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Orthopaedics & Traumatology, Surgery &... Oct 2022Spinal osteochondroma (or exostosis) is a rare benign tumour whose clinical manifestations are delayed due to their slow growth and location. Few studies have addressed... (Observational Study)
Observational Study
BACKGROUND
Spinal osteochondroma (or exostosis) is a rare benign tumour whose clinical manifestations are delayed due to their slow growth and location. Few studies have addressed the characteristics and the diagnostic and therapeutic peculiarities of spinal osteochondroma in children. The objective of this multicentre observational study was to assess the outcomes of a cohort of children after surgery for spinal osteochondroma.
HYPOTHESIS
Surgical excision of spinal osteochondroma in children is not followed by complications or recurrences.
MATERIAL AND METHODS
We included consecutive children who had surgery between 2010 and 2018 at any of eight participating centres to remove spinal osteochondromas. The cause, clinical manifestations, and location of the lesions were collected. The surgical outcomes were evaluated after at least 2 years' follow-up.
RESULTS
We identified 22 patients who had surgery to remove 26 spinal osteochondromas at a mean age of 12.8±2.6 years. Among them, 7 had a solitary osteochondroma (SO group) and 15 had hereditary multiple osteochondromas (HMO group). At diagnosis, 72% of patients had clinical signs (spinal pain, n=4; one or more lumps, n=5; and neurological manifestations, n=3). In the HMO group, the diagnosis was made during routine MRI screening for tumours involving the spinal canal. Most osteochondromas involved the cervical spine (n=13), with no difference between the two groups (p=0.9). The lamina was the most common location but 54% of the tumours were growing within the canal (92% in the HMO group). After a mean follow-up of 5.2±4.4 years, no patients had experienced any recurrences or complications related to the disease or treatment.
DISCUSSION
Surgical excision of spinal osteochondromas in children is effective, with no medium-term recurrences. Our results also confirm the low peri-operative morbidity, even when the canal is involved, and the absence of any effect at last follow-up on spinal alignment. All patients with neurological manifestations at diagnosis made a full recovery.
LEVEL OF EVIDENCE
IV, retrospective observational cohort study.
Topics: Adolescent; Cervical Vertebrae; Child; Humans; Osteochondroma; Retrospective Studies; Spinal Neoplasms; Treatment Outcome
PubMed: 35150927
DOI: 10.1016/j.otsr.2022.103239 -
Orphanet Journal of Rare Diseases Mar 2014Stüve-Wiedemann syndrome (STWS; OMIM #610559) is a rare bent-bone dysplasia that includes radiologic bone anomalies, respiratory distress, feeding difficulties, and... (Review)
Review
Stüve-Wiedemann syndrome (STWS; OMIM #610559) is a rare bent-bone dysplasia that includes radiologic bone anomalies, respiratory distress, feeding difficulties, and hyperthermic episodes. STWS usually results in infant mortality, yet some STWS patients survive into and, in some cases, beyond adolescence. STWS is caused by a mutation in the leukemia inhibitory factor receptor (LIFR) gene, which is inherited in an autosomally recessive pattern. Most LIFR mutations resulting in STWS are null mutations which cause instability of the mRNA and prevent the formation of LIFR, impairing the signaling pathway. LIFR signaling usually follows the JAK/STAT3 pathway, and is initiated by several interleukin-6-type cytokines. STWS is managed on a symptomatic basis since there is no treatment currently available.
Topics: Cytokines; Exostoses, Multiple Hereditary; Humans; Infant, Newborn; Leukemia Inhibitory Factor Receptor alpha Subunit; Mutation; Osteochondrodysplasias; Signal Transduction
PubMed: 24618404
DOI: 10.1186/1750-1172-9-34 -
Journal of Bone Oncology Nov 2018The most serious complication of hereditary multiple exostoses(HME) is chondrosarcoma transformation. Numerous authors have suggested that screening might allow early...
BACKGROUND
The most serious complication of hereditary multiple exostoses(HME) is chondrosarcoma transformation. Numerous authors have suggested that screening might allow early chondrosarcoma detection. However, literature-quoted incidences of malignant transformation are highly variable.
METHODS
A systematic review of malignant transformation by sex, exostosin-1 mutation(EXT1), age and site was conducted searching Medline, Embase and CINHAL. Three HME screening strategies were then developed and compared using cost per life-year gained and incremental cost-effectiveness ratio (ICER).
RESULTS
18 papers with 852 chondrosarcomas were identified. The incidence of chondrosarcoma transformation averaged 4%, 75.2% occurring between ages 20-40 and 56.2% at the pelvis and proximal femur. Screening model: In the general HME population, plain radiographs provided cost per life-year gain of £19,013 compared to £53,392 in MRIs. ICER in MRIs compared to X-rays was £80,218. However, for every generation of HME patients screened over 20 years, X-ray radiation induced 0.65 cancers. Psychological effects of false-positives were marginal. Screening only higher-risk groups (males or EXT1) reduced cost but benefited fewer patients.
CONCLUSIONS
Our results suggest that annual MRI screening for all HME patients between age 20-40 may be of value. However, the extent of anatomical imaging is subject to debate; it is possible that focused imaging protocols which scan from cervical spine to proximal femur may improve cost-effectiveness.
PubMed: 30591865
DOI: 10.1016/j.jbo.2018.09.011 -
Medicine Jan 2017Hereditary multiple exostoses (HME) or osteochondromatosis is a rare autosomal dominant disease characterized by multiple osteochondromas and skeletal deformities.
INTRODUCTION
Hereditary multiple exostoses (HME) or osteochondromatosis is a rare autosomal dominant disease characterized by multiple osteochondromas and skeletal deformities.
PATIENT CONCERNS & DIAGNOSES
We present the case of a 5 years and 9 month-old patient who presented with inferior limb pain for approximately 6 months, associating also deformity of the right index finger for a month. Hand X-ray revealed a radiologic abnormality of the right radius, therefore the child was referred to our clinic for further investigations. The X-rays revealed multiple osteochondromas of the radius, metacarpal bones, hand phalangeal bones, femur, tibia, fibula, metatarsal bones, and foot phalangeal bones. We mention that the same radiological aspect was identified in the case of the patient's mother, undiagnosed until that moment.
OUTCOMES
The particularity of this case consists in identification of a rare genetic pathology, HME in a 5-year-old patient, without any known familial history, after the occurrence of a nontraumatic joint dislocation of the right index finger.
CONCLUSION
HME is a rare genetic condition, without a curative treatment, burdened by multiple complications, and whose diagnosis is usually established during childhood.
Topics: Adult; Aftercare; Bone and Bones; Child, Preschool; Exostoses, Multiple Hereditary; Humans; Monitoring, Physiologic; Radiography
PubMed: 28072741
DOI: 10.1097/MD.0000000000005824 -
International Orthopaedics Aug 2013Frequent benign outgrowths from bone known as osteochondromas, exhibiting typical endochondral ossification, are reported from single to multiple lesions. Characterised... (Review)
Review
Frequent benign outgrowths from bone known as osteochondromas, exhibiting typical endochondral ossification, are reported from single to multiple lesions. Characterised by a high incidence of osteochondromas and skeletal deformities, multiple hereditary exostoses (MHE) is the most common inherited musculoskeletal condition. While factors for severity remain unknown, mutations in exostosin 1 and exostosin 2 genes, encoding glycosyltransferases involved in the biosynthesis of ubiquitously expressed heparan sulphate (HS) chains, are associated with MHE. HS-binding bone morphogenetic proteins (BMPs) are multifunctional proteins involved in the morphogenesis of bone and cartilage. HS and HS proteoglycans are involved in BMP-mediated morphogenesis by regulating their gradient formation and activity. Mutations in exostosin genes disturb HS biosynthesis, subsequently affecting its functional role in the regulation of signalling pathways. As BMPs are the primordial morphogens for bone development, we propose the hypothesis that BMP signalling may be critical in osteochondromas. For this reason, the outcomes of exostosin mutations on HS biosynthesis and interactions within osteochondromas and MHE are reviewed. Since BMPs are HS binding proteins, the interactions of HS with the BMP signalling pathway are discussed. The impact of mouse models in the quest to better understand the cell biology of osteochondromas is discussed. Several challenges and questions still remain and further investigations are needed to explore new approaches for better understanding of the pathogenesis of osteochondromas.
Topics: Animals; Bone Morphogenetic Proteins; Bone Neoplasms; Disease Models, Animal; Heparitin Sulfate; Humans; Mice; Mutation; N-Acetylglucosaminyltransferases; Osteochondroma; Signal Transduction
PubMed: 23771188
DOI: 10.1007/s00264-013-1906-5 -
Journal of Applied Genetics May 2014Hereditary multiple exostoses (HME) also known as multiple osteochondromas represent one of the most frequent bone tumor disorder in humans. Its clinical presentation is...
Hereditary multiple exostoses (HME) also known as multiple osteochondromas represent one of the most frequent bone tumor disorder in humans. Its clinical presentation is characterized by the presence of multiple benign cartilage-capped tumors located most commonly in the juxta-epiphyseal portions of long bones. HME are usually inherited in autosomal dominant manner, however de novo mutations can also occur. In most patients, the disease is caused by alterations in the EXT1 and EXT2 genes. In this study we investigated 33 unrelated Polish probands with the clinical and radiological diagnosis of HME by means of Sanger sequencing and MLPA for all coding exons of EXT1 and EXT2. We demonstrated EXT1 and EXT2 heterozygous mutations in 18 (54.6 %) and ten (30.3 %) probands respectively, which represents a total of 28 (84.9 %) index cases. Sequencing allowed for the detection of causative changes in 26 (78.8 %) probands, whereas MLPA showed intragenic deletions in two (6.1 %) further cases (15 mutations represented novel changes). Our paper is the first report on the results of exhaustive mutational screening of both EXT1/EXT2 genes in Polish patients. The proportion of EXT1/EXT2 mutations in our group was similar to other Caucasian cohorts. However, we found that EXT1 lesions in Polish patients cluster in exons 1 and 2 (55.6 % of all EXT1 mutations). This important finding should lead to the optimization of cost-effectiveness rate of HME diagnostic testing. Therefore, the diagnostic algorithm for HME should include EXT1 sequencing (starting with exons 1-2), followed by EXT2 sequencing, and MLPA/qPCR for intragenic copy number changes.
Topics: DNA Mutational Analysis; Exostoses, Multiple Hereditary; Genetic Predisposition to Disease; Humans; Mutation, Missense; N-Acetylglucosaminyltransferases; Poland
PubMed: 24532482
DOI: 10.1007/s13353-014-0195-z -
Italian Journal of Pediatrics Jun 2020Hereditary multiple osteochondromas (HMO) is a genetic condition characterized by the presence of multiple osteochondromas, usually at the lateral side of the most...
BACKGROUND
Hereditary multiple osteochondromas (HMO) is a genetic condition characterized by the presence of multiple osteochondromas, usually at the lateral side of the most active growth plate of a long bone. These lesions may persist, be asymptomatic during childhood, and may increase in number and size until growth plates close. Therefore, diagnosis of HMO in children and young people can be challenging; while short stature can be more evident at the onset of puberty, asymptomatic ostheocondromas can progress into different degrees of orthopedic deformity. Moreover, multiple complications may arise due to the presence of osteochondromas, including tendon and compression muscle pain, neurovascular disorders, obstetric problems, scoliosis and malignant transformation into secondary peripheral chondrosarcoma in adulthood.
CASE PRESENTATION
We report the case of a girl admitted to our Institute for growth delay. While laboratory tests, including growth hormone stimulation test, were normal, left hand X-ray revealed multiple osteochondromas, suggestive for HMO. The genetic test for EXT1 and EXT2 genes confirmed the radiological diagnosis, with a mutation inherited from the mother who displayed the same radiological abnormalities along with recurrent limb pain episodes.
CONCLUSIONS
HMO is a genetic condition whose diagnosis can be challenging, especially in females. Every pediatricians should consider a skeletal dysplasia in case of unexplained growth delay and a skeletal survey might be fundamental in reaching a diagnosis.
Topics: Adolescent; Exostoses, Multiple Hereditary; Female; Genetic Testing; Humans; Radiography
PubMed: 32522262
DOI: 10.1186/s13052-020-00846-z -
American Journal of Human Genetics Jan 1997Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by the formation of cartilage-capped prominences that develop from the growth centers...
Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by the formation of cartilage-capped prominences that develop from the growth centers of the long bones. EXT is genetically heterogeneous, with three loci, currently identified on chromosomes 8q24.1, 11p13, and 19q. The EXT1 gene, located on chromosome 8q24.1, has been cloned and is encoded by a 3.4-kb cDNA. Five mutations in the EXT1 gene have been identified--four germ-line mutations, including two unrelated families with the same mutation, and one somatic mutation in a patient with chondrosarcoma. Four of the mutations identified resulted in frameshifts and premature termination codons, while the fifth mutation resulted in a substitution of leucine for arginine. Loss of heterozygosity (LOH) analysis of chondrosarcomas and chondroblastomas revealed multiple LOH events at loci on chromosomes 3q, 8q, 10q, and 19q. One sporadic chondrosarcoma demonstrated LOH for EXT1 and EXT3, while a second underwent LOH for EXT2 and chromosome 10. A third chondrosarcoma underwent LOH for EXT1 and chromosome 3q. These results agree with previous findings that mutations at EXT1 and multiple genetic events that include LOH at other loci may be required for the development of chondrosarcoma.
Topics: Bone Neoplasms; Chondroblastoma; Chondrosarcoma; Exostoses, Multiple Hereditary; Female; Gene Deletion; Genetic Markers; Heterozygote; Humans; Male; Mutation; Pedigree
PubMed: 8981950
DOI: No ID Found -
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 -
Journal of Clinical and Diagnostic... Aug 2013Multiple maxillary and mandibular exostoses are common localized overgrowths of the bone. They are non-neoplastic and are thought to be reactive or developmental in...
Multiple maxillary and mandibular exostoses are common localized overgrowths of the bone. They are non-neoplastic and are thought to be reactive or developmental in origin. These exostoses need to be accurately distinguished from the other more diagnostically significant lesions, notably from the exosteal osteomas. The aetiology of exostosis has been investigated by different authors, but no consensus has been reached so far. We are reporting a rare case of an otherwise healthy 38 year old female with multiple exostoses in the mandibular anterior region, which correlated both clinically and radiographically.
PubMed: 24086919
DOI: 10.7860/JCDR/2013/5612.3283