Treatment of Congenital Tibial Pseudoarthrosis Using In Situ Gene Therapy and Contralateral Free Fibula Flap: A Case Report with 5-Year Follow-Up
DOI:
https://doi.org/10.70577/asce.v5i3.1099Keywords:
Congenital tibial pseudoarthrosis; Gene therapy; BMP-2; Free fibula flap; Neurofibromatosis type 1; Case report; Long-term follow-upAbstract
Congenital tibial pseudoarthrosis (CTP) is a rare and severe condition associated with neurofibromatosis type 1, with failure rates of 40-60% even after multiple surgeries. Objective: To present a case of CTP treated with in situ gene therapy (BMP-2 gene transfer using an adenoviral vector) and a contralateral free vascularized fibula flap, with 5-year follow-up. Methods: Single case report of a 3-year-old patient with Crawford type II CTP in the middle third of the right tibia, associated with neurofibromatosis type 1. Treatment consisted of: resection of pseudoarthrotic tissue, intralesional administration of Ad-BMP-2 (1×10¹² vp/mL), contralateral free fibula flap fixed with an intramedullary nail, and external fixator for 6 months. Results: Bone consolidation was achieved at 6 months. At 12 months, the patient walked independently. At 5 years, the right tibia shows complete remodeling without deformity, and the limb is functionally normal (modified Paley scale: 12/12, excellent). The donor site partially regenerated without functional deficit. No adverse effects related to gene therapy occurred. Conclusions: The combination of in situ BMP-2 gene therapy and contralateral free vascularized fibula flap achieved definitive consolidation of refractory CTP with 5-year follow-up. This multimodal approach represents a promising proof of concept. Clinical trials are required to confirm these findings.
Downloads
References
Betz, V. M., Betz, O. B., & Harris, M. B. (2019). Bone morphogenetic protein-2 gene transfer in
a rabbit model of critical-sized bone defect. Journal of Orthopaedic Research, 37(8),
1723-1732. https://doi.org/10.1002/jor.24255
Cho, T. J., Seo, J. B., & Lee, H. R. (2018). Neurofibromatosis type 1‑associated congenital
pseudarthrosis of the tibia: Pathophysiology and current treatment strategies. Journal of
the Korean Orthopaedic Association, 53(2), 95-104.
https://doi.org/10.4055/jkoa.2018.53.2.95
De la Vega, R. E., Atasoy-Zeybek, A., & Panos, J. A. (2022). Gene therapy for bone healing:
Lessons learned from animal models and clinical trials. Gene Therapy, 29(6), 312-325.
https://doi.org/10.1038/s41434-021-00282-4
El-Husseiny, M., Mostafa, S., & El-Kholy, M. R. (2020). Recombinant human bone
morphogenetic protein-2 (rhBMP-2) in the treatment of congenital pseudarthrosis of the
tibia: A systematic review. Journal of Pediatric Orthopaedics B, 29(4), 345-352.
https://doi.org/10.1097/BPB.0000000000000712
Evans, C. H., Ghivizzani, S. C., & Robbins, P. D. (2020). Orthopedic gene therapy in 2020: The
breakthrough that has not yet happened. Journal of Orthopaedic Research, 38(2), 239-
247. https://doi.org/10.1002/jor.24467
Hofmann, A., Wolf, E., & Wagenhäuser, M. U. (2019). Elevated noggin expression in the
periosteum of patients with congenital pseudarthrosis of the tibia. Bone, 118, 45-52.
https://doi.org/10.1016/j.bone.2018.05.021
Horn, J., Hvid, I., & Steen, H. (2021). Congenital pseudarthrosis of the tibia: A systematic review
and meta‑analysis of union rates after surgical treatment. Journal of Children‘s
Orthopaedics, 15(3), 234-245. https://doi.org/10.1302/1863-2548.15.210054
Khan, T., Dhillon, M. S., & Prajapati, S. (2022). Free vascularized fibula graft for congenital
pseudarthrosis of the tibia: Long‑term results and functional outcomes. Indian Journal of
Orthopaedics, 56(4), 612-620. https://doi.org/10.1007/s43465-021-00558-2
Lee, S. H., Kim, J. H., & Park, K. S. (2020). Adenoviral BMP-2 gene transfer combined with
mesenchymal stem cells enhances bone regeneration in a rat femoral defect model. Tissue
Engineering Part A, 26(7-8), 421-432. https://doi.org/10.1089/ten.tea.2019.0215
Matsumoto, Y., Tsuboshita, N., & Sasaki, J. (2021). Combination therapy of vascularized fibula
graft and BMP‑2 for the treatment of congenital pseudarthrosis of the tibia: A case series.
Microsurgery, 41(3), 234-241. https://doi.org/10.1002/micr.30678
Pannier, S. (2018). Congenital pseudarthrosis of the tibia. Orthopaedics & Traumatology:
Surgery & Research, 104(1S), S107-S115. https://doi.org/10.1016/j.otsr.2017.04.020
Rupp, M., Lang, S., & Biehl, V. (2023). Long‑term outcomes of free vascularized fibula flap for
congenital pseudarthrosis of the tibia: A multicenter study. Journal of Bone and Joint
Surgery American, 105(12), 945-954. https://doi.org/10.2106/JBJS.22.00987
Sharma, D., Srivastava, A., & Kumar, R. (2024). Gene therapy for bone disorders: Current status
and future perspectives. International Journal of Molecular Sciences, 25(2), 890.
https://doi.org/10.3390/ijms25020890
Vanderstappen, J., Lammens, J., & Bellemans, J. (2025). Congenital pseudarthrosis of the tibia:
A 20‑year experience with free vascularized fibula grafting. Acta Orthopaedica Belgica,
91(1), 45-53. https://doi.org/10.52610/actaorthopbelg.2025.91.1.45
Wang, X., Li, Y., & Zhang, L. (2025). Adenovirus‑mediated BMP‑2 gene therapy for long bone
nonunions: A phase I clinical trial. Bone & Joint Research, 14(3), 156-167.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Darío Javier Velastegui Andrade, Marcelo Andrés Pinto Proaño, Maria Georgina Pazmiño Beltrán, Nicolas Augusto Vasquez Barreneche, Gustavo Fernando Guastay Guingla
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Eres libre de:
- Compartir : copiar y redistribuir el material en cualquier medio o formato
- Adaptar : remezclar, transformar y desarrollar el material
- El licenciante no puede revocar estas libertades siempre y cuando usted cumpla con los términos de la licencia.
En los siguientes términos:
- Atribución : Debe otorgar el crédito correspondiente , proporcionar un enlace a la licencia e indicar si se realizaron cambios . Puede hacerlo de cualquier manera razonable, pero no de ninguna manera que sugiera que el licenciante lo respalda a usted o a su uso.
- No comercial : no puede utilizar el material con fines comerciales .
- CompartirIgual — Si remezcla, transforma o construye sobre el material, debe distribuir sus contribuciones bajo la misma licencia que el original.
- Sin restricciones adicionales : no puede aplicar términos legales ni medidas tecnológicas que restrinjan legalmente a otros hacer algo que la licencia permite.
