Skeletal abnormalities in neurofibromatosis type 1: Approaches to therapeutic options

Abstract

The skeleton is frequently affected in individuals with neurofibromatosis type 1, and some of these bone manifestations can result in significant morbidity. The natural history and pathogenesis of the skeletal abnormalities of this disorder are poorly understood and consequently therapeutic options for these manifestations are currently limited. The Children's Tumor Foundation convened an International Neurofibromatosis Type 1 Bone Abnormalities Consortium to address future directions for clinical trials in skeletal abnormalities associated with this disorder. This report reviews the clinical skeletal manifestations and available preclinical mouse models and summarizes key issues that present barriers to optimal clinical management of skeletal abnormalities in neurofibromatosis type 1. These concepts should help advance optimal clinical management of the skeletal abnormalities in this disease and address major difficulties encountered for the design of clinical trials. © 2009 Wiley‐Liss, Inc.

Multimodal Imaging in Neurofibromatosis Type 1-associated Nerve Sheath Tumors

“…Cutaneous clinical characteristics of NF1 include café-au-lait spots (light brown hyperpigmentation with smooth borders), axillary as well as inguinal freckling (freckle-like hyperpigmentation in areas usually not exposed to the sun) and Lisch nodules (benign iris hamartoma) [7 -10]. Musculoskeletal abnormalities are frequently observed and include scoliosis (in 10 -20 % of individuals), osteoporosis with significantly elevated risk of fractures, pseudoarthrosis and diagnostically revealing deformations such as congenital sphenoid wing dysplasia and tibial dysplasia [6,7,11,12]. Common cardiovascular manifestations are a frequent arterial hypertension, hypertrophic cardiomyopathies, pulmonary artery stenosis and other congenital heart defects as well as NF1-associated vasculopathy with stenosis of the renal and cerebral arteries [6, 13,14].…”

The Skeleton Abnormalities in Patients with Neurofibromatosis Type 1: Important Consequences of Abnormal Gene Function

“…Children should be treated as well, as soon as fracture complicates the osteopenic/osteoporotic bone dysplasia (Elefteriou, 2009). Unfortunately, anabolic substances available currently upon two forms of parathyroid hormone pose the increased risk of osteosarcoma development, proven in rats, and are contraindicated in children (Tashjian & Gagel, 2006).…”

“…Currently there is no effective treatment for Nf-1 related dural ectasia. If microfractures and vertebral wedging with subsequent development of scoliosis is diagnosed, then pharmacologic agents to increase vertebral strength may be appropriate (Elefteriou, 2009). The dumbbell tumors, most of which are located unilaterally in the spinal canal and paravertebral space, are excised through a hemilaminectomy and a facetectomy, because these techniques provide large space for tumors excision.…”

“…Anecdotally, early surgical intervention in children with Nf-1 and tibial pseudarthrosis results in poorer outcomes compared to later surgical management. The Consortium orthopedists recommended routine bracing of the dysplastic long bone upon diagnosis of bowing and agreed that prophylactic surgery should be avoided (Elefteriou, 2009). So, the current standard for treatment of long bone bowing in children is bracing to prevent fracture.…”

“…Thus, electrical stimulation, varying periods of postoperative immobilization, supplemental bone grafting, and more sophisticated techniques, such as application of bone morphogenetic proteins and monocytic progenitors stem cells are under the routine or experimental options. Summarizing, tibial dysplasia with pseudarthrosis is still challenging Nf-1 skeletal manifestation required further extensive elaboration, on both scientific and everyday practice fields (Elefteriou, 2009).…”