oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2022-21-4-98-109oncotomsk-2246Research ArticleОБЗОРЫREVIEWSАтипичные формы и гено-фенотипические корреляции нейрофиброматоза 1-го типаAtypical clinical manifestations and genotype-phenotype correlations of neurofibromatosis type 1https://orcid.org/0000-0002-4091-382XМустафинР. Н.MustafinR. N.

Мустафин Рустам Наилевич - кандидат биологических наук, доцент кафедры медицинской генетики и фундаментальной медицины.

450008, Уфа, ул. Ленина, 3.

SPIN-код: 4810-2535. Researcher ID (WOS): S-2194-2018. Author ID (Scopus): 56603137500.

Rustam N. Mustafin - PhD, Associate Professor of the Department of Medical Genetics and Fundamental Medicine, Bashkir State Medical University.

3, Lenin St., 450008, Ufa.

Researcher ID (WOS): S-2194-2018. Author ID (Scopus): 56603137500.

ruji79@mail.ruБашкирский государственный медицинский университетРоссияBashkir State Medical UniversityRussian Federation20220309202221498109Copyright © Мустафин Р.Н., 20222022Мустафин Р.Н.Mustafin R.N.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/2246

Цель исследования – анализ данных об атипичных формах нейрофиброматоза 1-го типа и генофенотипических корреляциях при этом заболевании. Материал и методы. Поиск соответствующих источников проводился в системах Scopus, Web of Science, PubMed с включением публикаций с мая 1993 г. по октябрь 2021 г. Из 318 найденных исследований 59 были использованы для написания систематического обзора. Результаты. Найдены работы с описанием атипичных форм нейрофиброматоза 1-го типа со стертым течением без проявления опухолевого синдрома, которые обусловлены специфическими мутациями в гене NF1 (вызывающими замены аминокислот в нейрофибромине: p.Arg1038, p.Met1149, p.Arg1809, или делецию аминокислот: p.Met990del, p.Met992del). Для больных с микроделециями всего гена NF1 и прилегающих областей характерны более тяжелые проявления нейрофиброматоза 1-го типа (чаще проявляются лицевой дизморфизм, скелетные и сердечно-сосудистые аномалии, трудности в обучении и симптоматические спинальные нейрофибромы). С ранней манифестацией опухолей ассоциированы мутации сайтов сплайсинга и протяженные делеции гена NF1, с глиомами зрительных нервов – мутации на 5’-конце гена, вызывающие укорочение белкового продукта, со структурным поражением головного мозга – мутация c.3721C>T (p.R1241*), с эндокринными расстройствами – мутация c.6855C>A (p.Y2285*). Описана клиническая картина нейрофиброматоза 1-го типа, схожая с липоматозом и синдромом Джаффе–Кампаначчи, не связанная с конкретным типом мутации. Заключение. Несмотря на выраженную клиническую вариабельность нейрофиброматоза 1-го типа даже у членов одной семьи, в ряде работ описаны гено-фенотипические корреляции. Так как белок нейрофибромин имеет сложную структуру с несколькими функциональными доменами, предполагается роль генов-модификаторов и эпигенетических факторов в патогенезе нейрофиброматоза 1-го типа. Показано, что на выраженность опухолевого синдрома влияют особенности метилирования гена NF1 и прилегающих областей, а сам ген взаимосвязан с определенными микроРНК. Поэтому перспективным способом лечения нейрофиброматоза 1-го типа может стать таргетная терапия, нацеленная на специфические некодирующие РНК для восстановления нормальной экспрессии гена NF1.

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.

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The authors declare that there are no conflicts of interest present.