The Effects of Neurofibromatosis Type 1 on Pseudoarthrosis and the Forensic Implications
DOI:
https://doi.org/10.29173/comp72Abstract
Pseudoarthrosis is the presentation of false joints or non-union, primarily in long bones. While pseudoarthrosis most often presents as the lack of union between parts of a fractured or broken bone, it is also suspected that pseudoarthrosis results from a congenital disorder of unknown origin. While the etiology is unclear, there is an association with a congenital defect in neurofibromatosis type 1 gene through the neurofibromin protein. This defect occurs during the germ line mutation of conception and is often identified during early childhood. Pseudoarthrosis is more often difficult to detect in adults as it is frequently corrected during childhood. Germ line defects along the neurofibromin protein often result in a lack of communication from the reticular activating system (RAS) molecular signaling, which, in turn, impacts skeletal osteon production. Consequently, osseous lesions may develop and lead to a lack of cellular control over osteoblast signaling in the long bones of the skeleton. Understanding the origins of congenital pseudoarthrosis and its relationship with neurofibromatosis type 1 could lead to a better understanding of both conditions. Understanding these conditions can be useful for interpreting forensic contexts. These contexts include having the histological knowledge of osteology in these diseases for identification purposes. Given that both neurofibromatosis type 1 and pseudoarthrosis are uncommon conditions, their presence may aid forensic practitioners in determining cause of death or identification of the individual. This paper reviews new advances towards understanding the root cause of pseudoarthrosis.
References
Aiyer, Amiethab. 2022. Fracture Healing. Orthobullets. https://www.orthobullets.com/basic-science/9009/fracture-healing
Bergoug, Mohammed, Michel Doudeau, Fabienne Godin, Christine Mosrin, Béatrice Vallée, and Hélène Bénédetti. 2020. Neurofibromin structure, functions and regulation. Cells 9(11): 2365. https://doi.org/10.3390/cells9112365
Breeland, Grant, Margaret Sinkler, and Ritesh G. Menezes. 2022. Embryology, bone ossification. In StatPearls [Internet]. Treasure Island, FL: StatPearls.
Calixto, Ana R., Cátia Moreira, Anna Pabis, Carsen Kötting, Klaus Gerwent, Till Rudack, and Shina C. L. Kamerlin. 2019. GTP hydrolysis without an active site base: a unifying mechanism for Ras and related GTPases. Journal of the American Chemical Society 141(27):10684–10701. https://doi.org/10.1021/jacs.9b03193
Canadian Society of Forensic Science. 2023. Royal Canadian Mounted Police Forensic Laboratory Services. https://www.csfs.ca/resources/government-labs-in-canada/rcmp-forensic-laboratory-services/
Davis, Donald D., and Steven M. Kane. 2022. Nightstick fractures. In StatPearls [Internet]. Treasure Island, StatPearls. https://www.ncbi.nlm.nih.gov/books/ NBK555951/
Friedman, J. M. 1998. Neurofibromatosis 1. In GeneReviews. Margaret P. Adam, Jerry Feldman, Ghayda M. Mirzaa, Roberta A. Pagon, Stephanie E. Wallace, Lora J. H. Bean, Karen W. Gripp, and Anne Amemiya, eds. Seattle: University of Washington Press.
Gaillard, Frank., Joshua Yap, Henry Knipe, Amanda Er, Yuranga Weerakkody, Ian Bickle, and Amir Mahmud. 2023. Monteggia fracture-dislocation. Radiopaedia.
Greenblatt, Matthew, Jae-Hyuck Shim, Seoyeon Bok, and Jung-Min Kim. 2022. The extracellular signal-regulated kinase mitogen-activated protein kinase pathway in osteoblasts. Journal of Bone Metabolism 29(1):1–15. https://doi.org/10.11005/jbm.2022.29.1.1
Hale, Amanda R., and Ann H. Ross. 2023. Investigating the timing and extent of juvenile and fetal bone diagenesis in a temperate environment. Biology 12(3):403. https://doi.org/10.3390/biology12030403
Harbaugh, Kimberly, Neel T. Patel, and Elias Rizk. 2021. Genetics of nerve tumors. In Diagnostic assessment and treatment of peripheral nerve tumours. Fernando Guedes, Eric L. Zager, Debora Garozzo, Lukas Rasculic, and Mariano Socolovsky, eds. Pp. 17–27. Cham, Switzerland: Springer.
Hurle, Belen. 2023. Germline. Talking glossary of genomic and genetic terms. National Human Genome Research Institute. https://www.genome.gov/genetics-glossary/germ-line
Koster, R., R. D. Brandão, D. Tserpelis, C. E. P. van Roozendaal, C. N. van Oosterhoud, K. B. M. Claes, A. D. C. Paulussen, et al. 2021. Pathogenic neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq. npj Genomic Medicine 6:95. https://doi.org/10.1038/s41525-021-00258-w
Kwok, Cheni, Polly A. Weller, Silvana Guioli, Jamie W. Foster, Sahar Mansour, Orsetta Zuffardi, Hope H. Punnett, et al. 1995. Mutations in SOX9, the gene responsible for campomelic dysplasia and autosomal sex reversal. American Journal of Human Genetics 57(5):1028–1036.
Lacal, Juan Carlos. 2001. GTPase. In Encyclopedic reference of cancer. Manfred Schwab, ed. Pp. 375–378. Berlin: Springer. https://doi.org/10.1007/3-540-30683-8_688
Lavoie, Hugo, Jessica Gagnon, and Marc Therrien. 2020. ERK signalling: a master regulator of cell behaviour, life and fate. Nature Reviews Molecular Cell Biology 21:607–632. https://doi.org/10.1038/s41580-020-0255-7
McCoy, Garrett, Joel Joyce, Donald Basel, and Dawn H. Siegel. 2016. Pseudoarthrosis of the ulna in neurofibromatosis type 1. Journal of Pediatrics 177:330. https://doi.org/10.1016/j.jpeds.2016.06.054
Narayana Kurup, J. K., and Hitesh H. Shah. 2020. Congenital pseudoarthrosis of the radius in Neurofibromatosis Type 1: an entity not to be missed! Journal of Orthopaedics 22:427–430. https://doi.org/10.1016/j.jor.2020.09.013
National Organization for Rare Disorders (NORD). 2022. Neurofibromatosis 1. https://rarediseases.org/rare-diseases/neurofibromatosis-type-1-nf1/
Papaioannou, Garyfallia, Fatemeh Mirzamohammadi, and Tatsuya Kobayashi. 2016. Ras signaling regulates osteoprogenitor cell proliferation and bone formation. Cell Death and Disease 7:e2405. https://doi.org/10.1038/cddis.2016.314
Plikus, Maksim V., Xiaojie Wang, Sarthak Sinha, Elvira Forte, Sean M. Thompson, Erica L. Herzog, Ryan R. Driskell, Nadia Rosenthal, Jeff Biernaskie, and Valerie Horsley. 2021. Fibroblasts: origins, definitions, and functions in health and disease. Cell 184(15):3852–3872. https://doi.org/10.1016/j.cell.2021.06.024.
Pountos, Ippokratis, and Peter V. Giannoudis. 2018. Fracture healing: back to basics and latest advances. In Fracture reduction and fixation techniques: upper extremities. Peter V. Giannoudis, ed. Pp. 3–17. Cham, Switzerland: Springer. https://doi.org/10.1007/978-3-319-68628-8_1
Qu, Liang, Chao Pan, Shi-Ming He, Bing Lang, Guo-Dong, Gao, Xue-Lian Wang, and Yuan Wang. 2019. The Ras superfamily of small GTPases in non-neoplastic cerebral diseases. Frontiers in Molecular Neuroscience 12:121. https://doi.org/10.3389/fnmol.2019.00121
Royal Canadian Mounted Police (RCMP). 2018. Forensic Science and Identification Services. https://www.rcmp-grc.gc.ca/fsis-ssji/index-eng.htm
Scheffzek, Klaus and Giridhar Shivalingaiah. 2019. Ras-specific GTPase-activating proteins—structures, mechanisms, and interactions. Cold Spring Harbor Perspectives in Medicine 9(3):a031500. https://doi.org/10.1101/cshperspect.a031500
The Histology Guide. n.d. Bone: types of cell found in bone. Cartilage, bone and ossification. Faculty of Biologocial Sciences, University of Leeds. https://www.histology.leeds.ac.uk/bone/bone_cell_types.php
Well, Lennart, Kimberly Döbel, Lan Kluwe, Peter Bannas, Said Farschtschi, Gerhard Adam, Victor-Felix Mautner, Johannes Salamon. 2021. Genotype-phenotype correlation in neurofibromatosis type-1: NF1 whole gene deletions lead to high tumor-burden and increased tumor-growth. PLOS Genetics 17(5): e1009517. https://doi.org/10.1371/journal.pgen.1009517
Wu, Xiaohua, Selina A. Estwick, Shi Chen, Menggang Yu, Wenyu Ming, Todd D. Nebesio, Yan Li, et al. 2006. Neurofibromin plays a critical role in modulating osteoblast differentiation of mesenchymal stem/progenitor cells. Human Molecular Genetics 15(19):2837–2845. https://doi.org/10.1093/hmg/ddl208
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