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Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis

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


There are three major clinically and genetically distinct forms of neurofibromatosis: neurofibromatosis types 1 and 2 (NF1 and NF2) and schwannomatosis. NF1, also known as von Recklinghausen disease, is the most common type. The hallmarks of NF1 are the multiple café-au-lait macules and neurofibromas. The condition is called segmental NF1 when clinical features are limited to one area of the body.

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


NF1 is an autosomal dominant genetic disorder with an incidence of approximately 1 in 2600 to 3000 individuals [1,2]. Approximately one-half of the cases are familial (inherited). The remainder are the result of de novo (sporadic) mutations [2]. The de novo mutations occur primarily in paternally derived chromosomes, and the likelihood of de novo NF1 increases with advanced paternal age [3]. The incidence of segmental NF1 is estimated at 1 in 36,000 to 40,000 [4].


NF1 is due to mutations in the NF1 gene, located at chromosome 17q11.2 [5,6]. Neurofibromin, the protein product encoded by the gene, is expressed in many tissues, including brain, kidney, spleen, and thymus [7]. It belongs to a family of guanosine triphosphate hydrolase (GTPase)-activating proteins (GAPs) that stimulate intrinsic GTPase activity in the ras p21 family (21 kD rat sarcoma viral oncogene homologs) [8-10]. Ras activates a number of signaling pathways that includes the stem cell factor (SCF)/c-kit signaling, mechanistic target of rapamycin (mTOR), and mitogen-activated protein kinase (MAPK) pathways.

Mutations in the NF1 gene result in loss of production or reduced function of protein, causing the wide spectrum of clinical findings, including NF1-associated tumors [7]. Penetrance, or the likelihood that the individual carrying the mutation will manifest the disease, is complete. NF1 is highly variable in its expression, however (ie, the severity of and specific manifestations of the disorder vary among affected individuals within the same family and from one family to another) [11]. Somatic mutation or loss of heterozygosity at the NF1 locus, in combination with a germline NF1 mutation, leads to complete loss of neurofibromin expression that is seen in NF1 lesions such as pseudoarthrosis [12] and neurofibromas [13]. NF1 therefore functions as a tumor suppressor gene.


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Literature review current through: Apr 2017. | This topic last updated: May 24, 2017.
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  1. Lammert M, Friedman JM, Kluwe L, Mautner VF. Prevalence of neurofibromatosis 1 in German children at elementary school enrollment. Arch Dermatol 2005; 141:71.
  2. Evans DG, Howard E, Giblin C, et al. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A 2010; 152A:327.
  3. Stephens K, Kayes L, Riccardi VM, et al. Preferential mutation of the neurofibromatosis type 1 gene in paternally derived chromosomes. Hum Genet 1992; 88:279.
  4. Ruggieri M, Huson SM. The clinical and diagnostic implications of mosaicism in the neurofibromatoses. Neurology 2001; 56:1433.
  5. Ledbetter DH, Rich DC, O'Connell P, et al. Precise localization of NF1 to 17q11.2 by balanced translocation. Am J Hum Genet 1989; 44:20.
  6. Feldkamp MM, Gutmann DH, Guha A. Neurofibromatosis type 1: piecing the puzzle together. Can J Neurol Sci 1998; 25:181.
  7. Shen MH, Harper PS, Upadhyaya M. Molecular genetics of neurofibromatosis type 1 (NF1). J Med Genet 1996; 33:2.
  8. Martin GA, Viskochil D, Bollag G, et al. The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 1990; 63:843.
  9. Weiss B, Bollag G, Shannon K. Hyperactive Ras as a therapeutic target in neurofibromatosis type 1. Am J Med Genet 1999; 89:14.
  10. Gutmann DH, Blakeley JO, Korf BR, Packer RJ. Optimizing biologically targeted clinical trials for neurofibromatosis. Expert Opin Investig Drugs 2013; 22:443.
  11. 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.
  12. Stevenson DA, Zhou H, Ashrafi S, et al. Double inactivation of NF1 in tibial pseudarthrosis. Am J Hum Genet 2006; 79:143.
  13. Maertens O, Brems H, Vandesompele J, et al. Comprehensive NF1 screening on cultured Schwann cells from neurofibromas. Hum Mutat 2006; 27:1030.
  14. Upadhyaya M, Huson SM, Davies M, et al. 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.
  15. Pinna V, Lanari V, Daniele P, et al. p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas. Eur J Hum Genet 2015; 23:1068.
  16. Santoro C, Maietta A, Giugliano T, et al. Arg(1809) substitution in neurofibromin: further evidence of a genotype-phenotype correlation in neurofibromatosis type 1. Eur J Hum Genet 2015; 23:1460.
  17. Korf BR, Henson JW, Stemmer-Rachamimov A. Case records of the Massachusetts General Hospital. Case 13-2005. A 48-year-old man with weakness of the limbs and multiple tumors of spinal nerves. N Engl J Med 2005; 352:1800.
  18. Gutmann DH, Collins FS. Neurofibromatosis 1. In: The metabolic and molecular bases of inherited disease, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds), McGraw-Hill, New York 2001. p.877.
  19. Tonsgard JH, Yelavarthi KK, Cushner S, et al. Do NF1 gene deletions result in a characteristic phenotype? Am J Med Genet 1997; 73:80.
  20. Leppig KA, Kaplan P, Viskochil D, et al. Familial neurofibromatosis 1 microdeletions: cosegregation with distinct facial phenotype and early onset of cutaneous neurofibromata. Am J Med Genet 1997; 73:197.
  21. Mensink KA, Ketterling RP, Flynn HC, et al. Connective tissue dysplasia in five new patients with NF1 microdeletions: further expansion of phenotype and review of the literature. J Med Genet 2006; 43:e8.
  22. Kluwe L, Friedrich RE, Peiper M, et al. Constitutional NF1 mutations in neurofibromatosis 1 patients with malignant peripheral nerve sheath tumors. Hum Mutat 2003; 22:420.
  23. Upadhyaya M, Spurlock G, Majounie E, et al. The heterogeneous nature of germline mutations in NF1 patients with malignant peripheral serve sheath tumours (MPNSTs). Hum Mutat 2006; 27:716.
  24. De Raedt T, Beert E, Pasmant E, et al. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature 2014; 514:247.
  25. Lee W, Teckie S, Wiesner T, et al. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat Genet 2014; 46:1227.
  26. Tinschert S, Naumann I, Stegmann E, et al. Segmental neurofibromatosis is caused by somatic mutation of the neurofibromatosis type 1 (NF1) gene. Eur J Hum Genet 2000; 8:455.
  27. Moss C, Green SH. What is segmental neurofibromatosis? Br J Dermatol 1994; 130:106.
  28. Trevisson E, Forzan M, Salviati L, Clementi M. Neurofibromatosis type 1 in two siblings due to maternal germline mosaicism. Clin Genet 2014; 85:386.
  29. Bottillo I, Torrente I, Lanari V, et al. Germline mosaicism in neurofibromatosis type 1 due to a paternally derived multi-exon deletion. Am J Med Genet A 2010; 152A:1467.
  30. Consoli C, Moss C, Green S, et al. Gonosomal mosaicism for a nonsense mutation (R1947X) in the NF1 gene in segmental neurofibromatosis type 1. J Invest Dermatol 2005; 125:463.
  31. 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.
  32. DeBella K, Szudek J, Friedman JM. Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics 2000; 105:608.
  33. Korf BR. Diagnostic outcome in children with multiple café au lait spots. Pediatrics 1992; 90:924.
  34. Nunley KS, Gao F, Albers AC, et al. Predictive value of café au lait macules at initial consultation in the diagnosis of neurofibromatosis type 1. Arch Dermatol 2009; 145:883.
  35. Friedman JM, Birch PH. Type 1 neurofibromatosis: a descriptive analysis of the disorder in 1,728 patients. Am J Med Genet 1997; 70:138.
  36. Lewis RA, Riccardi VM. Von Recklinghausen neurofibromatosis. Incidence of iris hamartomata. Ophthalmology 1981; 88:348.
  37. Gutmann DH. Recent insights into neurofibromatosis type 1: clear genetic progress. Arch Neurol 1998; 55:778.
  38. Seminog OO, Goldacre MJ. Risk of benign tumours of nervous system, and of malignant neoplasms, in people with neurofibromatosis: population-based record-linkage study. Br J Cancer 2013; 108:193.
  39. Airewele GE, Sigurdson AJ, Wiley KJ, et al. Neoplasms in neurofibromatosis 1 are related to gender but not to family history of cancer. Genet Epidemiol 2001; 20:75.
  40. Sørensen SA, Mulvihill JJ, Nielsen A. Long-term follow-up of von Recklinghausen neurofibromatosis. Survival and malignant neoplasms. N Engl J Med 1986; 314:1010.
  41. Walker L, Thompson D, Easton D, et al. A prospective study of neurofibromatosis type 1 cancer incidence in the UK. Br J Cancer 2006; 95:233.
  42. Tucker T, Riccardi VM, Sutcliffe M, et al. Different patterns of mast cells distinguish diffuse from encapsulated neurofibromas in patients with neurofibromatosis 1. J Histochem Cytochem 2011; 59:584.
  43. Sheela S, Riccardi VM, Ratner N. Angiogenic and invasive properties of neurofibroma Schwann cells. J Cell Biol 1990; 111:645.
  44. Jouhilahti EM, Peltonen S, Callens T, et al. The development of cutaneous neurofibromas. Am J Pathol 2011; 178:500.
  45. Carroll SL, Ratner N. How does the Schwann cell lineage form tumors in NF1? Glia 2008; 56:1590.
  46. Dugoff L, Sujansky E. Neurofibromatosis type 1 and pregnancy. Am J Med Genet 1996; 66:7.
  47. Lott IT, Richardson EP Jr. Neuropathological findings and the biology of neurofibromatosis. Adv Neurol 1981; 29:23.
  48. Dombi E, Solomon J, Gillespie AJ, et al. NF1 plexiform neurofibroma growth rate by volumetric MRI: relationship to age and body weight. Neurology 2007; 68:643.
  49. Plotkin SR, Bredella MA, Cai W, et al. Quantitative assessment of whole-body tumor burden in adult patients with neurofibromatosis. PLoS One 2012; 7:e35711.
  50. Prada CE, Rangwala FA, Martin LJ, et al. Pediatric plexiform neurofibromas: impact on morbidity and mortality in neurofibromatosis type 1. J Pediatr 2012; 160:461.
  51. Serletis D, Parkin P, Bouffet E, et al. Massive plexiform neurofibromas in childhood: natural history and management issues. J Neurosurg 2007; 106:363.
  52. Lewis RA, Gerson LP, Axelson KA, et al. von Recklinghausen neurofibromatosis. II. Incidence of optic gliomata. Ophthalmology 1984; 91:929.
  53. Gutmann DH, Rasmussen SA, Wolkenstein P, et al. Gliomas presenting after age 10 in individuals with neurofibromatosis type 1 (NF1). Neurology 2002; 59:759.
  54. Listernick R, Ferner RE, Piersall L, et al. Late-onset optic pathway tumors in children with neurofibromatosis 1. Neurology 2004; 63:1944.
  55. North K. Neurofibromatosis type 1: review of the first 200 patients in an Australian clinic. J Child Neurol 1993; 8:395.
  56. Riccardi VM. Neurofibromatosis: Phenotype, natural history, and pathogenesis, Johns Hopkins University Press, Baltimore 1992.
  57. Listernick R, Charrow J, Gutmann DH. Intracranial gliomas in neurofibromatosis type 1. Am J Med Genet 1999; 89:38.
  58. 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.
  59. Listernick R, Charrow J, Greenwald MJ, Esterly NB. Optic gliomas in children with neurofibromatosis type 1. J Pediatr 1989; 114:788.
  60. Listernick R, Charrow J, Greenwald M, Mets M. Natural history of optic pathway tumors in children with neurofibromatosis type 1: a longitudinal study. J Pediatr 1994; 125:63.
  61. Thiagalingam S, Flaherty M, Billson F, North K. Neurofibromatosis type 1 and optic pathway gliomas: follow-up of 54 patients. Ophthalmology 2004; 111:568.
  62. Szudek J, Birch P, Friedman JM. Growth in North American white children with neurofibromatosis 1 (NF1). J Med Genet 2000; 37:933.
  63. Clementi M, Milani S, Mammi I, et al. Neurofibromatosis type 1 growth charts. Am J Med Genet 1999; 87:317.
  64. Listernick R, Ferner RE, Liu GT, Gutmann DH. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol 2007; 61:189.
  65. Hersh JH, American Academy of Pediatrics Committee on Genetics. Health supervision for children with neurofibromatosis. Pediatrics 2008; 121:633.
  66. Créange A, Zeller J, Rostaing-Rigattieri S, et al. Neurological complications of neurofibromatosis type 1 in adulthood. Brain 1999; 122 ( Pt 3):473.
  67. 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.
  68. Ferner RE, Gutmann DH. International consensus statement on malignant peripheral nerve sheath tumors in neurofibromatosis. Cancer Res 2002; 62:1573.
  69. 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.
  70. Ducatman BS, Scheithauer BW, Piepgras DG, et al. Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer 1986; 57:2006.
  71. Ferner RE, Huson SM, Thomas N, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet 2007; 44:81.
  72. McGaughran JM, Harris DI, Donnai D, et al. A clinical study of type 1 neurofibromatosis in north west England. J Med Genet 1999; 36:197.
  73. Zöller ME, Rembeck B, Odén A, et al. Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population. Cancer 1997; 79:2125.
  74. Meis JM, Enzinger FM, Martz KL, Neal JA. Malignant peripheral nerve sheath tumors (malignant schwannomas) in children. Am J Surg Pathol 1992; 16:694.
  75. 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.
  76. Anghileri M, Miceli R, Fiore M, et al. Malignant peripheral nerve sheath tumors: prognostic factors and survival in a series of patients treated at a single institution. Cancer 2006; 107:1065.
  77. Ferrari A, Bisogno G, Macaluso A, et al. Soft-tissue sarcomas in children and adolescents with neurofibromatosis type 1. Cancer 2007; 109:1406.
  78. Sung L, Anderson JR, Arndt C, et al. Neurofibromatosis in children with Rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma study IV. J Pediatr 2004; 144:666.
  79. Southcott R, Lucraft HH. Association of soft tissue sarcomas other than neurofibrosarcoma with neurofibromatosis. Clin Oncol (R Coll Radiol) 2002; 14:431.
  80. 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.
  81. Takazawa Y, Sakurai S, Sakuma Y, et al. Gastrointestinal stromal tumors of neurofibromatosis type I (von Recklinghausen's disease). Am J Surg Pathol 2005; 29:755.
  82. Calabuig-Farinas S, Lopez-Guerrero JA, Llombart-Bosch A. The GIST paradigm: how to establish diagnostic and prognostic criteria. Arkh Patol 2011; 73:13.
  83. Stewart DR, Sloan JL, Yao L, et al. Diagnosis, management, and complications of glomus tumours of the digits in neurofibromatosis type 1. J Med Genet 2010; 47:525.
  84. Sharif S, Moran A, Huson SM, et al. Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening. J Med Genet 2007; 44:481.
  85. Madanikia SA, Bergner A, Ye X, Blakeley JO. Increased risk of breast cancer in women with NF1. Am J Med Genet A 2012; 158A:3056.
  86. Wang X, Levin AM, Smolinski SE, et al. Breast cancer and other neoplasms in women with neurofibromatosis type 1: a retrospective review of cases in the Detroit metropolitan area. Am J Med Genet A 2012; 158A:3061.
  87. Seminog OO, Goldacre MJ. Age-specific risk of breast cancer in women with neurofibromatosis type 1. Br J Cancer 2015; 112:1546.
  88. Korf BR. Malignancy in neurofibromatosis type 1. Oncologist 2000; 5:477.
  89. Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 1997; 278:51.
  90. Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol 1988; 45:575.
  91. Brunetti-Pierri N, Doty SB, Hicks J, et al. Generalized metabolic bone disease in Neurofibromatosis type I. Mol Genet Metab 2008; 94:105.
  92. Delucia TA, Yohay K, Widmann RF. Orthopaedic aspects of neurofibromatosis: update. Curr Opin Pediatr 2011; 23:46.
  93. 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.
  94. Stevenson DA, Viskochil DH, Schorry EK, et al. The use of anterolateral bowing of the lower leg in the diagnostic criteria for neurofibromatosis type 1. Genet Med 2007; 9:409.
  95. 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.
  96. Plon SE. The phakomatoses and other neurocutaneous syndromes. In: Oski's pediatrics: Principles and practice, 4th ed, McMillan JA, Feigin RD, DeAngelis C, Jones MD (Eds), Lippincott, Williams & Wilkins, Philadelphia 2006. p.2379.
  97. Heervä E, Koffert A, Jokinen E, et al. A controlled register-based study of 460 neurofibromatosis 1 patients: increased fracture risk in children and adults over 41 years of age. J Bone Miner Res 2012; 27:2333.
  98. Soucy EA, Gao F, Gutmann DH, Dunn CM. Developmental delays in children with neurofibromatosis type 1. J Child Neurol 2012; 27:641.
  99. North K. Neurofibromatosis type 1. Am J Med Genet 2000; 97:119.
  100. Lorenzo J, Barton B, Arnold SS, North KN. Developmental trajectories of young children with neurofibromatosis type 1: a longitudinal study from 21 to 40 months of age. J Pediatr 2015; 166:1006.
  101. Plasschaert E, Descheemaeker MJ, Van Eylen L, et al. Prevalence of Autism Spectrum Disorder symptoms in children with neurofibromatosis type 1. Am J Med Genet B Neuropsychiatr Genet 2015; 168B:72.
  102. Hyman SL, Shores A, North KN. The nature and frequency of cognitive deficits in children with neurofibromatosis type 1. Neurology 2005; 65:1037.
  103. 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.
  104. Cutting LE, Koth CW, Denckla MB. How children with neurofibromatosis type 1 differ from "typical" learning disabled clinic attenders: nonverbal learning disabilities revisited. Dev Neuropsychol 2000; 17:29.
  105. Galasso C, Lo-Castro A, Di Carlo L, et al. Planning deficit in children with neurofibromatosis type 1: a neurocognitive trait independent from attention-deficit hyperactivity disorder (ADHD)? J Child Neurol 2014; 29:1320.
  106. Kulkantrakorn K, Geller TJ. Seizures in neurofibromatosis 1. Pediatr Neurol 1998; 19:347.
  107. Hsieh HY, Fung HC, Wang CJ, et al. Epileptic seizures in neurofibromatosis type 1 are related to intracranial tumors but not to neurofibromatosis bright objects. Seizure 2011; 20:606.
  108. Ostendorf AP, Gutmann DH, Weisenberg JL. Epilepsy in individuals with neurofibromatosis type 1. Epilepsia 2013; 54:1810.
  109. Steen RG, Taylor JS, Langston JW, et al. Prospective evaluation of the brain in asymptomatic children with neurofibromatosis type 1: relationship of macrocephaly to T1 relaxation changes and structural brain abnormalities. AJNR Am J Neuroradiol 2001; 22:810.
  110. Sperfeld AD, Hein C, Schröder JM, et al. Occurrence and characterization of peripheral nerve involvement in neurofibromatosis type 2. Brain 2002; 125:996.
  111. Drouet A, Wolkenstein P, Lefaucheur JP, et al. Neurofibromatosis 1-associated neuropathies: a reappraisal. Brain 2004; 127:1993.
  112. Ferner RE, Hughes RA, Hall SM, et al. Neurofibromatous neuropathy in neurofibromatosis 1 (NF1). J Med Genet 2004; 41:837.
  113. Fossali E, Signorini E, Intermite RC, et al. Renovascular disease and hypertension in children with neurofibromatosis. Pediatr Nephrol 2000; 14:806.
  114. Nelson DB, Greer L, Wendel G. Neurofibromatosis and pregnancy: a report of maternal cardiopulmonary compromise. Obstet Gynecol 2010; 116 Suppl 2:507.
  115. Shimizu K, Okita R, Uchida Y, Hihara J. Long survival after resection for lung metastasis of malignant peripheral nerve sheath tumor in neurofibromatosis 1. Ann Thorac Cardiovasc Surg 2008; 14:322.
  116. Kitamura M, Wada N, Nagata S, et al. Malignant peripheral nerve sheath tumor associated with neurofibromatosis type 1, with metastasis to the heart: a case report. Diagn Pathol 2010; 5:2.
  117. Gumbiene L, Petrulioniene Z, Rucinskas K, et al. Pulmonary hypertension: a fatal complication of neurofibromatosis type 1. Respir Care 2011; 56:1844.
  118. Montani D, Coulet F, Girerd B, et al. Pulmonary hypertension in patients with neurofibromatosis type I. Medicine (Baltimore) 2011; 90:201.
  119. Carrascosa MF, Larroque IC, Rivero JL, et al. Pulmonary arterial hypertension associated with neurofibromatosis type 1. BMJ Case Rep 2010; 2010.
  120. Ben-Shachar S, Constantini S, Hallevi H, et al. Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype-phenotype correlation. Eur J Hum Genet 2013; 21:535.
  121. Shino MY, Rabbani S, Belperio JA, et al. Neurofibromatosis-associated diffuse lung disease: case report. Semin Respir Crit Care Med 2012; 33:572.
  122. Nardecchia E, Perfetti L, Castiglioni M, et al. Bullous lung disease and neurofibromatosis type-1. Monaldi Arch Chest Dis 2012; 77:105.
  123. 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.
  124. Boulkina LS, Newton CA, Drake AJ 3rd, Tanenberg RJ. Acute myocardial infarction attributable to adrenergic crises in a patient with pheochromocytoma and neurofibromatosis 1. Endocr Pract 2007; 13:269.
  125. Lie JT. Vasculopathies of Neurofibromatosis Type 1 (von Recklinghausen Disease). Cardiovasc Pathol 1998; 7:97.
  126. Listernick R, Mancini AJ, Charrow J. Segmental neurofibromatosis in childhood. Am J Med Genet A 2003; 121A:132.
  127. Payne JM, Moharir MD, Webster R, North KN. Brain structure and function in neurofibromatosis type 1: current concepts and future directions. J Neurol Neurosurg Psychiatry 2010; 81:304.
  128. DiPaolo DP, Zimmerman RA, Rorke LB, et al. Neurofibromatosis type 1: pathologic substrate of high-signal-intensity foci in the brain. Radiology 1995; 195:721.
  129. Rosenbaum T, Engelbrecht V, Krölls W, et al. MRI abnormalities in neurofibromatosis type 1 (NF1): a study of men and mice. Brain Dev 1999; 21:268.
  130. Van Es S, North KN, McHugh K, De Silva M. MRI findings in children with neurofibromatosis type 1: a prospective study. Pediatr Radiol 1996; 26:478.
  131. North K, Joy P, Yuille D, et al. Specific learning disability in children with neurofibromatosis type 1: significance of MRI abnormalities. Neurology 1994; 44:878.
  132. Denckla MB, Hofman K, Mazzocco MM, et al. Relationship between T2-weighted hyperintensities (unidentified bright objects) and lower IQs in children with neurofibromatosis-1. Am J Med Genet 1996; 67:98.
  133. Moore BD 3rd, Slopis JM, Jackson EF, et al. Brain volume in children with neurofibromatosis type 1: relation to neuropsychological status. Neurology 2000; 54:914.
  134. Cutting LE, Koth CW, Burnette CP, et al. Relationship of cognitive functioning, whole brain volumes, and T2-weighted hyperintensities in neurofibromatosis-1. J Child Neurol 2000; 15:157.
  135. Rea D, Brandsema JF, Armstrong D, et al. Cerebral arteriopathy in children with neurofibromatosis type 1. Pediatrics 2009; 124:e476.
  136. Cairns AG, North KN. Cerebrovascular dysplasia in neurofibromatosis type 1. J Neurol Neurosurg Psychiatry 2008; 79:1165.
  137. Rosser TL, Vezina G, Packer RJ. Cerebrovascular abnormalities in a population of children with neurofibromatosis type 1. Neurology 2005; 64:553.
  138. Messiaen LM, Callens T, Mortier G, 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.
  139. Brems H, Chmara M, Sahbatou M, et al. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet 2007; 39:1120.
  140. Pasmant E, Sabbagh A, Hanna N, et al. SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype. J Med Genet 2009; 46:425.
  141. Wimmer K, Etzler J. Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg? Hum Genet 2008; 124:105.
  142. Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet 2013; 381:333.
  143. Spits C, De Rycke M, Van Ranst N, et al. Preimplantation genetic diagnosis for neurofibromatosis type 1. Mol Hum Reprod 2005; 11:381.
  144. Messiaen L, Yao S, Brems H, et al. Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome. JAMA 2009; 302:2111.
  145. Kratz CP, Holter S, Etzler J, et al. Rhabdomyosarcoma in patients with constitutional mismatch-repair-deficiency syndrome. J Med Genet 2009; 46:418.
  146. Yeung JT, Pollack IF, Shah S, et al. Optic pathway glioma as part of a constitutional mismatch-repair deficiency syndrome in a patient meeting the criteria for neurofibromatosis type 1. Pediatr Blood Cancer 2013; 60:137.