Human complete NFAT1 deficiency causes a triad of joint contractures, osteochondromas, and B-cell malignancy.

The discovery of humans with monogenic disorders has a rich history of generating new insights into biology. Here we report the first human identified with complete deficiency of nuclear factor of activated T cells 1 (NFAT1). NFAT1, encoded by NFATC2, mediates calcium-calcineurin signals that drive cell activation, proliferation, and survival. The patient is homozygous for a damaging germline NFATC2 variant (c.2023_2026delTACC; p.Tyr675Thrfs∗18) and presented with joint contractures, osteochondromas, and recurrent B-cell lymphoma. Absence of NFAT1 protein in chondrocytes caused enrichment in prosurvival and inflammatory genes. Systematic single-cell-omic analyses in PBMCs revealed an environment that promotes lymphomagenesis with accumulation of naïve B cells (enriched for oncogenic signatures MYC and JAK1), exhausted CD4+ T cells, impaired T follicular helper cells, and aberrant CD8+ T cells. This work highlights the pleiotropic role of human NFAT1, will empower the diagnosis of additional patients with NFAT1 deficiency, and further defines the detrimental effects associated with long-term use of calcineurin inhibitors.

Osteochondrolipoma of the foot treated by surgical excision: a case report and literature review.

BACKGROUND: Osteochondromas, classified as a new benign subtype of lipomas and characterised by chondroid and osseous differentiation, are rare lesions that have been infrequently reported in previous literature. The maxillofacial region was reported as the most frequent localization, with infrequent occurrence in the lower limb. This paper represents the first documented case report of osteochondrolipoma in the foot. CASE PRESENTATION: A 51-year-old male patient presented with a chief complaint of right foot pain at the plantar aspect, accompanied by the observation of swelling between the first and the second metatarsal shafts. His complaint of pain and swelling started 10 and 4 years prior, respectively. Since their onset, both symptoms have progressed in nature. Imaging revealved a large mass exhibiting a nonhomogenous composition of fibrous tissue and bony structures. Surgical intervention through total excision was indicated. CONCLUSION: Osteochodrolipoma is a benign lesion that can affect the foot leading to decreased functionality of the foot due to the pain and swelling. Surgical excision is the recommended approach for this lesion, providing both symptomatic relief and confirmation of the diagnosis through histopathological examination.

Effect of Solitary Osteochondroma on Alignment and Length in the Lower Extremities.

BACKGROUND: There is a lack of information about the effects of untreated solitary osteochondroma (SO) on longitudinal growth of the lower extremities in children and adolescents. This study aimed to assess the coronal alignment and length of the lower extremity in patients with SO around the knee and to identify the factors related to the development of deformities. METHODS: We retrospectively reviewed 111 patients diagnosed with SO around the knee. The patients were classified into 2 groups depending on the location of the SO: 51 in the distal femur and 60 in the proximal tibia. Characteristics of the lesions, such as type, location, size, and distance from the joint line, were determined. Radiographic analysis of the lower limbs included mechanical lateral distal femoral angle, mechanical medial proximal tibial angle, whole-leg length, femoral length, and tibial length. RESULTS: The mean age at the time of diagnosis was 12.3±3.4 years. No statistically significant differences were found between the affected and contralateral sides for mechanical lateral distal femoral angle and mechanical medial proximal tibial angle in either the distal femur or the proximal tibia groups. In patients with femoral lesions, the femoral and whole-leg lengths were significantly shorter on the affected side than on the unaffected side ( P <0.001 and 0.002, respectively), and the mean differences were 2.1±3.6 and 2.1±4.4 mm, respectively. Univariate logistic regression analysis did not reveal any factors associated with limb length discrepancy (LLD). In patients with tibial lesions, no statistically significant differences were found in LLD. CONCLUSIONS: SOs around the knee did not cause clinically significant deformity of the lower extremity. However, in contrast to proximal tibia lesions, SO in the distal femur was associated with the shortening of the affected limb. Consideration should be given to the development of LLD in skeletally immature children with SO in the distal femur. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

BPOP in early childhood following resection of osteochondroma: report of a case.

The diagnosis of an osteochondroma in the short bones of the extremities is atypical and the presentation in infancy is unusual. A 3-month-old female presented for evaluation of radial deviation of the right index finger present since birth. Radiographs showed a broad-based osseous outgrowth with the usual features of an osteochondroma arising from the base of middle phalanx. Initial corrective surgery at 22 months was followed by recurrence of the lesion. Another resection at 4 years confirmed a final diagnosis of BPOP (bizarre parosteal osteochondromatous proliferation). The subsequent pathologic diagnosis of BPOP appears to support the hypotheses concerning the etiology of BPOP as possibly arising from repeated trauma to the metaphysis.

De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas.

SOX6 belongs to a family of 20 SRY-related HMG-box-containing (SOX) genes that encode transcription factors controlling cell fate and differentiation in many developmental and adult processes. For SOX6, these processes include, but are not limited to, neurogenesis and skeletogenesis. Variants in half of the SOX genes have been shown to cause severe developmental and adult syndromes, referred to as SOXopathies. We here provide evidence that SOX6 variants also cause a SOXopathy. Using clinical and genetic data, we identify 19 individuals harboring various types of SOX6 alterations and exhibiting developmental delay and/or intellectual disability; the individuals are from 17 unrelated families. Additional, inconstant features include attention-deficit/hyperactivity disorder (ADHD), autism, mild facial dysmorphism, craniosynostosis, and multiple osteochondromas. All variants are heterozygous. Fourteen are de novo, one is inherited from a mosaic father, and four offspring from two families have a paternally inherited variant. Intragenic microdeletions, balanced structural rearrangements, frameshifts, and nonsense variants are predicted to inactivate the SOX6 variant allele. Four missense variants occur in residues and protein regions highly conserved evolutionarily. These variants are not detected in the gnomAD control cohort, and the amino acid substitutions are predicted to be damaging. Two of these variants are located in the HMG domain and abolish SOX6 transcriptional activity in vitro. No clear genotype-phenotype correlations are found. Taken together, these findings concur that SOX6 haploinsufficiency leads to a neurodevelopmental SOXopathy that often includes ADHD and abnormal skeletal and other features.

Benign Brain and Spinal Tumors Originating from Bone or Cartilage.

Benign osseocartilaginous tumors of the spine are overall uncommon, representing between 1 and 13% of all primary bone tumors and less than 10% of all spinal tumors. Tumors in this category include osteoblastic lesions such as the related osteoid osteoma and osteoblastoma, and cartilage-forming lesions including osteochondroma, chondroma, and chondroblastoma. Aneurysmal bone cysts, giant cell tumors of bone, and eosinophilic granulomas also comprise benign tumors of the spine arising from bone. There is significant heterogeneity in the epidemiology, molecular biology, imaging features, and optimal treatment of these lesions. For example, osteoid osteoma is characterized by high expression of the cyclooxygenase enzymes, making it amenable to treatment with anti-inflammatory drugs initially, whereas other lesions such as osteoblastoma may require intralesional curettage or en bloc resection sooner. Generally, en bloc resection is preferred when possible to minimize risk of recurrence. Further, some tumors may arise in the setting of syndromic conditions, such as multiple chondromas arising in Ollier disease or Maffucci syndrome, or as part of genetic disorders, such as osteochondromas in the context of hereditary multiple exostosis. These lesions may present with local pain, cause neurological compromise or be discovered incidentally on routine imaging. The Enneking classification and Weinstein-Boriani-Biagini system are routinely used to classify lesions and assist in surgical planning. More novel techniques such as radiofrequency ablation and laser photocoagulation have been applied for the treatment of osteoid osteoma and may have utility in the treatment of other lesion types. A multidisciplinary approach is critical in the management of benign lesions of the spine, and both chemotherapeutic and surgical approaches are routinely used.

Osteochondroma Pathogenesis: Mouse Models and Mechanistic Insights into Interactions with Retinoid Signaling.

Osteochondromas are cartilage-capped tumors that arise near growing physes and are the most common benign bone tumor in children. Osteochondromas can lead to skeletal deformity, pain, loss of motion, and neurovascular compression. Currently, surgery is the only available treatment for symptomatic osteochondromas. Osteochondroma mouse models have been developed to understand the pathology and the origin of osteochondromas and develop therapeutic drugs. Several cartilage regulatory pathways have been implicated in the development of osteochondromas, such as bone morphogenetic protein, hedgehog, and WNT/ß-catenin signaling. Retinoic acid receptor-γ is an important regulator of endochondral bone formation. Selective agonists for retinoic acid receptor-γ, such as palovarotene, have been investigated as drugs for inhibition of ectopic endochondral ossification, including osteochondromas. This review discusses the signaling pathways involved in osteochondroma pathogenesis and their possible interactions with the retinoid pathway.

Role of nuclear factor of activated T cells in chondrogenesis osteogenesis and osteochondroma formation.

PURPOSE: Nuclear factor of activated T cells (NFATc) are transcription factors that play a function in the immune response and in osteoclast differentiation. In the present work, we define the function of NFATc2 in chondrogenic and osteogenic cells. METHODS: Nfatc2loxP/loxP and Nfatc1loxP/loxP;Nfatc2loxP/loxP conditional mice were crossed with Prx1-Cre transgenics to inactivate Nfatc2 singly and with Nfatc1. Femurs and vertebrae were examined by microcomputed tomography (µCT) X-Ray images and histology and analyzed for the presence of osteochondromas. RESULTS: µCT demonstrated that Prx1-Cre;Nfatc2∆/∆ female mice had transient osteopenia and male mice did not have a cancellous or a cortical bone phenotype when compared to control mice. In contrast, the dual inactivation of Nfatc1 and Nfatc2 in Prx1-expressing cells resulted in cancellous osteopenia and small bones at 1 month of age in both sexes. Nfatc1;Nfatc2 deleted mice exhibited a ~ 50% decrease in bone volume and connectivity. Total bone area, periosteal and endocortical bone perimeters and femoral length were reduced indicating smaller bones. As the mice matured, the shortening of the femoral length persisted, but the osteopenic phenotype resolved and cancellous femoral bone of 4-month-old Nfatc1;Nfatc2 deleted mice was not different from controls although male mice had vertebral osteopenia. In addition, Nfatc1;Nfatc2 deleted mice displayed distortion of the distal metaphysis and, as they matured, the articular presence of mineralized tumors with the appearance of osteochondromas. CONCLUSION: Our studies reveal that NFATc1 and NFATc2 are necessary for optimal bone homeostasis and the suppression of osteochondroma formation.

Neuromonitoring for Proximal Fibular Osteochondroma Excision.

BACKGROUND: The peroneal nerve is at risk when excising tumors in the proximal fibula. The rate of nerve injuries during proximal fibular tumor resection varies from 3% to 20%. Our goal was to report our experience with resection of osteochondromas in the proximal fibula and describe the technique and utility of neuromonitoring during excision of proximal fibular osteochondromas (PFO). METHODS: Patients with a diagnosis of symptomatic PFO who had undergone excision at one institution from 1994 to 2018 were included. An institutional review board-approved retrospective review was performed. Intraoperative neuromonitoring was provided from 2006 on by a single group utilizing a multimodality protocol. RESULTS: This study contains 29 patients who had excision of osteochondromas in the proximal fibula. Of these 29 consecutively monitored patients, there were 34 involved extremities. Intraoperative neuromonitoring alerts occurred in 10/29 (34.5%) procedures, which included 3 electromyography (EMG) (30%), 2 motor-evoked potential (20%), 1 somatosensory-evoked potential (10%), and 4 alerts with a combination of EMG/motor-evoked potential/somatosensory-evoked potential changes (40%). The interventions that were taken resulted in resolution of the neuromonitoring changes in all procedures. Postoperatively, we noted 2 (6.9%) new mild sensory deficits, which resolved during follow up. There were 3 patients in whom pre-existing sensory-motor deficits improved but not completely after surgery, 1 motor weakness, and 2 with residual paresthesia. In those initially presenting with paresis, there was improvement in 8 of the 8 extremities by the last follow-up visit. Pain as a symptom was resolved in all cases. There were no iatrogenic foot drop injuries. The average follow up was 32.2 months. CONCLUSIONS: Neuromonitoring during PFO excision demonstrated a high number of alerts, all of which resolved following timely corrective action. The use of neuromonitoring may help decrease the risk of iatrogenic postoperative neurological deficits following fibular osteochondroma surgery. LEVEL OF EVIDENCE: Level IV.

The Impact of Isolated Versus Multiple Osteochondromas: Analysis of the CoULD Registry.

PURPOSE: The burden of upper extremity (UE) osteochondromas on function and self-perception among pediatric patients is unclear. The purpose of our study was to study the impact of osteochondromas in comparison to population norms and to evaluate solitary versus multiple osteochondromas on subjective UE function as measured by patient rated outcomes. METHODS: We utilized the CoULD (Congenital Upper Limb Differences) Registry to review all pediatric patients presenting with osteochondromas between January 2014 and February 2021. Demographic information was collected and patients were classified as having either single or multiple osteochondromas. Patient-Reported Outcome Measurement Information System (PROMIS) and Pediatric Outcomes Data Collection Instrument (PODCI) tools were utilized for assessment. Scores for PODCI subscales of UE function, Pain/comfort, and Happiness and PROMIS domains of UE Function, Pain, Depression, Anxiety, and Peer Relations were reviewed. Differences between groups were analyzed using the Student t test. RESULTS: Ninety-nine patients met inclusion criteria for the study with an average age of presentation of 9.3 years and 61 patients (62%) were male. Overall, patients demonstrated worse UE Function as well as greater Anxiety and Depression in comparison to the population normals on PROMIS assessment. Patients also demonstrated worse patient and parent reported PODCI UE, Sports and Physical Functioning, Pain/Comfort and Global Functioning scores compared with population norms but demonstrated better than average happiness scores. Patients with multiple osteochondromas demonstrated greater PROMIS pain interference and more disability in PODCI Sports and Physical Functioning, Pain/Comfort and Global Functioning compared with those with solitary osteochondromas. CONCLUSION: Patients with UE osteochondromas have worse overall function in comparison to population norms, exceeding established minimally clinically important difference values. In addition, patients with multiple osteochondromas reported more pain and poorer physical function than those with solitary osteochondromas. Physicians should be alert to the physical and psychosocial burden of this disease. LEVEL OF EVIDENCE: Level II-prognostic.

Surgical Guides and Prebent Titanium Improve the Planning for the Treatment of Dentofacial Deformities Secondary to Condylar Osteochondroma.

PURPOSE: To investigate current Computer-Aided Design and Computer-Aided Manufacturing (CAD/CAM) technologies applied in the treatment of dentofacial deformities secondary to condylar osteochondroma and introduce a modified method with additional pre-bent titanium miniplates to improve the accuracy of operation. METHODS: Literature review about the application of CAD/CAM in the treatment of condylar osteochondroma and secondary dentofacial deformities was conducted. And 8 patients with condylar osteochondroma and secondary dentofacial deformities were treated by the CAD/CAM cutting and drilling surgical guides as well as pre-bent titanium miniplates. Pre- and post-operative 3D-cephalometric measurement were recorded and the difference between virtual simulation and postoperative modeling images was measured. Follow-up and radiographic examinations were performed. RESULTS: A total of 17 studies (including 216 patients) about the application of CAD/CAM in the treatment of dentofacial deformities secondary to condylar osteochondroma have been reported since 2010, including the 8 present patients. In our study, all patients were satisfied with the surgical outcome, without obvious relapse or evidence of temporomandibular joint disorder or other complications during follow-up; all patients avoided condylar reconstruction and sagittal split of ramus osteotomy on the ipsilateral mandible side. Comparison between simulated plans and actual postoperative outcomes showed surgical simulation plan was accurately transferred to the actual surgery. CONCLUSIONS: The application of CAD/CAM cutting and drilling guides as well as pre-bent titanium plates could achieve more accurate and favorable outcomes, improving the clinical planning and surgical execution for patients with condylar osteochondroma and secondary dentofacial deformities.

Simultaneous Management of Condylar Osteochondroma and Secondary Malformation With a New Intraoral Approach.

PURPOSE: The present study aimed to investigate the clinical efficacy of simultaneous management of condylar osteochondroma and its secondary dentofacial deformities using an intraoral surgical approach. METHODS: Six patients with condylar osteochondroma were treated with intraoral vertical ramus osteotomies and condylar resection. The free rising branch was used for reconstructing the temporomandibular joint. The simultaneous orthognathic surgery and plastic surgery were performed sequentially to correct the secondary dentofacial deformities. The indexes of aesthetic symmetry, occlusion relationship, temporomandibular joint function, condylar height, and volume change were assessed in the subsequential follow up. RESULTS: The mean follow up period was 31 months. All patients had no tumor recurrence. The ipsilateral joint function, occlusal relationship, and facial symmetry were satisfied. The ipsilateral condylar reconstruction had no obvious bone resorption and the ramus height was maintained well. Postoperative assessment showed the preoperative design was accurately fulfilled. CONCLUSIONS: The simultaneous condylar osteochondroma resection and temporomandibular joint reconstruction using intraoral approach avoids extraoral scars and correct facial asymmetry without compromising the long-term joint function and occlusal relationship.

An Adolescent With Intermittent Claudication.

ABSTRACT: Intermittent claudication is very uncommon in children and adolescents. We describe the case of a 14-year-old adolescent girl experiencing left calf pain for a year that occurs during running and becomes unbearable after around 2 km. She was ultimately diagnosed with extrinsic compression of the popliteal artery caused by an osteocartilaginous exostosis (osteochondroma) originating from the fibula.

False aneurysm of the popliteal artery revealing a solitary osteochondroma of the distal femur in an 11-year-old boy.

An 11-year-old boy presented with pain in the right knee, intermittent reverse ischemia of the right foot and paraesthesia of the right toes. An angio-CT showed a false aneurysm of the right superior popliteal artery, and a solitary osteochondroma of the posterior aspect of the distal femur. Excision of the aneurysm and the osteochondroma was performed in two-stages. The patient was clinically well at 1-year follow up.

The Rizzoli Multiple Osteochondromas Classification revised: describing the phenotype to improve clinical practice.

Multiple osteochondromas (MO) is a rare disorder, characterized by benign osteocartilaginous tumors (osteochondromas), arising from the perichondrium of bones. The osteochondromas increase during growth, frequently causing deformities and limitations. Our study aims to analyze the data captured by the Registry of Multiple Osteochondromas, to refine Istituto Ortopedico Rizzoli (IOR) Classification, providing a representative picture of the phenotypic manifestations throughout the lifespan. We conducted a single-institution cross-sectional study. Patients were categorized according to IOR Classification, which identifies three patients' classes on the presence/absence of deformities and/or limitations. The present dataset was compared with our previously published data, to refine the classification. Nine hundred sixty-eight patients were included: 243 children (<10 years), 136 adolescents (10-15 years), and 589 adults. Of the entire population, half patients presented at least one deformity, and one quarter reported at least one limitation. Compared with our previous study, the amount of children was more than doubled and the percentage of mild/moderate cases was notably increased, giving a better disease overview throughout the lifespan and suggesting a different cut-off for dividing Class II in subclasses. We confirmed that MO is characterized by phenotypic heterogeneity, suggesting that an early classification of the disease may offer a useful tool to follow disease pattern and evolution, to support clinical practice, and to propose timely interventions.

Popliteal Artery Thrombosis in a Young Patient Secondary to Proximal Tibial Osteochondroma.

Popliteal artery occlusion is mainly seen in elderly patients with late stage atherosclerotic occlusive disease. In young, nonsmoking patients, popliteal artery occlusion can be caused by a variety of other etiologies. The diagnosis is suspected clinically and confirmed with ultrasound, computed tomography angiogram (CTA) or angiography, which can also aid in understanding the underlying cause. We present a 40-year-old very active male, who developed progressive symptoms of claudication over a 4 months interval and was found to have a thrombosed popliteal artery secondary to external compression from a tibial osteochondroma. The patient was treated with in-situ saphenous vein bypass from the above knee popliteal artery to the anterior tibial artery. The bypass was widely patent at 24 months.

Osteochondroma of the pubic symphysis causing hematuria: a case report and literature review.

BACKGROUND: Osteochondroma is the most common benign bone neoplasm and is sometimes referred to as osteocartilaginous exostosis. The symptoms caused by osteochondroma are rare, especially the urogenital complications. Therefore, this tumour is sometimes misdiagnosed. CASE PRESENTATION: This report described a 70-year-old woman with hematuria who was initially misdiagnosed with a bladder tumour in the outpatient department by a urologist. However, during cystoscopy, we found that the mass did not resemble a bladder tumor. Multidisciplinary approach with careful analysis of the imaging data suggested the diagnosis of osteochondroma. Open surgical excision of the mass was done and histology confirmed the diagnosis of benign osteochondroma. After 6 months of follow-up, the patient was still asymptomatic. CONCLUSIONS: This case illustrates that hematuria is caused by not only urogenital disease but also osteochondroma. We present this case to draw the attention of clinicians to osteochondroma of the pubic symphysis.

Rituximab as a treatment option in a patient with rheumatoid arthritis and a history of malignancy-intracranial chondrosarcoma/osteochondroma-case based review.

When compared to general population, patients with rheumatoid arthritis are at higher risk of some malignancies (especially lymphomas and lung cancer). Genetic predisposition, chronic inflammatory stimuli and viral infections are some of the reasons untreated patients are at higher risk. Clinical studies and national/international registries collect the data about the malignancies with higher incidence (such as lung, skin and breast cancer) but on the other hand, malignancies with lower incidence (such as sarcomas) are rarely reported. We report a case of a 47-year-old male with a history of a malignant intracranial chondrosarcoma/osteochondroma who developed seropositive rheumatoid arthritis. Due to progression of erosions, the patient was initialy treated with conventional synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs) and later on with rituximab. The patient's rheumatoid arthritis went and remained in remission on maintenance therapy with rituximab (every 6-8 months) and low-dose methotrexate with no relapse of malignant intracranial chondrosarcoma/osteochondroma. Rituximab should be considered as a treatment option in patients with rare and agressive malignancies, such as sarcomas.

Bizarre Parosteal Osteochondromatous Proliferation (Nora's Lesion) of Mandible With Recurrence: Case Report and Review of Literature.

Bizarre parosteal osteochondromatous proliferation (BPOP) is a rare benign lesion exhibiting radiographic and histologic features that can be mistaken for malignancy. Most cases have been reported in the small tubular bones of the hands and feet, but involvement of the skull and jaws is extremely rare. Here, we present a case of BPOP involving the mandible in a 23-year-old male that, after initial excision, recurred within 18 months. To the best of our knowledge, this is only the third published case of BPOP arising in the mandible.

An unusual example of hereditary multiple exostoses: a case report and review of the literature.

BACKGROUND: Hereditary multiple exostoses (HME) is a rare skeletal disorder characterised by a widespread. distribution of osteochondromas originating from the metaphyses of long bones. CASE PRESENTATION: This case study examines a 55-year-old male cadaver bequeathed to the University of Liverpool who suffered from HME, thus providing an exceptionally rare opportunity to examine the anatomical changes associated with this condition. CONCLUSIONS: Findings from imaging and dissection indicated that this was a severe case of HME in terms of the quantity and distribution of the osteochondromas and the number of synostoses present. In addition, the existence of enchondromas and the appearance of gaps within the trabeculae of affected bones make this a remarkable case. This study provides a comprehensive overview of the morbidity of the disease as well as adding to the growing evidence that diseases concerning benign cartilaginous tumours may be part of a spectrum rather than distinct entities.