SciCombinator

Discover the most talked about and latest scientific content & concepts.

Concept: Hereditary multiple exostoses

28

The skeletal anatomy of the hip provides two main locations for impingement: abnormal contact between the acetabulum and femur (femoroacetabular impingement) or between the ischium and femur (ischiofemoral impingement). We report a case of bilateral ischiofemoral impingement in a patient with hereditary multiple exostoses. The association of exostoses and femoral metaphyseal widening resulted in the narrowing of the ischiofemoral spaces. Pain was improved on the left side by resection of the ischial exostosis.

Concepts: Skeletal system, Hip, Pelvis, Iliopsoas, Ilium, Hereditary multiple exostoses, Exostosis, Ischium

28

: Thirty to 60% of hereditary multiple exostoses patients have forearm deformities. There is no consensus regarding optimal therapy. This long-term retrospective study is the first to compare radiologic and clinical data with patient assessments, to define more precise surgical indications.

Concepts: Hereditary multiple exostoses, Exostosis

28

BACKGROUND: There is a high rate of knee deformity in patients with hereditary multiple exostoses (HME), and a quarter of patients have a limb length discrepancy. METHODS: A prospective database of 172 patients with HME was compiled. Patient demographics, knee deformity and range of movement, leg length and height, and number of exostoses around the knee were recorded. RESULTS: Nine out of 10 patients with HME were affected by exostoses around the knee, of which the distal femur was the most common site to be involved. Approximately 20% of patients had a valgus deformity and 16% had a fixed flexion deformity of the knee, with 25% having a diminished range of movement. Height was directly proportional to leg length and a quarter of patients were below the 10th centile for height. The presence of a distal femoral exostosis was an independent predictor of knee deformity (p=0.002), diminished range of movement (ROM) (p<0.001), and smaller stature (p<0.001) on multivariate analysis. In addition increasing age, prior surgery, genotype, and gender were also intendant predictors of ROM and height. CONCLUSION: Future studies analysing if surgical excision improves knee function and limits deformity would need to assess whether this is dependent upon anatomical site, as our results suggest that distal femoral exostoses may have the greatest affect upon these outcomes. LEVEL OF EVIDENCE: Level II.

Concepts: Biology, Function, Surgery, Varus deformity, Prediction, Height, Hereditary multiple exostoses, Exostosis

27

Osteochondroma is the most common benign bone tumour present multiple hereditary exostosis (HME). Scapular osteochondroma associated with pain and bursitis is rarely reported in literature. Here, we describe a 49-year-old male with the diagnosis of HME who was admitted to the Department of Thoracic Surgery with a painful and rapidly enlarging mass behind the left scapula. Computed tomography and magnetic resonance imaging indicated a large bursa formation associated with chest wall mass. Pre-operatively, the mass was diagnosed as osteochondroma and resected. Pathological findings confirmed that mass was a large bursa formation due to scapular osteochondroma without any evidence of malignancy. Osteochondroma should be considered in differential diagnosis of chest wall tumours located at this specific site. We discuss this rare complication of HME and emphasize the importance of early diagnosis and differentiation from malignant transformation of osteochondroma.

Concepts: Cancer, Oncology, Medical terms, Medical imaging, Brain tumor, Benign tumor, Medical diagnosis, Hereditary multiple exostoses

25

Patients with multiple hereditary exostoses (MHE) frequently present with a genu valgum deformity. Temporary hemiepiphysiodesis, such as hemiepiphyseal stapling, is a relatively safe surgical method to correct angular deformities in skeletally immature patients, but its outcomes for genu valgum deformity in MHE patients have not been extensively reported. We investigated the outcomes of hemiepiphyseal stapling in MHE patients (MHE group) and compared those with the outcomes in patients with idiopathic deformities (idiopathic group) after adjusting for potential bias.

Concepts: Varus deformity, Sociology, Skeletal disorders, Genu valgum, Genu varum, Deformity, Hereditary multiple exostoses, Exostosis

14

Multiple hereditary exostoses (MHE) is characterized by the development of numerous benign bony tumors (osteochondromas). Although it has been well established that MHE is caused by mutations in EXT1 and EXT2, which encode glycosyltransferase essential for heparan sulfate (HS) biosynthesis, the cellular origin and molecular mechanisms of MHE remain elusive. Here, we show that in Ext1 mutant mice, osteochondromas develop from mesenchymal stem cell-like progenitor cells residing in the perichondrium, and we show that enhanced BMP signaling in these cells is the primary signaling defect that leads to osteochondromagenesis. We demonstrate that progenitor cells in the perichondrium, including those in the groove of Ranvier, highly express HS and that Ext1 ablation targeted to the perichondrium results in the development of osteochondromas. Ext1-deficient perichondrial progenitor cells show enhanced BMP signaling and increased chondrogenic differentiation both in vitro and in vivo. Consistent with the functional role for enhanced BMP signaling in osteochondromagenesis, administration of the small molecule BMP inhibitor LDN-193189 suppresses osteochondroma formation in two MHE mouse models. Together, our results demonstrate a role for enhanced perichondrial BMP signaling in osteochondromagenesis in mice, and they suggest the possibility of pharmacological treatment of MHE with BMP inhibitors.

Concepts: Developmental biology, Molecule, In vivo, Enzyme inhibitor, In vitro, Hereditary multiple exostoses, Exostosis, Osteochondroma

2

Multiple hereditary exostoses (MHE), also known as multiple osteochondromas (MO), is an autosomal dominant disorder characterized by the development of multiple cartilage-capped bone tumors (osteochondromas). The large majority of patients with MHE carry loss-of-function mutations in the EXT1 or EXT2 gene, which encodes a glycosyltransferase essential for heparan sulfate (HS) biosynthesis. Increasing evidence suggests that enhanced BMP signaling resulting from loss of HS expression plays a role in osteochondroma formation in MHE. Palovarotene (PVO) is a retinoic acid receptor γ selective agonist, which is being investigated as a potential drug for fibrodysplasia ossificans progressiva (FOP), another genetic bone disorder with features that overlap with those of MHE. Here we show that PVO inhibits osteochondroma formation in the Fsp1(Cre) ;Ext1(flox/flox) model of MHE. Four-week daily treatment with PVO starting at postnatal day (P) 14 reduced the number of osteochondromas that develop in these mice by up to 91% in a dose-dependent manner. An inhibition of long bone growth observed in animals treated from P14 was almost entirely abrogated by delaying the initiation of treatment to P21. We also found that PVO attenuates BMP signaling in Fsp1(Cre) ;Ext1(flox/flox) mice, and that aberrant chondrogenic fate determination of Ext1-deficient perichondrial progenitor cells in these mice is restored by PVO. Together, the present data support further preclinical and clinical investigations of PVO as a potential therapeutic agent for MHE. This article is protected by copyright. All rights reserved.

Concepts: Genetics, Mutation, Fibrodysplasia ossificans progressiva, Rare diseases, Copyright, Retinoic acid receptor, Hereditary multiple exostoses, Exostosis

1

This systematic review aims to answer three research questions concerning the management of hereditary multiple osteochondromas of forearm in children: What is the best available evidence for the currently employed surgical procedures? What patient characteristics are associated with better prognosis? What disease characteristics are associated with better prognosis?

Concepts: Medicine, Medical terms, Surgery, Physician, Question, Hereditary multiple exostoses

0

Hereditary multiple osteochondroma (HMO) is an autosomal dominant genetic disorder characterized by multiple outgrowing bony tumors capped by cartilage, generally affecting the metaphyses. The disease is known as hereditary multiple exostoses, familial exostosis, multiple cartilaginous exostoses or hereditary malformation of cartilage. The prevalence of HMO in Europe and the Unites States is ~1:100,000, although it has not been reported in China. The disease is often accompanied by pain, asymmetry and skeletal malformations, including forearm and leg bending deformities, limb length discrepancies, and knee internal and external rotation abnormalities. Mutations to exostosin-1 (EXT1) andEXT2mutations cause insufficient heparan sulfate biosynthesis, leading to chondrocyte proliferation, abnormal bone growth in neighboring regions, multiple exostoses, and ultimately malignant transformation. The risk of malignant degeneration to osteochondrosarcoma increases with age, despite the low lifetime risk (~1%). The present study selected a clinical feature of typical HMO pedigrees, and examined mutations in family members by Sanger sequencing. Each of the five patients examined had a novel heterozygous nonsense mutation, c.67C>T p.Arg23*. The mutation is located prior to theEXT2exostosin domains in the amino acid sequence and results in a protein truncation of the 705 C-terminal amino acids. The present study provides molecular genetic evidence for a novel causal mechanism of HMO, and provides the basis for clinical genetic counseling for similar diseases.

Concepts: Protein, Cancer, Genetic disorder, Mutation, Amino acid, Cartilage, Hereditary multiple exostoses, Exostosis

0

Hereditary Multiple Exostoses (HME) is a pediatric disorder caused by heparan sulfate (HS) deficiency and is characterized by growth plate-associated osteochondromas. Previously, we found that osteochondroma formation in mouse models is preceded by ectopic bone morphogenetic protein (BMP) signaling in the perichondrium, but the mechanistic relationships between BMP signaling and HS deficiency remain unclear. Therefore, we used an HS antagonist (Surfen) to investigate the effects of this HS interference on BMP signaling, ligand availability, cell surface BMP receptor (BMPR) dynamics and BMPR interactions in Ad-293 and C3H/10T1/2 cells. As observed previously, the HS interference rapidly increased phosphorylated SMAD family member 1/5/8 levels. FACS analysis and immunoblots revealed that the cells possessed appreciable levels of endogenous cell surface BMP2/4 that were unaffected by the HS antagonist, suggesting that BMP2/4 proteins remained surface bound but became engaged in BMPR interactions and SMAD signaling. Indeed, surface mobility of Snap-tagged BMPRII, measured by fluorescence recovery after photobleaching (FRAP), was modulated during the drug treatment. This suggested that the receptors had transitioned to lipid rafts acting as signaling centers, confirmed for BMPRII via ultracentrifugation to separate membrane subdomains. In situ proximity ligation assays disclosed that the HS interference rapidly stimulates BMPRI-BMPRII interactions, measured by oligonucleotide-driven amplification signals. Our in vitro studies reveal that cell-associated HS controls BMP ligand availability and BMPR dynamics, interactions and signaling, and largely restrains these processes. We propose that HS deficiency in HME may lead to extensive local BMP signaling and altered BMPR dynamics, triggering excessive cellular responses and osteochondroma formation.

Concepts: Protein, Cell membrane, Cell biology, Receptor, Receptor antagonist, In vitro, Hereditary multiple exostoses, Exostosis