Approaches to Treating NF1 Tibial Pseudarthrosis

Stevenson, David A.; Little, David; Armstrong, Linlea; Crawford, Alvin H.; Eastwood, Deborah M.; Friedman, Jan M.; Greggi, Tiziana; Gutiérrez, Gloria; Hunter-Schaedle, Kim; Kendler, David L.; Kolanczyk, Mateusz; Monsell, Fergal; Oetgen, Matthew E.; Richards, B. Stephens; Schindeler, Aaron; Schorry, Elizabeth K.; Wilkes, David; Viskochil, David; Yang, Feng Chun; Elefteriou, Florent

doi:10.1097/bpo.0b013e31828121b8

Cited by 54 publications

(17 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pseudarthrosis and possibly dystrophic scoliosis can currently be treated only by invasive, and often repetitive, surgical orthopedic interventions 2,3 . Most approaches to date are corrective in nature, and only bracing techniques are available to reduce the incidence and severity of these complications.…”

Section: Discussionmentioning

confidence: 99%

“…Dystrophic scoliosis, tibia bowing, bone fragility, fracture and pseudarthrosis (non–union following fracture) are skeletal conditions associated with high morbidity in this population 7–10 . Despite recent progress in our understanding of the role of NF1 in skeletal tissues, it is still unclear why and how these bone pathologies arise, raising uncertainty regarding optimal treatment 2,3 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Asfotase-α improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1

Ndong¹,

Makowski

Uppuganti³

et al. 2014

Nat Med

Self Cite

View full text Add to dashboard Cite

Mineralization of the skeleton depends on the balance between levels of pyrophosphate (PPi), an inhibitor of hydroxyapatite formation, and phosphate generated from PPi breakdown by alkaline phosphatase (ALP). We report here that ablation of Nf1, encoding the RAS/GTPase–activating protein neurofibromin, in bone–forming cells leads to supraphysiologic PPi accumulation, caused by a chronic ERK–dependent increase in genes promoting PPi synthesis and extracellular transport, namely Enpp1 and Ank. It also prevents BMP2–induced osteoprogenitor differentiation and, consequently, expression of ALP and PPi breakdown, further contributing to PPi accumulation. The short stature, impaired bone mineralization and strength in mice lacking Nf1 in osteochondroprogenitors or osteoblasts could be corrected by enzyme therapy aimed at reducing PPi concentration. These results establish neurofibromin as an essential regulator of bone mineralization, suggest that altered PPi homeostasis contributes to the skeletal dysplasiae associated with neurofibromatosis type-1 (NF1), and that some of the NF1 skeletal conditions might be preventable pharmacologically.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Asfotase-α improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1

Ndong¹,

Makowski

Uppuganti³

et al. 2014

Nat Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…The resulting derangements in the sphenoid bone (or adjacent structures), perhaps due to abnormalities in cartilaginous growth [3] may explain its predilection to dysplasia. Focal bony lesions like sphenoid wing dysplasia, almost always unilateral, might be hastened by a “second hit” event in the gene NF1 , much like NF1-associated pseudoarthosis [22, 23]. In a series of 16 individuals with NF1-associated pseudoarthosis, biallelic, pathogenic variants in NF1 (or somatic loss of heterozygosity) was detected in 75% of tissues or cultured cells from surgically resected pseudoarthrosis pathologic material [24].…”

Section: Discussionmentioning

confidence: 99%

Cephalometry in adults and children with neurofibromatosis type 1: Implications for the pathogenesis of sphenoid wing dysplasia and the “NF1 facies”

Cung

Freedman

Khan

et al. 2015

European Journal of Medical Genetics

View full text Add to dashboard Cite

Background Neurofibromatosis type 1 (NF1) is a common, autosomal dominant tumor-predisposition disorder that arises secondary to mutations in the tumor suppressor gene NF1. Cephalometry is an inexpensive, readily available and non-invasive technique that is under-utilized in studying the NF1 craniofacial phenotype. An analysis of NF1 cephalometry was first published by Heervä et al. in 2011. We expand here on that first investigation with a larger cohort of adult and pediatric patients affected with NF1 and sought objective insight into the NF1 facies, said to feature hypertelorism and a broad nasal base, from cephalometric analysis. Methods We obtained cephalograms from 101 patients with NF1 (78 adults and 23 children) from two NF1 protocols at the National Institutes of Health. Each subject had an age-, gender- and ethnicity-matched control. We used Dolphin software to make the cephalometric measurements. We assessed the normality of differences between paired samples using the Shapiro-Wilk test and evaluated the significance of mean differences using paired t-tests and adjusted for multiple testing. We explored the relationship between the cephalometric measurements and height, head circumference and interpupillary distance. Results In this dataset of American whites with NF1, we confirmed in a modestly larger sample many of the findings found by Heerva et al. in an NF1 Finnish cohort. We found a shorter maxilla, mandible, cranial base, (especially anteriorly, p = 0.0001) and diminished facial height in adults, but not children, with NF1. Only one adult exhibited hypertelorism. Conclusions The cephalometric differences in adults arise in part from cranial base shortening and thus result in a shorter face, mid-face hypoplasia, reduced facial projection, smaller jaw, and increased braincase globularity. In addition, we suggest that NF1 sphenoid bone shortening, a common event, is consistent with an intrinsic NF1 bone cell defect, which renders the bone more vulnerable to a random “second hit” in NF1, leading to sphenoid wing dysplasia, a rare event.

show abstract

“…According to the previous reports, NF1 has been manifested first time with long bone dysplasia involving a single tibia [16, 17]. Anterolateral dysplasia with fracture is also identified in 5% of NF1 patients.…”

Section: Discussionmentioning

confidence: 99%

Novel phenotypes of NF1 patients from unrelated Chinese families with tibial pseudarthrosis and anemia

et al. 2016

View full text Add to dashboard Cite

Neurofibromatosis type 1 (NF1) is an autosomal dominant, multi-system, neurocutaneous disorder, manifested with neurofibromas and Cafe´-au-lait spots. Germline mutations in NF1 gene are associated with Neurofibromatosis type 1. NF1 gene encodes neurofibromin, a RAS-specific GTPase activating protein. In our study, we present a clinical molecular study of four Chinese probands with NF1 from four unrelated families, showing extreme phenotypic variation with rare phenotype. In family 1, the proband is a 16 months old girl with multiple café-au-lait spots throughout her whole body. In family 2, the proband is a 6 months old girl with several café-au-lait spots mostly in her trunk and in lower limbs. In family 3, the proband is a 4 months old boy with several café-au-lait spots, tibial pseudarthrosis, and chronic iron deficiency anemia. In family 4, the proband is a 14 years old boy with multiple café-au-lait spots of variable sizes. Targeted exome capture based next generation sequencing and Sanger sequencing identified a novel mutation and three previously reported mutations in these four probands. These four mutations in NF1 gene were causing disease phenotypes in these four probands and was absent in unaffected family members and in healthy controls. According to the variant interpretation guideline of American College of Medical Genetics and Genomics (ACMG), these four mutations, are classified as “likely pathogenic”. Our result expands the mutational spectrum of the NF1 gene associated with neurofibromatosis type1.

show abstract

Approaches to Treating NF1 Tibial Pseudarthrosis

Abstract: Level V, expert opinion.

Cited by 54 publications

References 58 publications

Asfotase-α improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1

Asfotase-α improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1

Cephalometry in adults and children with neurofibromatosis type 1: Implications for the pathogenesis of sphenoid wing dysplasia and the “NF1 facies”

Novel phenotypes of NF1 patients from unrelated Chinese families with tibial pseudarthrosis and anemia

Contact Info

Product

Resources

About