Background: Neurofibromatosis 1 (NF1) is an autosomal dominant disorder with various skeletal abnormalities occurring as part of a complex phenotype. Tibial dysplasia, which typically presents as anterolateral bowing of the leg with subsequent fracture and nonunion (pseudarthrosis), is a serious but infrequent osseous manifestation of NF1. Over the past several years, results from clinical and experimental studies have advanced our knowledge of the role of NF1 in bone. On the basis of current knowledge, we propose a number of concepts to consider as a theoretical approach to the optimal management of tibial pseudarthrosis.
Methods: A literature review for both clinical treatment and preclinical models for tibial dysplasia in NF1 was performed. Concepts were discussed and developed by experts who participated in the Children’s Tumor Foundation sponsored International Bone Abnormalities Consortium meeting in 2011.
Results: Concepts for a theoretical approach to treating tibial pseudarthrosis include: bone fixation appropriate to achieve stability in any given case; debridement of the “fibrous pseudarthrosis tissue” between the bone segments associated with the pseudarthrosis; creating a healthy vascular bed for bone repair; promoting osteogenesis; controlling overactive bone resorption (catabolism); prevention of recurrence of the “fibrous pseudarthrosis tissue”; and achievement of long-term bone health to prevent recurrence.
Conclusions: Clinical trials are needed to assess effectiveness of the wide variation of surgical and pharmacologic approaches currently in practice for the treatment of tibial pseudarthrosis in NF1.
Level of Evidence: Level V, expert opinion.
*Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, UT
†Department of Orthopaedic Research and Biotechnology, The Children’s Hospital at Westmead
‡Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, NSW, Australia
§Department of Medical Genetics, University of British Columbia, and Child and Family Research Institute
‡‡Department of Medicine, University of British Columbia, Vancouver, BC, Canada
∥Department of Orthopedics
†††Human Genetics Division, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
¶Great Ormond St Hospital for Children and the Royal National Orthopaedic Hospital, London
¶¶Bristol Royal Hospital for Children, Bristol, United Kingdom
#Spine Surgery Department, Rizzoli Orthopedic Institute, Bologna, Italy
**Southwest Research Institute, San Antonio
***Texas Scottish Rite Hospital for Children, Dallas, TX
††Children’s Tumor Foundation, New York, NY
§§Max Planck Institute for Molecular Genetics, FG Development and Disease
∥∥Institute for Medical Genetics, Charité, Universitätsmedizin Berlin, Berlin, Germany
##Children’s National Medical Center, Washington, DC
‡‡‡Department of Pediatrics, Indiana University School of Medicine
§§§Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN
∥∥∥Vanderbilt University Medical Center, Department of Medicine, Center for Bone Biology, Nashville, TN
Supported by an International NF1 Bone Abnormalities Consortium meeting in New York that was funded by the Children’s Tumor Foundation.
D.L. has current research agreements with Novartis Pharma, Amgen, Celgene Corp., and N8 Medical and serves on ad-hoc advisory boards for Amgen, Lilly, and Novartis. D.L. was previously supplied with bone morphogenetic protein-7 for animal research by Stryker Biotech and previously royalties from Novartis were provided to his institution. A.S. receives research support from Novartis Pharma, Acceleron, Celgene Corp., and N8 Medical and advisory fees on an ad-hoc basis from Celgene Corp. The remaining authors declare no conflict of interest.
Reprints: David A. Stevenson, MD, Department of Pediatrics, Division of Medical Genetics, University of Utah, 2C412 SOM, Salt Lake City, UT 84132. E-mail: firstname.lastname@example.org.