Skip to main content

Advertisement

SpringerLink
Log in

Genetic predisposition to peripheral nerve neoplasia: diagnostic criteria and pathogenesis of neurofibromatoses, Carney complex, and related syndromes

  • Review
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Neoplasms of the peripheral nerve sheath represent essential clinical manifestations of the syndromes known as the neurofibromatoses. Although involvement of multiple organ systems, including skin, central nervous system, and skeleton, may also be conspicuous, peripheral nerve neoplasia is often the most important and frequent cause of morbidity in these patients. Clinical characteristics of neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) have been extensively described and studied during the last century, and the identification of mutations in the NF1 and NF2 genes by contemporary molecular techniques have created a separate multidisciplinary field in genetic medicine. In schwannomatosis, the most recent addition to the neurofibromatosis group, peripheral nervous system involvement is the exclusive (or almost exclusive) clinical manifestation. Although the majority of cases of schwannomatosis are sporadic, approximately one-third occur in families and a subset of these has recently been associated with germline mutations in the tumor suppressor gene SMARCB1/INI1. Other curious syndromes that involve the peripheral nervous system are associated with predominant endocrine manifestations, and include Carney complex and MEN2b, secondary to inactivating mutations in the PRKAR1A gene in a subset, and activating mutations in RET, respectively. In this review, we provide a concise update on the diagnostic criteria, pathology and molecular pathogenesis of these enigmatic syndromes in relation to peripheral nerve sheath neoplasia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. (1988) National Institutes of Health Consensus Development Conference Statement: Neurofibromatosis. Arch Neurol 45:575-578

  2. (1994) Consensus Development Panel, National Institutes of Health Consensus Development Conference Statement n Acoustic Neuroma. Arch Neurol 51:201-207

  3. Almeida MQ, Muchow M, Boikos S, Bauer AJ, Griffin KJ, Tsang KM, Cheadle C, Watkins T, Wen F, Starost MF, Bossis I, Nesterova M, Stratakis CA (2010) Mouse Prkar1a haploinsufficiency leads to an increase in tumors in the Trp53 ± or Rb1 ± backgrounds and chemically induced skin papillomas by dysregulation of the cell cycle and Wnt signaling. Hum Mol Genet 19:1387–1398

    Article  PubMed  CAS  Google Scholar 

  4. Amieux PS, Cummings DE, Motamed K, Brandon EP, Wailes LA, Le K, Idzerda RL, McKnight GS (1997) Compensatory regulation of RIalpha protein levels in protein kinase A mutant mice. J Biol Chem 272:3993–3998

    Article  PubMed  CAS  Google Scholar 

  5. Antinheimo J, Sankila R, Carpen O, Pukkala E, Sainio M, Jaaskelainen J (2000) Population-based analysis of sporadic and type 2 neurofibromatosis-associated meningiomas and schwannomas. Neurology 54:71–76

    PubMed  CAS  Google Scholar 

  6. Atherton DJ, Pitcher DW, Wells RS, MacDonald DM (1980) A syndrome of various cutaneous pigmented lesions, myxoid neurofibromata and atrial myxoma: the NAME syndrome. Br J Dermatol 103:421–429

    Article  PubMed  CAS  Google Scholar 

  7. Bacci C, Sestini R, Provenzano A, Paganini I, Mancini I, Porfirio B, Vivarelli R, Genuardi M, Papi L (2010) Schwannomatosis associated with multiple meningiomas due to a familial SMARCB1 mutation. Neurogenetics 11:73–80

    Article  PubMed  CAS  Google Scholar 

  8. Baser ME, Friedman JM, Joe H, Shenton A, Wallace AJ, Ramsden RT, Evans DG (2011) Empirical development of improved diagnostic criteria for neurofibromatosis 2. Genet Med 13:576–581

    Article  PubMed  CAS  Google Scholar 

  9. Benhamouche S, Curto M, Saotome I, Gladden AB, Liu CH, Giovannini M, McClatchey AI (2010) Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver. Genes Dev 24:1718–1730

    Article  PubMed  CAS  Google Scholar 

  10. Bertherat J, Horvath A, Groussin L, Grabar S, Boikos S, Cazabat L, Libe R, Rene-Corail F, Stergiopoulos S, Bourdeau I, Bei T, Clauser E, Calender A, Kirschner LS, Bertagna X, Carney JA, Stratakis CA (2009) Mutations in regulatory subunit type 1A of cyclic adenosine 5’-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes. J Clin Endocrinol Metab 94:2085–2091

    Article  PubMed  CAS  Google Scholar 

  11. Biegel JA, Zhou JY, Rorke LB, Stenstrom C, Wainwright LM, Fogelgren B (1999) Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res 59:74–79

    PubMed  CAS  Google Scholar 

  12. Boikos SA, Stratakis CA (2006) Carney complex: pathology and molecular genetics. Neuroendocrinology 83:189–199

    Article  PubMed  CAS  Google Scholar 

  13. Bossis I, Voutetakis A, Bei T, Sandrini F, Griffin KJ, Stratakis CA (2004) Protein kinase A and its role in human neoplasia: the Carney complex paradigm. Endocr Relat Cancer 11:265–280

    Article  PubMed  CAS  Google Scholar 

  14. Bradbury AW, Carter DC, Miller WR, Cho-Chung YS, Clair T (1994) Protein kinase A (PK-A) regulatory subunit expression in colorectal cancer and related mucosa. Br J Cancer 69:738–742

    Article  PubMed  CAS  Google Scholar 

  15. Brems H, Chmara M, Sahbatou M, Denayer E, Taniguchi K, Kato R, Somers R, Messiaen L, De Schepper S, Fryns JP, Cools J, Marynen P, Thomas G, Yoshimura A, Legius E (2007) Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet 39:1120–1126

    Article  PubMed  CAS  Google Scholar 

  16. Brems H, Park C, Maertens O, Pemov A, Messiaen L, Upadhyaya M, Claes K, Beert E, Peeters K, Mautner V, Sloan JL, Yao L, Lee CC, Sciot R, De Smet L, Legius E, Stewart DR (2009) Glomus tumors in neurofibromatosis type 1: genetic, functional, and clinical evidence of a novel association. Cancer Res 69:7393–7401

    Article  PubMed  CAS  Google Scholar 

  17. Buchanan ME, Davis RL (2010) A distinct set of Drosophila brain neurons required for neurofibromatosis type 1-dependent learning and memory. J Neurosci 30:10135–10143

    Article  PubMed  CAS  Google Scholar 

  18. Carney JA (1990) Psammomatous melanotic schwannoma. A distinctive, heritable tumor with special associations, including cardiac myxoma and the Cushing syndrome. Am J Surg Pathol 14:206–222

    Article  PubMed  CAS  Google Scholar 

  19. Carney JA, Stratakis CA (1998) Epithelioid blue nevus and psammomatous melanotic schwannoma: the unusual pigmented skin tumors of the Carney complex. Semin Diagn Pathol 15:216–224

    PubMed  CAS  Google Scholar 

  20. Carroll S (2012) Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms. Acta Neuropathol

  21. Casey M, Vaughan CJ, He J, Hatcher CJ, Winter JM, Weremowicz S, Montgomery K, Kucherlapati R, Morton CC, Basson CT (2000) Mutations in the protein kinase A R1alpha regulatory subunit cause familial cardiac myxomas and Carney complex. J Clin Invest 106:R31–R38

    Article  PubMed  CAS  Google Scholar 

  22. Cawthon RM, Weiss R, Xu GF, Viskochil D, Culver M, Stevens J, Robertson M, Dunn D, Gesteland R, O’Connell P et al (1990) A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell 62:193–201

    Article  PubMed  CAS  Google Scholar 

  23. Christiaans I, Kenter SB, Brink HC, van Os TA, Baas F, van den Munckhof P, Kidd AM, Hulsebos TJ (2011) Germline SMARCB1 mutation and somatic NF2 mutations in familial multiple meningiomas. J Med Genet 48:93–97

    Article  PubMed  CAS  Google Scholar 

  24. Cichowski K, Jacks T (2001) NF1 tumor suppressor gene function: narrowing the GAP. Cell 104:593–604

    Article  PubMed  CAS  Google Scholar 

  25. Cras P, Ceuterick-de Groote C, Van Vyve M, Vercruyssen A, Martin JJ (1990) Malignant pigmented spinal nerve root schwannoma metastasizing in the brain and viscera. Clin Neuropathol 9:290–294

    PubMed  CAS  Google Scholar 

  26. Curto M, McClatchey AI (2008) Nf2/Merlin: a coordinator of receptor signalling and intercellular contact. Br J Cancer 98:256–262

    Article  PubMed  CAS  Google Scholar 

  27. Ducatman BS, Scheithauer BW (1984) Malignant peripheral nerve sheath tumors with divergent differentiation. Cancer 54:1049–1057

    Article  PubMed  CAS  Google Scholar 

  28. Evans DG, Huson SM, Donnai D, Neary W, Blair V, Newton V, Harris R (1992) A clinical study of type 2 neurofibromatosis. Q J Med 84:603–618

    PubMed  CAS  Google Scholar 

  29. Evans DG, Huson SM, Donnai D, Neary W, Blair V, Teare D, Newton V, Strachan T, Ramsden R, Harris R (1992) A genetic study of type 2 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity. J Med Genet 29:841–846

    Article  PubMed  CAS  Google Scholar 

  30. Evans DG, Baser ME, McGaughran J, Sharif S, Howard E, Moran A (2002) Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet 39:311–314

    Article  PubMed  CAS  Google Scholar 

  31. Evans DG, Birch JM, Ramsden RT, Sharif S, Baser ME (2006) Malignant transformation and new primary tumours after therapeutic radiation for benign disease: substantial risks in certain tumour prone syndromes. J Med Genet 43:289–294

    Article  PubMed  CAS  Google Scholar 

  32. Evans DG, Howard E, Giblin C, Clancy T, Spencer H, Huson SM, Lalloo F (2010) Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A 152A:327–332

    Article  PubMed  CAS  Google Scholar 

  33. Evans GR, Lloyd SK, Ramsden RT (2011) Neurofibromatosis type 2. Adv Otorhinolaryngol 70:91–98

    PubMed  Google Scholar 

  34. Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, Upadhyaya M, Towers R, Gleeson M, Steiger C, Kirby A (2007) Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet 44:81–88

    Article  PubMed  CAS  Google Scholar 

  35. Fossberg TM, Doskeland SO, Ueland PM (1978) Protein kinases in human renal cell carcinoma and renal cortex. A comparison of isozyme distribution and of responsiveness to adenosine 3′:5′-cyclic monophosphate. Arch Biochem Biophys 189:272–281

    Article  PubMed  CAS  Google Scholar 

  36. Fu YS, Kaye GI, Lattes R (1975) Primary malignant melanocytic tumors of the sympathetic ganglia, with an ultrastructural study of one. Cancer 36:2029–2041

    Article  PubMed  CAS  Google Scholar 

  37. Gaujoux S, Tissier F, Groussin L, Libe R, Ragazzon B, Launay P, Audebourg A, Dousset B, Bertagna X, Bertherat J (2008) Wnt/beta-catenin and 3′, 5′-cyclic adenosine 5′-monophosphate/protein kinase A signaling pathways alterations and somatic beta-catenin gene mutations in the progression of adrenocortical tumors. J Clin Endocrinol Metab 93:4135–4140

    Article  PubMed  CAS  Google Scholar 

  38. Goutagny S, Kalamarides M (2010) Meningiomas and neurofibromatosis. J Neurooncol 99:341–347

    Article  PubMed  Google Scholar 

  39. Greene EL, Horvath AD, Nesterova M, Giatzakis C, Bossis I, Stratakis CA (2008) In vitro functional studies of naturally occurring pathogenic PRKAR1A mutations that are not subject to nonsense mRNA decay. Hum Mutat 29:633–639

    Article  PubMed  CAS  Google Scholar 

  40. Griffin KJ, Kirschner LS, Matyakhina L, Stergiopoulos S, Robinson-White A, Lenherr S, Weinberg FD, Claflin E, Meoli E, Cho-Chung YS, Stratakis CA (2004) Down-regulation of regulatory subunit type 1A of protein kinase A leads to endocrine and other tumors. Cancer Res 64:8811–8815

    Article  PubMed  CAS  Google Scholar 

  41. Griffin KJ, Kirschner LS, Matyakhina L, Stergiopoulos SG, Robinson-White A, Lenherr SM, Weinberg FD, Claflin ES, Batista D, Bourdeau I, Voutetakis A, Sandrini F, Meoli EM, Bauer AJ, Cho-Chung YS, Bornstein SR, Carney JA, Stratakis CA (2004) A transgenic mouse bearing an antisense construct of regulatory subunit type 1A of protein kinase A develops endocrine and other tumours: comparison with Carney complex and other PRKAR1A induced lesions. J Med Genet 41:923–931

    Article  PubMed  CAS  Google Scholar 

  42. Groussin L, Horvath A, Jullian E, Boikos S, Rene-Corail F, Lefebvre H, Cephise-Velayoudom FL, Vantyghem MC, Chanson P, Conte-Devolx B, Lucas M, Gentil A, Malchoff CD, Tissier F, Carney JA, Bertagna X, Stratakis CA, Bertherat J (2006) A PRKAR1A mutation associated with primary pigmented nodular adrenocortical disease in 12 kindreds. J Clin Endocrinol Metab 91:1943–1949

    Article  PubMed  CAS  Google Scholar 

  43. Gujral TS, Singh VK, Jia Z, Mulligan LM (2006) Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2B. Cancer Res 66:10741–10749

    Article  PubMed  CAS  Google Scholar 

  44. Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A, Viskochil D (1997) The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 278:51–57

    Article  PubMed  CAS  Google Scholar 

  45. Gutmann DH, Collins FS (2002) Neurofibromatosis 1. In: Vogelstein B, Kinzler KW (eds) The genetic basis of human cancer. McGraw-Hill, New York

  46. Hadfield KD, Smith MJ, Trump D, Newman WG, Evans DG (2010) SMARCB1 mutations are not a common cause of multiple meningiomas. J Med Genet 47:567–568

    Article  PubMed  CAS  Google Scholar 

  47. Handschin JC, Eppenberger U (1979) Altered cellular ratio of type I and type II cyclic AMP-dependent protein kinase in human mammary tumors. FEBS Lett 106:301–304

    Article  PubMed  CAS  Google Scholar 

  48. Hanemann CO, Diebold R, Kaufmann D (2007) Role of NF2 haploinsufficiency in NF2-associated polyneuropathy. Brain Pathol 17:371–376

    Article  PubMed  CAS  Google Scholar 

  49. Horvath A, Boikos S, Giatzakis C, Robinson-White A, Groussin L, Griffin KJ, Stein E, Levine E, Delimpasi G, Hsiao HP, Keil M, Heyerdahl S, Matyakhina L, Libe R, Fratticci A, Kirschner LS, Cramer K, Gaillard RC, Bertagna X, Carney JA, Bertherat J, Bossis I, Stratakis CA (2006) A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia. Nat Genet 38:794–800

    Article  PubMed  CAS  Google Scholar 

  50. Horvath A, Bossis I, Giatzakis C, Levine E, Weinberg F, Meoli E, Robinson-White A, Siegel J, Soni P, Groussin L, Matyakhina L, Verma S, Remmers E, Nesterova M, Carney JA, Bertherat J, Stratakis CA (2008) Large deletions of the PRKAR1A gene in Carney complex. Clin Cancer Res 14:388–395

    Article  PubMed  CAS  Google Scholar 

  51. Horvath A, Stratakis CA (2009) Carney complex and lentiginosis. Pigment Cell Melanoma Res 22:580–587

    Article  PubMed  CAS  Google Scholar 

  52. Hulsebos TJ, Plomp AS, Wolterman RA, Robanus-Maandag EC, Baas F, Wesseling P (2007) Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am J Hum Genet 80:805–810

    Article  PubMed  CAS  Google Scholar 

  53. Huson SM, Compston DA, Clark P, Harper PS (1989) 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 26:704–711

    Article  PubMed  CAS  Google Scholar 

  54. Janzer RC, Makek M (1983) Intraoral malignant melanotic schwannoma. Ultrastructural evidence for melanogenesis by Schwann’s cells. Arch Pathol Lab Med 107:298–301

    PubMed  CAS  Google Scholar 

  55. Jett K, Friedman JM (2010) Clinical and genetic aspects of neurofibromatosis 1. Genet Med 12:1–11

    Article  PubMed  Google Scholar 

  56. Jouhilahti EM, Peltonen S, Callens T, Jokinen E, Heape AM, Messiaen L, Peltonen J (2011) The development of cutaneous neurofibromas. Am J Pathol 178:500–505

    Article  PubMed  Google Scholar 

  57. Kinderman FS, Kim C, von Daake S, Ma Y, Pham BQ, Spraggon G, Xuong NH, Jennings PA, Taylor SS (2006) A dynamic mechanism for AKAP binding to RII isoforms of cAMP-dependent protein kinase. Mol Cell 24:397–408

    Article  PubMed  CAS  Google Scholar 

  58. Kirschner LS, Carney JA, Pack SD, Taymans SE, Giatzakis C, Cho YS, Cho-Chung YS, Stratakis CA (2000) Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet 26:89–92

    Article  PubMed  CAS  Google Scholar 

  59. Kirschner LS, Kusewitt DF, Matyakhina L, Towns WH 2nd, Carney JA, Westphal H, Stratakis CA (2005) A mouse model for the Carney complex tumor syndrome develops neoplasia in cyclic AMP-responsive tissues. Cancer Res 65:4506–4514

    Article  PubMed  CAS  Google Scholar 

  60. Kissil JL, Wilker EW, Johnson KC, Eckman MS, Yaffe MB, Jacks T (2003) Merlin, the product of the Nf2 tumor suppressor gene, is an inhibitor of the p21-activated kinase, Pak1. Mol Cell 12:841–849

    Article  PubMed  CAS  Google Scholar 

  61. Kluwe L, Mautner V, Heinrich B, Dezube R, Jacoby LB, Friedrich RE, MacCollin M (2003) Molecular study of frequency of mosaicism in neurofibromatosis 2 patients with bilateral vestibular schwannomas. J Med Genet 40:109–114

    Article  PubMed  CAS  Google Scholar 

  62. Lallemand D, Curto M, Saotome I, Giovannini M, McClatchey AI (2003) NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions. Genes Dev 17:1090–1100

    Article  PubMed  CAS  Google Scholar 

  63. Le LQ, Shipman T, Burns DK, Parada LF (2009) Cell of origin and microenvironment contribution for NF1-associated dermal neurofibromas. Cell Stem Cell 4:453–463

    Article  PubMed  CAS  Google Scholar 

  64. Le LQ, Liu C, Shipman T, Chen Z, Suter U, Parada LF (2011) Susceptible stages in Schwann cells for NF1-associated plexiform neurofibroma development. Cancer Res 71:4686–4695

    Article  PubMed  CAS  Google Scholar 

  65. Ling BC, Wu J, Miller SJ, Monk KR, Shamekh R, Rizvi TA, Decourten-Myers G, Vogel KS, DeClue JE, Ratner N (2005) Role for the epidermal growth factor receptor in neurofibromatosis-related peripheral nerve tumorigenesis. Cancer Cell 7:65–75

    Article  PubMed  CAS  Google Scholar 

  66. Livesey SA, Kemp BE, Re CA, Partridge NC, Martin TJ (1982) Selective hormonal activation of cyclic AMP-dependent protein kinase isoenzymes in normal and malignant osteoblasts. J Biol Chem 257:14983–14987

    PubMed  CAS  Google Scholar 

  67. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds) (2007) WHO classification of tumours of the central nervous system, 4th edn. International Agency for Research on Cancer, Lyon

    Google Scholar 

  68. Lu-Emerson C, Plotkin SR (2009) The neurofibromatoses. Part 2: NF2 and schwannomatosis. Rev Neurol Dis 6:E81–E86

    PubMed  Google Scholar 

  69. Lu-Emerson C, Plotkin SR (2009) The neurofibromatoses. Part 1: NF1. Rev Neurol Dis 6:E47–E53

    PubMed  Google Scholar 

  70. MacCollin M, Chiocca EA, Evans DG, Friedman JM, Horvitz R, Jaramillo D, Lev M, Mautner VF, Niimura M, Plotkin SR, Sang CN, Stemmer-Rachamimov A, Roach ES (2005) Diagnostic criteria for schwannomatosis. Neurology 64:1838–1845

    Article  PubMed  CAS  Google Scholar 

  71. Mateus C, Palangie A, Franck N, Groussin L, Bertagna X, Avril MF, Bertherat J, Dupin N (2008) Heterogeneity of skin manifestations in patients with Carney complex. J Am Acad Dermatol 59:801–810

    Article  PubMed  Google Scholar 

  72. Mayes DA, Rizvi TA, Cancelas JA, Kolasinski NT, Ciraolo GM, Stemmer-Rachamimov AO, Ratner N (2011) Perinatal or adult Nf1 inactivation using tamoxifen-inducible PlpCre each cause neurofibroma formation. Cancer Res 71:4675–4685

    Article  PubMed  CAS  Google Scholar 

  73. McDaid HM, Cairns MT, Atkinson RJ, McAleer S, Harkin DP, Gilmore P, Johnston PG (1999) Increased expression of the RIalpha subunit of the cAMP-dependent protein kinase A is associated with advanced stage ovarian cancer. Br J Cancer 79:933–939

    Article  PubMed  CAS  Google Scholar 

  74. Meoli E, Bossis I, Cazabat L, Mavrakis M, Horvath A, Stergiopoulos S, Shiferaw ML, Fumey G, Perlemoine K, Muchow M, Robinson-White A, Weinberg F, Nesterova M, Patronas Y, Groussin L, Bertherat J, Stratakis CA (2008) Protein kinase A effects of an expressed PRKAR1A mutation associated with aggressive tumors. Cancer Res 68:3133–3141

    Article  PubMed  CAS  Google Scholar 

  75. Merel P, Hoang-Xuan K, Sanson M, Bijlsma E, Rouleau G, Laurent-Puig P, Pulst S, Baser M, Lenoir G, Sterkers JM et al (1995) Screening for germ-line mutations in the NF2 gene. Genes Chromosomes Cancer 12:117–127

    Article  PubMed  CAS  Google Scholar 

  76. Messiaen L, Yao S, Brems H, Callens T, Sathienkijkanchai A, Denayer E, Spencer E, Arn P, Babovic-Vuksanovic D, Bay C, Bobele G, Cohen BH, Escobar L, Eunpu D, Grebe T, Greenstein R, Hachen R, Irons M, Kronn D, Lemire E, Leppig K, Lim C, McDonald M, Narayanan V, Pearn A, Pedersen R, Powell B, Shapiro LR, Skidmore D, Tegay D, Thiese H, Zackai EH, Vijzelaar R, Taniguchi K, Ayada T, Okamoto F, Yoshimura A, Parret A, Korf B, Legius E (2009) Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome. JAMA 302:2111–2118

    Article  PubMed  CAS  Google Scholar 

  77. Moyhuddin A, Baser ME, Watson C, Purcell S, Ramsden RT, Heiberg A, Wallace AJ, Evans DG (2003) Somatic mosaicism in neurofibromatosis 2: prevalence and risk of disease transmission to offspring. J Med Genet 40:459–463

    Article  PubMed  CAS  Google Scholar 

  78. Mulvihill JJ, Parry DM, Sherman JL, Pikus A, Kaiser-Kupfer MI, Eldridge R (1990) NIH conference. Neurofibromatosis 1 (Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis). An update. Ann Intern Med 113:39–52

    PubMed  CAS  Google Scholar 

  79. Nakajima F, Imashuku S, Wilimas J, Champion JE, Green AA (1984) Distribution and properties of type I and type II binding proteins in the cyclic adenosine 3′:5′-monophosphate-dependent protein kinase system in Wilms’ tumor. Cancer Res 44:5182–5187

    PubMed  CAS  Google Scholar 

  80. Papageorgiou T, Stratakis CA (2002) Ovarian tumors associated with multiple endocrine neoplasias and related syndromes (Carney complex, Peutz-Jeghers syndrome, von Hippel-Lindau disease, Cowden’s disease). Int J Gynecol Cancer 12:337–347

    Article  PubMed  CAS  Google Scholar 

  81. Patil S, Perry A, Maccollin M, Dong S, Betensky RA, Yeh TH, Gutmann DH, Stemmer-Rachamimov AO (2008) Immunohistochemical analysis supports a role for INI1/SMARCB1 in hereditary forms of schwannomas, but not in solitary, sporadic schwannomas. Brain Pathol 18:517–519

    PubMed  CAS  Google Scholar 

  82. Perry A, Roth KA, Banerjee R, Fuller CE, Gutmann DH (2001) NF1 deletions in S-100 protein-positive and negative cells of sporadic and neurofibromatosis 1 (NF1)-associated plexiform neurofibromas and malignant peripheral nerve sheath tumors. Am J Pathol 159:57–61

    Article  PubMed  CAS  Google Scholar 

  83. Perry A, Kunz SN, Fuller CE, Banerjee R, Marley EF, Liapis H, Watson MA, Gutmann DH (2002) Differential NF1, p16, and EGFR patterns by interphase cytogenetics (FISH) in malignant peripheral nerve sheath tumor (MPNST) and morphologically similar spindle cell neoplasms. J Neuropathol Exp Neurol 61:702–709

    PubMed  CAS  Google Scholar 

  84. Razzaque MA, Nishizawa T, Komoike Y, Yagi H, Furutani M, Amo R, Kamisago M, Momma K, Katayama H, Nakagawa M, Fujiwara Y, Matsushima M, Mizuno K, Tokuyama M, Hirota H, Muneuchi J, Higashinakagawa T, Matsuoka R (2007) Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet 39:1013–1017

    Article  PubMed  CAS  Google Scholar 

  85. Reith JD, Goldblum JR (1996) Multiple cutaneous plexiform schwannomas. Report of a case and review of the literature with particular reference to the association with types 1 and 2 neurofibromatosis and schwannomatosis. Arch Pathol Lab Med 120:399–401

    PubMed  CAS  Google Scholar 

  86. Rhodes AR, Silverman RA, Harrist TJ, Perez-Atayde AR (1984) Mucocutaneous lentigines, cardiomucocutaneous myxomas, and multiple blue nevi: the “LAMB” syndrome. J Am Acad Dermatol 10:72–82

    Article  PubMed  CAS  Google Scholar 

  87. Riccardi VM (1992) Neurofibromatosis: Phenotpe, Natural History, and Pathogenesis, Second edn. The Johns Hopkins University Press, Baltimore

  88. Robinson-White A, Meoli E, Stergiopoulos S, Horvath A, Boikos S, Bossis I, Stratakis CA (2006) PRKAR1A Mutations and protein kinase A interactions with other signaling pathways in the adrenal cortex. J Clin Endocrinol Metab 91:2380–2388

    Article  PubMed  CAS  Google Scholar 

  89. Rodriguez FJ, Scheithauer BW, Abell-Aleff PC, Elamin E, Erlandson RA (2007) Low grade malignant peripheral nerve sheath tumor with smooth muscle differentiation. Acta Neuropathol 113:705–709

    Article  PubMed  Google Scholar 

  90. Rodriguez FJ, Scheithauer BW, George D, Midha R, MacCollin M, Stemmer-Rachamimov AO (2011) Superficial neurofibromas in the setting of schwannomatosis: nosologic implications. Acta Neuropathol 121:663–668

    Article  PubMed  Google Scholar 

  91. Rodriguez FJ, Folpe AL, Giannini C, Perry A (2012) pathology of peripheral nerve sheath tumors: diagnostic overview and update on selected diagnostic problems. Acta Neuropathol

  92. Rothenbuhler A, Stratakis CA (2010) Clinical and molecular genetics of Carney complex. Best Pract Res Clin Endocrinol Metab 24:389–399

    Article  PubMed  CAS  Google Scholar 

  93. Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C, Hoang-Xuan K, Demczuk S, Desmaze C, Plougastel B et al (1993) Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature 363:515–521

    Article  PubMed  CAS  Google Scholar 

  94. Roytta M, Elfversson J, Kalimo H (1988) Intraspinal pigmented schwannoma with malignant progression. Acta Neurochir (Wien) 95:147–154

    Article  CAS  Google Scholar 

  95. Sandrini F, Stratakis C (2003) Clinical and molecular genetics of Carney complex. Mol Genet Metab 78:83–92

    Article  PubMed  CAS  Google Scholar 

  96. Schaffer JV, Kamino H, Witkiewicz A, McNiff JM, Orlow SJ (2006) Mucocutaneous neuromas: an underrecognized manifestation of PTEN hamartoma-tumor syndrome. Arch Dermatol 142:625–632

    Article  PubMed  Google Scholar 

  97. Scheithauer BW, Woodruff JM, Erlandson RA (1997) Tumors of the Peripheral Nervous System. Armed Forces Institute of Pathology, Washington D.C

    Google Scholar 

  98. Scott JD (1991) Cyclic nucleotide-dependent protein kinases. Pharmacol Ther 50:123–145

    Article  PubMed  CAS  Google Scholar 

  99. Selvanathan SK, Shenton A, Ferner R, Wallace AJ, Huson SM, Ramsden RT, Evans DG (2010) Further genotype-phenotype correlations in neurofibromatosis 2. Clin Genet 77:163–170

    Article  PubMed  CAS  Google Scholar 

  100. Sestini R, Bacci C, Provenzano A, Genuardi M, Papi L (2008) Evidence of a four-hit mechanism involving SMARCB1 and NF2 in schwannomatosis-associated schwannomas. Hum Mutat 29:227–231

    Article  PubMed  CAS  Google Scholar 

  101. Shabb JB (2001) Physiological substrates of cAMP-dependent protein kinase. Chem Rev 101:2381–2411

    Article  PubMed  CAS  Google Scholar 

  102. Stratakis CA, Carney JA, Lin JP, Papanicolaou DA, Karl M, Kastner DL, Pras E, Chrousos GP (1996) Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2. J Clin Invest 97:699–705

    Article  PubMed  CAS  Google Scholar 

  103. Stratakis CA, Courcoutsakis NA, Abati A, Filie A, Doppman JL, Carney JA, Shawker T (1997) Thyroid gland abnormalities in patients with the syndrome of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas (Carney complex). J Clin Endocrinol Metab 82:2037–2043

    Article  PubMed  CAS  Google Scholar 

  104. Stratakis CA, Kirschner LS, Carney JA (1998) Carney complex: diagnosis and management of the complex of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas. Am J Med Genet 80:183–185

    Article  PubMed  CAS  Google Scholar 

  105. Stratakis CA (2000) Genetics of Peutz-Jeghers syndrome, Carney complex and other familial lentiginoses. Horm Res 54:334–343

    Article  PubMed  CAS  Google Scholar 

  106. Stratakis CA, Papageorgiou T, Premkumar A, Pack S, Kirschner LS, Taymans SE, Zhuang Z, Oelkers WH, Carney JA (2000) Ovarian lesions in Carney complex: clinical genetics and possible predisposition to malignancy. J Clin Endocrinol Metab 85:4359–4366

    Article  PubMed  CAS  Google Scholar 

  107. Stratakis CA, Kirschner LS, Carney JA (2001) Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab 86:4041–4046

    Article  PubMed  CAS  Google Scholar 

  108. Tadjine M, Lampron A, Ouadi L, Horvath A, Stratakis CA, Bourdeau I (2008) Detection of somatic beta-catenin mutations in primary pigmented nodular adrenocortical disease (PPNAD). Clin Endocrinol (Oxf) 69:367–373

    Article  CAS  Google Scholar 

  109. Takahashi M, Cooper GM (1987) ret transforming gene encodes a fusion protein homologous to tyrosine kinases. Mol Cell Biol 7:1378–1385

    PubMed  CAS  Google Scholar 

  110. Tasken K, Skalhegg BS, Tasken KA, Solberg R, Knutsen HK, Levy FO, Sandberg M, Orstavik S, Larsen T, Johansen AK, Vang T, Schrader HP, Reinton NT, Torgersen KM, Hansson V, Jahnsen T (1997) Structure, function, and regulation of human cAMP-dependent protein kinases. Adv Second Messenger Phosphoprot Res 31:191–204

    Article  CAS  Google Scholar 

  111. Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, Parry DM, Eldridge R, Kley N, Menon AG, Pulaski K et al (1993) A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 72:791–800

    Article  PubMed  CAS  Google Scholar 

  112. Val-Bernal JF, Figols J, Vazquez-Barquero A (1995) Cutaneous plexiform schwannoma associated with neurofibromatosis type 2. Cancer 76:1181–1186

    Article  PubMed  CAS  Google Scholar 

  113. Veugelers M, Wilkes D, Burton K, McDermott DA, Song Y, Goldstein MM, La Perle K, Vaughan CJ, O’Hagan A, Bennett KR, Meyer BJ, Legius E, Karttunen M, Norio R, Kaariainen H, Lavyne M, Neau JP, Richter G, Kirali K, Farnsworth A, Stapleton K, Morelli P, Takanashi Y, Bamforth JS, Eitelberger F, Noszian I, Manfroi W, Powers J, Mochizuki Y, Imai T, Ko GT, Driscoll DA, Goldmuntz E, Edelberg JM, Collins A, Eccles D, Irvine AD, McKnight GS, Basson CT (2004) Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice. Proc Natl Acad Sci USA 101:14222–14227

    Article  PubMed  CAS  Google Scholar 

  114. Wallace MR, Marchuk DA, Andersen LB, Letcher R, Odeh HM, Saulino AM, Fountain JW, Brereton A, Nicholson J, Mitchell AL et al (1990) Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249:181–186

    Article  PubMed  CAS  Google Scholar 

  115. Warrington NM, Gianino SM, Jackson E, Goldhoff P, Garbow JR, Piwnica-Worms D, Gutmann DH, Rubin JB (2010) Cyclic AMP suppression is sufficient to induce gliomagenesis in a mouse model of neurofibromatosis-1. Cancer Res 70:5717–5727

    Article  PubMed  CAS  Google Scholar 

  116. Watson DM, Hawkins RA, Bundred NJ, Stewart HJ, Miller WR (1987) Tumour cyclic AMP binding proteins and endocrine responsiveness in patients with inoperable breast cancer. Br J Cancer 56:141–142

    Article  PubMed  CAS  Google Scholar 

  117. Woodruff JM, Christensen WN (1993) Glandular peripheral nerve sheath tumors. Cancer 72:3618–3628

    Article  PubMed  CAS  Google Scholar 

  118. Woodruff JM, Perino G (1994) Non-germ-cell or teratomatous malignant tumors showing additional rhabdomyoblastic differentiation, with emphasis on the malignant Triton tumor. Semin Diagn Pathol 11:69–81

    PubMed  CAS  Google Scholar 

  119. Woodruff JM (1999) Pathology of tumors of the peripheral nerve sheath in type 1 neurofibromatosis. Am J Med Genet 89:23–30

    Article  PubMed  CAS  Google Scholar 

  120. Wu J, Williams JP, Rizvi TA, Kordich JJ, Witte D, Meijer D, Stemmer-Rachamimov AO, Cancelas JA, Ratner N (2008) Plexiform and dermal neurofibromas and pigmentation are caused by Nf1 loss in desert hedgehog-expressing cells. Cancer Cell 13:105–116

    Article  PubMed  CAS  Google Scholar 

  121. Yang FC, Ingram DA, Chen S, Zhu Y, Yuan J, Li X, Yang X, Knowles S, Horn W, Li Y, Zhang S, Yang Y, Vakili ST, Yu M, Burns D, Robertson K, Hutchins G, Parada LF, Clapp DW (2008) Nf1-dependent tumors require a microenvironment containing Nf1± and c-kit-dependent bone marrow. Cell 135:437–448

    Article  PubMed  CAS  Google Scholar 

  122. Yin Z, Jones GN, Towns WH 2nd, Zhang X, Abel ED, Binkley PF, Jarjoura D, Kirschner LS (2008) Heart-specific ablation of Prkar1a causes failure of heart development and myxomagenesis. Circulation 117:1414–1422

    Article  PubMed  CAS  Google Scholar 

  123. Yin Z, Williams-Simons L, Parlow AF, Asa S, Kirschner LS (2008) Pituitary-specific knockout of the Carney complex gene Prkar1a leads to pituitary tumorigenesis. Mol Endocrinol 22:380–387

    Article  PubMed  CAS  Google Scholar 

  124. Yu J, Deshmukh H, Payton JE, Dunham C, Scheithauer BW, Tihan T, Prayson RA, Guha A, Bridge JA, Ferner RE, Lindberg GM, Gutmann RJ, Emnett RJ, Salavaggione L, Gutmann DH, Nagarajan R, Watson MA, Perry A (2011) Array-based comparative genomic hybridization identifies CDK4 and FOXM1 alterations as independent predictors of survival in malignant peripheral nerve sheath tumor. Clin Cancer Res 17:1924–1934

    Article  PubMed  CAS  Google Scholar 

  125. Zheng H, Chang L, Patel N, Yang J, Lowe L, Burns DK, Zhu Y (2008) Induction of abnormal proliferation by nonmyelinating schwann cells triggers neurofibroma formation. Cancer Cell 13:117–128

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Drs Jaishri Blakeley, J. Aidan Carney, Caterina Giannini and Arie Perry who contributed pictures. They also thank Sharon Blackburn at the Johns Hopkins Pathology Photographic Arts Laboratory for graphical technical assistance.

Author information

Authors and Affiliations

  1. Division of Neuropathology, Department of Pathology, Johns Hopkins University, 720 Rutland Avenue, Ross Building, 512B, Baltimore, MD, 21205, USA

    Fausto J. Rodriguez

  2. Section on Endocrinology and Genetics Program on Developmental Endocrinology and Genetics, NICHD, NIH, Bethesda, USA

    Constantine A. Stratakis

  3. Department of Genetic Medicine, Manchester Academic Health Science Centre, St Mary’s Hospital, Oxford Road, Manchester, M13 9WL, UK

    D. Gareth Evans

Authors
  1. Fausto J. Rodriguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Constantine A. Stratakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Gareth Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fausto J. Rodriguez.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rodriguez, F.J., Stratakis, C.A. & Evans, D.G. Genetic predisposition to peripheral nerve neoplasia: diagnostic criteria and pathogenesis of neurofibromatoses, Carney complex, and related syndromes. Acta Neuropathol 123, 349–367 (2012). https://doi.org/10.1007/s00401-011-0935-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-011-0935-7

Keywords

Search

Navigation