Recent insights into bone development, homeostasis, and repair in type 1 neurofibromatosis (NF1)

Neurofibromatosis type 1 (NF1) is one of the most common single gene syndromes and is typified by a range of characteristic but variably penetrant manifestations. The orthopaedic manifestations of congenital pseudarthrosis of the tibia (CPT) and scoliosis, along with other skeletal defects including sphenoid wing dysplasia, rib penciling, and gracile bones have been classically associated with NF1. Added to this, several recent studies have reported a high prevalence of osteoporosis or osteopenia in NF1 cohorts. Clues to the underlying molecular and cellular deficiencies that cause these bony defects can be gleaned from genetically modified mouse models of Nf1 gene deficiency. These studies suggest that a variety of different cell lineages may be adversely affected by Nf1 haploinsufficiency or by double inactivation of the Nf1 gene. Osteoblasts, osteoclasts, chondrocytes, fibroblasts, and vascular endothelial cells all express the Nf1 gene product, neurofibromin, and may be functionally compromised when levels are decreased or absent. This paper reviews the current literature on NF1 bone development, homeostatic regulation, and repair, and highlights some emerging themes that may have relevance for managing orthopaedic disorders that can arise in individuals with NF1.