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Evaluation of the Anatomic Burden of Patients with Hereditary Multiple Exostoses
Abstract
Hereditary multiple exostosis (HME) is an autosomal dominant condition resulting predominantly from mutations in the exostosin 1 (EXT1) and exostosin 2 (EXT2) genes. We asked two questions in our study: first, what is the anatomic burden of subjects with HME; second, is there a difference in anatomic burden in subjects with EXT 1 versus EXT 2. The anatomic burden experienced by HME patients was defined according to three domains: (1) lesion quality; (2) limb malalignment and deformity; and (3) limb segment lengths and percentile height. Seventy-nine subjects with HME were included in this study. Of these 79 phenotypes were completed. Forty-eight genotypes were confirmed leaving 48 complete genotype-phenotype profiles for analysis. Analysis of the coding and flanking intronic regions of EXT1 and EXT2 was performed in each patient by direct sequencing of PCR-amplified genomic DNA. All three domains of anatomic burden showed a wide range of presentation in the HME study sample. More lesions and greater tendency to flat bone occurrence was associated with EXT1. EXT1 patients were shorter. All limb segments tended to be shorter for EXT1 subjects. EXT1 subjects showed more anatomic burden with respect to lesion quality and height.
... Hereditary Multiple Exostosis (HME) is characterized as dwarf stature, limb-length divergences, valgus distortions of the ankle and knee, irregularity of the pectoral and pelvic girdles, bowing of radius, ulnar deviation, wrist and subluxation of the radiocapitellar joint. Inheritance pattern of HME is AD (Alvarez et al., 2007). Causative genes of HME are EXT1 and EXT2 (Alvarez et al., 2007). ...
... Inheritance pattern of HME is AD (Alvarez et al., 2007). Causative genes of HME are EXT1 and EXT2 (Alvarez et al., 2007). ...
... Osteogenesis imperfecta type VI (OIVI) AD or AR (Cohen, 2006 AD (Alvarez et al., 2007). ...
Abstract | Bone is formed by minerals, predominantly specialized proteins, calcium hydroxyapatite which make the
bone matrix for proper function and bones strengthen. Bone is composed from osteoclasts, osteoblasts and collagen.
Vessels are fundamental for basic bone multicellular units which organizes formation of osteoblasts and osteoclasts.
Bone resorption is responded by osteoclasts (polynuclear cells). Osteoclasts function is vital in the maintenance, repair
and bone remodeling.Imbalance in bone matrix leads towards disorders of bone such as osteogenesis imperfecta,
paget’s disease of bone, osteoporosis, diastrophic dysplasia, cleidocranial dysplasia, kniest dysplasia, pycnodysostosis,
caffey disease and achondroplasia which leads toward severe and sometime skeleton anomalies, back bone pain, bone
fracture, extra toe, bent of tibia, head and neck anomalies, osteogenesis of skeleton muscles, stature, deteriorating
joints, pelvic deformities, skull, craniofacial defects, shortening and extensiveness in bones, brachydactyly, osteoarthritis,
clubbed foot, carpal and tarsal osteolysis and muscle weakness. Bone deformities occur at genetic level with different
mode of inheritance pattern. Changes at genetic level can cure only by gene therapy by using in vivo or ex vitro
gene therapy methods using either by viral or non-viral vectors, most common used is adeno-associated virus. Bone
anomalies are one of the major problems in Pakistan and it is increasing rapidly day by day. Approximately 72% Pakistanis
are suffering from bone anomalies, mostly women are affected. Paget’s disease of bone, osteogenesis imperfecta,
spondyloepimetaphyseal dysplasia and many other disorders are reported in Pakistan. The high prevalence of genetic
bone anomalies in Pakistan is due to lack of awareness and cousion marriage.
... 2 EXT1 genotype and male gender are both associated with an increased burden 1 Orthopaedic Registrar, Department of Orthopaedics and Trauma, The Royal Infirmary of Edinburgh, UK 2 Senior Clinical Lecturer, University of Edinburgh, UK of exostoses throughout the skeletal system. 2,8,9 It is not known, however, if the distribution of exostoses in relation to anatomical site varies according to genotype or gender for patients with HME. ...
... The total number of exostoses suffered by an individual has been used as a clinical marker of phenotype severity in patients with HME. 8,9 Due to the scarcity of HME patients and their wide spread geographical distribution, clinical examination is logistically difficult. If a specific area of the body could be identified that directly correlated with the anatomic burden of exostoses, this area could be assessed by the patients themselves and reported to the clinician or researcher without the need to review and physically examine every patient. ...
... Numerous studies have identified that HME patients with the EXT1 genotype have a more severe phenotype relative to those with an EXT2 genotype, 2,8,9 which we have also demonstrated in terms of the total number of exostoses suffered by an individual. A unique aspect of our study was the variability in the anatomical distribution of the exostoses according to genotype, with only some sites demonstrating a significant difference. ...
We describe the novel anatomical distribution of exostoses in patients with hereditary multiple exostoses according to their gender and genotype.
A prospective database of 143 patients from 65 families with hereditary multiple exostoses was compiled. Patient demographics, genotype and number of exostoses according to anatomical site were recorded. The hand was affected by the greatest proportion of exostoses for both EXT1 (19%) and EXT2 (14%) genotypes and was the most prevalent site for exostoses in patients with an EXT1 genotype (92%). Patients with an EXT1 genotype had a significantly greater number of exostoses compared to those with an EXT2 genotype (2680 vs. 1828, p = 0.006); however, this was only significantly different for 10 of the 19 anatomical regions examined. Male patients with an EXT1 genotype had a significantly (p < 0.05) greater number of exostoses affecting their hands, distal radius, proximal humerus, scapular and ribs compared to female patients with the same genotype and males with an EXT2 genotype.
The anatomical distribution of exostoses varies according to genotype and gender; however, the reason for this difference is not clear and may relate to different biochemical pathways.
... Several studies have suggested a more severe phenotype to be associated with EXT1 mutations [Alvarez et al., 2006[Alvarez et al., , 2007Francannet et al., 2001;Leube et al., 2008;Porter et al., 2004;Wuyts et al., 2005]. Francannet et al. [2001] reported a significant correlation between EXT1 mutations and severe phenotypes in MO patients, more specifically with large numbers of exostoses and short stature. ...
... Francannet et al. [2001] reported a significant correlation between EXT1 mutations and severe phenotypes in MO patients, more specifically with large numbers of exostoses and short stature. Other authors reported the same observations, completed with a correlation with skeletal deformities (shortening or bowing of the forearm, knee deformities) [Porter et al., 2004], functional limitations (reduced mobility in range of motion in elbow, forearm, and/or knee) [Porter et al., 2004;Wuyts et al., 2005], shorter limb segments, and more pelvic and flatbone involvement [Alvarez et al., 2006[Alvarez et al., , 2007. Flatbone lesions were reported to be a problem due to increased incidence of chondrosarcomas [Alvarez et al., 2007]. ...
... Other authors reported the same observations, completed with a correlation with skeletal deformities (shortening or bowing of the forearm, knee deformities) [Porter et al., 2004], functional limitations (reduced mobility in range of motion in elbow, forearm, and/or knee) [Porter et al., 2004;Wuyts et al., 2005], shorter limb segments, and more pelvic and flatbone involvement [Alvarez et al., 2006[Alvarez et al., , 2007. Flatbone lesions were reported to be a problem due to increased incidence of chondrosarcomas [Alvarez et al., 2007]. A correlation between EXT1 mutations and malignant transformation toward a chondrosarcoma was reported as well [Francannet et al., 2001;Porter et al., 2004], but severity of the phenotype did not seem to have a predictive value for malignant transformation [Porter et al., 2004]. ...
Multiple osteochondromas (MO) is an autosomal dominant skeletal disease characterized by the formation of multiple cartilage-capped bone tumors growing outward from the metaphyses of long tubular bones. MO is genetically heterogeneous, and is associated with mutations in Exostosin-1 (EXT1) or Exostosin-2 (EXT2), both tumor-suppressor genes of the EXT gene family. All members of this multigene family encode glycosyltransferases involved in the adhesion and/or polymerization of heparin sulfate (HS) chains at HS proteoglycans (HSPGs). HSPGs have been shown to play a role in the diffusion of Ihh, thereby regulating chondrocyte proliferation and differentiation. EXT1 is located at 8q24.11–q24.13, and comprises 11 exons, whereas the 16 exon EXT2 is located at 11p12–p11. To date, an EXT1 or EXT2 mutation is detected in 70–95% of affected individuals. EXT1 mutations are detected in ±65% of cases, versus ±35% EXT2 mutations in MO patient cohorts. Inactivating mutations (nonsense, frame shift, and splice-site mutations) represent the majority of MO causing mutations (75–80%). In this article, the clinical aspects and molecular genetics of EXT1 and EXT2 are reviewed together with 895 variants in MO patients. An overview of the reported variants is provided by the online Multiple Osteochondromas Mutation Database (http://medgen.ua.ac.be/LOVD). Hum Mutat 30:1–8, 2009. © 2009 Wiley-Liss, Inc.
... Cependant, de nombreuses études ont montré que les ostéochondromes sont liés à des mutations génétiques et qu'il s'agit donc de vraies tumeurs [5,14,15] . ...
... La sévérité de ces répercussions phénotypiques pourrait dépendre du type de mutation génétique, avec des atteintes qui seraient plus sévères pour les mutations du gène EXT1 [15,16,27,50] . 7 m m Figure 11. ...
... Many researchers have reported the genotype-phenotype correlation in HME [5,7,16,17]. Francannet et al. divided their subjects into severe or moderate groups by using five factors, and they found that most severe forms of the disease and malignant transformation were associated with EXT1 mutations [5]. ...
... However, we found no significant difference in the number of involved anatomical sites between genotypes, and these data are in contrast to those of previous studies [5][6][7]17]. An explanation for this finding may be that we did not evaluate exostosis involvement of flat bones, whereas some authors have reported a higher degree of anatomical burden and more flat bone involvement in EXT1 patients than in EXT2 patients [7,16]. Thus, we speculate that the different functions of the EXT genes in HS biosynthesis may lead to different exostosis involvement of the flat bones. ...
Background
Hereditary multiple exostoses (HME) is a rare autosomal dominant skeletal disorder that can cause a variety of clinical manifestations. We aimed to evaluate the general clinical phenotypic severity of HME by using a scoring system and correlate the genotypes with different clinical phenotypes in Chinese patients. Methods
Forty-six patients from different families were prospectively enrolled. The mutations were identified by direct sequencing of PCR-amplified genomic DNA or by multiplex ligation-dependent probe amplification (MLPA). Patients’ demographic data, height, age of onset, number of anatomical sites, forearm deformity, and lower extremity alignment were analysed according to genotype and gender. A scoring system was used to assess the severity of the clinical phenotype. ResultsThirty (60%) patients presented mutations in the EXT1 gene, and 16 (32%) presented mutations in the EXT2 gene. The mean age of onset was 2.96 years. The mean number of involved anatomic sites was 15.35. Male patients had more lesion sites than female patients (15.97 vs. 13.77, p = 0.046). The height evaluation illustrated that 67% of the patients (31 of 46) were below the 50th percentile, and the patients with EXT1 mutations were shorter than those with EXT2 mutations (p = 0.005). Forearm deformity showed a significant correlation with the number of involved anatomical sites (r = 0.382, p = 0.009). Moreover, a higher total score was found in patients with EXT1 mutations (p = 0.001). Conclusions
The clinical manifestations of 46 Chinese HME patients were similar to those in previous reports of Western populations. Patients with EXT1 mutations have a more severe clinical phenotype than patients with EXT2 mutations.
... La cause exacte du développement d'une exostose n'est pas clairement précisée. L'affection est liée à des anomalies (mutations des gènes EXT1 ou EXT2) observées par l'analyse cytogénétique des cas d'ostéochondromes familiaux (dans toutes les cellules du sujet porteur) ou sporadiques (dans la coiffe cartilagineuse) [3][4][5] . De façon simpliste, on peut considérer que le développement de l'ostéochondrome résulte d'une sorte de développement excessif d'une portion marginale du cartilage de conjugaison qui produit, en quelque sorte, un clone à développement transversal. ...
... En cas de maladie exostosante, des déformations peuvent résulter de perturbations de la croissance des os (comme si le cartilage de croissance perdait son activité longitudinale suite aux excroissances transversales). Les déformations les plus fréquentes sont des déviations en varus ou valgus des genoux, des raccourcissements souvent majeurs des ulnas avec incurvation des radius, des statures globales de petite taille... [24] La sévérité des répercussions phénotypiques paraît dépendre du type de mutation génétique, avec atteintes plus sévères pour les mutations du gène EXT1 [5,24] . ...
... In this respect, the MO study population is quite interesting due to the heterogeneity of the mutation expression (EXT1-EXT2) of the disease. Several studies on genotype and phenotype argue that patients with EXT1 mutations and males are more affected by the disease [2,5,[10][11][12] while others found no differences [13,14]. It is theorized that the later epiphyseal closure in boys prolongs the effect of EXT mutations and therefore generates more osteochondromas, greater deformities and consequently more functional limitations. ...
Background
Multiple Osteochondromas (MO) is a rare genetic disorder characterised by the presence of numerous benign bone tumours, known as osteochondromas. Within the spectrum of debilitating symptoms associated with MO, pain is recognized as a major problem. Interestingly, our clinical observations suggest that fatigue is also a significant concern but has merely been touched upon in MO literature. This study aims to (1) assess the level of pain and fatigue in adult patients with MO; (2) compare fatigue in MO to healthy subjects and patients with Rheumatoid Arthritis (RA); (3) identify associated variables for pain and fatigue in patients with MO.
Methods
In this cross-sectional study, 353 adult MO patients completed a survey with validated questionnaires on pain, fatigue and psychosocial factors. Pain and fatigue were assessed with the Numeric Rating Scale (NRS), and fatigue was also measured with the Checklist Individual Strength (CIS). Fatigue (CIS) was compared with reference scores of healthy subjects and patients with RA, using a one-sample t-test. Multiple linear regression models for pain and fatigue were developed using a-priori selected independent variables based on a theoretical framework (ICF-model).
Results
Pain was reported by 87.8% (NRS = 3.19±2.6) and fatigue by 90.4% (NRS = 4.1±2.6) of patients with MO. Fatigue scores for MO (CIS = 84.1±15.3) were significantly higher (p<0.001) compared to reference scores of healthy subjects and patients with RA. The multivariable analysis for pain provided a final regression model with six variables (R² = 0.445, p<0.001) of which fear avoidance beliefs and fatigue had the strongest association. For the fatigue models NRS (R² = 0.455, p<0.001) and CIS (R² = 0.233, p<0.001), the strongest associations were found with anxiety and depression respectively.
Conclusions
Pain and fatigue are highly prevalent in patients with MO. Fatigue is significantly higher compared to healthy subjects and patients with RA. Several variables associated with pain and fatigue have been identified that could help improve multidisciplinary treatment plans.
... Furthermore, analysis of the human gene mutation database (HGMD) indicates a higher frequency of causative alterations in EXT1 compared to EXT2 (23). Finally, patients with EXT1 mutations and multiple osteochondromas are more prone to malignant transformation than those with EXT2 mutations (51,52). In our study, genetic manipulation techniques established a clear correlation between EXT1 and cancer cell aggressiveness, which was inert for endogenous EXT2 expression. ...
The epithelial–mesenchymal transition (EMT) program is crucial for transforming carcinoma cells into a partially mesenchymal state, enhancing their chemoresistance, migration, and metastasis. This shift in cell state is tightly regulated by cellular mechanisms that are not yet fully characterized. One intriguing EMT aspect is the rewiring of the proteoglycan landscape, particularly the induction of heparan sulfate proteoglycan (HSPG) biosynthesis. This proteoglycan functions as a co-receptor that accelerates cancer-associated signaling pathways through its negatively-charged residues. However, the precise mechanisms through which EMT governs HSPG biosynthesis and its role in cancer cell plasticity remain elusive. Here, we identified exostosin glycosyltransferase 1 (EXT1), a central enzyme in HSPG biosynthesis, to be selectively upregulated in aggressive tumor subtypes and cancer cell lines, and to function as a key player in breast cancer aggressiveness. Notably, ectopic expression of EXT1 in epithelial cells is sufficient to induce HSPG levels and the expression of known mesenchymal markers, subsequently enhancing EMT features, including cell migration, invasion, and tumor formation. Additionally, EXT1 loss in MDA-MB-231 cells inhibits their aggressiveness-associated traits such as migration, chemoresistance, tumor formation, and metastasis. Our findings reveal that EXT1, through its role in HSPG biosynthesis, governs signal transducer and activator of transcription 3 (STAT3) signaling, a known regulator of cancer cell aggressiveness. Collectively, we present the EXT1/HSPG/STAT3 axis as a central regulator of cancer cell plasticity that directly links proteoglycan synthesis to oncogenic signaling pathways.
... Furthermore, the human gene mutation database (HGMD) analysis indicates that EXT1 has higher causative alterations than EXT2 22 . Finally, EXT1 mutation with multiple osteochondromas is more prone to display malignant transformation than patients with EXT2 mutations 49,50 . In this study, by applying genetic-based manipulation techniques, we demonstrate a clear correlation between EXT1 and cancer cell aggressiveness, (which was not certified by peer review) is the author/funder. ...
Carcinomas often exhibit aggressive characteristics, such as enhanced migration abilities, through the execution of the epithelial-mesenchymal transition (EMT) program. Heparan sulfate (HS) is a polysaccharide expressed on the surface of aggressive cancer cells, which acts as a co-receptor to stimulate EMT-associated signaling pathways. However, despite HS role in cancer aggressiveness, the mechanisms governing its EMT-dependent biosynthesis remains poorly understood. Here, we characterized the HS chain elongation enzyme, exostosin glycosyltransferase 1 (EXT1), as an essential component of the EMT program. We identified an EMT-dependent expression of EXT1 and its selective upregulation in aggressive tumor subtypes and cell lines. Overexpression of EXT1 in epithelial cells is sufficient to induce HS biosynthesis, cell migration, and invasion, form tumors in mice, and activate the STAT3 pathway. Moreover, its knockout in aggressive cells significantly inhibited their EMT-associated characteristics. These findings demonstrate a cellular mechanism by which metabolic processes regulate signaling pathways to govern cell state.
... 14 The EXT1 gene mutation carriers tend to show more severe symptoms of HME and a greater risk for malignant transformation than the EXT2 gene mutation carriers did. 18,19 The Human Gene Mutation Database, (HGMD, http:// www.hgmd.org) stored the EXT1 gene variants associated with HME that were published in the peer-reviewed literature. ...
To identify the pathogenic gene variation in a Chinese family with Hereditary Multiple Exostoses (HME). By examining blood‐sourced DNA and clinical manifestations of the proband and his family members, the whole exome sequencing (WES) and Sanger sequencing were used to detect possibly pathogenic mutations. A novel heterozygous mutation (c.325dup) was identified in exon 1 of the exostosin 1 (EXT1) gene from the proband and the affected family members. And we found this mutation was absent in all the unaffected family members. This c.325dup mutation is in the exon 1 domain of the EXT1 gene and the change of p.C109Lfs*80 cause the early termination of protein translation. The identification of the novel frameshift insertion mutation (c.325dup) expands the mutation spectrum of HME, which provides new evidence for HME diagnosis. Hereditary multiple exostoses (HME) is a rare skeletal disorder characterized by a widespread distribution of osteochondromas originating from the metaphyses of long bones. The proband was diagnosed with HME by clinical manifestations and gene test.
... Mutations in EXT1 account for 56-78% of HME cases, whereas mutations in EXT2 are detected in 21-44% of cases (Jennes et al., 2009). The EXT1 gene mutation carriers tend to show more severe symptoms of HME and a greater risk for malignant transformation than the EXT2 gene mutation carriers did (Francannet et al., 2001;Alvarez et al., 2007). The Human Gene Mutation Database, (HGMD,http://www.hgmd.org) ...
A novel heterozygous mutation (c.325dup) was identified in EXT1 gene from the proband and the affected family members; this mutation was absent in all the unaffected family members. The identification of the novel frameshift insertion mutation (c.325dup) expands the mutation spectrum of HME, which provides new evidence for HME diagnosis.
... These mutations lead to dysregulation of cell surface heparin sulfate proteoglycans and consequently cartilage hyperproliferation. 4 Exostoses of upper extremities may result in forearm deformities such as shortened ulna with secondary disproportionate radius bone overgrowth been frequently noticed ultimately leading to radial bowing deformity. 5 These lesions originate from perichondrium and flank the growth plate so these lesion tether the physis results in off balance growth of the bone. ...
Hereditary Multiple Exostoses is a skeletal dysplasia that is very rare and defined by formation of numerous cartilage capped benign tumours either pedunculated or sessile known as osteochondromas throughout skeleton especially around the growth plates of ribs, vertebrae, pelvis and long bones. Rarely it can present forearm problems such bowing deformity of radius, ulnar shortening and radiocapitellar dislocation or subluxation. We are presenting a case of 20 year old female who presented with left distal ulnar exostosis resulting in ulnar shortening and radial bowing with restricted supination and pronation range of movement. Other complaint was of multiple non tender bony hard lumps in both upper and lower limbs. Excision of distal ulnar exostosis was done which resulted in marked improvement in pronation and supination range of movement. Hereditary multiple exostoses with forearm deformities though very rare but can present and the treatment is conservative except if any bony swelling manifests any complications such as pain or associated deformity.
... Other skeletal disorders, such as the SOST gene mutations sclerosteosis and van Buchem disease, are associated with raised intracranial pressure and cranial nerve entrapment [99,100], while hereditary multiple exostoses (HME) [101] correlates with symptoms of autism [102] and frontotemporal dementia [103]. Although multiple genetic diseases with concurrent skeletal and mental deficits (selection see Supplementary Table S1) show individually altered brain and bone dysfunction, further evidence of bidirectional molecular interaction is warranted. ...
As brain and bone disorders represent major health issues worldwide, substantial clinical investigations demonstrated a bidirectional crosstalk on several levels, mechanistically linking both apparently unrelated organs. While multiple stress, mood and neurodegenerative brain disorders are associated with osteoporosis, rare genetic skeletal diseases display impaired brain development and function. Along with brain and bone pathologies, particularly trauma events highlight the strong interaction of both organs. This review summarizes clinical and experimental observations reported for the crosstalk of brain and bone, followed by a detailed overview of their molecular bases. While brain-derived molecules affecting bone include central regulators, transmitters of the sympathetic, parasympathetic and sensory nervous system, bone-derived mediators altering brain function are released from bone cells and the bone marrow. Although the main pathways of the brain-bone crosstalk remain ‘efferent’, signaling from brain to bone, this review emphasizes the emergence of bone as a crucial ‘afferent’ regulator of cerebral development, function and pathophysiology. Therefore, unraveling the physiological and pathological bases of brain-bone interactions revealed promising pharmacologic targets and novel treatment strategies promoting concurrent brain and bone recovery.
... [49] To date, most clinical and genotype-phenotype studies of MO have been cross-sectional. These studies have contributed to our understanding of the anatomic burden of MO. [22][23][24][25][26] However, they have offered limited insight into disease development during childhood and adolescence when MO is most active. Thus, we performed an analysis of longitudinal registry data from an Italian cohort of pediatric patients with MO, focusing on clinical indices of disease severity and evolution, and surgeries. ...
Importance
Multiple osteochondromas is a rare hereditary skeletal disorder, characterized by bony protrusions arising from growth plates on long bones during skeletal development. The disorder frequently leads to diminished stature, deformities and functional limitations. Understanding of the natural history of multiple osteochondromas and its evolution in children and adolescents is limited.
Objective
To provide valuable information on the natural history of multiple osteochondromas, to inform recommendations for treatment and prevent impairments caused by osteochondromas.
Design
This retrospective cohort study in children with multiple osteochondromas includes longitudinal data collected from first to last follow-up visit for patient demographics, and over 36 months for disease evolution.
Setting
Data were collected from the Registry of Multiple Osteochondromas, which includes data from circa 1200 patients with multiple osteochondromas treated from 2003 to 2017 at IRCCS Istituto Ortopedico Rizzoli in Bologna.
Participants
Patients ≤18 years with multiple osteochondromas, who provided written informed consent and had data for ≥1 12-month follow-up visit.
Main outcome(s) and measurement(s)
Demographics, clinical features, incidence of surgeries, and disease evolution (progression or regression) were assessed. Results were summarized using descriptive statistics, annual rates of new clinical features and surgeries, and Kaplan-Meier estimates. Patient height was evaluated following Italian growth charts.
Results
158 patients were included in these analyses. Throughout follow-up, 80.4% of patients developed new osteochondromas, 57.6% developed new deformities, 23.4% developed new functional limitation(s). New osteochondroma(s) were developed by 28.5% patients by Month 12, 39.9% at Month 24, 50% at Month 36. Most new osteochondromas were detected in the younger population; patients aged 0–4 years underwent a significantly higher number of lesions within 12, 24 and 36 months of follow-up. The overall incidence of patients with ≥1 new deformity within 12 months was 17.7%, with incidences decreasing with increasing age (p = .023). In addition, the analyses on height highlight that 13 years is a cut off age for slow growth of the stature (p < .0005). At last follow-up visit, 46.2% of patients had disease progression, while regression (spontaneous and surgical) occurred in 7.6% (p = .007).
Conclusions and relevance
This natural history study reports the main set of clinically relevant data for patients with multiple osteochondromas during skeletal development, providing insight for patient management and development of therapeutic interventions.
... Patients with EXT1 mutations have been more frequently associated with exostoses, exostosisrelated complications and a shorter stature. 63 Ten percent of the patients reported dimensional changes in exostosis during pregnancy and 63% of the pregnant women who had exostosis-related complications during delivery required a cesarean section. 1 ...
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.
... 5,6 Patients with this disease have symptoms due to stiff and protruding superficial lesions, limb deformities and pressure on neurovascular bundles. [7][8][9] Fewer than 5% of solitary osteochondromas originate in the spine. 5,10,11,12,13 Spinal osteochondromas in patients with HME had traditionally been considered an uncommon phenomenon, ranging from less than 1% to 9% of all exostoses, 14,15 but recent reports have shown an incidence reaching as high as 68%. ...
Introduction
Osteochondromas are usually found in the long bones of patients with hereditary multiple exostoses (HME). The spine is reported to be involved in over 50% of cases, but few of these patients are symptomatic as the result of an existing spinal exostosis.
Methods
We reviewed the current literature in order to find the right approach to patients with HME-complicated spinal exostosis and describe three paediatric patients that were diagnosed late with spinal cord compression due to cervical exostosis.
Results
Our three cases were all late presentations with neurology and unfortunately had minimal improvement of neurology after the lesion was surgically removed. There is general agreement that late presentation of spinal cord injury due to osteochondromas involving the cervical spine may cause severe and irreversible neurological sequelae. Our literature review revealed that there are no clear-cut guidelines to develop more comprehensive screening measures for these patients.
Conclusions
A high index of suspicion is the most important factor for correct diagnosis and appropriate management. Physicians who treat HME should bear in mind that thorough history taking and a neurological examination at follow up are essential for these patients. Clearer guidelines for the development of more comprehensive screening programmes are essential.
Level of evidence
IV
... Exostoses are rarely present at birth, but gradually arise and increase in size with age, with a wide spectrum of clinical presentation from only radiologically distinguishable signs to different skeletal deformities that remain minor physical anomalies of schizophrenics. 4 Genetic transmission, correlation of phenotype and genotype, and variable spectrum of clinical manifestation are comparable in both the condition of schizophrenia and multiple exostoses. All the shared features and the cases reported earlier guide us to believe in the important role of EXT genes and nearly chromosomal loci in further studies in the genetics of schizophrenia. ...
... The most severe clinical implication of osteochondromas is the risk of malignant degeneration in chondrosarcomas or osteosarcomas with a lifetime incidence ranging from 0.5% to 20% in HMO (7). Some preliminary genotype-phenotype correlations have been published and mostly include an apparently increased risk of malignant degeneration (8), a larger number of lesions (9), a more severe phenotype and male preponderance in families with variants in EXT1 (10). ...
Hereditary multiple osteochondromas (HMO) is a rare autosomal dominant skeletal disorder, caused by heterozygous variants in either EXT1 or EXT2, which encode proteins involved in the biogenesis of heparan sulphate. Pathogenesis and genotype-phenotype correlations remain poorly understood. We studied 114 HMO families (158 affected individuals) with causative EXT1 or EXT2 variants identified by Sanger sequencing, or MLPA and qPCR. Eighty-seven disease-causative variants (55 novel and 32 known) were identified including frameshift (42%), nonsense (32%), missense (11%), splicing (10%) variants and genomic rearrangements (5%). Informative clinical features were available for 42 EXT1 and 27 EXT2 subjects. Osteochondromas were more frequent in EXT1 as compared to EXT2 patients. Anatomical distribution of lesions showed significant differences based on causative gene. Microscopy analysis for selected EXT1 and EXT2 variants verified that EXT1 and EXT2 mutants failed to co-localize each other and loss Golgi localization by surrounding the nucleus and/or assuming a diffuse intracellular distribution. In a cell viability study, cells expressing EXT1 and EXT2 mutants proliferated more slowly than cells expressing wild-type proteins. This confirms the physiological relevance of EXT1 and EXT2 Golgi co-localization, and the key role of these proteins in the cell cycle. Taken together, our data expand genotype-phenotype correlations, offer further insights in the pathogenesis of HMO and open the path to future therapies.
... The more severe consequences of EXT1 mutations compared to EXT2 mutations likely reflect the fact that the EXT1 protein has a major catalytic function in HS polymerization, while EXT2-though required-may have structural or supportive roles within the Golgi-associated EXT1/EXT2 complexes [58]. We should note that despite several attempts, there is still no widely accepted system to evaluate and classify disease severity among HME patients [8,59], and similarly, there is no clear and reliable genotype-phenotype correlation [60,61]. Such difficulties may be due to the fact that clinically, HME is highly variable even within members of a family sharing a common mutation and among unrelated patients with the same mutation [61], making it difficult to critically assess and establish severity and disease course and raising the possibility that genetic background and the nature of "second hits" have a major influence in HME. ...
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.
... As a putative tumor-suppressor in the EXT gene family, EXT1 mutations have been suggested to be a major cause of MO, in addition, patients with MO who have EXT1 gene mutations tend to display more severe symptoms and suffer a greater risk for malignant transformation than patients with EXT2 gene mutations (25)(26)(27). EXT1 and EXT2 proteins form a stable complex as a glucuronic acid sugar-based transfer enzyme and N-acetylglucosamine glycosyltransferase, catalyzing the polymerization of HS chains in the endoplasmic reticulum and Golgi apparatus (28). HS is ubiquitously expressed on the cell surface, and as a component of extracellular matrix glycoprotein, it is involved in the mediation of cell adhesion, signal transduction and the receptor ligand binding process (29). ...
Multiple osteochondromas (MO) is an autosomal skeletal disease with an elusive molecular mechanism. To further elucidate the genetic mechanism of the disease a three‑generation Chinese family with MO was observed and researched, and a novel frameshift mutation (c.335_336insA) in the exotosin 1 (EXT1) gene of one patient with MO was observed through exome sequencing. This was further validated by Sanger sequencing and comparison with 200 unrelated healthy controls. Immunohistochemistry and multiple sequence alignment were performed to determine the pathogenicity of the candidate mutation. Multiple sequence alignment suggested that codon 335 and 336 in the EXT1 gene were highly conserved regions in vertebrates. Immunohistochemistry revealed that EXT1 protein expression levels were decreased in a patient with MO and this mutation compared with a patient with MO who had no EXT1 mutation. Owing to the appearance of c.335_336insA in exon 1 of EXT1, a premature stop codon was introduced, resulting in truncated EXT1. As a result integrated and functional EXT1 was reduced. EXT1 is involved in the biosynthesis of heparan sulfate (HS), an essential molecule, and its dysfunction may lead to MO. The novel mutation of c.335_336insA in the EXT1 gene reported in the present study has enlarged the causal mutation spectrum of MO, and may assist genetic counseling and prenatal diagnosis of MO.
... The same heterozygous exon 1 (c.115G>T; p.E39X) nonsense mutation and the synonymous mutation were detected in the patient's mother. c.115G>T; p.E39X has previously been reported as a disease-causing mutation (12). However, to the best of our knowledge, the current study is the first report this mutation in a Chinese individual. ...
Hereditary multiple osteochondromas (HMO) is an autosomal dominant bone disorder characterised by the presence of multiple benign cartilage-capped tumours. Exostosin-1 (EXT1) and EXT2 are the major morbigenous genes associated with HMO, mutations in which are responsible for 90% of all HMO cases. In patients with HMO, osteochondromas arise adjacent to the metaphysis and typically remain in the metaphyseal region of the long bones. Therefore, it is rare for osteochondromas to be identified intra-articularly, although they may manifest as loose bodies. The present study describes a rare case of HMO manifesting as limited flexing range in the right knee joint of a 27-year-old male patient. Computed tomography and magnetic resonance imaging (MRI) revealed three intra-articular osteochondromas located in the intercondylar fossa of the patient's right knee. The intra-articular osteochondromas and protuberant extra-articular osteochondromas around the right knee were resected, resulting in improved right knee function and no postoperative recurrence. Pathological analysis revealed that the intra-articular osteochondromas had a thinner cartilage cap layer than the extra-articular osteochondromas. In addition, genetic analysis of the patient and the patient's mother was conducted. From this, it was determined that a nonsense mutation, c.115G>T (p.E39X) in exon 1 of the EXT1 gene, was the cause of HMO in this case. Thus, it is proposed that osteochondromas with a pedicle within the knee, may tear and become loose intra-articular bodies, resulting in limited joint function and thereby contributing to the progression of HMO.
... In males, mutations in EXT-1 lead to a more severe HME phenotype as compared to mutations in EXT-2. Typically male carriers of mutations in EXT-1 present themselves with more and bigger exostoses [33][34][35][36][37][38][39]. The risk of malignant transformation cannot be linked to the specific genetic mutation. ...
Multiple hereditary exostoses is an autosomal dominant inherited disease causing exostoses: growth on the bones of children. The disease is mainly caused by mutated exostosin (EXT)-1 or EXT-2 genes. These mutations yield non-functional EXT-gene products. Lack of functional proteins cause a defect in heparan sulphate synthesis and therefore in proteoglycan modification and cell signalling. It is assumed that a subset of chondrocytes form an exostoses, through a growth and differentiation process which is only partially understood. The place of origin of these exostoses-forming chondrocytes is still unknown. We also do not know in detail which processes influence the exostoses growth, and what shelters the exostoses from being resorbed by osteoclast activity. In this paper we systematically review the major pathophysiological theories of exostoses, with a focus on the aforementioned knowledge gaps.
... Several studies have suggested that MO patients present a more severe phenotype due to EXT1 mutations than EXT2 mutations 16,18,21 while other studies could not confirm this observation 23,36 . Pedrini et al 2011 recently performed a genotype-phenotype association study in a large cohort of MO patients and identified some specific correlation according to a new clinical classification system 31 . ...
Multiple osteochondromatosis (MO), or EXT1/EXT2-CDG, is an autosomal dominant O-linked glycosylation disorder characterized by the formation of multiple cartilage-capped tumors (osteochondromas). In contrast, solitary osteochondroma (SO) is a non-hereditary condition. EXT1 and EXT2, are tumor suppressor genes that encode glycosyltransferases involved in heparan sulfate elongation. We present the clinical and molecular analysis of 33 unrelated Latin American patients (27 MO and 6 SO). Sixty-three percent of all MO cases presented severe phenotype and two malignant transformations to chondrosarcoma (7%). We found the mutant allele in 78% of MO patients. Ten mutations were novel. The disease-causing mutations remained unknown in 22% of the MO patients and in all SO patients. No second mutational hit was detected in the DNA of the secondary chondrosarcoma from a patient who carried a nonsense EXT1 mutation. Neither EXT1 nor EXT2 protein could be detected in this sample. This is the first Latin American research program on EXT1/EXT2-CDG.
... more severe phenotype than mutations in EXT2 [14][15][16] , many aspects of the phenotypic variability observed in patients have yet to be understood at the genetic level. As suggested by the Human Variome Project initiative, characterization of causative mutations in familial and sporadic cases in diverse populations is needed for full understanding of Mendelian diseases 17 . ...
... The majority of missense mutations also lead to defective EXT protein function [12]. Mutations in EXT1 seem associated with a more severe phenotype as compared to EXT2 [13,14]. Three additional loci designated EXTL1, EXTL2, and EXTL3 have been identified and mapped to chromosomes 1 (1p36), (1p11-p12) and chromosome 8 (8p12) [3]. ...
Hereditary multiple exostoses (HME) or multiple osteochondromas are an autosomal dominant condition and are genetically heterogeneous. It is characterized by development of two or more cartilage capped bony outgrowths (osteochondromas) of the long bones. Osteochondromas develop and increase in size in the first decade of life, ceasing to grow when the growth plates close at puberty. HME type-I is caused by mutation in the gene encoding exostosin-1 EXT1, which maps to chromosome 8q24. Type-II is caused by mutation in the gene encoding exostosin-2 EXT2 on chromosome 11p12-p11; and type III has been mapped to a locus on chromosome 19, EXT3. We report a de novo case of HME at the Kuwait medical genetic centre (KMGC) came for consultation regarding her poor school performance. She has painless bony swellings over her extremities, macrocephaly, congenital heart disease, obesity, history of developmental delay, and moderate mental retardation. Fluorescent In Situ Hybridization (FISH) analysis done using probes specific for regions 8p22/CEP8/& 8q24.12-8q24.13 showed delineation of two copies of normal sized chromosome 8; also Cycline D1 for 11q13 locus and CEP11, telomeric regions 11q & 11p, all showed normal signals. Telomeric 19p was used to rule out any deletion of 19p and was normal too.
... Most of the mutations (80%) are nonsense, frame-shift and splice-site mutations, resulting in a premature termination of translation, or involve partial or total deletion of the gene. Although it has been suggested that mutations in EXT1 are associated with a more severe phenotype than mutations in EXT2141516, many aspects of the phenotypic variability observed in patients have yet to be understood at the genetic level. As suggested by the Human Variome Project initiative, characterization of causative mutations in familial and sporadic cases in diverse populations is needed for full understanding of Mendelian diseases17. ...
Multiple osteochondromas is an autosomal dominant skeletal disorder characterized by the formation of multiple cartilage-capped tumours. Two causal genes have been identified, EXT1 and EXT2, which account for 65% and 30% of cases, respectively. We have undertaken a mutation analysis of the EXT1 and EXT2 genes in 39 unrelated Spanish patients, most of them with moderate phenotype, and looked for genotype-phenotype correlations. We found the mutant allele in 37 patients, 29 in EXT1 and 8 in EXT2. Five of the EXT1 mutations were deletions identified by MLPA. Two cases of mosaicism were documented. We detected a lower number of exostoses in patients with missense mutation versus other kinds of mutations. In conclusion, we found a mutation in EXT1 or in EXT2 in 95% of the Spanish patients. Eighteen of the mutations were novel.
... Unlike previous correlation studies [Francannet et al., 2001;Porter et al., 2004;Alvarez et al., 2006Alvarez et al., , 2007J€ ager et al., 2007] that evaluated a maximum of 76 variables, we started from 150 different features. After the first analysis, some of them (i.e., weight) were deemed not influential and/or equally/comparably occurring in the control population. ...
Multiple osteochondromas (MO), previously known as hereditary multiple exostoses (HME), is an autosomal dominant disease characterized by the formation of several benign cartilage-capped bone growth defined osteochondromas or exostoses. Various clinical classifications have been proposed but a consensus has not been reached. The aim of this study was to validate (using a machine learning approach) an "easy to use" tool to characterize MO patients in three classes according to the number of bone segments affected, the presence of skeletal deformities and/or functional limitations. The proposed classification has been validated (with a highly satisfactory mean accuracy) by analyzing 150 different variables on 289 MO patients through a Switching Neural Network approach (a novel classification technique capable of deriving models described by intelligible rules in if-then form). This approach allowed us to identify ankle valgism, Madelung deformity and limitation of the hip extra-rotation as "tags" of the three clinical classes. In conclusion, the proposed classification provides an efficient system to characterize this rare disease and is able to define homogeneous cohorts of patients to investigate MO pathogenesis. © 2013 Wiley Periodicals, Inc.
... The degree of severity was represented in two groups, M (moderate) or S (severe). Group S was classified into four clinical subgroups according to the increasing grade of severity (type IS, type IIS, type IIIS, and type IVS), especially with regard to the lower percentile [14][15][16] . In our patient, we defined the phenotype as severe (type IVS) based on the fair functional rating, the large number of exostoses (>25) and their vertebral locations, and very short stature (below the third percentile) 15 . ...
Multiple hereditary exostoses (MHE), also known as multiple osteochondromatosis, is an autosomal-dominant O-linked glycosylation disorder recently classified as EXT1/EXT2-CDG in the congenital disorder of glycosylation (CDG) nomenclature1. MHE is characterized by the presence of multiple cartilage-capped tumors, called “osteochondromas,” which usually develop in the juxta-epiphyseal regions of the long bones. The prevalence of MHE is estimated at 1:50,000 in the general population2,3. The Online Mendelian Inheritance in Man (OMIM) database classified it as either 133700 or 133701, according to whether the mutations occurred in the EXT1 or the EXT2 gene. These genes are located at 8q24 and 11p11-11p12, respectively, and they encode the co-polymerases responsible for heparan sulfate biosynthesis. EXT1 and EXT2 are tumor suppressor genes of the EXT gene family. The EXT1 gene contains eleven exons with a coding region of 2238 base pairs (bp), and the EXT2 gene contains sixteen exons with a coding region of 2154 bp4-7. These genes encode two glycosyltransferases involved in heparan sulfate biosynthesis, exostosin-1 (EXT1) (EC2.4.1.224) and exostosin-2 (EXT2) (EC2.4.1.225), whose impairment leads to the formation of exostoses5,8-10. Inactivating mutations (nonsense, frameshift, and splice site mutations) in EXT1 and EXT2 genes represent the majority of mutations that cause MHE. An overview of the reported variants is provided by the online Multiple Osteochondroma Mutation Database11.
The most important complication of MHE is the malignant transformation of osteochondroma to chondrosarcoma, which is estimated to occur in 0.5% to 5% of patients7. Chondrosarcomas arise de novo (primary) or as a result of a preexisting cartilage lesion (secondary). The biological aggressiveness of chondrosarcomas can be predicted by means of a histological grading system (grade I to grade III), based on three parameters: cellularity, degree of nuclear atypia, …
... The majority of missense mutations also lead to defective EXT protein function [33]. Mutations in EXT1 seem associated with a more severe phenotype as compared to EXT2 [34][35][36][37]. ...
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.
Multiple osteochondromas (MO) occur in approximately 1 in 50,000 people/yr. One in 3 patients with MO will develop valgus knee deformity (VKD), but the predictive factors for VKD are unclear. The purpose of this study was to examine the factors associated with VKD in patients with MO. From January 2003 to December 2018, 64 patients with MO visited the Nagoya University Hospital for the 1st time. Thirty-three patients with 66 limbs were sequentially included in the study after excluding 12 patients with a history of lower extremity surgery, 15 patients whose knee X-rays were unavailable, and 4 patients whose age at the last examination was <7 years. Limbs with femorotibial angle (FTA) ≥ 175° were defined as the normal group (Group N) and limbs with FTA < 175° as the valgus group (Group V), and clinical factors collected retrospectively from the medical records were compared between the 2 groups. The initial and final X-rays were compared in a subgroup analysis of 8 patients whose initial examination was <10 years old and who were followed for more than 5 years. Twenty-four males and 9 females with a median age of 17 years at the last X-rays were included in the study. The mean follow-up period was 43 ± 53 months, and the median FTA was 174.5°. Group N consisted of 32 limbs and Group V consisted of 34 limbs. Multivariate analysis was performed using the 5 factors with P -values <.15 in the univariate analysis of comparison between the 2 groups, and only medial proximal tibial angle showed significant differences ( P < .001). In the subgroup analysis, multivariate analysis showed that the femoral neck-shaft angle showed significant differences between the 2 groups at the initial evaluation ( P < .001). Our study suggests that medial proximal tibial angle is associated with VKD in patients with MO. Small neck-shaft angle was significantly associated with VKD, even before it became obvious. In order to study how VKD is formed, imaging of the hip and ankle joints and X-rays of the entire lower extremity should be performed in more cases.
Benign bone lesions in the lower extremities of children may produce pain, pathologic fracture, shortening, restriction of joint motion, or angular deformity. The common benign lesions seen in the lower extremities include osteochondromas, nonossifying fibromas, and fibrous dysplasia, while conditions such as multiple enchondromatosis, dysplasia epiphysealis hemimelica, and osteofibrous dysplasia are seen very rarely. Treatment is usually guided by the symptoms of the patients. Patients with conditions which create masses such as osteochondromas and dysplasia epiphysealis hemimelica frequently require excision for symptomatic improvement. Lesions with abnormal ossification, such as fibrous dysplasia and enchondromatosis, can cause pain and decreased osseous integrity while complicating treatment as a result of compromised bone mechanics. Extraosseous involvement may be seen in children with McCune Albright Syndrome (precocious puberty) and Maffucci’s syndrome (enchondromatosis, hemangiomatosis, and increased risk of malignancy). Malignant transformation may rarely occur in some conditions, namely osteochondromas, enchondromatosis, and osteofibrous dysplasia. This chapter will describe the etiologies, presentations, radiographic and histologic characteristics, and common treatments for these benign conditions.
Genu valgus is one of the most common limb deformities in hereditary multiple exostoses (HME). However, it is easily concealed and may account for subsequent osteoarthritis of the knee. The knees of 56 patients (33 men and 23 women) with HME were investigated bilaterally. Knee valgus was described by the mechanical axis deviation (MAD), mechanical lateral distal femoral angle (LDFA), and medial proximal tibial angle (MPTA). We investigated sex, age, BMI, total number of palpable osteochondromas, number of radiographic osteochondromas around the knee, forearm deformities, morphology and distribution of lesions, and correlations between these factors and genu valgus. The measurement of LDFA and MPTA was performed to identify the sources of genu valgus deformity. Based on the measurement of the mechanical axis, limbs were classified as genu valgus (n = 22) or normal mechanical axis groups (n = 90). The different severities of the genu valgus patients were classified by MAD. By bivariate logistic regression, genu valgus was significantly associated with more sessile and flared metaphyseal lesions. However, only the number of flared metaphyseal lesions had a significant influence on the severity of genu valgus. By analyzing the LDFA and MPTA, it was found that abnormalities of both proximal tibia and distal femur play important roles in genu valgus. Early detection of sessile and flared metaphyseal knee lesions in patients with HME can contribute to early intervention of genu valgus. Level of relevance: Level 2.
Hereditary Multiple Exostoses (HME) is a rare, pediatric disorder characterized by osteochondromas that form along growth plates and provoke significant musculoskeletal problems. HME is caused by mutations in heparan sulfate (HS)-synthesizing enzymes EXT1 or EXT2. Seemingly paradoxically, osteochondromas were found to contain excessive extracellular heparanase (Hpse) that could further reduce HS levels and exacerbate pathogenesis. To test Hpse roles, we asked whether its ablation would protect against osteochondroma formation in a conditional HME model consisting of mice bearing floxed Ext1 alleles in Agr-CreER background (Ext1 f/f ;Agr-CreER mice). Mice were crossed with a new global Hpse-null (Hpse -/- ) mice to produce compound Hpse -/- ;Ext1 f/f ;Agr-CreER mice. Tamoxifen injection of standard juvenile Ext1 f/f ;Agr-CreER mice elicited stochastic Ext1 ablation in growth plate and perichondrium followed by osteochondroma formation, as revealed by micro-computed tomography and histochemistry. When we examined companion conditional Ext1-deficient mice lacking Hpse also, we detected no major decreases in osteochondroma number, skeletal distribution and overall structure by the analytical criteria above. The Ext1 mutants used here closely mimic human HME pathogenesis but have not been previously tested for responsiveness to treatments. To exclude some innate therapeutic resistance in this stochastic model, tamoxifen-injected Ext1 f/f ;Agr-CreER mice were administered daily doses of the retinoid Palovarotene, previously shown to prevent ectopic cartilage and bone formation in other mouse disease models. This treatment did inhibit osteochondroma formation compared to vehicle-treated mice. Our data indicate that heparanase is not a major factor in osteochondroma initiation and accumulation in mice. Possible roles of heparanase upregulation in disease severity in patients are discussed.
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Background: Genu valgus is one of the most common limb deformities in hereditary multiple exostoses (HME). However, it is easily concealed and may account for subsequent osteoarthritis of the knee. The potential influence of factors for genu valgus is still not well known.
Methods: The knees of 56 patients (33 male, 23 female) with HME were investigated bilaterally. The mean age at evaluation was 8.9 years (range, 1.5–15.8 years). Knee valgus was described by the mechanical axis deviation (MAD), mechanical lateral distal femoral angle (LDFA), and medial proximal tibial angle (MPTA). We investigated gender, age, body mass index (BMI), total number of palpable osteochondromas, number of radiographic osteochondromas around the knee, forearm deformities, morphology and distribution of lesions, and correlations between these factors and genu valgus. The measurement of LDFA and MPTA was to identify the sources of genu valgus deformity.
Results: Based on the measurement of the mechanical axis, limbs were classified as genu valgus (n = 22) or normal mechanical axis groups (n = 90). The different severities of the genu valgus patients were classified by MAD. By bivariate logistic regression, genu valgus was significantly associated with more sessile and flared metaphyseal lesions. However only the number of flared metaphyseal lesions had a significant influence on the severity of genu valgus. By analyzing the LDFA and medial proximal tibial angle MPTA, it was found that abnormalities of both proximal tibia and distal femur play important roles in genu valgus. There were no differences between the genu valgus and normal mechanical axis groups in forearm deformities caused by HME, nor did this differ by severity of genu valgus.
Conclusions: Early detection of sessile and flared metaphyseal knee lesions in patients with HME can contribute to early intervention of genu valgus.
Level of Relevance: Level 2.
Aims:
Identification of genetic mutations linked to hereditary multiple osteochondromas (HMO) is crucial for understanding the molecular mechanisms leading to disease pathogenesis. In this study, we investigated four patients and eight healthy individuals from a family with HMO.
Methods:
Clinical HMO data and Sanger sequences of the coding regions of the exostosin glycosyltransferase 1 (EXT1) gene (18q24.11) and EXT2 gene (11p12) of all 12 members of the family were analyzed.
Results:
A novel nonsense mutation in the EXT2 gene (c.526C>T; p.Gln176*) was detected, which was present in all four patients but absent in their healthy relatives. This mutation encodes a stop codon that results in a truncated EXT2 protein that consists of only 176 amino acids and lacks the remaining 522 amino acids at its C-terminal, missing the entire glycosyltransferase domain.
Conclusions:
Association of a truncated EXT2 protein with HMO provides new insights into exostosis pathogenesis, highlighting potential roles of the EXT2 gene and its glycosyltransferase domain. Further research is required to understand the mechanisms underlying the development of exostosis.
Multiple osteochondromas (MOs) or hereditary multiple exostoses is a rare autosomal‐dominant disease characterized by growths of MOs, which are benign cartilage‐capped bone tumors that grow away from the growth plates. Almost 90% of MOs have a molecular explanation and 10% are unexplained. MOs are genetically heterogeneous with two causal genes on 8q24.11 (EXT1) and 11p12 (EXT2), with a higher frequency in EXT1. MO is a very rare genetic disorder, and the genotype–phenotype of MO with EXT2 mutation has not been well investigated in Korea. We present the clinical radiographic and molecular analysis of a four‐generation Korean family with 11 MO‐affected members (seven males and four females). The affected members from the third generation available for molecular analysis and their detailed medical histories showed moderate‐to‐severe phenotypes (clinical classes II–III), including bony deformities and limb misalignment with pain requiring surgical correction. The x‐rays showed MOs in multiple sites. A novel EXT2 frameshift mutation (c.590delC, p.P197Qfs*73) was revealed by targeted exome sequencing in the affected members of this family. In this article, we not only expand the phenotypic–genotypic spectrum of MOs but also highlight the phenotypic heterogeneity in a family with the same mutation. In addition, we compiled the mutation spectrum of EXT2 from a literature review and identified that exon 2 of EXT2 is a mutation hot spot. Early medical attention with diagnosis of MO through careful examination of the clinical manifestations and genetic analysis can provide the opportunity to establish coordinated multispecialty management of the patient.
Background:
Multiple hereditary exostoses (MHE) is an autosomal dominant condition leading to development of osteochondromas throughout the body. Although long bones are most often affected, spine involvement may occur and usually requires advanced imaging for diagnosis. However, the high cost of detection, infrequent occurrence, and very low likelihood of spinal cord compression and neurological injury, create a management conundrum. The purpose of our investigation is to identify patients at greatest risk for spinal lesions and refine indications for advanced imaging.
Methods:
All MHE patients in a 24-year period were retrospectively reviewed. Skeletally immature patients with advanced imaging of the spine were further evaluated. The demographic characteristics, family history, clinical presentation, past surgical history, tumor burden, and distribution of patients with spinal lesions were compared with those without.
Results:
In total, 227 MHE patients were identified and 21 underwent advanced spinal imaging. Spinal lesions were found in 8 of the 21 screened patients (38.1%, 3.5% overall), of which 4 were intracanal and 1 was symptomatic (4.8%, 0.4% overall). Only the symptomatic patient underwent excision of the spinal lesion. Patients with spinal lesions had higher tumor burden than those without (median, 28.5 vs. 19 locations; P=0.010). There was a significant association with rib (P=0.018) and pelvic (P=0.007) lesions, which may serve as "harbinger" lesions. The presence of both a rib and a pelvic lesion used as a screening tool for spinal lesions produces a sensitivity of 100% and specificity of 69%.
Conclusions:
Symptomatic spinal involvement in children with MHE is rare and tends to occur in patients with higher tumor burden. We recommend limiting advanced spine imaging to children with neurological symptoms or with rib and pelvic "harbinger" lesions. Patients without these findings are unlikely to have spine involvement needing intervention. This approach offers an opportunity to avoid unnecessary testing and substantially reduce costs of diagnostic imaging.
Level of evidence:
Level III.
Purpose:
To report on the outcomes of using ulnar lengthening combined with acute angular correction for the treatment of forearm deformities in patients affected by multiple hereditary exostoses (MHE). Our hypothesis was that this procedure would improve both radiographic measurements and clinical outcomes with minimal complications.
Methods:
A retrospective chart review was performed on patients who had a diagnosis of MHE and had undergone ulnar lengthening via a uniplanar external fixator over a 12-year period. Clinical outcomes such as range of motion, pain, and surgical complications were assessed. Radiographic changes were measured using interval radiographs.
Results:
The series included 17 patients. Median age at surgery was 7 years (range, 3-14 years). Median follow up was 55 months (range, 5-125 months). Improvements occurred in radial and ulnar radii of curvature, carpal slip, ulnar variance, and carrying angle at the elbow. There was 1 major pin track infection. There were 2 failures of the external fixator requiring exchange. Premature consolidation occurred in 1 case. Elbow, forearm, and wrist motion was not affected. Radiocapitellar joint congruency did not change. No patient reported pain at final follow-up.
Conclusions:
Our approach of using distraction osteogenesis of the ulna with angular correction in the radius and ulna as needed is able to correct carpal slip as well as to improve forearm bowing and elbow carrying angle. All of the patients maintained congruency of the radiocapitellar joint with no postoperative dislocations. Because of the low complication rate, the resolution of pain in patients who presented with pain, and the improvement of forearm bowing, this approach should be considered as a treatment option for children with MHE who are at risk for radiocapitellar dislocation.
Type of study/level of evidence:
Therapeutic IV.
Benign bone lesions in the lower extremities of children may produce pain, pathologic fracture, shortening, restriction of joint motion, or angular deformity. The common benign lesions seen in the lower extremities include osteochondromas, nonossifying fibromas, and fibrous dysplasia, while conditions such as multiple enchondromatosis, dysplasia epiphysealis hemimelica, and osteofibrous dysplasia are seen very rarely. Treatment is usually guided by the symptoms of the patients. Patients with conditions which create masses such as osteochondromas and dysplasia epiphysealis hemimelica frequently require excision of lesions for symptomatic improvement. Those lesions which are lytic in nature, such as fibrous dysplasia and enchondromatosis, may present skeletal fixation challenges due to compromised bone mechanics. Extraosseous involvement may be seen in children with fibrous dysplasia (precocious puberty) and Maffucci’s syndrome (enchondromatosis, hemangiomatosis, and increased risk of malignancy). Malignant transformation may occur in some conditions, namely osteochondromas, enchondromatosis, and osteofibrous dysplasia. This chapter will describe the etiologies, presentations, radiographic and histologic characteristics, and common treatments for these benign conditions.
Heparan sulfate proteoglycans are ubiquitously expressed at cell surfaces and in extra-cellular matrices. They are composed of a core protein and one or more heparan sulfate glycosaminoglycan chains (linear polysaccharides formed by alternating N-acetylated or N-sulfated glucosamine units and uronic acid) that interact with numerous proteins, including growth factors, morphogens and extra-cellular-matrix proteins. The heparan sulfate proteoglycans play crucial roles in physiology. On the other hand, under certain conditions, they also contribute to pathophysiology of some diseases. In this sense, the truncated HS chains within the HS proteoglycans cause the loss of binding to specific growth factors in chondrocytes, resulting in an abnormal signalization that leads to altered endochondral ossification. This produces a multiple osteochondroma formation leading to multiple osteochondromatosis / multiple hereditary exostosis, an autosomal dominant O-linked-glycosylation disorder recently classified as EXT1/EXT2-CDG in the new Congenital Disorder of Glycosylation (CDG) nomenclature. Products of the EXT genes are involved in heparan sulfate biosynthesis. Three loci have been identified, EXT1 in chromosome 8q24, EXT2 in chromosome 11p11-p13, and EXT3, in chromosome 19. The existence of this third locus is not clear, since most of the cases are caused by mutations in either EXT1 (65%) or EXT2 (35%). EXT1 and EXT2 genes code for two glycosyltransferases named exostosin 1 and 2, and both enzymes are part of a hetero-oligomeric complex localized within the Golgi complex. The O-linked xylosylation initiates the synthesis of a tetrasaccharide linker consisting of xylose-galactose-galactose-glucuronic acid (Xyl-Gal-Gal-GlcA) that links glycosaminoglycan moieties with the protein backbone in proteoglycans such as heparan sulfate. Recent studies have proposed a hypothetical model for hereditary exostoses formation, where a dominant germline mutation in either EXT1 or EXT2 in chondrocytes, inactivates the second copy of the same gene, leading to impaired heparan sulfate biosynthesis and expression. This will result in abnormal endochondral ossification, during the process of bone remodeling in childhood and early adolescence. Multiple osteochondromatosis has an estimated occurrence of about 1 in 50,000 in Western populations and is clinically characterized by cartilage-capped tumors developed from the growth plates of long bones or the surface of flat bones. Some common manifestations are orthopedic deformities of forearm, ankle, varus or valgus of knee, arthritis, vessels and nerves compression, but the most important complication is malignant transformation to chondrosarcoma. This review describes the clinical, biochemical and genetic basis of multiple osteochondromatosis (EXT1/EXT2-CDG), a congenital disorder of glycosylation.
This study was aimed to analyze the incidence and the anatomical distributions of HME (Hereditary Multiple Exostoses) on upper limbs and its related change in alignment of the upper limbs in HME patients.
Multiple osteochondromas (MO), an autosomal dominant skeletal disease, is characterized by the presence of multiple cartilage-capped bone tumors (exostoses). Two genes with mutations that are most commonly associated with MO have been identified as EXT1 and EXT2, which are Exostosin-1 and Exostosin-2. In this study, a variety of EXT1 and EXT2 gene mutations were identified in ten Chinese families with MO.
We investigated ten unrelated Chinese families involving a total of 46 patients who exhibited typical features of MO. The coding exons of EXT1 and EXT2 were sequenced after PCR amplification in ten probands. Radiological investigation was conducted simultaneously.
Nine mutations were identified, five in EXT1 and four in EXT2, of which three were de novo mutations and six were novel mutations. One proband carried mutations in both EXT1 and EXT2 simultaneously, and three probands, including one sporadic case and two familial cases, had no detectable mutations.
Our findings are useful for extending the mutational spectrum in EXT1 and EXT2 and understanding the genetic basis of MO in Chinese patients.
El punto común de la exostosis osteocartilaginosa solitaria y la exostosis múltiple es la expresión tumoral uniforme caracterizada por un doble componente, óseo y cartilaginoso, que evoluciona a lo largo del crecimiento. Ambas pertenecen al ámbito de la cirugía ortopédica pediátrica y del adulto. En su forma única, la exostosis osteocartilaginosa u osteocondroma tiene una semiología clínica y radiológica típica que permite formular un diagnóstico de certeza sin biopsia previa: tumor de superficie en estricta continuidad radiológica con la cortical metafisaria (de donde proviene) con inclusión de un capuchón cartilaginoso. Rara vez plantea dificultades de diagnóstico diferencial con un osteosarcoma paraóseo. El riesgo de degeneración es excepcional en la forma solitaria, en la cual la exéresis está indicada en las formas sintomáticas, en especial compresivas y localizadas en el fémur proximal, el omóplato y la pelvis. La exostosis múltiple es infrecuente, secundaria a tres mutaciones cromosómicas de transmisión autosómica dominante. En dos tercios de los casos hay un antecedente familiar que permite sospechar el diagnóstico en un recién nacido de padres afectados. La aparición esporádica es posible y obedece a una mutación de novo. La exostosis múltiple se caracteriza por una gran heterogeneidad clínica en relación con el número y el volumen de las unidades tumorales y con su diseminación. Las localizaciones más frecuentes, con repercusión sobre el crecimiento, son la muñeca, la rodilla y el tobillo. Las indicaciones terapéuticas respecto a estas localizaciones se han precisado mejor para prevenir las deformaciones ortopédicas, cuya repercusión funcional y social no es nada desdeñable. El riesgo de degeneración condrosarcomatosa en el adulto es claramente más elevado, sobre todo en las formas graves y en las cinturas escapular y pélvica. Los progresos de la genética permitirán la identificación precoz de las formas graves en el plano funcional y las de riesgo oncológico.
This study was done to analyze the alignment and deformity of the lower extremity in hereditary multiple exostoses patients.
Multiple osteochondromas (MO) is an autosomal dominant hereditary disorder caused by heterozygous germline mutations in the exostonsin-1 (EXT1) or exostosin-2 (EXT2) genes. In this study, we screened mutations in the EXT1/EXT2 genes in four Chinese MO kindreds by direct sequencing. Three point mutations were detected, including a nonsense mutation in the EXT2 gene (c.544C > T) and two splice site mutations in the EXT1 and EXT2 genes, respectively (EXT1: c.1883 + 1G > A and EXT2: c.1173 + 1G > T). Although splice site mutations constitute at least 10% of all mutations that cause MO, there has been limited research on their pathogenic effect on RNA processing due to poor availability of patient RNA samples. In this study, ex vivo and in vivo splicing assays were used to investigate the effect of EXT1 and EXT2 mutations on aberrant splicing at the mRNA level. Our results indicate that identified splice site mutations can cause either cryptic splice site usage or exon skipping. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res.
Hereditary multiple exostoses (HME) is a rare genetic disorder, which can be associated with severe complications that may significantly affect the health-related quality of life (HRQL). Our primary objective was to describe the baseline HRQL in HME individuals at the British Columbia's Children's Hospital HME clinic and the Multiple Hereditary Exostoses Coalition compared with relevant Canadian and US population norms. This is the first study to explore the HRQL among adults and children with HME.
Previously validated instruments Short Form-36 version 2, Short form-6D, and Child Health Questionnaire Parent Form 50 were used to assess the HRQL of individuals with HME. The scores from these instruments were compared with the relevant population norms. The British Columbia's Children's Hospital and Multiple Hereditary Exostoses coalition populations were also compared with each other.
The study sample consisted of 100 participants including 57 adults and 43 children. The mean age for Short Form 36 version 2 survey was 40.10±13.01 years and for Child Health Questionnaire Parent Form 50 was 9.93±3.48 years. Adult HME population had lower scores than both the US and Canadian general population in all domains except for emotional role limitations. Short Form -6D utility scores (0.65) indicates the quality of life for some individuals is near death and for others it is comparable or better than individuals with rheumatoid arthritis. Children with HME scored less than the US general population; particularly lower scores were seen in bodily pain (51.2 vs. 81.7) and emotional self-esteem (52.0 vs. 79.8).
HME population has lower HRQL than the general population. These data provide a benchmark for individuals with HME. From such data, future research on HME disease progression and effectiveness of treatments/interventions can be tracked over time.
Level II, This is a prognostic, prospective study with participants enrolled at different points in their disease.
Background:
Mutations in Exostosin-1 (EXT1) or Exostosin-2 (EXT2) cause the autosomal dominant disorder multiple osteochondromas (MO). This disease is mainly characterized by the appearance of multiple cartilage-capped protuberances arising from children's metaphyses and is known to display clinical inter- and intrafamilial variations. EXT1 and EXT2 are both tumor suppressor genes encoding proteins that function as glycosyltransferases, catalyzing the biosynthesis of heparan sulfate. At present, however, very little is known about the regulation of these genes. Two of the most intriguing questions concerning the pathogenesis of MO are how disruption of a ubiquitously expressed gene causes this cartilage-specific disease and how the clinical intrafamilial variation can be explained. Since mutations in the EXT1 gene are responsible for ~65% of the MO families with known causal mutation, our aim was to isolate and characterize the EXT1 promoter region to elucidate the transcriptional regulation of this tumor suppressor gene.
Methods:
In the present study, luciferase reporter gene assays were used to experimentally confirm the in silico predicted EXT1 core promoter region. Subsequently, we evaluated the effect of single nucleotide polymorphisms (SNP's) on EXT1 promoter activity and transcription factor binding using luciferase assays, electrophoretic mobility shift assays (EMSA), and enzyme-linked immunosorbent assays (ELISA). Finally, a genotype-phenotype study was performed with the aim to identify one or more genetic modifiers influencing the clinical expression of MO.
Results:
Transient transfection of HEK293 cells with a series of luciferase reporter constructs mapped the EXT1 core promoter at approximately -917 bp upstream of the EXT1 start codon, within a 123 bp region. This region is conserved in mammals and located within a CpG-island containing a CAAT- and a GT-box. A polymorphic G/C-SNP at -1158 bp (rs34016643) was demonstrated to be located in a USF1 transcription factor binding site, which is lost with the presence of the C-allele resulting in a ~56% increase in EXT1 promoter activity. A genotype-phenotype study was suggestive for association of the C-allele with shorter stature, but also with a smaller number of osteochondromas.
Conclusions:
We provide for the first time insight into the molecular regulation of EXT1. Although a larger patient population will be necessary for statistical significance, our data suggest the polymorphism rs34016643, in close proximity of the EXT1 promoter, to be a potential regulatory SNP, which could be a primary modifier that might explain part of the clinical variation observed in MO patients.
I report a case of a patient who suffered schizophrenia and multiple exostoses and argue the possible role of EXT gene and nearly chromosomal loci in further genetic investigations related to schizophrenia.
To identify the gene causing hereditary multiple exostoses in a Chinese pedigree.
Linkage analysis was carried out in the family using microsatellite markers close linkage to the EXT1 and EXT2 genes to define the candidate gene. Then the whole coding sequence and the intron-exon boundaries of the candidate gene were amplified and sequenced.
The disease-causing gene of the family was linked to the EXT2 gene. A nonsense mutation of 536G>A in exon3 of the EXT2 gene was detected, which was co-segregated with the disease phenotype. The mutation resulted in a stop codon in codon 180. A nonpenetrant case was found in the family.
The mutation 536G>A in the EXT2 gene is the disease-causing mutation in the pedigree with hereditary multiple exostoses.
Osteochondromas represent the largest group of benign tumors of bone. Multiple osteochondromatosis or hereditary multiple exostoses (EXT) is an autosomal dominant inherited disorder characterized by the presence of multiple benign cartilage-capped exostoses. EXT is genetically heterogeneous with at least 3 chromosomal loci: EXT1 (8q24.1), EXT2 (11p11–p13), and EXT3 (19p). In <5% of EXT patients, the inactivation of both copies of EXT alleles (LOH) is associated with malignant transformation. We have analyzed the EXT1 and EXT2 genes in 9 unrelated EXT families and in a patient with a sporadic osteochondroma, all originating from Italy. Four families show an EXT1 mutation, consisting of a small deletion in 3 of them and a small insertion in the 4th. All these mutations lead to premature termination of translation and thus a truncated EXT1 protein. Three families presented EXT2 mutations consisting of nucleotide substitutions leading to alterations of the third intron splice-site, to an amino acid substitution and to a nonsense mutation. All these mutations cosegregate with the disease phenotype. The sporadic osteochondroma patient carried a novel missense mutation in exon 11 of EXT2 gene, leading to an amino acid substitution. Seven of these mutations have never been described before. EXT2 missense mutations were also confirmed by amino acids conservation between human and mouse and by analysis of a healthy control population. In conclusion, our study provide further evidence that loss of function of the EXT1 or EXT2 gene is the main cause of EXT supporting the putative tumor-suppressor function of these genes. © 2001 Wiley-Liss, Inc.
Hereditary multiple exostoses (EXT; MIM 133700) is an autosomal dominant bone disorder characterized by the presence of multiple benign cartilage-capped tumors (exostoses). Besides suffering complications caused by the pressure of these exostoses on the surrounding tissues, EXT patients are at an increased risk for malignant chondrosarcoma, which may develop from an exostosis. EXT is genetically heterogeneous, and three loci have been identified so far: EXT1, on chromosome 8q23-q24; EXT2, on 11p11-p12; and EXT3, on the short arm of chromosome 19. The EXT1 and EXT2 genes were cloned recently, and they were shown to be homologous. We have now analyzed the EXT1 and EXT2 genes, in 26 EXT families originating from nine countries, to identify the underlying disease-causing mutation. Of the 26 families, 10 families had an EXT1 mutation, and 10 had an EXT2 mutation. Twelve of these mutations have never been described before. In addition, we have reviewed all EXT1 and EXT2 mutations reported so far, to determine the nature, frequency, and distribution of mutations that cause EXT. From this analysis, we conclude that mutations in either the EXT1 or the EXT2 gene are responsible for the majority of EXT cases. Most of the mutations in EXT1 and EXT2 cause premature termination of the EXT proteins, whereas missense mutations are rare. The development is thus mainly due to loss of function of the EXT genes, consistent with the hypothesis that the EXT genes have a tumor- suppressor function.
Hereditary multiple exostoses (HME) is an autosomal dominant disorder characterized by the formation of cartilage-capped tumours (exostoses) that develop from the growth plate of endochondral bone. This condition can lead to skeletal abnormalities, short stature and malignant transformation of exostoses to chondrosarcomas or osteosarcomas. Linkage analyses have identified three different genes for HME, EXT1 on 8q24.1, EXT2 on 11p11-13 and EXT3 on 19p (refs 6-9). Most HME cases have been attributed to missense or frameshift mutations in these tumour-supressor genes, whose functions have remained obscure. Here, we show that EXT1 is an ER-resident type II transmembrane glycoprotein whose expression in cells results in the alteration of the synthesis and display of cell surface heparan sulfate glycosaminoglycans (GAGs). Two EXT1 variants containing aetiologic missense mutations failed to alter cell-surface glycosaminoglycans, despite retaining their ER-localization.
Multiple hereditary exostoses is an autosomal dominant skeletal disorder in which there are numerous cartilage-capped excrescences in areas of actively growing bone. The condition is genetically heterogeneous, and at least three genes, ext1, ext2 and ext3 are involved. The reported risk for malignant transformation to chondrosarcoma has been from 0.6% to 2.8%. We have reviewed six generations of a family with 114 living adult members, 46 of them with multiple exostoses. Four have had operations for chondrosarcoma, giving the risk for malignant transformation as 8.3% in this family. Clinical and radiological examination revealed two additional patients with a suspicion of malignancy, but in whom the histological findings were benign. Reported elsewhere in detail, genetic linkage analysis mapped the causative gene to chromosome 11 and molecular studies revealed a guanine-to-thymine transversion in the ext2 gene. Patients with multiple hereditary exostoses carry a relatively high risk of malignant transformation. They should be informed of this possibility and regularly reviewed.
Hereditary multiple exostoses (HME) is a genetically heterogeneous autosomal dominant disorder characterised by the development of bony protuberances mainly located on the long bones. Three HME loci have been mapped to chromosomes 8q24 (EXT1), 11p11-13 (EXT2), and 19p (EXT3). The EXT1 and EXT2 genes encode glycosyltransferases involved in biosynthesis of heparan sulphate proteoglycans. Here we report on a clinical survey and mutation analysis of 42 HME French families and show that EXT1 and EXT2 accounted for more than 90% of HME cases in our series. Among them, 27/42 cases were accounted for by EXT1 (64%, four nonsense, 19 frameshift, three missense, and one splice site mutations) and 9/42 cases were accounted for by EXT2 (21%, four nonsense, two frameshift, two missense, and one splice site mutation). Overall, 31/36 mutations were expected to cause loss of protein function (86%). The most severe forms of the disease and malignant transformation of exostoses to chondrosarcomas were associated with EXT1 mutations. These findings provide the first genotype-phenotype correlation in HME and will, it is hoped, facilitate the clinical management of these patients.
We performed a prospective genotype-phenotype study using molecular screening and clinical assessment to compare the severity of disease and the risk of sarcoma in 172 individuals (78 families) with hereditary multiple exostoses. We calculated the severity of disease including stature, number of exostoses, number of surgical procedures that were necessary, deformity and functional parameters and used molecular techniques to identify the genetic mutations in affected individuals. Each arm of the genotype-phenotype study was blind to the outcome of the other. Mutations EXT1 and EXT2 were almost equally common, and were identified in 83% of individuals. Non-parametric statistical tests were used.
There was a wide variation in the severity of disease. Children under ten years of age had fewer exostoses, consistent with the known age-related penetrance of this condition. The severity of the disease did not differ significantly with gender and was very variable within any given family. The sites of mutation affected the severity of disease with patients with EXT1 mutations having a significantly worse condition than those with EXT2 mutations in three of five parameters of severity (stature, deformity and functional parameters). A single sarcoma developed in an EXT2 mutation carrier, compared with seven in EXT1 mutation carriers. There was no evidence that sarcomas arose more commonly in families in whom the disease was more severe.
The sarcoma risk in EXT1 carriers is similar to the risk of breast cancer in an older population subjected to breast-screening, suggesting that a role for regular screening in patients with hereditary multiple exostoses is justifiable.
Osteochondromas represent the largest group of benign tumors of bone. Multiple osteochondromatosis or hereditary multiple exostoses (EXT) is an autosomal dominant inherited disorder characterized by the presence of multiple benign cartilage‐capped exostoses. EXT is genetically heterogeneous with at least 3 chromosomal loci: EXT1 (8q24.1), EXT2 (11p11–p13), and EXT3 (19p). In <5% of EXT patients, the inactivation of both copies of EXT alleles (LOH) is associated with malignant transformation. We have analyzed the EXT1 and EXT2 genes in 9 unrelated EXT families and in a patient with a sporadic osteochondroma, all originating from Italy. Four families show an EXT1 mutation, consisting of a small deletion in 3 of them and a small insertion in the 4th. All these mutations lead to premature termination of translation and thus a truncated EXT1 protein. Three families presented EXT2 mutations consisting of nucleotide substitutions leading to alterations of the third intron splice‐site, to an amino acid substitution and to a nonsense mutation. All these mutations cosegregate with the disease phenotype. The sporadic osteochondroma patient carried a novel missense mutation in exon 11 of EXT2 gene, leading to an amino acid substitution. Seven of these mutations have never been described before. EXT2 missense mutations were also confirmed by amino acids conservation between human and mouse and by analysis of a healthy control population. In conclusion, our study provide further evidence that loss of function of the EXT1 or EXT2 gene is the main cause of EXT supporting the putative tumor‐suppressor function of these genes. © 2001 Wiley‐Liss, Inc.
Many theories of osteochondroma pathogenesis have been advanced. Genetic research into the inherited multiple form, hereditary multiple exostoses, has revealed a new family of tumour suppressor genes denoted EXT. Patterns of EXT gene mutation in hereditary multiple exostoses, in solitary and multiple osteochondromas, and in chondrosarcoma are analogous to those found in other tumour suppressor genes responsible for family cancer traits and associated malignancies. With one exception, most features of osteochondroma behaviour are comparable to those of benign neoplasms. The neoplastic pathogenesis of osteochondromas provides an alternative to the traditional ‘skeletal dysplasia’ theory to explain the growth disturbance associated with hereditary multiple exostoses. Recent studies on the physiological function of EXT genes are reviewed and implications for osteochondroma ‘cell‐of‐origin’ theories are discussed. Copyright © 1999 John Wiley & Sons, Ltd.
Multiple hereditary exostoses is an autosomal dominant skeletal disorder in which there are numerous cartilage-capped excrescences in areas of actively growing bone. The condition is genetically heterogeneous, and at least three genes, ext1, ext2 and ext3 are involved. The reported risk for malignant transformation to chondrosarcoma has been from 0.6% to 2.8%. We have reviewed six generations of a family with 114 living adult members, 46 of them with multiple exostoses. Four have had operations for chondrosarcoma, giving the risk for malignant transformation as 8.3% in this family. Clinical and radiological examination revealed two additional patients with a suspicion of malignancy, but in whom the histological findings were benign. Reported elsewhere in detail, genetic linkage analysis mapped the causative gene to chromosome 11 and molecular studies revealed a guanine-to-thymine transversion in the ext2 gene. Patients with multiple hereditary exostoses carry a relatively high risk of malignant transformation. They should be informed of this possibility and regularly reviewed.
We established a database of hereditary multiple exostoses for the state of Washington, on the basis of a retrospective review of the medical records and a clinical evaluation of family members, to determine the prevalence, clinical range of expression, and rate of malignant degeneration. The database comprised forty-six kindreds with 113 affected members; all kindreds had at least one member living in the state of Washington. The over-all prevalence was at least one in 50,000. Approximately 10 per cent of the subjects had no family history of multiple exostoses. With the use of twenty-three pedigrees that demonstrated an adequate multigenerational history for determination of penetrance of the gene, we identified one unaffected individual among twenty-six obligate heterozygotes, a rate of penetrance of 96 per cent. There was no evidence for a substantial reduction of penetrance in female subjects. The median age at the time of the diagnosis in the 113 affected individuals was three years (range, birth to twelve years). In a cohort of eighty-four subjects for whom we had complete information, the clinical range of expression was wide: thirty-three (39 per cent) had an obvious deformity of the forearm, eight (10 per cent) had an inequality in the lengths of the limbs, seven (8 per cent) had an angular deformity of the knee, and two (2 per cent) had a deformity of the ankle. The average number of operations for the patients for whom the operative history was known was two.(ABSTRACT TRUNCATED AT 250 WORDS)
Based upon observations on 48 cases of retinoblastoma and published reports, the hypothesis is developed that retinoblastoma is a cancer caused by two mutational events. In the dominantly inherited form, one mutation is inherited via the germinal cells and the second occurs in somatic cells. In the nonhereditary form, both mutations occur in somatic cells. The second mutation produces an average of three retinoblastomas per individual inheriting the first mutation. Using Poisson statistics, one can calculate that this number (three) can explain the occasional gene carrier who gets no tumor, those who develop only unilateral tumors, and those who develop bilateral tumors, as well as explaining instances of multiple tumors in one eye. This value for the mean number of tumors occurring in genetic carriers may be used to estimate the mutation rate for each mutation. The germinal and somatic rates for the first, and the somatic rate for the second, mutation, are approximately equal. The germinal mutation may arise in some instances from a delayed mutation.
Hereditary multiple exostoses (EXT) is an autosomal dominant bone disease characterized by the formation of cartilage-capped prominences. EXT is genetically heterogeneous with at least four chromosomal loci. Among the four loci, the exostosis type 1 gene (EXT1) and type 2 gene (EXT2) have been cloned. Previous studies have shown that disease-type-specific frequency of mutations is different among various ethnic populations. To determine those frequencies in the Japanese, we conducted a large-scale mutation screening on both genes. In 23 of 43 Japanese families examined, we found 21 different mutations, of which 18 are novel. Seventeen (40%) of the 23 families had a mutation in EXT1 and six (14%) had a mutation in EXT2, suggesting that the former mutations are more frequent than the latter in Japanese EXT families. Of the 17 families with EXT1 mutations, 13 had those causing premature termination of the EXT1 protein and four showed missense mutations, whereas five of the six families with EXT2 mutations had those causing premature termination and one showed missense mutation. Interestingly, all four EXT1 missense mutations occurred in an arginine residue at codon 340 (R340) that is known as a critical site for expression of heparan sulfate glycosaminoglycans, suggesting that the region encompassing the arginine residue may play an important role in the function of the EXT1 protein. These results expand our knowledge of the ethnic difference of EXT and the structure-function relationship of the EXT genes. © Wiley-Liss. Inc.
Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by growth of benign bone tumors. Three chromosomal loci have been implicated in this genetically heterogeneous disease: EXT1 at 8q24, EXT2 at 11p13, and EXT3 on 19p. EXT1 and EXT2 were recently cloned. We evaluated 34 families with EXT to estimate the proportion of disease attributable to EXT1, EXT2, and EXT3 and to investigate the spectrum of EXT1 mutations. Linkage analyses combined with heterogeneity testing provides strong evidence in favor of linkage of disease to both chromosomes 8 and 11, but does not support evidence of linkage to chromosome 19 in this data set. The 11 EXT1 exons were PCR-amplified and sequenced in all 11 isolated cases and in 20 of the 23 familial cases. Twelve different novel EXT1 mutations were detected, including 5 frame-shift deletions or insertions, 1 codon deletion, and 6 single base-pair substitutions distributed across 8 of the exons. Only 2 of the mutations were detected in more than one family. Three mutations affect sites in which alterations were previously reported. Nonchain-terminating missense mutations were identified in codons 280 and 340, both coding for conserved arginine residues. These residues may be crucial to the function of this protein. Although the prevalence of EXT has been estimated to be approximately 1/50,000 individuals, the disease has been reported to occur much more frequently in the Chamorro natives on Guam. Our detection of an EXT1 mutation in one Chamorro subject will allow investigation of a possible founder effect in this population. Combined mutational and heterogeneity analyses in this set of families with multiple exostoses suggest that 66% of our total sample, including 45% of isolated and 77% of familial cases, are attributable to abnormalities in EXT1. Hum Mutat 11:231–239, 1998. © 1998 Wiley-Liss, Inc.
Based on a series of 120 normal subjects of different gender and age, the geometry of the knee joint was analyzed using a full-length weight-bearing roentgenogram of the lower extremity. A special computer program based on the theory of a rigid body spring model was applied to calculate the important anatomic and biomechanical factors of the knee joint. The tibiofemoral mechanical angle was 1.2 degrees varus. Hence, it is difficult to rationalize the 3 degree varus placement of the tibial component in total knee arthroplasty suggested by some authors. The distal femoral anatomic valgus (measured from the lower one-half of the femur) was 4.2 degrees in reference to its mechanical axis. This angle became 4.9 degrees when the full-length femoral anatomic axis was used. When simulating a one-legged weight-bearing stance by shifting the upper-body gravity closer to the knee joint, 75% of the knee joint load passed through the medial tibial plateau. The knee joint-line obliquity was more varus in male subjects. The female subjects had a higher peak joint pressure and a greater patello-tibial Q angle. Age had little effect on the factors relating to axial alignment of the lower extremity and load transmission through the knee joint.
Based upon observations on 48 cases of retinoblastoma and published reports, the hypothesis is developed that retinoblastoma is a cancer caused by two mutational events. In the dominantly inherited form, one mutation is inherited via the germinal cells and the second occurs in somatic cells. In the nonhereditary form, both mutations occur in somatic cells.
The second mutation produces an average of three retinoblastomas per individual inheriting the first mutation. Using Poisson statistics, one can calculate that this number (three) can explain the occasional gene carrier who gets no tumor, those who develop only unilateral tumors, and those who develop bilateral tumors, as well as explaining instances of multiple tumors in one eye.
This value for the mean number of tumors occurring in genetic carriers may be used to estimate the mutation rate for each mutation. The germinal and somatic rates for the first, and the somatic rate for the second, mutation, are approximately equal. The germinal mutation may arise in some instances from a delayed mutation.
Hereditary multiple exostosis (EXT) is an autosomal dominant disorder in which the clinical hallmark is the growth of bony protuberances from long bones and which can cause a variety of orthopedic deformities. This study sought to further delineate the natural history of EXT. In addition, since previous studies have suggested that there are deviations from Mendelian expectations in EXT, including incomplete penetrance and a skewed sex ratio, we attempted to confirm or refute these suggestions. Both portions of the study were carried out through retrospective review of 43 affected probands and 137 of their affected relatives. Data are presented concerning frequency and severity of complications of EXT including short stature, sequelae of exostoses, occurrence of malignant degeneration of exostoses, and problems in pregnancy and delivery of affected females. Only 2.8% of the total affected population had experienced exostosis-related malignancy, an estimate which is considerably less than earlier reports would suggest. Penetrance was 100%. There was an excess of males within the entire affected population (104:76) and within identified probands (28:15). However, the male to female ratio was unskewed in nuclear families (probands, affected sibs, and parents). The excess of males appears to be related to males having more severe and more frequent complications of EXT than having any primary genetic origin.
We established a database of hereditary multiple exostoses for the state of Washington, on the basis of a retrospective review of the medical records and a clinical evaluation of family members, to determine the prevalence, clinical range of expression, and rate of malignant degeneration. The database comprised forty-six kindreds with 113 affected members; all kindreds had at least one member living in the state of Washington. The over-all prevalence was at least one in 50,000. Approximately 10 per cent of the subjects had no family history of multiple exostoses. With the use of twenty-three pedigrees that demonstrated an adequate multigenerational history for determination of penetrance of the gene, we identified one unaffected individual among twenty-six obligate heterozygotes, a rate of penetrance of 96 per cent. There was no evidence for a substantial reduction of penetrance in female subjects. The median age at the time of the diagnosis in the 113 affected individuals was three years (range, birth to twelve years). In a cohort of eighty-four subjects for whom we had complete information, the clinical range of expression was wide: thirty-three (39 per cent) had an obvious deformity of the forearm, eight (10 per cent) had an inequality in the lengths of the limbs, seven (8 per cent) had an angular deformity of the knee, and two (2 per cent) had a deformity of the ankle. The average number of operations for the patients for whom the operative history was known was two.(ABSTRACT TRUNCATED AT 250 WORDS)
From 1986 through 1988, 266 persons (149 adults and 117 children) were screened for multiple hereditary exostosis (MHE) in an isolated northern Ojibway community. Physical examination and confirmation by roentgenogram skeletal survey disclosed 21 children (19.4%) and 14 adults (9.5%) affected with MHE. Forty-one percent of children had lesions detectable before ten years of age, some as early as two years of age. Seventy-four percent of the lesions were characteristically sessile. Although lesions about the knee were most common, sites previously thought to be uncommon such as the metatarsals, hand, and spine were involved in 40% of the children. No cases of malignant degeneration have occurred in the adult population. Severity and multiplicity of lesions in successive generations point to an oncogenic gene origin. This study shows striking variance from current literature and provides a unique and valuable baseline assessment of research on the cause and natural history of MHE.
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.
Hereditary multiple exostoses (EXT) is a genetically heterogeneous bone disorder caused by genes segregating on human chromosomes 8, 11, and 19 and designated EXT1, EXT2 and EXT3, respectively. Recently, the EXT1 gene has been isolated and partially characterized and appears to encode a tumor suppressor gene. We have identified six mutations in the human EXT1 gene from six unrelated multiple exostoses families segregating for the EXT gene on chromosome 8. One of the mutations we detected is the same 1-bp deletion in exon 6 that was previously reported in two independent EXT families. The other five mutations, in exons 1, 6, 9, and the splice junction at the 3' end of exon 2, are novel. In each case, the mutation is likely to result in a truncated or nonfunctional EXT1 protein. These results corroborate and extend the previous report of mutations in this gene in two EXT families, and provide additional support for the EXT1 gene as the cause of hereditary multiple exostoses in families showing linkage to chromosome 8.
Hereditary multiple exostoses (HME), the most frequent of all skeletal dysplasias, is an autosomal dominant disorder characterized by the presence of multiple exostoses localized mainly at the end of long bones. HME is genetically heterogeneous, with at least three loci, on 8q24.1 (EXT1), 11p11-p13 (EXT2), and 19p (EXT3). Both the EXT1 and EXT2 genes have been cloned recently and define a new family of potential tumor suppressor genes. This is the first study in which mutation screening has been performed for both the EXT1 and EXT2 genes prior to any linkage analysis. We have screened 17 probands with the HME phenotype, for alterations in all translated exons and flanking intronic sequences, in the EXT1 and EXT2 genes, by conformation-sensitive gel electrophoresis. We found the disease-causing mutation in 12 families (70%), 7 (41%) of which have EXT1 mutations and 5 (29%) EXT2 mutations. Together with the previously described 1-bp deletion in exon 6, which is present in 2 of our families, we report five new mutations in EXT1. Two are missense mutations in exon 2 (G339D and R340C), and the other three alterations (a nonsense mutation, a frameshift, and a splicing mutation) are likely to result in truncated nonfunctional proteins. Four new mutations are described in EXT2. A missense mutation (D227N) was found in 2 different families; the other three alterations (two nonsense mutations and one frameshift mutation) lead directly or indirectly to premature stop codons. The missense mutations in EXT1 and EXT2 may pinpoint crucial domains in both proteins and therefore give clues for the understanding of the pathophysiology of this skeletal disorder.
Many theories of osteochondroma pathogenesis have been advanced. Genetic research into the inherited multiple form, hereditary multiple exostoses, has revealed a new family of tumour suppressor genes denoted EXT. Patterns of EXT gene mutation in hereditary multiple exostoses, in solitary and multiple osteochondromas, and in chondrosarcoma are analogous to those found in other tumour suppressor genes responsible for family cancer traits and associated malignancies. With one exception, most features of osteochondroma behaviour are comparable to those of benign neoplasms. The neoplastic pathogenesis of osteochondromas provides an alternative to the traditional 'skeletal dysplasia' theory to explain the growth disturbance associated with hereditary multiple exostoses. Recent studies on the physiological function of EXT genes are reviewed and implications for osteochondroma 'cell-of-origin' theories are discussed.
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.
Hereditary multiple exostoses (EXT; MIM 133700) is an autosomal dominant bone disorder. It is genetically heterogeneous with at least three chromosomal loci: EXT1 on 8q24.1, EXT2 on 11p11, and EXT3 on 19p. EXT1 and EXT2, the two genes responsible for EXT1 and EXT2, respectively, have been cloned. Recently, three other members of the EXT gene family, named the EXT-like genes (EXTL: EXTL1, EXTL2, and EXTL3), have been isolated. EXT1, EXT2, and the three EXTLs are homologous with one another. We have identified the intron-exon boundaries of EXTL1 and EXTL3 and analyzed EXT1, EXT2, EXTL1, and EXTL3, in 36 Chinese families with EXT, to identify underlying disease-related mutations in the Chinese population. Of the 36 families, five and 12 family groups have mutations in EXT1 and EXT2, respectively. No disease-related mutation has been found in either EXTL1 or EXTL2, although one polymorphism has been detected in EXTL1. Of the 15 different mutations (three families share a common mutation in EXT2), 12 are novel. Most of the mutations are either frameshift or nonsense mutations (12/15). These mutations lead directly or indirectly to premature stop codons, and the mutations generate truncated proteins. This finding is consistent with the hypothesis that the development of EXT is mainly attributable to loss of gene function. Missense mutations are rare in our families, but these mutations may reflect some functionally crucial regions of these proteins. EXT1 is the most frequent single cause of EXT in the Caucasian population in Europe and North America. It accounts for about 40% of cases of EXT. Our study of 36 EXT Chinese families has found that EXT1 seems much less common in the Chinese population, although the frequency of the EXT2 mutation is similar in the Caucasian and Chinese populations. Our findings suggest a possibly different genetic spectrum of this disease in different populations.
Hereditary multiple exostosis (HME) is an autosomal dominant disorder leading to polyostotic periphyseal osteochondroma formation. These tumorous lesions can cause growth disturbances, painful local symptoms, restriction of joint motion, and neurologic compromise. Malignant transformation has been noted. The reports of the incidence of these complications vary widely in the literature. Recently, genetic lineage mapping disclosed three locations for HME with loci on chromosomes 8, 11, and 19. It is possible that these three genotypes may result in different phenotypic expression of HME and thus explain the variable manifestations of the disease. This study attempts to record the clinical findings of HME patients who have undergone genetic mapping to determine whether varying clinical patterns may exist for each genotype of HME.
Hereditary multiple exostoses (HME) is traditionally described as a skeletal dysplasia. However, the discovery that the EXT family of tumour suppressor genes are responsible for HME suggests that it is more appropriate to classify HME as a familial neoplastic trait. In a clinical and radiographic analysis of paired bone length and exostoses number and dimensions in a HME cohort, the local presence of osteochondromas was consistently associated with growth disturbance. In particular, an inverse correlation between osteochondroma size and relative bone length (p<0.01) was found. These data suggest that the growth retardation in HME may result from the local effects of enlarging osteochondromas rather than a skeletal dysplasia effect. This study provides the first clinical rationale for ablation of rapidly enlarging exostoses to reduce growth disturbance.
Osteochondromas represent the largest group of benign tumors of bone. Multiple osteochondromatosis or hereditary multiple exostoses (EXT) is an autosomal dominant inherited disorder characterized by the presence of multiple benign cartilage-capped exostoses. EXT is genetically heterogeneous with at least 3 chromosomal loci: EXT1 (8q24.1), EXT2 (11p11-p13), and EXT3 (19p). In <5% of EXT patients, the inactivation of both copies of EXT alleles (LOH) is associated with malignant transformation. We have analyzed the EXT1 and EXT2 genes in 9 unrelated EXT families and in a patient with a sporadic osteochondroma, all originating from Italy. Four families show an EXT1 mutation, consisting of a small deletion in 3 of them and a small insertion in the 4th. All these mutations lead to premature termination of translation and thus a truncated EXT1 protein. Three families presented EXT2 mutations consisting of nucleotide substitutions leading to alterations of the third intron splice-site, to an amino acid substitution and to a nonsense mutation. All these mutations cosegregate with the disease phenotype. The sporadic osteochondroma patient carried a novel missense mutation in exon 11 of EXT2 gene, leading to an amino acid substitution. Seven of these mutations have never been described before. EXT2 missense mutations were also confirmed by amino acids conservation between human and mouse and by analysis of a healthy control population. In conclusion, our study provide further evidence that loss of function of the EXT1 or EXT2 gene is the main cause of EXT supporting the putative tumor-suppressor function of these genes.
1. The widespread deformities commonly associated with diaphysial aclasis have been studied in seventy-six patients. Apart from the adaptations of growth due to pressure by neighbouring exostoses, all the deformities of the tubular bones can be explained in terms of the same underlying factor–diminished length of the bones affected by the disease.
2. When the condition first manifests itself the future pattern of bone growth is completely unpredictable except in so far as it is known that the more actively growing ends of the long bones are the more severely affected in each case. It has also been shown in this series that, in general, the bones with the smallest cross-sectional area at the epiphysial plates (such as the ulna and the fibula) are the most severely shortened of all.
3. The cause of this disturbance of growth is still unknown, but there is an undoubted relationship between the presence of exostoses or thickening of the metaphysial region and shortening of the bone involved.
4. The phenomena of migrating exostoses and disappearing exostoses are also described and are shown to be examples of the normal process of bone modelling applied in special circumstances.
5. Although the importance of the cartilage-capped exostoses is not underestimated, it is hoped that this study will stimulate further work on what is probably the basic defect in this disease–namely, the disturbance of bone growth.
Medical education is currently undergoing a phase of transition. Many of the traditional teaching methods and standard curricula are under active scrutiny and, in several schools, have given way to radical new approaches. The objectives of these modifications are directed toward more individualized, broader, liberal education of the student and keeping pace with the tremendously expanding volume of medical knowledge without lengthening (perhaps shortening) the total period of training. In this light, it is of interest to compare the casual treatment of radiology in the medical curriculum of ten years ago with what is currently being offered in a number of teaching centers in the country. Our own experiences in the past five years with a new approach to the teaching of radiology to medical students has been most gratifying in the enthusiasm of the response of our students and faculty. Our concept of the role of radiology in the undergraduate teaching program is that of a discipline in which the anatomy, no...
Retrospective review of spinal exostoses treated at our institution and literature review.
Review of 12 cases of spinal exostoses treated at our institution compared with 165 cases of spinal exostoses reported in the literature.
Spinal exostoses are uncommon. Most reports consist of 1 to 3 cases. The relationship between solitary exostoses and those associated with multiple hereditary exostoses (MHE), as well as the incidence of intraspinal and extraspinal location, symptoms presentation, and results of treatment are unclear.
The medical records, operative reports, and diagnostic imaging of 12 patients with spinal exostoses treated at our institution between 1972 and 2002 were reviewed. The literature was reviewed using MEDLINE search of English literature and bibliographies of published manuscripts.
Solitary spinal exostoses were more common than those associated with MHE. Lesions were most common in the upper cervical spine and originated from the posterior elements. Patients with exostoses associated with MHE were significantly younger and had a higher incidence of symptoms consistent with neural structure compression than patients with solitary exostoses. Complete excision resulted in resolution of preoperative symptoms. Intralesional excision resulted in recurrence in all cases.
Spinal exostoses are more common than reported previously. Patients with MHE that present with back pain or neurological symptoms should produce a high index of suspicion. Evaluation should include both computed tomography and magnetic resonance imaging to define the origin of the exostosis and the presence of neural structure compression. Surgical excision should be preformed en bloc.
This study was undertaken to characterize pain in individuals with hereditary multiple exostosis (HME). Two hundred ninety-three patients with HME completed a questionnaire designed to assess pain as well as its impact on their life. Eighty-four percent of participants reported having pain, indicating that pain is a real problem in HME. Of those with pain, 55.1% had generalized pain. Two factors were found to be associated with pain outcome: HME-related complications and surgery. Individuals who had HME-related complications were five times more likely to have pain, while those who had surgery were 3.8 more likely to have pain. No differences were found between males and females with respect to pain, surgery, or HME-related complications. The results of this study indicate that the number of individuals with HME who have pain has been underestimated and that pain is a problem that must be addressed when caring for individuals with HME.
Hereditary multiple exostoses (HME) is an autosomal dominant condition with a wide spectrum of clinical presentations. The purpose of this study was to determine the relationship between the genotype and the phenotype in HME. Thirty-two affected individuals from 10 families participated in the study. An extensive description of HME phenotype in terms of the anatomical burden of disease involved clinical and radiographic examinations and evaluation of 76 parameters. Mutations were determined by sequencing the EXT 1 and EXT 2 genes. Mutations were found in eight families (26 individuals), with one mutation previously reported in the literature and seven novel mutations. There were seven subjects with an EXT 1 mutation and 16 with an EXT 2 mutation. Patients with EXT 1 mutation were found to have more exostoses, more limb malalignment with shorter limb segments and height, and more pelvic and flatbone involvement. A genotype-phenotype correlation exists in HME, with patients with EXT 1 mutations having a higher degree of anatomical burden.
Mutation analysis of hereditary multiple exostoses in the Chinese.
- Xu
3rd, Matsushita M, Wijsman EM, Wells DE, Chapman N, Sandell LJ, Wagner M, Houck J. Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses.
- Raskind