Multiple Exostoses Research Articles

Pain and Depression in Pediatric Hereditary Multiple Exostoses Patients

Amaç: Çalışmamızda Herediter Multipl Egzostozis (HME) hasta grubunda başta ağrı olmak üzere hastalığa ait komplikasyonların çocuk ve adölesan dönemdeki etkilerini değerlendirmeyi amaçladık. Hastalar ve Yöntem: 10-19 yaş arası 72 (37Erkek/ 32Kadın) hasta değerlendirmeye dahil edildi. Ortalama yaş 13.8±2.6 idi. Hastaların demografik verileri, lezyonların ilk ortaya çıktığı yaş, lezyon sayıları, deformite varlığı ve VAS skoru ile ağrı durumları değerlendirildi. Çalışmaya katılan hastalara, ağrının yaşam kalitesi üzerine etkilerini değerlendirmeye yönelik bir anket yöneltildi. Depresyon değerlendirmesi 17 yaş ve altı hastalarda Çocuklar için Depresyon Ölçeği (ÇDÖ) ve 18 yaş ve üstü hastalar için Hamilton Depresyon Ölçeği (HAM-D) ile değerlendirildi. Grup değişkenlerinin frekans ve yüzdelik değerleri, iki grup ortalaması arasındaki farkları belirlemede “t-testi”; ikiden fazla ortalamanın karşılaştırılmasında; tek yönlü varyans analizi kullanıldı Bulgular: Hastaların %68.1’i (n=49) HME nedeniyle bir veya daha fazla cerrahi girişim geçirmiş olgulardan oluşmaktaydı. Ağrı, hastaların %72.2’sinde (n=52) en belirgin şikayet idi. Ağrıyı başlatan en sık sebepler hastaların %52.8’inde koşma iken, %50’sinde kontakt sporlar (futbol, basketbol vb.) idi. Hastaların %31.9’u ağrının günlük yaşam aktivitelerini kısıtlayabildiğini bildirirken ortalama tüm gruplarda ortalama VAS skoru 7.4±2.4 idi. VAS skoru azaldıkça ÇDÖ puanlarında anlamlı bir artış tespit edildi. (p=0.005) Yüksek ÇDÖ ve HAM-D puanlarının geçirilen ameliyat sayısı (p=0.015), bir aydaki ağrılı gün sayısı (p<0.001), düşük VAS skoru (p=0.005) ve ekstremitelerde yer alan lezyon sayıları (p=0.003) ile anlamlı olarak ilişkili olduğu belirlendi. Sonuç: Ağrı pediatrik HME hastalarında sosyokültürel aktiviteleri ve etkileşimi kısıtlayabilen en önemli sorunlardan biridir. Geçirilen ameliyat sayısı, bir ayda yaşanan ağrılı gün sayısı, düşük VAS skorları ve artmış lezyon sayıları HME hastalarında yaşam kalitesini negatif etkileyen ve pediatrik yaş grubunda depresyona yol açabilen faktörlerdir. HME hastalığın süresi pediatrik hastalarda depresyon ile ilişkilidir.

Less Is More: Ulnar Lengthening Alone without Radial Corrective Osteotomy in Forearm Deformity Secondary to Hereditary Multiple Exostoses.

Ulnar lengthening has gained popularity in treating forearm deformity due to hereditary multiple exostoses (HME). Whether a simultaneous radius angular correction is necessary for bowing deformity remains debatable. We aimed to evaluate effectiveness and safety of ulnar lengthening alone in HME children. HME patients with forearm deformity who underwent ulnar lengthening between 2011 and 2016 were included. Patients were divided into two groups: eight juniors (age ≤ 10 years) and six seniors (>10 years). The mean age of two groups was 8.1 ± 2.5 and 16.7 ± 4.4 years, respectively. The juniors underwent ulnar lengthening alone, and the seniors received an additional radial corrective osteotomy. Pre-operative and post-operative parameters of supination, pronation, ulnar variance (UV), radial articular angles (RAA), and carpal slip (CS) were assessed. The juniors rather the seniors had an improvement in supination (p < 0.05 and p = 0.109, respectively). The juniors and seniors improved in pronation (p < 0.05). UV, RAA, and CS were corrected in the seniors (p < 0.05). In the juniors, parameters improved in UV, RAA, and CS (p < 0.05). For HME children, ulnar lengthening alone can restore radiologic anatomy and functions, providing comparable surgical outcomes in cosmetic results and clinical parameters.

Ankle Mortise Instability in Multiple Hereditary Exostoses

Category:Ankle, Ankle Arthritis, Pediatric Foot and AnkleIntroduction/Purpose:Ankle valgus has been reported in 50% of patients with multiple hereditary exostoses (MHE) and, untreated, results in early arthrosis. Widening of the ankle mortise has also been reported; however, there has been a lack of data regarding its natural history and management. Alterations of mortise anatomy result in poor functional outcomes and accelerated arthrosis of the ankle. The aim of our study was to report the characteristics and outcomes of mortise widening in a group of patients with MHE.Methods:A total of 13 patients with MHE and mortise widening (16 ankles) were identified. Age, sex, BMI, laterality, origin of osteochondroma, pain, instability, clinical deformity, operative data, and complications were recorded. Mortise (M), Talocrural angle (TC), and Tibiotalar angle (TT) measurements were collected on preoperative and last follow up radiographs. The majority of patients underwent medial distal tibia hemiepiphysiodesis. Post-surgical AOFAS and SF36 scores were collected.Results:Preoperatively, no patient complained of instability, however, 9/16 ankles were painful and 14/16 were clinically in valgus. Patients underwent surgery at an age of 11.8 years (9.7-15). Radiographic and clinical follow up were 2.6 years (0.2-7.3) and 6 years (1.5-11.7), respectively. There were no significant differences between pre/postoperative M, TC, TT angles. Operative patients improved mean M (5.17 to 4.63 mm) and TT (8.71 to 4.54 degrees), neither angle reached normal values. TC (fibular length) was within normal limits (82.2 to 84.8). Questionnaires were obtained for 8/16 ankles, at a mean age of 19 years (13-25.1). The average AOFAS score was 66.7 out of 100. Patients scored 8.6/10 for alignment, 32/40 for pain, 25.6/50 for function. SF-36 scores were excellent.Conclusion:The improvement in M and TT was modest and their values remained outside the normal limits. TC angle was within normal limits but displayed an overall fibular shortening and thus, decreased lateral buttress with potential for talar shift. This was reflected in the mean functional and overall AOFAS score. However, our patients are functionally compensating as evidenced by SF36 scores. More studies are needed to optimize the management of MHE patients with ankle malalignment. Earlier valgus correction and possible addition of fibular lengthening to simultaneously address mortise widening may need to be considered to prevent early ankle arthritis.

Late presentation of spinal cord compression in hereditary multiple exostosis: case reports and review of the literature.

IntroductionOsteochondromas are usually found in the long bones of patients with hereditary multiple exostoses (HME). The spine is reported to be involved in over 50% of cases, but few of these patients are symptomatic as the result of an existing spinal exostosis.MethodsWe reviewed the current literature in order to find the right approach to patients with HME-complicated spinal exostosis and describe three paediatric patients that were diagnosed late with spinal cord compression due to cervical exostosis.ResultsOur three cases were all late presentations with neurology and unfortunately had minimal improvement of neurology after the lesion was surgically removed. There is general agreement that late presentation of spinal cord injury due to osteochondromas involving the cervical spine may cause severe and irreversible neurological sequelae. Our literature review revealed that there are no clear-cut guidelines to develop more comprehensive screening measures for these patients.ConclusionsA high index of suspicion is the most important factor for correct diagnosis and appropriate management. Physicians who treat HME should bear in mind that thorough history taking and a neurological examination at follow up are essential for these patients. Clearer guidelines for the development of more comprehensive screening programmes are essential.Level of evidenceIV

Identification of pathogenic variations in two Chinese pedigrees affected with hereditary multiple exostosis

To identify pathogenic variations of EXT1 and EXT2 genes in two Chinese pedigrees affected with hereditary multiple exostosis (HME). Genomic DNA was extracted from peripheral blood samples using a phenol-chloroform method. PCR and Sanger sequencing was conducted to amplify the exons and the flanking intronic regions of the EXT1 and EXT2 genes. DNA sequencing has revealed a heterozygous missense variation c.812A>G (p.Tyr271Cys) in the exon 1 of EXT1 in pedigree 1, and a heterozygous frameshift variation c.1431dup (p.Ser478Leufs*43) in the exon 6 of EXT1 in the proband from pedigree 2. Both variations have co-segregated with the disease phenotype, which was also consistent with previous report. Two heterozygous pathogenic variations underlying HME have been identified. The result has facilitated genetic counseling and prenatal diagnosis for the affected pedigrees.

Clinical and radiological characteristics of children's forearm deformations with hereditary multiple exostosis (Clinical observation)

Clinical and radiological characteristics of children's forearm deformations with hereditary multiple exostosis (Clinical observation)

Whole-body MRI in assessing malignant transformation in multiple hereditary exostoses and enchondromatosis: audit results and literature review.

To analyze the results of annual screening using whole-body magnetic resonance imaging (WBMRI) in patients with multiple hereditary exostoses (MHE) and enchondromatosis (EC), and estimate the risk for transformation to chondrosarcoma (CS) in these disorders. A total of 62 patients (57 with MHE and five with EC) screened during a mean follow-up period of 4.6years (range, 1-10years) using 253 WBMRIs (median four WBMRIs per patient, range, 1-10) were analyzed retrospectively. The time of WBMRIs was compared with dates for diagnosed CSs. A supplementary literature review was performed focusing on the risk of malignant transformation. Ten patients had CS before being enrolled in the screening program, nine with MHE and one with EC. Three asymptomatic CSs were detected by screening; one in a patient with EC and two in patients with MHE, one of whom had CS previously. During the screening period, there was no occurrence of CS not detected by WBMRI in the study group. Histopathologically, the CSs were predominantly grade 1 and were, except for in two patients, located at the truncus, proximal femur, and shoulder girdle. Based on the current material and literature review, the risk of CS seems to be in the range of 2-3.7% for MHE and up to 50% for EC patients. MRI may be used as a screening method detecting malignant transformation in MHE and EC patients, but the efficacy has to be confirmed in long-term follow-up studies including cost analysis.

Occurrence of hereditary multiple osteochondromatosis with multiple exostoses in a patient from Bahia, Brazil

Occurrence of hereditary multiple osteochondromatosis with multiple exostoses in a patient from Bahia, Brazil

Multiple cartilaginous exostoses in a Swiss Mountain dog causing thoracolumbar compressive myelopathy

BackgroundMultiple cartilaginous exostoses are a rare, benign, proliferative condition of cartilage and bone. They can be asymptomatic, or they may cause pain, lameness, paresis and even paralysis, depending on their location and size. In cases of spinal cord or nerve root compression, surgery is the treatment of choice. Therefore, an advanced imaging diagnostic work-up is indicated. Due to the unclear pathophysiology and progression of this condition, it is difficult to predict its prognosis.Case presentationA 9-month-old female Swiss Mountain dog was presented with a history of gait abnormalities, kyphosis and hypersensitivity consistent with a thoracolumbar myelopathy. Multiple calcified masses, most prominent at the Th7–Th9 level and the L2–L3 level, were observed. Magnetic resonance imaging of the thoracolumbar vertebral column revealed severe dorsal spinal cord compressions near the dorsal arch of the Th7–Th9 and L2–L3 vertebrae. Two of these masses were removed surgically. The successful removal of both masses was confirmed by postoperative computed tomography. The histopathological examination of the resected tissue revealed multiple cartilaginous exostoses. The first neurological and magnetic resonance follow up examination carried out 6 months postoperatively showed improvement of the clinical status. At that time, no mass regrowth was observed. The last follow up neurological examination carried out 15 months postoperatively showed gait improvement and resolution of pain.ConclusionThis is the first case report of multiple cartilaginous exostoses with a complete pre- and postoperative evaluation and a 15 month follow-up.

Insights into the molecular regulatory network of pathomechanisms in osteochondroma.

Osteochondroma is a benign autosomal dominant hereditary disease characterized by abnormal proliferation of cartilage in the long bone. It is divided into solitary osteochondroma and hereditary multiple exostoses (HMEs). The exostosin-1 (EXT-1) and exostosin-2 (EXT-2) gene mutations are well-defined molecular mechanisms in the pathogenesis of HME. EXT-1 and EXT-2 encode glycosyltransferases that are necessary for the synthesis of heparin sulfate. Accumulating evidence suggests that mutations in the EXT family induce changes in isolated hypogonadotropic hypogonadism-parathyroid hormone-related protein, bone morphogenetic protein, and fibroblast growth factor signaling pathways. Studies have also found that a large number of microRNAs (miRNAs) are abnormally expressed in osteochondroma tissues, and some of them also participate in several major signaling pathways. The regulation of miRNA expression could be another breakthrough in the treatment of osteochondroma. Although the pathogenesis of osteochondroma is very complicated, significant progress has been made in recent years. It is hoped that the pathogenesis of osteochondroma will be clearly understood and the most effective methods for the prevention and treatment of osteochondroma will be determined. This review provides an update on the recent progress in the interpretation of the underlying molecular mechanisms of osteochondroma.

Morphological and Molecular Characterization of Human Gingival Tissue Overlying Multiple Oral Exostoses

Gingival and osseous augmentations are reported as hypertrophic or hyperplastic reactions to different factors including chronic traumatisms and surgeries such as free gingival graft (FGG) that induce an abnormal growth of both hard and soft tissues in genetically predisposed subjects. Since an imbalance in collagen turnover plays a key role in the development of gingival overgrowth leading to an accumulation of collagen in gingival connective tissue, in this study we described the histological and molecular features of three oral overgrowths obtained from a 34-year-old woman previously operated for FGG in order to evaluate a possible relationship between exostoses and overgrown tissue. Healthy and overgrown gingiva were analyzed by histological methods, and the expression of genes and proteins involved in collagen synthesis, maturation, and degradation was assessed in cultured fibroblasts obtained from gingival fragments at the molecular level. Our results show that general morphology and collagen content were similar in healthy and overgrown gingivae. However, fibroblasts obtained from the overgrown gingiva revealed an anabolic phenotype characterized by an increased collagen turnover and maturation. These findings indicate that an exostosis could act as a mechanical stimulus stretching the overlying connective tissue and triggering an anabolic phenotype of gingival fibroblasts and suggest to use minimally invasive surgical techniques to avoid traumatizing the periosteal tissues for the eradication of the exostosis with minimal relapses.

Analysis of EXT1 and EXT2 gene mutations in two Chinese pedigrees affected with hereditary multiple exostosis

To detect EXT1 and EXT2 gene mutations in two pedigrees affected with hereditary multiple exostosis (HME). The coding regions and exon/intron boundaries of the EXT1 and EXT2 genes were analyzed by targeted next-generation sequencing (NGS). Suspected mutations were confirmed by Sanger sequencing of the probands, their family members and 200 unrelated healthy controls. Gross deletion was confirmed by quantitative PCR (qPCR) analysis and multiple ligation-dependent probe amplification (MLPA) analysis. Two mutations were detected in the pedigrees, which included EXT2 gene c.337_338insG mutation in pedigree 1 and deletion of entire EXT1 in pedigree 2. Analysis of sequencing data revealed that a novel heterozygous mutation (c.337_338insG) in EXT2 gene in proband 1 and his father. The same mutation was not found among healthy family members and 200 unrelated healthy controls. As shown by NGS and MLPA analysis, proband 2 carried a heterozygous deletion of entire EXT1 gene. The same deletion was also found in her mother by qPCR. Mutations of the EXT1 and EXT2 genes probably underlie the HME in both pedigrees. NGS combined with Sanger sequencing, qPCR and MLPA is effective for attaining the diagnosis.

Multiple Cartilaginous Exostoses In A Pediatric Dog

Background: Multiple cartilaginous exostosis (MCE) is a rare neoplastic disease in dogs that is characterized by the presence of osteochondromas in multiple bones. MCE is a disorder of development during growth and maturation, the real etiology of which has yet to be elucidated, but is believed to have a genetic basis. Usually affected animals have a history of a palpable mass on the bone surface, causing anatomical deformities and compression of adjacent structures. Since MCE is a rare neoplastic disease in dogs it may be difficult to recognize in the clinic. The aim of this study was to report a case of MCE in a pediatric dog.Case: A female 4-month-old Rottweiler dog with a history of bone neoformation on the left hind limb, anorexia, weight loss, and difficulty walking received clinical care. The disease had its initial onset 2 months prior. At physical examination, the animal showed paresis of the hind limbs and a bony tumor on the lateral part of the left tibia. A complete blood cell count and serum biochemical profile were obtained. The only abnormality diagnosed was hyperproteinemia due to hyperglobulinemia. Other diagnostic tests were not authorized and the animal was euthanized. At the necropsy, an intrathoracic neoformation was observed from the sixth to the eighth rib on the right antimer. Some tumors were also observed on the fourth lumbar vertebra and between the first and the second sacral vertebra, and a left tibial tumor, which had been observed at physical examination. The sagittal section of the spine revealed the presence of extradural compression of the spinal cord due to vertebral proliferations with compression of the nerve roots. All of the proliferations had macroscopic similarities, being firm, sessile, irregular, and with complete adherence to deep planes. Tumor samples were submitted to histopathological analysis and the tissue morphology was compatible with osteochondroma. Based on the clinical, necroscopical, and histopathological findings, a diagnosis of MCE was established.Discussion: In MCE, animals less than one year of age are the most frequently affected, as was observed in the case reported. Clinical signs in MCE usually result from poor bone and cartilaginous anatomical formations and from compression of adjacent tissue structures. In the described patient, the proliferations located in the vertebrae and tibia and the consequent compression of nerve roots and nerves caused the neurological deficits. Unlike in canines, the etiology of MCE in humans is already well established and it is classified as an autosomal dominant genetic disorder. The diagnosis is usually obtained through the association of clinical examination with radiographic and histopathological findings. However, in the animal studied, since it was not possible to perform radiographs, confirmation was obtained only after performing histopathological examination of the neoformations, which is considered the standard for the diagnosis of MCE. Although it corresponds to a benign neoplastic process affecting dogs during their growth stage, it may significantly decrease the animal’s quality of life. In this situation, the prognosis of MCE is considered to be reserved to bad, and animals are often referred for euthanasia, as occurred in the animal under discussion, due to the progression of neurological dysfunction. Early recognition of MCE in routine pet hospital practice is of fundamental importance in order to properly institute treatment and monitoring.

Bone development and remodeling in metabolic disorders.

There are many metabolic disorders that present with bone phenotypes. In some cases, the pathological bone symptoms are the main features of the disease whereas in others they are a secondary characteristic. In general, the generation of the bone problems in these disorders is not well understood and the therapeutic options for them are scarce. Bone development occurs in the early stages of embryonic development where the bone formation, or osteogenesis, takes place. This osteogenesis can be produced through the direct transformation of the pre-existing mesenchymal cells into bone tissue (intramembranous ossification) or by the replacement of the cartilage by bone (endochondral ossification). In contrast, bone remodeling takes place during the bone's growth, after the bone development, and continues throughout the whole life. The remodeling involves the removal of mineralized bone by osteoclasts followed by the formation of bone matrix by the osteoblasts, which subsequently becomes mineralized. In some metabolic diseases, bone pathological features are associated with bone development problems but in others they are associated with bone remodeling. Here, we describe three examples of impaired bone development or remodeling in metabolic diseases, including work by others and the results from our research. In particular, we will focus on hereditary multiple exostosis (or osteochondromatosis), Gaucher disease, and the susceptibility to atypical femoral fracture in patients treated with bisphosphonates for several years.

Multiple Maxillar Exostosis: Teaching point: Multiple buccal exostosis are rare but asymptomatic, unequivocal, and always benign conditions of the jaws.

Teaching point: Multiple buccal exostosis are rare but asymptomatic, unequivocal, and always benign conditions of the jaws

A 40-Year-Old Male Presenting with Hereditary Multiple Exostosis: Management and Considerations

Hereditary multiple exostosis is a rare condition in which numerous benign osteochondromas form throughout the body, typically in areas of high bone turnover such as the metaphyseal plates of long bones. While many of these lesions remain clinically asymptomatic, other growth locations can lead to excruciating pain, limit a joint's range of motion, and compromise neurovascular structures. These patients undergo multiple surgeries throughout their lifetime in order to remove symptomatic osteochondromas. Due to deformities and changes in bone structure, these patients also suffer from significant arthritis which may also require surgery. It is important that a skilled orthopedic surgeon follow these patients in order to help them make informed decisions and limit the number of surgeries within their lifetime. The purpose of this case report is to discuss one instance in which a patient's significant arthritis was operatively managed in the setting of hereditary multiple exostosis.

Hypertension in Potocki-Shaffer syndrome: A case report

Potocki-Shaffer syndrome (PSS) is a rare contiguous gene deletion syndrome caused by heterozygous deletion of 11p11.2p12. Typical features described in patients with PSS include developmental delay, intellectual disability, multiple cartilaginous exostoses, biparietal foramina, craniofacial abnormalities, and genitourinary anomalies. While hypertension has been noted in three patients with PSS, it has not been described in most patients with this syndrome. This report details the evaluation and treatment of a teenager with PSS who presented on several occasions during childhood with elevated blood pressure measurements. The renin level was elevated, likely indicating a secondary cause for the HTN. The patient's BP responded to monotherapy with Angiotensin Converting Enzyme Inhibitor (ACEI).

Identification and characterization of a novel member of the EXT gene family, EXTL2.

Recently, two homologous genes, EXT1 and EXT2, with a putative tumor suppressor function have been described. Mutations in both genes are responsible for multiple exostosis syndrome (EXT), an autosomal dominant condition characterized by the presence of multiple osteochondromas, bony excrescences that sometimes undergo malignant transformation to chondrosarcoma. This family of EXT genes has been extended by the identification of an EXT-like (EXTL) gene showing a high degree of homology with the EXT genes. We report here a second EXT-like gene (EXTL2) which is homologous to the EXT and EXTL genes. EXTL2 consists of 5 exons encoding an ubiquitously expressed protein of 330 amino acids. In addition, a putative pseudogene, EXTL2P was also identified. The EXTL2 gene was assigned to chromosome 1p11-p12, whereas EXTL2P was mapped on chromosome 2q24-q31.

Identification of a novel mutation in EXT2 in a fourth-generation Korean family with multiple osteochondromas and overview of mutation spectrum.

Multiple osteochondromas (MOs) or hereditary multiple exostoses is a rare autosomal-dominant disease characterized by growths of MOs, which are benign cartilage-capped bone tumors that grow away from the growth plates. Almost 90% of MOs have a molecular explanation and 10% are unexplained. MOs are genetically heterogeneous with two causal genes on 8q24.11 (EXT1) and 11p12 (EXT2), with a higher frequency in EXT1. MO is a very rare genetic disorder, and the genotype-phenotype of MO with EXT2 mutation has not been well investigated in Korea. We present the clinical radiographic and molecular analysis of a four-generation Korean family with 11 MO-affected members (seven males and four females). The affected members from the third generation available for molecular analysis and their detailed medical histories showed moderate-to-severe phenotypes (clinical classes II-III), including bony deformities and limb misalignment with pain requiring surgical correction. The x-rays showed MOs in multiple sites. A novel EXT2 frameshift mutation (c.590delC, p.P197Qfs*73) was revealed by targeted exome sequencing in the affected members of this family. In this article, we not only expand the phenotypic-genotypic spectrum of MOs but also highlight the phenotypic heterogeneity in a family with the same mutation. In addition, we compiled the mutation spectrum of EXT2 from a literature review and identified that exon 2 of EXT2 is a mutation hot spot. Early medical attention with diagnosis of MO through careful examination of the clinical manifestations and genetic analysis can provide the opportunity to establish coordinated multispecialty management of the patient.

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.