Clinical Presentation and Novel Pathogenic Variants among 68 Chinese Neurofibromatosis 1 Children
Abstract
:1. Introduction
2. Material and Methods
2.1. Patients
2.2. Molecular Genetic Analysis
3. Results
3.1. Genetic Findings
3.2. Clinical Characteristics
3.3. Variant Distribution and Short Stature
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Lammert, M.; Friedman, J.M.; Kluwe, L.; Mautner, V.F. Prevalence of neurofibromatosis 1 in German children at elementary school enrollment. Arch. Dermatol. 2005, 141, 71–74. [Google Scholar] [CrossRef] [PubMed]
- Evans, D.G.; Howard, E.; Giblin, C.; Clancy, T.; Spencer, H.; Huson, S.M.; Lalloo, F. Birth incidence and prevalence of tumor-prone syndromes: Estimates from a UK family genetic register service. Am. J. Med. Genet. A 2010, 152, 327–332. [Google Scholar] [CrossRef] [PubMed]
- Uusitalo, E.; Leppävirta, J.; Koffert, A.; Suominen, S.; Vahtera, J.; Vahlberg, T.; Pöyhönen, M.; Peltonen, J.; Peltonen, S. Incidence and mortality of neurofibromatosis: A total population study in Finland. J. Investig. Dermatol. 2015, 135, 904–906. [Google Scholar] [CrossRef] [PubMed]
- Tidyman, W.E.; Rauen, K.A. The RASopathies: Developmental syndromes of Ras/MAPK pathway dysregulation. Curr. Opin. Genet. Dev. 2009, 19, 230–236. [Google Scholar] [CrossRef] [PubMed]
- Yao, R.; Wang, L.; Yu, Y.; Wang, J.; Shen, Y. Diagnostic value of multiple café-au-lait macules for neurofibromatosis 1 in Chinese children. J. Dermatol. 2016, 43, 537–542. [Google Scholar] [CrossRef]
- Mao, B.; Chen, S.; Chen, X.; Yu, X.; Zhai, X.; Yang, T.; Li, L.; Wang, Z.; Zhao, X.; Zhang, X. Clinical characteristics and spectrum of NF1 mutations in 12 unrelated Chinese families with neurofibromatosis type 1. BMC Med. Genet. 2018, 19, 101. [Google Scholar] [CrossRef]
- Shofty, B.; Constantini, S.; Ben-Shachar, S. Advances in molecular diagnosis of neurofibromatosis type 1. Semin. Pediatr. Neurol. 2015, 22, 234–239. [Google Scholar] [CrossRef]
- Chai, P.; Luo, Y.; Zhou, C.; Wang, Y.; Fan, X.; Jia, R. Clinical characteristics and mutation spectrum of NF1 in 12 Chinese families with orbital/periorbital plexiform neurofibromatosis type 1. BMC Med. Genet. 2019, 20, 158. [Google Scholar] [CrossRef]
- Zhang, J.; Tong, H.; Fu, X.; Zhang, Y.; Liu, J.; Cheng, R.; Liang, J.; Peng, J.; Sun, Z.; Liu, H.; et al. Molecular characterization of NF1 and neurofibromatosis type 1 genotype-phenotype correlations in a Chinese population. Sci. Rep. 2015, 5, 11291. [Google Scholar] [CrossRef]
- Lee, M.J.; Su, Y.N.; You, H.L.; Chiou, S.C.; Lin, L.C.; Yang, C.C.; Lee, W.C.; Hwu, W.L.; Hsieh, F.J.; Stephenson, D.A.; et al. Identification of forty-five novel and twenty-three known NF1 mutations in Chinese patients with neurofibromatosis type 1. Hum. Mutat. 2006, 27, 832. [Google Scholar] [CrossRef]
- Richards, S.; Aziz, N.; Bale, S.; Bick, D.; Das, S.; Gastier-Foster, J.; Grody, W.W.; Hegde, M.; Lyon, E.; Spector, E.; et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 2015, 17, 405–424. [Google Scholar] [CrossRef] [PubMed]
- NIH. National Institutes of Health Consensus Development Conference Statement: Neurofibromatosis. Bethesda, MD, USA, July 13–15, 1987. Neurofibromatosis 1988, 1, 172–178. [Google Scholar]
- Dunning-Davies, B.M.; Parker, A.P. Annual review of children with neurofibromatosis type 1. Arch. Dis. Child. Educ. Pract. Ed. 2016, 101, 102–111. [Google Scholar] [CrossRef] [PubMed]
- Evans, D.G.; Bowers, N.; Burkitt-Wright, E.; Miles, E.; Garg, S.; Scott-Kitching, V.; Penman-Splitt, M.; Dobbie, A.; Howard, E.; Ealing, J.; et al. Comprehensive RNA analysis of the NF1 gene in classically affected NF1 affected individuals meeting NIH criteria has high sensitivity and mutation negative testing is reassuring in isolated cases with pigmentary features only. EBioMedicine 2016, 7, 212–220. [Google Scholar] [CrossRef]
- Wu-Chou, Y.H.; Hung, T.C.; Lin, Y.T.; Cheng, H.W.; Lin, J.L.; Lin, C.H.; Yu, C.C.; Chen, K.T.; Yeh, T.H.; Chen, Y.R. Genetic diagnosis of neurofibromatosis type 1: Targeted next-generation sequencing with Multiple Ligation-Dependent Probe Amplification analysis. J. Biomed. Sci. 2018, 25, 72. [Google Scholar] [CrossRef]
- Ferner, R.E.; Hughes, R.A.; Hall, S.M.; Upadhyaya, M.; Johnson, M.R. Neurofibromatous neuropathy in neurofibromatosis 1 (NF1). J. Med. Genet. 2004, 41, 837–841. [Google Scholar] [CrossRef] [Green Version]
- Torres Nupan, M.M.; Velez Van Meerbeke, A.; LópezCabra, C.A.; Herrera Gomez, P.M. Cognitive and behavioral disorders in children with neurofibromatosis type 1. Front. Pediatr. 2017, 5, 227. [Google Scholar] [CrossRef]
- Lehtonen, A.; Howie, E.; Trump, D.; Huson, S.M. Behaviour in children with neurofibromatosis type 1: Cognition, executive function, attention, emotion, and social competence. Dev. Med. Child. Neurol. 2013, 55, 111–125. [Google Scholar] [CrossRef]
- Soucy, E.A.; van Oppen, D.; Nejedly, N.L.; Gao, F.; Gutmann, D.H.; Hollander, A.S. Height assessments in children with neurofibromatosis type 1. J. Child. Neurol. 2013, 28, 303–307. [Google Scholar] [CrossRef]
- Clementi, M.; Milani, S.; Mammi, I.; Boni, S.; Monciotti, C.; Tenconi, R. Neurofibromatosis type 1 growth charts. Am. J. Med. Genet. 1999, 87, 317–323. [Google Scholar] [CrossRef]
- Pasmant, E.; Sabbagh, A.; Spurlock, G.; Laurendeau, I.; Grillo, E.; Hamel, M.J.; Martin, L.; Barbarot, S.; Leheup, B.; Rodriguez, D.; et al. NF1 microdeletions in neurofibromatosis type 1: From genotype to phenotype. Hum. Mutat. 2010, 31, 1506–1518. [Google Scholar] [CrossRef] [PubMed]
- Upadhyaya, M.; Huson, S.M.; Davies, M.; Thomas, N.; Chuzhanova, N.; Giovannini, S.; Evans, D.G.; Howard, E.; Kerr, B.; Griffiths, S.; et al. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): Evidence of a clinically significant NF1 genotype-phenotype correlation. Am. J. Hum. Genet. 2007, 80, 140–151. [Google Scholar] [CrossRef] [PubMed]
- Rojnueangnit, K.; Xie, J.; Gomes, A.; Sharp, A.; Callens, T.; Chen, Y.; Liu, Y.; Cochran, M.; Abbott, M.A.; Atkin, J.; et al. High incidence of Noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.Arg1809: Genotype-phenotype correlation. Hum. Mutat. 2015, 36, 1052–1063. [Google Scholar] [CrossRef] [PubMed]
Novel Variants | |||
---|---|---|---|
de Novo | Inherited | ||
Null Variants | Other Variants | Null Variants | Other Variants |
c.98_104delAAGTCAG p.K33fs*9 | c.758_760delTGG p.V253del | c.1373delC p.P458fs*15 | c.281T > C p.L94P |
c.964delA p.I322fs*54 | c.2521A > C p.T841P | c.1920dupC p.S641fs*8 | c.1394G > A p.S465N |
c.1527 + 1C > T | c.2850G > A p.Q950Q | c.2326-2A > C | c.3875A > G p.Y1292C |
c.3113 + 1dupG | c.4984A > T p.N1662Y | ||
c.4770_4777delAAGTATTT p.L1590fs | c.4180A > C p.N1394H | ||
c.4950_4978dup p.N1660fs*27 | c.5081T > C p.L1694P | ||
c.5206-1G > T | c.5269-8C > G |
NF1 Related Features | Patients with Pathogenic NF1 Variants | Patients without Pathogenic NF1 Variants | ||
---|---|---|---|---|
Café-au-lait macules at birth | 86.76% | (59/68) | 33.33% | (9/27) |
More than six café au lait macules | 94.11% | (64/68) | 70.37% | (19/27) |
Cutaneous neurofibromas | 19.11% | (13/68) | 2.94% | (2/27) |
Plexiform neurofibromas | 1.47% | (1/68) | 0% | (0/27) |
Ocular findings | 23.53% | (16/68) | 18.52% | (5/27) |
Neurologic manifestations | 45.59% | (31/68) | 11.11% | (3/27) |
Musculoskeletal features | 10.29% | (7/68) | 1.47% | (1/27) |
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Yao, R.; Yu, T.; Xu, Y.; Yu, L.; Wang, J.; Wang, X.; Wang, J.; Shen, Y. Clinical Presentation and Novel Pathogenic Variants among 68 Chinese Neurofibromatosis 1 Children. Genes 2019, 10, 847. https://doi.org/10.3390/genes10110847
Yao R, Yu T, Xu Y, Yu L, Wang J, Wang X, Wang J, Shen Y. Clinical Presentation and Novel Pathogenic Variants among 68 Chinese Neurofibromatosis 1 Children. Genes. 2019; 10(11):847. https://doi.org/10.3390/genes10110847
Chicago/Turabian StyleYao, Ruen, Tingting Yu, Yufei Xu, Li Yu, Jiwen Wang, Xiumin Wang, Jian Wang, and Yiping Shen. 2019. "Clinical Presentation and Novel Pathogenic Variants among 68 Chinese Neurofibromatosis 1 Children" Genes 10, no. 11: 847. https://doi.org/10.3390/genes10110847
APA StyleYao, R., Yu, T., Xu, Y., Yu, L., Wang, J., Wang, X., Wang, J., & Shen, Y. (2019). Clinical Presentation and Novel Pathogenic Variants among 68 Chinese Neurofibromatosis 1 Children. Genes, 10(11), 847. https://doi.org/10.3390/genes10110847