Hereditary Multiple Exostoses Research Articles

Is Routine Spine MRI Necessary in Skeletally Immature Patients With MHE? Identifying Patients at Risk for Spinal Osteochondromas

Multiple hereditary exostoses (MHE) is an autosomal dominant condition leading to development of osteochondromas throughout the body. Although long bones are most often affected, spine involvement may occur and usually requires advanced imaging for diagnosis. However, the high cost of detection, infrequent occurrence, and very low likelihood of spinal cord compression and neurological injury, create a management conundrum. The purpose of our investigation is to identify patients at greatest risk for spinal lesions and refine indications for advanced imaging. All MHE patients in a 24-year period were retrospectively reviewed. Skeletally immature patients with advanced imaging of the spine were further evaluated. The demographic characteristics, family history, clinical presentation, past surgical history, tumor burden, and distribution of patients with spinal lesions were compared with those without. In total, 227 MHE patients were identified and 21 underwent advanced spinal imaging. Spinal lesions were found in 8 of the 21 screened patients (38.1%, 3.5% overall), of which 4 were intracanal and 1 was symptomatic (4.8%, 0.4% overall). Only the symptomatic patient underwent excision of the spinal lesion. Patients with spinal lesions had higher tumor burden than those without (median, 28.5 vs. 19 locations; P=0.010). There was a significant association with rib (P=0.018) and pelvic (P=0.007) lesions, which may serve as "harbinger" lesions. The presence of both a rib and a pelvic lesion used as a screening tool for spinal lesions produces a sensitivity of 100% and specificity of 69%. Symptomatic spinal involvement in children with MHE is rare and tends to occur in patients with higher tumor burden. We recommend limiting advanced spine imaging to children with neurological symptoms or with rib and pelvic "harbinger" lesions. Patients without these findings are unlikely to have spine involvement needing intervention. This approach offers an opportunity to avoid unnecessary testing and substantially reduce costs of diagnostic imaging. Level III.

Identification of risk factors affecting bone formation in gradual ulnar lengthening in children with hereditary multiple exostoses: A retrospective study.

The forearm deformity classified by Masada is a characteristic trait of patients with hereditary multiple exostoses (HME). Ulnar gradual lengthening, which was considered to be a safe and reliable procedure, was popular in treating these difficult deformities, however, delayed consolidation of the callus is uncommon but not rare in literature review. The purpose of this study was to try to identify the risk factors influencing bone healing in gradual ulnar lengthening in HME.We retrospectively reviewed patients with HME-induced forearm deformity who underwent gradual ulnar lengthening at our hospital from 2010 to 2016. Patients’ demographic data, forearm deformity of Masada type, surgical procedure, ulnar diameter of osteotomy site, and external fixator type were recorded. We also reviewed radiographical data included gained length, axis deviation, callus form. Clinical outcome was assessed by the bone healing index (HI). Multiple linear regression was used to analyze the relationships between diffident parameters and the HI, the level of significance was set P <.05.Thirty-three patients were included in this study. The mean follow-up period was 1.5 (range 0.5–8) years. Circular external fixators were used in 5 patients and monolateral external fixators were used in 28 patients. The mean achieved length was 4.24 cm. The mean HI was 50.3 (range 26.6–99.3) days/cm. In patient with monolateral external fixator, patient's age was positively correlated with the bone HI (P = .001), while diameter and body mass index (BMI) were negatively correlated with the HI (P = .040, .018, respectively). Patient's sex, removal of distal ulnar exostoses, lengthening percentage, and axis deviation were non-significant in the regression model.When using monolateral external fixator for ulnar lengthening, patient's age, diameter of osteotomy site, and BMI are the most important risk factors related to bone formation. Pediatric orthopedic surgeons should consider these variables in order to avoid delayed union.

Knee locked in flexion: incarcerated semitendinosus tendon around a proximal tibial osteochondroma

This case reports on a knee locked in flexion due to incarceration of the semitendinosus tendon around an osteochondroma in a patient with a history of multiple hereditary exostoses (MHE). An 18-year-old female with history of MHE presented with acute right medial knee pain and inability to extend her knee. Radiographs confirmed multiple lower extremity osteochondromas, notably a large, 3-cm pedunculated osteochondroma about her right medial proximal tibia. This was assessed as a locked knee secondary to incarcerated hamstring tendons around an osteochondroma. Excision of the osteochondroma restored normal flexion and extension of her knee. At the 3-month follow-up visit, she had returned to all activities with no recurrent medial knee pain or locking. The differential diagnosis for a locked knee joint can be broad, but tendon incarceration should be considered in appropriate patients with significant symptoms. In patients with a history of MHE, osteochondromas may be the cause of tendon entrapment.

A Young Boy with Multiple Bony Overgrowths

Hereditary multiple exostoses is a rare autosomal dominant pediatric disorder with an incidence of about 1:50000 characterized by multiple cartilage-capped bony protuberances, called osteochondromas or exostoses, projecting from the metaphyses of long bones. It is caused by loss of function mutations in exostosin-1 and exostosin-2 genes that encode glycosyltransferase enzymes involved in the synthesis of heparan sulfate which has fundamental role in extracellular matrix formation during bone development. It commonly presents with compressive symptoms due to bony overgrowth involving all bones except calvarium and rarely transformed into malignancy. No definite treatment is available, but careful screening of these exostoses with timely referral to respective surgeon prevents long term complications and improves quality of life.&#x0D; J Enam Med Col 2019; 9(1): 60-63

A novel splice mutation induces exon skipping of the EXT1 gene in patients with hereditary multiple exostoses.

The molecular mechanism of hereditary multiple exostoses (HME) remains ambiguous and a limited number of studies have investigated the pathogenic mechanism of mutations in patients with HME. In the present study, a novel heterozygous splice mutation (c.1284+2del) in exostosin glycosyltransferase 1 (EXT1) gene was identified in a three-generation family with HME. Bioinformatics and TA clone-sequencing indicated that the splice site mutation would result in exon 4 skipping. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) revealed that the expression levels of wild-type EXT1/EXT2 mRNA in patients with HME were significantly decreased, compared with normal control participants (P<0.05). Abnormal EXT1 transcript lacking exon 4 (EXT1-DEL) and full-length EXT1 mRNA (EXT1-FL) were overexpressed in 293-T cells and Cos-7 cells using lentivirus infection. RT-qPCR demonstrated that the expression level of EXT1-DEL was significantly increased, compared with EXT1-FL (17.032 vs. 6.309, respectively; P<0.05). The protein encoded by EXT1-DEL was detected by western blot analysis, and the level was increased, compared with EXT1-FL protein expression. Immunofluorescence indicated that the protein encoded by EXT1-DEL was located in the cytoplasm of Cos-7 cells, which was consistent with the localization of the EXT1-FL protein. In conclusion, the present study identified a novel splice mutation that causes exon 4 skipping during mRNA splicing and causes reduced expression of EXT1/EXT2. The mutation in EXT1-DEL generated a unique peptide that is located in the cytoplasm in vitro, and it expands the mutation spectrum and provides molecular genetic evidence for a novel pathogenic mechanism of HME.

Hemothorax caused by vertebral exostoses.

Spontaneous hemothorax is a rare condition and sometimes occurs during anticoagulant therapy for venous thromboembolism. Other causes of the condition are bleeding disorders, complication of spontaneous pneumothorax and pleural malignancy. Vertebral exostosis represents an exceptional etiology of hemothorax, as a result of direct traumatic injury of the pleura or diaphragm by the intrathoracic tumour. Exostosis often occurs in hereditary multiple exostoses, but can also be isolated. We present a case of spontaneous hemothorax in a patient with vertebral exostoses and propose a new etiology of hemothorax. A 22-year-old man with no specific history elements and no previous trauma presented has been experiencing a right-sided pleuritic chest pain and respiratory discomfort for 6 days. Physical examination revealed dullness to percussion and decreased breath sounds on the right side of the chest. Chest x-ray showed right pleural effusion and diagnostic thoracocentesis revealed gross blood. Pleural effusion's hematocrit was 52%, while that of the peripheral blood was 39%. Hemothorax was diagnosed. Thoracic Computed tomography scan (CT-scan) (A and B, arrows) followed by magnetic resonance imaging (MRI) showed the presence of two vertebral exostoses arising from the right transverse processes of the 10th and 11th thoracic vertebrae (C and D, arrows). These, encroached on the 11th intercostal space. The hemothorax was managed successfully with chest-tube insertion. However, surgical resection of exostoses was indicated in our patient given the risk of loco-regional complications, and the recurrence of the hemothorax. The postoperative course was uneventful and the patient was followed without recurrent hemothorax for two years.

Gradual ulnar lengthening by an Ilizarov ring fixator for correction of Masada IIb forearm deformity without tumor excision in hereditary multiple exostosis: preliminary results.

Bony exostoses are benign osteocartilaginous growths that start close to growth plates. Approximately 30-60% of patients have forearm deformities. The commonly encountered forearm deformities in these patients are bowing of the radius, with or without ulnar drift of the carpus, radial head dislocation, shortening of the ulna, and radial head dislocation. The current study reported on the results of management of radial head dislocation for type IIb Masada and Oho classification of forearm deformities by Ilizarov ulnar lengthening and without tumor excision. A series of 12 patients with Masada type IIb deformity were treated by Ilizarov lengthening at AlHadra University Hospital, Alexandria, Egypt, during the period from January 2008 to June 2014. There were eight males and four females; the right forearm was affected in seven patients. The mean age of the patients was 8.7 years (range: 7.5-10 years). All cases showed ulnar shortening with distal ulnar exostosis and radial head dislocation (Masada type IIb). All patients were operated on under general anesthesia, with application of the Ilizarov frame to the forearm. The frame used was assembled of two complete rings; the proximal one was fixed to the proximal ulna and the distal ring was fixed to both radius and ulna. Ulnar osteotomy was performed between the two rings, followed by ulnar lengthening 10 days postoperatively to lengthen the ulna and pull down the radius. Over a follow-up period of 33.2 months (24-48 months), all patients showed spontaneous reduction of the radial head and correction of the forearm deformity. The range of motion improved: flexion increased from 117.5° (110-130°) to 145° (130-160°) and extension increased to 4.6° (0-10°), whereas it was 13.8° (10-20°) preoperatively and the supination increased from 46.3° (40-50°) preoperatively to 73.6° (65-80°) postoperatively. Pronation improved from a preoperative average of 37.9° (30-40°) to 70.8° (60-80°) at the end of follow-up. The average amount of ulnar length was 27.9 mm (25-35) and the duration of external fixation was 103.3 days on average, with a range of 90-130. Thus, the average external fixation index was 3.7 days/mm (range: 3.6-4.0). Gradual lengthening of the ulna and pulling down the radius with an Ilizarov frame is an excellent method for correction of forearm deformity in patients with multiple hereditary exostosis (Masada IIb). Early intervention is the key to achieving spontaneous reduction of the radial head in all patients without the need for corrective osteotomy or tumor excision. Level of evidence: level IV.

Symptomatic osteochondroma in the ventral aspect of the scapula in a child with hereditary multiple exostoses

Symptomatic osteochondroma in the ventral aspect of the scapula in a child with hereditary multiple exostoses

Use of hexapod frame to gradually correct congenital and acquired forearm deformity

Introduction: Forearm deformity affects patients with Multiple Hereditary Exostosis (MHE), Ollier's disease, and other various congenital deformities as well as those with physeal growth arrest secondary to trauma. Acute correction of such deformities is complicated by risk of neurovascular compromise and as such, techniques that allow for gradual deformity correction are of great interest in this clinical setting. We hypothesized that the use of hexapod frame would allow for reliable correction without neurovascular compromise. Methods: This retrospective, case series reviewed all patients who underwent osteoplasty of the radius and ulna between January 1, 2008, and December 31, 2017, among two surgeons. Patient demographics, comorbidities, radiographic parameters, external fixation index (EFI), and complications were recorded from chart review. Six patients presented with a diagnosis of MHE, two patients with a diagnosis of Ollier's disease, one with short stature homeobox (SHOX) deletion, and one with physeal growth arrest. Results: Of the ten patients identified, the rate of lengthening proceeded between 0.5 and 1 mm/day with an average EFI of 3.7 months/cm for the radius and 7.4 months/cm for the ulna. Average radius and ulna lengthening were 1.5 cm and 2.7 cm, respectively. Average radial bow preoperatively was 1.7 cm with a location of the maximal radial bow at an average of 61% from the radial tuberosity. Radial bow was corrected to 0.6 cm on average with a location of the maximal radial bow at an average of 64%. Neither patients exhibited nerve deficit nor neurapraxia at the conclusion of treatment. One fracture occurred after frame removal, which was treated with open reduction and internal fixation. Conclusion: Hexapod frames can be used to safely correct forearm deformities without neurovascular compromise.

La maladie des exostoses multiples

Hereditary multiple exostosis (HEM) is one of the most common hereditary diseases. It is characterized by the proliferation of bone protuberances, especially located in the metaphysis of long bones. The disease phenotype may also associate abnormalities in the shape and length of long bones, such as the typical “Bessel Hagen” deformity. Clinically, the main complaint of patients remains pain, but the psychological and social consequences should not be minimized. The rare complication (2 to 5% of cases) but the most feared is the transformation into chondrosarcoma, which motivates regular clinical and radiological monitoring of these patients. This follow-up, although essential, remains poorly defined, including at a minimum, an annual clinical examination and radiological follow-up based on the symptoms described by the patients. The treatment remains mainly surgical, with patients being most often multi-operated during the course of the disease. Medical treatment remains secondary. In recent years, progress has been made in understanding the pathophysiology of this disease, particularly with the discovery of the mutation of EXT genes, found in 80% of HME cases. These tumor suppressor genes encode proteins that act in the synthesis of heparan sulfates (HS). The decrease in the amount of HS leads to changes in certain metabolic pathways, which explains the development of ectopic growth plaques, which are the cause of bone exostosis, but also the poor longitudinal growth of long bones. The greater knowledge of the mechanisms underlying this disease makes it possible to consider potential therapeutic targets.

Structural Features of Heparan Sulfate from Multiple Osteochondromas and Chondrosarcomas.

Multiple osteochondromas (MO) is a hereditary disorder associated with benign cartilaginous tumors, known to be characterized by absence or highly reduced amount of heparan sulfate (HS) in the extracellular matrix of growth plate cartilage, which alters proper signaling networks leading to improper bone growth. Although recent studies demonstrated accumulation of HS in the cytoplasm of MO chondrocytes, nothing is known on the structural alterations which prevent HS from undergoing its physiologic pathway. In this work, osteochondroma (OC), peripheral chondrosarcoma, and healthy cartilaginous human samples were processed following a procedure previously set up to structurally characterize and compare HS from pathologic and physiologic conditions, and to examine the phenotypic differences that arise in the presence of either exostosin 1 or 2 (EXT1 or EXT2) mutations. Our data suggest that HS chains from OCs are prevalently below 10 kDa and slightly more sulfated than healthy ones, whereas HS chains from peripheral chondrosarcomas (PCSs) are mostly higher than 10 kDa and remarkably more sulfated than all the other samples. Although deeper investigation is still necessary, the approach here applied pointed out, for the first time, structural differences among OC, PCS, and healthy HS chains extracted from human cartilaginous excisions, and could help in understanding how the structural features of HS are modulated in the presence of pathological situations also involving different tissues.

Trigger finger in a hereditary multiple exostoses disease: A unique case report

Trigger finger is one of the most common upper extremity problems seen by hand surgeons. Lesions occupying space in the tendon bed can prevent tendon gliding. We describe a unique case of trigger finger in a patient known for a hereditary multiple exostoses disease where an exostosis in the tendon bed constricted the tendon sheath, leading to triggering and locking. Open surgical treatment was performed by removing of the exostosis which relieved the problem. Level of Evidence: Level V, therapeutic study.

Evaluation of the results of ulnar lengthening for correction of forearm deformities in multiple exostoses (Diaphyseal aclasis)

Evaluation of the results of ulnar lengthening for correction of forearm deformities in multiple exostoses (Diaphyseal aclasis)

Chondrosarcoma transformation in hereditary multiple exostoses: A systematic review and clinical and cost-effectiveness of a proposed screening model

BackgroundThe most serious complication of hereditary multiple exostoses(HME) is chondrosarcoma transformation. Numerous authors have suggested that screening might allow early chondrosarcoma detection. However, literature-quoted incidences of malignant transformation are highly variable. MethodsA systematic review of malignant transformation by sex, exostosin-1 mutation(EXT1), age and site was conducted searching Medline, Embase and CINHAL. Three HME screening strategies were then developed and compared using cost per life-year gained and incremental cost-effectiveness ratio (ICER). ResultsSystematic review: 18 papers with 852 chondrosarcomas were identified. The incidence of chondrosarcoma transformation averaged 4%, 75.2% occurring between ages 20-40 and 56.2% at the pelvis and proximal femur. Screening model: In the general HME population, plain radiographs provided cost per life-year gain of £19,013 compared to £53,392 in MRIs. ICER in MRIs compared to X-rays was £80,218. However, for every generation of HME patients screened over 20 years, X-ray radiation induced 0.65 cancers. Psychological effects of false-positives were marginal. Screening only higher-risk groups (males or EXT1) reduced cost but benefited fewer patients. ConclusionsOur results suggest that annual MRI screening for all HME patients between age 20-40 may be of value. However, the extent of anatomical imaging is subject to debate; it is possible that focused imaging protocols which scan from cervical spine to proximal femur may improve cost-effectiveness.

Heterogeneous spectrum of EXT gene mutations in Chinese patients with hereditary multiple osteochondromas.

Hereditary multiple osteochondroma (HMO) is one of the most common genetic skeletal disorders. It is caused by mutations in either EXT1 or EXT2 resulting in abnormal skeletal growth and morphogenesis. However, the spectrum and frequency of EXT1 and EXT2 mutations in Chinese patients with HMO was not previously investigated.Mutations were identified by performing Sanger sequencing analysis of the complete coding regions and flanking intronic sequences of EXT1 and EXT2, followed by multiplex ligation-dependent probe amplification (MLPA) analysis to detect gene deletions or duplications that could not be identified by the Sanger sequencing method.The present study identified pathogenic mutations in 93% (68/73) of unrelated HMO probands from 73 pedigrees. Mutations in EXT1 and EXT2 were identified in 53% (39/73) and 40% (29/73) of families. We identified 58 distinct mutations in EXT1 and EXT2, including 20 frameshift mutations, 16 nonsense mutations, 7 missense mutations, 9 splice site mutations, 5 large deletions, and 1 in-frame deletion mutation. Twenty-six of these mutations were novel and 32 were previously reported. Most of the mutations in EXT1 were base deletions or insertions (21/33), whereas the majority of those in EXT2 were single base substitution (18/25).Complete sequencing of both the EXT1 and EXT2 followed by MLPA analysis is recommended for genetic analysis of Chinese patients with HMO. This study provides a comprehensive characterization of the genetic aberrations found in Chinese patients with HMO and highlights the diagnostic value of molecular genetic analysis in this particular disease.

A Rare Presentation and Management of Forearm Deformity in a Patient with Hereditary Multiple Exostoses

We report the case of a patient with a long-standing and progressive forearm deformity, secondary to underlying hereditary multiple exostoses (HME). A salvage surgery was performed with excision of the pathologic parts of the radius and the ulna, followed by the creation of a 1-bone forearm. One of the common manifestations of HME is forearm deformity due to abnormal ossification and osteochondromas that affect the radius and/or the ulna. Progressive deformity can lead to increasing pain, joint instability, limited motion, and functional decline. Neglected or recalcitrant deformities pose a treatment challenge. At 1.5 years after surgery, the patient had a satisfactory outcome with a fully functional, pain-free forearm in a fixed, neutral position.

Poster 220: Management of an Adult With Symptomatic Hereditary Multiple Exostoses: A Case Report

Poster 220: Management of an Adult With Symptomatic Hereditary Multiple Exostoses: A Case Report

Effect of multiple hereditary exostoses on sports activity in children

ObjectiveThe purpose of this clinical case-control study was to assess the level of sports activity in children with hereditary multiple exostoses (HME) and to compare with the degree of physical activity in children of the same age without pathology. MethodsA case-control study was designed. Cases were drawn from children with HME diagnosed on the basis of clinical and radiographic evaluation with an age less then 12 years. Controls were chosen from a group of children with the same age and a negative family history for HME. All patients and controls were completed with the help of parents using the following evaluations: Tegner Activity Level Scale and University of California Los Angeles (UCLA) activity scale. ResultsA total of 154 individuals participated (54 cases and 100 controls). In the case groups, the mean age was 9.07; the mean number of exostoses resulted 29.51, while the mean value of UCLA and Tegner score resulted respectively 6.04 and 5.09. In the controls, the mean age was 8.88; mean UCLA and Tegner resulted respectively 7.17 and 5.64. Comparing the two groups, the only difference was between UCLA score (p = 0.0053). Moreover, comparing the results between female children affected by HME and female controls, we found a significant difference as regards UCLA score (p = 0.0045). ConclusionChildren affected by HME reported lower sports activity, in particular as regards female patients. Moreover, physical activity is not correlated with any other independent factor leading different patients to a similar level of ability in performing sport. Study designLevel III – Case Control Study.

A novel EXT2 frameshift mutation identified in a family with multiple osteochondromas.

Multiple osteochondromas (MO) is an autosomal inherited disease that is characterized by benign bone tumors. However, the underlying mechanism of MO at a molecular level requires further investigation. The majority of mutations associated with MO occur in the exostosin glycosyltransferase genes (EXT)1 or EXT2. In the present study, the genetic causes of the disease were investigated. Polymerase chain reaction amplification, followed by DNA sequencing of the complete EXT1 and EXT2 coding regions, were conducted in a family with MO (n=5). A novel frameshift mutation in exon 3 of EXT2 (c.660delG) was detected. The production of a defective EXT2 protein, lacking 450 C-terminal amino acid residues is predicted to be caused by the c.660delG mutation, located within the exostosin domain of EXT2. The missing residues contain the exostosin and glycosyltransferase family 64 domains, which are critical for the function of EXT2. The novel c.660delG frameshift mutation in the EXT2 gene extends the etiological understanding of MO and may provide an effective reference for genetic counseling and prenatal diagnosis in this family.

A Novel EXT1 Mutation Identified in a Family with Multiple Osteochondromas.

Multiple exostoses (MO), also referred to as hereditary multiple exostoses (HME), is an autosomal dominant inherited skeletal disorder that has been found to be associated with mutations in the EXT1 and EXT2 genes. In the present study, we report a Chinese family with HME and our mutational analyses of the EXT1 and EXT2 genes in affected and unaffected individuals. All exons of the EXT1 and EXT2 genes in seven family members were polymerase chain reaction amplified from blood and sequenced. A heterozygous mutation (c.1056G>T) was identified in exon 2 of the EXT1 gene in the proband and other affected family members; this mutation was not found in the unaffected family members. This c.1056G>T mutation is located in the exostosin domain of the EXT1 protein and leads to an amino acid change of Glutamine (Gln) to Histidine (His) at position 352. Homology searches reveal that Gln352 is highly conserved in many species and may play an essential role in the normal function of the EXT1 protein. This study contributes to a better understanding of the genetic basis of HME, expands the known mutational spectrum of EXT1, and provides a reference for genetic counseling and prenatal diagnosis of this family.