Clinical characteristics and in silico analysis of congenital pseudarthrosis of the tibia combined with neurofibromatosis type 1 caused by a novel NF1 mutation

Xu, Jingfang; Zhang, Ying; Li, Jiabin; Guan, Yaoyao; He, Xinyu; Jin, Xuejing; Bai, Guannan; Hu, Lidan

doi:10.3389/fgene.2022.991314

Cited by 4 publications

(3 citation statements)

References 40 publications

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“…This disorder poses significant challenges in treatment due to its complex etiology, which is often associated with neurofibromatosis type 1 (NF1) and results in a high rate of complications including refractures, leg length discrepancies, and joint deformities [1] . The pathophysiology of CPT involves abnormal periosteal and endosteal bone formation, leading to segmental weakness and a predisposition to fracture and nonunion [2] . Traditional management strategies for CPT have included bracing, surgical resection of the pseudarthrosis site, intramedullary fixation, and bone grafting.…”

Section: Introductionmentioning

confidence: 99%

Treatment of Congenital Pseudarthrosis Tibia by Ilizarov Principle

2024

The Egyptian Journal of Hospital Medicine

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Background: Congenital pseudarthrosis of the tibia (CPT) presents significant treatment challenges due to its complex pathology and high complication risk. The Ilizarov technique, based on the principles of distraction osteogenesis, offers a promising approach to manage this condition. Objective: To assess the effectiveness of Ilizarov technique in resecting congenital pseudarthrosis and lengthening the tibia, with evaluations of union rates, mechanical axis deviation, range of motion in ankle and knee joints, and complications. Patients and Methods: In a prospective, retrospective cohort study at Benha University Hospitals, 30 patients with CPT underwent treatment using the Ilizarov technique. Clinical and radiological evaluations were conducted to assess union, while mechanical axis deviation and joint range of motion were measured. Results: The mean age of the participants was 11.3 ± 3.65 years, with a male predominance (60%). The Ilizarov technique, involving corticotomy and bone transport in 83.33% of patients, showed union in 93.33% of cases, with treatment duration averaging 9.9 ± 4.06 months. Radiological outcomes were rated as excellent in 20%, good in 46.67%, fair in 26.67%, and poor in 6.67% of patients. Complications included pin tract infections in all patients, pain in 13.33%, non-union in 6.67%, refracture in 20%, ankle stiffness in 10%, and valgus deformity at the ankle in 16.67%. The final leg-length discrepancy was corrected to a mean of 2.7 ± 1.04 cm. Conclusion:The Ilizarov technique demonstrates a high efficacy in treating CPT, with significant improvements in bone lengthening, union rates, and mechanical alignment.

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Section: Introductionmentioning

confidence: 99%

Treatment of Congenital Pseudarthrosis Tibia by Ilizarov Principle

2024

The Egyptian Journal of Hospital Medicine

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“…28.23292011 doi: medRxiv preprint associated with neurofibromatosis type 1(NF1), a common autosomal dominant genetic disorder [3]. Previous research has reported that 80%-84% of CPT cases present with NF1(NF1-CPT) in the epidemiology and the genomic mutations in the NF1 gene have been linked to CPT in the genomics [4][5][6][7]. The double inactivation model has been proposed as a hypothesis to explain these associations [8][9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

Unraveling the Molecular Landscape of Congenital Pseudoarthrosis of the Tibia: Insights from a Comprehensive Analysis of 162 Probands

Zhu,

Li,

Zheng

et al. 2023

Preprint

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Congenital pseudarthrosis of the tibia (CPT, HP:0009736), commonly known as bowing of the tibia, is a rare congenital tibia malformation characterized by spontaneous tibial fractures and the difficulty of reunion after tibial fractures during early childhood, with a very low prevalence between 1/250,000 ~ 1/140,000. While 80% ~ 84% of CPT cases present with neurofibromatosis type 1, caused by the mutations in NF1, the underlying cause of CPT is still unclear. Considering the congenital nature and the low prevalence of CPT, we hypothesized that the rare genomic mutations may contribute to CPT. In this study, we conducted whole exome sequencing on 159 patients with CPT and full-length transcriptome sequencing on an additional 3 patients with CPT. The data analysis showed there were 179 significantly up-regulated genes which were enriched in 40 biological processes among which 21 biological processes hold their loss of function (LoF) excesses between 159 cases against 208 controls from 1000 Genomes Project. From those 21 biological processes with LoF excesses, there were 259 LoF-carried genes among which 40 genes with 56 LoF variations in 63 patients were enriched in osteoclast differentiation pathway (hsa04380) with its 3 directly regulated pathways including MAPK signaling pathway (hsa04010), calcium signaling pathway (hsa04020) and PI3K-Akt signaling pathway (hsa04151), as well as fluid shear stress and atherosclerosis pathway (hsa05418) while 12 patients carried 9 LoF variations in the NF1 gene. The rare LoF variations in these pathways accounted for ~39.6% of this CPT cohort. These findings shed light on the novel genetic mutations and molecular pathways involved in CPT, providing a new framework for understanding how the genetic variations regulate the biological processes in the pathology of CPT and indicating potential next directions to further elucidate the pathogenesis of CPT.

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“…Approximately 50% of the reported mutations are de novo mutations, and postzygotic NF1 mutations that can lead to a mosaic phenotype have also been reported [ 6 ]. Most of the pathogenic mutations have produced truncated neurofibromin proteins, and 30% of them are splicing mutations that affect mRNA processing [ 7 , 8 ]. Destruction of the 3′ or 5′ splice site caused by splicing variants results in abnormal neurofibromins including exon skipping and intron retention [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Childhood-Onset Refractory Hypertension Results from Neurofibromatosis Type 1 Caused by a Splicing <i>NF1</i> Mutation

Lu,

Rejiepu,

Zhang

et al. 2023

Kidney Blood Press Res

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Background: Neurofibromatosis type 1 (NF-1) is caused by mutations in the NF1 gene that encodes neurofibromin, a negative regulator of RAS proto-oncogene. Approximately one-third of the reported pathogenic mutations in NF1 are splicing mutations, but most consequences are unclear. The objective of this study was to identify the pathogenicity of splicing mutation in a Chinese family with NF-1 and determine the effects of the pre-mRNA splicing mutation by in vitro functional analysis. Methods: Next-generation sequencing was used to screen candidate mutations. We performed a minigene splicing assay to determine the effect of the splicing mutation on NF1 expression and three-dimensional structure models of neurofibromin were generated using SWISS-MODEL and PROCHECK method, respectively. Results: A pathogenic splicing mutation c.479+1G>C in NF1 was found in the proband characterized by childhood-onset refractory hypertension. In vitro analysis demonstrated that c.479+1G>C mutation caused skipping of exon 4, leading to a Glutamine to Valine substitution at position 97 in neurofibromin and an open reading frame shift terminating at codon 108. Protein modelling showed that several major domains were missing in the truncated neurofibromin protein. Conclusion: The splicing mutation c.479+1G>C identified in a Chinese patient with NF-1 and childhood-onset refractory hypertension caused skipping of exon 4 and a truncated protein. Our findings offered new evidence for the molecular diagnosis of NF-1.

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Clinical characteristics and in silico analysis of congenital pseudarthrosis of the tibia combined with neurofibromatosis type 1 caused by a novel NF1 mutation

Cited by 4 publications

References 40 publications

Treatment of Congenital Pseudarthrosis Tibia by Ilizarov Principle

Treatment of Congenital Pseudarthrosis Tibia by Ilizarov Principle

Unraveling the Molecular Landscape of Congenital Pseudoarthrosis of the Tibia: Insights from a Comprehensive Analysis of 162 Probands

Childhood-Onset Refractory Hypertension Results from Neurofibromatosis Type 1 Caused by a Splicing <i>NF1</i> Mutation

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