Hereditary Multiple Exostoses Syndrome Research Articles

Peroneal Nerve Palsy Resulting From Fibular Head Osteochondroma

This article describes a case of a 11-year-old boy with an osteochondroma of the peroneal head causing peroneal nerve palsy. Physical examination disclosed large exostoses palpated at the right fibular head. Neurological examination revealed paresis of the tibialis anterior, lateral peroneal, and extensor digitorum muscles with a muscle strength grade of 2. Electrophysiological studies confirmed denervation of the muscles supplied by the right peroneal nerve. Radiological examination showed an osteochondroma in the head of the right fibula. The patient underwent surgical decompression of the right peroneal nerve after resection of the bone tumor. At 36-month follow-up, there was a complete recovery of the deficits. Peroneal mononeuropathy in children is uncommon. Osteochondroma is a benign tumor consisting of projecting bone capped by cartilage. These tumors may be solitary or multiple and occur in hereditary multiple exostoses syndrome. The conjunction of this lesion with peroneal nerve palsy has been exceptionally reported for children, usually linked to hereditary multiple exostoses syndrome. Most peroneal nerve trauma occurs at the fibular head, where the common nerve has not yet divided into its deep and superficial peroneal nerve and where most peroneal nerve lesions, therefore, involve both branches, although motor deficits are more frequently involved than sensory ones. Surgical treatment should not be delayed because neurological improvement may be achieved if surgery is performed before severe neurological deficits become irreversible.

Anatomical variation of co-existence of 4th and 5thshort metacarpal bones, sesamoid ossicles and exostoses of ulna and radius in the same hand: a case report

IntroductionThe anatomical variations of bones in the hand are common. The existence of exostosis and shortening of metacarpal bones has been described in the literature as part of the hereditary multiple exostosis syndrome but no case has been reported with the co-existence of sesamoid ossicles in the same patient.Case presentationWe report a case with co-existence of distal ulnar and radial exostoses, 4th and 5th short metacarpals and sesamoid ossicles in the wrist area.ConclusionThis variation may help the interpretation of pain or sensory disorders in the hand and wrist areas.

Occlusion of the Popliteal Artery in Hereditary Multiple Exostosis Syndrome

IntroductionHereditary multiple exostosis syndrome is a rare condition which can occasionally cause arterial occlusion. Case reportA 50-year-old man was treated for acute leg ischaemia but no cause found. Two years later, acute ischaemia recurred and attempts at limb salvage failed. Hereditary multiple exostosis syndrome was then recognised as the cause due to a femoral exostosis compressing the popliteal artery. DiscussionThe case highlights a rare cause of acute limb ischaemia and emphasises the importance of arterial imaging when no embolic source is found.

Occlusion of the Popliteal Artery in Hereditary Multiple Exostosis Syndrome

IntroductionHereditary multiple exostosis syndrome is a rare condition which can occasionally cause arterial occlusion. Case reportA 50-year-old man was treated for acute leg ischaemia but no cause found. Two years later, acute ischaemia recurred and attempts at limb salvage failed. Hereditary multiple exostosis syndrome was then recognised as the cause due to a femoral exostosis compressing the popliteal artery. DiscussionThe case highlights a rare cause of acute limb ischaemia and emphasises the importance of arterial imaging when no embolic source is found.

Peroneal nerve compression resulting from fibular head osteophyte-like lesions

Background The anatomical relationship of the fibular head with the fibular nerve is a critical point in regard to injuries of peripheral nerves in the lower extremities. In this location, the peroneal nerve may be injured due to several mechanisms, and osteophyte-like lesions can be considered as a differential diagnosis. Methods The suitable literature concerning this association is reviewed and a case is presented. A 15-year-old adolescent boy presented with right peroneal nerve palsy on admission. The radiological examinations (computed tomography and magnetic resonance imaging) demonstrated an osteophytic lesion in the head of the right fibula. The patient underwent surgical decompression of the nerve and resection of the lesion. Postoperatively, there was a complete recovery of the deficits. Conclusions The association of osteophyte-like bone changes and peroneal nerve palsy is rare. The differential diagnoses of these lesions include cartilaginous exostoses and osteochondromas, which may be related to hereditary multiple exostoses syndrome. The timing of the treatment plays an important role in the neurological recovery.

Differentiation-induced loss of heparan sulfate in human exostosis derived chondrocytes

An exostosis or osteochondroma is an aberrant bony growth occurring next to the growth plate either as an isolated growth abnormality or as part of the Hereditary Multiple Exostosis (HME) syndrome. Mutations in either exostosin 1 (EXT1) or exostosin 2 (EXT2) gene cause the HME syndrome and also some isolated osteochondromas. The EXT1 and EXT2 genes are glycosyltransferases that function as hetero-oligomers in the Golgi to add repeating glycosaminoglycans (GAGs) to heparan sulfate (HS) chains. Previously, we demonstrated that HS is markedly diminished in the exostosis cartilage cap and that the HS proteoglycan, perlecan, has an abnormal distribution in these caps. The present studies were undertaken to evaluate which chondrocyte-specific functions are associated with diminished HS synthesis in human chondrocytes harboring either EXT1 or EXT2 mutations. Systematic evaluation of exostosis cartilage caps and chondrocytes, both in vitro and in vivo, suggests that chondrocyte-specific cell functions account for diminished HS levels. In addition, we provide evidence that perichondrial cells give rise to chondrocytes that clonally expand and develop into an exostosis. Undifferentiated EXT chondrocytes synthesized amounts of HS similar to control chondrocytes; however, EXT chondrocytes displayed very poor survival in vitro under conditions that promote normal chondrocyte differentiation with high efficiency. Collectively, these observations suggest that loss of one copy of either the EXT1 or EXT2 gene product compromises the perichondrial chondrocytes' ability to differentiate normally and to survive in a differentiated state in vitro. In vivo, these compromised responses may lead to abnormal chondrocyte growth, perhaps from a perichondrial stem cell reserve.

Syndecan-3: a cell-surface heparan sulfate proteoglycan important for chondrocyte proliferation and function during limb skeletogenesis

Syndecans are single-pass integral membrane components that serve as co-receptors for growth factors and cytokines and can elicit signal transduction via their cytoplasmic tails. We review here previous studies from our groups on syndecan-3 biology and function in the growth plates of developing long bones in chick and mouse embryos. Gain- and loss-of-function data indicate that syndecan-3 has important roles in restricting mitotic activity to the proliferative zone of growth plate and may do so in close cooperation and interaction with the signaling molecule Indian hedgehog (IHH). Biochemical and protein-modeling data suggest a dimeric/oligomeric syndecan-3 configuration on the chondrocyte's cell surface. Analyses of embryos misexpressing syndecan-3 or lacking IHH provide further clues on syndecan-3/IHH interdependence and interrelationships. The data and the conclusions reached provide insights into mechanisms fine-tuning chondrocyte proliferation, maturation, and function in the developing and growing skeleton and into how abnormalities in these fundamental mechanisms may subtend human congenital pathologies, including osteochondromas in hereditary multiple exostoses syndrome.

Epigenetic loss of the familial tumor-suppressor gene exostosin-1 (EXT1) disrupts heparan sulfate synthesis in cancer cells.

Germline mutations in the Exostoses-1 gene (EXT1) are found in hereditary multiple exostoses syndrome, which is characterized by the formation of osteochondromas and an increased risk of chondrosarcomas and osteosarcomas. However, despite its putative tumor-suppressor function, little is known of the contribution of EXT1 to human sporadic malignancies. Here, we report that EXT1 function is abrogated in human cancer cells by transcriptional silencing associated with CpG island promoter hypermethylation. We also show that, at the biochemical and cellular levels, the epigenetic inactivation of EXT1, a glycosyltransferase, leads to the loss of heparan sulfate (HS) synthesis. Reduced HS production can be reversed by the use of a DNA demethylating agent. Furthermore, the re-introduction of EXT1 into cancer cell lines displaying methylation-dependent silencing of EXT1 induces tumor-suppressor-like features, e.g. reduced colony formation density and tumor growth in nude mouse xenograft models. Screening a large collection of human cancer cell lines (n=79) and primary tumors (n=454) from different cell types, we found that EXT1 CpG island hypermethylation was common in leukemia, especially acute promyelocytic leukemia and acute lymphoblastic leukemia, and non-melanoma skin cancer. These findings highlight the importance of EXT1 epigenetic inactivation, leading to an abrogation of HS biosynthesis, in the processes of tumor onset and progression.

Developmental pathways in musculoskeletal neoplasia: involvement of the Indian Hedgehog-parathyroid hormone-related protein pathway.

There are many crucial genes and signaling pathways in the proper development of an organism. Pathologies may arise from a deregulation of these pathways. The Indian Hedgehog-PTH-related protein (Ihh-PTHrP) pathway is vital in the proper development of endochondral bones, such as the long bones. The Ihh-PTHrP pathway regulates the rate at which chondrocytes within the growth plate proliferate and differentiate. Thus, this pathway allows for the longitudinal growth of bones. However, a disruption in this pathway may lead to enchondromas and osteochondromas, which are both childhood cartilaginous neoplasms. Recently, our lab identified a mutant receptor for PTHrP in enchondroma samples. Mice expressing this mutant receptor and mice with increased Ihh activity develop conditions similar to human enchondromatosis. Linkage analysis shows an association between EXT genes and osteochondromas in hereditary multiple exostoses syndrome. Studies in Drosophila and mice suggest EXT gene products play a role in the diffusion of hedgehog proteins. A mutation in EXT genes may result in an abnormal Ihh diffusion pattern leading to an osteochondroma. There are agents that inhibit Hedgehog signaling. These agents may be useful in the treatment of enchondromas and osteochondromas. This review will discuss the discovery of the Ihh-PTHrP pathway and its involvement in neoplasia, and will suggest possible novel therapeutic agents in the treatment of these cartilaginous neoplasms.

EXT-Mutation Analysis and Loss of Heterozygosity in Sporadic and Hereditary Osteochondromas and Secondary Chondrosarcomas

Osteochondromas occur as sporadic solitary lesions or as multiple lesions, characterizing the hereditary multiple exostoses syndrome (EXT). Approximately 15% of all chondrosarcomas arise within the cartilaginous cap of an osteochondroma. EXT is genetically heterogeneous, and two genes, EXT1 and EXT2, located on 8q24 and 11p11-p12, respectively, have been cloned. It is still unclear whether osteochondroma is a developmental disorder or a true neoplasm. Furthermore, it is unclear whether inactivation of both alleles of an EXT gene, according to the tumor-suppressor model, is required for osteochondroma development, or whether a single EXT germline mutation acts in a dominant negative way. We therefore studied loss of heterozygosity and DNA ploidy in eight sporadic and six hereditary osteochondromas. EXT1- and EXT2-mutation analysis was performed in a total of 34 sporadic and hereditary osteochondromas and secondary peripheral chondrosarcomas. We demonstrated osteochondroma to be a true neoplasm, since aneuploidy was found in 4 of 10 osteochondromas. Furthermore, LOH was almost exclusively found at the EXT1 locus in 5 of 14 osteochondromas. Four novel constitutional cDNA alterations were detected in exon 1 of EXT1. Two patients with multiple osteochondromas demonstrated a germline mutation combined with loss of the remaining wild-type allele in three osteochondromas, indicating that, in cartilaginous cells of the growth plate, inactivation of both copies of the EXT1 gene is required for osteochondroma formation in hereditary cases. In contrast, no somatic EXT1 cDNA alterations were found in sporadic osteochondromas. No mutations were found in the EXT2 gene.