genet. 2001;68:1110-8. [PMID: 11283797] CrossrefMedlineGoogle Scholar14. Lázaro C, Ravella A, Gaona A, Volpini V, Estivill X. Neurofibromatosis type 1 due to germ-line mosaicism in a clinically normal father. N Engl J Med. 1994;331:1403-7. [PMID: 7969279] CrossrefMedlineGoogle Scholar15. Ruggieri M, Polizzi A. Segmental neurofibromatosis [Letter]. J Neurosurg. 2000;93:530-2. [PMID: 10969965] MedlineGoogle Scholar16. Tinschert S, Naumann I, Stegmann E, Buske A, Kaufmann D, Thiel G, et al. Segmental neurofibromatosis is caused by somatic mutation of the neurofibromatosis type 1 (NF1) gene. Eur J Hum Genet. 2000;8:455-9. [PMID: 10878667] CrossrefMedlineGoogle Scholar17. Wu BL, Boles RG, Yaari H, Weremowicz S, Schneider GH, Korf BR. Somatic mosaicism for deletion of the entire NF1 gene identified by FISH. Hum Genet. 1997;99:209-13. [PMID: 9048923] CrossrefMedlineGoogle Scholar18. Xu GF, O'Connell P, Viskochil D, Cawthon R, Robertson M, Culver M, et al. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell. 1990;62:599-608. [PMID: 2116237] CrossrefMedlineGoogle Scholar19. Ballester R, Marchuk D, Boguski M, Saulino A, Letcher R, Wigler M, et al. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell. 1990;63:851-9. [PMID: 2121371] CrossrefMedlineGoogle Scholar20. Daston MM, Scrable H, Nordlund M, Sturbaum AK, Nissen LM, Ratner N. The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes. Neuron. 1992;8:415-28. [PMID: 1550670] CrossrefMedlineGoogle Scholar21. Khosravi-Far R, Der CJ. The Ras signal transduction pathway. Cancer Metastasis Rev. 1994;13:67-89. [PMID: 8143346] CrossrefMedlineGoogle Scholar22. Messiaen LM, Callens T, Mortier G, Beysen D, Vandenbroucke I, Van Roy N, et al. Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat. 2000;15:541-55. [PMID: 10862084] CrossrefMedlineGoogle Scholar23. Leppig KA, Kaplan P, Viskochil D, Weaver M, Ortenberg J, Stephens K. Familial neurofibromatosis 1 microdeletions: cosegregation with distinct facial phenotype and early onset of cutaneous neurofibromata. Am J Med Genet. 1997;73:197-204. [PMID: 9409873] CrossrefMedlineGoogle Scholar24. De Raedt T, Brems H, Wolkenstein P, Vidaud D, Pilotti S, Perrone F, et al. Elevated risk for MPNST in NF1 microdeletion patients. Am J Hum Genet. 2003;72:1288-92. [PMID: 12660952] CrossrefMedlineGoogle Scholar25. Messiaen L, Riccardi V, Peltonen J, Maertens O, Callens T, Karvonen SL, et al. Independent NF1 mutations in two large families with spinal neurofibromatosis [Letter]. J Med Genet. 2003;40:122-6. [PMID: 12566521] CrossrefMedlineGoogle Scholar26. Easton DF, Ponder MA, Huson SM, Ponder BA. An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes. Am J Hum Genet. 1993;53:305-13. [PMID: 8328449] MedlineGoogle Scholar27. Legius E, Marchuk DA, Collins FS, Glover TW. Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis. Nat Genet. 1993;3:122-6. [PMID: 8499945] CrossrefMedlineGoogle Scholar28. Serra E, Rosenbaum T, Winner U, Aledo R, Ars E, Estivill X, et al. Schwann cells harbor the somatic NF1 mutation in neurofibromas: evidence of two different Schwann cell subpopulations. Hum Mol Genet. 2000;9:3055-64. [PMID: 11115850] CrossrefMedlineGoogle Scholar29. Jacks T, Shih TS, Schmitt EM, Bronson RT, Bernards A, Weinberg RA. Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat Genet. 1994;7:353-61. [PMID: 7920653] CrossrefMedlineGoogle Scholar30. Brannan CI, Perkins AS, Vogel KS, Ratner N, Nordlund ML, Reid SW, et al. Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev. 1994;8:1019-29. [PMID: 7926784] CrossrefMedlineGoogle Scholar31. McClatchey AI, Cichowski K. Mouse models of neurofibromatosis. Biochim Biophys Acta. 2001;1471:M73-80. [PMID: 11342186] MedlineGoogle Scholar32. Zhu Y, Ghosh P, Charnay P, Burns DK, Parada LF. Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science. 2002;296:920-2. [PMID: 11988578] CrossrefMedlineGoogle Scholar33. Legius E, Dierick H, Wu R, Hall BK, Marynen P, Cassiman JJ, et al. TP53 mutations are frequent in malignant NF1 tumors. Genes Chromosomes Cancer. 1994;10:250-5. [PMID: 7522538] CrossrefMedlineGoogle Scholar34. Williams BO, Remington L, Albert DM, Mukai S, Bronson RT, Jacks T. Cooperative tumorigenic effects of germline mutations in Rb and p53. Nat Genet. 1994;7:480-4. [PMID: 7951317] CrossrefMedlineGoogle Scholar35. Reilly KM, Loisel DA, Bronson RT, McLaughlin ME, Jacks T. Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nat Genet. 2000;26:109-13. [PMID: 10973261] CrossrefMedlineGoogle Scholar36. Vogel KS, Klesse LJ, Velasco-Miguel S, Meyers K, Rushing EJ, Parada LF. Mouse tumor model for neurofibromatosis type 1. Science. 1999;286:2176-9. [PMID: 10591653] CrossrefMedlineGoogle Scholar37. Bajenaru ML, Hernandez MR, Perry A, Zhu Y, Parada LF, Garbow JR, et al. Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity. Cancer Res. 2003;63:8573-7. [PMID: 14695164] MedlineGoogle Scholar38. Shannon KM, Watterson J, Johnson P, O'Connell P, Lange B, Shah N, et al. Monosomy 7 myeloproliferative disease in children with neurofibromatosis, type 1: epidemiology and molecular analysis. Blood. 1992;79:1311-8. [PMID: 1536955] CrossrefMedlineGoogle Scholar39. Emanuel PD. Juvenile myelomonocytic leukemia. Curr Hematol Rep. 2004;3:203-9. [PMID: 15087069] MedlineGoogle Scholar40. Eisenbarth I, Assum G, Kaufmann D, Krone W. Evidence for the presence of the second allele of the neurofibromatosis type 1 gene in melanocytes derived from café au lait macules of NF1 patients. Biochem Biophys Res Commun. 1997;237:138-41. [PMID: 9266845] CrossrefMedlineGoogle Scholar41. Silva AJ, Elgersma Y, Friedman E, Stern J, Kogan J. A mouse model for learning and memory defects associated with neurofibromatosis type I. Pathol Biol (Paris). 1998;46:697-8. [PMID: 9885821] MedlineGoogle Scholar42. Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol. 1988;45:575-8. [PMID: 3128965] MedlineGoogle Scholar43. Heim RA, Silverman LM, Farber RA, Kam-Morgan LN, Luce MC. Screening for truncated NF1 proteins [Letter]. Nat Genet. 1994;8:218-9. [PMID: 7874161] CrossrefMedlineGoogle Scholar44. Poussaint TY, Jaramillo D, Chang Y, Korf B. Interobserver reproducibility of volumetric MR imaging measurements of plexiform neurofibromas. AJR Am J Roentgenol. 2003;180:419-23. [PMID: 12540445] CrossrefMedlineGoogle Scholar45. Ferner RE, Lucas JD, O'Doherty MJ, Hughes RA, Smith MA, Cronin BF, et al. Evaluation of (18)fluorodeoxyglucose positron emission tomography ((18)FDG PET) in the detection of malignant peripheral nerve sheath tumours arising from within plexiform neurofibromas in neurofibromatosis 1. J Neurol Neurosurg Psychiatry. 2000;68:353-7. [PMID: 10675220] CrossrefMedlineGoogle Scholar46. Head JE, Johnston SR. Protein farnesyltransferase inhibitors. Expert Opin Emerg Drugs. 2003;8:163-78. [PMID: 14610919] CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAffiliations: From the University of Alabama at Birmingham, Birmingham, Alabama.Disclosures: Grants received: B.R. Korf (National Institutes of Health, U.S. Army).Corresponding Author: Bruce R. Korf, MD, PhD, Department of Genetics, University of Alabama at Birmingham, 1530 3rd Avenue South, Birmingham, AL 35294; e-mail, [email protected]edu.Current Author Addresses: Dr. Theos: Department of Dermatology, University of Alabama at Birmingham, 1530 3rd Avenue South, Birmingham, AL 35294.Dr. Korf: Department of Genetics, University of Alabama at Birmingham, 1530 3rd Avenue South, Birmingham, AL 35294. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited ByIntact procedural learning and motor intracortical inhibition in adult neurofibromatosis type 1 gene carriersIdentification of a germline CSPG4 variation in a family with neurofibromatosis type 1-like phenotypeCharacterization of Two Loss-of-Function NF1 Variants in Chinese Patients and Potential Molecular Interpretations of PhenotypesA novel mutation in NF1 gene of patient with Neurofibromatosis type 1: A case report and functional studyNeurofibromatosis Type 1-Associated Optic Pathway Glioma in Children: A Follow-Up of 10 Years or MoreImaging Features of Neurofibromatosis Type 1 in the Abdomen and PelvisIntraoral and extraoral hyperpigmentation and an expansile mandibular lesionAn Adjunctive Use Of Asfotase Alfa and Zoledronic Acid After Spinal Surgery In Neurofibromatosis Type 1 Related Dystrophic ScoliosisUnderstanding the Biological Activities of Vitamin D in Type 1 Neurofibromatosis: New Insights into Disease Pathogenesis and Therapeutic DesignCognitive functioning and pain interference mediate pain predictive effects on health-related quality of life in pediatric patients with Neurofibromatosis Type 1Sporadic and Familial Variants in NF1: An Explanation of the Wide Variability in Neurocognitive Phenotype?A rare case report of neurofibromatosis type 1 in a 12-year-old child: A 15-month follow-upTriple malignancy (NET, GIST and pheochromocytoma) as a first manifestation of neurofibromatosis type-1 in an adult patientThe NeurofibromatosesNeurofibromatosis with vitiligo: an uncommon association rather than coexistence?Affinity Purification of NF1 Protein–Protein Interactors Identifies Keratins and Neurofibromin Itself as Binding PartnersAcute Deterioration of Pulmonary Arterial Hypertension (PAH) in a Patient with Neurofibromatosis Type 1 (NF1)Computational insights of K1444N substitution in GAP-related domain of NF1 gene associated with neurofibromatosis type 1 disease: a molecular modeling and dynamics approachThe effect of parental age on NF1 patients in TurkeyCorkscrew retinal vessels and retinal arterial macroaneurysm in a patient with neurofibromatosis type 1Possible modifier genes in the variation of neurofibromatosis type 1 clinical phenotypesPedsQL Neurofibromatosis Type 1 Module for children, adolescents and young adults: feasibility, reliability, and validityImmunohistochemical Markers for Prospective Studies in Neurofibromatosis-1 Porcine ModelsA Comprehensive Review of Pediatric Tumors and Associated Cancer Predisposition SyndromesNF1 Gene Mutations are the Major Molecular Event in Neurofibromatosis-Noonan SyndromeNeurofibromatosis segmentariaβ‐Catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implicationsBrain and behaviour phenotyping of a mouse model of neurofibromatosis type-1: an MRI/DTI study on social cognitionA case of portal hypertension by presumed as plexiform neurofibroma at the hepatic hilumDual mTORC1/2 inhibition induces anti-proliferative effect in NF1-associated plexiform neurofibroma and malignant peripheral nerve sheath tumor cellsRetroperitoneal malignant peripheral nerve sheath tumor in a preschool childTumor maligno de la vaina del nervio periférico retroperitoneal en un niño preescolarSegmental eruptive neurofibromatosis infliximab-inducedClear Discrepancy in Neurofibromin Expression between NF1 Pheochromocytoma Cells and Non-Tumorous Adrenal Medullary CellsTeaching reading to children with neurofibromatosis type 1: a clinical trial with random assignment to different approachesVon Recklinghausens Disease: A Series of Four Cases with Variable ExpressionAmniotic Fluid Embolism Triggered By Hypertensive Crisis Due to Undiagnosed Pheochromocytoma in a Pregnant Subject With Neurofibromatosis Type 1Heat Hyperalgesia and Mechanical Hypersensitivity Induced by Calcitonin Gene-Related Peptide in a Mouse Model of NeurofibromatosisNeurofibromatosis type 1-associated hypertension secondary to coarctation of the thoracic aortaThe mutational spectrum of the NF1 gene in neurofibromatosis type I patients from UAEMosaic Generalized Neurofibromatosis 1: Report of Two CasesMolecular Testing in Bone and Soft Tissue TumorsHyperactive Ras/MAPK signaling is critical for tibial nonunion fracture in neurofibromin-deficient micePopulation Pharmacokinetics of Sirolimus in Pediatric Patients With Neurofibromatosis Type 1A novel neurofibromin (NF1) interaction with the leucine-rich pentatricopeptide repeat motif-containing protein links neurofibromatosis type 1 and the french canadian variant of leigh's syndrome in a common molecular complexThe Characterisation of Pax3 Expressant Cells in Adult Peripheral NerveThe importance of advanced parental age in the origin of neurofibromatosis type 1Molecular Targets for the Treatment of Juvenile Myelomonocytic LeukemiaT-cell lymphoblastic lymphoma shows differences and similarities with T-cell acute lymphoblastic leukemia by genomic and gene expression analysesRuptured Left Subclavian Artery Aneurysm in a 41-Year-Old Woman with Neurofibromatosis Type 1Rasopatías: trastornos del desarrollo con predisposición al cáncer y manifestaciones cutáneasRasopathies: Developmental Disorders That Predispose to Cancer and Skin ManifestationsThe NeurofibromatosesNon-Cytogenetic Markers and their Impact on PrognosisOther Genetic Syndromes (TSC, VHL, NF1, etc.)Pheochromocytoma associated with neurofibromatosis type 1: concepts and current trendsHereditary Genodermatoses with Cancer PredispositionGlomus tumour of the thumb in a child with neurofibromatosis: a case reportFormulation and Release Behavior of Doxycycline–Alginate Hydrogel Microparticles Embedded into Pluronic F127 Thermogels as a Potential New Vehicle for Doxycycline Intradermal Sustained DeliveryGenetic Predispositions for Hematologic and Lymphoid DisordersAutosomal Dominant and Recessive InheritanceMalignant peripheral nerve sheath tumour (MPNST): the clinical implications of cellular signalling pathwaysCancer-Selective Targeting and Cytotoxicity by Liposomal-Coupled Lysosomal Saposin C ProteinPlexiform Neurofibroma in the Hepatic Hilum Associated with Neurofibromatosis Type 1: A Case ReportSuccessful use of posterior instrumented spinal fusion alone for scoliosis in 19 patients with neurofibromatosis type-1 followed up for at least 25 monthsNeurofibromatosis type 1Chronic eosinophilic pneumonia associated with neurofibromatosis type 1: an unusual complicationA rare association between neurofibromatosis type I and Cogan's syndrome: Case reportMcCune-Albright syndromeHow does the Schwann cell lineage form tumors in NF1?Neurofibromatous sensory neuropathy of the thigh in a 7-year-old boyTwenty questions in genetic medicine—an assessment of World Wide Web databases for genetics information at the point of careComplex vascular reconstruction of abdominal aorta and its branches in the pediatric populationNeurofibromatose tipo 1 na infância: revisão dos aspectos clínicosLeukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosisMalignant peripheral nerve sheath tumor: Molecular pathogenesis and current management considerationsGiant café-au-lait macule in neurofibromatosis 1: A type 2 segmental manifestation of neurofibromatosis 1?Neurofibromin as a regulator of melanocyte development and differentiationNeurofibromatosis Type I: Genetics and Clinical ManifestationsProgesterone and Estrogen Receptors in Neurofibromas of Patients with NF1Neurofibromatose Typ I und MegadolichobasilarisMagnetic Resonance Imaging of Soft-Tissue TumorsMagnetic Resonance Imaging of Soft-Tissue Tumors: Determinate and Indeterminate LesionsForensic Considerations in Cases of Neurofibromatosis?An OverviewGenodermatoses with malignant potentialAnalysis of Mitochondrial DNA in Discordant Monozygotic Twins With Neurofibromatosis Type 1Oncolytic HSV and Erlotinib Inhibit Tumor Growth and Angiogenesis in a Novel Malignant Peripheral Nerve Sheath Tumor Xenograft ModelGenomic Rearrangements and Gene Copy-Number Alterations as a Cause of Nervous System DisordersSyndromes Involving Melanocytic Lesions 6 June 2006Volume 144, Issue 11Page: 842-849KeywordsAllelesCellsDysplasiaLesionsNervesNeurofibromatosis type 1PathogenesisPhenotypesProteins ePublished: 6 June 2006 Issue Published: 6 June 2006 CopyrightCopyright © 2006 by American College of Physicians. All Rights Reserved.PDF DownloadLoading ...