Skeletal anomalies in patients with neurofibromatosis type 1
Authors:   Bashkir State Medical University, Ufa, Russian Federation, Mustafin R.N. 
Published: April 2022

Introduction Neurofibromatosis type 1 (NF1) is one of the most common hereditary tumor syndromes. The average incidence of NF1 in the world is 1:3000 of the population. The characteristic signs of the disease are neurofibromas and café-au-lait macules on the skin. 60 % of patients with NF1 develop specific skeletal anomalies: scoliosis, chest deformity, pseudarthrosis, requiring surgical treatment and long-term rehabilitation. It is necessary to develop prognostic criteria for the development of severe skeletal anomalies in NF1 and take early measures to prevent their progression. Congenital pseudarthrosis of the tibia is diagnosed in 5 % of children with NF1, accounting for 80 % of all cases of this pathology in the general population. Spinal scoliosis is detected in 60 %, osteoporosis in 50 %, chest deformity in 37.6 %, microgenia in 53 %, increased head circumference in 25 %, sphenoid wing dysplasia in 12 %, facial asymmetry in 10 % of patients with NF1. The aim of the review is to focus on the pathogenesis of skeletal anomalies development in NF1 that result in disorders of the musculoskeletal system in NF1 in order to take early measures for the prevention and treatment of the disease. Materials and method The review is based on numerous studies found in the databases: PubMed, Scopus, Web of Science, published mainly over the past 5 years. The suitable studies were searched by keywords and their combinations «neurofibromatosis type 1» with the words «skeletal abnormalities», «musculoskeletal system», «pseudarthrosis», «scoliosis», «pathogenesis», «deformation», «treatment», «frequency», «prevalence», «genotype-phenotype correlation», « modifier genes». Results and discussion The pathogenesis of skeletal anomalies is due to both the loss of heterozygosity of the NF1 gene in pseudoarthrosis and the effect of neurofibromin deficiency on the development of connective tissue. Currently, the only effective drugs for the treatment of tumor syndrome in NF1 are inhibitors of mitogen-activated kinase (MEK), which suppress the increased activity of Ras oncogenes. A promising issue is the study of the effect of MEK inhibitors on the progression of skeletal anomalies in patients with NF1 in the treatment of tumor syndrome. Therefore, dynamic observation by an orthopedic surgeon with an objective assessment of the observed changes is of great importance in the management of patients. It is necessary to widely introduce molecular genetics methods for confirming the diagnosis of NF1 in the clinic in cases of a combination of skeletal anomalies with individual signs of the disease, since the manifestations of NF1 are steadily progressing with age, even in the presence of erased and atypical forms of the disease. Since the analysis of scientific literature has shown the possible influence of modifier genes on the pathogenesis of NF1, the search for mutations in these genes is promising. Conclusion Most patients with NF1 develop orthopedic pathology, which is associated with the role of the NF1 gene in the development of connective tissue. The increased mutability of this gene causes the loss of heterozygosity in the development of congenital pseudoarthrosis of the tibia. At the same time, NF1 driver mutations are detected in 10 % of sporadic malignant neoplasms. Therefore, the role of somatic mutations in the NF1 gene in the development of skeletal anomalies in the general population is probable. The methods of NF1 therapy that are under investigation may become the basis for the complex treatment of oncological and orthopedic patients.