Decreased bone mineral density in patients with neurofibromatosis 1

Abstract

Neurofibromatosis 1 (NF1) is one of the most common autosomal dominant diseases. Although there is a considerable variability in clinical expression, NF1 is almost fully penetrant in adult patients and may be associated with a variety of skeletal anomalies. Spinal deformities are the most common skeletal manifestation, with an incidence estimated from 10-25% in various studies. Some NF1 patients have a dystrophic form of scoliosis, which is characterized by early age at onset and rapid progression. Complications have been reported during spinal instrumentation of dystrophic curves due to soft, non-resistant vertebral bony tissue, suggesting that an alteration of bone quality may occur in NF1 patients. Recent studies have suggested that decreased bone mineral density (BMD) may occur among patients with NF1. We performed a cross-sectional study on 104 adults with NF1, using quantitative ultrasonometry (QUS) to investigate whether decreased BMD is a general phenomenon in NF1 patients. The data reveal that BMD, as measured by age- and gender- adjusted Z-scores, is significantly lower in NF1 patients than in the normal reference population. The decrease in BMD appears to be even more marked among NF1 patients with scoliosis that requires surgical treatment. The findings indicate that NF1 produces a generalized alteration of bone in addition to the focal osseous dysplasias of the vertebrae, tibia, and sphenoid wing that characterize this condition. The pathological mechanism underlying these bony changes remains to be elucidated.

Skeletal abnormalities in neurofibromatosis type 1: Approaches to therapeutic options

“…Decreased BMD in both sexes at an early age has been reported in up to 50% of individuals with NF1 [Illes et al, 2001;Kuorilehto et al, 2004b;Lammert et al, 2005;Dulai et al, 2007;Stevenson et al, 2007;Yilmaz et al, 2007;Brunetti-Pierri et al, 2008;Duman et al, 2008]. This may be related to an inadequate increase in bone remodeling observed by both bone histomorphometry and changes in circulating bone markers [Stevenson et al, 2008;Seitz et al, 2009].…”

“…An increased incidence of fractures in patients with NF1 has been reported, but sample sizes were small [Brunetti-Pierri et al, 2008;Tucker et al, 2008]. Another challenge to interpreting low BMD in patients with NF1 correctly is posed by recent reports of low vitamin D (14-21 ng/ml serum 25-dihydroxy-vitamin D, 25-OH-D) and osteomalacia in a subset of patients with NF1 [Lammert et al, 2005;Seitz et al, 2009]. Controlled studies that are adequately powered, normalize calcium homeostasis and consider age, sex, and race/ ethnicity norms, are needed to determine if the apparent high prevalence of low BMD in patients with NF1 predicts increased fracture risk and a need for intervention.…”

An Osteoblast Origin for Craniofacial Dysplasia in Neurofibromatosis Type I

“…We find significant and robust changes in the nasal region of Nf1ob-/-mice. This pattern of deformed frontal midface region of the skull in Nf1ob-/-mice parallels the quantitative changes in the analogous structures in human NF1 craniofacial skeleton resulting in unilateral proptosis of an eye and facial asymmetry [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. NF1 patients often exhibit macrocephaly.…”

“…In rare cases plexiform Neurofibromas have been reported to be associated with impacted teeth and deformed alveolar ridge while optic nerve gliomas have been associated with orbit defects [12][13][14][15]. NF1 patients may also display generalized defects in bone metabolism and bone turnover, resulting in osteoporosis in up to one half of affected individuals [16,17]. Recently a neurofibromin osteoblast conditional knockout mouse was developed to study the skeletal manifestations of NF1.…”

Variable expression of neurofibromatosis 1 in monozygotic twins

“…There is increasing evidence from animal models and human data that the heterozygous NF1 state can cause generalized bone abnormalities such as osteopenia [Kuorilehto et al, 2004;Lammert et al, 2005;Stevenson et al, 2007;Brunetti-Pierri et al, 2008]. Other skeletal complications occur with a great deal of variability of expression; some such as tibial dysplasia/pseudarthrosis occur very rarely, with an incidence of only 3-5% of NF1 patients.…”