Vascular changes in the periosteum of congenital pseudarthrosis of the tibia

Abstract

The etiology and the pathogenesis of congenital pseudarthrosis of the tibia (CPT) are still unknown. The affected tibia exhibits insufficient mechanical strength and osteogenetic capability. CPT is frequently associated with neurofibromatosis type 1 (NF1; von Recklinghausen's disease); however, both diseases have not yet been linked pathogenetically. This study presents the pathomorphologic findings of CPT under special consideration of NF1. Therefore, samples from patients operated on for CPT ($n=4$) with ($n=3$) and without ($n=1$) neurofibromatosis were investigated by light microscopy, immunohistochemistry, and electron microscopy. The most striking finding in all patients was thickened periosteum with accumulation of nerval cells surrounding small arteries, causing subtotal or complete obliteration.

In conclusion, impaired vascularization can result in decreased osteogenic capabilities. The similarity of ultrastructural findings in the abnormal periosteum and in skin neurofibromas of neurofibromatosis patients may indicate a pathogenetic association of both diseases.

Introduction

Congenital pseudarthrosis of the tibia (CPT) is characterized by recurrent pathologic fractures of the lower leg in early childhood. Callus formation fails, and bone healing tends to be insufficient [5], [6], [28]. Usually, the first symptom of CPT is antero-lateral bowing of the tibia and secondary bowing of the fibula. X-ray examination reveals focal cortical sclerosis and broadening of the tibia and the fibula, with the apex of the bowing between the middle and the lower third of the diaphysis (prefracture state). The periosteum is markedly thickened in the region where the pseudarthrosis develops. Fracture of either the tibia or the fibula occurs spontaneously or follows a minor trauma. Consecutive bone healing is insufficient, with development of fibrous tissue forming the pseudarthrosis.

Numerous models of pathogenesis such as mechanical stress [9], [24], neurofibroma interfering with bone union [12], or abnormalities of the blood vessels feeding the tibia [34] have been proposed. However, these features were neither found consistently in CPT patients nor could they conclusively explain the clinical and pathologic properties of CPT. The periosteal cuff surrounding the CPT may play a major role in the advent of the bone lesion [23]. Pseudarthrosis was induced in rats by cellophane stripes [19] and in the rabbit by placing a synthetic Marlex-Mesh^® around the tibia, mimicking the thickened periosteum in CPT [33]. In agreement with these findings, CPT healing rates were higher when the pathologic periosteum and fibromatous tissue were entirely removed [2], [32].

Up to 50–75% of patients with CPT show clinical symptoms of neurofibromatosis type I (NF1; von Recklinghausen's disease) [16], [18]. The character of the correlation between both diseases is unknown. NF1 is caused by germline mutations (one out of two is sporadic) or somatic mosaicism in the neurofibromin gene on the long arm of chromosome 17 [11], [29]. The phenotype of NF1 mutations varies considerably, including typical benign skin tumors and café au lait spots, as well as gliomas of the optic and acoustic nerves [22].

The purpose of this study was to analyze and compare the pathomorphology of the periosteum and tibial pseudarthrosis of CPT patients with and without NF. In addition, we attempted to evaluate the role of the thickened periosteum in the set up of CPT.