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Frontiers in Genetics 2021Hereditary multiple exostoses (HMEs) syndrome, also known as multiple osteochondromas, represents a rare and severe human skeletal disorder. The disease is characterized... (Review)
Review
Hereditary multiple exostoses (HMEs) syndrome, also known as multiple osteochondromas, represents a rare and severe human skeletal disorder. The disease is characterized by multiple benign cartilage-capped bony outgrowths, termed exostoses or osteochondromas, that locate most commonly in the juxta-epiphyseal portions of long bones. Affected individuals usually complain of persistent pain caused by the pressure on neighboring tissues, disturbance of blood circulation, or rarely by spinal cord compression. However, the most severe complication of this condition is malignant transformation into chondrosarcoma, occurring in up to 3.9% of HMEs patients. The disease results mainly from heterozygous loss-of-function alterations in the or genes, encoding Golgi-associated glycosyltransferases, responsible for heparan sulfate biosynthesis. Some of the patients with HMEs do not carry pathogenic variants in those genes, hence the presence of somatic mutations, deep intronic variants, or another genes/loci is suggested. This review presents the systematic analysis of current cellular and molecular concepts of HMEs along with clinical characteristics, clinical and molecular diagnostic methods, differential diagnosis, and potential treatment options.
PubMed: 34956317
DOI: 10.3389/fgene.2021.759129 -
Orthopedic Research and Reviews 2019Hereditary multiple exostoses (HME), also called hereditary multiple osteochondromas, is a rare genetic disorder characterized by multiple osteochondromas that grow near... (Review)
Review
Hereditary multiple exostoses (HME), also called hereditary multiple osteochondromas, is a rare genetic disorder characterized by multiple osteochondromas that grow near the growth plates of bones such as the ribs, pelvis, vertebrae and especially long bones. The disease presents with various clinical manifestations including chronic pain syndromes, restricted range of motion, limb deformity, short stature, scoliosis and neurovascular alteration. Malignant transformation of exostosis is rarely seen. The disease has no medical treatment and surgery is only recommended in symptomatic exostoses or in cases where a malignant transformation is suspected. HME is mainly caused by mutations and functional loss of the EXT1 and EXT2 genes which encode glycosyltransferases, an enzyme family involved in heparan sulfate (HS) synthesis. However, the peculiar molecular mechanism that leads to the structural changes of the cartilage and to osteochondroma formation is still being studied. Basic science studies have recently shown new insights about altering the molecular and cellular mechanism caused by HS deficiency. Pediatricians, geneticists and orthopedic surgeons play an important role in the study and treatment of this severe pathology. Despite the recent significant advances, we still need novel insights to better specify the role of HS in signal transduction. The purpose of this review was to analyze the most relevant aspects of HME from the literature review, give readers an important tool to understand its clinical features and metabolic-pathogenetic mechanism, and to identify an effective treatment method. We focused on the aspects of the disease related to clinical management and surgical treatment in order to give up-to-date information that could be useful for following best clinical practice.
PubMed: 31853203
DOI: 10.2147/ORR.S183979 -
Clinical Cases in Mineral and Bone... 2016Hereditary multiple exostoses (HME) is an inherited genetic condition characterized by the presence of multiple exostoses (osteochondromas). MHE is a relatively rare... (Review)
Review
Hereditary multiple exostoses (HME) is an inherited genetic condition characterized by the presence of multiple exostoses (osteochondromas). MHE is a relatively rare autosomal dominant disorder, mainly caused by loss of function mutations in two genes: exostosin-1 (EXT1) and exostosin-2 (EXT2). These genes are linked to heparan sulfate (HS) synthesis, but the specific molecular mechanism leading to the disruption of the cartilage structure and the consequent exostoses formation is still not resolved. The aim of this paper is to encounter the main aspects of HME reviewing the literature, in order to improve clinical features and evolution, and the metabolic-pathogenetic mechanisms underlying. Although MHE may be asymptomatic, a wide spectrum of clinical manifestations is found in paediatric patients with this disorder. Pain is experienced by the majority of patients, even restricted motion of the joint is often encountered. Sometimes exostoses can interfere with normal development of the growth plate, giving rise to limb deformities, low stature and scoliosis. Other many neurovascular and associated disorders can lead to surgery. The most feared complication is the malignant transformation of an existing osteochondroma into a secondary peripheral chondrosarcoma, during adulthood. The therapeutic approach to HME is substantially surgical, whereas the medical one is still at an experimental level. In conclusion, HME is a complex disease where the paediatrician, the geneticist and the orthopaedic surgeon play an interchangeable role in diagnosis, research and therapy. We are waiting for new studies able to explain better the role of HS in signal transduction, because it plays a role in other bone and cartilage diseases (in particular malignant degeneration) as well as in skeletal embryology.
PubMed: 27920806
DOI: 10.11138/ccmbm/2016.13.2.110 -
SAGE Open Medical Case Reports 2022Osteochondroma is the most common bone tumor representing 20%-50% of all benign bone tumors and 10%-15% of all bone tumors. Osteochondroma has similar radiological...
Osteochondroma is the most common bone tumor representing 20%-50% of all benign bone tumors and 10%-15% of all bone tumors. Osteochondroma has similar radiological appearance in both solitary and multiple forms; the latter is an autosomal dominant disorder termed hereditary multiple exostoses. Associated complications of osteochondroma include deformity, fracture, neurovascular compromise, bursa formation, and malignant transformation. Measurement of the cartilage cap thickness is an important index suggesting secondary malignancy of osteochondroma. The upper limit of cap thickness after skeletal maturation is 1.5 cm which can be reliably measured on ultrasound or magnetic resonance imaging. Hereditary multiple exostoses are linked to the mutations of different exostoses genes located on chromosome 8, 11, and 19. We reported cases of two siblings presented with multiple osteochondromas managed by surgical excision. We evaluated their clinical and radiological presentation, genetic correlations and compared with the literature.
PubMed: 35693925
DOI: 10.1177/2050313X221103732 -
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 -
Danish Medical Journal Sep 2014Hereditary multiple cartilaginous exostoses is a syndrome characterised by the development of multiple osteochondromas. The diagnosis is typically made around the age of... (Review)
Review
INTRODUCTION
Hereditary multiple cartilaginous exostoses is a syndrome characterised by the development of multiple osteochondromas. The diagnosis is typically made around the age of 12 years, and the prevalence is estimated at 1:50,000. During skeletal growth, the osteochondromas are benign, but in adult life malignant transformation into chondrosarcomas can occur.
METHODS
This study was a literature survey based on a systematic search of the PubMed database for articles with the term "hereditary multiple exostoses chondrosarcoma". The search returned 157 articles, of which 13 had a sufficient level of evidence. These publications were examined thoroughly, focusing on the development of sarcomas, symptoms and the risk of malignant degeneration.
RESULTS
There is no consensus regarding the frequency of malignant transformation of multiple cartilaginous exostoses into sarcomas, which varies from less than 1% to 25%. The most reliable estimation seems to be 1-2%. The survey of the literature shows that no risk groups can be identified. However, exostoses in the axial skeleton are more prone to develop into chondrosarcomas than peripheral exostoses.
CONCLUSION
It is indisputable that malignant transformation occurs, and we therefore propose that a follow-up programme be launched with clinical examination by magnetic resonance imaging or bone scintigraphy every second year. The purpose of such programme would be to discover the sarcomatous development as early as possible to improve the survival prognosis of the patients. This screening programme should be centralised at tumour departments.
Topics: Bone Neoplasms; Cell Transformation, Neoplastic; Chondrosarcoma; Early Detection of Cancer; Exostoses, Multiple Hereditary; Humans; Precancerous Conditions
PubMed: 25186537
DOI: No ID Found -
Cureus Jul 2021Hereditary multiple exostoses (HME) are an autosomal dominant skeletal disorder characterized by the development of multiple benign osteochondromas (exostoses) that... (Review)
Review
Hereditary multiple exostoses (HME) are an autosomal dominant skeletal disorder characterized by the development of multiple benign osteochondromas (exostoses) that frequently involve long bones of the body. Less commonly, the ribs are a site of involvement, and long-term friction between an exostosis and pleura can produce a hemothorax or pneumothorax. The purpose of this study is to provide a comprehensive review of existing literature on pneumothorax or hemothorax secondary to costal exostosis in HME patients. We reviewed the databases of PubMed and Embase and included data as current as of February 15, 2021. All case reports included cases of hemothorax or pneumothorax in patients with a known personal or family history of HME. After evaluation for inclusion based on eligibility criteria, 18 cases were included. The average age at presentation was 11.7 years (range: 3-32), and most patients were male (83%). Hemothoraces occurred in 15 cases, while pneumothoraces occurred in three cases. All cases were evaluated using chest X-ray and CT scan, and the majority of the cases were treated with surgical resection of the exostosis, either with video-assisted thoracoscopic surgery (VATS; 61%) or thoracotomy (22%). Outcomes were successful with no cases of recurrence after surgical intervention. Although rare, costal exostosis should be considered as a differential in patients presenting with pneumothorax or hemothorax and past medical history or physical exam findings suggestive of HME. Immediate evaluation and surgical intervention to resect costal exostosis are essential to reduce the risk of recurrent life-threatening injury.
PubMed: 34395113
DOI: 10.7759/cureus.16326 -
Diagnostic and Interventional Imaging Jan 2017Exostoses are the most common benign bone tumors, accounting for 10 to 15% of all bone tumors. They develop at the bone surface by enchondral ossification and stop... (Review)
Review
Exostoses are the most common benign bone tumors, accounting for 10 to 15% of all bone tumors. They develop at the bone surface by enchondral ossification and stop growing when skeletal maturity has been reached. At first, exostoses are covered by a smooth cartilage cap that progressively ossifies with skeleton maturity. Then they may regress, partly or even completely. Osteochondromas may be solitary or multiple, with the latter associated with hereditary multiple exostoses (HME). Exostoses develop during childhood and become symptomatic during the third decade of life in the case of solitary exostoses, or earlier, in case of HME. They stop growing after puberty, when the epiphyseal plates close. Most exostoses remain asymptomatic. Local complications, usually benign, may occur, such as fractures or mechanical impingements upon nearby structures. In rare cases, sarcomatous degeneration occurs. Most of these complications have been described in case reports. This article describes the imaging features of benign complications of exostoses of the shoulder, pelvic girdles and appendicular.
Topics: Aneurysm, False; Bone Neoplasms; Bone and Bones; Bursa, Synovial; Exostoses; Fractures, Bone; Humans; Nerve Compression Syndromes; Osteochondroma; Shoulder Impingement Syndrome; Vascular Diseases
PubMed: 27316575
DOI: 10.1016/j.diii.2015.11.021 -
Orphanet Journal of Rare Diseases Feb 2008Multiple osteochondromas (MO) is characterised by development of two or more cartilage capped bony outgrowths (osteochondromas) of the long bones. The prevalence is... (Review)
Review
Multiple osteochondromas (MO) is characterised by development of two or more cartilage capped bony outgrowths (osteochondromas) of the long bones. The prevalence is estimated at 1:50,000, and it seems to be higher in males (male-to-female ratio 1.5:1). Osteochondromas develop and increase in size in the first decade of life, ceasing to grow when the growth plates close at puberty. They are pedunculated or sessile (broad base) and can vary widely in size. The number of osteochondromas may vary significantly within and between families, the mean number of locations is 15-18. The majority are asymptomatic and located in bones that develop from cartilage, especially the long bones of the extremities, predominantly around the knee. The facial bones are not affected. Osteochondromas may cause pain, functional problems and deformities, especially of the forearm, that may be reason for surgical removal. The most important complication is malignant transformation of osteochondroma towards secondary peripheral chondrosarcoma, which is estimated to occur in 0.5-5%. MO is an autosomal dominant disorder and is genetically heterogeneous. In almost 90% of MO patients germline mutations in the tumour suppressor genes EXT1 or EXT2 are found. The EXT genes encode glycosyltransferases, catalyzing heparan sulphate polymerization. The diagnosis is based on radiological and clinical documentation, supplemented with, if available, histological evaluation of osteochondromas. If the exact mutation is known antenatal diagnosis is technically possible. MO should be distinguished from metachondromatosis, dysplasia epiphysealis hemimelica and Ollier disease. Osteochondromas are benign lesions and do not affect life expectancy. Management includes removal of osteochondromas when they give complaints. Removed osteochondromas should be examined for malignant transformation towards secondary peripheral chondrosarcoma. Patients should be well instructed and regular follow-up for early detection of malignancy seems justified. For secondary peripheral chondrosarcoma, en-bloc resection of the lesion and its pseudocapsule with tumour-free margins, preferably in a bone tumour referral centre, should be performed.
Topics: Adult; Animals; Bone Neoplasms; Cell Transformation, Neoplastic; Child; Chondrosarcoma; Diagnosis, Differential; Exostoses, Multiple Hereditary; Female; Genetic Counseling; Humans; Male; Mutation; N-Acetylglucosaminyltransferases; Prognosis; Sex Factors
PubMed: 18271966
DOI: 10.1186/1750-1172-3-3