Osseous Abnormalities in Neurofibromatosis Type 1

Summary

Principal Investigator: DAVID ANDREW STEVENSON
Affiliation: University of Utah
Country: USA
Abstract: Neurofibromatosis type 1 (NF1) is a common genetic disorder with a high degree of variability of clinical expression, including skeletal abnormalities in over 1/3 of patients. These osseous manifestations are unpredictable, and the pathogenesis, natural history and clinical outcome remain relatively obscure. I propose to test the hypothesis that NF1 is a constitutional disorder of bone with generalized osseous abnormalities by addressing 3 Specific Aims. The first Specific Aim is to determine the differences in bone health variables between NF1 individuals and individuals without NF1, and between NF1 individuals with and without osseous abnormalities. Bone-health measurements from imaging modalities [dual energy x-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT)], and biochemical markers of bone metabolism including urinary pyridinium cross-links will be used to test the hypothesis that there are subtle bone abnormalities in NF1 compared to the general population. The second Specific Aim is to determine genotype-phenotype correlations of the NF1 gene and osseous abnormalities. High-throughput DNA sequencing will be used to determine if a specific mutation class contributes to the NF1 osseous phenotype. In addition, a cohort of NF1 families will be recruited to assess osseous phenotypes through sib-pair and parent-child analyses, including NF1 haplotype analysis. The third Specific Aim is to assess health status and health-related quality of life (HRQL) in children and adolescents with NF1 and scoliosis. Utilizing a 1:3 case-control design through a multi-center collaborative network, HRQL measures from a battery of questionnaire instruments between NF1 individuals with and without scoliosis will be obtained and analyzed. The principal investigator has developed an interdisciplinary plan utilizing mentors, a scientific advisory committee, didactic courses and resources at the University of Utah, General Clinical Research Center in order to become an independent researcher.
Funding Period: 2005-08-16 - 2010-03-31
more information: NIH RePORT

Top Publications

  1. pmc Familial congenital non-immune hydrops, chylothorax, and pulmonary lymphangiectasia
    David A Stevenson
    Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah 84132, USA
    Am J Med Genet A 140:368-72. 2006
  2. pmc Tibial geometry in individuals with neurofibromatosis type 1 without anterolateral bowing of the lower leg using peripheral quantitative computed tomography
    David A Stevenson
    Division of Medical Genetics, Department of Pediatrics, University of Utah, SLC, UT 84132, USA
    Bone 44:585-9. 2009
  3. pmc Autosomal recessive hypophosphatasia manifesting in utero with long bone deformity but showing spontaneous postnatal improvement
    David A Stevenson
    Division of Medical Genetics, Department of Pediatrics, 2C412 SOM, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA
    J Clin Endocrinol Metab 93:3443-8. 2008
  4. pmc Evidence of increased bone resorption in neurofibromatosis type 1 using urinary pyridinium crosslink analysis
    David A Stevenson
    Department of Pediatrics, University of Utah, Salt Lake City, Utah 84132, USA
    Pediatr Res 63:697-701. 2008
  5. pmc A novel multiple congenital anomaly-mental retardation syndrome with Pierre Robin sequence and cerebellar hypoplasia in two sisters
    David A Stevenson
    Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, Utah 84132, USA
    Am J Med Genet A 143:2221-6. 2007
  6. pmc Gastric rupture and necrosis in Prader-Willi syndrome
    David A Stevenson
    Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, UT 84132, USA
    J Pediatr Gastroenterol Nutr 45:272-4. 2007
  7. pmc The use of anterolateral bowing of the lower leg in the diagnostic criteria for neurofibromatosis type 1
    David A Stevenson
    Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah 84132, USA
    Genet Med 9:409-12. 2007
  8. pmc Mandibulofacial dysostosis in a patient with a de novo 2;17 translocation that disrupts the HOXD gene cluster
    David A Stevenson
    Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah 84132, USA
    Am J Med Genet A 143:1053-9. 2007
  9. pmc Bone mineral density in children and adolescents with neurofibromatosis type 1
    David A Stevenson
    Department of Pediatrics, University of Utah, Salt Lake City, Utah 84132, USA
    J Pediatr 150:83-8. 2007
  10. pmc A new distal arthrogryposis syndrome characterized by plantar flexion contractures
    D A Stevenson
    Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA
    Am J Med Genet A 140:2797-801. 2006

Scientific Experts

Detail Information

Publications13

  1. pmc Familial congenital non-immune hydrops, chylothorax, and pulmonary lymphangiectasia
    David A Stevenson
    Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah 84132, USA
    Am J Med Genet A 140:368-72. 2006
    ....
  2. pmc Tibial geometry in individuals with neurofibromatosis type 1 without anterolateral bowing of the lower leg using peripheral quantitative computed tomography
    David A Stevenson
    Division of Medical Genetics, Department of Pediatrics, University of Utah, SLC, UT 84132, USA
    Bone 44:585-9. 2009
    ..The objective of the study is to determine if the geometry of the lower limb in individuals with neurofibromatosis type 1 (NF1) differs from controls, and to characterize the osseous components of the tibia in NF1...
  3. pmc Autosomal recessive hypophosphatasia manifesting in utero with long bone deformity but showing spontaneous postnatal improvement
    David A Stevenson
    Division of Medical Genetics, Department of Pediatrics, 2C412 SOM, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA
    J Clin Endocrinol Metab 93:3443-8. 2008
    ..Patient age when skeletal problems first manifest generally predicts the clinical course, with perinatal HPP causing bone disease in utero with postnatal lethality...
  4. pmc Evidence of increased bone resorption in neurofibromatosis type 1 using urinary pyridinium crosslink analysis
    David A Stevenson
    Department of Pediatrics, University of Utah, Salt Lake City, Utah 84132, USA
    Pediatr Res 63:697-701. 2008
    ..The effects of NF1 haploinsufficiency likely contribute to abnormal bone remodeling, either directly or indirectly by aberrant Ras signaling, potentially predisposing NF1 individuals to localized skeletal defects...
  5. pmc A novel multiple congenital anomaly-mental retardation syndrome with Pierre Robin sequence and cerebellar hypoplasia in two sisters
    David A Stevenson
    Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, Utah 84132, USA
    Am J Med Genet A 143:2221-6. 2007
    ..We propose that the distinct pattern in these sisters constitutes a previously undescribed syndrome of likely autosomal recessive inheritance...
  6. pmc Gastric rupture and necrosis in Prader-Willi syndrome
    David A Stevenson
    Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, UT 84132, USA
    J Pediatr Gastroenterol Nutr 45:272-4. 2007
    ..The physician should consider an emergent evaluation for gastric rupture and necrosis in individuals with PWS who present with vomiting and abdominal pain...
  7. pmc The use of anterolateral bowing of the lower leg in the diagnostic criteria for neurofibromatosis type 1
    David A Stevenson
    Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah 84132, USA
    Genet Med 9:409-12. 2007
    ..Clarification of this diagnostic criterion is important for the clinician and for research protocols. Appropriate interpretation will improve understanding of the natural history and pathophysiology of neurofibromatosis type 1...
  8. pmc Mandibulofacial dysostosis in a patient with a de novo 2;17 translocation that disrupts the HOXD gene cluster
    David A Stevenson
    Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah 84132, USA
    Am J Med Genet A 143:1053-9. 2007
    ..Based on the agreement of our findings with one previous case of mandibulofacial dysostosis with a 2q31.1 transocation, we hypothesize that misexpression of genes in the HOXD gene cluster produced the described phenotype in this patient...
  9. pmc Bone mineral density in children and adolescents with neurofibromatosis type 1
    David A Stevenson
    Department of Pediatrics, University of Utah, Salt Lake City, Utah 84132, USA
    J Pediatr 150:83-8. 2007
    ..To assess whether children and adolescents with neurofibromatosis type 1 (NF1) have decreased bone mineral density (BMD)...
  10. pmc A new distal arthrogryposis syndrome characterized by plantar flexion contractures
    D A Stevenson
    Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA
    Am J Med Genet A 140:2797-801. 2006
    ..All affected individuals had normal neurological examinations; electromyography and creatinine kinase levels were normal on selected individuals. We have tentatively labeled this condition distal arthrogryposis type 10 (DA10)...
  11. pmc Deaths due to choking in Prader-Willi syndrome
    David A Stevenson
    Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, Utah 84132, USA
    Am J Med Genet A 143:484-7. 2007
    ....
  12. pmc Clinical and molecular aspects of an informative family with neurofibromatosis type 1 and Noonan phenotype
    D A Stevenson
    Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, UT 84132, USA
    Clin Genet 69:246-53. 2006
    ..We hypothesize that an NF1 mutant allele can lead to diagnostic manifestations of Noonan syndrome, supporting the hypothesis that NF1 allelic heterogeneity causes NFNS...
  13. pmc Analysis of radiographic characteristics of anterolateral bowing of the leg before fracture in neurofibromatosis type 1
    David A Stevenson
    Shriners Hospitals for Children, Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT 84132, USA
    J Pediatr Orthop 29:385-92. 2009
    ..Anterolateral leg bowing is associated with neurofibromatosis type 1 (NF1) frequently leading to fracture and nonunion of the tibia. The objective of the study was to characterize the radiographic findings of tibial dysplasia in NF1...