How to Cite
Abstract
Neurofibromatosis type I (NF1) is the monogenic inherited syndrome with established variability of clinical manifestations and the predisposition to the development of malignant tumors. Studying NF1 association with different types of cancers in children is necessary to understand the risk of their occurrence and the prognosis of the disease as well as subsequent studies of this predisposition.
Aim. Analysis the clinical data of patients with NF1 and malignant and benign tumors arisen in them.
Methods. A retrospective analysis of clinical data of 19 patients from 0 to 18 years old with a malignant tumor, carried out in N.N. Blokhin NMRCO from 1997 to 2018.
Results. The clinical signs of NF1 showed an age-dependent timing of their onset. Embryonal tumors were the most common and occurred in 11 out of 19 patients (57.9%), embryonal rhabdomyosarcoma predominated (42.1%), more often affecting the urogenital tract. Familial NF1 was found in 31.6% of patients. NF1 disease of the parents of these children (in four mothers and two fathers) was limited to pigmented skin lesions and multiple neurofibromas. Genetic testing of NF1 gene in three families of children with embryonal tumors revealed 2 de novo mutations — p.V2635FS & p.W1314X and one inherited from father to son (p.2363_2365del). Malignant peripheral nerve sheath tumors developed in 15.8% of patients by puberty. Soft tissue sarcomas and hematopoietic tumors occurred in 10.5% of patients, respectively. Melanoma was found in one patient (5.3%).
Conclusion. The data obtained make it possible to supplement the diapason of types of malignant tumors in children associated with NF1 and the possibility of their use in clinical practice for a more rational and targeted observation for patients. Further study of the molecular genetics and clinical aspects of NF1 is necessary for the development of promising therapies for NF1.
References
Lloyd SK, Evans DG. Neurofibromatosis type 2 (NF2): diagnosis and management // Clin Neurol. 2013;115:957–967. https: // doi: 10.1016/B978-0-444-52902-2.00054-0
Ferner RE, Huson SM, Thomas N et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1 // J Med Genet. 2007;44:(2):81–86. https: // doi: 10.1136/jmg.2006.045906
Stumpf DA, Alksne JF, Annegers JF et al. Neurofibromatosis conference statement. National Institutes of Health Consensus Development Conference // Arch Neurol. 1988;45:575–578.
Goldgar DE, Green P, Parry DM, Mulvihill JJ. Multipoint linkage analysis in neurofibromato sis type I: an international collaboration // Am J Hum Genet. 1989;44:6–12. PMID: 2491784.
Fain PR, Goldgar DE, Wallace MR et al. Refined physical and genetic mapping of the NF1 region on chromosome 17 // Am J Hum Genet. 1989;45:721–728. PubMed: 2573276.
Larribere L, Utika lJ. Multiple role of NF1 in the melanocyte lineage // Pigment Cell Melanoma Res. 2016;29:417–425. https: // doi: 10.1111/pcmr.12488
Xu GF, O’Connell P, Viskochil D et al. The neurofibromatosis type 1 gene encodes a protein related to GAP // Cell. 1990;62(3):599–608. https: // doi: 10.1016/0092-8674(90)90024-9.
Klose A, Ahmadian MR, Schuelke M et al. Selective disactivation of neurofibromin GAP activity in neurofibromatosis type 1 // Hum Mol Genet. 1998;7(8):1261–8. https: // doi: 10.1093/hmg/7.8. 1261
Ballester R, Marchuk D, Boguski M et al. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins // Cell. 1990;63(4):851–859. https: // doi: 10.1016/0092-8674(90)90151-4
DeClue JE, Cohen BD, Lowy DR. Identification and characterization of the neurofibromatosis type 1 protein product // Proc Natl. Acad. Sci. USA. 1991;88:9914–9918–28. https: // doi: 10.1073/pnas.88.22.9914
Cichowski K, Jacks T. NF1 tumor suppressor gene function: narrowing the GAP // Cell 2001;4(4):593–604. https: // doi: 10.1016/s0092-8674(01)00245-8
David H ,Viskochil DH, William T, Couldwell WT. Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications // Neurosurg Focus. 2010;28(1):E8. https: // doi: 10.3171/2009.11
Tidyman W, Rauen K. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation // Curr Opin Genet Dev. 2009;19(3):230–236. https: // doi: 10.1016/ j.gde.2009. 04.001
Rauen KA, Huson SM, Burkitt-Wright E et al. Recent developments in neurofibromatoses and RASopathies: management, diagnosis and current and future therapeutic avenues // Am J Med Genet A. 2015;167A(1):1–10. https: // doi: 10.1002/ajmg.a.36793.]
Kratz CP, Rapisuwon S, Reed H et al. Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes // Am J Med Genet C Semin Med Genet. 2011;157C(2):83–89. https: // doi: 10.1002/ajmg.c.30300
Ratner N, Miller SJ.A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor // Nat Rev Cancer. 2015;15(5):290–301. https: // doi: 10.1038/nrc 391125
Tidyman WE, Rauen KA. Mutational and functional analysis in human Ras/MAP kinase genetic syndromes. // Methods Mol Biol. 2010;661:433–47. https: // doi: 10.1007/978-1-60761-795-2_2
John AM, Ruggieri M, Ferner R, Upadhyaya M. A search for evidence of somatic mutations in the NF1 gene // J Med Genet. 2000;37(1):44–9. https: // doi: 10.1136/jmg.37.1.44.
Weihong Xu, Xiao Yang, Xiaoxia Hu, Shibo Li. Fifty-four novel mutations in the NF1 gene and integrated analyses of the mutations that modulate splicing // Int J Mol Med. 2014;34:53–60. https: // doi: 10.3892/ijmm.2014.1756
Koczkowska M, Chen Y, Callens T et al. Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848 // Am J Hum Gen. 2017;102:1–19. https: // doi: 10.1016/j.ajhg.2017.12.001
Messiaen LM, Callens T, Mortier G et al. Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects // Hum Mutat. 2000;15:541–555. https: // doi: 10.1002/1098-1004(200006)15:6<541
.Ars E, Serra E, García J et al. Mutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1 // Hum Mol Genet. 2000;9:237–247. https: // doi: 10.1093/hmg/9.2.237
Serra E, Ars E, Ravella A et al. Somatic NF1 mutational spectrum in benign neurofibromas: mRNA splice defects are common among point mutations // Hum Genet. 2001;108:416–429. https: // doi: 10.1007/s004390100514
Zoller ME, Rembeck B, Oden A et al. Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population // Cancer. 1997;79:2125–2131. PMID: 9179058.
Albers AC, Gutmann DH. Gliomas in patients with neurofibromatosis type 1 // Expert Rev Neurother. 2009;9:535–539. https: // doi: 10.1586/ern.09.4
Rasmussen SA, Yang Q, Friedman JM. Mortality in neurofibromatosis 1: an analysis using U.S. death certificates // Am J Hum Genet. 2001;68:1110–1118. https: // doi: 10.1086/320121
Pasmant E, Vidaud M, Vidaud D, Wolkenstein P. Neurofibromatosis type 1: from genotype to phenotype // J Med Genet. 2012;49:483–489. https: // doi: 10.1186/s13023-020-1310-3
Descheemaeker M, Roelandts K, De Raedt T et al. Intelligence in individuals with a neurofibromatosis type 1 microdeletion // Am J Med Genet. 2004;131:325–3263. https: // doi: 10.1002/ajmg.a.30346
Maertens O, Brems H, Vandesompele J et al. Comprehensive NF1 screening on cultured Schwann cells from neurofibromas // Hum Mutat. 2006;7:030–1040. https: // doi: 10.1002/humu.20389
Jouhilahti EM, Peltonen S, Heape AM, Peltonen J. The pathoetiology of neurofibromatosis 1. // Am J Pathol. 2011;178(5):1932–39. https: // doi: 10.1016
Listernick R, Ferner RE, Liu GT, Gutmann DH. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations // Ann Neurol. 2007;61:189–198. https: // doi: 10.1097/ WNO. 0000000000000550
Evans D, Baser M, McGaughran J et al. Malignant peripheral nerves heath tumours in neurofibromatosis 1 // J Med Genet .2002;39:311–314. https: // doi: 10.1136 / jmg.39.5.311
Maertens O, Brems H, Vandesompele J T et al. Comprehensive NF1 screening on cultured Schwann cells from neurofibromas // Hum Mutat. 2006;27:1030–1040. https: // doi: 10.1002/humu.20389
Serra E, Rosenbaum T, Winner U et al. Schwann cells harbor the somatic NF1 mutation in neurofibromas: evidence of two different Schwann cell subpopulations // Hum Mol Genet. 2000;9:3055–3064. https: // doi: 10.1093/hmg/ 9.20.3055
Peltonen J, Peltonen S. Composition of neurofibromas, NF1 expression, and comparison of normal and NF1 haploinsufficient cells // In: Neurofibromatoses. Ed by D Kaufmann. Basel, Karger, 2008:129–142.
Smolle MA, Parry M, Jeys L, Abudu S, Grimer R. Synovial sarcoma: Do children do better? // Eur J Surg Oncol. 2019;45(2):254–260. https: // doi: 10.1016/j.ejso
De Raedt T, Maertens O, Serra E, Legius E: Somatic NF1 mutation s I tumors and other tissue // In: Neurofibromatoses. Edited by D Kaufmann. Basel, Karger, 2008:143–153
Side L.E, Emanuel P.D, Taylor B et al. Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1 // Blood. 1998;2:267–272. PMID: 9639526
Seminog OO, Goldacre MJ. Risk of benign tumours of nervous system, and of malignant neoplasms, in people with neurofibromatosis: population-based record-linkage study // Br J Cancer. 2013;108:193–198. https: // doi: 10.1038/bjc.2012.535
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
© АННМО «Вопросы онкологии», Copyright (c) 2021