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Hereditary multiple exostoses

Hereditary multiple exostoses (HME), also known as hereditary multiple osteochondromas, is an autosomal dominant genetic disorder characterized by the development of multiple benign bone tumors called osteochondromas, which are cartilage-capped bony projections that typically arise from the metaphyses of long bones near growth plates.^[1]^[2] These osteochondromas usually appear in childhood and can affect any bone preformed in cartilage, including the pelvis, scapula, and ribs, leading to skeletal abnormalities.^[1] The condition has an estimated prevalence of 1 in 50,000 individuals worldwide, though it is higher in certain populations such as 1 in 1,000 among the Chamorro people of Guam.^[1]^[2] HME is primarily caused by heterozygous pathogenic variants in the EXT1 gene on chromosome 8q24 (accounting for 65%-70% of cases) or the EXT2 gene on chromosome 11p11 (30%-35% of cases), which encode glycosyltransferases essential for heparan sulfate biosynthesis in the extracellular matrix of cartilage.^[1]^[3] These mutations disrupt normal chondrocyte proliferation and organization, resulting in the formation of exostoses; approximately 10% of cases arise de novo, and penetrance is nearly complete (96% in females, 100% in males).^[1] Clinical manifestations often include short stature, limb length discrepancies, angular deformities (such as forearm valgus or coxa valga), restricted joint range of motion, chronic pain, and potential neurovascular compression syndromes.^[1]^[3] The median age at diagnosis is 3 years, with nearly all individuals identified by age 12 through radiographic imaging showing multiple osteochondromas.^[1] Diagnosis is confirmed by the presence of multiple osteochondromas on X-rays, supplemented by molecular genetic testing for EXT1 and EXT2 variants when family history or clinical suspicion warrants it.^[1]^[2] Management is primarily surgical, involving excision of symptomatic or enlarging lesions to alleviate pain, correct deformities, or prevent complications like premature osteoarthritis; routine surveillance is recommended to monitor for malignant transformation into chondrosarcoma, which carries a lifetime risk of 2%-5%, particularly in pelvic or axial lesions.^[1]^[3] There is no curative medical therapy, though emerging research explores targeted agents like heparanase inhibitors or retinoic acid receptor agonists to modulate heparan sulfate pathways.^[3] Overall, HME significantly impacts quality of life due to physical limitations and psychological effects, with affected individuals often requiring multidisciplinary care from orthopedists, geneticists, and pain specialists.^[3]

Clinical presentation

Physical manifestations

Hereditary multiple exostoses is characterized by the development of multiple osteochondromas, which are benign bone tumors featuring a cartilage cap and arising from the metaphysis of long bones, such as the femur, tibia, and humerus, as well as flat bones including the ribs and scapula.^[1] These tumors are typically multiple, with affected individuals developing an average of 15-18 lesions, though the number can vary widely.^[4] The most common sites for osteochondromas are the proximal tibia and fibula, followed by the distal femur and proximal humerus, while involvement of the spine or pelvis occurs less frequently.^[5] These lesions present as either pedunculated forms with a stalk-like projection or sessile forms with a broad base, often appearing as palpable bony lumps under the skin due to their superficial location near joints.^[6] Osteochondromas usually become detectable in early childhood, with approximately 50% of cases identified by age 5 and 80% by age 10; their growth parallels overall skeletal maturation and typically stops after puberty.^[7] Beyond the tumors themselves, the condition can lead to associated skeletal changes, including limb length discrepancies in 10-15% of individuals, angular deformities such as valgus or varus alignments in 30-60%, and short stature in up to 67% of cases, particularly those linked to EXT1 mutations.^[1]

Symptoms and complications

Hereditary multiple exostoses (HME) manifests through a range of symptoms stemming from the mechanical interference of osteochondromas with surrounding tissues. Chronic pain is prevalent, affecting about 60% of affected children and up to 80% of adults, often resulting from mechanical irritation by the lesions, associated bursitis, or pathologic fractures of the exostoses themselves.^[3] Reduced range of motion is common in joints near exostoses, such as the shoulder, hip, or knee, leading to functional limitations like gait abnormalities or difficulties with daily activities, including walking due to leg deformities.^[3] For instance, forearm pronation and supination may be significantly restricted in severe cases, impacting upper limb use.^[8] Complications arise from the growth and location of osteochondromas, with nerve and vascular compression reported in 22-23% of patients; this can cause conditions such as radial or peroneal nerve palsy, leading to sensory loss or weakness, or vascular occlusion like popliteal artery thrombosis.^[3] Spinal involvement occurs in approximately 68% of cases, though symptomatic compression of the spinal cord is rare and may result in neurological deficits including paresthesia, myelopathy, or acute syndromes following trauma.^[8] Joint instability is another key complication, with genu valgum affecting around 33% of individuals and contributing to progressive deformities or pseudoparalysis in the arms from mechanical impingement.^[8] Beyond physical effects, HME leads to cosmetic concerns from visible bony protuberances and deformities, particularly on the limbs or ribs, which can influence self-esteem and social interactions.^[3] Psychological impacts are notable, with over 50% of affected children experiencing challenges in school or socialization, and adults reporting diminished quality of life, including avoidance of sports in 30-50% of cases or workplace changes in 22%.^[3] Rare acute events, such as pathologic fractures, can occur due to weakened bone structure at exostosis sites.^[9] The symptomatic burden is often greater in males, who exhibit a higher number of lesions and more pronounced disease severity, particularly with EXT1 mutations, compared to females where penetrance is incomplete at about 96%.^[10] Additionally, rare associative neurological features have been observed, including autism spectrum-like traits such as socio-communicative deficits, reported in case studies of patients with EXT1 mutations.^[11] These are linked to heparan sulfate deficiency and supported by animal models of EXT1/EXT2 mutants demonstrating impaired social interaction and stereotyped behaviors.^[12] Rare neurodevelopmental associations, including intellectual disability, have been noted in some cases as of 2021.^[13]

Genetics

Inheritance patterns

Hereditary multiple exostoses (HME), also known as hereditary multiple osteochondromas, follows an autosomal dominant inheritance pattern, meaning a single mutated copy of the relevant gene in each cell is sufficient to cause the disorder.^[1] This mode of transmission results in a 50% chance that each child of an affected individual will inherit the condition.^[14] Approximately 90% of cases are inherited from an affected parent, while ~10% arise from de novo mutations that occur spontaneously in the egg, sperm, or early embryo of unaffected parents.^[1]^[14] The disorder exhibits high penetrance, approaching nearly 100% overall, though it is slightly lower in females at around 96%, potentially due to milder manifestations that may lead to underdiagnosis.^[1] This incomplete penetrance in females contributes to an apparent male predominance, with reported male-to-female ratios ranging from 1.5:1 to 3:1, largely attributed to the underrecognition of less severe cases in females rather than a true sex-linked effect.^[14]^[9] Variable expressivity is a hallmark of HME, with the number, size, location, and severity of exostoses differing widely even among family members carrying the same mutation.^[1] Cases linked to mutations in the EXT1 gene tend to show earlier onset, a greater number of exostoses, and more severe complications compared to those involving EXT2.^[1] These variations underscore the importance of genetic counseling, where families are informed of the 50% transmission risk and the potential for unpredictable phenotypic outcomes in offspring.^[14]

Molecular basis

Hereditary multiple exostoses (HME) is caused by heterozygous germline mutations in the EXT1 or EXT2 genes, which encode glycosyltransferase enzymes involved in heparan sulfate biosynthesis.^[15] The EXT1 gene, located on chromosome 8q24.11, accounts for 65%-70% of HME cases, while the EXT2 gene on chromosome 11p11.2 is responsible for 30%-35%.^[1]^[9] In rare instances, HME has been linked to mutations at an unmapped locus designated EXT3 on chromosome 19p, though no specific gene has been identified there.^[16] These mutations are predominantly loss-of-function, including nonsense, frameshift, splice-site alterations, and small deletions or insertions that result in premature protein truncation.^[17] Missense mutations are uncommon.^[18] As tumor suppressor genes, EXT1 and EXT2 require biallelic inactivation for osteochondroma development, following Knudson's two-hit hypothesis: the inherited mutation provides the first hit, and a somatic second hit—often loss of heterozygosity—targets the wild-type allele in affected cells.^[15] EXT1 mutations are associated with a more severe clinical phenotype than EXT2 mutations, including a greater number of osteochondromas, earlier disease onset, and increased risk of malignant transformation.^[15] Genetic testing detects pathogenic variants in EXT1 or EXT2 in 70-95% of familial HME cases, aiding in diagnosis and counseling.^[15]

Pathophysiology

Heparan sulfate role

Heparan sulfate (HS) is a linear glycosaminoglycan composed of repeating disaccharide units of glucuronic acid (GlcA) and N-acetyl-D-glucosamine (GlcNAc), attached to core proteins to form proteoglycans such as syndecans and perlecan.^[19] These HS chains, typically 20–25 kDa in length, are synthesized in the Golgi apparatus by the EXT1/EXT2 enzyme complex, which functions as a copolymerase adding alternating GlcA and GlcNAc residues to initiate and elongate the chains.^[19] EXT1 and EXT2 act as glycosyltransferases, with EXT1 providing the primary catalytic activity for both glucuronyl- and N-acetylglucosaminyl-transferase functions, while EXT2 enhances complex stability and processivity.^[20] In normal skeletal development, HS plays a critical role in regulating morphogen signaling pathways, including Hedgehog (Hh), fibroblast growth factor (FGF), and bone morphogenetic protein (BMP), which are essential for chondrocyte proliferation and the process of endochondral ossification.^[19] HS binds to these growth factors via specific sulfated domains, facilitating their distribution, gradient formation, and bioavailability to modulate cellular responses in the growth plate.^[19] This regulation ensures ordered chondrocyte differentiation from proliferation to hypertrophy, preventing aberrant cartilage formation outside the growth plate.^[21] Mutations in EXT1 or EXT2, which cause hereditary multiple exostoses, result in heterozygous loss-of-function leading to a systemic reduction in HS levels by approximately 50%, with local "second-hit" events further depleting HS in affected cells.^[19] This deficiency impairs the formation of HS-dependent morphogen gradients in the growth plate, disrupting signaling homeostasis and promoting ectopic chondrogenesis through enhanced BMP activity and disorganized chondrocyte polarity.^[19] Evidence from animal models supports this mechanism; conditional knockout of Ext1 or Ext2 in mice chondrocytes leads to HS absence, resulting in disorganized growth plates, excessive chondrocyte proliferation, and the development of exostosis-like lesions resembling human osteochondromas.^[22]

Osteochondroma development

Osteochondromas in hereditary multiple exostoses (HME) arise through a pathogenic model known as the "two-hit" hypothesis, analogous to Knudson's tumor suppressor gene model. Individuals with HME carry a germline heterozygous loss-of-function mutation in EXT1 or EXT2, and osteochondroma formation requires a somatic second hit, such as loss of heterozygosity (LOH), in progenitor cells near the growth plate, leading to biallelic inactivation and clonal expansion of mutant chondrocytes.^[23]^[24] This second hit has been detected in approximately 63% of analyzed osteochondromas, confirming the necessity of complete EXT loss for tumor initiation.^[24] The process begins with growth plate disruption due to heparan sulfate (HS) deficiency from EXT mutations, which impairs normal signaling gradients. In the perichondrium or periosteum adjacent to the physis, HS normally restricts bone morphogenetic protein (BMP) and Indian hedgehog (IHH) signaling to maintain progenitor cell quiescence; its reduction shifts these cells toward a chondrogenic fate, forming ectopic cartilage foci that migrate outward.^[23] These foci develop into osteochondromas via endochondral ossification, where the cartilage cap undergoes progressive hypertrophy and mineralization, forming a bony stalk continuous with the underlying cortex and medulla.^[1] Lesions characteristically orient away from the nearest joint, perpendicular to the growth plate, preserving joint function and maintaining cortical continuity with the host bone.^[1] They appear as sessile (broad-based) or pedunculated (stalked) outgrowths, with the cartilage cap thinning with age—typically 1-3 cm in children but less than 2 cm in adults—reflecting cessation of growth at skeletal maturity.^[25]^[1] Malignant potential initiates rarely through additional somatic mutations in EXT-independent pathways, such as upregulation of heparanase or alterations in TP53, leading to progression toward secondary chondrosarcoma in about 2-5% of cases over a lifetime.^[23]^[1] Histologically, osteochondromas feature a benign hyaline cartilage cap overlying a stalk of cancellous bone, with disorganized chondrocytes in the cap showing reduced HS content and a mixture of mutant and wild-type cells.^[23]^[1]

Diagnosis

Clinical evaluation

Clinical evaluation of hereditary multiple exostoses (HME), also known as hereditary multiple osteochondromas, begins with a thorough history and physical examination to establish clinical suspicion, particularly in children presenting with bony protuberances. A detailed family history is essential, as HME exhibits autosomal dominant inheritance in approximately 90% of cases, with a notable paternal bias in transmission. Age of onset is typically in early childhood, with a median diagnosis age of 3 years and nearly all cases identified by age 12; patients often report the development of painless lumps or progressive deformities affecting limbs or the axial skeleton.^[1]^[26]^[3] During the physical examination, palpation is key to identifying multiple bony protuberances, which are most commonly located near the metaphyses of long bones such as the distal femur, proximal tibia, proximal humerus, and distal radius, with a mean of 15-18 lesions per affected individual.^[14] Assessment of limb alignment reveals potential deformities, including forearm pronation/supination limitations in up to 60% of cases, valgus knee deformities in around 33%, and leg length discrepancies. Range of motion is evaluated for joint restrictions due to mechanical interference from exostoses, while neurological and vascular status is checked for signs of compression, such as nerve entrapment affecting 22-23% of patients or vascular compromise in about 11.5%.^[1]^[26]^[3] Red flags warranting urgent evaluation include sudden onset of pain, rapid growth of an exostosis after skeletal maturity, or neurological symptoms suggestive of compression, such as myelopathy in up to 15% of cases with spinal involvement, which may indicate complications like bursitis, fracture, or rarely, malignant transformation. Differential considerations include solitary osteochondroma, metachondromatosis, Langer-Giedion syndrome, or Potocki-Shaffer syndrome, distinguished primarily by the multiplicity and familial pattern in HME.^[1]^[26]^[3] The World Health Organization criteria for diagnosis require at least two osteochondromas on imaging in juxta-epiphyseal regions of long bones, but initial clinical suspicion based on history and examination guides the evaluation process, with imaging used for confirmation.^[26]

Imaging techniques

Imaging in hereditary multiple exostoses (HME) primarily involves radiological modalities to detect, characterize, and monitor osteochondromas, with a focus on identifying benign features and potential malignant transformation. Plain radiography serves as the initial imaging tool, while advanced techniques like magnetic resonance imaging (MRI) provide detailed assessment of soft tissues and cartilage caps. These methods help confirm cortical and medullary continuity, lesion morphology, and complications such as deformities or impingements.^[26] Plain radiography is the first-line imaging modality for HME, readily identifying osteochondromas as sessile or pedunculated metaphyseal protrusions with continuity of the cortex and medulla between the lesion and underlying bone. It effectively demonstrates key benign features, including saucerization of the adjacent cortex (a scooped-out appearance) and absence of periosteal reaction, while also allowing whole-body surveys to quantify lesion burden and detect skeletal deformities like the Erlenmeyer flask appearance. However, it cannot visualize the cartilage cap or soft tissue involvement, limiting its utility for malignancy assessment.^[26]^[27] MRI is considered the gold standard for evaluating osteochondromas in HME, particularly for assessing cartilage cap thickness, which appears as high signal intensity on T2-weighted or STIR sequences and intermediate on T1-weighted images. A cap thickness exceeding 1.5–2 cm in skeletally mature adults raises suspicion for malignant transformation to chondrosarcoma, alongside irregular margins or soft tissue masses; caps under 15–20 mm are typically benign. MRI excels in delineating soft tissue complications, spinal lesions, and vascular/nerve involvement, making it essential for symptomatic or suspicious cases.^[26]^[27]^[3] Computed tomography (CT) is valuable for complex anatomical regions such as the pelvis or spine, providing high-resolution bone detail, 3D reconstructions for surgical planning, and detection of calcifications within the cartilage cap. It confirms cortical and medullary continuity but is less accurate for cap thickness due to potential artifact from calcifications. CT is particularly useful when MRI is contraindicated or for evaluating bony erosions suggestive of malignancy.^[26]^[27] Ultrasound is an effective initial screening tool, especially in children, for measuring cartilage cap thickness in superficial lesions, where the hypoechoic cap is bounded by hyperechoic bone and soft tissues. It can detect vascularity within the cap and is operator-dependent, with limitations for deep or intra-articular exostoses; a thickness greater than 2 cm may indicate concern for malignancy.^[26]^[27] Advanced imaging includes whole-body MRI, which has improved in 2025 for malignancy surveillance by enabling comprehensive screening of multiple lesions without radiation, recommended periodically (e.g., every 2 years) in adults to monitor for growth or cap changes. PET-CT is rarely used but can assess metabolic activity with FDG uptake (SUVmax >3.1 suggestive of malignancy), aiding in equivocal cases despite its radiation exposure and cost.^[26]^[3]

Genetic testing

Genetic testing for hereditary multiple exostoses (HME), also known as hereditary multiple osteochondromas, is indicated primarily in familial cases with a history of autosomal dominant inheritance, atypical presentations that require confirmation of etiology, or situations necessitating genetic counseling for at-risk relatives.^[1] It is not routinely recommended for sporadic solitary osteochondromas, as these are typically non-hereditary.^[1] Approximately 10% of cases arise de novo without family history, prompting testing in index cases with multiple lesions.^[1] The primary methods involve targeted sequencing of the EXT1 and EXT2 genes using next-generation sequencing (NGS) panels to detect point mutations, small insertions/deletions, and other small variants.^[1] Multiplex ligation-dependent probe amplification (MLPA) is used to identify large deletions or duplications, which account for 5-10% of pathogenic variants.^[1] These approaches yield pathogenic variants in 70-95% of suspected HME cases, with EXT1 mutations detected in 65-70% and EXT2 in 25-35%.^[1]^[9] Interpretation focuses on identifying pathogenic variants, such as nonsense, frameshift, or splice-site mutations, which disrupt exostosin function and confirm the diagnosis.^[1] Variants of uncertain significance (VUS) are common and require family segregation studies or functional assays to assess pathogenicity, as they may not clearly correlate with phenotype.^[1] EXT1 variants are often associated with more severe disease, informing prognostic discussions.^[9] Prenatal testing is available for high-risk pregnancies via chorionic villus sampling (CVS) or amniocentesis if a familial pathogenic variant is known, allowing early detection of HME risk.^[1] Postnatal testing, including newborn screening, can be performed in at-risk families using the same targeted methods on blood or saliva samples.^[1] Preimplantation genetic diagnosis is also an option for in vitro fertilization in affected families.^[1] As of 2025, genetic testing panels have expanded to include candidate loci for rare unsolved cases beyond EXT1 and EXT2, such as the potential EXT3 region on chromosome 19p, though no confirmed mutations have been identified there.^[16] Integration of genetic results with imaging data enhances prognostic accuracy, particularly for malignancy risk stratification in EXT1-positive individuals.^[9]

Treatment

Monitoring and conservative approaches

For asymptomatic or mildly symptomatic cases of hereditary multiple exostoses (HME), management emphasizes watchful waiting through regular clinical evaluations and imaging to track lesion growth and detect complications early.^[9] Observation protocols typically involve annual clinical examinations, including assessment of range of motion, limb alignment, and neurological function, combined with radiographic skeletal surveys of key areas such as the long bones, pelvis, and spine until skeletal maturity is reached, after which imaging frequency may reduce to every 2-3 years or as clinically indicated.^[9] These surveys help monitor for progressive deformities or suspicious changes without unnecessary radiation exposure.^[28] Pain management in HME focuses on non-invasive measures to alleviate discomfort from mechanical irritation or joint stress. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, are commonly prescribed for mild to moderate pain, providing relief by reducing inflammation around exostoses.^[29] Physical therapy plays a central role, incorporating flexibility exercises, strengthening of affected muscle groups, and modalities like heat or ice to maintain joint mobility and prevent functional decline.^[30] Orthotics, including shoe lifts or custom braces, are recommended to correct limb length discrepancies or angular deformities, thereby reducing uneven loading on joints and associated pain.^[30] Monitoring for complications involves targeted assessments to identify potential issues such as malignant transformation or nerve impingement. Serial MRI is used to evaluate cartilage cap thickness of exostoses, with caps exceeding 1-2 cm in adults raising concern for chondrosarcoma and warranting further investigation; benign caps are typically less than 1 cm thick post-maturity.^[31] Neurological evaluations, including sensory and motor testing, are performed regularly, particularly for spinal or pelvic lesions, with MRI reserved for symptomatic cases to assess for compression.^[9] Lifestyle modifications are advised to minimize injury risk and support overall well-being. Patients are encouraged to avoid high-impact or contact sports to reduce the likelihood of fractures through exostoses or exacerbation of deformities, opting instead for low-impact activities like swimming under medical supervision.^[30] Genetic counseling is recommended for affected individuals and families to discuss inheritance patterns, reproductive options, and psychosocial implications.^[32] Emerging non-surgical approaches include retinoid receptor gamma (RARγ) agonists aimed at inhibiting chondrocyte proliferation and osteochondroma formation. Palovarotene, a selective RARγ agonist, was evaluated in the phase II MO-Ped trial (NCT03442985) for pediatric HME patients; the study was terminated early in 2020 following an FDA partial clinical hold due to safety concerns from related studies, alongside lack of efficacy in reducing new osteochondromas or lesion volume, and dose-dependent reductions in bone mineral density. Full results published in 2025 confirmed no significant efficacy signals.^[33] As of 2025, no approved pharmacological treatments exist, but research continues to explore targeted therapies based on EXT1/EXT2 pathway disruptions.^[9]

Surgical interventions

Surgical interventions are indicated for hereditary multiple exostoses (HME) when lesions cause persistent pain unresponsive to conservative management, functional impairment such as restricted joint motion or limb length discrepancies, neurovascular compression, or skeletal deformities affecting daily activities.^[9]^[34] Suspicion of malignant transformation, particularly with a cartilage cap thickness exceeding 1.5–2 cm on MRI, also warrants operative evaluation and potential resection, as this feature correlates with secondary chondrosarcoma in 1–5% of HME cases overall.^[28]^[25]^[3] The primary procedure for symptomatic osteochondromas is marginal excision, involving complete removal of the lesion at its base with a thin cuff of normal bone to minimize recurrence, while carefully avoiding violation of adjacent joints or growth plates.^[8] For forearm involvement, where radial head subluxation or ulnar tethering is common, ulnar lengthening—either gradual distraction or acute osteotomy—is performed to restore alignment and forearm rotation.^[34] Site-specific interventions address localized complications; for lower extremity deformities like genu valgum at the knee or ankle valgus, realignment osteotomies correct mechanical axes and improve gait stability.^[9] In cases of spinal osteochondromas causing cord compression (present in approximately 36% of pediatric patients), decompression surgery removes the lesion to alleviate neurological symptoms without destabilizing the spine.^[8]^[35] Outcomes of surgical excision are generally favorable, with a low local recurrence rate of approximately 2% when resection is complete, though incomplete removal in young children increases this risk.^[9] Complications occur in 5–10% of cases, including infection, nerve injury, or wound issues, but overall morbidity remains low for straightforward excisions.^[8] Patients often require multiple procedures, averaging 2–3 per lifetime but exceeding 20 in severe cases, to manage recurrent symptoms or progressive deformities.^[9]^[8]^[36] By 2025, advances include minimally invasive techniques using small incisions and muscle-sparing approaches for exostosis removal, reducing recovery time and complications.^[37] Additionally, 3D-printed anatomical models and navigation systems enable precise preoperative planning, particularly for complex spinal or pelvic resections, improving accuracy and outcomes in pediatric cases.^[9]^[38]^[39]

Prognosis

Malignancy risk

Hereditary multiple exostoses (HME) carries a lifetime risk of approximately 1-10% for the malignant transformation of osteochondromas into secondary chondrosarcoma (with estimates varying from 1-5% in established reviews to up to 10% in recent studies as of 2025), with rare cases progressing to osteosarcoma or other sarcomas.^[1]^[5]^[9] This risk is notably higher in patients with pathogenic variants in the EXT1 gene (approximately 1.5-2 times that of EXT2 variants), due to more severe phenotypic expression and greater propensity for oncogenic progression.^[40]^[41] Transformation typically occurs in adulthood, with about 75% of cases diagnosed between ages 20 and 40.^[42] Several risk factors influence the likelihood of malignancy. Axial lesions, particularly those in the pelvis, scapula, or proximal femur, are more prone to transformation, accounting for over 50% of cases.^[42] A cartilage cap thickness exceeding 2 cm on imaging, rapid growth after puberty, and a family history of malignancy further elevate the risk, often signaling underlying genetic instability.^[1]^[9] Males also face a slightly higher incidence, at around 6.3% versus 4.6% in females.^[42] Surveillance is essential for early detection in high-risk individuals. Annual MRI or CT scans are recommended for patients aged 20-40, focusing on symptomatic or enlarging lesions, while whole-body MRI may aid in comprehensive monitoring.^[42]^[9] Biopsy is indicated for suspicious features such as new-onset pain, nodularity, or increased metabolic activity on FDG-PET (SUV max >2).^[1] At the histological level, progression begins with biallelic loss of EXT1 or EXT2 function, disrupting heparan sulfate biosynthesis and leading to chromosomal instability, including frequent deletions at 9p21 (affecting CDKN2A).^[40]^[43] This second-hit mechanism drives dedifferentiation of chondrocytes within the cartilage cap, culminating in low-grade chondrosarcoma. Surgical resection of detected malignancies offers favorable outcomes, with 5-year survival rates of 75-90%.^[42]^[44]

Long-term functional outcomes

Patients with hereditary multiple exostoses (HME) often experience significant orthopedic sequelae in the long term, including limb length discrepancies in approximately 50% of cases, with about 23% requiring surgical correction.^[3] Chronic pain affects 60% of children and up to 80% of adults, frequently resulting from mechanical irritation, joint stress, or secondary arthritis, which can limit mobility and daily activities.^[3] Additionally, deformities such as genu valgum occur in 33% of patients, contributing to ongoing joint instability and potential for accelerated osteoarthritis.^[3] Despite these challenges, the majority of individuals with HME achieve a functional status that allows for normal daily living, with most participating in education, employment, and recreational activities, though adaptations may be necessary.^[45] In severe cases, affecting around 9-10% of patients, profound deformities—such as those involving the pelvis or lower extremities—can lead to significant disability, including reliance on mobility aids like wheelchairs.^[3] Employment impacts are notable, with 22-28% of adults changing jobs or requiring workplace modifications due to physical limitations.^[45]^[8] Psychological and social outcomes are influenced by visible deformities and activity restrictions, with over 50% of children reporting difficulties in school, including challenges with physical education and socialization.^[8] Adults may face body image concerns and reduced participation in sports (46% cessation rate), leading to lower quality of life scores compared to general populations, particularly in physical and social functioning domains.^[45] Multidisciplinary care, including psychological support, has been shown to mitigate these effects and improve overall well-being.^[3] Life expectancy in HME is generally normal, unaffected by the benign osteochondromas themselves, and fertility remains unimpaired, though exostoses may occasionally complicate pregnancy without altering reproductive capacity.^[4] Lifelong follow-up is essential, with recommendations for monitoring every 6-12 months in children transitioning to annual or biennial assessments in adults, often involving imaging to track exostoses and functional status.^[8] This care facilitates early intervention for emerging issues and supports a smooth shift from pediatric to adult orthopedics.^[3]

Epidemiology

Prevalence and incidence

Hereditary multiple exostoses (HME), also known as hereditary multiple osteochondromas, is a rare autosomal dominant disorder with a global incidence of approximately 1 in 50,000 to 1 in 100,000 live births.^[1] This estimate has remained consistent across epidemiological studies conducted in diverse populations, reflecting the genetic basis of the condition without evidence of significant temporal fluctuations in occurrence rates.^[26] The stability of these figures underscores the absence of environmental or lifestyle factors substantially altering the disorder's frequency over time. Prevalence is estimated at about 1 in 50,000 individuals worldwide, though true rates may be higher due to underdiagnosis, particularly in females presenting with mild symptoms.^[1] Incomplete penetrance, reported at 96% in females compared to nearly 100% in males, contributes to this underrecognition, as subtle or asymptomatic cases often go undetected without comprehensive family history evaluation.^[1] Approximately 10% of HME cases result from de novo pathogenic variants in the EXT1 or EXT2 genes, while the majority are inherited, further supporting the consistent prevalence patterns observed.^[1] Geographically, HME distribution is uniform across most global populations, with no substantial ethnic variations beyond potential reporting biases in under-resourced areas.^[3] An exception occurs in the Chamorro population of Guam, where prevalence reaches as high as 1 in 1,000, likely due to founder effects rather than broader genetic differences.^[1] Similar elevated rates are reported in other isolated groups, such as approximately 1 in 77 among the Ojibway Indian population of Manitoba, Canada.^[2]

Demographic variations

Hereditary multiple exostoses (HME) exhibits a notable sex distribution, with a male predominance reported at ratios ranging from 1.5:1 to 3:1.^[14]^[9] This disparity is attributed to incomplete penetrance in females, leading to milder manifestations and potentially lower detection rates among women.^[9]^[46] As a result, affected females often experience fewer and less symptomatic osteochondromas compared to males.^[6] Diagnosis of HME typically peaks in childhood, with a median age of 3 years and nearly all cases identified by age 12.^[6] Osteochondromas develop and enlarge primarily during the first decade of life, coinciding with active skeletal growth.^[14] Progression generally stabilizes after puberty, as growth ceases with the closure of growth plates.^[14] Reports of HME prevalence are higher among Caucasians, though this may reflect ascertainment bias rather than true ethnic predisposition.^[9] Genetic studies show no strong racial differences, with EXT1 and EXT2 mutations identified across Caucasian, Asian, and other populations without distinct hotspots.^[14] The condition is less frequently reported in certain groups, such as black Africans, potentially due to underdiagnosis.^[47] Socioeconomic factors significantly influence HME detection, as access to diagnostic imaging and orthopedic care varies globally; higher reporting occurs in developed countries with routine screening programs.^[48] Severity in HME is gene-specific, with EXT1 mutations associated with more severe disease across all demographics, including greater numbers of osteochondromas, increased deformity, reduced stature, and higher functional impairment compared to EXT2 mutations.^[49]^[9] This pattern holds regardless of sex, age, or ethnic background.^[49]

References

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Hereditary multiple exostosis is a benign disorder characterized by multiple chondrogenic lesions (osteochondromas) found on the surfaces of bones.
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Hereditary Multiple Exostoses—A Review of the Molecular ... - NIH
Hereditary multiple exostoses (HMEs) syndrome, also known as multiple osteochondromas, represents a rare and severe human skeletal disorder.
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Entry - %600209 - EXOSTOSES, MULTIPLE, TYPE III; EXT3 - OMIM
A gene for hereditary multiple exostoses maps to chromosome 19p. Hum. Molec. Genet. 3: 717-722, 1994.
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Large-scale mutational analysis in the EXT1 and EXT2 genes for ...
Mar 9, 2016 · Fifty-two mutations in 47 families with MO in either EXT1 or EXT2, and 42.3 % (22/52) of mutations were novel mutations. Twenty-nine families ( ...
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Mutations in the EXT1 and EXT2 genes in hereditary ... - PubMed - NIH
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 ...
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The pathogenic roles of heparan sulfate deficiency in Hereditary ...
Dec 24, 2017 · Heparan sulfate (HS) is an essential component of cell surface and matrix proteoglycans (HS-PGs) that include syndecans and perlecan.
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Structure of the human heparan sulfate polymerase complex EXT1 ...
Nov 19, 2022 · Mutations in either the EXT1 or EXT2 gene in humans are associated with hereditary multiple exostoses, a skeletal disorder characterized by ...
[19]
Heparan sulfate in skeletal development, growth, and pathology ...
Jul 2, 2013 · Heparan sulfate inhibition leads to ectopic bone morphogenetic protein signaling and cartilage formation.
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Mice deficient in Ext2 lack heparan sulfate and develop exostoses
Nov 15, 2005 · HME results from mutations in EXT1 and EXT2,genes that encode glycosyltransferases that synthesize heparan sulfate chains. To study the ...
[21]
Hereditary Multiple Exostoses: New Insights into Pathogenesis ... - NIH
Most HME cases are linked to loss-of-function mutations in EXT1 or EXT2 that encode glycosyltrasferases responsible for heparan sulfate (HS) synthesis, leading ...Missing: neurological | Show results with:neurological
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No Haploinsufficiency but Loss of Heterozygosity for EXT in Multiple ...
We found a second hit in 63% of analyzed osteochondromas, supporting the hypothesis that osteochondromas arise via loss of heterozygosity. The detection of the ...
[23]
Hereditary multiple exostoses: A case report and literature review
The cartilage thickness varies greatly from 1 to 3 cm in young patients to just few millimeters in adults. The cartilage cap also has areas of calcifications ...
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Hereditary multiple exostoses: an educational review - PMC
Feb 21, 2025 · HME is a disorder characterised by the formation of osteochondromas arising from long and flat bones.
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Multimodality imaging features of hereditary multiple exostoses - NIH
Plain radiographs of the affected region remain the mainstay of radiological diagnosis in HME helping to readily identify exostoses and bony deformities.
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Entry - #133700 - EXOSTOSES, MULTIPLE, TYPE I; EXT1 - OMIM
Multiple hereditary exostoses (EXT) is an autosomal dominant disorder characterized by multiple projections of bone capped by cartilage, most numerous in ...<|control11|><|separator|>
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Osteochondroma & Multiple Hereditary Exostosis - Pathology
Oct 10, 2024 · Osteochondromas are benign chondrogenic lesions derived from aberrant cartilage from the perichondral ring that may take the form of solitary ...
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List of drugs/medicines used for Multiple Osteochondromas ...
... manage Multiple Osteochondromas / Hereditary Multiple Exostoses. With a ... Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID), prescribed for mild to ...
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[PDF] Physical Therapy for Patients with Multiple Hereditary Exostoses
Conservative treatment of exostoses may include physical modalities for pain relief.
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Hereditary Multiple Exostoses - Radsource
Osteochondromas continue to grow until the child reaches skeletal maturity at which point no new lesions will occur.2 Spontaneous regression has been reported ...
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Hereditary multiple osteochondromas (HMO) - AboutKidsHealth
Mar 6, 2023 · The average age of diagnosis is three years. Nearly all people with HMO are diagnosed before 12 years of age.
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Palovarotene for patients with multiple hereditary exostosis: results of MO-Ped, a terminated, randomized, placebo-controlled, double-blind phase 2 trial - Scientific Reports
### Summary of Phase II Trial Results for Palovarotene in Pediatric MHE (MO-Ped Trial)
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Current paediatric orthopaedic practice in hereditary multiple ...
Mar 21, 2018 · There is poor evidence to suggest that surgery improves quality of life or function. Predictors of surgical success in regard to patient and ...
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A 40‐Year‐Old Male Presenting with Hereditary Multiple Exostosis ...
Mar 13, 2019 · followed 50 patients with HME who had a mean number of 18.12 osteochondromas per individual, and each patient had undergone a mean of 5.62 ...
[35]
Minimally‐invasive excision of a scapular osteochondroma on the ...
Aug 27, 2024 · The surgery was performed using a minimally invasive approach based on 3D printing model, with a minor incision and muscle-sparing technique ...
[36]
Minimal-invasive, image guided, 360-degree resection of ilio-lumbo ...
Dec 30, 2024 · We describe a 360-degree surgical resection with application of a 3D printed model, navigation, and mini-invasive techniques.Missing: advances | Show results with:advances
[37]
Minimal-invasive, image guided, 360-degree resection of ilio-lumbo ...
Aug 7, 2025 · Conclusion We describe a 360-degree surgical resection with application of a 3D printed model, navigation, and mini-invasive techniques. Our ...Missing: advances | Show results with:advances
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Hereditary Multiple Exostoses—A Review of the Molecular ...
However, some researchers estimate that HMEs occur in one per 50,000 in the Western population and affect more often males reaching male to female ratio as high ...
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[PDF] Hereditary Multiple Exostoses Panel - GeneDx
de novo variant or reduced penetrance of a variant in a parent. The literature suggests that disease penetrance is high (95-100%) and that most non ...
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Chondrosarcoma transformation in hereditary multiple exostoses - NIH
The most serious complication of hereditary multiple exostoses(HME) is chondrosarcoma transformation. Numerous authors have suggested that screening might allow ...
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EXT-Mutation Analysis and Loss of Heterozygosity in Sporadic and ...
Approximately 15% of all chondrosarcomas arise within the cartilaginous cap of an osteochondroma. EXT is genetically heterogeneous, and two genes, EXT1 and EXT2 ...
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Chondrosarcoma secondary to hereditary multiple ...
Nov 3, 2023 · Hereditary multiple osteochondromas (HMOs) are a rare genetic disorder characterized by the formation of multiple benign osteochondromas ...Chondrosarcoma Secondary To... · Genetics Of Hmo · Surgical Resection To...Missing: hits | Show results with:hits
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Pain, Physical and Social Functioning, and Quality of Life in ...
Aug 10, 2025 · This study aimed to assess pain and quality of life in a large cohort of patients with multiple hereditary exostoses.
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[PDF] Hereditary Multiple Exostosis: A Pediatrician's Perspective
Oct 10, 2013 · Females tend to have an incomplete penetrance leading to a milder ... The molecular and cellular basis of exostosis formation in hereditary ...
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Hereditary multiple exostosis in two Nigerian siblings - PMC - NIH
Hereditary multiple exostosis (HME) is a rare disease, and is rarely reported in black Africans. Two siblings with HME are presented, both of whom are children ...Missing: ethnicity | Show results with:ethnicity
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Hereditary Multiple Exostosis: rare or undiagnosed? - ResearchGate
Sep 2, 2022 · Over the past year 2013/2014 we have encountered 4 separate cases of hereditary multiple exostosis all of whom had been seen in primary care ...
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Severity of disease and risk of malignant change in hereditary ...
The sites of mutation affected the severity of disease with patients with EXT1 mutations having a significantly worse condition than those with EXT2 mutations ...