Pathological mandibular fracture complicated by osteonecrosis in an adult patient with pycnodysostosis: clinical report and review of the literature.

Pycnodysostosis is an ultra-rare osteosclerotic skeletal disorder characterized by short stature, susceptibly to fractures, acroosteolysis of the distal phalanges, and craniofacial features (frontal bossing, prominent nose, obtuse mandibular angle, micrognathia). Dental abnormalities (delayed eruption of teeth, hypodontia, malocclusion, dental crowding, persistence of deciduous teeth, enamel hypoplasia, and increased caries) are also frequent; due to bone metabolism alteration, the patients have an increased risk for jaw osteomyelitis, especially after tooth extraction or mandible fracture. Other complications are obstructive sleep apnea, endocrine alterations and cytopenia. Pycnodysostosis is caused by biallelic loss of function variants in CTSK gene, coding the lysosomal protease cathepsin K. CTSK is involved in the degradation of bone matrix proteins, such as type I and type II collagen. In pycnodysostosis, this degradation is decreased, leading to increased bone density and bone fragility with pathological fractures and poor healing. We present a clinical report of a female adult patient with typical pycnodysostosis phenotype. At the age of 52 years, she had a pathological spontaneous fracture of the right mandible complicated by osteonecrosis, treated with load bearing osteosynthesis. The direct sequencing of CTSK gene revealed the presence of the pathogenic homozygous variant c.746T>A, (p.Ile249Asn), that confirmed the diagnosis of pycnodysostosis. We also review the literature case series published to date, that suggest to always consider the diagnosis of pycnodysostosis in case of osteosclerosis, even in the absence of brachydactyly or short stature. This report details the natural history of the disease in this patient, from childhood to adulthood, and highlights the importance of a quality of life assessment. In addition, we describe a case of mandibular osteonecrosis and spontaneous fracture in pycnodysostosis, drawing attention on the maxillofacial complications in these patients and on the importance of a personalized follow-up.

Microarray Analysis of Differential Gene Expression Between Traumatic Temporomandibular Joint Fibrous and Bony Ankylosis in a Sheep Model.

BACKGROUND The type of traumatic temporomandibular joint (TMJ) ankylosis depends on the degree of severity of TMJ trauma. Here, we performed comprehensive differential molecular profiling between TMJ fibrous and bony ankylosis. MATERIAL AND METHODS Six sheep were used and a bilateral different degree of TMJ trauma was performed to induce fibrous ankylosis in one side and bony ankylosis in the other side. The ankylosed calluses were harvested at days 14 and 28 postoperatively and analyzed by Affymetrix OviGene-1_0-ST microarrays. DAVID was used to perform the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis for the different expression genes (DEGs). The DEGs were also typed into protein-protein interaction (PPI) networks to get the interaction data. Ten DEGs, including 7 hub genes from PPI analysis, were confirmed by real-time PCR. RESULTS We found 90 and 323 DEGs at least 2-fold at days 14 and 28, respectively. At day 14, bony ankylosis showed upregulated DEGs, such as TLR8, SYK, NFKBIA, PTPRC, CD86, ITGAM, and ITGAL, indicating a stronger immune and inflammatory response and cell adhesion, while genes associated with anti-adhesion (PRG4) and inhibition of osteoblast differentiation (SFRP1) had higher expression in fibrous ankylosis. At day 28, bony ankylosis showed increased biological process related to new bone formation, while fibrous ankylosis was characterized by a prolonged immune and inflammatory reaction. CONCLUSIONS This study provides a differential gene expression profile between TMJ fibrous and bony ankylosis. Further study of these key genes may provide new ideas for future treatment of TMJ bony ankylosis.

A pilot trial on the molecular pathophysiology of traumatic temporomandibular joint bony ankylosis in a sheep model. Part II: The differential gene expression among fibrous ankylosis, bony ankylosis and condylar fracture.

OBJECTIVE: The purpose of the study was to preliminarily explore the differential expressions of a series of genes regulating bone formation in temporomandibular joint (TMJ) fibrous ankylosis, bony ankylosis and condylar fracture healing. METHODS: The cDNA from either the bony ankylosed callus or fracture callus of the 6 sheep, as described in the part I, were both used in the study. The differences of gene expressions between bony ankylosis and condylar fracture at 1, 3, and 6 months postoperatively were measured by real-time PCR, with 2 samples at each time point. In addition, another 2 sheep were added to have fibrous ankylosis induced on the right TMJ, and 1 sheep was sacrificed at 3 and 6 months after surgery, respectively. The differences of gene expressions between fibrous and bony ankylosis at 3 and 6 months postoperatively were measured by real-time PCR. RESULTS: Bony ankylosis showed higher mRNA expression trends in Wnt2b, Wnt5a, ß-Catenin, Lef1, CyclinD1, Runx2, Osterix, Sox9, Col10a1, Alp, Ocn, Bmp2, and Bmp7 compared to fibrous ankylosis, although no statistical analysis was performed due to the very small sample size. Whereas bony ankylosis showed a significant lower expression of Wnt5a, ß-Catenin, Lef1, Runx2, Osterix, Sox9, Col10a1, Alp, Ocn and Bmp4 compared to condylar fracture at several time points (P < 0.05). CONCLUSION: Our data provided a preliminary molecular evidence for the hypothesis that the development of traumatic TMJ bony ankylosis was the course of delayed bone healing or hypertrophic nonunion, and deserved to be further studied.

Genotoxicity of fixation devices analyzed by the frequencies of sister chromatid exchange.

BACKGROUND: Metal alloys utilized in the management of jaw fractures may exert genotoxic effects. Our purpose was to compare the genotoxicity of intermaxillary fixation devices containing nickel and chromium to that of titanium miniplates utilized in treatment of jaw fractures through the analysis of sister chromatid exchange. METHODS: In this prospective study, in a total of 28 non-smoker patients (10 females, 18 males; mean age 33.43±10.76; range 15 to 60 years) with jaw fractures, 14 were treated with intermaxillary fixation by administration of nickel-chromium wire and arch bar and 14 with titanium miniplates to investigate the genotoxicity of different metal alloys. The outcome variable was the frequency of sister chromatide exchange in peripheral lymphoctyes, determined through the analysis of venous blood samples obtained preoperatively and 4 to 6 weeks postoperatively. RESULTS: The frequency of the average sister chromatid exchange was found to be significantly higher in patients treated with the nickel-chromium intermaxillary fixation devices than those treated by titanium miniplates (1.29±0.29 vs. 0.46±0.39, p<0.001). CONCLUSION: Although titanium miniplate osteosynthesis is an invasive technique in comparison with the nickel-chromium-containing intermaxillary fixation devices, titanium seems to exert less genotoxic effect than the nickel-chromium alloy. However, this finding should be supported in clinical studies with a larger sampling size.

Fractura de mandíbula en paciente con neurodegeneración asociada al déficit de pantotenatocinasa (síndrome de Hallervorden-Spatz) / Mandibular fracture in a patient with pantothenate kinase-associated neurodegeneration (Hallervorden-Spatz syndrome)

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Expression of BMP-2 and TGF-beta 1 mRNA during healing of the rabbit mandible.

To identify the cell types which produce BMP and TGF-beta during fracture healing and to elucidate the interactions between BMP and TGF-beta in regulating cell proliferation and differentiation at various stages, an experimental model of fracture healing in the rabbit mandible was established and the expression of BMP-2 and TGF-beta 1 mRNA was studied at different healing stages by in situ hybridization. The results showed that undifferentiated mesenchymal cells, differentiating osteoblasts and chondroblasts, had higher levels of BMP-2 mRNA at the stage of intramembranous bone formation and early chondrogenesis, while the level of TGF-beta 1 mRNA was higher in chondrocytes and active differentiated osteoblasts during chondrogenesis and endochondral ossification, respectively. We conclude that BMP-2 expression was correlated with the differentiation of mesenchymal cells into osteoblasts and chondrocytes. TGF-beta 1 mRNA expression was closely associated with the active synthetic stage of osteoblasts and chondrocytes. These observations suggest that both BMP and TGF-beta are involved in the regulation of fracture healing. BMP may play an important role in bone induction and early chondrogenesis, while TGF-beta regulates the proliferation and active synthetic ability of chondrocytes and osteoblasts.