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Current Osteoporosis Reports Jun 2017Hereditary multiple exostoses (HME) is a complex musculoskeletal pediatric disorder characterized by osteochondromas that form next to the growth plates of many skeletal... (Review)
Review
PURPOSE OF REVIEW
Hereditary multiple exostoses (HME) is a complex musculoskeletal pediatric disorder characterized by osteochondromas that form next to the growth plates of many skeletal elements, including long bones, ribs, and vertebrae. Due to its intricacies and unresolved issues, HME continues to pose major challenges to both clinicians and biomedical researchers. The purpose of this review is to describe and analyze recent advances in this field and point to possible targets and strategies for future biologically based therapeutic intervention.
RECENT FINDINGS
Most HME cases are linked to loss-of-function mutations in EXT1 or EXT2 that encode glycosyltransferases responsible for heparan sulfate (HS) synthesis, leading to HS deficiency. Recent genomic inquiries have extended those findings but have yet to provide a definitive genotype-phenotype correlation. Clinical studies emphasize that in addition to the well-known skeletal problems caused by osteochondromas, HME patients can experience, and suffer from, other symptoms and health complications such as chronic pain and nerve impingement. Laboratory work has produced novel insights into alterations in cellular and molecular mechanisms instigated by HS deficiency and subtending onset and growth of osteochondroma and how such changes could be targeted toward therapeutic ends. HME is a rare and orphan disease and, as such, is being studied only by a handful of clinical and basic investigators. Despite this limitation, significant advances have been made in the last few years, and the future bodes well for deciphering more thoroughly its pathogenesis and, in turn, identifying the most effective treatment for osteochondroma prevention.
Topics: Chronic Pain; Exostoses, Multiple Hereditary; Humans; Mutation; N-Acetylglucosaminyltransferases; Nerve Compression Syndromes
PubMed: 28466453
DOI: 10.1007/s11914-017-0355-2 -
Matrix Biology : Journal of the... Oct 2018Heparan sulfate (HS) is an essential component of cell surface and matrix proteoglycans (HS-PGs) that include syndecans and perlecan. Because of their unique structural... (Review)
Review
Heparan sulfate (HS) is an essential component of cell surface and matrix proteoglycans (HS-PGs) that include syndecans and perlecan. Because of their unique structural features, the HS chains are able to specifically interact with signaling proteins -including bone morphogenetic proteins (BMPs)- via their HS-binding domain, regulating protein availability, distribution and action on target cells. Hereditary Multiple Exostoses (HME) is a rare pediatric disorder linked to germline heterozygous loss-of-function mutations in EXT1 or EXT2 that encode Golgi-resident glycosyltransferases responsible for HS synthesis, resulting in a systemic HS deficiency. HME is characterized by cartilaginous/bony tumors -called osteochondromas or exostoses- that form within perichondrium in long bones, ribs and other elements. This review examines most recent studies in HME, framing them in the context of classic studies. New findings show that the spectrum of EXT mutations is larger than previously realized and the clinical complications of HME extend beyond the skeleton. Osteochondroma development requires a somatic "second hit" that would complement the germline EXT mutation to further decrease HS production and/levels at perichondrial sites of osteochondroma induction. Cellular studies have shown that the steep decreases in local HS levels: derange the normal homeostatic signaling pathways keeping perichondrium mesenchymal; cause excessive BMP signaling; and provoke ectopic chondrogenesis and osteochondroma formation. Data from HME mouse models have revealed that systemic treatment with a BMP signaling antagonist markedly reduces osteochondroma formation. In sum, recent studies have provided major new insights into the molecular and cellular pathogenesis of HME and the roles played by HS deficiency. These new insights have led to the first ever proof-of-principle demonstration that osteochondroma formation is a druggable process, paving the way toward the creation of a clinically-relevant treatment.
Topics: Animals; Bone Morphogenetic Proteins; Disease Models, Animal; Exostoses, Multiple Hereditary; Heparitin Sulfate; Humans; Mice; Mutation; N-Acetylglucosaminyltransferases; Signal Transduction
PubMed: 29277722
DOI: 10.1016/j.matbio.2017.12.011 -
Reumatologia Clinica Feb 2021
PubMed: 33582024
DOI: 10.1016/j.reuma.2020.12.003 -
Reumatologia Clinica Dec 2021
Topics: Chondromatosis, Synovial; Humans; Knee; Knee Joint; Lower Extremity
PubMed: 34823830
DOI: 10.1016/j.reumae.2020.12.003 -
Arthroscopy Techniques Feb 2022Surgical treatment has been recommended as the first choice of therapy in second and third stages of the disease. Complete synovectomy and removal of all loose bodies is...
Surgical treatment has been recommended as the first choice of therapy in second and third stages of the disease. Complete synovectomy and removal of all loose bodies is advisable for prevention of recurrence of the disease. Recently, arthroscopic treatment of synovial chondromatosis is gaining popularity because of its favorable outcomes and very low complication and recurrence rates. Arthroscopic approach also allows management of concomitant pathology. The purpose of this Technical Note is to describe the technique of arthroscopic synovectomy and removal of loose bodies as treatment of synovial chondromatosis localized in the anterior compartment of the ankle joint.
PubMed: 35155111
DOI: 10.1016/j.eats.2021.10.002 -
Cureus Nov 2023Synovial osteochondromatosis or synovial chondromatosis is a benign joint pathology characterized by the development of multiple cartilaginous nodules or loose bodies in...
Synovial osteochondromatosis or synovial chondromatosis is a benign joint pathology characterized by the development of multiple cartilaginous nodules or loose bodies in the synovial membrane that typically arise in the larger joints of the body. It usually presents as joint pain and, as seen in the present case, can occasionally be missed. Diagnosis involves a combination of clinical evaluation, imaging studies, and histopathological evaluation (which is confirmatory). Treatment depends on the severity of the disease, symptoms, and the patient's social situation, and may include monitoring for asymptomatic cases, non-surgical management (pain medications and physical therapy), or surgical intervention. Surgical intervention may include arthroscopic removal of loose bodies, synovectomy, or reconstruction/replacement in severe situations. Prognosis has a direct relationship to how early the disease is diagnosed. Early intervention with appropriate management can help alleviate symptoms; however, if left unmanaged, it can lead to joint damage and osteoarthritis or very rarely, malignant transformation into chondrosarcoma. This report describes the case of a 62-year-old female with complaints of bilateral knee pain who was originally diagnosed with osteoarthritis based on clinical exam and X-rays. Two magnetic resonance imaging (MRI) scans were done three years apart, with synovial osteochondromatosis being on the differential after the second scan. A left knee major synovectomy was conducted after the second MRI reading, where rubbery masses of tissue along with loose fragments were removed. Fluid from the tissue masses was sent to culture and pathology for interpretation. Two weeks post the surgery, the patient's pain improved tremendously, with adequate ambulation independently. Histopathology came back positive for synovial osteochondromatosis. This case report highlights the importance of keeping this joint pathology on the differential when treating patients with joint pain and interpreting imaging.
PubMed: 38073924
DOI: 10.7759/cureus.48498 -
Bone Apr 2018The majority of skeletal elements develop via endochondral ossification. This process starts with formation of mesenchymal cell condensations at prescribed sites and... (Review)
Review
The majority of skeletal elements develop via endochondral ossification. This process starts with formation of mesenchymal cell condensations at prescribed sites and times in the early embryo and is followed by chondrogenesis, growth plate cartilage maturation and hypertrophy, and replacement of cartilage with bone and marrow. This complex stepwise process is reactivated and recapitulated in physiologic conditions such as fracture repair, but can occur extraskeletally in pathologies including heterotopic ossification (HO), Ossification of the Posterior Longitudinal Ligament (OPLL) and Hereditary Multiple Exostoses (HME). One form of HO is common and is triggered by trauma, invasive surgeries or burns and is thus particularly common amongst severely wounded soldiers. There is also a congenital and very severe form of HO that occurs in children with Fibrodysplasia Ossificans Progressiva (FOP) and is driven by activating mutations in ACVR1 encoding the type I bone morphogenetic protein (BMP) receptor ALK2. Current treatments for acquired HO, including NSAIDs and local irradiation, are not always effective and can have side effects, and there is no effective treatment for HO in FOP. This review article describes the research path we took several years ago to develop a new and effective treatment for both congenital and acquired forms of HO and specifically, the testing of synthetic retinoid agonists to block the initial and critical chondrogenic step leading to HO onset and progression. We summarize studies with mouse models of injury-induced and congenital HO demonstrating the effectiveness and mode of action of the retinoid agonists, including Palovarotene. Our studies have provided the rationale for, directly led to, an ongoing phase 2 FDA clinical trial to test efficacy and safety of Palovarotene in FOP. Top-line results released a few months ago by the pharmaceutical sponsor Clementia are very encouraging. Given shared developmental pathways amongst pathologies of extraskeletal tissue formation, Palovarotene may also be effective in HME as preliminary in vitro data suggest.
Topics: Animals; Chondrogenesis; Humans; Myositis Ossificans; Ossification, Heterotopic; Osteogenesis; Retinoids; Signal Transduction
PubMed: 28826842
DOI: 10.1016/j.bone.2017.08.010 -
Spinal Cord Series and Cases May 2020Osteochondromas are benign bone tumors which occur as solitary lesions or as part of the syndrome multiple hereditary exostoses. While most osteochondromas occur in the...
INTRODUCTION
Osteochondromas are benign bone tumors which occur as solitary lesions or as part of the syndrome multiple hereditary exostoses. While most osteochondromas occur in the appendicular skeleton, they can also occur in the spine. Most lesions are asymptomatic however some may encroach on the spinal cord or the nerve roots causing neurological symptoms. While most patients with osteochondromas undergo laminectomy without fusion, laminectomy with fusion is indicated in appropriately selected cases of spinal decompression.
CASE PRESENTATION
We present a case of a 32-year-old male with history of multiple hereditary exostoses who presented with symptoms of bilateral upper extremity numbness and complaints of gait imbalance and multiple falls. He reported rapid progression of his symptoms during the 10 days before presentation. Computed tomography of the cervical spine revealed a lobulated bony tumor along the inner margin of the cervical 4 lamina. He underwent cervical 3 and 4 laminectomies, partial cervical 2 and 5 laminectomies and cervical 3-5 mass screw placement. Pathology was consistent with osteochondroma. The patient's symptoms had markedly improved at follow-up.
CONCLUSION
According to our literature review, osteochondromas most commonly occur at cervical 2 and cervical 5. We present a case of an osteochondroma at a less common level, cervical 4. While most osteochondromas are addressed with laminectomy without arthrodesis, the decision of whether arthrodesis is necessary should be considered in all patients with osteochondroma as with any cervical decompression.
Topics: Adult; Arthrodesis; Cervical Vertebrae; Clinical Decision-Making; Humans; Male; Osteochondroma; Spinal Neoplasms
PubMed: 32467563
DOI: 10.1038/s41394-020-0292-7 -
Clinical Rheumatology Aug 2022Synovial osteochondromatosis is an extremely rare benign condition in children and adolescents that have joint pain as a presenting manifestation. It is usually... (Review)
Review
Synovial osteochondromatosis is an extremely rare benign condition in children and adolescents that have joint pain as a presenting manifestation. It is usually monoarticular with the knee as the most common affected joint. In this article, we describe the case of a female adolescent suffering from debilitating chronic right knee pain initially mimicking juvenile idiopathic arthritis, who was subsequently diagnosed with primary synovial osteochondromatosis. We present a review of synovial osteochondromatosis focusing on the clinical manifestations, radiographic features, histopathologic findings, and treatment, with a summarized review of pediatric patients with initial musculoskeletal presentations who were ultimately diagnosed as synovial osteochondromatosis. Although synovial osteochondromatosis is rare in children and adolescents, this condition should be included in the differential diagnosis of joint pain and may mimic juvenile idiopathic arthritis. Appropriate diagnostic radiography, including both plain radiography and magnetic resonance imaging, is necessary to accurately diagnose this condition. We also emphasize the importance of a multidisciplinary team approach to managing patients with synovial osteochondromatosis.
Topics: Adolescent; Arthralgia; Arthritis, Juvenile; Child; Chondromatosis, Synovial; Diagnosis, Differential; Female; Humans; Magnetic Resonance Imaging; Radiography
PubMed: 35641775
DOI: 10.1007/s10067-022-06224-w -
Connective Tissue Research 2015Heparan sulfate (HS) is a component of cell surface and matrix-associated proteoglycans (HSPGs) that, collectively, play crucial roles in many physiologic processes... (Review)
Review
Heparan sulfate (HS) is a component of cell surface and matrix-associated proteoglycans (HSPGs) that, collectively, play crucial roles in many physiologic processes including cell differentiation, organ morphogenesis and cancer. A key function of HS is to bind and interact with signaling proteins, growth factors, plasma proteins, immune-modulators and other factors. In doing so, the HS chains and HSPGs are able to regulate protein distribution, bio-availability and action on target cells and can also serve as cell surface co-receptors, facilitating ligand-receptor interactions. These proteins contain an HS/heparin-binding domain (HBD) that mediates their association and contacts with HS. HBDs are highly diverse in sequence and predicted structure, contain clusters of basic amino acids (Lys and Arg) and possess an overall net positive charge, most often within a consensus Cardin-Weintraub (CW) motif. Interestingly, other domains and residues are now known to influence protein-HS interactions, as well as interactions with other glycosaminoglycans, such as chondroitin sulfate. In this review, we provide a description and analysis of HBDs in proteins including amphiregulin, fibroblast growth factor family members, heparanase, sclerostin and hedgehog protein family members. We discuss HBD structural and functional features and important roles carried out by other protein domains, and also provide novel conformational insights into the diversity of CW motifs present in Sonic, Indian and Desert hedgehogs. Finally, we review progress in understanding the pathogenesis of a rare pediatric skeletal disorder, Hereditary Multiple Exostoses (HME), characterized by HS deficiency and cartilage tumor formation. Advances in understanding protein-HS interactions will have broad implications for basic biology and translational medicine as well as for the development of HS-based therapeutics.
Topics: Amino Acid Motifs; Animals; Exostoses, Multiple Hereditary; Heparitin Sulfate; Humans; Intercellular Signaling Peptides and Proteins; Protein Structure, Tertiary; Signal Transduction; Translational Research, Biomedical
PubMed: 26076122
DOI: 10.3109/03008207.2015.1045066