Table 1.
Frequency of scoliotic deformities in Nf1flox/flox and Nf1flox/−;PeriCre and Col2.3 mice.
Fig 1.
Nf1flox/−;Col2.3Cre mice exhibit characteristic features of NF1 dystrophic scoliosis.
(A) Anterior-posterior radiographs of two NF1 patients with dystrophic scoliosis involving the thoracic (top) and lumbar spine (bottom). (B) Anterior-posterior radiographs demonstrate representative cases of short-segmented scoliotic deformities in Nf1flox/−;Col2.3Cre mice involving the thoracic (second panel) and lumbar spine (fourth panel). Significant vertebral rotation is further evident in the representative Nf1flox/−;Col2.3Cre mouse with thoracic scoliosis as shown (second panel). (C) Vertebral wedging, another hallmark feature of NF1 dystrophic scoliosis, is illustrated in representative lateral radiographs of the lumbar spine. The wedging angle was measured by the intersection of lines drawn parallel to the rostral and caudal vertebral endplates as shown.
Fig 2.
Nf1flox/−;PeriCre mice exhibit thoracic kyphosis.
(A) Representative lateral radiographs demonstrate the presence of severe thoracic kyphosis in Nf1flox/−;PeriCre mice as compared to WT, Nf1+/−, and Nf1flox/flox;PeriCre control animals. (B) The mean kyphotic angle was measured using the Cobb technique as defined by the intersection of lines drawn parallel to the rostral T7 and caudal L4 vertebral endplates. Error bars represent the standard error of the mean (SEM). ***P < 0.001 comparing Nf1flox/−;PeriCre mice versus other genotypes.
Fig 3.
Reduced bone mass and altered trabecular microarchitecture in dystrophic Nf1flox/−;Col2.3Cre vertebrae.
(A) Percent bone volume (BV/TV, %) was determined following μCT reconstruction of vertebral bone samples. n = 5. **P < 0.01 versus WT. (B) Trabecular number (Tb.N, mm−1) was computed as shown. n = 5. **P < 0.01 as compared to WT. (C) Trabecular spacing (Tb.Sp, μm) was calculated by μCT as shown above. n = 5. *P < 0.05 as compared to WT.
Fig 4.
Defective bone remodeling in the lumbar spine of Nf1flox/−;Col2.3Cre mice.
Bone remodeling within the L5 vetebral body was examined in WT and Nf1flox/−;Col2.3Cre mice without evidence of dystrophic spinal deformities. (A) Representative photomicrographs show calcein and alizarin labeling of L5 vertebrae at 200x magnification from. (B) The mineralizing surface (MS/BS, %) was computed as shown. n = 5. *P < 0.05 as compared to WT. (C) The mineral apposition rate (MAR, μm/day) was calculated according to standard formulas. n = 5. **P < 0.01 as compared to WT. (D) The bone formation rate (BFR, μm3/μm2/year) was quantified as shown in the bar graph. n = 5. **P < 0.01 versus WT.
Table 2.
Vertebral fusion anomalies in Nf1flox/flox and Nf1flox/−;PeriCre and Col2.3 mice.
Fig 5.
Interarticular fusion in Nf1flox/−;Col2.3Cre mice.
(A) Representative μCT reconstructions of dystrophic vertebral segments in coronal (top, i and ii) or sagittal (bottom, iii and iv) cross-section. Dysplastic bone growth within the intervertebral disc space has led to interarticular fusion of the dystrophic vertebrae. (B) Representative H&E stained histological sections characterize progressive boney dysplasia within the intervertebral disc space of mice at one month (i and ii), two months (iii and iv), six months (v and vi), and 12 months (vii and viii) of age.
Fig 6.
Bone mass and microarchitecture defects in an NF1 patient presenting with dystrophic scoliosis.
(A) Representative μCT reconstructions of the T7 facet from a sex matched scoliosis patient without NF1 and (B) the T5 facet from an NF1 patient with dystrophic scoliosis. (C) Representative H&E stained cross sections of vertebral bone of the T7 facet from an age/sex matched scoliosis patient without NF1 and (D) the T5 facet from an NF1 patient with dystrophic scoliosis at 40x magnification.
Table 3.
Quantitative parameters of bone microarchitecture were assessed by μCT in the T5 facet of an NF1 patient with dystrophic scoliosis versus the T7 facet of a control patient with idiopathic scoliosis but without NF1.
Fig 7.
Spinal fusion anomalies in NF1 patients.
(A) Congenital C6–7 vertebral fusion in a 24 year old, female patient with NF1. MRI shows congenital fusion of the 6th and 7th thoracic vertebrae with an absent disc in a 24 year old woman with a clinical diagnosis of neurofibromatosis type 1 (NF1) based on her history of multiple cafe-au-lait spots, axillary freckling and dermal neurofibromas. (B) Segmental fusion anomalies at T8-T10 in a 7 year old female NF1 patient with dystrophic scoliosis. An anterior-posterior standing radiograph of a 7 year old girl with the clinical diagnosis of NF1 (i.e. >6 café au lait macules >0.5cm, axillary and groin freckling, and a first-degree relative with NF1) shows a right thoracic curve measuring 32 degrees between the 8th and 12th thoracic vertebrae and a left thoracolumbar curve measuring 23 degree between the 12th thoracic and 3rd lumbar vertebrae with segmentation and vertebral fusion anomalies at the 8th-10th thoracic vertebrae.