Submitted to: Molecular Genetics and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/1/2007
Publication Date: 3/4/2008
Citation: Brunetti-Pierri, N., Doty, S.B., Hicks, J., Phan, K., Mendoza-Londono, R., Blazo, M., Tran, A., Carter, S., Lewis, R.A., Plon, S.E., Phillips, W.A., Smith, O.E., Ellis, K.J., Lee, B. 2008. Generalized metabolic bone disease in Neurofibromatosis type I. Molecular Genetics and Metabolism. 94:105-111. Interpretive Summary: Some genetic diseases can involve bone growth abnormalities. Neurofibromatosis, which is the most common autosomal dominant disease, is one of these, but little is known about how it alters bone growth in childhood. We compared the whole-body skeleton mass of children with this disease with our reference healthy pediatric population, matching for age, height, and gender. We also used techniques to examine how bone was being formed, and how vitamin D affected this process. We found that the children with neurofibromatosis had bone significantly below normal, and that treatment for these defects did not show improvements after two years.
Technical Abstract: Skeletal abnormalities are a recognized component of Neurofibromatosis type I (NF1), but a generalized metabolic bone defect in NF1 has not been fully characterized thus far. The purpose of this study was to characterize at the densitometric, biochemical, and pathological level the bone involvement in NF1 patients. Using dual energy X-ray absorptiometry (DXA) we analyzed bone status in 73 unselected NF1 subjects, 26 males and 47 females, mainly children and adolescents (mean age: 16.6 years). In a subgroup of subjects with low bone mass, we measured indices of calcium–phosphate metabolism, bone turnover, and bone density before and after vitamin D and calcium treatment. We found statistically significant and generalized reduction in bone mass with the mean lumbar bone mineral density (BMD) z-score being -1.38 +/- 1.05 (CI 95% -1.62 to -1.13), and whole body bone mineral content (BMC) z-score -0.61 +/- 1.19 (CI 95% -0.94 to -0.29), both significantly reduced compared to normal controls (p < .001). PTH was moderately elevated, and after 4 months of supplemental therapy with calcium and vitamin D, it decreased to the normal range. However, BMD z-scores did not significantly improve after 2 years of follow-up. Histological analysis of bone samples from NF1 patients revealed substantial alteration of bone microarchitecture due mainly to reduced trabecular bone. Our observations are consistent with a generalized bone metabolic defect due to loss of the function of neurofibromin. Early identification of patients with osteoporosis may permit more timely and aggressive treatments to prevent the likely substantial morbidity associated with increased fracture risk later in life.