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Bone mineral metabolism in patients with neurofibromatosis type 1 (von Recklingausen disease)

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Abstract

The neurofibromatosis type 1 (NF1) is characterized by specific cutaneous features (neurofibromas, “café-au-lait” spots of the skin) and alterations of several tissue (nervous, vascular) and bone deformities, such as scoliosis, congenital pseudoarthrosis and bone dysplasia of tibia. Moreover, several studies have shown systemic involvement of bone tissue in NF1 patients, leading to reduced bone mass. The aim of our study was to evaluate some bone mineral metabolism parameters before and after calcium and vitamin D supplementation in NF1 patients. We evaluated in 70 NF1 consecutive patients the mineral metabolism and bone mineral density compared with 40 normal subjects. We showed bone alterations in 35% of patients and the increase of bone formation markers, such as bone isoenzyme of alkaline phosphatase (41.2 ± 15.5 vs. 25.6 ± 8.7 UI; P < 0.05, respectively) and osteocalcin (18.1 ± 5.6 vs. 7.6 ± 1.9 ng/ml; P < 0.05) and reduction of circulating levels of (25OH)-vitamin D (21.8 ± 12.3 ng/ml) with an high percentage of hypovitaminosys D (>60%). Moreover, we revealed a significant reduction of bone mass density at spine (L1–L4) (0.935 ± 0.13 vs. 1.110 ± 0.17 g/cm2; P < 0.001) and femoral neck side (0.765 ± 0.09 vs. 0.839 ± 0.12 g/cm2; P < 0.02), with high prevalence of osteopenia (44%) and osteoporosis (18%). After 12 months of calcium (1,200 mg/die) and cholecalciferol (800 UI/die) supplementation, we found a significant increase of (25) OH-vitamin D level (21.8 ± 12.3 vs. 35 ± 13 ng/ml; P < 0.01), without changes in bone mass density. In conclusion, NF1 patients may present a mineral bone involvement, with vitamin D deficiency; calcium and vitamin D supplementation is necessary to restore these bone mineral metabolic alterations.

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References

  1. Abdel-Wanis M, Kawahara N (2002) Hypophosphatemic osteomalacia in neurofibromatosis 1: hypotheses for pathogenesis and higher incidence of spinal deformity. Med Hypotheses 59:183–185

    Article  PubMed  CAS  Google Scholar 

  2. Adami S, Bertoldo F, Brandi ML, Cepollaro C, Filipponi P, Fiore E, Frediani B, Giannini S, Gonnelli S, Isaia GC, Luisetto G, Mannarino E, Marcocci C, Masi L, Mereu C, Migliaccio S, Minisola S, Nuti R, Rini G, Rossini M, Varenna M, Ventura L, Bianchi G, Società Italiana dell’Osteoporosi, del Metabolismo Minerale e delle Malattie dello Scheletro (2009) Guidelines for the diagnosis, prevention and treatment of osteoporosis. Reumatismo 61:260–284

    Google Scholar 

  3. Asthagiri AR, Parry DM, Butman JA, Kim HJ, Tsilou ET, Zhuang Z, Lonser RR (2009) Neurofibromatosis type 2. Lancet 373:1974–1986

    Article  PubMed  CAS  Google Scholar 

  4. Atit RP, Crowe MJ, Greenhalgh DG, Wenstrup RJ, Ratner N (1999) The Nf1 tumor suppressor regulates mouse skin wound healing, fibroblast proliferation, and collagen deposited by fibroblasts. J Invest Dermatol 112:835–842

    Article  PubMed  CAS  Google Scholar 

  5. Bollag G, Clapp DW, Shih S, Adler F, Zhang YY, Thompson P, Lange BJ, Freedman MH, McCormick F, Jacks T, Shannon K (1996) Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells. Nat Genet 12:144–148

    Article  PubMed  CAS  Google Scholar 

  6. Brunetti-Pierri N, Doty SB, Hicks J, Phan K, Mendoza-Londono R, Blazo M, Tran A, Carter S, Lewis RA, Plon SE, Phillips WA, O’Brian Smith E, Ellis KJ, Lee B (2008) Generalized metabolic bone disease in neurofibromatosis type I. Mol Genet Metab 94:105–111

    Article  PubMed  CAS  Google Scholar 

  7. Cho TJ, Seo JB, Lee HR, Yoo WJ, Chung CY, Choi IH (2008) Biologic characteristics of fibrous hamartoma from congenital pseudarthrosis of the tibia associated with neurofibromatosis type 1. J Bone Joint Surg Am 90:2735–2744

    Article  PubMed  Google Scholar 

  8. Crawford AH Jr, Bagamery N (1986) Osseous manifestations of neurofibromatosis in childhood. J Pediatr Orthop 6:72–88

    Article  PubMed  Google Scholar 

  9. Dulai S, Briody J, Schindeler A, North KN, Cowell CT, Little DG (2007) Decreased bone mineral density in neurofibromatosis type 1: results from a pediatric cohort. J Pediatr Orthop 27:472–475

    Article  PubMed  Google Scholar 

  10. Elefteriou F, Benson MD, Sowa H, Starbuck M, Liu X, Ron D, Parada LF, Karsenty G (2006) ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metab 4:441–451

    Article  PubMed  CAS  Google Scholar 

  11. Ferner RE (2010) The neurofibromatosis. Pract Neurol 10:82–93

    Article  PubMed  Google Scholar 

  12. Friedman JM (2002) Neurofibromatosis 1: clinical manifestations and diagnostic criteria. J Child Neurol 17:548–554

    Article  PubMed  CAS  Google Scholar 

  13. Gutmann DH, Wood DL, Collins FS (1991) Identification of the neurofibromatosis type 1 gene product. Proc Natl Acad Sci USA 88:9658–9662

    Article  PubMed  CAS  Google Scholar 

  14. Heervä E, Alanne MH, Peltonen S, Kuorilehto T, Hentunen T, Väänänen K, Peltonen J (2010) Osteoclasts in neurofibromatosis type 1 display enhanced resorption capacity, aberrant morphology, and resistance to serum deprivation. Bone 47:583–590

    Article  PubMed  Google Scholar 

  15. Hermanns-Sachweh B, Senderek J, Alfer J, Klosterhalfen B, Büttner R, Füzesi L, Weber M (2005) Vascular changes in the periosteum of congenital pseudarthrosis of the tibia. Pathol Res Pract 201(4):305–312

    Article  PubMed  Google Scholar 

  16. Huson SM, Harper PS, Compston DA (1988) Von Recklinghausen neurofibromatosis. A clinical and population study in south-east Wales. Brain 111:1355–1381

    Article  PubMed  Google Scholar 

  17. Illés T, Halmai V, de Jonge T, Dubousset J (2001) Decreased bone mineral density in neurofibromatosis-1 patients with spinal deformities. Osteoporos Int 12:823–827

    Article  PubMed  Google Scholar 

  18. Kanis JA (1994) Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: synopsis of a WHO report. Osteoporos Int 4:368–381

    Article  PubMed  CAS  Google Scholar 

  19. Klein BY, Rojansky N, Gal I, Shlomai Z, Liebergall M, Ben-Bassat H (1995) Analysis of cell-mediated mineralization in culture of bone-derived embryonic cells with neurofibromatosis. J Cell Biochem 57:530–542

    Article  PubMed  CAS  Google Scholar 

  20. Klose A, Ahmadian MR, Schuelke M, Scheffzek K, Hoffmeyer S, Gewies A, Schmitz F, Kaufmann D, Peters H, Wittinghofer A, Nürnberg P (1998) Selective disactivation of neurofibromin GAP activity in neurofibromatosis type 1. Hum Mol Genet 7:1261–1268

    Article  PubMed  CAS  Google Scholar 

  21. Kolanczyk M, Kossler N, Kühnisch J, Lavitas L, Stricker S, Wilkening U, Manjubala I, Fratzl P, Spörle R, Herrmann BG, Parada LF, Kornak U, Mundlos S (2007) Multiple roles for neurofibromin in skeletal development and growth. Hum Mol Genet 16:874–886

    Article  PubMed  CAS  Google Scholar 

  22. Korf BR, Henson JW, Stemmer-Rachamimov A (2005) 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 352:1800–1808

    Article  PubMed  CAS  Google Scholar 

  23. Kretzschmar M, Doody J, Massagué J (1997) Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1. Nature 389:618–622

    Article  PubMed  CAS  Google Scholar 

  24. Kuorilehto T, Nissinen M, Koivunen J, Benson MD, Peltonen J (2004) NF1 tumor suppressor protein and mRNA in skeletal tissues of developing and adult normal mouse and NF1-deficient embryos. J Bone Miner Res 19:983–989

    Article  PubMed  CAS  Google Scholar 

  25. Kuorilehto T, Pöyhönen M, Bloigu R, Heikkinen J, Väänänen K, Peltonen J (2005) Decreased bone mineral density and content in neurofibromatosis type 1: lowest local values are located in the load-carrying parts of the body. Osteoporos Int 16:928–936

    Article  PubMed  CAS  Google Scholar 

  26. Lammert M, Kappler M, Mautner VF, Lammert K, Störkel S, Friedman JM, Atkins D (2005) Decreased bone mineral density in patients with neurofibromatosis 1. Osteoporos Int 16:1161–1166

    Article  PubMed  Google Scholar 

  27. Lee MJ, Stephenson DA (2007) Recent developments in neurofibromatosis type 1. Curr Opin Neurol 20:135–141

    Article  PubMed  CAS  Google Scholar 

  28. McCormick F (1995) Ras signaling and NF1. Curr Opin Genet Dev 5:51–55

    Article  PubMed  CAS  Google Scholar 

  29. Miyazaki T, Katagiri H, Kanegae Y, Takayanagi H, Sawada Y, Yamamoto A, Pando MP, Asano T, Verma IM, Oda H, Nakamura K, Tanaka S (2000) Reciprocal role of ERK and NF-kappaB pathways in survival and activation of osteoclasts. J Cell Biol 148:333–342

    Article  PubMed  CAS  Google Scholar 

  30. Morrissy RT, Riseborough EJ, Hall JE (1981) Congenital pseudarthrosis of the tibia. J Bone Joint Surg Br 63B:367–375

    Google Scholar 

  31. Nakamura H, Hirata A, Tsuji T, Yamamoto T (2003) Role of osteoclast extracellular signal-regulated kinase (ERK) in cell survival and maintenance of cell polarity. J Bone Miner Res 18:1198–1205

    Article  PubMed  CAS  Google Scholar 

  32. Nakamura M, Udagawa N, Matsuura S, Mogi M, Nakamura H, Horiuchi H, Saito N, Hiraoka BY, Kobayashi Y, Takaoka K, Ozawa H, Miyazawa H, Takahashi N (2003) Osteoprotegerin regulates bone formation through a coupling mechanism with bone resorption. Endocrinology 144:5441–5449

    Article  PubMed  CAS  Google Scholar 

  33. Nakayama K, Tamura Y, Suzawa M, Harada S, Fukumoto S, Kato M, Miyazono K, Rodan GA, Takeuchi Y, Fujita T (2003) Receptor tyrosine kinases inhibit bone morphogenetic protein-Smad responsive promoter activity and differentiation of murine MC3T3-E1 osteoblast-like cells. J Bone Miner Res 18:827–835

    Article  PubMed  CAS  Google Scholar 

  34. The Consensus Development Panel (1994) National Institutes of Health Consensus Development Conference Statement on Acoustic Neuroma, 11–13 December 1991. Arch Neurol 51:201–207

    Google Scholar 

  35. Reed AA, Joyner CJ, Brownlow HC, Simpson AH (2002) Human atrophic fracture non-unions are not avascular. J Orthop Res 20:593–599

    Article  PubMed  CAS  Google Scholar 

  36. Riccardi VM (1981) Von Recklinghausen neurofibromatosis. N Engl J Med 305:1617–1627

    Article  PubMed  CAS  Google Scholar 

  37. Schindeler A, Little DG (2008) Recent insights into bone development, homeostasis, and repair in type 1 neurofibromatosis (NF1). Bone 42:616–622

    Article  PubMed  CAS  Google Scholar 

  38. Seitz S, Schnabel C, Busse B, Schmidt HU, Beil FT, Friedrich RE, Schinke T, Mautner VF, Amling M (2010) High bone turnover and accumulation of osteoid in patients with neurofibromatosis 1. Osteoporos Int 21:119–127

    Article  PubMed  CAS  Google Scholar 

  39. Shapira S, Barkan B, Friedman E, Kloog Y, Stein R (2007) The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways. Cell Death Differ 14:895–906

    PubMed  CAS  Google Scholar 

  40. Stevenson DA, Zhou H, Ashrafi S, Messiaen LM, Carey JC, DʼAstous JL, Santora SD, Viskochil DH (2006) Double inactivation of NF1 in tibial pseudarthrosis. Am J Hum Genet 79:143–148

    Article  PubMed  CAS  Google Scholar 

  41. Viskochil D (2002) Genetics of neurofibromatosis 1 and the NF1 gene. J Child Neurol 17:562–570 discussion 571–572, 646–651

    Article  PubMed  Google Scholar 

  42. Wada T, Nakashima T, Hiroshi N, Penninger JM (2006) RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med 12:17–25

    Article  PubMed  CAS  Google Scholar 

  43. Weinstein RS, Harris RL (1990) Hypercalcemic hyperparathyroidism and hypophosphatemic osteomalacia complicating neurofibromatosis. Calcif Tissue Int 46:361–366

    Article  PubMed  CAS  Google Scholar 

  44. Writing Group for the ISCD Position Development Conference (2004) Position statement : executive summary. J Clin Densitom 7:7–12

    Google Scholar 

  45. Yang FC, Chen S, Robling AG, Yu X, Nebesio TD, Yan J, Morgan T, Li X, Yuan J, Hock J, Ingram DA, Clapp DW (2006) Hyperactivation of p21ras and PI3K cooperate to alter murine and human neurofibromatosis type 1-haploinsufficient osteoclast functions. J Clin Invest 116:2880–2891

    Article  PubMed  CAS  Google Scholar 

  46. Young H, Hyman S, North K (2002) Neurofibromatosis 1: clinical review and exceptions to the rules. J Child Neurol 17:613–621

    Article  PubMed  Google Scholar 

  47. Zhu Y, Parada LF (2001) Neurofibromin, a tumor suppressor in the nervous system. Exp Cell Res 264:19–28

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank sig. Giovanni Clemente and sig. Maurizio Angelozzi for their technical assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Internal Medicine and Medical Specialties, Secondary Hypertension Unit, University ‘‘Sapienza’’, Viale del Policlinico 155, 00161, Rome, Italy

    Luigi Petramala, Laura Zinnamosca, Cristiano Marinelli, Luciano Colangelo, Giuseppina Cilenti, Maria Chiara Formicuccia, Emilio D’Erasmo & Claudio Letizia

  2. Department of Dermatology, University ‘‘Sapienza’’, Rome, Italy

    Sandra Giustini & Stefano Calvieri

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  1. Luigi Petramala
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Correspondence to Claudio Letizia.

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Petramala, L., Giustini, S., Zinnamosca, L. et al. Bone mineral metabolism in patients with neurofibromatosis type 1 (von Recklingausen disease). Arch Dermatol Res 304, 325–331 (2012). https://doi.org/10.1007/s00403-011-1191-3

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  • DOI: https://doi.org/10.1007/s00403-011-1191-3

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