Congenital pseudarthrosis of neurofibromatosis type 1: Impaired osteoblast differentiation and function and altered NF1 gene expression

Leskelä, Hannu-Ville; Kuorilehto, Tommi; Risteli, Juha; Koivunen, Jussi; Nissinen, Marja; Peltonen, Sirkku; Kinnunen, Pentti; Messiaen, Ludwine; Lehenkari, Petri; Peltonen, Juha

doi:10.1016/j.bone.2008.10.050

Cited by 52 publications

(47 citation statements)

References 41 publications

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“…Two of them were "de novo" mutations, and the others originated from their parents. Similar to previous studies [8,11,12,16], our results further confirmed that CPT always existed in the NF1 families and each patient with both NF1 and CPT was found harboring mutations in the NF1 gene, suggesting these mutations were closely associated with the complex phenotypes. In addition, the age of patients sustaining tibial fracture was found to be distinctly different.…”

Section: Discussionsupporting

confidence: 90%

“…A majority of the cells of this hamartoma have been identified as fibroblasts [7]. A certain amount of fibrocartilage and hyaline cartilage [8] is also associated with the fibrous tissue, as well as, several areas of endochondral ossification. The composition of the pseudarthrotic tissue does not vary significantly, irrespective of its association with NF1 [9].…”

Section: Introductionmentioning

confidence: 90%

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Identification of One BOCR Mutation and Five NF1 Mutations in Male Patients with Neurofibromatosis Type 1 and Congenital Pseudarthrosis of the Tibia

Zhou¹,

Zeng

et al. 2016

Preprint

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Neurofibromatosis type1 (NF1) is an autosomal dominant disorder caused by mutations in the NF1gene. Although congenital pseudarthrosis of the tibia (CPT) has frequently been associated with NF1, the underlying molecular mechanism of CPT in these NF1 patients is yet ill-understood. The aim of the present study was to detect NF1 mutations from genomic DNA and to harbor variants associated with CPT in NF1 patients. Whole-exome sequencing was first carried out with samples from two patients with CPT in one NF1 family, and a novel mutation c.2324A>G (p.E775G) in NF1 gene was identified. Additionally, a missense variant c.455C>T (p.P152L) in BCOR gene completely co-segregated with the CPT phenotype within this family. Subsequently, NF1 and NF2 genes in four other unrelated patients with both NF1 and CPT were screened using targeted sequencing. Four mutations in NF1 gene, including two known mutations (c.2288T>C/p.L763P, c.574 C>T/p.R192*) and two novel mutations (c.768delT/p.F256Lfs*25, c.2229_2230delTG/ p.V744Qfs*23) were detected. Further study confirmed that CPT was present in NF1 families, and NF1 mutations were closely associated with these complex phenotypes. Moreover, the data from the current study indicated that male gender might be a susceptibility factor for CPT in NF1. Therefore, we speculated that BCOR variants might be related to CPT phenotype among male NF1 patients.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 90%

Identification of One BOCR Mutation and Five NF1 Mutations in Male Patients with Neurofibromatosis Type 1 and Congenital Pseudarthrosis of the Tibia

Zhou¹,

Zeng

et al. 2016

Preprint

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“…Stevenson et al 16 suggested double inactivation of the Nf1 gene in fibrous hamartoma tissue as a pathogenic mechanism, but this contradicts with the longstanding view that NF1 bone dysplasia arises due to an abnormal response of Nf1 haploinsufficient periosteum to mechanical force. 11,26 Leskela et al 8 reported not finding LOH in their study of mesenchymal stem cells cultured from red bone marrow next to sites of pseudarthrosis. But this study was not conducted on tissues from sites of pseudarthrosis.…”

Section: Discussionmentioning

confidence: 99%

“…8 Neurofibromin negatively regulates the activity of an intracellular signaling molecule p21 ras (Ras) by functioning as a GTPase activating protein (Ras-GAP). 9,10 Furthermore, haploinsufficiency or a complete deficiency in Nf1 results in a dose-dependent elevation in Ras activity, which can activate the MAPK (mitogen-activated protein kinase) and the PI-3K (phosphatidylinositol-3-phosphate kinase) pathways.…”

mentioning

confidence: 99%

Is double inactivation of the Nf1 gene responsible for the development of congenital pseudarthrosis of the tibia associated with NF1?

Lee

Choi

Lee

et al. 2012

Journal Orthopaedic Research

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The pathogenic mechanism responsible for congenital pseudarthrosis of the tibia (CPT) is not well understood although the possibility of double inactivation of the neurofibromatosis type 1 (Nf1) gene has been suggested. In the present study, loss of heterozygosity was investigated in fibrous hamartoma tissues harvested from 16 patients with CPT associated with NF1 using four genetic markers that span the Nf1 gene. Based on the assumption that a single cell with double inactivation of Nf1 would undergo clonal growth and cause fibrous hamartoma, we investigated clonality in fibrous hamartoma tissues by analyzing X-chromosome inactivation patterns in 11 female patients. Loss of Nf1 heterozygosity in fibrous hamartoma tissues was observed at one or two genetic markers in 4 out of the 16 patients tested. In clonality assays, 3 of 11 patients showed a clonal growth pattern, 5 a non-clonal pattern, and 3 were non-informative. These findings support that double inactivation of the Nf1 gene and subsequent clonal growth could be a pathogenic feature of the fibrous hamartoma tissue at least in some of the CPT but might not be essential requirements of CPT development. ß

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“…Presentation occurs from infancy to childhood as tibial dysplasia, with anterolateral bowing, eventually leading to pathological fracture, which typically occurs at the junction of the middle and distal thirds of the tibia [1][2][3][4][5]. Neurofibromatosis type 1 (NF), (Von Recklinghausen's disease), is a genetic disorder frequently associated with CPT [3,6] and bone remodelling defects are further exaggerated in this condition [4][5][6][7].…”

mentioning

confidence: 99%

Delayed presentation of congenital tibial pseudarthrosis and neurofibromatosis: a difficult union

Hatton¹,

Ly²,

Noor³

et al. 2014

Asian Biomedicine

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Background: A new case of congenital pseudarthrosis of the tibia (CPT) presents yearly to CSC, but treatment is prolonged, and not always successful. Objective: To study the outcomes of treatment, and to determine whether a relationship with neurofibromatosis (NF) was of significance. Methods: A review of the medical records at our centre revealed 11 cases of CPT, 5 of which were associated with neurofibromatosis. Results: Most patients had multiple operations for their case of CPT, which did finally lead to union in 6 out of 6 cases with no NF, but in only 1 case out of 5 when NF was present. Conclusion: Late presentation and severe deformity can be overcome, and union can be achieved, but NF has a deleterious effect on obtaining union.

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Congenital pseudarthrosis of neurofibromatosis type 1: Impaired osteoblast differentiation and function and altered NF1 gene expression

Cited by 52 publications

References 41 publications

Identification of One <em>BOCR</em> Mutation and Five <em>NF1</em> Mutations in Male Patients with Neurofibromatosis Type 1 and Congenital Pseudarthrosis of the Tibia

Identification of One <em>BOCR</em> Mutation and Five <em>NF1</em> Mutations in Male Patients with Neurofibromatosis Type 1 and Congenital Pseudarthrosis of the Tibia

Is double inactivation of the Nf1 gene responsible for the development of congenital pseudarthrosis of the tibia associated with NF1?

Delayed presentation of congenital tibial pseudarthrosis and neurofibromatosis: a difficult union

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