RARE DISEASE
Multiple osteochondromas
Multiple osteochondromas
Multiple osteochondromas
Synonyms: Bessel-Hagen disease, Multiple cartilaginous exostoses
Synonyms: Bessel-Hagen disease, Multiple cartilaginous exostoses
Synonyms: Bessel-Hagen disease, Multiple cartilaginous exostoses
Drug discovery
2
drugs
With orphan designations
Overview
Multiple Osteochondromas (MO), also termed Hereditary Multiple Exostoses (HME), is an autosomal dominant disorder caused by EXT1 or EXT2 mutations, leading to benign osteochondromas. These growths arise near growth plates, causing limb deformities, restricted mobility, and limb-length discrepancies. MO presents in childhood, with 96% developing tumors by age 12. Lifetime malignant transformation risk is 1–5% (chondrosarcoma). Management focuses on symptom relief, deformity correction, and monitoring for malignancy [5][8][12][17].
Burden
Functional: Chronic pain (50–84% of patients), reduced range of motion, and limb-length discrepancies ≥2 cm in 70% [4][19][20].
Psychosocial: Higher anxiety/depression rates vs. population norms; 30–44% report reduced quality of life [4][16].
Oncologic: Lifetime sarcoma risk (1–5%) requires lifelong surveillance post-puberty [5][8][17].
Therapies
Surgical excision: Primary approach for symptomatic osteochondromas causing pain, nerve compression, or functional impairment [1][11][13].
Reconstructive surgery: Addresses limb deformities (guided growth plates, osteotomies) [10][11].
Emerging therapies: BMP signaling inhibitors (e.g., LDN-193189) and retinoid agonists (e.g., Palovarotene) in clinical trials [3][7].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare inborn errors of metabolism, rare neoplastic diseases
Research Papers
364 drug discovery papers about Multiple osteochondromas, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
364 drug discovery papers about Multiple osteochondromas, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-02-18 | Strategies for surgical reconstruction of complex elbow deformities based on patient-specific instruments - a case series and narrative review.
The application of 3D-based methods for deformity correction of the upper extremity, including patient-specific instruments (PSIs), is attracting increasing attention in clinical practice and requires the collaboration of orthopaedic surgeons and medical engineers. The management of various elbow deformities using 3D-based surgical methods, including PSIs, is presented. A narrative literature review with a defined search strategy using PubMed as a database was conducted to identify further applications around the elbow that have been published to date. This case series presents with one case each the correction of the following deformities: cubitus varus, dorsal radial head subluxation, translational deformity of the distal humerus, cubitus valgus (CVL) and radial head dislocation in hereditary multiple exostoses (HME). The Supplementary literature with 28 studies presents further deformities that were corrected on a 3D basis: intra-articular fracture of the capitulum radii, extension deformity of the distal humerus and malunited radial neck fractures. These 3D-based procedures have been used most frequently to correct cubitus varus and are superior to conventional methods in terms of accuracy in comparative studies. The application of 3D-based planning methods, including PSIs use, offers excellent opportunities and accuracy for corrective osteotomies around the elbow. In addition to the correction of cubitus varus, extension to the correction of chronic dislocation of the radial head after Monteggia fracture and HME appears promising. The future implementation of 3D-based planning based on magnetic resonance imaging (MRI) would be highly desirable.
2025-10-29 | Management of Lower Extremity Deformity in Children with Hereditary Multiple Exostoses.
Hereditary multiple exostoses (HME) is a rare genetic disorder characterized by multiple benign, cartilage-capped bony tumors, most often found at the juxta-epiphyseal regions of long bones. Patients with HME often present with lower limb deformities, including coxa valga, genu valga or vara, and ankle valgus. This review aims to thoroughly examine the existing literature on surgical options for addressing angular deformities of the hip, knee, and ankle associated with HME in children and to recommend the most effective surgical management. It does not cover the simple removal of exostoses or isolated treatment for limb-length discrepancy. (1)The most common lower extremity malalignment deformities secondary to hereditary multiple exostoses (HME) are coxa valga of the hips, genu valgum or varum of the knees, and ankle valgus.(2)Temporary hemiepiphysiodesis (growth guidance) using transphyseal screws, staples, and tension band plates has become a mainstay for treating deformity in children with HME, but there is still much unknown.(3)Tibial deformities are largely proximal and/or distal valgus angulations, which are associated with short fibulas.(4)Ankle valgus should be addressed to prevent late ankle pain and degeneration.
2025-03-20 | External fixators and lengthening systems in pediatric upper limb.
The use of external fixators is part of the cultural background of orthopedic surgeons in treating numerous clinical conditions. Over the years, fixator design and biomechanical knowledge have led to different solutions and techniques, and bone lengthening and its better understanding come together with the development of external fixators and the application of the biological principle of distraction osteogenesis. The authors conducted a literature review about using external fixators and lengthening systems in pediatric upper limbs. Despite the applications of external fixators in upper limbs remaining much more limited than those of the lower limbs, there are indications of traumatic, congenital, tumor, and infectious etiologies. However, despite the spread of new systems of plate and screws and intramedullary lengthening nails, the problems about when to use external fixation remain unsolved. Another debated point is about using monolateral or circular frames for humeral lengthening and the correction of forearm deformities in multiple hereditary exostoses disease (MHE) or radial longitudinal deficiency sequelae. Monoaxial fixators retain a prominent role for skeletal lengthening in all the districts examined, although their role could be outclassed by the motorized intramedullary nails, especially for humeral lengthening. Hexapod systems are likely to represent the future for the correction of multiplanar forearm deformities; however, multicenter studies on larger series will be necessary to better validate their applications and advantages.
2025-01-09 | Short-term outcomes of gradual ulnar lengthening in multiple hereditary osteochondromas of the forearm with monolateral external fixator.
Hereditary multiple exostoses is an autosomal dominant genetic condition primarily affecting long bones. Forearm deformities, including wrist ulnar deviation, ulnar shortening, radial or ulnar bowing, and radial head dislocation, are common manifestations. Gradual ulnar lengthening is suggested as a viable treatment option for managing these deformities. This retrospective single-center study included 15 forearms treated with gradual ulnar lengthening using a monolateral external fixator by a single surgeon. Clinical and radiological characteristics were recorded preoperatively and during follow-ups. The Wilcoxon signed-rank test compared preoperative and postoperative radiological and clinical parameters, while McNemar's test assessed changes in radial head dislocation or subluxation. Significant radiological improvements were observed post-treatment. Proportional ulnar length increased from a mean of 0.85 ± 0.10 preoperatively to 1.11 ± 0.03 at the last follow-up ( P < 0.001). Ulnar variance decreased from a mean of 17.6 ± 5.58 mm preoperatively to 0.13 ± 1.81 mm at the last follow-up ( P < 0.001), while radial bowing decreased from a mean of 0.06 ± 0.02 to 0.05 ± 0.01 at the last follow-up ( P < 0.001). In addition, the radioarticular angle decreased significantly from a mean of 29.93 ± 7.34 to 20.20 ± 5.71° ( P < 0.001). The incidence of radial head dislocation or subluxation decreased significantly, from 11 patients preoperatively to only one at the last follow-up. These findings demonstrate the effectiveness of gradual ulnar lengthening with a monolateral external fixator in correcting forearm deformities and reducing the incidence of radial head dislocation or subluxation.
2024-11-14 | Double Trouble No More: A Case Report of En-bloc Resection and Total Hip Replacement for Secondary Hip Osteoarthritis Due to Femur Neck Osteochondroma.
Osteochondroma is a long bone benign tumor presenting at the metaphysis. Most of the occurrences are isolated lesions with very rare intra-articular extensions. Some occur as part of multiple hereditary exostoses. Isolated lesions are typically asymptomatic and diagnosed incidentally but, in some cases, present with bursa inflammation, pain, decreased range of motion and neurovascular deficit due to the mass effect of the tumor. Osteochondroma of the femur neck presents as an intra-articular pathology. A 41-year-old lady presented with right inguinal pain and swelling for 7 years, with an associated decreased range of movements of the right hip. Clinical examination revealed gross bony hard swelling, non-tender, and no local warmth. ROM was restricted, particularly internal rotation with additional abduction contracture and anterior joint line tenderness. A plain radiograph revealed a bony mass over metaphyseal-diaphyseal swelling over the medial aspect of the proximal femur with loss of femur head morphology and joint space narrowing. MRI confirmed the lesion as osteochondroma and a provisional diagnosis of Sessile solitary osteochondroma with probable sarcomatous with secondary degenerative osteoarthritis of the right hip was made. The patient underwent right total hip replacement with wide excision of the entire proximal femur using a REEF stem. The samples sent for histopathology confirmed the diagnosis as osteochondroma with no sarcomatous changes. Over a 10-year period of follow up, the patient showed no evidence of recurrence with improvement of hip movements assessed by Modified Harris Hip Score. By planning and executing total hip replacement with REEF stem and wide excision of the tumor in a single sitting, both the progress of the tumor and the secondary degenerative arthritis were met with, in a single procedure.
antibodies
2024-12-18 | Identification of novel germline mutations in FUT7 and EXT1 linked with hereditary multiple exostoses.
Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder primarily linked with mutations in Exostosin-1 (EXT1) and Exostosin-2 (EXT2) genes. However, not all HME cases can be explained by these mutations, and its pathogenic mechanisms are not fully understood. Herein, utilizing whole-exome sequencing and genetic screening with a family trio design, we identify two novel rare mutations co-segregating with HME in a Chinese family, including a nonsense mutation (c.204G>A, p.Trp68*) in EXT1 and a missense mutation (c.893T>G, p.Phe298Cys) in FUT7. Functional assays reveal that the FUT7 mutation affects the cellular localization of FUT7 protein and regulates cell proliferation. Notably, the simultaneous loss of fut7 and ext1 in a zebrafish model results in severe chondrodysplasia, indicating a functional link between FUT7 and EXT1 in chondrocyte regulation. Additionally, we unveil that FUT7 p.Phe298Cys reduces EXT1 expression through IL6/STAT3/SLUG axis at the transcription level and through ubiquitination-related proteasomal degradation at the protein level. Together, our findings not only identify novel germline mutations in FUT7 and EXT1 genes, but also highlight the critical interaction between these genes, suggesting a potential 'second-hit' mechanism over EXT1 mutations in HME pathogenesis. This insight enhances our understanding of the mechanisms underlying HME and opens new avenues for potential therapeutic interventions.
2002-01-01 | Natural history of multiple hereditary osteochondromatosis of the lower extremity and ankle.
In this study the authors evaluated the natural history of the ankle joint in patients with multiple hereditary osteochondromatosis. Thirty-eight subjects with an average age of 42 years completed a detailed subjective questionnaire and underwent clinical and radiographic evaluation of their ankles. Three subjects (8%) indicated their ankle involvement affected their vocation, and 12 (32%) were limited in recreational sports. Seven patients (18%) had pain in at least one ankle on a weekly basis, with an average ankle pain score of 2.2. Ankle range of motion averaged 50 degrees and subtalar motion was considered normal in two thirds of ankles. Radiographic evaluation documented an average tibiotalar tilt of 9 degrees of ankle valgus, with evidence of degenerative joint disease noted in 14 ankles (19%). Those with arthritic changes had significantly more tibiotalar tilt and diminished ankle range of motion compared with those without radiographic signs of osteoarthritis. These findings document measurable decreases in ankle function and suggest that correction or prevention of excessive tibiotalar tilt may be warranted to improve outcome.
small molecules
2026-02-27 | A Complex Case of Langer-Giedion Syndrome, Cornelia de Lange Syndrome Type 4, and Hereditary Multiple Osteochondromas with Mosaic 8q23.1-q24.12 Deletion.
Langer-Giedion syndrome (LGS), also known as trichorhinophalangeal syndrome type II (TRPS II; OMIM #150230), is a contiguous-gene deletion disorder caused by haploinsufficiency of TRPS1 and EXT1. Cornelia de Lange syndrome (CdLS) is genetically heterogeneous; heterozygous variants in RAD21 cause the milder CdLS type 4 phenotype (OMIM #614701). Because RAD21 lies between TRPS1 and EXT1, overlapping phenotypes may arise when all three genes are deleted. We report a unique case of a 4-year-old female presenting with a blended phenotype of Langer-Giedion Syndrome (LGS) and Cornelia de Lange Syndrome (CdLS) type 4. This case is distinct from previously reported 8q deletions in three key aspects: (1) Complex Genomic Architecture: Chromosomal microarray revealed a novel complex rearrangement consisting of a 13.01 Mb mosaic interstitial deletion at 8q23.1-q24.12, flanked by two large duplications (21.5 Mb at 8q11.23-q23.1 and 25.78 Mb at 8q24.12-q24.3). (2) Rare Mosaicism: This represents only the second reported case of mosaicism affecting this contiguous gene region. Notably, the patient demonstrates a "mosaic rescue" effect, where the mosaicism appears to have mitigated the neurodevelopmental phenotype (the patient is bilingual and ambulatory) while failing to protect the skeleton. (3) First Bone-Specific Therapy: The patient suffered from severe, recurrent fractures due to a synergistic "double hit" of TRPS1-related osteopenia and EXT1-related exostoses. We report the first successful use of bisphosphonate therapy (pamidronate) in this specific mosaic profile, which resulted in a complete cessation of fractures during a 12-month follow-up. This case underscores the utility of detailed microarray analysis in complex phenotypes and suggests bisphosphonates as a viable rescue therapy for refractory syndromic osteoporosis.
2025-12-22 | Hereditary Multiple Exostoses: A Narrative Review of Clinical Spectrum, Molecular Pathogenesis, Diagnostic Advances, and Emerging Therapeutic Approaches
Hereditary Multiple Exostoses (HME), also known as multiple osteochondromas, is a rare autosomal dominant skeletal disorder characterised by multiple benign cartilage-capped bony outgrowths that develop along the metaphyses of long and flat bones. Clinically, HME presents as palpable lesions, which are usually painless, but complications such as mechanical pain, skeletal deformities, joint restriction, neurovascular compression, and, rarely, malignant transformation to chondrosarcoma can occur. Classical radiography remains the first-line diagnostic tool, while advanced imaging modalities, including Magnetic Resonance Imaging (MRI), Computed Tomography (CT), whole-body MRI, and PET/CT, are used to detect complex lesions and early signs of malignancy. Uncertain cases can be confirmed by molecular analysis of EXT1/EXT2 genes and Next-Generation Sequencing (NGS). Treatment is largely symptomatic and includes surveillance, surgical resection, and corrective orthopaedic procedures for deformities. Emerging disease-modifying agents, such as palovarotene and heparanase inhibitors, may alter osteochondroma formation, as suggested by preclinical trials. This narrative review summarises current knowledge on the clinical spectrum of HME, its pathogenesis, diagnostic methods, treatment options, and emerging therapeutic approaches.
2025-10-07 | An ectopic Hedgehog signaling axis drives directional tumor outgrowth in a mouse model of hereditary multiple osteochondromas.
Osteochondromas characterize the rare pediatric disorder hereditary multiple osteochondromas (HMO). The tumors originate from the growth plate perichondrium along skeletal elements, appear first as ectopic cartilage, and then grow unidirectionally, colliding with and damaging surrounding structures. HMO is caused by mutations that affect the heparan sulfate (HS) synthases EXT1 or EXT2, leading to HS deficiency and aberrant activity of HS-binding growth factors. We investigated the signaling pathways and mechanisms underlying tumor growth in HMO using mice with conditional Ext1 deficiency in the growth plate and perichondrium. Developing tumors displayed active Hedgehog (Hh) signaling within their cartilaginous moiety and the presence of parathyroid hormone-related protein (PTHrP) at their distal edge, generating an ectopic Hh-PTHrP axis orthogonal to the one directing normal bone lengthening at the adjacent growth plate. In Ext1 mutants, loss of the Hh signaling effector Smoothened (Smo) reduced tumor growth, whereas heterozygous loss of the Smo inhibitor Patched1 (Ptch1) increased tumor growth. Two HS-binding growth factors that promote normal cartilage growth in the growth plate, BMP2 and activin A, did not exert their normal prochondrogenic activity when Hh signaling was blocked, demonstrating that Hh signaling is essential for chondrogenesis. Together, our findings show that osteochondromas usurp a physiological signaling mechanism to guide and propel their directional outgrowth, enabling them to damage surrounding tissues, and suggest potential targets for therapeutic intervention.
2025-09-12 | Tumor promotion or suppression: Revisiting the role of EXT1 and Heparan sulfate.
Heparan sulfate (HS), a linear sulfated polysaccharide attached to proteoglycans, modulates the availability and activity of growth factors and cytokines to regulate cell signaling, adhesion, and migration. Exostosin-1 (EXT1), a key glycosyltransferase for HS chain elongation, is increasingly implicated in cancer development and progression. Although originally identified as a tumor suppressor in hereditary multiple exostoses, EXT1 exhibits a complex, context-dependent role in cancer. The effects of EXT1 in cancer differ by cell and tumor type, exerting both tumor-suppressing and tumor-promoting effects. Notably, EXT1 also alters the tumor microenvironment via its expression in stromal fibroblasts and endothelial cells, further influencing tumor behavior. This review discusses the functions of HS and EXT1, emphasizing the roles of EXT1 in cancer and its microenvironment. A deeper understanding of these mechanisms may offer novel therapies targeting the HS biosynthetic pathway.
2024-12-10 | Intrathecal Fentanyl Pump Placement in a Patient With Chronic Pain Caused by Hereditary Multiple Exostoses: A Case Report.
Hereditary multiple exostoses (HME) is a genetic disorder defined by the formation of benign bone tumors known as exostoses, which can lead to chronic pain and functional impairment. This case report details a 57-year-old man with a long-standing history of severe diffuse bone pain attributed to HME. Despite various treatments, his pain remained poorly controlled until an intrathecal pump with fentanyl was implanted. This intervention significantly improved his pain management and overall quality of life. The manuscript explores clinical presentation, diagnostic approach, and treatment outcomes, highlighting the challenges and benefits of intrathecal drug delivery systems in managing refractory pain associated with HME.
gene therapies
2026-08-22 | Hereditary Multiple Exostoses Presenting with Urinary Tract Obstruction Secondary to Imaging-Suspected Malignant Transformation: A Case Report.
Hereditary multiple exostoses is a rare autosomal dominant skeletal disorder characterized by the development of multiple osteochondromas, with imaging findings suggestive of malignant transformation to chondrosarcoma occurring in a small proportion of patients. Such transformation typically presents with localized pain or deformity. Few reports describe urinary tract manifestations of pelvic osteochondromas; however, presentation with urinary obstruction secondary to imaging-suspected malignant transformation appears to be exceptionally rare. A 28-year-old Iranian man presented with a three-week history of dull right lower back pain and progressive urinary difficulty. No gross hematuria was reported although microscopic hematuria was detected on urinalysis. Ultrasonography demonstrated moderate right-sided hydronephrosis. Contrast-enhanced computed tomography of the abdomen and pelvis revealed multiple osteochondromatous lesions arising from the bilateral iliac and femoral bones, along with an infiltrative heterogeneous soft-tissue mass originating from the largest pelvic exostosis, were suspicious for malignant transformation to chondrosarcoma. The mass caused extrinsic compression of the right distal ureter, explaining the patient's urinary symptoms. Based on imaging findings, a provisional diagnosis of hereditary multiple exostoses complicated by secondary chondrosarcoma was made. Histopathological confirmation was not obtained because the patient was lost to follow-up, therefore the diagnosis remained presumptive. This case highlights a rare and atypical presentation of hereditary multiple exostoses with suspected malignant transformation manifesting primarily as urinary tract obstruction. Clinicians should consider underlying skeletal pathology in patients with unexplained urinary obstruction, particularly when imaging reveals pelvic masses. Early recognition of imaging features suspicious for malignant transformation through cross-sectional imaging is crucial for timely diagnosis and management in patients with hereditary multiple exostoses.
2026-07-11 | Hereditary Multiple Osteochondromas Across Four Successive Generations Presenting During Evaluation of Upper Gastrointestinal Symptoms: A Case Report with Pedigree and Radiological Analysis.
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2026-05-27 | Chronic pain and fatigue in multiple osteochondroma and Ollier disease, a systematic review.
Multiple osteochondromas (MO) and Ollier disease are characterized by multiple tumours in the skeletal bones. They lead to bone deformity, restricted joint motion, interference with skeletal growth and increased risk of malignant transformation. The aim of this systematic review is to increase knowledge on chronic pain and fatigue in these diagnoses and identify gaps and topics for future research. A systematic literature search was conducted in various databases in 2022 and updated in 2023. All types of studies were included that reported data on chronic pain and/or fatigue/vitality in patients with either multiple osteochondromas or Ollier disease. Study quality was assessed with Joanna Briggs Institute JBI's critical appraisal tools. A total of 63 studies (55 on multiple osteochondromas, 7 on Ollier disease, 1 on both), with a total of 1252 participants was found. The majority were case reports. No RCT was found. Fifty-six of 63 studies reported data only on pain; seven reported data on both pain and fatigue/vitality. Out of 63 studies, 29 used standardized assessment methods for pain, and seven for fatigue. Prevalence for chronic pain (when reporting non-site-specific pain) was reported as ranging from 80% - 95% for adults and 54-64% for children with multiple osteochondromas. Studies reporting fatigue showed a higher prevalence of severe fatigue or lower vitality scores when compared to other patient groups or the normal population. Pain and fatigue impacted ADL, mood, sleep, social and physical activities. Different interference factors for pain and fatigue were reported. Treatment strategies included "wait-and-see", surgery, physiotherapy, and medication. Chronic pain and fatigue appear to be an important complaint in patients with multiple osteochondromas impacting the patient's life. There is limited evidence on this topic for patients with Ollier disease. More research, particularly with larger cohort studies, is needed to be able to identify causation and associated factors, define optimal treatment and better understand the impact on patients' life and their coping strategies. PROSPERO CRD42022379329.
2025-12-29 | Assessment of radiological and clinical follow-up strategies for intrathoracic osteochondromas in hereditary multiple osteochondromas patients
Joint Diseases and Related Surgery (JDRS), the official journal of the Turkish Joint Diseases Foundation, is an international, peer-reviewed, immediate open access journal. All published articles in JDRS has been free for everyone, without embargo, since 1990.
2025-12-13 | Gene Variants Characterize and Distinguish Osteochondromas in Patients With Hereditary Multiple Osteochondromas.
Hereditary Multiple Osteochondromas (HMO) is a rare, pediatric skeletal disorder characterized by osteochondromas that form along the growth plates. These benign tumors can cause skeletal deformities, joint dysfunction, chronic pain and other health problems. Most HMO patients are born with a heterozygous mutation in EXT1 or EXT2 that encode Golgi enzymes responsible for heparan sulfate synthesis. However, prior studies have established that these mutations alone are insufficient to trigger osteochondroma formation, but additional genetic changes are needed. Loss-of-heterozygosity (LOH) has been invoked in some cases, but the full genomic landscape of osteochondromas remains unclear. Here, we carried out a proof-of-principle study and asked whether gene variants occur in osteochondromas in addition to EXT mutations, whether the variants are shared by osteochondromas in same or different patients and what putative pathogenic roles they may have. A total of 8 tumors from 4 patients were subjected to whole exome sequencing (WES) along with saliva DNA from the 4 patients and 3 parents that was used as specific reference. WES identified over 1,600 somatic single nucleotide variants or insertion/deletions that were only partially shared amongst the tumors and were absent in the saliva DNA. Six genes were commonly mutated, including PABC1, TDG and ANKRD36. These genes exert action which could directly or indirectly influence chondrogenesis, the first differentiation step in osteochondroma formation. The study reveals that osteochondromas do possess gene variants distinguishing them in the same or different patients. These traits could modulate their tumorigenic character and add complexity to HMO pathogenesis. Clinical Significance: This study provides insights into the genomic landscape of osteochondromas, potentially leading to development of disease diagnostic and prognostic tools.
cell therapies
2026-02-18 | Strategies for surgical reconstruction of complex elbow deformities based on patient-specific instruments - a case series and narrative review.
The application of 3D-based methods for deformity correction of the upper extremity, including patient-specific instruments (PSIs), is attracting increasing attention in clinical practice and requires the collaboration of orthopaedic surgeons and medical engineers. The management of various elbow deformities using 3D-based surgical methods, including PSIs, is presented. A narrative literature review with a defined search strategy using PubMed as a database was conducted to identify further applications around the elbow that have been published to date. This case series presents with one case each the correction of the following deformities: cubitus varus, dorsal radial head subluxation, translational deformity of the distal humerus, cubitus valgus (CVL) and radial head dislocation in hereditary multiple exostoses (HME). The Supplementary literature with 28 studies presents further deformities that were corrected on a 3D basis: intra-articular fracture of the capitulum radii, extension deformity of the distal humerus and malunited radial neck fractures. These 3D-based procedures have been used most frequently to correct cubitus varus and are superior to conventional methods in terms of accuracy in comparative studies. The application of 3D-based planning methods, including PSIs use, offers excellent opportunities and accuracy for corrective osteotomies around the elbow. In addition to the correction of cubitus varus, extension to the correction of chronic dislocation of the radial head after Monteggia fracture and HME appears promising. The future implementation of 3D-based planning based on magnetic resonance imaging (MRI) would be highly desirable.
2025-10-29 | Management of Lower Extremity Deformity in Children with Hereditary Multiple Exostoses.
Hereditary multiple exostoses (HME) is a rare genetic disorder characterized by multiple benign, cartilage-capped bony tumors, most often found at the juxta-epiphyseal regions of long bones. Patients with HME often present with lower limb deformities, including coxa valga, genu valga or vara, and ankle valgus. This review aims to thoroughly examine the existing literature on surgical options for addressing angular deformities of the hip, knee, and ankle associated with HME in children and to recommend the most effective surgical management. It does not cover the simple removal of exostoses or isolated treatment for limb-length discrepancy. (1)The most common lower extremity malalignment deformities secondary to hereditary multiple exostoses (HME) are coxa valga of the hips, genu valgum or varum of the knees, and ankle valgus.(2)Temporary hemiepiphysiodesis (growth guidance) using transphyseal screws, staples, and tension band plates has become a mainstay for treating deformity in children with HME, but there is still much unknown.(3)Tibial deformities are largely proximal and/or distal valgus angulations, which are associated with short fibulas.(4)Ankle valgus should be addressed to prevent late ankle pain and degeneration.
2025-03-20 | External fixators and lengthening systems in pediatric upper limb.
The use of external fixators is part of the cultural background of orthopedic surgeons in treating numerous clinical conditions. Over the years, fixator design and biomechanical knowledge have led to different solutions and techniques, and bone lengthening and its better understanding come together with the development of external fixators and the application of the biological principle of distraction osteogenesis. The authors conducted a literature review about using external fixators and lengthening systems in pediatric upper limbs. Despite the applications of external fixators in upper limbs remaining much more limited than those of the lower limbs, there are indications of traumatic, congenital, tumor, and infectious etiologies. However, despite the spread of new systems of plate and screws and intramedullary lengthening nails, the problems about when to use external fixation remain unsolved. Another debated point is about using monolateral or circular frames for humeral lengthening and the correction of forearm deformities in multiple hereditary exostoses disease (MHE) or radial longitudinal deficiency sequelae. Monoaxial fixators retain a prominent role for skeletal lengthening in all the districts examined, although their role could be outclassed by the motorized intramedullary nails, especially for humeral lengthening. Hexapod systems are likely to represent the future for the correction of multiplanar forearm deformities; however, multicenter studies on larger series will be necessary to better validate their applications and advantages.
2025-01-09 | Short-term outcomes of gradual ulnar lengthening in multiple hereditary osteochondromas of the forearm with monolateral external fixator.
Hereditary multiple exostoses is an autosomal dominant genetic condition primarily affecting long bones. Forearm deformities, including wrist ulnar deviation, ulnar shortening, radial or ulnar bowing, and radial head dislocation, are common manifestations. Gradual ulnar lengthening is suggested as a viable treatment option for managing these deformities. This retrospective single-center study included 15 forearms treated with gradual ulnar lengthening using a monolateral external fixator by a single surgeon. Clinical and radiological characteristics were recorded preoperatively and during follow-ups. The Wilcoxon signed-rank test compared preoperative and postoperative radiological and clinical parameters, while McNemar's test assessed changes in radial head dislocation or subluxation. Significant radiological improvements were observed post-treatment. Proportional ulnar length increased from a mean of 0.85 ± 0.10 preoperatively to 1.11 ± 0.03 at the last follow-up ( P < 0.001). Ulnar variance decreased from a mean of 17.6 ± 5.58 mm preoperatively to 0.13 ± 1.81 mm at the last follow-up ( P < 0.001), while radial bowing decreased from a mean of 0.06 ± 0.02 to 0.05 ± 0.01 at the last follow-up ( P < 0.001). In addition, the radioarticular angle decreased significantly from a mean of 29.93 ± 7.34 to 20.20 ± 5.71° ( P < 0.001). The incidence of radial head dislocation or subluxation decreased significantly, from 11 patients preoperatively to only one at the last follow-up. These findings demonstrate the effectiveness of gradual ulnar lengthening with a monolateral external fixator in correcting forearm deformities and reducing the incidence of radial head dislocation or subluxation.
2024-11-14 | Double Trouble No More: A Case Report of En-bloc Resection and Total Hip Replacement for Secondary Hip Osteoarthritis Due to Femur Neck Osteochondroma.
Osteochondroma is a long bone benign tumor presenting at the metaphysis. Most of the occurrences are isolated lesions with very rare intra-articular extensions. Some occur as part of multiple hereditary exostoses. Isolated lesions are typically asymptomatic and diagnosed incidentally but, in some cases, present with bursa inflammation, pain, decreased range of motion and neurovascular deficit due to the mass effect of the tumor. Osteochondroma of the femur neck presents as an intra-articular pathology. A 41-year-old lady presented with right inguinal pain and swelling for 7 years, with an associated decreased range of movements of the right hip. Clinical examination revealed gross bony hard swelling, non-tender, and no local warmth. ROM was restricted, particularly internal rotation with additional abduction contracture and anterior joint line tenderness. A plain radiograph revealed a bony mass over metaphyseal-diaphyseal swelling over the medial aspect of the proximal femur with loss of femur head morphology and joint space narrowing. MRI confirmed the lesion as osteochondroma and a provisional diagnosis of Sessile solitary osteochondroma with probable sarcomatous with secondary degenerative osteoarthritis of the right hip was made. The patient underwent right total hip replacement with wide excision of the entire proximal femur using a REEF stem. The samples sent for histopathology confirmed the diagnosis as osteochondroma with no sarcomatous changes. Over a 10-year period of follow up, the patient showed no evidence of recurrence with improvement of hip movements assessed by Modified Harris Hip Score. By planning and executing total hip replacement with REEF stem and wide excision of the tumor in a single sitting, both the progress of the tumor and the secondary degenerative arthritis were met with, in a single procedure.
antibodies
2024-12-18 | Identification of novel germline mutations in FUT7 and EXT1 linked with hereditary multiple exostoses.
Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder primarily linked with mutations in Exostosin-1 (EXT1) and Exostosin-2 (EXT2) genes. However, not all HME cases can be explained by these mutations, and its pathogenic mechanisms are not fully understood. Herein, utilizing whole-exome sequencing and genetic screening with a family trio design, we identify two novel rare mutations co-segregating with HME in a Chinese family, including a nonsense mutation (c.204G>A, p.Trp68*) in EXT1 and a missense mutation (c.893T>G, p.Phe298Cys) in FUT7. Functional assays reveal that the FUT7 mutation affects the cellular localization of FUT7 protein and regulates cell proliferation. Notably, the simultaneous loss of fut7 and ext1 in a zebrafish model results in severe chondrodysplasia, indicating a functional link between FUT7 and EXT1 in chondrocyte regulation. Additionally, we unveil that FUT7 p.Phe298Cys reduces EXT1 expression through IL6/STAT3/SLUG axis at the transcription level and through ubiquitination-related proteasomal degradation at the protein level. Together, our findings not only identify novel germline mutations in FUT7 and EXT1 genes, but also highlight the critical interaction between these genes, suggesting a potential 'second-hit' mechanism over EXT1 mutations in HME pathogenesis. This insight enhances our understanding of the mechanisms underlying HME and opens new avenues for potential therapeutic interventions.
2002-01-01 | Natural history of multiple hereditary osteochondromatosis of the lower extremity and ankle.
In this study the authors evaluated the natural history of the ankle joint in patients with multiple hereditary osteochondromatosis. Thirty-eight subjects with an average age of 42 years completed a detailed subjective questionnaire and underwent clinical and radiographic evaluation of their ankles. Three subjects (8%) indicated their ankle involvement affected their vocation, and 12 (32%) were limited in recreational sports. Seven patients (18%) had pain in at least one ankle on a weekly basis, with an average ankle pain score of 2.2. Ankle range of motion averaged 50 degrees and subtalar motion was considered normal in two thirds of ankles. Radiographic evaluation documented an average tibiotalar tilt of 9 degrees of ankle valgus, with evidence of degenerative joint disease noted in 14 ankles (19%). Those with arthritic changes had significantly more tibiotalar tilt and diminished ankle range of motion compared with those without radiographic signs of osteoarthritis. These findings document measurable decreases in ankle function and suggest that correction or prevention of excessive tibiotalar tilt may be warranted to improve outcome.
small molecules
2026-02-27 | A Complex Case of Langer-Giedion Syndrome, Cornelia de Lange Syndrome Type 4, and Hereditary Multiple Osteochondromas with Mosaic 8q23.1-q24.12 Deletion.
Langer-Giedion syndrome (LGS), also known as trichorhinophalangeal syndrome type II (TRPS II; OMIM #150230), is a contiguous-gene deletion disorder caused by haploinsufficiency of TRPS1 and EXT1. Cornelia de Lange syndrome (CdLS) is genetically heterogeneous; heterozygous variants in RAD21 cause the milder CdLS type 4 phenotype (OMIM #614701). Because RAD21 lies between TRPS1 and EXT1, overlapping phenotypes may arise when all three genes are deleted. We report a unique case of a 4-year-old female presenting with a blended phenotype of Langer-Giedion Syndrome (LGS) and Cornelia de Lange Syndrome (CdLS) type 4. This case is distinct from previously reported 8q deletions in three key aspects: (1) Complex Genomic Architecture: Chromosomal microarray revealed a novel complex rearrangement consisting of a 13.01 Mb mosaic interstitial deletion at 8q23.1-q24.12, flanked by two large duplications (21.5 Mb at 8q11.23-q23.1 and 25.78 Mb at 8q24.12-q24.3). (2) Rare Mosaicism: This represents only the second reported case of mosaicism affecting this contiguous gene region. Notably, the patient demonstrates a "mosaic rescue" effect, where the mosaicism appears to have mitigated the neurodevelopmental phenotype (the patient is bilingual and ambulatory) while failing to protect the skeleton. (3) First Bone-Specific Therapy: The patient suffered from severe, recurrent fractures due to a synergistic "double hit" of TRPS1-related osteopenia and EXT1-related exostoses. We report the first successful use of bisphosphonate therapy (pamidronate) in this specific mosaic profile, which resulted in a complete cessation of fractures during a 12-month follow-up. This case underscores the utility of detailed microarray analysis in complex phenotypes and suggests bisphosphonates as a viable rescue therapy for refractory syndromic osteoporosis.
2025-12-22 | Hereditary Multiple Exostoses: A Narrative Review of Clinical Spectrum, Molecular Pathogenesis, Diagnostic Advances, and Emerging Therapeutic Approaches
Hereditary Multiple Exostoses (HME), also known as multiple osteochondromas, is a rare autosomal dominant skeletal disorder characterised by multiple benign cartilage-capped bony outgrowths that develop along the metaphyses of long and flat bones. Clinically, HME presents as palpable lesions, which are usually painless, but complications such as mechanical pain, skeletal deformities, joint restriction, neurovascular compression, and, rarely, malignant transformation to chondrosarcoma can occur. Classical radiography remains the first-line diagnostic tool, while advanced imaging modalities, including Magnetic Resonance Imaging (MRI), Computed Tomography (CT), whole-body MRI, and PET/CT, are used to detect complex lesions and early signs of malignancy. Uncertain cases can be confirmed by molecular analysis of EXT1/EXT2 genes and Next-Generation Sequencing (NGS). Treatment is largely symptomatic and includes surveillance, surgical resection, and corrective orthopaedic procedures for deformities. Emerging disease-modifying agents, such as palovarotene and heparanase inhibitors, may alter osteochondroma formation, as suggested by preclinical trials. This narrative review summarises current knowledge on the clinical spectrum of HME, its pathogenesis, diagnostic methods, treatment options, and emerging therapeutic approaches.
2025-10-07 | An ectopic Hedgehog signaling axis drives directional tumor outgrowth in a mouse model of hereditary multiple osteochondromas.
Osteochondromas characterize the rare pediatric disorder hereditary multiple osteochondromas (HMO). The tumors originate from the growth plate perichondrium along skeletal elements, appear first as ectopic cartilage, and then grow unidirectionally, colliding with and damaging surrounding structures. HMO is caused by mutations that affect the heparan sulfate (HS) synthases EXT1 or EXT2, leading to HS deficiency and aberrant activity of HS-binding growth factors. We investigated the signaling pathways and mechanisms underlying tumor growth in HMO using mice with conditional Ext1 deficiency in the growth plate and perichondrium. Developing tumors displayed active Hedgehog (Hh) signaling within their cartilaginous moiety and the presence of parathyroid hormone-related protein (PTHrP) at their distal edge, generating an ectopic Hh-PTHrP axis orthogonal to the one directing normal bone lengthening at the adjacent growth plate. In Ext1 mutants, loss of the Hh signaling effector Smoothened (Smo) reduced tumor growth, whereas heterozygous loss of the Smo inhibitor Patched1 (Ptch1) increased tumor growth. Two HS-binding growth factors that promote normal cartilage growth in the growth plate, BMP2 and activin A, did not exert their normal prochondrogenic activity when Hh signaling was blocked, demonstrating that Hh signaling is essential for chondrogenesis. Together, our findings show that osteochondromas usurp a physiological signaling mechanism to guide and propel their directional outgrowth, enabling them to damage surrounding tissues, and suggest potential targets for therapeutic intervention.
2025-09-12 | Tumor promotion or suppression: Revisiting the role of EXT1 and Heparan sulfate.
Heparan sulfate (HS), a linear sulfated polysaccharide attached to proteoglycans, modulates the availability and activity of growth factors and cytokines to regulate cell signaling, adhesion, and migration. Exostosin-1 (EXT1), a key glycosyltransferase for HS chain elongation, is increasingly implicated in cancer development and progression. Although originally identified as a tumor suppressor in hereditary multiple exostoses, EXT1 exhibits a complex, context-dependent role in cancer. The effects of EXT1 in cancer differ by cell and tumor type, exerting both tumor-suppressing and tumor-promoting effects. Notably, EXT1 also alters the tumor microenvironment via its expression in stromal fibroblasts and endothelial cells, further influencing tumor behavior. This review discusses the functions of HS and EXT1, emphasizing the roles of EXT1 in cancer and its microenvironment. A deeper understanding of these mechanisms may offer novel therapies targeting the HS biosynthetic pathway.
2024-12-10 | Intrathecal Fentanyl Pump Placement in a Patient With Chronic Pain Caused by Hereditary Multiple Exostoses: A Case Report.
Hereditary multiple exostoses (HME) is a genetic disorder defined by the formation of benign bone tumors known as exostoses, which can lead to chronic pain and functional impairment. This case report details a 57-year-old man with a long-standing history of severe diffuse bone pain attributed to HME. Despite various treatments, his pain remained poorly controlled until an intrathecal pump with fentanyl was implanted. This intervention significantly improved his pain management and overall quality of life. The manuscript explores clinical presentation, diagnostic approach, and treatment outcomes, highlighting the challenges and benefits of intrathecal drug delivery systems in managing refractory pain associated with HME.
gene therapies
2026-08-22 | Hereditary Multiple Exostoses Presenting with Urinary Tract Obstruction Secondary to Imaging-Suspected Malignant Transformation: A Case Report.
Hereditary multiple exostoses is a rare autosomal dominant skeletal disorder characterized by the development of multiple osteochondromas, with imaging findings suggestive of malignant transformation to chondrosarcoma occurring in a small proportion of patients. Such transformation typically presents with localized pain or deformity. Few reports describe urinary tract manifestations of pelvic osteochondromas; however, presentation with urinary obstruction secondary to imaging-suspected malignant transformation appears to be exceptionally rare. A 28-year-old Iranian man presented with a three-week history of dull right lower back pain and progressive urinary difficulty. No gross hematuria was reported although microscopic hematuria was detected on urinalysis. Ultrasonography demonstrated moderate right-sided hydronephrosis. Contrast-enhanced computed tomography of the abdomen and pelvis revealed multiple osteochondromatous lesions arising from the bilateral iliac and femoral bones, along with an infiltrative heterogeneous soft-tissue mass originating from the largest pelvic exostosis, were suspicious for malignant transformation to chondrosarcoma. The mass caused extrinsic compression of the right distal ureter, explaining the patient's urinary symptoms. Based on imaging findings, a provisional diagnosis of hereditary multiple exostoses complicated by secondary chondrosarcoma was made. Histopathological confirmation was not obtained because the patient was lost to follow-up, therefore the diagnosis remained presumptive. This case highlights a rare and atypical presentation of hereditary multiple exostoses with suspected malignant transformation manifesting primarily as urinary tract obstruction. Clinicians should consider underlying skeletal pathology in patients with unexplained urinary obstruction, particularly when imaging reveals pelvic masses. Early recognition of imaging features suspicious for malignant transformation through cross-sectional imaging is crucial for timely diagnosis and management in patients with hereditary multiple exostoses.
2026-07-11 | Hereditary Multiple Osteochondromas Across Four Successive Generations Presenting During Evaluation of Upper Gastrointestinal Symptoms: A Case Report with Pedigree and Radiological Analysis.
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2026-05-27 | Chronic pain and fatigue in multiple osteochondroma and Ollier disease, a systematic review.
Multiple osteochondromas (MO) and Ollier disease are characterized by multiple tumours in the skeletal bones. They lead to bone deformity, restricted joint motion, interference with skeletal growth and increased risk of malignant transformation. The aim of this systematic review is to increase knowledge on chronic pain and fatigue in these diagnoses and identify gaps and topics for future research. A systematic literature search was conducted in various databases in 2022 and updated in 2023. All types of studies were included that reported data on chronic pain and/or fatigue/vitality in patients with either multiple osteochondromas or Ollier disease. Study quality was assessed with Joanna Briggs Institute JBI's critical appraisal tools. A total of 63 studies (55 on multiple osteochondromas, 7 on Ollier disease, 1 on both), with a total of 1252 participants was found. The majority were case reports. No RCT was found. Fifty-six of 63 studies reported data only on pain; seven reported data on both pain and fatigue/vitality. Out of 63 studies, 29 used standardized assessment methods for pain, and seven for fatigue. Prevalence for chronic pain (when reporting non-site-specific pain) was reported as ranging from 80% - 95% for adults and 54-64% for children with multiple osteochondromas. Studies reporting fatigue showed a higher prevalence of severe fatigue or lower vitality scores when compared to other patient groups or the normal population. Pain and fatigue impacted ADL, mood, sleep, social and physical activities. Different interference factors for pain and fatigue were reported. Treatment strategies included "wait-and-see", surgery, physiotherapy, and medication. Chronic pain and fatigue appear to be an important complaint in patients with multiple osteochondromas impacting the patient's life. There is limited evidence on this topic for patients with Ollier disease. More research, particularly with larger cohort studies, is needed to be able to identify causation and associated factors, define optimal treatment and better understand the impact on patients' life and their coping strategies. PROSPERO CRD42022379329.
2025-12-29 | Assessment of radiological and clinical follow-up strategies for intrathoracic osteochondromas in hereditary multiple osteochondromas patients
Joint Diseases and Related Surgery (JDRS), the official journal of the Turkish Joint Diseases Foundation, is an international, peer-reviewed, immediate open access journal. All published articles in JDRS has been free for everyone, without embargo, since 1990.
2025-12-13 | Gene Variants Characterize and Distinguish Osteochondromas in Patients With Hereditary Multiple Osteochondromas.
Hereditary Multiple Osteochondromas (HMO) is a rare, pediatric skeletal disorder characterized by osteochondromas that form along the growth plates. These benign tumors can cause skeletal deformities, joint dysfunction, chronic pain and other health problems. Most HMO patients are born with a heterozygous mutation in EXT1 or EXT2 that encode Golgi enzymes responsible for heparan sulfate synthesis. However, prior studies have established that these mutations alone are insufficient to trigger osteochondroma formation, but additional genetic changes are needed. Loss-of-heterozygosity (LOH) has been invoked in some cases, but the full genomic landscape of osteochondromas remains unclear. Here, we carried out a proof-of-principle study and asked whether gene variants occur in osteochondromas in addition to EXT mutations, whether the variants are shared by osteochondromas in same or different patients and what putative pathogenic roles they may have. A total of 8 tumors from 4 patients were subjected to whole exome sequencing (WES) along with saliva DNA from the 4 patients and 3 parents that was used as specific reference. WES identified over 1,600 somatic single nucleotide variants or insertion/deletions that were only partially shared amongst the tumors and were absent in the saliva DNA. Six genes were commonly mutated, including PABC1, TDG and ANKRD36. These genes exert action which could directly or indirectly influence chondrogenesis, the first differentiation step in osteochondroma formation. The study reveals that osteochondromas do possess gene variants distinguishing them in the same or different patients. These traits could modulate their tumorigenic character and add complexity to HMO pathogenesis. Clinical Significance: This study provides insights into the genomic landscape of osteochondromas, potentially leading to development of disease diagnostic and prognostic tools.
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Drug Discovery Landscape
2 orphan drug designations for Multiple osteochondromas.
2 orphan drug designations for Multiple osteochondromas.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Palovarotene | small molecules | EMA | Ipsen Pharma | |
palovarotene | small molecules | FDA | Clementia Pharmaceuticals, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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