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Purpose of the study: Analysis of available data on geno-phenotypic correlations and atypical forms of neurofibromatosis type 1. Material and methods. We searched for relevant sources in the Scopus, Web of Science, PubMed systems, including publications from May 1993 to October 2021. Of the 318 studies we identified, 59 were used to write a systematic review. Results. We found studies describing atypical forms of neurofibromatosis type 1 with an erased course without manifestation of a tumor syndrome, which are caused by specific mutations in the NF1 gene (causing substitutions of amino acids in neurofibromin: p.Arg1038, p.Met1149, p.Arg1809, or deletion of amino acids: p.Met990del, p.Met992del). NF1 patients with microdeletions are characterized by more severe disease symptoms (more often facial dysmorphism, skeletal and cardiovascular abnormalities, learning difficulties, and symptomatic spinal neurofibromas). mutations of splicing sites and extended deletions of the NF1 gene are associated with early manifestation of tumors, mutations at the 5’-end of the gene, causing a shortening of the protein product, are associated with optic nerve gliomas. the mutation c.3721C>T (p.R1241*) correlated with structural brain damage, and c.6855C>A (p.Y2285*) with endocrine disorders. the manifestations of NF1, similar to lipomatosis and Jaffe-Campanacci syndrome, not associated with a specific type of mutation are described. Conclusion. In spite of pronounced clinical variability of the disease, even among members of the same family, several studies have described genotype-phenotype correlations. Therefore, the role of modifier genes and epigenetic factors in the pathogenesis of NF1 is assumed, since the neurofibromin protein has a complex structure with several functional domains. It has been shown that the severity of the tumor syndrome is influenced by the methylation characteristics of NF1 gene and adjacent areas. in addition, NF1 gene is associated with a variety of microRNAs. therefore, targeted therapy aimed at specific non-coding RNAs to restore normal expression of NF1 gene can become a promising treatment for NF1.

Neurofibromatosis type 1 is the most common autosomal dominant tumor syndrome. The prevalence of the disease is 1 in 3000 people. Neurofibromatosis type 1 is characterized by the gradual appearance of signs of the disease and pronounced clinical polymorphism from erased and atypical forms to severe classical manifestations. The review is devoted to the consideration of diseases, the manifestations of which are significantly similar to neurofibromatosis type 1, and therefore, molecular diagnosis of the disease is an important method for differential diagnosis. To make a diagnosis of neurofibromatosis type 1, it is necessary to find mutations in the NF1 gene using sequencing. In 10% of cases, neurofibromatosis type 1 is caused by large deletions of the 17q11.2 locus, therefore, multiplex ligation-dependent probe amplification is also necessary. Typically, the initial manifestations of neurofibromatosis type 1 are multiple café-au-lait spots, which may be the only external signs of the disease for many years. Therefore, patients with neurofibromatosis type 1 may be mistakenly diagnosed with diseases for which these pigmentary changes are characteristic: Bloom, LEOPARD, Carney, Costello, Cowden, Legius, Nijmegen, Noonan, Peitz-Jägers, Silver-Russell, cardio-facio-cutaneous syndromes. The detection of subcutaneous tumors can become the basis for an incorrect diagnosis of the clinically similar Legius syndrome and multiple endocrine neoplasia. In addition, multiple lipomas are specific manifestations of Madelung or Dercum lipomatosis, familial angiolipomatosis, the etiology of which is considered unknown. Therefore, I assume that these diseases are atypical forms of neurofibromatosis type 1, since a number of authors have described the identification of mutations in NF1 gene in patients with multiple lipomatosis. Therefore, it is important to widely introduce into clinical practice the possibility of molecular genetic identification of the disease in order to identify cases of neurofibromatosis type 1 that do not meet the diagnostic criteria adopted by the NIH. It is promising to create a panel for the study of all genes, mutations in which can cause manifestations similar to neurofibromatosis. Early diagnosis of the disease is necessary for timely initiation of treatment and prevention of severe manifestations, since effective methods of antitumor therapy of neurofibromatosis type 1, such as inhibitors of mitogen-activated kinase, are being introduced into clinical practice.

Introduction. Neurofibromatosis type 1 (NF1) is the most common hereditary tumor syndrome (frequency of its occurrence in the world is 1 : 3000 of the population). The main clinical manifestations of the disease are multiple café-au-lait macules on the skin and neurofibromas, skeletal abnormalities and cognitive deficits. The disease is based on mutations in the oncosuppressor gene NF1. This disease is characterized by significant clinical polymorphism of manifestations, even among members of the same family. No geno-phenotypic correlations were found for NF1. Therefore, it is assumed that modifier genes are the cause of the varying expressiveness of the disease. Materials and methods. Clinical-epidemiological and molecular-genetic research of patients with NF1 in the Republic of Bashkortostan (RB) was carried out. Sequencing was used to search for intragenic mutations in 57 exons of the NF1 gene. Microsatellite analysis was used to detect the deletion of the entire gene.Results. The frequency of occurrence of NF1 in RB was 1 : 10153 of the population. Analysis of the clinical manifestations of NF1 in RB patients showed a lower incidence of brain cysts in patients born in mixed marriages, which indicates the protective role of mestization. In patients with NF1 who inherited the disease from the mother, a more frequent development of skeletal anomalies and facial dysmorphism was determined. We identified 1 deletion of the entire NF1 gene in 1 patient and 14 intragenic mutations (c.205-1G>C, с.1278G>A, c.1369_1370insGGGTC, с.1570G>A, с.1973_1974delTC, c.2806A>T, с.2991-1G>C, c.3158C>G, с.3526_3528delAGA, с.3826delC, с.4514+5G>A, с.4537С>Т, c.5758_5761delTTGA, с.6792С>A) in 20 patients with NF1. We determined the random distribution of the types of mutations and did not reveal the specific features of the NF1 clinic depending on the type of mutations.Conclusions. The protective role of crossbreeding in relation to brain cysts, as well as the predominance of skeletal anomalies in patients with NF1 inheritance from the mother, indicate the role of modifier genes in the pathogenesis of the disease. The identified mutations in the NF1 gene will allow us to perform prenatal prevention of NF1 in RB patients.