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Concept: Exostosis

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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

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: 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

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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

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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

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Background: The trigger finger is characterized by the painful blocking of finger flexor tendons of the hand, while crossing the A1 pulley. It is a rare disease in children and, when present, is usually located in the thumb, and does not have any defined cause. Methods: We report 2 pediatric trigger finger cases affecting the long digits of the hand that were caused by an osteochondroma located at the proximal phalanx. Both children held the diagnosis of juvenile multiple osteochondromatosis. They had presented at the initial visit with a painful finger blocking. Surgical approach was decided with wide regional exposure, as compared with the trigger finger traditional surgical techniques, with the opening of the A1 pulley and the initial portion of the A2 pulley, along with bone tumor resection. Results: Patients evolved uneventfully, and recovered the affected finger motion. Conclusion: It is important to highlight that pediatric trigger finger is a distinct ailment from the adult trigger finger, and also in children is important to differentiate whenever the disease either affects the thumb or the long fingers. A secondary cause shall be sought whenever the long fingers are affected by a trigger finger.

Concepts: Medicine, Affect, Finger, Rare diseases, Phalanx bones, Fingers, Thumb, 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

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

0

Heparan sulfate (HS) is an essential component of cell surface and matrix proteoglycans (HS-PGs) that include syndecans and perlecan. Because of their unique structural features, the HS chains are able to specifically interact with signaling proteins -including bone morphogenetic proteins (BMPs)- via their HS-binding domain, regulating protein availability, distribution and action on target cells. Hereditary Multiple Exostoses (HME) is a rare pediatric disorder linked to germline heterozygous loss-of-function mutations in EXT1 or EXT2 that encode Golgi-resident glycosyltransferases responsible for HS synthesis, resulting in a systemic HS deficiency. HME is characterized by cartilaginous/bony tumors -called osteochondromas or exostoses- that form within perichondrium in long bones, ribs and other elements. This review examines most recent studies in HME, framing them in the context of classic studies. New findings show that the spectrum of EXT mutations is larger than previously realized and the clinical complications of HME extend beyond the skeleton. Osteochondroma development requires a somatic “second hit” that would complement the germline EXT mutation to further decrease HS production and/levels at perichondrial sites of osteochondroma induction. Cellular studies have shown that the steep decreases in local HS levels: derange the normal homeostatic signaling pathways keeping perichondrium mesenchymal; cause excessive BMP signaling; and provoke ectopic chondrogenesis and osteochondroma formation. Data from HME mouse models have revealed that systemic treatment with a BMP signaling antagonist markedly reduces osteochondroma formation. In sum, recent studies have provided major new insights into the molecular and cellular pathogenesis of HME and the roles played by HS deficiency. These new insights have led to the first ever proof-of-principle demonstration that osteochondroma formation is a druggable process, paving the way toward the creation of a clinically-relevant treatment.

Concepts: Immune system, DNA, Mutation, Heparan sulfate, Bone morphogenetic protein, Hereditary multiple exostoses, Exostosis, Ext2