Type 1 neurofibromatosis (NF1), also known as Von Recklinghausen disease or peripheral neurofibromatosis, is an autosomal dominant disorder with an incidence of 1/ 3,000 to 1/ 3,500, of which 50% is due to genetic mutations, making it one of the most common genetic disorders. The National Institutes of Health in the United States in 1987 proposed clinical diagnostic criteria for NF1, which can be diagnosed with two or more of the following clinical manifestations:
(1) 6 or more coffee milk spots with a maximum diameter of at least 15 mm in adults and at least 5 mm in children;
(2) More than 2 neurofibromas of any type, or at least 1 plexiform neurofibroma;
(3) pigmented spots in the axilla or groin;
(4) optic nerve glioma;
(5) 1 or more Lisch nodes (iris malformation tumor);
(6) Characteristic skeletal changes;
(One of the diagnostic criteria for NF1 is a characteristic skeletal lesion.
I. Clinical manifestations of skeletal deformities in NF1 patients
The clinical manifestations of skeletal dysplasia in NF1 patients are diverse and include scoliosis, lateral kyphosis, cervical spine lesions, spondylolisthesis, bone growth lesions, congenital bowing and pseudarthrosis, subperiosteal bone growth, thinning of the bone cortex, short stature and large head deformity, and butterfly wing dysplasia. Other skeletal deformities include overgrowth, thoracic deformity, knee valgus, osteolytic destruction, osteosclerosis, rib fusion, patellar agenesis, syndactyly, and other congenital skeletal deformities.
1.Spinal deformity
The most common manifestation of NF1 is scoliosis, which affects about 10-30% of patients. scoliosis in NF1 is usually predominantly thoracic, followed by thoracolumbar, and less frequently lumbar and cervicothoracic. The type of scoliosis is more common with a single bend, followed by a double major bend. There are two main clinical classifications: non-dystrophic scoliosis and dystrophic scoliosis, which can be divided into two types according to the presence or absence of structural changes in the spine, and four types according to the sagittal plane morphology:
(1) No abnormal sagittal morphology;
(2) With anterior kyphosis;
(3) with arcuate kyphosis;
(4) angular kyphosis.
Non-dystrophic scoliosis is very similar to idiopathic scoliosis, while dystrophic scoliosis has its own very characteristic imaging features:
(1) Pencil-like rib changes (narrowest rib width is less than the minimum diameter of the second rib);
(2) Moe Nash measurement of vertebral body rotation exceeding 7.5 mm;
(3) posterior edge of the vertebral body scalloped notch (distance from the apex of the arc to the posterior edge of the vertebral body is greater than 3 mm in the thoracic spine and greater than 4 mm in the lumbar spine);
(4) anterior vertebral body scalloped notch;
(5) lateral scalloping of the vertebral body;
(6) coronal or sagittal wedge shape of the vertebral body;
(7) transverse pyknotic changes;
(8) Increased spacing between the pedicles;
(9) enlargement of the intervertebral foramen.
The most common of these changes are pencil-like changes of the ribs, rotation of the vertebral body, and scalloped incision of the posterior edge of the vertebral body. Dystrophic scoliosis usually develops early and progresses rapidly, often involving less than five vertebrae, and is difficult to treat. Common complications in the treatment of dystrophic scoliosis include softness and poor strength of the vertebral body and the tendency for scoliosis to progress after patient fixation, both of which predict abnormal bone quality or bone mass in patients with NF1. Zhu Feng et al. analyzed the imaging of NF1 with dystrophic scoliosis and concluded that there were significant imaging differences between NF1 with dystrophic scoliosis and idiopathic scoliosis. The most common imaging changes were non-uniform changes in the short arc of the spine in 100%, enlargement of the spinal membrane or bulging in the spinal canal in 100%, scallop-shaped disruption of the vertebral body edges in 87%, and enlargement of the spinal canal in 85%.
2. Tibial pseudarthrosis or arch changes
NF1 pseudarthrosis often occurs in the unilateral tibia, with an incidence of about 3%. The typical anterolateral bowing of the tibia in patients with NF1 is easily distinguishable from the mild lateral tibial bowing in other children, and the bowing of the tibia is usually evident at the age of 1 year when children with NF1 begin to stand and walk. Despite surgical intervention, such as bone grafting or bone grafting with a vascularized tip, the lower healing capacity after tibial fracture often leads to pseudarthrosis at 1 year of age. Long bone dysplasia, which mainly involves the tibia, usually causes fractures and osteonecrosis, sometimes requiring amputation.
3. Pterygoid dysplasia
The most obvious craniofacial lesion in NF1 patients is the unilateral deformity of the large wing of the butterfly. It is usually asymptomatic but can be diagnosed by applying cranial plain film or CT. Pterygoid pterygoid lesions are relatively rare in the general population and are associated with NF1 in more than 50% of cases. The incidence is 3-7% of patients with NF1. The abnormal growth of the skull with pterygoid pterygoid lesions in children with NF1 can also lead to progressive facial deformities. a statistical analysis of 3377 patients with NF1 by Alwan et al. showed a strong correlation between the incidence of pterygoid pterygoid lesions and the incidence of long bone and vertebral lesions. Their findings suggest that the typical pterygoid pterygoid lesions in NF1 patients may have a common pathogenesis with vertebral and long bone lesions.
4. Other skeletal dysplasia
In addition to unilateral tibial arch changes, other long bones, including the radius and clavicle, have been reported. These lesions can appear in infancy and early childhood before confirmed indicators such as milk-like café-au-lait spots. The imaging presentation includes cystic changes, osteosclerosis, cortical bowing and thinning. pathological fractures occur around the age of 10 years, usually resulting in pseudarthrosis. Treatment of pseudarthrosis is difficult due to the re-fracture that occurs after treatment. In affected limbs, progressive deformity and disuse atrophy often lead to amputation.
Reduced bone mass or osteoporosis
The study of reduced bone mass or osteoporosis in NF1 patients started in the early 21st century. 2001, Illes and his collaborators applied dual-energy X-ray absorptiometry (DXA) to the lumbar spine (L1-L4) in 12 patients with NF1 with spinal deformity to measure bone mineral density (BMD). mineral density) was measured at a mean age of 19.1 years (7.6-42.7 years). The BMD of the lumbar spine was found to be significantly lower in these patients, and there was a possible negative correlation between the severity of scoliosis and the Z value of lumbar spine BMD, but no statistically significant difference was found.Illes et al. measured the BMD of 12 patients with NF1 with spinal deformity at the same time that serum and urine metabolite tests were performed on these patients. However, there were no significant findings from the laboratory tests. In addition, this study did not have age- and sex-matched controls for BMD measurements.
In 2005, Lammert et al. applied quantitative ultrasonometry (QUS, quantitative ultrasonometry) for BMD measurements to the right heel of 104 adult NF1 patients, 66 women (median age 41.5 years, 20-80 years) and 38 men (median age 44 years, 20-75 years) and found that NF1 Z values in patients were lower than expected for a normal reference population. The control reference data were BMD-T values and age- and sex-corrected Z values for 5368 healthy adults in Germany. In addition, the distribution of Z values in NF1 patients was significantly lower compared to normal controls, suggesting that decreased BMD is a general characteristic of NF1 patients rather than a single problem affecting only a small group of patients. Two of the individuals in their study were athletes who had significantly increased Z values, suggesting that increased physical activity in NF1 patients may significantly improve BMD and thus enhance the effectiveness of treatment.
The reduction in BMD may be more pronounced in patients with NF1 with scoliosis who require surgical treatment. After correction for age and sex, BMD-T values were significantly lower in patients with NF1 with scoliosis who required surgery than in patients who did not require surgery, and there was a statistically significant difference. All of these patients had severe scoliosis with a preoperative Cobb angle greater than 50 degrees and were classified as dystrophic scoliosis. 33 patients with NF1 with scoliosis who did not require surgical treatment had approximately equivalent BMD-Z values to the 60 patients with NF1 without scoliosis. Kuorilehto et al. performed a comparative study of 35 patients with NF1 and 26 normal pairs. All of the normal controls and 26 NF1 patients were older than 20 years of age. Among the NF1 patients older than 20 years 14 were male and 12 were female, 7 of whom were premenopausal.
Mild thoracic scoliosis accounted for 34.3% (12/35) of patients. 1 patient underwent scoliosis orthopedic surgery. 2 patients with scoliosis were younger than 20 years of age. The results of this study showed that BMD and bone mineral content (BMC) were significantly lower in both male and female NF1 patients. The incidence of osteoporosis and bone loss was significantly higher in NF1 patients compared to controls. the lowest local BMD in NF1 patients was concentrated in weight-bearing areas of the body, which did not occur in controls. the physiological activity and medical history of NF1 patients did not provide a reasonable explanation for the decrease in BMD and BMC. These results suggest that the pathological mechanisms of skeletal disease in NF1 patients may involve impaired development of the skeletal system and damage to the maintenance of skeletal structures. However, a normal control population younger than 20 years of age was not available in this study.
In 2006, Lammert et al. studied the number of serum 25-hydroxyvitamin D and cutaneous neurofibromas in 55 NF1 patients and 58 healthy controls and found that serum 25-hydroxyvitamin D values were significantly and statistically lower in NF1 patients than in normal controls. the decrease in serum 25-hydroxyvitamin D levels in NF1 patients may lead to lower BMD.
In 2007, Stevenson et al. conducted a comparative study of 84 pediatric and adolescent patients with NF1 (5-18 years) and 293 normal controls (3-21 years) and found a statistically significant decrease in hip, femoral neck, lumbar spine, and total body BMD in NF1 patients.BMD was significantly lower in patients with NF1 with or without skeletal deformities than in controls, but the decrease in patients with skeletal Patients with NF1 were divided into groups with and without skeletal deformities, and patients with NF1 without skeletal deformities had significantly lower BMD compared to controls. There was no statistical difference in BMD between the groups with and without skeletal deformities.
This study measured BMD in adolescent NF1 patients, predicting that they are prone to osteoporosis and fractures as they develop into adults. Although NF1 gene inactivation leads to decreased BMD, other genes that act as modifiers may trigger the appearance of focal skeletal malformations along with somatic mutations. Furthermore, without information from prospective studies prior to the appearance of skeletal deformities, it is difficult to determine whether skeletal deformities cause decreased BMD or whether decreased BMD triggers skeletal deformities.
If declining BMD increases the risk of localized skeletal deformities, clinicians should intervene early in these patients. However, it is likely that decreased BMD will result from decreased motion in patients due to scoliosis or long bone dysplasia. Therefore, further studies should pay attention to the biological functions of osteoblasts and osteoclasts in haploinsufficient NF1 patients and the changes in signaling pathways regulating their functions.
Dulai et al. applied DXA to measure BMD in 23 pediatric and adolescent patients (5-18 years old) with NF1 without skeletal deformities at whole body BMD, lumbar spine and proximal femur.QUS measured broadband ultrasound attenuation of both heels. The results showed that the mean BMD age and sex matched Z values were lower than normal in all groups. The mean heel broadband ultrasound attenuation Z-values were also significantly lower than normal. Yilmaz et al. applied DXA to 31 children with NF1 (3.1-18 years) to measure BMD of the lumbar spine, whole body, proximal femur, and forearm. 11 patients had skeletal deformities, including 5 patients with mild scoliosis. The results showed a significant decrease in BMD in the lumbar spine and proximal femur of children with NF1, especially in patients with skeletal deformities. However, there was no significant reduction in systemic BMD in children with NF1. In addition, there was no age- and sex-matched control group in this study.
In 2008, Brunetti-Pierri et al. applied DXA to analyze 73 non-selective NF1 patients, 26 males and 47 females, mainly children and adolescents (mean age: 16.6 years, 2.8-58.9 years). Measured parameters included BMC, bone area, and BMD (total body, lumbar spine, trochanter, and femoral neck). For the low bone mass group, calcium and phosphorus metabolism, bone turnover, and BMD were measured after the application of vitamin D and calcium treatment. The results revealed that the mean lumbar spine BMD and total body bone mineral content were significantly and statistically lower compared to the control group. 54 NF1 patients younger than 20 years old had significantly lower than normal corrected BMC-Z values. histological analysis of bone samples from NF1 patients showed significant alterations in the microarchitecture of bone due to cancellous bone reduction in NF1 patients. The results of this study suggest a possible systemic bone metabolism disorder due to neurofibromatosis protein dysfunction.
In 2009, Tucker et al. studied 72 adult patients with NF1 for BMD, 18 bone metabolic indices, and fracture history. More than 10% of NF1 patients had 8 of the 18 bone metabolic parameters exceeding normal reference values. 56% of NF1 patients had decreased serum 25-(OH) vitamin D concentrations. 34% of NF1 patients had increased serum PTH concentrations and 50% had increased urinary concentrations of deoxypyridinoline cross-linking products. mean serum 25-(OH) vitamin D concentrations in NF1 patients were lower than in normal controls and were statistically significant. 36 NF1 patients (50%) had reduced bone mass and 14 (19%) NF1 patients had osteoporosis. high serum PTH concentrations, high blood calcium concentrations and high serum antitartaric acid phosphate concentrations in NF1 patients were associated with reduced BMD. Male NF1 patients were more likely to have reduced BMD. the incidence of pathological fractures was significantly increased in NF1 patients. Their findings suggest abnormal bone metabolism in NF1.
In 2010, Seitz et al. clinically evaluated 14 adult NF1 patients with age- and sex-matched controls. The results showed that serum 25-(OH)-VD3 and BMD were lower in NF1 patients than in controls. Histomorphometric analysis did not suggest a decrease in cancellous bone volume in bone tissue biopsy specimens from NF1 patients, but a significant increase in osteoid volume and osteoblast and osteoclast numbers.
In addition, qBEI (quantitative backscattered electron imaging) analysis showed a significant decrease in calcium content in bone biopsy specimens from NF1 patients. The results of this study suggest that decreased serum 25-(OH)-VD3 in NF1 patients promotes the development of skeletal lesions in NF1 patients. The apparent accumulation of osteoid suggests that NF1 patients are associated with a high rate of bone turnover, suggesting that impaired bone matrix mineralization may affect BMD in NF1 patients.
The above studies suggest that NF1 patients have reduced bone mass or osteoporosis in both adults and adolescents, but the pathogenesis remains unclear, and the product encoded by the NF1 gene, neurofibromin, may play an important role in cell proliferation and differentiation. Altered functions of osteoblasts and osteoclasts, as well as abnormalities in the process of osteogenesis within cartilage by different chondrocytes may be important causes of reduced bone mass or altered skeletal deformities.