Eagle syndrome: A rare neuropathic disorder affecting head and neck.

To investigate the clinical characteristics of Eagle syndrome (ES) and evaluate psychological distress of the patients. Ten cases of ES were enrolled, clinical characteristics and management were analyzed. Psychological disorders of the patients were assessed by the test of self-rating anxiety scale (SAS) and self-rating depression scale (SDS). There were 8 females and 2 males varying from 34 to 56 years with a mean age of 44.86 ± 8.38 years. The main complaints included foreign body sensation of pharynx, odynophagia, vertigo with turning of the head-neck, pain of anterolateral neck, and toothache. Three cases were right-side affected, 6 cases were left-sided and 1 case was bilateral. Radiographic examination showed the elongated styloid process of bilateral in all cases, however, hypertrophy, improper inclination, abnormal angulation of styloid process and more complete calcification of stylohoid ligament of the complained side were observed compared to the opposite side. Eight cases suffered from anxiety and/or depression. A surgical intervention was carried out on 6 patients to resect the elongated styloid process, the symptoms and mental distress disappeared after the operation and no recurrence was found in their follow-ups. Meticulous interrogation of illness history, proper examination, and radiological studies may be valuable in diagnostic confirmation of ES. It is the hyperostosis, abnormal angulation of the styloid process rather than the simple elongation which is more likely to be attributed to the development of ES. Psychological disorders in ES patients were observed in our study and should be paid more attention in the future research.

Comparison of the Outcomes of Anterior Cervical Discectomy and Fusion and Cervical Disc Replacement for Cervical Disc Disease.

OBJECTIVE: To compare the radiological outcome and development of heterotopic ossification (HO) following single-segment anterior cervical discectomy and fusion (ACDF) and cervical disc replacement (CDR) for cervical disc herniation and evaluate their impact on surgical success. STUDY DESIGN: Descriptive comparative study. Place and Duration of the Study: Neurosurgery Department at Bozyaka Education and Research Hospital, Izmir, Turkiye, between January 2020 and June 2022. METHODOLOGY: Patients aged 18-70 years with radicular neck pain unresponsive to conventional medical treatment and an MRI-confirmed diagnosis were included. Patients with osteoporosis (OP) were excluded. Patients were randomised into two treatment groups (ACDF and CDR) and stratified by age and symptom severity. Radiographic assessments and HO classification according to McAfee were performed. RESULTS: Among the included patients, 56 underwent ACDF and 45 underwent CDR. The mean patient age was 48.29 ± 9.530 and 41.84 ± 7.239 years in the ACDF and CDR groups, respectively (p <0.001). The postoperative disc height increased in both groups. The T1 slope was significantly higher preoperatively and in the early postoperative period in the CDR group than in the ACDF group (p = 0.001). HO was graded as 1, 2, 3, and 4 in 28 (27.7%), 6 (5.9%), 7 (6.9%), and 4 (3%) patients, respectively. CONCLUSION: ACDF and CDR provided similar improvements in radiological measurements and pain relief. Although both procedures significantly enhanced the patient's quality of life and disability scores, HO was more prevalent following CDR during long-term follow-up. KEY WORDS: Cervical disc replacement, Anterior cervical discectomy and fusion, Spinal surgery techniques, Heterotopic ossification.

Ischemic stroke due to stylocarotid artery syndrome: a case report and review.

Stylocarotid artery syndrome (SAS) is a rare variant of Eagle's syndrome that may lead to transient ischemic attack or stroke. The underlying pathophysiological mechanism involves compression of the internal carotid artery by an elongated styloid process (ESP), potentially resulting in vascular occlusion or dissection. An ESP exceeding 2.5 cm is deemed elongated, with a length of 3.0 cm considered clinically significant. Although the prevalence of ESP ranges from 4.0% to 7.3%, symptomatic cases are rare; symptoms are present in only approximately 4.0% of individuals with an ESP. Unlike the typical symptoms of Eagle's syndrome, SAS may not cause pharyngeal discomfort, the sensation of a foreign body in the throat, dysphagia, or facial pain. This absence of characteristic symptoms as well as the development of central nervous system symptoms often leads patients to seek care from neurologists instead of otolaryngologists, increasing the likelihood of misdiagnosis or underdiagnosis. We herein report a unique case of ischemic stroke caused by SAS and present a literature review on cases of SAS-associated ischemic stroke published in the past decade. The reporting of this study conforms to the CARE guidelines.

Heterotopic ossification following COVID-19 infections: systematic literature review of case reports and case series.

BACKGROUND: This review aims to study the clinical characteristics, diagnostic results, treatments, and outcomes in patients with heterotopic ossification following COVID-19 infection. METHODS: A literature search for eligible articles was conducted using MEDLINE/Pubmed, Global Health, and Scopus databases (January 12th, 2023), including all case reports and case series from any country and language. The criteria for inclusion in this review were cases of COVID-19 infection subsequently developing heterotopic ossification. RESULTS: This systematic review analysed 15 reports (n = 20 patients) documenting cases of heterotopic ossification following COVID-19 infection. 80% of the patients were male, with a median age of 59 years. All patients required intensive care unit stay with an average duration of 48.5 days. Mechanical ventilation was necessary for all patients and 30% of them underwent tracheostomy. Common symptoms included stiffness and pain, most frequently affecting multiple locations (70%), with the hips and shoulders being predominantly involved. X-rays were the most commonly used imaging modality, followed by computed tomography. Although treatment was given, some of the patients continued to experience symptoms, particularly stiffness. CONCLUSION: 20 patients who developed heterotopic ossification after COVID-19 have been reported, the majority of which had at least two independent risk factors for this condition. The link between those two clinical entities is therefore uncertain, requiring further investigation. It is nonetheless important to suspect heterotopic ossification in patients with severe COVID-19 infection, prolonged immobilisation, mechanical ventilation, who develop joint pain and stiffness, as this condition can significantly impact patients' quality of life. PROTOCOL REGISTRATION: CRD42023393516.

Presumed Lacrimal Gland Pleomorphic Adenoma With Extensive Ossification and Necrosis.

Calcification within pleomorphic adenomas of the lacrimal gland is well recognized but uncommon, being seen more readily in lacrimal gland carcinomas. Bony formation, ossification, in pleomorphic adenomas of the lacrimal glands is even rarer. Together with extensive sclerosis, or "coagulative necrosis," ossification and necrosis should alert the clinician to the risk of malignant transformation. However, both can mimic carcinomatous change, leading to misinterpretation of malignancy in an otherwise benign lacrimal gland neoplasm. We present 2 case reports of patients with clinically presumed pleomorphic adenomas of the lacrimal gland whose histopathology demonstrated lacrimal gland ossification and necrosis without features of malignancy or invasive disease.

Genetic regulation of injury-induced heterotopic ossification in adult zebrafish.

Heterotopic ossification is the inappropriate formation of bone in soft tissues of the body. It can manifest spontaneously in rare genetic conditions or as a response to injury, known as acquired heterotopic ossification. There are several experimental models for studying acquired heterotopic ossification from different sources of damage. However, their tenuous mechanistic relevance to the human condition, invasive and laborious nature and/or lack of amenability to chemical and genetic screens, limit their utility. To address these limitations, we developed a simple zebrafish injury model that manifests heterotopic ossification with high penetrance in response to clinically emulating injuries, as observed in human myositis ossificans traumatica. Using this model, we defined the transcriptional response to trauma, identifying differentially regulated genes. Mutant analyses revealed that an increase in the activity of the potassium channel Kcnk5b potentiates injury response, whereas loss of function of the interleukin 11 receptor paralogue (Il11ra) resulted in a drastically reduced ossification response. Based on these findings, we postulate that enhanced ionic signalling, specifically through Kcnk5b, regulates the intensity of the skeletogenic injury response, which, in part, requires immune response regulated by Il11ra.

An ALK2 inhibitor, BLU-782, prevents heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease driven by gain-of-function variants in activin receptor-like kinase 2 (ALK2), the most common variant being ALK2R206H. In FOP, ALK2 variants display increased and dysregulated signaling through the bone morphogenetic protein (BMP) pathway resulting in progressive and permanent replacement of skeletal muscle and connective tissues with heterotopic bone, ultimately leading to severe debilitation and premature death. Here, we describe the discovery of BLU-782 (IPN60130), a small-molecule ALK2R206H inhibitor developed for the treatment of FOP. A small-molecule library was screened in a biochemical ALK2 binding assay to identify potent ALK2 binding compounds. Iterative rounds of structure-guided drug design were used to optimize compounds for ALK2R206H binding, ALK2 selectivity, and other desirable pharmacokinetic properties. BLU-782 preferentially bound to ALK2R206H with high affinity, inhibiting signaling from ALK2R206H and other rare FOP variants in cells in vitro without affecting signaling of closely related homologs ALK1, ALK3, and ALK6. In vivo efficacy of BLU-782 was demonstrated using a conditional knock-in ALK2R206H mouse model, where prophylactic oral dosing reduced edema and prevented cartilage and heterotopic ossification (HO) in both muscle and bone injury models. BLU-782 treatment preserved the normal muscle-healing response in ALK2R206H mice. Delayed dosing revealed a short 2-day window after injury when BLU-782 treatment prevented HO in ALK2R206H mice, but dosing delays of 4 days or longer abrogated HO prevention. Together, these data suggest that BLU-782 may be a candidate for prevention of HO in FOP.

KLF5 promotes the ossification process of ligamentum flavum by transcriptionally activating CX43.

BACKGROUND: Ossification of ligamentum flavum (OLF) is a prevalent degenerative spinal disease, typically causing severe neurological dysfunction. Kruppel-like factor 5 (KLF5) plays an essential role in the regulation of skeletal development. However, the mechanism KLF5 plays in OLF remains unclear, necessitating further investigative studies. METHODS: qRT-PCR, immunofluorescent staining and western blot were used to measure the expression of KLF5. Alkaline Phosphatase (ALP) staining, Alizarin red staining (ARS), and the expression of Runt-related transcription factor 2 (RUNX2), osteopontin (OPN), and osteocalcin (OCN) were used to evaluate the osteogenic differentiation. Luciferase activity assay and ChIP-PCR were performed to investigate the molecular mechanisms. RESULTS: KLF5 was significantly upregulated in OLF fibroblasts in contrast to normal ligamentum flavum (LF) fibroblasts. Silencing KLF5 diminished osteogenic markers and mineralized nodules, while its overexpression had the opposite effect, confirming KLF5's role in promoting ossification. Moreover, KLF5 promotes the ossification of LF by activating the transcription of Connexin 43 (CX43), and overexpressing CX43 could reverse the suppressive impact of KLF5 knockdown on OLF fibroblasts' osteogenesis. CONCLUSION: KLF5 promotes the OLF by transcriptionally activating CX43. This finding contributes significantly to our understanding of OLF and may provide new therapeutic targets.

"Bone in the penis" or fasciitis ossificans of the penis - a first time description of a pseudo-tumor at an extraordinary site.

BACKGROUND: Fasciitis ossificans is a rare subtype of nodular fasciitis, a benign soft tissue tumor with reactive characteristics. Due to its rapid growth, it is often misdiagnosed as a malignant tumor. While fasciitis ossificans commonly originates from the subcutaneous tissue and can appear throughout the body, it may also arise from extraordinary sites. CASE PRESENTATION: We report the first-ever documented case of fasciitis ossificans arising from the penis in a male patient who presented with a tumor on the glans penis. The tumor was surgically resected due to suspicion of penile cancer. Initial histopathological analysis led to a misdiagnosis of squamous cell carcinoma. However, pathological consultation ultimately confirmed the diagnosis of fasciitis ossificans of the penis originating from the glans penis by demonstrating ossification. CONCLUSION: This case underscores the importance of considering fasciitis ossificans in the differential diagnosis of soft tissue tumors, even in unusual locations such as penile soft tissue.

Calcified apoptotic vesicles from PROCR+ fibroblasts initiate heterotopic ossification.

Heterotopic ossification (HO) comprises the abnormal formation of ectopic bone in extraskeletal soft tissue. The factors that initiate HO remain elusive. Herein, we found that calcified apoptotic vesicles (apoVs) led to increased calcification and stiffness of tendon extracellular matrix (ECM), which initiated M2 macrophage polarization and HO progression. Specifically, single-cell transcriptome analyses of different stages of HO revealed that calcified apoVs were primarily secreted by a PROCR+ fibroblast population. In addition, calcified apoVs enriched calcium by annexin channels, absorbed to collagen I via electrostatic interaction, and aggregated to produce calcifying nodules in the ECM, leading to tendon calcification and stiffening. More importantly, apoV-releasing inhibition or macrophage deletion both successfully reversed HO development. Thus, we are the first to identify calcified apoVs from PROCR+ fibroblasts as the initiating factor of HO, and might serve as the therapeutic target for inhibiting pathological calcification.

Vegfc-expressing cells form heterotopic bone after musculoskeletal injury.

Heterotopic ossification (HO) is a challenging condition that occurs after musculoskeletal injury and is characterized by the formation of bone in non-skeletal tissues. While the effect of HO on blood vessels is well established, little is known about its impact on lymphatic vessels. Here, we use a mouse model of traumatic HO to investigate the relationship between HO and lymphatic vessels. We show that injury triggers lymphangiogenesis at the injury site, which is associated with elevated vascular endothelial growth factor C (VEGF-C) levels. Through single-cell transcriptomic analyses, we identify mesenchymal progenitor cells and tenocytes as sources of Vegfc. We demonstrate by lineage tracing that Vegfc-expressing cells undergo osteochondral differentiation and contribute to the formation of HO. Last, we show that Vegfc haploinsufficiency results in a nearly 50% reduction in lymphangiogenesis and HO formation. These findings shed light on the complex mechanisms underlying HO formation and its impact on lymphatic vessels.

Accuracy in the Diagnostics of Styloid Process - Panoramic Radiograph vs. Computed Tomography: A Comparative Study.

BACKGROUND/AIM: The styloid process (SP) becomes clinically relevant when it shows enlargement (>30 mm) in the sense of an elongated SP (ESP) and/or increasing calcification leading to Eagle Syndrome (ES). Panoramic radiograph (PR) or computed tomography (CT) are part of the routine diagnostics in ES. Currently, CT is considered the gold standard. The aim of this study was to investigate the accuracy in the diagnostics/measurements of SP/ESP throughout a comparative study between PR and CT. Furthermore, in addition to measuring established parameters, this study aimed to determine the currently unexamined width in the base and tip of the SP. PATIENTS AND METHODS: The present study examined the radiological findings of bilateral SP in 100 patients who received both PR and CT on the same day. Measurements of the length of the SP and width at the basis and tip were performed. Furthermore, calcification patterns, Langlais classification and the prevalence of ESP were analyzed. RESULTS: There was a highly significant correlation between PR and CT measuring SP for every parameter. Males showed significantly longer SP than females among the age group between 18-75 years. The results of the length measurements of the SP (male: right SP=32.98 mm; left SP=35.21 mm; female: right SP=30.31 mm; left SP=30.92 mm) significantly exceeded the values of comparable studies. CONCLUSION: Consequently, it can be concluded that PR provides accurate measurements when compared to CT for measuring and diagnosing SP/ESP/Eagle syndrome. This study was one of the first to examine the width of the SP in the base and tip, thus these measurements can serve as a baseline for further studies. Since the mean lengths of SP exceeded 30.0 mm in the present study, these findings raise the question of whether the cut-off of 30.0 mm is adequate for the diagnosis of ESP.

A rare case of extensive neurogenic heterotopic ossification: a case report.

INTRODUCTION: Neurogenic Heterotopic ossification (NHO) is a potential sequalae and a detrimental complication following neurological insult. It is characterized by formation of localized gradually progressive, peri-articular lamellar bone formation in extra-skeletal tissues. We would like to report a rare case of heterotopic ossification involving all 4 limbs, in which we tried to restore joint mobility to improve his functional status so that he could perform his daily tasks. CASE PRESENTATION: We present a case of a 33-year-old bed ridden male, diagnosed with NHO involving all 4 limbs (bilateral hip, right knee, right shoulder, left elbow). The patient had a crippled posture, significant pain and impaired range of motion hampering movement of all four limbs which prevented him from lying down supine, sitting, walking and performing activities of daily living. After three surgeries, the patient achieved wheelchair mobilization and upright posture with the assistance of calipers. CONCLUSION: The management of NHO requires a multidisciplinary approach involving orthopaedic surgeons, neurologists & rehabilitation specialists. Prognosis of NHO depends on factors such as extent of ossification, underlying neurological condition & patients overall health.

Malvidin attenuates trauma-induced heterotopic ossification of tendon in rats by targeting Rheb for degradation via the ubiquitin-proteasome pathway.

The pathogenesis of trauma-induced heterotopic ossification (HO) in the tendon remains unclear, posing a challenging hurdle in treatment. Recognizing inflammation as the root cause of HO, anti-inflammatory agents hold promise for its management. Malvidin (MA), possessing anti-inflammatory properties, emerges as a potential agent to impede HO progression. This study aimed to investigate the effect of MA in treating trauma-induced HO and unravel its underlying mechanisms. Herein, the effectiveness of MA in preventing HO formation was assessed through local injection in a rat model. The potential mechanism underlying MA's treatment was investigated in the tendon-resident progenitor cells of tendon-derived stem cells (TDSCs), exploring its pathway in HO formation. The findings demonstrated that MA effectively hindered the osteogenic differentiation of TDSCs by inhibiting the mTORC1 signalling pathway, consequently impeding the progression of trauma-induced HO of Achilles tendon in rats. Specifically, MA facilitated the degradation of Rheb through the K48-linked ubiquitination-proteasome pathway by modulating USP4 and intercepted the interaction between Rheb and the mTORC1 complex, thus inhibiting the mTORC1 signalling pathway. Hence, MA presents itself as a promising candidate for treating trauma-induced HO in the Achilles tendon, acting by targeting Rheb for degradation through the ubiquitin-proteasome pathway.

Neurogenic heterotopic ossification of the hip: Magnetic resonance imaging versus computed tomography for pre-surgical assessment.

PURPOSE: Neurogenic heterotopic ossification (NHO) of the hip is a frequent complication of spinal cord injuries, often requiring surgical management. Pre-surgical imaging assessment is essential, usually with computed tomography (CT)-scan. We aimed to compare magnetic resonance imaging (MRI) and CT for pre-surgical imaging assessment of the NHO, particularly for their relationships with vessels and nerves. METHOD: This prospective study included consecutive patients who underwent surgery for NHO from July 2019 to April 2022. All patients had CT angiography and MRI including Zero Echo Time and TRICKS sequences. Radiologists used standardized reports for CT and MRI to evaluate NHO and their features, bone mineralization, and relation to the arteries, veins and nerves. Agreement between pre-surgical CT and MRI was evaluated. RESULTS: Twenty-four patients (mean age: 53.5 ± 12.2 years) were included, among which 7 had bilateral NHO (31 hips). NHO were anterior in 15/31 hips (48 %), multifragmented in 25/31 hips (81 %). Mild and significant demineralization was most frequent. Gutter and tunnel were reported in 11.1 % of the arteries. Nerves were more often identified in MRI than in CT-scan. Agreement coefficients between CT and MRI were excellent for NHO location (0.95) and implantation (0.92), good for fragmentation (0.70), contact with joint capsule (0.66), bone mineralization (0.74), and relation to arteries (0.85), veins (0.76), sciatic nerve (0.7) and moderate for femoral nerve (0.47). CONCLUSION: MRI exhibited a good agreement with CT for pre-surgical assessment of NHO of the hip, especially to evaluate their relationships with the arteries, veins and sciatic nerve. Femoral nerves were more often identified in MRI than in CT-scan.

Cell Senescence in Heterotopic Ossification.

The formation of bone outside the normal skeleton, or heterotopic ossification (HO), occurs through genetic and acquired mechanisms. Fibrodysplasia ossificans progressiva (FOP), the most devastating genetic condition of HO, is due to mutations in the ACVR1/ALK2 gene and is relentlessly progressive. Acquired HO is mostly precipitated by injury or orthopedic surgical procedures but can also be associated with certain conditions related to aging. Cellular senescence is a hallmark of aging and thought to be a tumor-suppressive mechanism with characteristic features such as irreversible growth arrest, apoptosis resistance, and an inflammatory senescence-associated secretory phenotype (SASP). Here, we review possible roles for cellular senescence in HO and how targeting senescent cells may provide new therapeutic approaches to both FOP and acquired forms of HO.

Ossification of Bilateral Sacrotuberous Ligaments: Two Cases Report and Literature Review.

Ossification of the sacrotuberous ligament is a rare occurrence in soft tissue, with only 15 cases reported in the past few decades. We reported two cases of bilateral ossification in sacrotuberous ligaments and provided a concise review of the literature on this pathology. Clinical data, radiographic outcomes, and diagnostic and treatment details were obtained. This study aimed to summarize this disease's characteristics and investigate its pathogenesis through a review of literature from the last thirty years. This condition is often incidentally confirmed in elderly males via imagiological examination or gross anatomy and presents a low morbidity rate. Its pathogenesis may be related to stress concentration, excessive intake of element ions, injury repair, and improper operative technique. The majority of patients may not exhibit any clinical symptoms or signs and typically do not require medical interventions. It may be complicated with pudendal nerve entrapment syndrome. The long-term effects of surgical resection and the most effective treatment approach remain areas for further research.