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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 -
Archivos Argentinos de Pediatria Jun 2022Hereditary osteochondromatosis is an uncommon, autosomal, dominant condition characterized by the presence of multiple bone growths.
INTRODUCTION
Hereditary osteochondromatosis is an uncommon, autosomal, dominant condition characterized by the presence of multiple bone growths.
OBJECTIVE
To analyze factors associated with health-related quality of life (HRQoL) among children > 2 years and adults receiving follow-up at a tertiary care children's hospital in Argentina.
POPULATION AND METHODS
Cross-sectional study of a follow-up cohort. HRQoL was measured using the Pediatric Quality of Life Inventory® (PedsQL) and the Short Form Health Survey (SF- 36). Sex, age, sociodemographic characteristics, height, radiology, axis alteration and limb function, presence of pain, and malignant change were recorded. Severity was classified as per Pedrini et al. Parametric and non-parametric tests and regression analysis were done.
RESULTS
A total of 66 cases (47 children and 19 adults) were included. Male/female ratio: 1.7/1. Median age: 13.4 years (r: 2.21-55.3). Pain was observed in 30/47 children and in 17/19 adults. Considering the adult bone age (or epiphyseal closure) as the cutoff point to define adult status, 11/37 children and 18/27 adults had a severe disease and 2/38 children and 9/27 adults had short stature. The average value of the physical component of HRQoL in children was 65.9 (SD: 22.5) and, in adults, 27.2 (IQR: 18.5- 34.7). The presence of pain and clinical severity were significantly associated with a lower HRQoL, both in children and adults.
CONCLUSIONS
This study found that pain and disease severity had a negative effect on HRQoL.
Topics: Adolescent; Adult; Child; Cross-Sectional Studies; Female; Humans; Male; Osteochondromatosis; Pain; Quality of Life; Severity of Illness Index; Surveys and Questionnaires
PubMed: 35533120
DOI: 10.5546/aap.2022.eng.180 -
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 -
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 -
Matrix Biology : Journal of the... Apr 2014Heparan sulfates are complex sulfated molecules found in abundance at cell surfaces and in the extracellular matrix. They bind to and influence the activity of a variety... (Review)
Review
Heparan sulfates are complex sulfated molecules found in abundance at cell surfaces and in the extracellular matrix. They bind to and influence the activity of a variety of molecules like growth factors, proteases and morphogens and are thus involved in various cell-cell and cell-matrix interactions. The mammalian EXT proteins have glycosyltransferase activities relevant for HS chain polymerization, however their exact role in this process is still confusing. In this review, we summarize current knowledge about the biochemical activities and some proposed functions of the members of the EXT protein family and their roles in human disease.
Topics: Amino Acid Sequence; Base Sequence; Exostoses, Multiple Hereditary; Extracellular Matrix; Glycosyltransferases; Heparitin Sulfate; Humans; Models, Molecular; Molecular Sequence Data; Multigene Family; N-Acetylglucosaminyltransferases; Phylogeny; Polymerization; Sequence Alignment; Sequence Analysis, DNA; Species Specificity
PubMed: 24128412
DOI: 10.1016/j.matbio.2013.10.001 -
Annals of Surgery Oct 1930
PubMed: 17866406
DOI: 10.1097/00000658-193010000-00019 -
Orphanet Journal of Rare Diseases Dec 2019Rare bone diseases account for 5% of all birth defects yet very few have personalised treatments. Developments in genetic diagnosis, molecular techniques and treatment... (Review)
Review
BACKGROUND
Rare bone diseases account for 5% of all birth defects yet very few have personalised treatments. Developments in genetic diagnosis, molecular techniques and treatment technologies however, are leading to unparalleled therapeutic advance. This review explores the evolving therapeutic landscape of genetic skeletal disorders (GSDs); the key conditions and there key differentials.
METHODS
A retrospective literature based review was conducted in December 2018 using a systematic search strategy for relevant articles and trials in Pubmed and clinicaltrials.gov respectively. Over 140 articles and 80 trials were generated for review.
RESULTS
Over 20 personalised therapies are discussed in addition to several novel disease modifying treatments in over 25 GSDs. Treatments discussed are at different stages from preclinical studies to clinical trials and approved drugs, including; Burosumab for X-linked hypophosphatemia, Palovarotene for Hereditary Multiple Exostoses, Carbamazepine for Metaphyseal Chondrodysplasia (Schmid type), Lithium carbonate and anti-sclerostin therapy for Osteoporosis Pseudoglioma syndrome and novel therapies for Osteopetrosis. We also discuss therapeutic advances in Achondroplasia, Osteogenesis Imperfecta (OI), Hypophosphotasia (HPP), Fibrodysplasia Ossificans Progressiva, and RNA silencing therapies in preclinical studies for OI and HPP.
DISCUSSION
It is an exciting time for GSD therapies despite the challenges of drug development in rare diseases. In discussing emerging therapies, we explore novel approaches to drug development from drug repurposing to in-utero stem cell transplants. We highlight the improved understanding of bone pathophysiology, genetic pathways and challenges of developing gene therapies for GSDs.
Topics: Animals; Bone Diseases; Female; Humans; Male; Myositis Ossificans; Osteogenesis Imperfecta; Osteopetrosis; Rare Diseases
PubMed: 31888683
DOI: 10.1186/s13023-019-1222-2 -
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