Neurofibromatosis type 1 (NF1) is a multisystem disorder characterized by progressive manifestations, which is inherited in an autosomal dominant manner. The majority of patients with NF1 experience a diffuse, significant reduction in bone mass over time, with osteoporosis, osteopenia in the absence of severe scoliosis, or gross bone deformities. This study aimed to determine the bone mineral density (BMD) status, evaluate bone metabolism, and to determine the relevant factors in children with NF1.
The study population included 33 pediatric NF1 patients (20 males and 13 females). Bone metabolic markers, such as total calcium, phosphorus, magnesium, alkaline phosphatase, parathyroid hormone, and 25-OH vitamin D, the urinary calcium/creatine ratio were measured. In addition, BMD was measured at both the lumbar spine (LS) and the femoral neck in all the patients.
All the patients had a low 25-OH vitamin D level, but it was significantly lower in the females than in the males (p<0.009). Overall, 18.2% of the patients had skeletal abnormalities. The lumbar Z-score was ≤2 in 21.2% of the patients, whereas the femoral neck Z-score was ≤2 in 9.1%. The urinary calcium/creatine ratio was significantly higher in the female than in the male patients (p<0.027). In all, six patients had skeletal abnormalities.
It is widely known that bone mineral metabolism markers and BMD are significantly affected in NF1 patients; however, the present study did not identify any effective parameters that could be used to predict skeletal abnormalities, or diagnose early osteoporosis and osteopenia in pediatric NF1 patients.
We would like to thank all patients and families for their participation in this study. We also thank Fehan Elmali for statistical analysis.
Author contributions: PHG conceived the study, BVN, GH, and PH reviewed the literature, PHG, BVN, GH, PH, CM and KS were involved in patients care, including the process of procedure and routine clinical follow-up, AA, BF made helpful collection of data, PHG and AA performed literature review and written manuscript. BF, CM, and KS reviewed the manuscript. All authors were responsible for patient management. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
1. Riccardi VM, Womack JE, Jacks T. Neurofibromatosis and related tumors. Natural occurrence and animal models. Am J Pathol 1994;145:994–1000.Search in Google Scholar
2. Vitale MG, Guha A, Skaggs DL. Orthopaedic manifestations of neurofibromatosis in children: an update. Clin Orthop Relat Res 2002;401:107–18.Search in Google Scholar
3. Cichowski K, Jacks T. NF- 1 tumor suppressor gene function: narrowing the GAP. Cell 2001;104:593–604.Search in Google Scholar
4. Petramala L, Giustini S, Zinnamosca L, Marinelli C, Colangelo L, et al. Bone mineral metabolism in patients with neurofibromatosis type 1 (von Recklinghausen disease). Arch Dermatol Res 2012;304:325–31.Search in Google Scholar
5. Hockett CW, Eelloo J, Huson SM, Roberts SA, Berry JL, et al. Vitamin D status and muscle function in children with neurofibromatosis type 1 (NF1). J Musculoskelet Neuronal Interact 2013;13:111–9.Search in Google Scholar
6. Brunetti-Pierri N, Doty SB, Hicks J, Phan K, Mendoza-Londono R, et al. Generalized metabolic bone disease in Neurofibromatosis type I. Mol Genet Metab 2008;94:105–11.Search in Google Scholar
7. Dulai S, Briody J, Schindeler A, North KN, Cowell CT, et al. Decreased bone mineral density in neurofibromatosis type 1: results from a pediatric cohort. J Pediatr Orthop 2007;27:472–5.Search in Google Scholar
8. Illes T, Halmai V, de Jonge T, Dubousset J. Decreased bone mineral density in neurofibromatosis-1 patients with spinal deformities. Osteoporos Int 2001;12:823–7.Search in Google Scholar
9. Kuorilehto T, Pöyhönen M, Bloigu R, Heikkinen J, Väänänen K, et al. Decreased bone mineral density and content in neurofibromatosis type 1: lowest local values are located in the load-carrying parts of the body. Osteoporosis Int 2005;16:928–36.Search in Google Scholar
10. Lammert M, Kappler M, Mautner VF, Lammert K, Störkel S, et al. Decreased bone mineral density in patients with neurofibromatosis 1. Osteoporos Int 2005;16:1161–6.Search in Google Scholar
11. Yang FC, Chen S, Robling AG, Yu X, Nebesio TD, et al. Hyperactivation of p 21ras and p13k cooperate to alter murine and human neurofibromatosis type 1-haploinsufficient osteoclast functions. J Clin Invest 2006;116:2880–91.Search in Google Scholar
12. Wu X, Estwick SA, Chen S, Yu M, Ming W, et al. Neurofibromin plays a critical role in modulating osteoblast differentiation of mesenchymal stem/progenitor cells. Hum Mol Genet 2006;15:2837–45.Search in Google Scholar
13. Crawford AH, Schorry EK. Neurofibromatosis in children: the role of orthopaedist. J Am Acad Orthop Surg 1999;7:217–30.Search in Google Scholar
14. Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. J Am Med Assoc 1997;278:51–7.Search in Google Scholar
15. Goksen D, Darcan S, Coker M, Kose T. Bone mineral density of healthy Turkish children and adolescents. J Clin Densitom 2006;9:84–0.Search in Google Scholar
16. Writing group fort the ISCD position development conference. Diagnosis of osteoporosis in men, premenopausal woman, and children. J Clin Densitom 2004;7:17–6.Search in Google Scholar
17. Stevenson DA, Moyer-Mileur LJ, Murray M, Slater H, Sheng X, et al. Bone mineral density in children and adolescents with neurofibromatosis type 1. J Pediatr 2007;150:83–8.Search in Google Scholar
18. Seitz S, Schnabel C, Busse B, Schmidt HU, Beil FT, et al. High bone turnover and accumulation of osteoid in patients with neurofibromatosis 1. Osteoporos Int 2010;21:119–27.Search in Google Scholar
19. Kühnisch J, Seto J, Lange C, Schrof S, Stumpp S, et al. Multiscale, converging defects of macro-porosity microstructure and matrix mineralization impact long bone fragility in NF1. PLoS One 2014;9:e86115.Search in Google Scholar
20. Duman O, Ozdem S, Turkkahraman D, Olgac ND, Gungor F, et al. Bone metabolism markers and bone mineral density in children with neurofibromatosis type-1. Brain Dev 2008;30:584–8.Search in Google Scholar
21. Yilmaz K, Ozmen M, Bora Goksan S, Eskiyurt N. Bone mineral density in children with neurofibromatosis 1. Acta Paediatr 2007;96:1220–2.Search in Google Scholar
22. Lammert M, Friedman JM, Roth HJ, Friedrich RE, Kluwe L, et al. Vitamin D deficiency associated with number of neurofibromas in neurofibromatosis 1. J Med Genet 2006;43:810–3.Search in Google Scholar
©2017 Walter de Gruyter GmbH, Berlin/Boston