The Pathoetiology of Neurofibromatosis 1
2011; Elsevier BV; Volume: 178; Issue: 5 Linguagem: Inglês
10.1016/j.ajpath.2010.12.056
ISSN1525-2191
AutoresEeva‐Mari Jouhilahti, Sirkku Peltonen, Anthony M. Heape, Juha Peltonen,
Tópico(s)Soft tissue tumors and treatment
ResumoAlthough a mutation in the NF1 gene is the only factor required to initiate the neurocutaneous-skeletal neurofibromatosis 1 (NF1) syndrome, the pathoetiology of the multiple manifestations of this disease in different organ systems seems increasingly complex. The wide spectrum of different clinical phenotypes and their development, severity, and prognosis seem to result from the cross talk between numerous cell types, cell signaling networks, and cell–extracellular matrix interactions. The bi-allelic inactivation of the NF1 gene through a “second hit” seems to be of crucial importance to the development of certain manifestations, such as neurofibromas, café-au-lait macules, and glomus tumors. In each case, the second hit involves only one cell type, which is subsequently clonally expanded in a discrete lesion. Neurofibromas, which are emphasized in this review, and cutaneous neurofibromas in particular, are known to contain a subpopulation of NF1-diploinsufficient Schwann cells and a variety of NF1-haploinsufficient cell types. A recent study identified a multipotent precursor cell population with an NF1+/− genotype that resides in human cutaneous neurofibromas and that has been suggested to play a role in their pathogenesis. Although a mutation in the NF1 gene is the only factor required to initiate the neurocutaneous-skeletal neurofibromatosis 1 (NF1) syndrome, the pathoetiology of the multiple manifestations of this disease in different organ systems seems increasingly complex. The wide spectrum of different clinical phenotypes and their development, severity, and prognosis seem to result from the cross talk between numerous cell types, cell signaling networks, and cell–extracellular matrix interactions. The bi-allelic inactivation of the NF1 gene through a “second hit” seems to be of crucial importance to the development of certain manifestations, such as neurofibromas, café-au-lait macules, and glomus tumors. In each case, the second hit involves only one cell type, which is subsequently clonally expanded in a discrete lesion. Neurofibromas, which are emphasized in this review, and cutaneous neurofibromas in particular, are known to contain a subpopulation of NF1-diploinsufficient Schwann cells and a variety of NF1-haploinsufficient cell types. A recent study identified a multipotent precursor cell population with an NF1+/− genotype that resides in human cutaneous neurofibromas and that has been suggested to play a role in their pathogenesis. Neurofibromatosis 1 (NF1; Online Mendelian Inheritance of Man no. 162200; http://www.ncbi.nlm.nih.gov/omim, last accessed March 10, 2011), previously known as von Recklinghausen disease, is an autosomal dominant disorder that affects approximately 1 in 3500 persons worldwide.1Huson S. Compston D. Clark P. Harper P. A genetic study of von Recklinghausen neurofibromatosis in south east Wales, I: prevalence, fitness, mutation rate, and effect of parental transmission on severity.J Med Genet. 1989; 26: 704-711Crossref PubMed Scopus (430) Google Scholar, 2Lammert M. Friedman J. Kluwe L. Mautner V. Prevalence of neurofibromatosis 1 in German children at elementary school enrollment.Arch Dermatol. 2005; 141: 71-74Crossref PubMed Scopus (277) Google Scholar Half of the patients with NF1 have inherited their NF1 mutation, and the other half are caused by a de novo NF1 mutation. The findings and the degree of severity of NF1 are highly variable. The hallmarks of NF1 include café-au-lait macules and multiple benign cutaneous neurofibromas, which, typically, are detectable in adulthood by simple visual inspection. NF1 can affect nearly every organ system, and the complications vary between individuals, even within a single family. The clinical diagnosis is based on the presence of two or more of the following findings: six or more café-au-lait macules with diameters >5 mm in prepubertal patients and >15 mm in postpubertal patients; two or more neurofibromas of any type or one plexiform neurofibroma; axillary or inguinal freckling; optic glioma; two or more Lisch nodules of the iris; a distinctive osseous lesion, such as sphenoid wing dysplasia or pseudarthrosis; or a first-degree relative diagnosed as having NF1 according to the preceding criteria.3Stumpf D. Alksne J. Annegers J. Brown S. Conneally P. Housman D. Leppert M. Miller J. Moss M. Pileggi A. Rapin I. Strohman R. Swanson L. Zimmerman A. Neurofibromatosis: conference statement: National Institutes of Health Consensus Development Conference.Arch Neurol. 1988; 45: 575-578Crossref PubMed Scopus (1940) Google Scholar It has been suggested that a pathogenic mutation in the NF1 gene be added to the list of diagnostic criteria.4Huson S.M. The neurofibromatosis: classification, clinical features and genetic counselling.in: Kaufmann D. Neurofibromatoses. Karger, Basel2008: 1-20Crossref Scopus (37) Google Scholar The most common complications of NF1 are included in the previously listed diagnostic criteria. Additional features include short stature, scoliosis, headache, speech disorders, attention deficit disorder and attention-deficit/hyperactivity disorder, and learning disabilities. Rare complications, affecting 80%) of new mutations being of paternal origin,12Jadayel D. Fain P. Upadhyaya M. Ponder M. Huson S. Carey J. Fryer A. Mathew C. Barker D. Ponder B. Paternal origin of new mutations in von Recklinghausen neurofibromatosis.Nature. 1990; 343: 558-559Crossref PubMed Scopus (153) Google Scholar whereas most of the so-called microdeletions seem to be of maternal origin.13Upadhyaya M. Ruggieri M. Maynard J. Osborn M. Hartog C. Mudd S. Penttinen M. Cordeiro I. Ponder M. Ponder B. Krawczak M. Cooper D. Gross deletions of the neurofibromatosis type 1 (NF1) gene are predominantly of maternal origin and commonly associated with a learning disability, dysmorphic features and developmental delay.Hum Genet. 1998; 102: 591-597Crossref PubMed Scopus (137) Google Scholar Microdeletions cover the entire NF1 gene and its flanking regions, which contain 17 genes.14De Raedt T. Brems H. Lopez-Correa C. Vermeesch J. Marynen P. Legius E. Genomic organization and evolution of the NF1 microdeletion region.Genomics. 2004; 84: 346-360Crossref PubMed Scopus (33) Google Scholar The penetrance of NF1 is 100%, meaning that all patients with an NF1 mutation have NF1. A comprehensive NF1 mutation screen can detect gene mutations in more than 92% of tested patients fulfilling the NIH diagnostic criteria.15Messiaen L. Wimmer K. NF1 mutational spectrum.in: Kaufmann D. Neurofibromatoses. Karger, Basel2008: 63-77Crossref Scopus (77) Google Scholar, 16Messiaen L. Callens T. Mortier G. Beysen D. Vandenbroucke I. Van Roy N. Speleman F. Paepe A. 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: 541-555Crossref PubMed Scopus (418) Google Scholar Mutation analysis is especially important in very young children with a negative family history and who only partially fulfill the NIH diagnostic criteria. Molecular testing for NF1 is also useful for diagnostic confirmation in the case where an adult patient with café-au-lait macules and axillary freckles has no neurofibromas. These patients with a mild phenotype but fulfilling NF1 diagnostic criteria might have Legius syndrome; the mutation is, in this case, in another gene, SPRED1.17Brems H. Chmara M. Sahbatou M. Denayer E. Taniguchi K. Kato R. Somers R. Messiaen L. De Schepper S. Fryns J. Cools J. Marynen P. Thomas G. Yoshimura A. Legius E. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype.Nat Genet. 2007; 39: 1120-1126Crossref PubMed Scopus (350) Google Scholar Approximately 1% to 2% of patients meeting NIH clinical diagnostic criteria for NF1 in fact harbor SPRED1 mutations.18Messiaen L. Yao S. Brems H. Callens T. Sathienkijkanchai A. Denayer E. et al.Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome.JAMA. 2009; 302: 2111-2118Crossref PubMed Scopus (142) Google Scholar The NF1 gene is transcribed into an 11- to 13-kb mRNA with an approximately 9-kb open reading frame and is translated into a ubiquitously expressed, 280-kDa protein called neurofibromin.9Upadhyaya M. NF1 gene structure and NF1 genotype/phenotype correlations.in: Kaufmann D. Neurofibromatoses. Karger, Basel2008: 46-62Crossref Scopus (13) Google Scholar, 19Hermonen J. Hirvonen O. Ylä-Outinen H. Lakkakorpi J. Björkstrand A. Laurikainen L. Kallioinen M. Oikarinen A. Peltonen S. Peltonen J. Neurofibromin: expression by normal human keratinocytes in vivo and in vitro and in epidermal malignancies.Lab Invest. 1995; 73: 221-228PubMed Google Scholar Direct or indirect interactions have been reported between neurofibromin and several other proteins, including the transmembrane proteoglycan syndecan, actin, tubulin, and intermediate filaments, but very little is known about its function, and none of the known interactions alone can explain the different symptoms related to NF1. Only two potentially functional domains of neurofibromin have been described, RasGAP and Sec14,20Bonneau F. D'Angelo I. Welti S. Stier G. Ylänne J. Scheffzek K. Expression, purification and preliminary crystallographic characterization of a novel segment from the neurofibromatosis type 1 protein.Acta Crystallogr D Biol Crystallogr. 2004; 60: 2364-2367Crossref PubMed Scopus (11) Google Scholar, 21Ballester R. Marchuk D. Boguski M. Saulino A. Letcher R. Wigler M. Collins F. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins.Cell. 1990; 63: 851-859Abstract Full Text PDF PubMed Scopus (652) Google Scholar, 22Martin G. Viskochil D. Bollag G. McCabe P. Crosier W. Haubruck H. Conroy L. Clark R. O'Connell P. Cawthon R. The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21.Cell. 1990; 63: 843-849Abstract Full Text PDF PubMed Scopus (737) Google Scholar, 23Xu G. Lin B. Tanaka K. Dunn D. Wood D. Gesteland R. White R. Weiss R. Tamanoi F. The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae.Cell. 1990; 63: 835-841Abstract Full Text PDF PubMed Scopus (552) Google Scholar but the biological role of the Sec14 domain is unknown. The RasGAP-related domain (Ras-GRD) accelerates the conversion of active Ras-GTP to inactive Ras-GDP in various cell types and acts as a negative regulator of the p21ras signaling pathway. The Ras GTPases interact with multiple pathways, including the Raf/Mek/Erk mitogen-activated protein kinase cascade, which regulates cellular growth and differentiation.24Le L. Parada L. Tumor microenvironment and neurofibromatosis type I: connecting the GAPs.Oncogene. 2007; 26: 4609-4616Crossref PubMed Scopus (144) Google Scholar NF1 belongs to a class of developmental syndromes called RASopathies, which are caused by germline mutations in genes that encode protein components of the Ras/mitogen-activated protein kinase pathway.25Tidyman W. Rauen K. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation.Curr Opin Genet Dev. 2009; 19: 230-236Crossref PubMed Scopus (552) Google Scholar Several clinical syndromes with disease-causing mutations in genes encoding proteins of the Ras signaling pathway have phenotypes overlapping with those of NF1.26Denayer E. de Ravel T. Legius E. Clinical and molecular aspects of RAS related disorders.J Med Genet. 2008; 45: 695-703Crossref PubMed Scopus (71) Google Scholar, 27Stevenson D.A. Swensen J.J. Viskochil D.H. Neurofibromatosis type 1 and other syndromes of the Ras pathway.in: Kaufmann D. Neurofibromatoses. Karger, Basel2008: 32-45Crossref Scopus (8) Google Scholar These syndromes include Noonan syndrome, LEOPARD syndrome, cardiofaciocutaneous syndrome, Costello syndrome, and Legius syndrome. These conditions all share a variable degree of learning difficulty, cardiac defects, facial dysmorphism, short stature, macrocephaly, and skin abnormalities.4Huson S.M. The neurofibromatosis: classification, clinical features and genetic counselling.in: Kaufmann D. Neurofibromatoses. Karger, Basel2008: 1-20Crossref Scopus (37) Google Scholar The clinical features of the recently described Legius syndrome resemble and partially overlap with those of NF1, including multiple café-au-lait spots, axillary freckling, and macrocephaly.17Brems H. Chmara M. Sahbatou M. Denayer E. Taniguchi K. Kato R. Somers R. Messiaen L. De Schepper S. Fryns J. Cools J. Marynen P. Thomas G. Yoshimura A. Legius E. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype.Nat Genet. 2007; 39: 1120-1126Crossref PubMed Scopus (350) Google Scholar, 28Spurlock G. Bennett E. Chuzhanova N. Thomas N. Jim H. Side L. Davies S. Haan E. Kerr B. Huson S. Upadhyaya M. SPRED1 mutations (Legius syndrome): another clinically useful genotype for dissecting the neurofibromatosis type 1 phenotype.J Med Genet. 2009; 46: 431-437Crossref PubMed Scopus (70) Google Scholar Legius syndrome also seems to be associated with cognitive abnormalities.17Brems H. Chmara M. Sahbatou M. Denayer E. Taniguchi K. Kato R. Somers R. Messiaen L. De Schepper S. Fryns J. Cools J. Marynen P. Thomas G. Yoshimura A. Legius E. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype.Nat Genet. 2007; 39: 1120-1126Crossref PubMed Scopus (350) Google Scholar However, patients with Legius syndrome have neither Lisch nodules in the iris nor neurofibromas or central nervous system tumors. The syndrome is caused by a mutation in the SPRED1 gene at 15q14, and the gene product is part of the Sprouty/SPRED proteins, which are negative regulators of Ras. Only two genotype-phenotype correlations have been reported for the NF1 gene, leading to speculations on possible modifiers of the haploinsufficient state of the NF1 gene product. The first correlation relates to patients with NF1 and NF1 microdeletions, which cover the entire NF1 gene and lead to a severe form of NF1.29Descheemaeker M. Roelandts K. De Raedt T. Brems H. Fryns J. Legius E. Intelligence in individuals with a neurofibromatosis type 1 microdeletion.Am J Med Genet A. 2004; 131: 325-326Crossref PubMed Scopus (41) Google Scholar, 30Venturin M. Guarnieri P. Natacci F. Stabile M. Tenconi R. Clementi M. Hernandez C. Thompson P. Upadhyaya M. Larizza L. Riva P. Mental retardation and cardiovascular malformations in NF1 microdeleted patients point to candidate genes in 17q11.2.J Med Genet. 2004; 41: 35-41Crossref PubMed Scopus (96) Google Scholar Patients with an NF1 microdeletion have a higher burden of cutaneous neurofibromas, may have dysmorphic features, and often develop learning disabilities. The second association involves a specific, 3-bp, in-frame deletion in exon 17 (c.2970-2972 delAAT) of the NF1 gene, a condition that is characterized by a mild phenotype in many patients.31Upadhyaya M. Huson S. Davies M. Thomas N. Chuzhanova N. Giovannini S. Evans D. Howard E. Kerr B. Griffiths S. Consoli C. Side L. Adams D. Pierpont M. Hachen R. Barnicoat A. Li H. Wallace P. Van Biervliet J. Stevenson D. Viskochil D. Baralle D. Haan E. Riccardi V. Turnpenny P. Lazaro C. Messiaen L. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c. 2970–2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation.Am J Hum Genet. 2007; 80: 140-151Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar These patients show typical pigmentary features of NF1 and Lisch nodules but do not develop cutaneous or clinically detectable plexiform neurofibromas.32Maertens O. Brems H. Vandesompele J. De Raedt T. Heyns I. Rosenbaum T. De Schepper S. De Paepe A. Mortier G. Janssens S. Speleman F. Legius E. Messiaen L. Comprehensive NF1 screening on cultured Schwann cells from neurofibromas.Hum Mutat. 2006; 27: 1030-1040Crossref PubMed Scopus (96) Google Scholar Mild forms of NF1 can be caused by mosaicism, a situation in which the NF1 mutation occurs after fertilization. Somatic mutations occurring early during embryonic development produce generalized mosaicism, which is characterized by a mild disease indistinguishable from classic NF1. Mutations occurring at a later stage of embryonic development result in segmental NF1, where manifestations are restricted to one segment of the body. Gonadal mosaicism is a rare form of mosaicism; the mutation is present only in the gonads, and it can be suspected if two or more children of unaffected parents have NF1.33De Raedt T. Maertens O. Serra E. Legius E. Somatic NF1 mutations in tumors and other tissue.in: Kaufmann D. Neurofibromatoses. Karger, Basel2008: 143-153Crossref Scopus (8) Google Scholar It has been speculated but, to our knowledge, not published that mosaicism can explain at least some of the cases in which a mildly affected patient with no family history of NF1 has a child who develops a severe form of the disease. The expression of NF1 is regulated at multiple levels, resulting in levels of NF1 mRNA and protein that can vary considerably, even within minutes (Table 1).34Peltonen J. Peltonen S. Composition of neurofibromas, NF1 expression, and comparison of normal and NF1 haploinsufficient cells.in: Kaufmann D. Neurofibromatoses. Karger, Basel2008: 129-142Crossref Scopus (3) Google Scholar, 35Cichowski K. Santiago S. Jardim M. Johnson B. Jacks T. Dynamic regulation of the Ras pathway via proteolysis of the NF1 tumor suppressor.Genes Dev. 2003; 17: 449-454Crossref PubMed Scopus (111) Google Scholar Proteins interacting with either NF1 mRNA or the protein or causing their degradation can be considered as modifiers of NF1 expression. Only one protein, the tumor antigen HuR, is known to interact with NF1 mRNA, binding specifically to one of the five potential protein-binding sites of its 3′ untranslated region.51Haeussler J. Haeusler J. Striebel A. Assum G. Vogel W. Furneaux H. Krone W. 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Peltonen J. NF1 tumor suppressor mRNA is targeted to the cell-cell contact zone in Ca(2+)-induced keratinocyte differentiation.Lab Invest. 2002; 82: 353-361Crossref PubMed Scopus (11) Google ScholarTable 1Regulation of NF1 ExpressionTargetEffectsReferencesPromotor methylationNF1 gene silencing.36Fishbein L. Eady B. Sanek N. Muir D. Wallace M. Analysis of somatic NF1 promoter methylation in plexiform neurofibromas and Schwann cells.Cancer Genet Cytogenet. 2005; 157: 181-186Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 37Harder A. Rosche M. Reuss D. Holtkamp N. Uhlmann K. Friedrich R. Mautner V. von Deimling A. Methylation analysis of the neurofibromatosis type 1 (NF1) promoter in peripheral nerve sheath tumours.Eur J Cancer. 2004; 40: 2820-2828Abstract Full Text Full Text PDF PubMed Scopus (26) Google ScholarTranscriptional controlbFGF-, PDGF-, and EGF-induced up-regulated transcription of NF1 gene.35Cichowski K. Santiago S. Jardim M. Johnson B. Jacks T. 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