Genetic Variants in KCTD1 Are Associated with Isolated Dental Anomalies.

KCTD1 plays crucial roles in regulating both the SHH and WNT/ß-catenin signaling pathways, which are essential for tooth development. The objective of this study was to investigate if genetic variants in KCTD1 might also be associated with isolated dental anomalies. We clinically and radiographically investigated 362 patients affected with isolated dental anomalies. Whole exome sequencing identified two unrelated families with rare (p.Arg241Gln) or novel (p.Pro243Ser) variants in KCTD1. The variants segregated with the dental anomalies in all nine patients from the two families. Clinical findings of the patients included taurodontism, unseparated roots, long roots, tooth agenesis, a supernumerary tooth, torus palatinus, and torus mandibularis. The role of Kctd1 in root development is supported by our immunohistochemical study showing high expression of Kctd1 in Hertwig epithelial root sheath. The KCTD1 variants in our patients are the first variants found to be located in the C-terminal domain, which might disrupt protein-protein interactions and/or SUMOylation and subsequently result in aberrant WNT-SHH-BMP signaling and isolated dental anomalies. Functional studies on the p.Arg241Gln variant are consistent with an impact on ß-catenin levels and canonical WNT signaling. This is the first report of the association of KCTD1 variants and isolated dental anomalies.

Hereditary multiple exostoses with a giant osteochondroma degenerated into chondrosarcoma.

We present a case of hereditary multiple exostoses with malignant transformation to chondrosarcoma in a woman complaining of enlargement and pain in the right thigh. Hereditary multiple exostoses is a rare genetic disorder characterized by multiple osteochondromas. Malignant transformation to chondrosarcoma of a pre-existing osteochondroma is a possible significant manifestation of this hereditary syndrome. Imaging modalities such as X-ray, Ultrasound, and computed tomography play a crucial role in the diagnosis and management of these patients, as described in this case.

Surgical Proposition of a Slow-Growing Calvarial Exostosis in a Female Patient With a Congenital Iris Cyst of the Anterior Chamber and Mandibular Tori.

We present an unusual case of a woman in her early 50s with a slow-growing calvarial exostosis. Exostoses are bony spurs or osteomas extending outward beyond a bone's surface and may be benign or malignant. Calvarial exostoses are a less common bone tumor that can occur in the population. We present a case of a rare, slow-growing calvarial exostosis with a combination of mandibular tori and a congenital iris cyst. We discuss differentials of this exostosis and different syndromes that may cause it such as hereditary multiple exostoses and Gardner syndrome. The current article aims to spread awareness of this atypical presentation of exostoses and present our institution's surgical proposition for removing a calvarial exostosis to obtain a further histological analysis of its composition. As these masses may commonly be benign, a definitive diagnosis cannot be made through imaging alone to rule out more threatening conditions. We have addressed radiological findings and diagnostic and treatment options offered to the patient. The patient decided not to move forward with removing the mass and would continue to monitor and return should she notice any unusual or acute changes.

Multiple Hereditary Exostoses instigating a popliteal pseudoaneurysm in a young Middle Eastern male: A case report and literature review.

INTRODUCTION AND IMPORTANCE: Multiple Hereditary Exostoses is a rare autosomal dominant bone disorder that predominantly affects males at an incidence of (1:50,000 to 1:100,000) in Western populations. The etiology is owed to mutations in the EXT gene group, specifically EXT1 and EXT2 which cause the formation of Osteochondromas. Diagnosis is typically established in childhood. Nevertheless, vascular complications are extremely rare while being potentially fatal. Therefore, timely diagnosis and treatment are vital for such patients. CASE PRESENTATION: We present the case of a 37-year-old Middle Eastern male with Multiple Hereditary Exostoses who experienced sudden-onset left lower limb pain persisting for a month prior to admission. It was associated with coldness and paresthesia of the ipsilateral lower limb. The presurgical radiological workup uncovered a popliteal pseudoaneurysm subsequent to Multiple Hereditary Exostoses. CLINICAL DISCUSSION: Through open surgery, the vascular perfusion was successfully restored, and a subsequent supra- to infra-geniculate popliteal artery anastomosis via saphenous vein grafting was done. Furthermore, the Osteochondroma was utterly resected to limit recurrence of another vascular injury. The following histopathological analysis confirmed the diagnosis of an Osteochondroma as a result of MHE. CONCLUSION: Multiple Hereditary Exostoses is a rare occurrence leading to pseudoaneurysms. This event underscores the need for further documentation to aid in establishing a prompt diagnosis and carrying out suitable interventions. Considering this pathology in a multidisciplinary approach ensures proper treatment. Following a comprehensive literature review, our case stands as the first case in the published literature from our country which emphasizes its value and rarity.

Pediatric diaphragmatic hernia induced by a rib osteochondroma.

Diaphragmatic hernia in children is uncommon, especially when not congenital. We present a case of an 11-year old boy with a diaphragmatic hernia caused by a rib osteochondroma. The osteochondroma was surgically removed and the laceration in the diaphragm was repaired. This case shows the importance of being familiar with acquired diaphragmatic hernia in children, to recognize and prevent possible complications in an early stage.

Fibrodysplasia Ossificans Progressiva: A rare disease due to unawareness, case report and literature review.

INTRODUCTION AND IMPORTANCE: Fibrodysplasia Ossificans Progressiva is an ultra-rare genetic disorder of progressive soft tissue ossification. Due to unawareness and poor clinical suspicion, the rate of misdiagnosis, delay in diagnosis, and unnecessary diagnostic procedures leading to permanent injury and lifelong disability is common. Here we report this rare genetic disorder in a six years old child who was initially misdiagnosed as multiple exostoses and operated on. CASE PRESENTATION: A 6 year old child presented with swellings over the posterior neck and back for four years. The patient was misdiagnosed as a case of multiple exostoses and an excisional biopsy was done a year back. The swelling worsened after the excision; currently, she cannot move her neck from side to side, and flex and extend. Examination revealed multiple hard and slightly tender masses over the posterior neck, para scapular and thoracolumbar para spinal region. She also has hallux valgus deformity that had been present since birth. CT (computed tomography) scan confirmed extensive extra-skeletal soft tissue ossification. CLINICAL DISCUSSION: The progression of heterotopic ossification is characteristically anatomic and orderly, typically initially involving the body's dorsal, axial, cranial, and proximal regions and later in the ventral, appendicular, caudal, and distal regions. Skeletal muscles of the tongue, diaphragm, extra-ocular muscles, cardiac muscles, and smooth muscles are inexplicably spared. CONCLUSION: Early diagnosis prevents potentially harmful diagnostic and therapeutic procedures. The characteristic big toes malformation is the most important and best key for the early suspicion of the diagnosis.

Surgical and conservative treatment outcomes of medication-related osteonecrosis of the jaw located at tori: a retrospective study.

PURPOSE: Tori and exostoses are considered risk factors for the development of medication-related osteonecrosis of the jaw (MRONJ). The aims of this study were to present the prevalence of MRONJ located at tori in the Copenhagen ONJ Cohort, evaluate the surgical treatment of MRONJ located at tori and explore trauma to tori as an additional risk factor in patients on antiresorptive medication. METHODS: Data from a consecutive series of 506 patients with MRONJ (Copenhagen ONJ Cohort) were reviewed for the presence of tori and MRONJ located at tori. Demographic and medical data were analyzed, and healing outcomes and pain after the prophylactic removal of tori, surgical treatment of MRONJ located at tori, and conservative treatment of MRONJ located at tori were evaluated and compared using Fisher's exact test. RESULTS: MRONJ located at tori was frequent and could be identified in 53% of the patients with tori, which accounts for a prevalence of 5.1% in the entire cohort. Of the 28 surgically treated patients, 27 (96.4%) healed uneventfully with no exposed bone after their first or second revision surgery. Fourteen (41.2%) patients with tori underwent therapeutic removal, eight (23.5%) underwent prophylactic removal, and six (17.6%) underwent both therapeutic and prophylactic removals. Two (33.3%) of the six conservatively treated patients healed spontaneously. Both treatment types resulted in a significant decrease in pain. CONCLUSION: Prophylactic and therapeutic surgical removal of tori are reliable treatments and should be considered if a patient's general health allows surgery. TRIAL REGISTRATION: The study was approved by the Regional Scientific Ethical Committee (H-6-2013-010) on November 20, 2013, and was retrospectively registered.

Rare coexistence of multiple osteochondromas and solitary osteoid osteoma: A case report.

Multiple osteochondromas (MOs) are inherited in an autosomal-dominant manner, with a penetrance of ~96 and 100% in female and male patients, respectively. Osteochondromas primarily involve the metaphyses and diaphyses of long bones, including the ribs. Osteoid osteomas account for ~3 and 11% of all bone tumors and benign bone tumors, respectively. Furthermore,1 the male-to-female ratio is 2-3:1, and they generally occur in the long bones of the lower extremities, with the femoral neck being the most frequent site. The present study describes the case of a 16-year-old male patient with a bony mass around the left knee joint and pain in the left calf. Radiography revealed MOs in the upper and lower extremities, while computed tomography showed a nidus in the cortex of the tibial shaft. The patient's family history included the presence of MOs, and the patient was diagnosed with MOs and a solitary osteoid osteoma. Surgical excision of the osteochondroma and curettage of the osteoid osteoma in the proximal tibia and tibial shaft, respectively, were performed simultaneously. Postoperative pathological examination revealed osteochondroma and osteoid osteoma. Furthermore, the pain resolved, and no recurrence was observed 7 months post-operation. To the best of our knowledge, no reports exist on coexisting MOs and osteoid osteoma; therefore, the present study describes the first case of such a condition. Marginal excision for osteochondroma and curettage for osteoid osteoma effectively improved the symptoms.

Chondrosarcoma secondary to hereditary multiple osteochondromas with spinal cord compression: A case report and systematic review.

Background: Hereditary multiple osteochondromas (HMOs) are a rare genetic disorder characterized by the formation of multiple benign osteochondromas that can undergo malignant transformation into chondrosarcoma. Case Description: A 24-year-old male with a history of HMO and osteochondroma surgery 4 years ago, presented with back pain and paresthesias. The magnetic resonance showed a right paravertebral infiltrating mass at the T12-L1 level causing spinal cord compression. Following en bloc resection of the tumor, the patient's symptoms/ signs resolved. The final pathological diagnosis was consistent with a chondrosarcoma. Conclusion: Chondrosarcomas secondary to HMO with spinal cord compression are rare. These patients often presenting with significant myelopathy/cord compression should undergo gross total resection where feasible to achieve the best outcomes.

Chest wall osteochondroma resection with biologic acellular bovine dermal mesh reconstruction in pediatric hereditary multiple exostoses: A case report and review of literature.

BACKGROUND: Hereditary multiple exostoses is a rare genetic disorder characterized by the growth of multiple osteochondromas affecting primarily long bones. Chest wall lesions may represent a challenge, particularly in pediatric patients. Pain is a common manifestation. However, life-threatening complications can result from direct involvement of adjacent structures. Surgical resection with appropriate reconstruction is often required. CASE SUMMARY: A 5-year-old male who was diagnosed with hereditary multiple exostoses presented with significant pain from a large growing chest wall exostosis lesion. After appropriate preoperative investigations, he underwent surgical resection with reconstruction of his chest wall using a biologic bovine dermal matrix mesh. CONCLUSION: Resection of chest wall lesions in children represents a challenge. Preoperative planning to determine the appropriate reconstruction strategy is essential.

Hereditary multiple exostoses caused by a chromosomal inversion removing part of EXT1 gene.

BACKGROUND: Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder characterized by the development of multiple, circumscript and usually symmetric bony protuberances called osteochondromas. Most HME are caused by EXT1 and EXT2 loss of function mutations. Most pathogenic mutations are nonsense followed by missense mutations and deletions. CASE PRESENTATION: Here we report on a patient with a rare and complex genotype resulting in a typical HME phenotype. Initial point mutation screening in EXT1 and EXT2 genes by Sanger sequencing did not reveal any pathogenic variants. The patient along with the healthy parents was subsequently referred for karyotype and array-Comparative Genomic Hybridization (CGH) analyses. Chromosomal analysis revealed two independent de novo apparently balanced rearrangements: a balanced translocation between the long arms of chromosomes 2 and 3 at breakpoints 2q22 and 3q13.2 and a pericentric inversion with breakpoints at 8p23.1q24.1. Both breakpoints were confirmed by Fluorescence In Situ Hybridization (FISH). Subsequently, array-CGH revealed a novel heterozygous deletion within the EXT1 gene at one of the inversion breakpoints, rendering the inversion unbalanced. The mode of inheritance, as well as the size of the deletion were further investigated by Quantitative Real-time PCR (qPCR), defining the deletion as de novo and of 3.1 kb in size, removing exon 10 of EXT1. The inversion in combination with the 8p23.1 deletion most likely abolishes the transcription of EXT1 downstream of exon 10 hence resulting in a truncated protein. CONCLUSIONS: The identification of a rare and novel genetic cause of HME, highlights the importance of additional comprehensive investigation of patients with typical clinical manifestations, even when EXT1 and EXT2 mutation analysis is negative.

Osteochondroma of the Acromion Process: A Rare Case with an Unusual Presentation.

Introduction: Osteochondroma is the most common primary benign bone tumor. It's radiologic characteristics are often pathognomonic. Osteochondromas usually occur at the metaphysis of long bones. The distal end of femur, proximal humerus, proximal tibia, and fibula are the common locations. Most cases present within the first three decades. Case Report: A 12-year-old boy presented with osteochondroma of left acromion process. It is very unusual for its location with a mass over the left shoulder extending laterally into deltoid muscle. Radiologic studies showed large pedunculated mass arising from the acromion process. On surgical exploration, we found a pedunculated and well encapsulated mass on the lateral aspect of the left shoulder with a thin hyaline cartilaginous cap. The mass was carefully separated from nearby structures and resected en bloc. Results: No post-operative complications were noticed. Patient was prescribed physiotherapy and we have him advised 6-month follow-up till skeletal maturity. Patient had complete range of motion at the last follow-up. He was able to do his all daily activities. Conclusion: The acromion is very rare site for osteochondroma with mass extending into lateral deltoid muscle. Careful blunt dissection and protection of nearby structures and fairly good learning curve of surgeon is needed in operating such cases.

Venous malformation may be a feature of EXT1-related hereditary multiple exostoses: A report of two unrelated probands.

Hereditary multiple exostoses (HME), also known as hereditary multiple osteochondroma (HMO), is an autosomal dominant disorder caused by pathogenic variants in exostosin-1 or -2 (EXT1 or EXT2). It is characterized by the formation of multiple benign growing osteochondromas (exostoses) that most commonly affect the long bones; however, it may also occur throughout the body. Although many of these lesions are clinically asymptomatic, some can lead to chronic pain and skeletal deformities and interfere with adjacent neurovascular structures. Here, we report two unrelated probands that presented with a clinical and molecular diagnosis of HME with venous malformation, a clinical feature not previously reported in individuals with HME.

Expanding the clinical and molecular features of trichorhino- phalangeal syndrome with a novel variant.

BACKGROUND: Tricho-rhino-phalangeal syndrome (TRPS) is a rare, autosomal dominant disorder characterized by typical craniofacial features, ectodermal and skeletal findings. TRPS type 1 (TRPS1) is caused by pathogenic variations in the TRPS1 gene, which relates to the vast majority of cases. TRPS type 2 (TRPS2) is a contiguous gene deletion syndrome involving loss of functional copies of the TRPS1, RAD21, and EXT1. Herein, we reported the clinical and genetic spectrum of seven TRPS patients with a novel variant. We also reviewed the musculoskeletal and radiological findings in the literature. METHODS: Seven Turkish patients (three female, four male) from five unrelated families aged between 7 to 48 years were evaluated. The clinical diagnosis was confirmed by either molecular karyotyping or TRPS1 sequencing analysis via next-generation sequencing. RESULTS: Both TRPS1 and TRPS2 patients had some common distinctive facial features and skeletal findings. All patients had a bulbous nose with hypoplastic alae nasi, brachydactyly, short metacarpals and phalanges in variable stages. Low bone mineral density (BMD) was identified in two TRPS2 family members presenting with bone fracture, and growth hormone deficiency was detected in two patients. Skeletal X-ray imaging revealed cone-shaped epiphysis of the phalanges in all, and multiple exostoses were present in three patients. Cerebral hamartoma, menometrorrhagia and long bone cysts were among the new/rare conditions. Three pathogenic variants in TRPS1 were identified in four patients from three families, including a frameshift (c.2445dup, p.Ser816GlufsTer28), one missense (c.2762G > A), and a novel splice site variant (c.2700+3A > G). We also reported a familial inheritance in TRPS2 which is known to be very rare. CONCLUSIONS: Our study contributes to the clinical and genetic spectrum of patients with TRPS while also providing a review by comparing with previous cohort studies.

Alveolar bone exostoses following orthodontic treatment. Diagnostic considerations and clinical management.

Alveolar bone exostoses (ABE) are benign localized convex outgrowths of buccal or lingual bone, which could be delineated from the surrounding cortical plate, also known as a buttress bone formation. Our review and case series demonstrate the development of alveolar bone exostoses during orthodontic therapy. It is crucial to keep in mind that every case presented had a history of palatal tori. In our clinical observations, higher precedence of ABE development was seen in participants during incisor retraction, especially with preexisting palatal tori. Additionally, we have successfully demonstrated surgical techniques to eliminate ABE in the event that self-remission does not occur once orthodontic forces are discontinued.

NFATC1 and NFATC2 expression patterns in human osteochondromas.

Background: Our previous study in genetic mouse models found that NFATc1 and NFATc2 suppress osteochondroma formation from entheseal progenitors. However, it remains unclear whether NFAT signaling is also involved in human osteochondromagenesis. As the first step in addressing this question, the current study aimed to determine the expression patterns of NFATC1 and NFATC2 in human osteochondroma samples. Methods: Immunohistochemistry (IHC) was used to examine and analyze NFATC1 and NFATC2 expression in human osteochondroma samples. The human periosteum was used to map the expression of NFATC1 under physiological conditions by IHC. Furthermore, human periosteal progenitors were isolated and identified from the periosteal tissues of bone fracture healing patients. The expression of NFATC1 in human periosteal progenitors was characterized by Western blotting compared to human bone marrow stromal cells (BMSC). Results: The IHC results showed that the expression of NFATC1 was undetectable in most human osteochondromas cells, and only a small proportion of osteochondroma cells, especially clonally grown chondrocytes, showed positive staining of NFATC1. NFATC2 expression was also undetectable in most chondrocytes in human osteochondromas. The mouse and human periosteum showed a comparable ratio of NFATC1 positive cells (9.56 ± 0.80% vs 11.04 ± 2.05%, P = 0.3101). Furthermore, Western blotting analysis revealed that NFATC1 expression was highly enriched in human periosteal progenitors compared to BMSC. Conclusions: NFATC1 and NFATC2 are undetectable in most human osteochondroma chondrocytes. The expression pattern of NFATC1 in human osteochondromas and the normal periosteum suggests that NFAT signaling could be suppressed during human osteochondromagenesis.

Rare Variants in LRP4 Are Associated with Mesiodens, Root Maldevelopment, and Oral Exostoses in Humans.

BACKGROUND: Low density lipoprotein receptor-related protein 4 (LRP4; MIM 604270) modulates WNT/ß-catenin signaling, through its binding of WNT ligands, and to co-receptors LRP5/6, and WNT inhibitors DKK1, SOSTDC1, and SOST. LRP4 binds to SOSTDC1 and WNT proteins establishing a negative feedback loop between Wnt/ß-catenin, Bmp, and Shh signaling during the bud and cap stages of tooth development. Consistent with a critical role for this complex in developing teeth, mice lacking Lrp4 or Sostdc1 have multiple dental anomalies including supernumerary incisors and molars. However, there is limited evidence supporting variants in LRP4 in human dental pathologies. METHODS: We clinically, radiographically, and molecularly investigated 94 Thai patients with mesiodens. Lrp4 mutant mice were generated in order to study the effects of aberrant Lrp4 expression in mice. RESULTS: Whole exome and Sanger sequencing identified three extremely rare variants (c.4154A>G, p.Asn1385Ser; c.3940G>A, p.Gly1314Ser; and c.448G>A, p.Asp150Asn) in LRP4 in seven patients with mesiodens. Two patients had oral exostoses and two patients had root maldevelopments. Supernumerary incisors were observed in Lrp4 mutant mice. CONCLUSIONS: Our study implicates heterozygous genetic variants in LRP4 as contributing factors in the presentation of mesiodens, root maldevelopments, and oral exostoses, possibly as a result of altered WNT/ß-catenin-BMP-SHH signaling.

Evaluation of mandibular bone density in bruxers: the value of panoramic radiographs.

OBJECTIVES: This study aimed to establish a difference in mandibular bone density between bruxer and non-bruxer patients, based on panoramic radiographs. METHODS: Panoramic radiographs of bruxer and non-bruxer patients were analyzed with ImageJ®. Several radiological determinants were studied on the patients' panoramic radiographs: gray values of cancellous bone and cortical bone, and bony exostoses at the mandibular angle. RESULTS: Thirty-seven bruxers and forty-seven non-bruxers were included in the study. A statistically significant difference (p < 0.05) was noted in the cancellous to cortical bone ratios of bruxers and non-bruxers: the density of cancellous bone was greater in bruxers than in non-bruxers. The number of bony exostoses at the mandibular angle was significantly higher in bruxers (p < 0.05). CONCLUSIONS: This study obtained radiological determinants of bruxism from panoramic radiographs. Further studies are needed to supplement this preliminary approach, especially via the analysis of three-dimensional imaging to overcome the limitations of panoramic radiography.