A skeleton in a huff: insights in etiologies of osteosclerosis.

A 30-yr-old man developed right lower leg pain and a palpable solid mass. Radiographic imaging revealed a periosteal reaction with an exostotic mass arising from the right distal fibula. Generalized skeletal osteosclerosis with periosteal reaction was discovered on a radiographic skeletal survey. A biopsy of the right fibular mass revealed reactive woven bone. The patient was referred to a metabolic bone disease clinic, where laboratory values were consistent with secondary hyperparathyroidism and increased bone turnover. A DXA bone density scan revealed high bone density, with an L1-4 spine Z-score of +9.3, a left femoral neck Z-score of +8.5, and a total hip Z-score of +6.5. A dental exam revealed generalized gingival inflammation, teeth mobility, generalized horizontal alveolar bone loss and widening of the periodontal ligament space, increased bone density around the teeth, and thickening of the radicular lamina dura. An extensive evaluation was performed, with the result of a single test revealing the diagnosis. The differential diagnoses of osteosclerosis affecting the skeleton, teeth, and oral cavity are discussed.

A 30-yr-old man developed, over a short period, pain in his lower right leg accompanied by a hard mass. He also reported weight loss and night sweats for the past 6 months. After evaluation by his primary physician, an X-ray was ordered that reported a bony mass arising from the right fibula bone. A biopsy was performed of the mass, but no evidence of cancer or any other specific abnormality was found. The patient was then referred to a bone disease specialty clinic. Laboratory tests revealed a large increase in how quickly the patient's skeleton was remodeling, affecting the balance of bone formation and removal involved in maintaining a healthy skeleton. A bone density scan reported that the patient had very dense bones. Other unusual changes were also discovered in a dental exam, suggesting bone thickening. After an extensive evaluation, a single blood test revealed the cause of the fibular bone mass and dense bones.

Performance evaluation of a deep learning model for automatic detection and localization of idiopathic osteosclerosis on dental panoramic radiographs.

Idiopathic osteosclerosis (IO) are focal radiopacities of unknown etiology observed in the jaws. These radiopacities are incidentally detected on dental panoramic radiographs taken for other reasons. In this study, we investigated the performance of a deep learning model in detecting IO using a small dataset of dental panoramic radiographs with varying contrasts and features. Two radiologists collected 175 IO-diagnosed dental panoramic radiographs from the dental school database. The dataset size is limited due to the rarity of IO, with its incidence in the Turkish population reported as 2.7% in studies. To overcome this limitation, data augmentation was performed by horizontally flipping the images, resulting in an augmented dataset of 350 panoramic radiographs. The images were annotated by two radiologists and divided into approximately 70% for training (245 radiographs), 15% for validation (53 radiographs), and 15% for testing (52 radiographs). The study employing the YOLOv5 deep learning model evaluated the results using precision, recall, F1-score, mAP (mean Average Precision), and average inference time score metrics. The training and testing processes were conducted on the Google Colab Pro virtual machine. The test process's performance criteria were obtained with a precision value of 0.981, a recall value of 0.929, an F1-score value of 0.954, and an average inference time of 25.4 ms. Although radiographs diagnosed with IO have a small dataset and exhibit different contrasts and features, it has been observed that the deep learning model provides high detection speed, accuracy, and localization results. The automatic identification of IO lesions using artificial intelligence algorithms, with high success rates, can contribute to the clinical workflow of dentists by preventing unnecessary biopsy procedure.

Raine syndrome: Prenatally identified severe craniofacial phenotype with multisuture synostosis and brain abnormalities associated with variants in FAM20C.

Raine syndrome (MIM 259775) is a rare autosomal recessive disorder, first described by Raine et al. in 1989, with an estimated prevalence of <1/1,000,000. This is due to pathogenic variants in FAM20C characterized by osteosclerosis, typical craniofacial features, and brain calcifications. Here, we report a novel variant in FAM20C, describe a uniquely severe craniofacial and CNS phenotype of Raine syndrome, and correlate it with prenatal findings. Fetal phenotyping was based on ultrasound and MRI. Solo exome sequencing was performed from DNA extracted from postmortem skin biopsy. Targeted parental variant testing was subsequently performed. A homozygous missense variant NM_020223.4 (c.1445 G > A (p.Gly482Glu)) was identified in FAM20C associated with Raine syndrome. The infant had the characteristic dysmorphic features seen in Raine syndrome. He had particularly significant CNS manifestations consisting of multisuture craniosynostosis with protrusion of the brain parenchyma through fontanelles and cranial lacunae. Histological sections of the brain showed marked periventricular gliosis with regions of infarction, hemorrhage, and cavitation with global periventricular leukomalacia. Numerous dystrophic calcifications were diffusely present. Here, we demonstrate the identification of a novel variant in FAM20C in an infant with the characteristic features seen in Raine syndrome. The patient expands the characteristic phenotype of Raine syndrome to include a uniquely severe CNS phenotype, first identified on prenatal imaging.

How does the clinical and tomographic appearance of MRONJ influences its treatment prognosis?

OBJECTIVES: To identify clinical and tomographic prognostic factors for conservative and surgical treatment of medication-related osteonecrosis of the jaws (MRONJ). METHODS: A retrospective search identified patients treated with antiresorptive drugs (ARDs), diagnosed with Stage 1, 2 or 3 MRONJ, and having CBCT scans previous to conservative or surgical treatment. Following data collection, imaging assessment of the following parameters on each MRONJ site was performed: involvement of teeth and/or implants, presence of osteosclerosis, osteolysis, sequestrum formation, periosteal reaction, and pathological fractures. For statistical analysis, patients and lesions were divided into conservative and surgical treatment. Comparisons were made between successful and unsuccessful outcomes. Significance was set at p ≤ 0.05. RESULTS: 115 ARD-treated patients who developed 143 osteonecrosis lesions were selected. 40 patients and 58 lesions received conservative treatment, of which 14 patients (35%) and 25 lesions (43%) healed. Additionally, 75 patients and 85 lesions underwent surgery, with 48 patients (64%) and 55 lesions (65%) that healed. Clinical and tomographic risk factors for conservative treatment were MRONJ staging, tooth involvement, extensive osteosclerosis, and deep sequestrum formation (p < 0.05). Complementarily, poor prognostic indicators for surgical therapy were a short bisphosphonate (BP) holiday, MRONJ staging, absence of sequestrum formation, and presence of periosteal reaction (p < 0.05). CONCLUSIONS: Lesions at Stage 3 MRONJ, with tooth involvement, or sequestrum formation showed poor outcomes when conservative treatment is chosen. Alternatively, surgical treatment is most effective when BPs are discontinued, in Stage 1 lesions, in the presence of sequestrum formation, and absence of periosteal reaction.

Assessing the reliability of CBCT-based AI-generated STL files in diagnosing osseous changes of the mandibular condyle: a comparative study with ground truth diagnosis.

OBJECTIVES: This study aims to evaluate the reliability of AI-generated STL files in diagnosing osseous changes of the mandibular condyle and compare them to a ground truth (GT) diagnosis made by six radiologists. METHODS: A total of 432 retrospective CBCT images from four universities were evaluated by six dentomaxillofacial radiologists who identified osseous changes such as flattening, erosion, osteophyte formation, bifid condyle formation, and osteosclerosis. All images were evaluated by each radiologist blindly and recorded on a spreadsheet. All evaluations were compared and for the disagreements, a consensus meeting was held online to create a uniform GT diagnosis spreadsheet. A web-based dental AI software was used to generate STL files of the CBCT images, which were then evaluated by two dentomaxillofacial radiologists. The new observer, GT, was compared to this new STL file evaluation, and the interclass correlation (ICC) value was calculated for each pathology. RESULTS: Out of the 864 condyles assessed, the ground truth diagnosis identified 372 cases of flattening, 185 cases of erosion, 70 cases of osteophyte formation, 117 cases of osteosclerosis, and 15 cases of bifid condyle formation. The ICC values for flattening, erosion, osteophyte formation, osteosclerosis, and bifid condyle formation were 1.000, 0.782, 1.000, 0.000, and 1.000, respectively, when comparing diagnoses made using STL files with the ground truth. CONCLUSIONS: AI-generated STL files are reliable in diagnosing bifid condyle formation, osteophyte formation, and flattening of the condyle. However, the diagnosis of osteosclerosis using AI-generated STL files is not reliable, and the accuracy of diagnosis is affected by the erosion grade.

Novel mutation in LRP5 gene cause rare osteosclerosis: cases studies and literature review.

To study the effects of low-density lipoprotein receptor-related protein 5 (LRP5) gene mutations on bone, and to open up our view of LRP5 and Wnt pathways on bone mass regulation. Three patients with increased bone mineral density or thickened bone cortex were included, who were 30-year-old, 22-year-old and 50-year-old men, respectively. The latter two patients were son and father of a same family. The characteristics of bone X-rays were evaluated in detail. Bone turnover markers were detected, such as procollagen type 1 amino-terminal peptide (P1NP), alkaline phosphatase (ALP), and type 1 collagen carboxyl terminal peptide (ß-CTX). Dual energy X-ray absorptiometry (DXA) was used to measure the bone mineral density (BMD) at lumbar spine and proximal femur of the patients. The targeted next-generation sequencing (NGS) technology was used to detect pathogenic gene mutations, which were further verified by Sanger sequencing. Moreover, the gene mutation spectrum and phenotypic characteristics of reported patients with LRP5 gain-of-function mutations were summarized by reviewing the literature. The main characteristics of the first patient were headache, facial paralysis, high BMD (lumbar vertebrae 1-4: 1.877 g/cm2, Z-score: 5.8; total hip: 1.705 g/cm2, Z-score: 5.7), slightly increased P1NP (87.0 ng/mL) and ß-CTX (0.761 ng/mL) level, and with thickened bone cortex, especially the cranial vault. The latter two patients showed enlargement of the mandible and enlarged osseous prominence of the tours palatinus. X-rays showed that the bone cortex of skull and long bones were thickened. The bone turnover markers and BMD were normal. All three cases carried novel missense mutations in LRP5 gene, which were mutation in exon 3 (c.586 T > G, p.Trp196Gly) of the first patient, and mutation in exon 20 (c.4240C > A, p.Arg1414Ser) of the latter two patients. Combined with the reported literature, a total of 19 gain-of-function mutations in LRP5 were detected in 113 patients from 33 families. Hotspot mutations included c.724G > A, c.512G > T and c.758C > T. Furthermore, mutations in the exon 3 of LRP5 may cause severe phenotypes. LRP5 gain-of-function mutations can lead to rare autosomal dominant osteosclerosis type Ι (ADO Ι), which was characterized by increased bone mass and thickened bone cortex. In-depth research on the Wnt pathway will be benefit for discovering important mechanisms of bone mass regulation.

Intracranial calcification in Fam20c-deficient mice recapitulates human Raine syndrome.

FAM20C (family with sequence similarity 20-member C) is a protein kinase that phosphorylates secretory proteins, including the proteins that are essential to the formation and mineralization of calcified tissues. FAM20C loss-of-function mutations cause Raine syndrome in humans, characterized by generalized osteosclerosis, distinctive craniofacial dysmorphism, along with extensive intracranial calcification. Our previous studies revealed that inactivation of Fam20c in mice led to hypophosphatemic rickets. In this study, we examined the expression of Fam20c in the mouse brain and investigated brain calcification in Fam20c-deficient mice. Reverse transcription polymerase chain reaction (RT-PCR), Western-blotting and in situ hybridization analyses demonstrated the broad expression of Fam20c in the mouse brain tissue. X-ray and histological analyses showed that the global deletion of Fam20c (mediated by Sox2-cre) resulted in brain calcification in mice after postnatal 3 months and that the calcifications were bilaterally distributed within the brain. There was mild perifocal microgliosis as well as astrogliosis around calcospherites. The calcifications were first observed in the thalamus, and later in the forebrain and hindbrain. Furthermore, brain-specific deletion (mediated by Nestin-cre) of Fam20c in mice also led to cerebral calcification at an older age (postnatal 6 months), but no obvious skeletal or dental defects. Our results suggest that the local loss of FAM20C function in the brain may directly account for intracranial calcification. We propose that FAM20C plays an essential role in maintaining normal brain homeostasis and preventing ectopic brain calcification.

Osteopetrosis: Gene-based nosology and significance Dysosteosclerosis.

Dysosteosclerosis (DSS) refers to skeletal dysplasias that radiographically feature focal appendicular osteosclerosis with variable platyspondyly. Genetic heterogeneity is increasingly reported for the DSS phenotype and now involves mutations of SLC29A3, TNFRSF11A, TCIRG1, LRRK1, and CSF1R. Typical radiological findings are widened radiolucent long bones with thin cortices yet dense irregular metaphyses, flattened vertebral bodies, dense ribs, and multiple fractures. However, the radiographic features of DSS evolve, and the metaphyseal and/or appendicular osteosclerosis variably fades with increasing patient age, likely due to some residual osteoclast function. Fractures are the principal presentation of DSS, and may even occur in infancy with SLC29A3-associated DSS. Cranial base sclerosis can lead to cranial nerve palsies such as optic atrophy, and may be the initial presentation, though not observed with SLC29A3-associated DSS. Gene-specific extra-skeletal features can be the main complication in some forms of DSS such as CSF1R- associated DSS. Further genetic heterogeneity is likely, especially for X-linked recessive DSS and cases currently with an unknown genetic defect. Distinguishing DSS can be challenging due to variable clinical and radiological features and an evolving phenotype. However, defining the DSS phenotype is important for predicting complications, prognosis, and instituting appropriate health surveillance and treatment.

Neurological manifestations in patients and disease carriers in an Italian family with osteosclerosis.

BACKGROUND: Hereditary cranial hyperostosis is a rare disease never described in Italy, so the neurological manifestations in patients and carriers of the disease have been little studied. METHODS: We describe the neurological and neuroimaging features of patients and carriers of the gene from a large Italian family with sclerosteosis. RESULTS: In this family, genetic testing detected the homozygous p.Gln24X (c.70C > T) mutation of the SOST gene in the proband and a heterozygous mutation in 9 siblings. In homozygous adults, severe craniofacial hyperostosis was manifested by cranial neuropathy in childhood, chronic headache secondary to intracranial hypertension, and an obstructive sleep apnea syndrome in adults. In one of the adult patients, there was a compressible subcutaneous swelling in the occipital region caused by transosseous intracranial-extracranial occipital venous drainage, a compensation mechanism of obstructed venous drainage secondary to cranial hyperostosis. Mild cranial hyperostosis causing frequent headache and snoring was evident in the nine heterozygous subjects. CONCLUSIONS: Multiple cranial neuropathies and headache in children, while severe chronic headache and sleep disturbances in adults, are the neurological manifestations of the first Italian family with osteosclerosis. It is reasonable to extend neurological and neuroimaging evaluation to gene carriers as well.

Idiopathic Osteosclerosis and Condensing Osteitis in a Sample of the Lebanese Population: A Digital Panoramic Based Study.

Background: Idiopathic osteosclerosis (IO) is an area of enlarged bone production in the jaw that usually appears radiopaque and round, elliptical, or irregular in shape. Condensing osteitis (CO) is a focalized osseous reaction leading to periapical sclerotic bone growth. Objective: The aim of this study was to investigate the prevalence, localization, shape, and dental relationship of IO and CO in a group of Lebanese patients and to correlate these findings to age and gender. Methods: 520 digital panoramic radiographs of patients (215 men and 305 women) ranging in age from 18 to 77 (mean age 40.89 years) who visited the Faculty of Dental Medicine, Lebanese University, for dental treatment were included in this study and assessed for IO and CO. The prevalence of the two lesions according to gender and age, as well as their localization, and dental relationship, were recorded and saved in an Excel sheet. Results: Among the 520 radiographs, 47 (9%) showed IO, and 30 (5.8%) showed CO. Both lesions are more frequent among females in their third decade and are essentially found in the mandible, mainly in relation to the root apices. Conclusion: Within the limits of this study, we concluded that in our sample of the Lebanese population, the prevalence of IO and CO is low and supports the theory that IO can be defined as developmental variations of normal bony architecture unrelated to a local stimulant, and CO could be considered reactive bone formations related to pulpitis, deep restoration, or caries.

HIF-1α-mediated autophagy and canonical Wnt/ß-catenin signalling activation are involved in fluoride-induced osteosclerosis in rats.

Fluoride (F) exposure can cause osteosclerosis, which is characterised by a high bone mass, but its mechanism is not fully illustrated. Here, we aimed to evaluate the effects of excessive F exposure on the bone lesion by treating female Sprague-Dawley rats with different concentrations of sodium fluoride (NaF) (0, 55, 110 and 221 mg/L) for 90 days and the corresponding concentrations of fluorine ion (0, 25, 50 and 100 mg/L, respectively). Histopathological results showed that excessive F exposure caused the enlargement of trabeculae and their integration into one large piece, growth plate thickening, articular cartilage impairment and bone collagen abnormality. Meanwhile, F promoted calcium deposition and bone mineralisation, and induced abnormal osteogenesis increased. The results of micro-computed tomography also confirmed that excessive F destroyed the bone microstructure and induced a high-bone-mass phenotype, consistent with the results of pathomorphology. Mechanistically, excessive amounts of F led to angiogenesis inhibition and HIF-1α signalling enhancement. Subsequently, F induced autophagy and canonical Wnt/ß-catenin signalling pathway activation. Collectively, these results manifested that F enhanced the hypoxia inducible factor-1α signalling, which in turn triggered autophagy and canonical Wnt/ß-catenin signalling activation, ultimately leading to osteosclerosis in the rats.

A Deep Learning Model for Idiopathic Osteosclerosis Detection on Panoramic Radiographs.

OBJECTIVE: The purpose of the study was to create an artificial intelligence (AI) system for detecting idiopathic osteosclerosis (IO) on panoramic radiographs for automatic, routine, and simple evaluations. SUBJECT AND METHODS: In this study, a deep learning method was carried out with panoramic radiographs obtained from healthy patients. A total of 493 anonymized panoramic radiographs were used to develop the AI system (CranioCatch, Eskisehir, Turkey) for the detection of IOs. The panoramic radiographs were acquired from the radiology archives of the Department of Oral and Maxillofacial Radiology, Faculty of Dentistry, Eskisehir Osmangazi University. GoogLeNet Inception v2 model implemented with TensorFlow library was used for the detection of IOs. Confusion matrix was used to predict model achievements. RESULTS: Fifty IOs were detected accurately by the AI model from the 52 test images which had 57 IOs. The sensitivity, precision, and F-measure values were 0.88, 0.83, and 0.86, respectively. CONCLUSION: Deep learning-based AI algorithm has the potential to detect IOs accurately on panoramic radiographs. AI systems may reduce the workload of dentists in terms of diagnostic efforts.

Osteosclerotic metaphyseal dysplasia, dysosteosclerosis or osteomyelitis? Paediatric case presentation with associated mandibular swelling and a review of the literature.

Osteosclerotic metaphyseal dysplasia (OMD) is an extremely rare form of osteopetrosis, which bears significant clinical similarities to dysosteosclerosis (DSS). We aim to present a rare case of OMD with mandibular swelling and osteomyelitis infection including diagnosis journey as well as management in 7-year-old patient. Literature review completed for OMD cases. Case report investigative methods include genetic testing, CT facial bones and MRI scan, orthopantogram and bone biopsies. An initial suspected diagnosis of DSS with chronic osteomyelitis was made. However, following genetic testing, a diagnosis of OMD was confirmed. Our patient underwent a surgical debulking procedure and antibiotic treatment. Less than 10 patients with this condition have been reported within the international literature. There is a wide range of presentation. OMD, DSS and osteomyelitis are all within a similar spectrum of bone conditions. Our understanding, regarding OMD, remains limited and, hence, further research is required to elucidate a thorough clinical picture.

Periarticular calcifications containing giant pseudo-crystals of francolite in skeletal fluorosis from 1,1-difluoroethane "huffing".

Inhalant use disorder is a psychiatric condition characterized by repeated deliberate inhalation from among a broad range of household and industrial chemical products with the intention of producing psychoactive effects. In addition to acute intoxication, prolonged inhalation of fluorinated compounds can cause skeletal fluorosis (SF). We report a young woman referred for hypophosphatasemia and carrying a heterozygous ALPL gene variant (c.457T>C, p.Trp153Arg) associated with hypophosphatasia, the heritable metabolic bone disease featuring impaired skeletal mineralization, who instead suffered from SF. Manifestations of her SF included recurrent articular pain, axial osteosclerosis, elevated bone mineral density, maxillary exostoses, and multifocal periarticular calcifications. SF was suspected when a long history was discovered of 'huffing' a computer cleaner containing 1,1-difluoroethane. Investigation revealed markedly elevated serum and urine levels of F-. Histopathology and imaging techniques including backscattered electron mode scanning electron microscopy, X-ray microtomography, energy dispersive and wavelength dispersive X-ray emission microanalysis, and polarized light microscopy revealed that her periarticular calcifications were dystrophic deposition of giant pseudo-crystals of francolite, a carbonate-rich fluorapatite. Identifying unusual circumstances of F- exposure is key for diagnosing non-endemic SF. Increased awareness of the disorder can be lifesaving.

Case 298: Skeletal Fluorosis Secondary to Huffing.

History A 37-year-old man from the United States presented with a 1-year history of neck pain and stiffness that had been unsuccessfully treated with manipulative therapy by a chiropractor at another institution. Past medical history was remarkable only for marijuana and air duster abuse. He denied use of any prescription medications. Physical examination was notable for markedly reduced range of motion of the cervical spine. Laboratory work-up revealed an elevated alkaline phosphatase level (302 U/L [5.0 µkat/L]; normal range, 40-100 U/L [0.7-1.67 µkat/L]), but all other laboratory findings, including complete blood count, renal function, liver function, vitamin A level, serum protein electrophoresis, and hepatitis C antibodies were within normal limits. Cervical spine radiography was performed, followed by MRI. Subsequently, a full skeletal survey was ordered. Included are representative radiographs of the pelvis, left forearm, and distal right leg with ankle.

Differential diagnosis of a diffuse sclerosis in an identified male skull (early 20th century Coimbra, Portugal): A multimethodological approach for the identification of osteosclerotic dysplasias in skeletonized individuals.

OBJECTIVE: This work aims to discuss the difficulties in diagnosing osteosclerotic changes in skeletonized individuals and to raise awareness of osteosclerotic dysplasias as a group of rare ancient diseases. MATERIALS: The skull of a 62-year-old male individual from the International Exchange Skull Collection, curated by the University of Coimbra, who died in 1928 presenting albuminous nephritis (Bright disease)/uraemia as the registered cause of death. METHODS: The skull was macroscopically and radiologically examined and bone elemental analysis was investigated. The genealogy and medical records of the individual were also searched. RESULTS: The lesions are in accordance with an osteosclerotic process possibly pointing to osteosclerosis, osteosclerotic metaphyseal dysplasia, or dysosteosclerosis, but osteoclasia with hyperphosphatasia, endosteal hyperostosis, sclerosteosis, or osteopathia striata with cranial sclerosis cannot be ruled out. CONCLUSIONS: Representativeness of the skeleton is a crucial feature in diagnosing rare diseases and, to avoid a misdiagnosis, the final diagnosis should include a group of diseases rather than a definite disease. SIGNIFICANCE: Difficulties in diagnosing rare diseases are discussed and best approaches in the study osteosclerotic dysplasias in skeletonized individuals are offered in the light of current clinical knowledge. LIMITATIONS: The absence of the postcranial skeleton and of pathognomonic lesions associated with osteosclerotic dysplasias limits diagnosis. Although rare diseases often have a genetic basis, specific genetic testing for the diagnosis of rare diseases in paleopathological cases are not yet available. SUGGESTIONS FOR FURTHER RESEARCH: Future genetic studies might help narrow down the diagnosis.