oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2023-22-3-119-124oncotomsk-2584Research ArticleОБЗОРЫREVIEWSВозможности диагностики и лечения нейрофиброматоза 1-го типа в РоссииProspects for diagnostics and treatment of neurofibromatosis type 1 in Russiahttps://orcid.org/0000-0002-4091-382XМустафинР. Н.MustafinR. N.

Мустафин Рустам Наилевич - доцент кафедры медицинской генетики и фундаментальной медицины.

450008, Уфа, ул. Ленина, 3

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

3, Lenin St., Ufa, 450008

ruji79@mail.ruФГБОУ ВО «Башкирский государственный медицинский университет» Минздрава РоссииРоссияBashkir State Medical University of the Ministry of Health of the RussiaRussian Federation202328062023223119124Copyright © Мустафин Р.Н., 20232023Мустафин Р.Н.Mustafin R.N.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/2584

Цель исследования - анализ имеющихся данных о современных методах диагностики и лечения нейрофиброматоза 1-го типа (НФ1) и их применения в Российской Федерации. Материал и методы. Поиск соответствующих источников проводился в системах Scopus, Web of Science, PubMed, Elibrary с включением публикаций с февраля 1992 г. по декабрь 2022 г. Из 1873 найденных научных статей 48 были использованы для написания систематического обзора. Результаты. Нейрофиброматоз 1-го типа обусловлен герминальными гетерозиготными мутациями в гене NF1, который кодирует белок нейрофибромин, подавляющий митоген-активируемые сигнальные пути, необходимые для пролиферации клеток. Клинические проявления НФ1 сходны с синдромами Пейтца-Егерса, Ложье-Хунцикера, Русалкаба-Мюре-Смита, Баннаяна-Зоннаны, LEOPARD, нейрофиброматозом 2-го типа и липоматоза-ми, поэтому для подтверждения диагноза болезни важнейшим критерием является выявление генной мутации методом секвенирования, так как в гене NF1 нет горячих точек мутагенеза. Для обнаружения микроделеций локуса 17q11.2 используется мультиплексная лигазная цепная реакция. В России такие методы молекулярно-генетической идентификации НФ1 применялись в Москве и Республике Башкортостан. Для лечения опухолевого синдрома наиболее эффективны хирургические вмешательства с помощью неодимового лазера и терапия ингибиторами митоген-активированной протеинкиназы. В России опубликованы работы о применении хирургического лазера в лечении плексиформных нейрофибром и экстрамедуллярных опухолей спинного мозга. Лечение НФ1 селуметинибом в России анонсировано Межрегиональной общественной организацией содействия помощи пациентам с нейрофиброматозом «22/17», которая бесплатно обеспечивает препаратом детей с неоперабельными нейрофибромами. Заключение. В современной медицине необходимо широкое использование методов идентификации мутаций в гене NF1 с помощью создания универсальных панелей таргетного секвенирования. Это позволит не только проводить дифференциальную диагностику НФ1, но и выявлять причину химиорезистентности спорадических злокачественных новообразований для внедрения ингибиторов митоген-активированной протеинкиназы в их лечение. Наиболее оптимальна комбинация с хирургическим иссечением нейрофибром с помощью неодимового лазера.

Purpose of the study. Analysis of available data on modern methods of diagnosis and treatment of neurofibromatosis type 1 (NF1) and their application in the Russian Federation. Material and Methods. The search for relevant sources was carried out in the Scopus, Web of Science, PubMed, Elibrary systems, including publications from February 1992 to December 2022. Of the 1873 scientific articles found, 48 were used to write a systematic review. Results. Neurofibromatosis type 1 (NF1) is caused by germline heterozygous mutations in the NF1 gene, which encodes the neurofibromin protein, which suppresses mitogen-activated signaling pathways necessary for cell proliferation. Clinical manifestations of NF1 are similar to Peutz–Jeghers, Laugier–Hunziker, Rusalkab–Muret–Smith, Bannayan–Zonnana, LEOPARD syndromes, neurofibromatosis type 2 and lipomatosis; therefore, to confirm the diagnosis, the most important criterion is the detection of a gene mutation by sequencing, since there are no mutagenesis hotspots in the NF1 gene. To detect 17q11.2 locus microdeletions, MLPA method is used. In Russia, such methods of molecular genetic identification of NF1 were carried out in Moscow and in the Republic of Bashkortostan. Surgical interventions using a neodymium laser and therapy with mitogen-activated protein kinase inhibitors are the most effective for the treatment of tumor syndrome. Scientific results of the use of a surgical laser in the treatment of plexiform neurofibromas and extramedullary tumors of the spinal cord have been published in Russia. Treatment of NF1 with selumetinib in Russia was announced by the interregional public organization for assistance to patients with neurofibromatosis “22/17”, which provides the drug to children with inoperable neurofibromas free of charge. Conclusion. In modern medicine, it is necessary to widely use methods for identifying mutations in the NF1 gene by creating universal panels of targeted sequencing. This will allow not only the differential diagnosis of NF1, but also the identification of the cause of chemoresistance of sporadic malignant neoplasms for the introduction of mitogen-activated protein kinase inhibitors in their treatment. Combination of this method with surgical excision of neurofibromas using a neodymium laser is optimal.

лазермитоген-активированная протеинкиназанейрофибромынейрофиброматоз 1-го типаопухолиселуметинибlasermitogen-activated protein kinaseneurofibromastype 1 neurofibromatosistumorsselumetinibReferencesGutmann D.H., Ferner R.E., Listernick R.H., Korf B.R., Wolters P.L., Johnson K.J. Neurofibromatosis type 1. Nat Rev Dis Primers. 2017; 3. doi: 10.1038/nrdp.2017.4.Gutmann D.H., Ferner R.E., Listernick R.H., Korf B.R., Wolters P.L., Johnson K.J. Neurofibromatosis type 1. Nat Rev Dis Primers. 2017; 3. doi: 10.1038/nrdp.2017.4.Kang E., Kim Y.M., Seo G.H., Oh A., Yoon H.M., Ra Y.S., Kim E.K., Kim H., Heo S.H., Kim G.H., Osborn M.J., Tolar J., Yoo H.W., Lee B.H. Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types. J Hum Genet. 2020; 65(2): 79–89. doi: 10.1038/s10038-019-0695-0.Kang E., Kim Y.M., Seo G.H., Oh A., Yoon H.M., Ra Y.S., Kim E.K., Kim H., Heo S.H., Kim G.H., Osborn M.J., Tolar J., Yoo H.W., Lee B.H. Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types. J Hum Genet. 2020; 65(2): 79–89. doi: 10.1038/s10038-019-0695-0.van Minkelen R., van Bever Y., Kromosoeto J.N., Withagen-Hermans C.J., Nieuwlaat A., Halley D.J., van den Ouweland A.M. A clinical and genetic overview of 18 years neurofibromatosis type 1 molecular diagnostics in the Netherlands. Clin Genet. 2014; 85(4): 318–27. doi: 10.1111/cge.12187.van Minkelen R., van Bever Y., Kromosoeto J.N., Withagen-Hermans C.J., Nieuwlaat A., Halley D.J., van den Ouweland A.M. A clinical and genetic overview of 18 years neurofibromatosis type 1 molecular diagnostics in the Netherlands. Clin Genet. 2014; 85(4): 318–27. doi: 10.1111/cge.12187.Bata B.M., Hodge D.O., Mohney B.G. Neurofibromatosis Type 1: A Population-Based Study. J Pediatr Ophthalmol Strabismus. 2019; 56(4): 243–7. doi: 10.3928/01913913-20190321-02.Bata B.M., Hodge D.O., Mohney B.G. Neurofibromatosis Type 1: A Population-Based Study. J Pediatr Ophthalmol Strabismus. 2019; 56(4): 243–7. doi: 10.3928/01913913-20190321-02.Мустафин Р.Н. Атипичные формы и гено-фенотипические корреляции нейрофиброматоза 1-го типа. Сибирский онкологический журнал. 2022; 21(4): 98–109. doi: 10.21294/1814-4861-2022-21-4-98-109.Mustafin R.N. Atypical clinical manifestations and genotype-phenotype correlations of neurofbromatosis type 1. Siberian Journal of Oncology. 2022; 21(4): 98–109. (In Russian). doi: 10.21294/1814-4861-2022-21-4-98-109.Ly K.I., Blakeley J.O. The Diagnosis and Management of Neuro-fibromatosis Type 1. Med Clin North Am. 2019; 103(6): 1035–54. doi: 10.1016/j.mcna.2019.07.004.Ly K.I., Blakeley J.O. The Diagnosis and Management of Neuro-fibromatosis Type 1. Med Clin North Am. 2019; 103(6): 1035–54. doi: 10.1016/j.mcna.2019.07.004.Anderson J.L., Gutmann D.H. Neurofibromatosis type 1. Handb Clin Neurol. 2015; 132: 75–86. doi: 10.1016/B978-0-444-62702-5.00004-4.Anderson J.L., Gutmann D.H. Neurofibromatosis type 1. Handb Clin Neurol. 2015; 132: 75–86. doi: 10.1016/B978-0-444-62702-5.00004-4.Costa A.D.A., Gutmann D.H. Brain tumors in neurofibromatosis type 1. Neurooncol Adv. 2020; 2: 85–7. doi: 10.1093/noajnl/vdz040.Costa A.D.A., Gutmann D.H. Brain tumors in neurofibromatosis type 1. Neurooncol Adv. 2020; 2: 85–7. doi: 10.1093/noajnl/vdz040.Glombova M., Petrak B., Lisy J., Zamecnik J., Sumerauer D., Liby P. Brain gliomas, hydrocephalus and idiopathic aqueduct stenosis in children with neurofibromatosis type 1. Brain Dev. 2019; 41(8): 678–90. doi: 10.1016/j.braindev.2019.04.003.Glombova M., Petrak B., Lisy J., Zamecnik J., Sumerauer D., Liby P. Brain gliomas, hydrocephalus and idiopathic aqueduct stenosis in children with neurofibromatosis type 1. Brain Dev. 2019; 41(8): 678–90. doi: 10.1016/j.braindev.2019.04.003.Bernardo P., Cinalli G., Santoro C. Epilepsy in NF1: a systematic review of the literature. Childs Nerv Syst. 2020; 36(10): 2333–50. doi: 10.1007/s00381-020-04710-7.Bernardo P., Cinalli G., Santoro C. Epilepsy in NF1: a systematic review of the literature. Childs Nerv Syst. 2020; 36(10): 2333–50. doi: 10.1007/s00381-020-04710-7.Philpott C., Tovell H., Frayling I.M., Cooper D.N., Upadhyaya M. The NF1 somatic mutational landscape in sporadic human cancers. Hum Genomics. 2017; 11(1): 13. doi: 10.1186/s40246-017-0109-3.Philpott C., Tovell H., Frayling I.M., Cooper D.N., Upadhyaya M. The NF1 somatic mutational landscape in sporadic human cancers. Hum Genomics. 2017; 11(1): 13. doi: 10.1186/s40246-017-0109-3.Пащенко М.С., Карандашева К.О., Кузнецова Е.Б., Анисимова И.В., Бессонова Л.А., Галкина В.А., Гусева Д.М., Демина Н.А., Макиенко О.Н., Маркова Т.В., Матющенко Г.Н., Петухова М.С., Семенова Н.А., Танас А.С., Залетаев Д.В., Стрельников В.В. Молекулярно-генетический анализ 617 российских пациентов с клиническим диагнозом «нейрофиброматоз»: новые патогенные и редкие непатогенные генетические варианты. Медицинская генетика. 2018; 17(11): 20–4. doi: %20 10.25557/2073-7998.2018.11.20-24.Pashchenko M.S., Karandasheva K.O., Kuznetsova E.B., Anisimova I.V., Bessonova L.A., Galkina V.A., Guseva D.M., Demina N.A., Makienko O.N., Markova T.V., Matyushchenko G.N., Petuhova M.S., Semenova M.A., Tanas A.S., Zaletaev D.V., Strelnikov V.V. Genetic analysis of 617 Russian neurofibromatosis patients: novel pathogenic and rare non-pathogenic mutations. Medical Genetics. 2018; 17(11): 20–4. (in Russian). doi: %20 10.25557/2073-7998.2018.11.20-24.Hölzel M., Huang S., Koster J., Ora I., Lakeman A., Caron H., Nijkamp W., Xie J., Callens T., Asgharzadeh S., Seeger R.C., Messiaen L., Versteeg R., Bernards R. NF1 is a tumor suppressor in neuroblastoma that determines retinoic acid response and disease outcome. Cell. 2010; 142(2): 218–29. doi: 10.1016/j.cell.2010.06.004.Hölzel M., Huang S., Koster J., Ora I., Lakeman A., Caron H., Nijkamp W., Xie J., Callens T., Asgharzadeh S., Seeger R.C., Messiaen L., Versteeg R., Bernards R. NF1 is a tumor suppressor in neuroblastoma that determines retinoic acid response and disease outcome. Cell. 2010; 142(2): 218–29. doi: 10.1016/j.cell.2010.06.004.Beauchamp E.M., Woods B.A., Dulak A.M., Tan L., Xu C., Gray N.S., Bass A.J., Wong K.K., Meyerson M., Hammerman P.S. Acquired resistance to dasatinib in lung cancer cell lines conferred by DDR2 gatekeeper mutation and NF1 loss. Mol Cancer Ther. 2014; 13(2): 475–82. doi: 10.1158/1535-7163.MCT-13-0817.Beauchamp E.M., Woods B.A., Dulak A.M., Tan L., Xu C., Gray N.S., Bass A.J., Wong K.K., Meyerson M., Hammerman P.S. Acquired resistance to dasatinib in lung cancer cell lines conferred by DDR2 gatekeeper mutation and NF1 loss. Mol Cancer Ther. 2014; 13(2): 475–82. doi: 10.1158/1535-7163.MCT-13-0817.de Bruin E.C., Cowell C., Warne P.H., Jiang M., Saunders R.E., Melnick M.A., Gettinger S., Walther Z., Wurtz A., Heynen G.J., Heideman D.A., Gómez-Román J., García-Castaño A., Gong Y., Ladanyi M., Varmus H., Bernards R., Smit E.F., Politi K., Downward J. Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer. Cancer Discov. 2014; 4(5): 606–19. doi: 10.1158/2159-8290.CD-13-0741.de Bruin E.C., Cowell C., Warne P.H., Jiang M., Saunders R.E., Melnick M.A., Gettinger S., Walther Z., Wurtz A., Heynen G.J., Heideman D.A., Gómez-Román J., García-Castaño A., Gong Y., Ladanyi M., Varmus H., Bernards R., Smit E.F., Politi K., Downward J. Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer. Cancer Discov. 2014; 4(5): 606–19. doi: 10.1158/2159-8290.CD-13-0741.Patch A.M., Christie E.L., Etemadmoghadam D., Garsed D.W., George J., Fereday S., Nones K., Cowin P., Alsop K., Bailey P.J., Kassahn K.S., Newell F., Quinn M.C., Kazakoff S., Quek K., Wilhelm-Benartzi C., Curry E., Leong H.S.; Australian Ovarian Cancer Study Group; Hamilton A., Mileshkin L., Au-Yeung G., Kennedy C., Hung J., Chiew Y.E., Harnett P., Friedlander M., Quinn M., Pyman J., Cordner S., O’Brien P., Leditschke J., Young G., Strachan K., Waring P., Azar W., Mitchell C., Traficante N., Hendley J., Thorne H., Shackleton M., Miller D.K., Arnau G.M., Tothill R.W., Holloway T.P., Semple T., Harliwong I., Nourse C., Nourbakhsh E., Manning S., Idrisoglu S., Bruxner T.J., Christ A.N., Poudel B., Holmes O., Anderson M., Leonard C., Lonie A., Hall N., Wood S., Taylor D.F., Xu Q., Fink J.L., Waddell N., Drapkin R., Stronach E., Gabra H., Brown R., Jewell A., Nagaraj S.H., Markham E., Wilson P.J., Ellul J., McNally O., Doyle M.A., Vedururu R., Stewart C., Lengyel E., Pearson J.V., Waddell N., deFazio A., Grimmond S.M., Bowtell D.D. Whole-genome characterization of chemoresistant ovarian cancer. Nature. 2015; 521(7553): 489–94. doi: 10.1038/nature14410. Erratum in: Nature. 2015; 527(7578): 398.Patch A.M., Christie E.L., Etemadmoghadam D., Garsed D.W., George J., Fereday S., Nones K., Cowin P., Alsop K., Bailey P.J., Kassahn K.S., Newell F., Quinn M.C., Kazakoff S., Quek K., Wilhelm-Benartzi C., Curry E., Leong H.S.; Australian Ovarian Cancer Study Group; Hamilton A., Mileshkin L., Au-Yeung G., Kennedy C., Hung J., Chiew Y.E., Harnett P., Friedlander M., Quinn M., Pyman J., Cordner S., O’Brien P., Leditschke J., Young G., Strachan K., Waring P., Azar W., Mitchell C., Traficante N., Hendley J., Thorne H., Shackleton M., Miller D.K., Arnau G.M., Tothill R.W., Holloway T.P., Semple T., Harliwong I., Nourse C., Nourbakhsh E., Manning S., Idrisoglu S., Bruxner T.J., Christ A.N., Poudel B., Holmes O., Anderson M., Leonard C., Lonie A., Hall N., Wood S., Taylor D.F., Xu Q., Fink J.L., Waddell N., Drapkin R., Stronach E., Gabra H., Brown R., Jewell A., Nagaraj S.H., Markham E., Wilson P.J., Ellul J., McNally O., Doyle M.A., Vedururu R., Stewart C., Lengyel E., Pearson J.V., Waddell N., deFazio A., Grimmond S.M., Bowtell D.D. Whole-genome characterization of chemoresistant ovarian cancer. Nature. 2015; 521(7553): 489–94. doi: 10.1038/nature14410. Erratum in: Nature. 2015; 527(7578): 398.Sokol E.S., Feng Y.X., Jin D.X., Basudan A., Lee A.V., Atkinson J.M., Chen J., Stephens P.J., Frampton G.M., Gupta P.B., Ross J.S., Chung J.H., Oesterreich S., Ali S.M., Hartmaier R.J. Loss of function of NF1 is a mechanism of acquired resistance to endocrine therapy in lobular breast cancer. Ann Oncol. 2019; 30(1): 115–23. doi: 10.1093/annonc/mdy497.Sokol E.S., Feng Y.X., Jin D.X., Basudan A., Lee A.V., Atkinson J.M., Chen J., Stephens P.J., Frampton G.M., Gupta P.B., Ross J.S., Chung J.H., Oesterreich S., Ali S.M., Hartmaier R.J. Loss of function of NF1 is a mechanism of acquired resistance to endocrine therapy in lobular breast cancer. Ann Oncol. 2019; 30(1): 115–23. doi: 10.1093/annonc/mdy497.Pearson A., Proszek P., Pascual J., Fribbens C., Shamsher M.K., Kingston B., O’Leary B., Herrera-Abreu M.T., Cutts R.J., Garcia-Murillas I., Bye H., Walker B.A., Gonzalez De Castro D., Yuan L., Jamal S., Hubank M., Lopez-Knowles E., Schuster E.F., Dowsett M., Osin P., Nerurkar A., Parton M., Okines A.F.C., Johnston S.R.D., Ring A., Turner N.C. Inactivating NF1 Mutations Are Enriched in Advanced Breast Cancer and Contribute to Endocrine Therapy Resistance. Clin Cancer Res. 2020; 26(3): 608–22. doi: 10.1158/1078-0432.CCR-18-4044.Pearson A., Proszek P., Pascual J., Fribbens C., Shamsher M.K., Kingston B., O’Leary B., Herrera-Abreu M.T., Cutts R.J., Garcia-Murillas I., Bye H., Walker B.A., Gonzalez De Castro D., Yuan L., Jamal S., Hubank M., Lopez-Knowles E., Schuster E.F., Dowsett M., Osin P., Nerurkar A., Parton M., Okines A.F.C., Johnston S.R.D., Ring A., Turner N.C. Inactivating NF1 Mutations Are Enriched in Advanced Breast Cancer and Contribute to Endocrine Therapy Resistance. Clin Cancer Res. 2020; 26(3): 608–22. doi: 10.1158/1078-0432.CCR-18-4044.Georgiou A., Stewart A., Cunningham D., Banerji U., Whittaker S.R. Inactivation of NF1 Promotes Resistance to EGFR Inhibition in KRAS/ NRAS/BRAFV600 -Wild-Type Colorectal Cancer. Mol Cancer Res. 2020; 18(6): 835–46. doi: 10.1158/1541-7786.MCR-19-1201.Georgiou A., Stewart A., Cunningham D., Banerji U., Whittaker S.R. Inactivation of NF1 Promotes Resistance to EGFR Inhibition in KRAS/ NRAS/BRAFV600 -Wild-Type Colorectal Cancer. Mol Cancer Res. 2020; 18(6): 835–46. doi: 10.1158/1541-7786.MCR-19-1201.Мустафин Р.Н., Бермишева М.А., Валиев Р.Р., Хуснутдинова Э.К. Нейрофиброматоз 1-го типа: результаты собственного исследования (Республика Башкортостан). Успехи молекулярной онкологии. 2021; 8(1): 17–25. doi: 10.17650/2313-805X-2021-8-1-17-25.Mustafin R.N., Bermisheva M.A., Valiev R.R., Khusnutdinova E.E. Neurofibromatosis type 1: results of our own study (Republic of Bashkortostan). Advances in Molecular Oncology. 2021; 8(1): 17–25. (in Russian). doi: 10.17650/2313-805X-2021-8-1-17-25.Friedrich R.E., Tuzcu C.T. Surgery for Peripheral Nerve Sheath Tumours of the Buttocks, Legs and Feet in 90 Patients With Neurofibromatosis Type 1. In Vivo. 2021; 35(2): 889–905. doi: 10.21873/invivo.12329.Friedrich R.E., Tuzcu C.T. Surgery for Peripheral Nerve Sheath Tumours of the Buttocks, Legs and Feet in 90 Patients With Neurofibromatosis Type 1. In Vivo. 2021; 35(2): 889–905. doi: 10.21873/invivo.12329.Gottfried O.N., Viskochil D.H., Fults D.W., Couldwell W.T. Molecular, genetic, and cellular pathogenesis of neurofibromas and surgical implications. Neurosurgery. 2006; 58(1): 1–16. doi: 10.1227/01.neu.0000190651.45384.8b.Gottfried O.N., Viskochil D.H., Fults D.W., Couldwell W.T. Molecular, genetic, and cellular pathogenesis of neurofibromas and surgical implications. Neurosurgery. 2006; 58(1): 1–16. doi: 10.1227/01.neu.0000190651.45384.8b.Hirbe A.C., Gutmann D.H. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol. 2014; 13(8): 834–43. doi: 10.1016/S1474-4422(14)70063-8.Hirbe A.C., Gutmann D.H. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol. 2014; 13(8): 834–43. doi: 10.1016/S1474-4422(14)70063-8.Needle M.N., Cnaan A., Dattilo J., Chatten J., Phillips P.C., Shochat S., Sutton L.N., Vaughan S.N., Zackai E.H., Zhao H., Molloy P.T. Prognostic signs in the surgical management of plexiform neurofibroma: the Children’s Hospital of Philadelphia experience, 1974–1994. J Pediatr. 1997; 131(5): 678–82. doi: 10.1016/s0022-3476(97)70092-1.Needle M.N., Cnaan A., Dattilo J., Chatten J., Phillips P.C., Shochat S., Sutton L.N., Vaughan S.N., Zackai E.H., Zhao H., Molloy P.T. Prognostic signs in the surgical management of plexiform neurofibroma: the Children’s Hospital of Philadelphia experience, 1974–1994. J Pediatr. 1997; 131(5): 678–82. doi: 10.1016/s0022-3476(97)70092-1.Prada C.E., Rangwala F.A., Martin L.J., Lovell A.M., Saal H.M., Schorry E.K., Hopkin R.J. Pediatric plexiform neurofibromas: impact on morbidity and mortality in neurofibromatosis type 1. J Pediatr. 2012; 160(3): 461–7. doi: 10.1016/j.jpeds.2011.08.051.Prada C.E., Rangwala F.A., Martin L.J., Lovell A.M., Saal H.M., Schorry E.K., Hopkin R.J. Pediatric plexiform neurofibromas: impact on morbidity and mortality in neurofibromatosis type 1. J Pediatr. 2012; 160(3): 461–7. doi: 10.1016/j.jpeds.2011.08.051.Diao X., Liu W., Zhang B., Yan D. [Head and neck neurofibromas: analysis of 46 cases]. Zhonghua Zhong Liu Za Zhi. 2015; 37(7): 526–9.Diao X., Liu W., Zhang B., Yan D. [Head and neck neurofibromas: analysis of 46 cases]. Zhonghua Zhong Liu Za Zhi. 2015; 37(7): 526–9.Ahsan S., Ge Y., Tainsky M.A. Combinatorial therapeutic targeting of BMP2 and MEK-ERK pathways in NF1-associated malignant peripheral nerve sheath tumors. Oncotarget 2016; 7(35): 57171–85. doi: 10.18632/oncotarget.11036.Ahsan S., Ge Y., Tainsky M.A. Combinatorial therapeutic targeting of BMP2 and MEK-ERK pathways in NF1-associated malignant peripheral nerve sheath tumors. Oncotarget 2016; 7(35): 57171–85. doi: 10.18632/oncotarget.11036.Hill C.S., Khan M., Phipps K., Green K., Hargrave D., Aquilina K. Neurosurgical experience of managing optic pathway gliomas. Childs Nerv Syst. 2021; 37(6): 1917–29. doi: 10.1007/s00381-021-05060-8.Hill C.S., Khan M., Phipps K., Green K., Hargrave D., Aquilina K. Neurosurgical experience of managing optic pathway gliomas. Childs Nerv Syst. 2021; 37(6): 1917–29. doi: 10.1007/s00381-021-05060-8.Chamseddin B.H., Hernandez L., Solorzano D., Vega J., Le L.Q. Robust surgical approach for cutaneous neurofibroma in neurofibromatosis type 1. JCI Insight. 2019; 5(11). doi: 10.1172/jci.insight.128881.Chamseddin B.H., Hernandez L., Solorzano D., Vega J., Le L.Q. Robust surgical approach for cutaneous neurofibroma in neurofibromatosis type 1. JCI Insight. 2019; 5(11). doi: 10.1172/jci.insight.128881.Yuan S.M., Cui L., Guo Y., Wang J., Hu X.B., Jiang H.Q., Hong Z.J. Surgical management of giant neurofibroma in soft tissue: a single-center retrospective analysis. Int J Clin Exp Med. 2015; 8(4): 5245–53.Yuan S.M., Cui L., Guo Y., Wang J., Hu X.B., Jiang H.Q., Hong Z.J. Surgical management of giant neurofibroma in soft tissue: a single-center retrospective analysis. Int J Clin Exp Med. 2015; 8(4): 5245–53.Levine S.M., Levine E., Taub P.J., Weinberg H. Electrosurgical excision technique for the treatment of multiple cutaneous lesions in neurofibromatosis type I. J Plast Reconstr Aesthet Surg. 2008; 61(8): 958–62. doi: 10.1016/j.bjps.2007.03.035.Levine S.M., Levine E., Taub P.J., Weinberg H. Electrosurgical excision technique for the treatment of multiple cutaneous lesions in neurofibromatosis type I. J Plast Reconstr Aesthet Surg. 2008; 61(8): 958–62. doi: 10.1016/j.bjps.2007.03.035.Katalinic D. Laser surgery of Neurofibromatosis 1 (NF 1). J Clin Laser Med Surg. 1992; 10(3): 185–92. doi: 10.1089/clm.1992.10.185.Katalinic D. Laser surgery of Neurofibromatosis 1 (NF 1). J Clin Laser Med Surg. 1992; 10(3): 185–92. doi: 10.1089/clm.1992.10.185.Moreno J.C., Mathoret C., Lantieri L., Zeller J., Revuz J., Wolkenstein P. Carbon dioxide laser for removal of multiple cutaneous neurofibromas. Br J Dermatol. 2001; 144(5): 1096–8. doi: 10.1046/j.1365-2133.2001.04214.x.Moreno J.C., Mathoret C., Lantieri L., Zeller J., Revuz J., Wolkenstein P. Carbon dioxide laser for removal of multiple cutaneous neurofibromas. Br J Dermatol. 2001; 144(5): 1096–8. doi: 10.1046/j.1365-2133.2001.04214.x.Algermissen B., Muller U., Katalinic D., Berlien H.P. CO2 Laser Treatment of Neurofibromas of Patients with Neurofibromatosis Type 1: Five Years Experience. Medical Laser Application. 2001; 16(4): 265–74. https://doi.org/10.1078/1615-1615-00031.Algermissen B., Muller U., Katalinic D., Berlien H.P. CO2 Laser Treatment of Neurofibromas of Patients with Neurofibromatosis Type 1: Five Years Experience. Medical Laser Application. 2001; 16(4): 265–74. https://doi.org/10.1078/1615-1615-00031.Kriechbaumer L.K., Susani M., Kircher S.G., Happak W. Vaporization of cutaneous neurofibromas with an erbium: yttrium-aluminum-garnet laser: a comparative histologic evaluation. Plast Reconstr Surg. 2012; 129(3): 602–4. doi: 10.1097/PRS.0b013e3182419d22.Kriechbaumer L.K., Susani M., Kircher S.G., Happak W. Vaporization of cutaneous neurofibromas with an erbium: yttrium-aluminum-garnet laser: a comparative histologic evaluation. Plast Reconstr Surg. 2012; 129(3): 602–4. doi: 10.1097/PRS.0b013e3182419d22.Неробеев А.И., Голубева С.Н. Возможности применения лазерных технологий при лечении пациентов с нейрофиброматозом 1 типа. Институт стоматологии. 2011; 2(51): 58–9.Nerobeev A.I., Golubeva S.N. Laser technologies in the treatment of patients with type 1 neurofibromatosis. Institute of Dentistry. 2011; 2(51): 58–9. (in Russian).Ступак В.В., Моисеев В.В. ND-YAG-лазер в хирургии экстрамедуллярных опухолей. Хирургия позвоночника 2004; (1): 71–7.Stupak V.V., Moiseev V.V. ND-YAG laser in extramedullar tumor surgery. Spine Surgery. 2004; (1): 71–7. (in Russian).Елисеенко И.А., Ступак В.В. Неодимовый лазер в хирургии опухолей спинного мозга типа «песочные часы». Лазерная медицина 2019; 23(S3): 36–7.Eliseenko I.A., Stupak V.V. Neodymium laser in surgery for hourglass-type spinal cord tumors. Laser Medicine 2019; 23(S3): 36–7. (in Russian).Елисеенко И.А., Лукинов В.Л., Струц С.Г., Ступак В.В. Результаты применения неодимового лазера в хирургии экстрамедуллярных опухолей: многоцентровое ретроспективное исследование 412 клинических случаев. Современные проблемы науки и образования. 2021; 5: 98. doi: 10.17513/spno.31161.Eliseenko I.A., Lukinov V.L., Struts S.G., Stupak V.V. Results of neodymium laser application in extramedullary tumor surgery: a multicenter retrospective study of 412 clinical cases. Modern Problems of Science and Education. 2021; 5: 98. (in Russian). doi: 10.17513/spno.31161.Елисеенко И.А., Струц С.Г., Васильев И.А., Ступак В.В. Хирургия неврином спинного мозга: анализ отдаленных результатов 203 больных. Современные проблемы науки и образования. 2022; 1: 92.Eliseenko I.A., Struts S.G., Vasiliev I.A., Stupak V.V. Surgery for spinal neuromas: analysis of long-term results of 203 patients. Modern Problems of Science and Education. 2022; 1: 92. (in Russian).Ratner N., Miller S.J. A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat Rev Cancer. 2015; 15(5): 290–301. doi: 10.1038/nrc3911.Ratner N., Miller S.J. A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat Rev Cancer. 2015; 15(5): 290–301. doi: 10.1038/nrc3911.Baldo F., Grasso A.G., Cortellazzo Wiel L., Maestro A., Trojniak M.P., Murru F.M., Basso L., Magnolato A., Bruno I., Barbi E. Selumetinib in the Treatment of Symptomatic Intractable Plexiform Neurofibromas in Neurofibromatosis Type 1: A Prospective Case Series with Emphasis on Side Effects. Paediatr Drugs. 2020; 22(4): 417–23. doi: 10.1007/s40272-020-00399-y.Baldo F., Grasso A.G., Cortellazzo Wiel L., Maestro A., Trojniak M.P., Murru F.M., Basso L., Magnolato A., Bruno I., Barbi E. Selumetinib in the Treatment of Symptomatic Intractable Plexiform Neurofibromas in Neurofibromatosis Type 1: A Prospective Case Series with Emphasis on Side Effects. Paediatr Drugs. 2020; 22(4): 417–23. doi: 10.1007/s40272-020-00399-y.Dombi E., Baldwin A., Marcus L.J., Fisher M.J., Weiss B., Kim A., Whitcomb P., Martin S., Aschbacher-Smith L.E., Rizvi T.A., Wu J., Ershler R., Wolters P., Therrien J., Glod J., Belasco J.B., Schorry E., Brofferio A., Starosta A.J., Gillespie A., Doyle A.L., Ratner N., Widemann B.C. Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med. 2016; 375(26): 2550–60. doi: 10.1056/NEJMoa1605943.Dombi E., Baldwin A., Marcus L.J., Fisher M.J., Weiss B., Kim A., Whitcomb P., Martin S., Aschbacher-Smith L.E., Rizvi T.A., Wu J., Ershler R., Wolters P., Therrien J., Glod J., Belasco J.B., Schorry E., Brofferio A., Starosta A.J., Gillespie A., Doyle A.L., Ratner N., Widemann B.C. Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med. 2016; 375(26): 2550–60. doi: 10.1056/NEJMoa1605943.Fangusaro J., Onar-Thomas A., Young Poussaint T., Wu S., Ligon A.H., Lindeman N., Banerjee A., Packer R.J., Kilburn L.B., Goldman S., Pollack I.F., Qaddoumi I., Jakacki R.I., Fisher P.G., Dhall G., Baxter P., Kreissman S.G., Stewart C.F., Jones D.T.W., Pfister S.M., Vezina G., Stern J.S., Panigrahy A., Patay Z., Tamrazi B., Jones J.Y., Haque S.S., Enterline D.S., Cha S., Fisher M.J., Doyle L.A., Smith M., Dunkel I.J., Fouladi M. Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. Lancet Oncol. 2019; 20(7): 1011–22. doi: 10.1016/S1470-2045(19)30277-3.Fangusaro J., Onar-Thomas A., Young Poussaint T., Wu S., Ligon A.H., Lindeman N., Banerjee A., Packer R.J., Kilburn L.B., Goldman S., Pollack I.F., Qaddoumi I., Jakacki R.I., Fisher P.G., Dhall G., Baxter P., Kreissman S.G., Stewart C.F., Jones D.T.W., Pfister S.M., Vezina G., Stern J.S., Panigrahy A., Patay Z., Tamrazi B., Jones J.Y., Haque S.S., Enterline D.S., Cha S., Fisher M.J., Doyle L.A., Smith M., Dunkel I.J., Fouladi M. Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. Lancet Oncol. 2019; 20(7): 1011–22. doi: 10.1016/S1470-2045(19)30277-3.Espírito Santo V., Passos J., Nzwalo H., Carvalho I., Santos F., Martins C., Salgado L., Silva C.E., Vinhais S., Vilares M., Salgado D., Nunes S. Selumetinib for plexiform neurofibromas in neurofibromatosis type 1: a single-institution experience. J Neurooncol. 2020; 147(2): 459–63. doi: 10.1007/s11060-020-03443-6.Espírito Santo V., Passos J., Nzwalo H., Carvalho I., Santos F., Martins C., Salgado L., Silva C.E., Vinhais S., Vilares M., Salgado D., Nunes S. Selumetinib for plexiform neurofibromas in neurofibromatosis type 1: a single-institution experience. J Neurooncol. 2020; 147(2): 459–63. doi: 10.1007/s11060-020-03443-6.Gross A.M., Wolters P.L., Dombi E., Baldwin A., Whitcomb P., Fisher M.J., Weiss B., Kim A., Bornhorst M., Shah A.C., Martin S., Roderick M.C., Pichard D.C., Carbonell A., Paul S.M., Therrien J., Kapustina O., Heisey K., Clapp D.W., Zhang C., Peer C.J., Figg W.D., Smith M., Glod J., Blakeley J.O., Steinberg S.M., Venzon D.J., Doyle L.A., Widemann B.C. Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med. 2020; 382(15): 1430–42. doi: 10.1056/NEJ-Moa1912735. Erratum in: N Engl J Med. 2020; 383(13): 1290.Gross A.M., Wolters P.L., Dombi E., Baldwin A., Whitcomb P., Fisher M.J., Weiss B., Kim A., Bornhorst M., Shah A.C., Martin S., Roderick M.C., Pichard D.C., Carbonell A., Paul S.M., Therrien J., Kapustina O., Heisey K., Clapp D.W., Zhang C., Peer C.J., Figg W.D., Smith M., Glod J., Blakeley J.O., Steinberg S.M., Venzon D.J., Doyle L.A., Widemann B.C. Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med. 2020; 382(15): 1430–42. doi: 10.1056/NEJ-Moa1912735. Erratum in: N Engl J Med. 2020; 383(13): 1290.Jackson S., Baker E.H., Gross A.M., Whitcomb P., Baldwin A., Derdak J., Tibery C., Desanto J., Carbonell A., Yohay K., O’Sullivan G., Chen A.P., Widemann B.C., Dombi E. The MEK inhibitor selumetinib reduces spinal neurofibroma burden in patients with NF1 and plexiform neurofibromas. Neurooncol Adv. 2020; 2(1). doi: 10.1093/noajnl/vdaa095.Jackson S., Baker E.H., Gross A.M., Whitcomb P., Baldwin A., Derdak J., Tibery C., Desanto J., Carbonell A., Yohay K., O’Sullivan G., Chen A.P., Widemann B.C., Dombi E. The MEK inhibitor selumetinib reduces spinal neurofibroma burden in patients with NF1 and plexiform neurofibromas. Neurooncol Adv. 2020; 2(1). doi: 10.1093/noajnl/vdaa095.Yang X., Desai K., Agrawal N., Mirchandani K., Chatterjee S., Sarpong E., Sen S. Characteristics, treatment patterns, healthcare resource use, and costs among pediatric patients diagnosed with neurofibromatosis type 1 and plexiform neurofibromas: a retrospective database analysis of a medicaid population. Curr Med Res Opin. 2021; 37(9): 1555–61. doi: 10.1080/03007995.2021.1940907.Yang X., Desai K., Agrawal N., Mirchandani K., Chatterjee S., Sarpong E., Sen S. Characteristics, treatment patterns, healthcare resource use, and costs among pediatric patients diagnosed with neurofibromatosis type 1 and plexiform neurofibromas: a retrospective database analysis of a medicaid population. Curr Med Res Opin. 2021; 37(9): 1555–61. doi: 10.1080/03007995.2021.1940907.

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