Ⅰ型神经纤维瘤病基因型小鼠的破骨细胞功能研究

目的 观察Ⅰ型神经纤维瘤病基因型小鼠的破骨细胞功能变化,探讨Ⅰ型神经纤维瘤病引起骨质疏松的发病机制.方法 选取神经纤维瘤病基因杂合型(Nfl+/-)和野生型(Nfl+/+)小鼠为研究对象,取胫骨干骺端行抗酒石酸酸性磷酸酶(TRAP)染色,比较两组小鼠骨内破骨细胞含量.体外实验取两种基因型小鼠的骨髓单核细胞,观察在巨噬细胞集落刺激因子(M-CSF)和细胞核因子KB受体活化因子配基(RANKL)诱导下的破骨细胞分化能力,测定两组破骨细胞形成、分化、贴附、迁移和骨吸收功能.结果 Nfl+/一小鼠骨内成熟破骨细胞数量比Nn+/+增多,细胞体积明显增大(TRAP阳性区面积占总面积的百分比分别为Nfl+/+,(0.8800±0.0014)%;Nfl+/-,(2.3300±0.0013)%,P<0.01),差异有统计学意义;体外培养的Nn+/-破骨细胞形成增多,(每1×105骨髓单核细胞形成的破骨细胞数分别为Nfl+/+,41.75±13.14:N仃+/-,61.17±18.17,P<0.01)差异有统计学意义;体外诱导培养的破骨细胞的黏附、迁移、骨吸收功能强(黏附细胞数量Nn+/+,53.00±11.08;Nil+/-,108.00±11.67,JP<0.01;迁移细胞数量Nn+/+,88.33±12.40;Nn+/-,239.83±67.77,P<0.01骨吸收面积百分比Nfl+/+.18.37%±0.0367;Nfl+/-,(40.4400±0.1052)%,P<0.01).两者差异有统计学意义.结论 破骨细胞增多,功能增强是Ⅰ型神经纤维瘤病引起骨质疏松的发病机制之一.     

Neuro-oncology of neurofibromatosis type 1

Opinion statement  Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with an incidence of about 1:2500 to 1:3000. It is caused by a germline inactivating mutation of the NF1 gene on chromosome 17. Patients with NF1 are at increased risk of developing a variety of tumors of the peripheral and central nervous system, including neurofibromas, plexiform neurofibromas, malignant peripheral nerve sheath tumors, and low-grade gliomas of the optic nerves and other cerebral structures. Rarely, they develop high-grade gliomas. Although they are rare, these hereditary tumor syndromes involving the nervous system must be recognized in patients and their families, as early diagnosis may alter management and ultimately improve outcome. Additional insight into the molecular mechanisms causing these syndromes and their relationship with the clinical features will allow the development and implementation of screening and prevention strategies for these diseases. Management of these lesions is difficult and requires specific skills and the collaborative work of neurosurgeons, radiation therapists, neurologists, and oncologists. Ideally, patients should be managed in comprehensive centers with specific expertise in the management of patients with NF1. This review describes current and developing therapies for managing the neuro-oncologic manifestations of NF1.     

A murine model of neurofibromatosis type 1 tibial pseudarthrosis featuring proliferative fibrous tissue and osteoclast‐like cells

Neurofibromatosis type 1 (NF1) is a common genetic condition caused by mutations in the NF1 gene. Patients often suffer from tissue‐specific lesions associated with local double‐inactivation of NF1. In this study, we generated a novel fracture model to investigate the mechanism underlying congenital pseudarthrosis of the tibia (CPT) associated with NF1. We used a Cre‐expressing adenovirus (AdCre) to inactivate Nf1 in vitro in cultured osteoprogenitors and osteoblasts, and in vivo in the fracture callus of Nf1^flox/flox and Nf1^flox/? mice. The effects of the presence of Nf1^null cells were extensively examined. Cultured Nf1^null‐committed osteoprogenitors from neonatal calvaria failed to differentiate and express mature osteoblastic markers, even with recombinant bone morphogenetic protein‐2 (rhBMP‐2) treatment. Similarly, Nf1^null‐inducible osteoprogenitors obtained from Nf1 mouse muscle were also unresponsive to rhBMP‐2. In both closed and open fracture models in Nf1^flox/flox and Nf1^flox/? mice, local AdCre injection significantly impaired bone healing, with fracture union being <50% that of wild type controls. No significant difference was seen between Nf1^flox/flox and Nf1^flox/? mice. Histological analyses showed invasion of the Nf1^null fractures by fibrous and highly proliferative tissue. Mean amounts of fibrous tissue were increased upward of 10‐fold in Nf1^null fractures and bromodeoxyuridine (BrdU) staining in closed fractures showed increased numbers of proliferating cells. In Nf1^null fractures, tartrate‐resistant acid phosphatase–positive (TRAP+) cells were frequently observed within the fibrous tissue, not lining a bone surface. In summary, we report that local Nf1 deletion in a fracture callus is sufficient to impair bony union and recapitulate histological features of clinical CPT. Cell culture findings support the concept that Nf1 double inactivation impairs early osteoblastic differentiation. This model provides valuable insight into the pathobiology of the disease, and will be helpful for trialing therapeutic compounds. © 2012 American Society for Bone and Mineral Research     

Primary cerebellar pilocytic astrocytoma with anaplastic features in a patient with neurofibromatosis type 1 - case report -

A 70-year-old woman with neurofibromatosis type 1 (NF-1) presented with a primary cerebellar pilocytic astrocytoma (PA) with anaplastic features manifesting as worsening headache and ataxia. Magnetic resonance (MR) imaging on admission showed a diffusely enhanced solid mass in the left cerebellar hemisphere, although MR imaging showed no abnormalities 2 years before admission. Histological examination after gross total removal of the tumor exhibited a biphasic pattern with marked Rosenthal fibers, together with some malignant features including frequent mitoses and invasive growth pattern. The final diagnosis was PA with anaplastic features. Previous PA cases with mitotic activity and endothelial proliferation, and/or palisading necrosis have been classified as anaplastic PA (or PA with anaplastic features). In the present case, the tumor histology corresponded to this designation. The present case indicates that PAs with anaplastic features can occur in patients with NF-1.     

Intrapulmonary neurofibroma independent of neurofibromatosis type 1

Intrapulmonary neurofibromas without neurofibromatosis type 1 are rare—so rare that only 11 cases have been reported previously. This case report describes a 37-year-old woman who was otherwise healthy. Chest radiography and computed tomography showed a solitary nodule, 20 mm diameter, in the left lung. The tumor was removed and examined. It was not encapsulated but was covered with an intact bronchial mucosa and lacked a clear partition into two areas of Antoni A (a palisading cellular component) and Antoni B (a loose myxoid component). Tumor cells were strongly positive for neuron-specific enolase and S-100 protein. These data characterized the tumor as a rare benign neurofibroma. The patient shows no sign of recurrence after 12 months of follow-up. We reviewed and characterized surgically resected cases of intrapulmonary neurofibroma without neurofibromatosis type 1 especially in comparison with cases of endotracheobronchial neurofibroma.     

Vertebral scalloping in neurofibromatosis type 1: a quantitative approach.

OBJECTIVE: To investigate quantitative differences in vertebral scalloping between children who have scoliosis with and without neurofibromatosis type 1 (NF1). DESIGN: A retrospective study. SETTING: A university-affiliated children's hospital. PATIENTS: Twenty-seven children with scoliosis, 13 of whom had NF1 and 14 of whom did not. METHOD: Existing radiographs of the lumbar vertebrae were used to measure and compare the degree of vertebral scalloping. MAIN OUTCOME MEASURES: The distribution of posterior scalloping ratios in the 2 groups and the most extreme ratio in each subject in each group were compared. RESULTS: Scalloping ratios from the children with NF1 were not normally distributed: 31% had ratios greater than 1.20. Scalloping ratios from the non-NF1 children were normally distributed, with a mean ratio (and standard deviation) of 1.13 (0.03). The distribution between the 2 groups was significantly different (p < 0.05). CONCLUSIONS: In children who have scoliosis but no NF1 there was a range of mild scalloping whereas those with NF1 has severe scalloping. Further studies are needed to determine the possible role of vertebral scalloping in scoliosis severity and progression in children who have NF1.     

Primary cytomegalovirus infection following cardiac transplantation in a murine model

A murine cytomegalovirus (CMV) model was utilized to determine the source of primary CMV infection in cardiac transplantation. Hearts were taken from actively or latently infected BALB/C mice and then transplanted as primary, heterotopic isografts into CMV-negative BALB/C recipients. The transplantation of hearts from acutely infected donors into nonimmunosuppressed recipients resulted in asymptomatic primary infection as manifested by detectable virus in both donor and recipient hearts, liver, spleen, and salivary glands and by the development of anti-CMV antibody. When hearts from latently infected animals were transplanted into nonimmunosuppressed recipients, a transient primary infection occurred that was manifested by detectable virus in the spleen and salivary glands and the appearance of anti-CMV antibody. When recipient animals were immunosuppressed with cortisone acetate (125 mg/kg/day i.p.) and rabbit antimouse thymocyte globulin (0.2 ml i.p. twice weekly), after transplantation of hearts from acutely and latently infected mice, lethal primary CMV infection developed. High titers of virus were recovered in all organs tested in these animals, including both the donor and recipient hearts. We conclude that the heart is infected during the course of primary murine CMV infection, and that hearts from latently infected animals are a source of serious primary infection in immunosuppressed recipients. This experimental system should be a useful model relevant to human cardiac transplantation.     

Ruptured inferior mesenteric artery aneurysm in a patient with a type 1 neurofibromatosis

We describe the case of a 61-year-old woman having a type 1 neurofibromatosis (von Recklinghausen disease), whose acute abdominal pain revealed a voluminous retroperitoneal hemorrhage caused by a 25-mm ruptured inferior mesenteric artery aneurysm. She underwent emergent aneurysm and left colonic resection. This report of a rare digestive artery aneurysm rupture, which added to increasing reports of vascular abnormalities in type 1 neurofibromatosis patients, underlines the need to maintain a high suspicion index of a vascular etiology in case of any abdominal complaint in these patients.     

Spontaneous hemothorax in a patient with neurofibromatosis type 1 and undiagnosed pheochromocytoma

Spontaneous hemothorax in neurofibromatosis type 1 rarely occurs, is potentially life-threatening, and requires expedient management. We present a case of massive hemothorax in a patient with neurofibromatosis type 1 caused by spontaneous rupture of the right internal mammary artery. A subsequently diagnosed underlying pheochromocytoma may be implicated in rupture of the arterial wall.     

Multiple gastrointestinal stromal tumors in neurofibromatosis type 1: Report of a case

This report presents a case of multiple gastrointestinal stromal tumors (GIST) with neurofibromatosis type 1 (NF1). A 68-year-old woman was admitted to the hospital because of a tumor close to the head of the pancreas. Imaging studies revealed submucosal tumors of the duodenum. The retroperitoneal tumor was diagnosed before surgery. Besides the main tumor in the duodenum, multiple small submucosal tumors were found in the duodenum and upper part of the jejunum during the operation. All of these tumors were resected. The histological diagnosis of all these tumors was GISTs. These tumors were immunohistochemically positive for KIT, but they demonstrated no mutation in c-kit exons 9, 11, 13, and 17, and platelet-derived growth factor receptor α exons 12 and 18. No recurrence occurred for a year after surgery.