RESEARCH PROGRESS OF PATHOGENESIS MECHANISM OF SPINAL DEFORMITY IN NEUROFIBROMATOSIS TYPE 1_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

YANGHuiliang , ZHOUChunguang ,  SONGYueming

Department of Orthopedics, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P. R. China;

Corresponding author：

SONGYueming, Email: sym_cd@yahoo.com.cn

Keywords：

Neurofibromatosis type 1; Spinal deformity; Pathogenesis mechanism

DOI：

10.7507/1002-1892.20160239

Video：

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Objective To review the research progress of pathogenesis mechanism of spinal deformity in neurofibromatosis type 1 (NF1). Methods Recent literature concerning the pathogenesis mechanism of spinal deformity in NF1 was extensively reviewed, and current developments of the correction of spinal deformity and NF1 and the pathogenesis mechanism were summarized. Results The pathogenesis mechanism of spinal deformity in NF1 is not yet clearly known. Current theories include erosion and stress of neurofibromas, melatonin-related decreased contractility of paraspinal muscles, osteopenia and osteoporosis, sexual precocity and mesoderm dysplasia. Conclusion The clinical manifestations of NF1 may cause the spinal deformities in patients with NF1. The research of pathogenesis mechanism of spinal deformity in NF1 will be conducive to further understanding, diagnosis and treatment of NF1-related spinal deformity.

Citation： YANGHuiliang, ZHOUChunguang, SONGYueming. RESEARCH PROGRESS OF PATHOGENESIS MECHANISM OF SPINAL DEFORMITY IN NEUROFIBROMATOSIS TYPE 1. Chinese Journal of Reparative and Reconstructive Surgery, 2016, 30(9): 1174-1178. doi: 10.7507/1002-1892.20160239 Copy

1.	Zhou Y, He Y, Sharma R, et al. Hyperactive RAS/PI3-K/MAPK Signaling Cascade in Migration and Adhesion of Nf1 Haploinsufficient Mesenchymal Stem/Progenitor Cells. Int J Mol Sci, 2015, 16(6):12345-12359.
2.	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(1):140-151.
3.	Abdel-Wanis ME, Kawahara N. Aetiology of spinal deformities in neurofibromatosis 1:new hypotheses. Med Hypotheses, 2001, 56(3):400-404.
4.	Tsirikos AI, Saifuddin A, Noordeen MH. Spinal deformity in neurofibromatosis type-1:diagnosis and treatment. Eur Spine J, 2005, 14(5):427-439.
5.	Guha A, Lau N, Huvar I, et al. Ras-GTP levels are elevated in human NF1 peripheral nerve tumors. Oncogene, 1996, 12(3):507-513.
6.	Cho SK, Stoker GE, Bridwell KH. Spinal reconstruction with pedicle screw-based instrumentation and rhBMP-2 in patients with neurofibromatosis and severe dural ectasia and spinal deformity:report of two cases and a review of the literature. J Bone Joint Surg (Am), 2011, 93(15):e86.
7.	Fares Y, Haddad GF, Khazim R, et al. Vertebral scalloping in neurofibromatosis-1. Neurosciences (Riyadh), 2007, 12(2):155-157.
8.	Casselman ES, Mandell GA. Vertebral scalloping in neurofibromatosis. Radiology, 1979, 131(1):89-94.
9.	Lim C, Kwon K, Lee K. Plexiform neurofibroma treated with pharmacopuncture. J Pharmacopuncture, 2014, 17(3):74-77.
10.	Rutkowski JL, Wu K, Gutmann DH, et al. Genetic and cellular defects contributing to benign tumor formation in neurofibromatosis type 1. Hum Mol Genet, 2000, 9(7):1059-1066.
11.	Zhu Y, Ghosh P, Charnay P, et al. Neurofibromas in NF1:Schwann cell origin and role of tumor environment. Science, 2002, 296(5569):920-922.
12.	Munchhof AM, Li F, White HA, et al. Neurofibroma-associated growth factors activate a distinct signaling network to alter the function of neurofibromin-deficient endothelial cells. Hum Mol Genet, 2006, 15(11):1858-1869.
13.	Pasmant E, Sabbagh A, Masliah-Planchon J, et al. Role of noncoding RNA ANRIL in genesis of plexiform neurofibromas in neurofibromatosis type 1. J Natl Cancer Inst, 2011, 103(22):1713-1722.
14.	Chai G, Liu N, Ma J, et al. MicroRNA-10b regulates tumorigenesis in neurofibromatosis type 1. Cancer Sci, 2010, 101(9):1997-2004.
15.	Wang PW, Pan TL, Lin CH, et al. Characterization of plasma protein profiles from patients with neurofibromatosis I. Clin Chim Acta, 2007, 380(1-2):139-144.
16.	Schonauer C, Tessitore E, Frascadore L, et al. Lumbosacral dural ectasia in type 1 neurofibromatosis. Report of two cases. J Neurosurg Sci, 2000, 44(3):165-169.
17.	Woon CY. Dural ectasia:a manifestation of type 1 neurofibromatosis. CMAJ, 2010, 182(13):1448.
18.	Lee WJ, Park OJ, Won CH, et al. Neurofibromatosis type 1 with dural ectasia. J Dermatol, 2012, 39(7):655-656.
19.	Kita K, Yamashita K, Abe M, et al. Eight-year follow-up findings of surgical treatment for severe dystrophic changes in the cervical spine associated with neurofibromatosis type I:a case report. J Pediatr Orthop B, 2016.[Epub ahead of print].
20.	Lovblad KO, Remonda L, Ozdoba C, et al. Dural ectasia of the optic nerve sheath in neurofibromatosis type 1:CT and MR features. J Comput Assist Tomogr, 1994, 18(5):728-730.
21.	García-Estevez DA, Arce-Pérez M. Dural ectasia in the cervical spine and neurofibromatosis type 1. Rev Neurol, 2009, 48(1):51.
22.	孔祥英, 左萍萍, 蔡哲.褪黑素与神经退行性疾病相关的研究进展.中国康复理论与实践, 2007, 13(7):634-636.
23.	Cunnane SC, Manku MS, Horrobin DF. The pineal and regulation of fibrosis:pinealectomy as a model of primary biliary cirrhosis:roles of melatonin and prostaglandins in fibrosis and regulation of T lymphocytes. Med Hypotheses, 1979, 5(4):403-414.
24.	Mizrak B, Parlakpinar H, Acet A, et al. Effects of pinealectomy and exogenous melatonin on rat hearts. Acta Histochem, 2004, 106(1):29-36.
25.	Chaglassian JH, Riseborough EJ, Hall JE. Neurofibromatous scoliosis. Natural history and results of treatment in thirty-seven cases. J Bone Joint Surg (Am), 1976, 58(5):695-702.
26.	Kossler N, Stricker S, Rödelsperger C, et al. Neurofibromin (Nf1) is required for skeletal muscle development. Hum Mol Genet, 2011, 20(14):2697-2709.
27.	Schindeler A, Little DG. Recent insights into bone development, homeostasis, and repair in type 1 neurofibromatosis (NF1). Bone, 2008, 42(4):616-622.
28.	Halmai V, Szász K, Morava E, et al. Decreased bone mineral density as a risk factor in the development of spinal deformities in neurofibromatosis. Orv Hetil, 2001, 142(52):2893-2897.
29.	Heervä E, Alanne MH, Peltonen S, et al. Osteoclasts in neurofibromatosis type 1 display enhanced resorption capacity, aberrant morphology, and resistance to serum deprivation. Bone, 2010, 47(3):583-590.
30.	He Y, Rhodes SD, Chen S, et al. c-Fms signaling mediates neurofibromatosis Type-1 osteoclast gain-in-functions. PLoS One, 2012, 7(11):e46900.
31.	He Y, Staser K, Rhodes SD, et al. Erk1 positively regulates osteoclast differentiation and bone resorptive activity. PLoS One, 2011, 6(9):e24780.
32.	Ma J, Li M, Hock J, et al. Hyperactivation of mTOR critically regulates abnormal osteoclastogenesis in neurofibromatosis Type 1. J Orthop Res, 2012, 30(1):144-152.
33.	Glantschnig H, Fisher JE, Wesolowski G, et al. M-CSF, TNFalpha and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase. Cell Death Differ, 2003, 10(10):1165-1177.
34.	Sugatani T, Hruska KA. Akt1/Akt2 and mammalian target of rapamycin/Bim play critical roles in osteoclast differentiation and survival, respectively, whereas Akt is dispensable for cell survival in isolated osteoclast precursors. J Biol Chem, 2005, 280(5):3583-3589.
35.	Rhodes SD, Wu X, He Y, et al. Hyperactive transforming growth factor-betal signaling potentiates skeletal defects in a neurofibromatosis type 1 mouse model. J Bone Miner Res, 2013, 28(12):2476-2489.
36.	Sharma R, Wu X, Rhodes SD, et al. Hyperactive Ras/MAPK signaling is critical for tibial nonunion fracture in neurofibromin-deficient mice. Hum Mol Genet, 2013, 22(23):4818-4828.
37.	Glass DA 2nd, Bialek P, Ahn JD, et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell, 2005, 8(5):751-764.
38.	Sullivan K, El-Hoss J, Little DG, et al. JNK inhibitors increase osteogenesis in Nf1-deficient cells. Bone, 2011, 49(6):1311-1316.
39.	Heervä E, Leinonen P, Kuorilehto T, et al. Neurofibromatosis 1-related osteopenia often progresses to osteoporosis in 12 years. Calcif Tissue Int, 2013, 92(1):23-27.
40.	Seitz S, Schnabel C, Busse B, et al. High bone turnover and accumulation of osteoid in patients with neurofibromatosis 1. Osteoporos Int, 2010, 21(1):119-127.
41.	Bahadir C, Gürleyik G, Ocak E. Neurofibromatosis type 1 and primary hyperparathyroidism with spinal deformity and osteoporosis. Acta Chir Belg, 2009, 109(1):123-125.
42.	Namazi H. Von Recklinghausen disease may be a pineal deficiency disease. Med Hypotheses, 2007, 69(2):458.
43.	Machida M, Dubousset J, Imamura Y, et al. Melatonin. A possible role in pathogenesis of adolescent idiopathic scoliosis. Spine (Phila Pa 1976), 1996, 21(10):1147-1152.
44.	Cheung KM, Wang T, Hu YG, et al. Primary thoracolumbar scoliosis in pinealectomized chickens. Spine (Phila Pa 1976), 2003, 28(22):2499-2504.
45.	Boulanger JM, Larbrisseau A. Neurofibromatosis type 1 in a pediatric population:Ste-Justine's experience. Can J Neurol Sci, 2005, 32(2):225-231.
46.	Virdis R, Sigorini M, Laiolo A, et al. Neurofibromatosis type 1 and precocious puberty. J Pediatr Endocrinol Metab, 2000, 13 Suppl 1:841-844.
47.	Virdis R, Street ME, Bandello MA, et al. Growth and pubertal disorders in neurofibromatosis type 1. J Pediatr Endocrinol Metab, 2003, 16 Suppl 2:289-292.
48.	Khoo Bao JN, Ogunwale B, Huson SM, et al. Spinal bone defects in neurofibromatosis type I with dural ectasia:stress fractures or dysplastic? A case series. Eur Radiol, 2013, 23(12):3418-3421.
49.	Sabbagh A, Pasmant E, Laurendeau I, et al. Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1. Hum Mol Genet, 2009, 18(15):2768-2778.
50.	Pasmant E, Sabbagh A, Vidaud M, et al. ANRIL, a long, noncoding RNA, is an unexpected major hotspot in GWAS. FASEB J, 2011, 25(2):444-448.

1. Zhou Y, He Y, Sharma R, et al. Hyperactive RAS/PI3-K/MAPK Signaling Cascade in Migration and Adhesion of Nf1 Haploinsufficient Mesenchymal Stem/Progenitor Cells. Int J Mol Sci, 2015, 16(6):12345-12359.
2. 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(1):140-151.
3. Abdel-Wanis ME, Kawahara N. Aetiology of spinal deformities in neurofibromatosis 1:new hypotheses. Med Hypotheses, 2001, 56(3):400-404.
4. Tsirikos AI, Saifuddin A, Noordeen MH. Spinal deformity in neurofibromatosis type-1:diagnosis and treatment. Eur Spine J, 2005, 14(5):427-439.
5. Guha A, Lau N, Huvar I, et al. Ras-GTP levels are elevated in human NF1 peripheral nerve tumors. Oncogene, 1996, 12(3):507-513.
6. Cho SK, Stoker GE, Bridwell KH. Spinal reconstruction with pedicle screw-based instrumentation and rhBMP-2 in patients with neurofibromatosis and severe dural ectasia and spinal deformity:report of two cases and a review of the literature. J Bone Joint Surg (Am), 2011, 93(15):e86.
7. Fares Y, Haddad GF, Khazim R, et al. Vertebral scalloping in neurofibromatosis-1. Neurosciences (Riyadh), 2007, 12(2):155-157.
8. Casselman ES, Mandell GA. Vertebral scalloping in neurofibromatosis. Radiology, 1979, 131(1):89-94.
9. Lim C, Kwon K, Lee K. Plexiform neurofibroma treated with pharmacopuncture. J Pharmacopuncture, 2014, 17(3):74-77.
10. Rutkowski JL, Wu K, Gutmann DH, et al. Genetic and cellular defects contributing to benign tumor formation in neurofibromatosis type 1. Hum Mol Genet, 2000, 9(7):1059-1066.
11. Zhu Y, Ghosh P, Charnay P, et al. Neurofibromas in NF1:Schwann cell origin and role of tumor environment. Science, 2002, 296(5569):920-922.
12. Munchhof AM, Li F, White HA, et al. Neurofibroma-associated growth factors activate a distinct signaling network to alter the function of neurofibromin-deficient endothelial cells. Hum Mol Genet, 2006, 15(11):1858-1869.
13. Pasmant E, Sabbagh A, Masliah-Planchon J, et al. Role of noncoding RNA ANRIL in genesis of plexiform neurofibromas in neurofibromatosis type 1. J Natl Cancer Inst, 2011, 103(22):1713-1722.
14. Chai G, Liu N, Ma J, et al. MicroRNA-10b regulates tumorigenesis in neurofibromatosis type 1. Cancer Sci, 2010, 101(9):1997-2004.
15. Wang PW, Pan TL, Lin CH, et al. Characterization of plasma protein profiles from patients with neurofibromatosis I. Clin Chim Acta, 2007, 380(1-2):139-144.
16. Schonauer C, Tessitore E, Frascadore L, et al. Lumbosacral dural ectasia in type 1 neurofibromatosis. Report of two cases. J Neurosurg Sci, 2000, 44(3):165-169.
17. Woon CY. Dural ectasia:a manifestation of type 1 neurofibromatosis. CMAJ, 2010, 182(13):1448.
18. Lee WJ, Park OJ, Won CH, et al. Neurofibromatosis type 1 with dural ectasia. J Dermatol, 2012, 39(7):655-656.
19. Kita K, Yamashita K, Abe M, et al. Eight-year follow-up findings of surgical treatment for severe dystrophic changes in the cervical spine associated with neurofibromatosis type I:a case report. J Pediatr Orthop B, 2016.[Epub ahead of print].
20. Lovblad KO, Remonda L, Ozdoba C, et al. Dural ectasia of the optic nerve sheath in neurofibromatosis type 1:CT and MR features. J Comput Assist Tomogr, 1994, 18(5):728-730.
21. García-Estevez DA, Arce-Pérez M. Dural ectasia in the cervical spine and neurofibromatosis type 1. Rev Neurol, 2009, 48(1):51.
22. 孔祥英, 左萍萍, 蔡哲.褪黑素与神经退行性疾病相关的研究进展.中国康复理论与实践, 2007, 13(7):634-636.
23. Cunnane SC, Manku MS, Horrobin DF. The pineal and regulation of fibrosis:pinealectomy as a model of primary biliary cirrhosis:roles of melatonin and prostaglandins in fibrosis and regulation of T lymphocytes. Med Hypotheses, 1979, 5(4):403-414.
24. Mizrak B, Parlakpinar H, Acet A, et al. Effects of pinealectomy and exogenous melatonin on rat hearts. Acta Histochem, 2004, 106(1):29-36.
25. Chaglassian JH, Riseborough EJ, Hall JE. Neurofibromatous scoliosis. Natural history and results of treatment in thirty-seven cases. J Bone Joint Surg (Am), 1976, 58(5):695-702.
26. Kossler N, Stricker S, Rödelsperger C, et al. Neurofibromin (Nf1) is required for skeletal muscle development. Hum Mol Genet, 2011, 20(14):2697-2709.
27. Schindeler A, Little DG. Recent insights into bone development, homeostasis, and repair in type 1 neurofibromatosis (NF1). Bone, 2008, 42(4):616-622.
28. Halmai V, Szász K, Morava E, et al. Decreased bone mineral density as a risk factor in the development of spinal deformities in neurofibromatosis. Orv Hetil, 2001, 142(52):2893-2897.
29. Heervä E, Alanne MH, Peltonen S, et al. Osteoclasts in neurofibromatosis type 1 display enhanced resorption capacity, aberrant morphology, and resistance to serum deprivation. Bone, 2010, 47(3):583-590.
30. He Y, Rhodes SD, Chen S, et al. c-Fms signaling mediates neurofibromatosis Type-1 osteoclast gain-in-functions. PLoS One, 2012, 7(11):e46900.
31. He Y, Staser K, Rhodes SD, et al. Erk1 positively regulates osteoclast differentiation and bone resorptive activity. PLoS One, 2011, 6(9):e24780.
32. Ma J, Li M, Hock J, et al. Hyperactivation of mTOR critically regulates abnormal osteoclastogenesis in neurofibromatosis Type 1. J Orthop Res, 2012, 30(1):144-152.
33. Glantschnig H, Fisher JE, Wesolowski G, et al. M-CSF, TNFalpha and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase. Cell Death Differ, 2003, 10(10):1165-1177.
34. Sugatani T, Hruska KA. Akt1/Akt2 and mammalian target of rapamycin/Bim play critical roles in osteoclast differentiation and survival, respectively, whereas Akt is dispensable for cell survival in isolated osteoclast precursors. J Biol Chem, 2005, 280(5):3583-3589.
35. Rhodes SD, Wu X, He Y, et al. Hyperactive transforming growth factor-betal signaling potentiates skeletal defects in a neurofibromatosis type 1 mouse model. J Bone Miner Res, 2013, 28(12):2476-2489.
36. Sharma R, Wu X, Rhodes SD, et al. Hyperactive Ras/MAPK signaling is critical for tibial nonunion fracture in neurofibromin-deficient mice. Hum Mol Genet, 2013, 22(23):4818-4828.
37. Glass DA 2nd, Bialek P, Ahn JD, et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell, 2005, 8(5):751-764.
38. Sullivan K, El-Hoss J, Little DG, et al. JNK inhibitors increase osteogenesis in Nf1-deficient cells. Bone, 2011, 49(6):1311-1316.
39. Heervä E, Leinonen P, Kuorilehto T, et al. Neurofibromatosis 1-related osteopenia often progresses to osteoporosis in 12 years. Calcif Tissue Int, 2013, 92(1):23-27.
40. Seitz S, Schnabel C, Busse B, et al. High bone turnover and accumulation of osteoid in patients with neurofibromatosis 1. Osteoporos Int, 2010, 21(1):119-127.
41. Bahadir C, Gürleyik G, Ocak E. Neurofibromatosis type 1 and primary hyperparathyroidism with spinal deformity and osteoporosis. Acta Chir Belg, 2009, 109(1):123-125.
42. Namazi H. Von Recklinghausen disease may be a pineal deficiency disease. Med Hypotheses, 2007, 69(2):458.
43. Machida M, Dubousset J, Imamura Y, et al. Melatonin. A possible role in pathogenesis of adolescent idiopathic scoliosis. Spine (Phila Pa 1976), 1996, 21(10):1147-1152.
44. Cheung KM, Wang T, Hu YG, et al. Primary thoracolumbar scoliosis in pinealectomized chickens. Spine (Phila Pa 1976), 2003, 28(22):2499-2504.
45. Boulanger JM, Larbrisseau A. Neurofibromatosis type 1 in a pediatric population:Ste-Justine's experience. Can J Neurol Sci, 2005, 32(2):225-231.
46. Virdis R, Sigorini M, Laiolo A, et al. Neurofibromatosis type 1 and precocious puberty. J Pediatr Endocrinol Metab, 2000, 13 Suppl 1:841-844.
47. Virdis R, Street ME, Bandello MA, et al. Growth and pubertal disorders in neurofibromatosis type 1. J Pediatr Endocrinol Metab, 2003, 16 Suppl 2:289-292.
48. Khoo Bao JN, Ogunwale B, Huson SM, et al. Spinal bone defects in neurofibromatosis type I with dural ectasia:stress fractures or dysplastic? A case series. Eur Radiol, 2013, 23(12):3418-3421.
49. Sabbagh A, Pasmant E, Laurendeau I, et al. Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1. Hum Mol Genet, 2009, 18(15):2768-2778.
50. Pasmant E, Sabbagh A, Vidaud M, et al. ANRIL, a long, noncoding RNA, is an unexpected major hotspot in GWAS. FASEB J, 2011, 25(2):444-448.

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RESEARCH PROGRESS OF PATHOGENESIS MECHANISM OF SPINAL DEFORMITY IN NEUROFIBROMATOSIS TYPE 1

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