Neurofibromatosis type 1‐related pseudarthrosis: Beyond the pseudarthrosis site

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder affecting approximately 1 in 2,000 newborns. Up to 5% of NF1 patients suffer from pseudarthrosis of a long bone (NF1‐PA). Current treatments are often unsatisfactory, potentially leading to amputation. To gain more insight into the pathogenesis we cultured cells from PA tissue and normal‐appearing periosteum of the affected bone for NF1 mutation analysis. PA cells were available from 13 individuals with NF1. Biallelic NF1 inactivation was identified in all investigated PA cells obtained during the first surgery. Three of five cases sampled during a later intervention showed biallelic NF1 inactivation. Also, in three individuals, we examined periosteum‐derived cells from normal‐appearing periosteum proximal and distal to the PA. We identified the same biallelic NF1 inactivation in the periosteal cells outside the PA region. These results indicate that NF1 inactivation is required but not sufficient for the development of NF1‐PA. We observed that late‐onset NF1‐PA occurs and is not always preceded by congenital bowing. Furthermore, the failure to identify biallelic inactivation in two of five later interventions and one reintervention with a known somatic mutation indicates that NF1‐PA can persist after the removal of most NF1 negative cells.

Clinical characteristics and in silico analysis of congenital pseudarthrosis of the tibia combined with neurofibromatosis type 1 caused by a novel NF1 mutation

“…The highly conserved protein consists of a cysteine-serine-rich domain (CSRD), a GAP-related domain (GRD), a tubulin-binding domain (TBD), a Sec14-homologous domain, a pleckstrin homology domain (SEC14-PH) and a C-terminal domain (CTD) ( Figure 6A ). The pathogenic mechanism of CPT is not clear yet and the deletion or inactivation of the NF1 gene is considered as an important cause ( Xu et al, 1990 ; Basu et al, 1992 ; Cichowski and Jacks, 2001 ; Viskochil, 2002 ; Brekelmans et al, 2019 ). NF1 gene is a tumor suppressor gene with a high mutation rate and extreme mutation heterogeneity.…”

Bioinspired Development of an In Vitro Engineered Fracture Callus for the Treatment of Critical Long Bone Defects

“…However, this tissue engineered treatment strategy is designed for niche indications typically for patients with non‐union fractures in compromised conditions, such as children with neurofibromatosis type 1‐related pseudarthrosis. [ 40 ] These children are typically patients who are directed to specialized clinics and for whom standard of care treatments failed. In these orphan indications, second line treatment strategies as described may be the only alternative option to amputation.…”

Sphenoid Bone Pneumatisation on Lateral Cephalograms of Patients With Neurofibromatosis Type 1

“…Haploinsufficiency of the bone is an important factor for pseudarthrosis of long bones in NF1 (10,69). On the other hand, the constitutive mutation of the NF1 gene may exert an effect on cellular components of the mucous membrane of the sinus that results in impaired aeration of the bone (70).…”

“…While the disease has been known for a long time (2), there are many obvious and hidden skeletal alterations in NF1 (3) of which the public is not aware (4,5). NF1 patients usually have a lower-than-normal body height (6), may show macrocranium (7), develop early osteoporosis (8), may develop scalloping and pseudarthrosis of bones (9,10) and have skull defects (11). Particularly striking findings of the skull are calvarial defects (11,12) and the diagnostically relevant sphenoid dysplasia (13).…”