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

Abstract

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

β‐Catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications

“…Osteoclastogenesis can be activated by RAS signaling, such as occurs in Nf1 deficiency (5,11,(41)(42)(43)(44)(45)(46)(47)(48)(49)(50). We observed a gain in the number of osteoclasts at the Nf1-null murine fracture site, in agreement with previous studies (51)(52)(53)(54)(55)(56)(57).…”

Neurofibromin Deficiency-Associated Transcriptional Dysregulation Suggests a Novel Therapy for Tibial Pseudoarthrosis in NF1

“…All samples were collected from individuals after obtaining written informed consent approved by the Institutional Review Board of the University of Texas Southwestern Medical Center, the University of Utah, or Seoul National University Hospital. Five of the 16 samples included in this study were reported previously with inconsistent results after genotyping four polymorphic markers (D17S1863, GXALU, IN38, and 3 NF1 ‐1) near the NF1 locus . In this study, no sample showed evidence of LOH across all markers in the pseudoarthrosis compared to matched blood/saliva, and this method is unable to distinguish copy‐neutral LOH from LOH caused by somatic gene deletion.…”

“…Long‐bone dysplasia and pseudoarthrosis were previously proposed to result from localized biallelic inactivation of NF1 owing to somatic LOH . However, subsequent studies reported inconsistent or inconclusive results in additional patients, and the genomewide spectrum of somatic mutations in pseudoarthrosis tissue was never investigated …”

A Combination of rhBMP-2 (Recombinant Human Bone Morphogenetic Protein-2) and MEK (MAP Kinase/ERK Kinase) Inhibitor PD0325901 Increases Bone Formation in a Murine Model of Neurofibromatosis Type I Pseudarthrosis

“…Animal studies have provided a definitive link between Nf1 2/2 progenitor cells and a fibrous nonunion, but the precise role of Nf1 2/2 cells in fibrosis is still unresolved 18,33 . Biopsies from fractures have identified loss of heterozygosity in NF1 fractures, but exceptions have been reported 13,34,35 . Cultures of the pseudarthrosis tissue expressed high levels of the proosteoclastic cytokine RANKL, in parallel with clinical findings 13,36 .…”