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William G. Cole - One of the best experts on this subject based on the ideXlab platform.
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cytoskeletal abnormalities in chondrocytes with ext1 and ext2 mutations
Journal of Bone and Mineral Research, 2010Co-Authors: Mark A Bernard, Tiffany Sanford, Jackie P Duke, Allison Scott, Dina Montufarsolis, Deborah Hogue, Mark B Snuggs, William G. Cole, Daniel D Carson, Barry W Van WinkleAbstract:The EXT genes are a group of putative tumor suppressor genes that previously have been shown to participate in the development of hereditary multiple exostoses (HME), HME-associated and isolated chondrosarcomas. Two HME disease genes, EXT1 and EXT2, have been identified and are expressed ubiquitously. However, the only known effect of mutations in the EXT genes is on chondrocyte function as evidenced by aberrant proliferation of chondrocytes leading to formation of bony, cartilage-capped projections (exostoses). In this study, we have characterized Exostosis chondrocytes from three patients with HME (one with EXT1 and two with EXT2 germline mutations) and from one individual with a non-HME, isolated Exostosis. At the light microscopic level, Exostosis chondrocytes have a stellate appearance with elongated inclusions in the cytoplasm. Confocal and immunofluorescence of in vitro and in vivo chondrocytes showed that these massive accumulations are composed of actin bundled by 1.5-μm repeat cross-bridges of α-actinin. Western blot analysis shows that Exostosis chondrocytes from two out of three patients aberrantly produce high levels of muscle-specific α-actin, whereas β-actin levels are similar to normal chondrocytes. These findings suggest that mutations in the EXT genes cause abnormal processing of cytoskeleton proteins in chondrocytes.
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differentiation induced loss of heparan sulfate in human Exostosis derived chondrocytes
Differentiation, 2005Co-Authors: Richard Haynes, William G. Cole, Jacqueline T. Hecht, Elizabeth Hayes, Robert J Long, Mary C Farachcarson, Daniel D CarsonAbstract:An Exostosis or osteochondroma is an aberrant bony growth occurring next to the growth plate either as an isolated growth abnormality or as part of the Hereditary Multiple Exostosis (HME) syndrome. Mutations in either exostosin 1 (EXT1) or exostosin 2 (EXT2) gene cause the HME syndrome and also some isolated osteochondromas. The EXT1 and EXT2 genes are glycosyltransferases that function as hetero-oligomers in the Golgi to add repeating glycosaminoglycans (GAGs) to heparan sulfate (HS) chains. Previously, we demonstrated that HS is markedly diminished in the Exostosis cartilage cap and that the HS proteoglycan, perlecan, has an abnormal distribution in these caps. The present studies were undertaken to evaluate which chondrocyte-specific functions are associated with diminished HS synthesis in human chondrocytes harboring either EXT1 or EXT2 mutations. Systematic evaluation of Exostosis cartilage caps and chondrocytes, both in vitro and in vivo, suggests that chondrocyte-specific cell functions account for diminished HS levels. In addition, we provide evidence that perichondrial cells give rise to chondrocytes that clonally expand and develop into an Exostosis. Undifferentiated EXT chondrocytes synthesized amounts of HS similar to control chondrocytes; however, EXT chondrocytes displayed very poor survival in vitro under conditions that promote normal chondrocyte differentiation with high efficiency. Collectively, these observations suggest that loss of one copy of either the EXT1 or EXT2 gene product compromises the perichondrial chondrocytes' ability to differentiate normally and to survive in a differentiated state in vitro. In vivo, these compromised responses may lead to abnormal chondrocyte growth, perhaps from a perichondrial stem cell reserve.
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reevaluation of a genetic model for the development of Exostosis in hereditary multiple Exostosis
American Journal of Medical Genetics, 2002Co-Authors: Catherine Rhoades Hall, Richard Haynes, William G. Cole, Jacqueline T. HechtAbstract:EXT1 and EXT2 are genes that have been shown to cause hereditary multiple Exostosis (HME), a syndrome marked by the formation of bony growths juxtaposed to the growth plate. These genes are members of a growing family of proteins with glycosyltransferase activity required for the synthesis of heparan sulfate chains. This protein activity is predicted to play a role in the expression of proteoglycans on the cell surface and in the extracellular matrix. We and others have previously suggested that a two-hit mutational model applies to the development of an Exostosis where a germline mutation coupled with a somatic mutation results in the loss of EXT1 or EXT2 function and subsequent tumor formation. We report the direct sequencing and loss of heterozygosity (LOH) analysis of 12 exostoses from 10 HME families, 4 solitary exostoses, and their corresponding constitutional DNA. Of the 16 exostoses screened, we find only one solitary case in which two somatic mutations, a deletion and an LOH, are present. This provides limited support for the two-hit hypothesis involving the EXT1 and EXT2 genes for the development of an Exostosis. Alternative models are developed based on the functional significance of EXT proteins in heparan sulfate biosynthesis. © 2002 Wiley-Liss, Inc.
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Heparan sulfate abnormalities in Exostosis growth plates
Bone, 2002Co-Authors: Jacqueline T. Hecht, Catherine Rhoades Hall, Richard Haynes, Mark B Snuggs, E. Hayes, William G. ColeAbstract:Abstract Hereditary multiple exostoses (HME), a condition associated with development and growth of bony exostoses at the ends of the long bones, is caused by germline mutations in the EXT genes. EXT1 and EXT2 function as glycosyltransferases that participate in the biosynthesis of heparan sulfate (HS) to modify proteoglycans. HS proteoglycans, synthesized by chondrocytes and secreted to the extracellular matrix of the growth plate, play critical roles in growth plate signaling and remodeling. As part of studies to delineate the mechanism(s) by which an Exostosis develops, we have systematically evaluated four growth plates from two HME and two solitary exostoses. Mutational events were correlated with the presence/absence and distribution of HS and the normally abundant proteoglycan, perlecan (PLN). DNA from the HME exostoses demonstrated heterozygous germline EXT1 or EXT2 mutations, and DNA from one solitary Exostosis demonstrated a somatic EXT1 mutation. No loss of heterozygosity was observed in any of these samples. The chondrocyte zones of four Exostosis growth plates showed absence of HS, as well as diminished and abnormal distribution of PLN. These results indicate that, although multiple mutational events do not occur in the EXT1 or EXT2 genes, a complete loss of HS was found in the Exostosis growth plates. This functional knockout of the Exostosis chondrocytes’ ability to synthesize HS chains further supports the observations of cytoskeletal abnormalities and chondrocyte disorganization associated with abnormal cell signaling.
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Heparan sulfate abnormalities in Exostosis growth plates.
Bone, 2002Co-Authors: Jacqueline T. Hecht, Catherine Rhoades Hall, Richard Haynes, Mark B Snuggs, E. Hayes, William G. ColeAbstract:Abstract Hereditary multiple exostoses (HME), a condition associated with development and growth of bony exostoses at the ends of the long bones, is caused by germline mutations in the EXT genes. EXT1 and EXT2 function as glycosyltransferases that participate in the biosynthesis of heparan sulfate (HS) to modify proteoglycans. HS proteoglycans, synthesized by chondrocytes and secreted to the extracellular matrix of the growth plate, play critical roles in growth plate signaling and remodeling. As part of studies to delineate the mechanism(s) by which an Exostosis develops, we have systematically evaluated four growth plates from two HME and two solitary exostoses. Mutational events were correlated with the presence/absence and distribution of HS and the normally abundant proteoglycan, perlecan (PLN). DNA from the HME exostoses demonstrated heterozygous germline EXT1 or EXT2 mutations, and DNA from one solitary Exostosis demonstrated a somatic EXT1 mutation. No loss of heterozygosity was observed in any of these samples. The chondrocyte zones of four Exostosis growth plates showed absence of HS, as well as diminished and abnormal distribution of PLN. These results indicate that, although multiple mutational events do not occur in the EXT1 or EXT2 genes, a complete loss of HS was found in the Exostosis growth plates. This functional knockout of the Exostosis chondrocytes’ ability to synthesize HS chains further supports the observations of cytoskeletal abnormalities and chondrocyte disorganization associated with abnormal cell signaling.
Maurizio Pacifici - One of the best experts on this subject based on the ideXlab platform.
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assessing the general population frequency of rare coding variants in the ext1 and ext2 genes previously implicated in hereditary multiple exostoses
Bone, 2016Co-Authors: Diana L Cousminer, Benjamin F Voight, Alexandre Arkader, Struan F.a. Grant, Maurizio PacificiAbstract:Abstract Hereditary multiple exostoses (HME) is a rare childhood-onset skeletal disease linked to mutations in exostosin glycosyltransferase 1 ( EXT1 ) or 2 ( EXT2 ). Patients are heterozygous for either an EXT1 or EXT2 mutation, and it is widely assumed that Exostosis formation and associated defects, such as growth retardation and skeletal deformities, require loss-of-heterozygosity or a second hit in affected cells. However, the relevance and phenotypic impact of many presumed pathogenic EXT variants remain uncertain. We extracted all amino acid-altering (missense) and loss of function (LoF; nonsense, frameshift, or splice-site) variants from the Exome Aggregation Consortium (ExAC), a large population-based repository of exome sequence data from diverse ancestries that has screened out severe pediatric disease, to assess the overall mutation spectrum of predicted protein-damaging variants across these two genes in the general population. We then determined whether clinically-identified, presumably pathogenic variants implicated in HME exist among healthy individuals. We found six EXT1 and four EXT2 missense mutations in ExAC, suggesting that these mutations have either been misclassified as pathogenic or are not fully penetrant. Furthermore, EXT1 is heavily selectively constrained, while EXT2 is more tolerant to protein-damaging variants, especially at its C-terminus, possibly explaining the genotype–phenotype correlation that EXT1 variants usually result in more severe disease. In conclusion, population-based exome data is a useful filter for determining whether clinically detected variants are likely pathogenic, as well as revealing biological insight into rare disease genes such as EXT1 and EXT2 .
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heparanase stimulates chondrogenesis and is up regulated in human ectopic cartilage a mechanism possibly involved in hereditary multiple exostoses
American Journal of Pathology, 2015Co-Authors: Julianne Huegel, Motomi Enomotoiwamoto, Federica Sgariglia, Eiki Koyama, Maurizio PacificiAbstract:Hereditary multiple exostoses is a pediatric skeletal disorder characterized by benign cartilaginous tumors called exostoses that form next to growing skeletal elements. Hereditary multiple exostoses patients carry heterozygous mutations in the heparan sulfate (HS)-synthesizing enzymes EXT1 or EXT2, but studies suggest that EXT haploinsufficiency and ensuing partial HS deficiency are insufficient for Exostosis formation. Searching for additional pathways, we analyzed presence and distribution of heparanase in human exostoses. Heparanase was readily detectable in most chondrocytes, particularly in cell clusters. In control growth plates from unaffected persons, however, heparanase was detectable only in hypertrophic zone. Treatment of mouse embryo limb mesenchymal micromass cultures with exogenous heparanase greatly stimulated chondrogenesis and bone morphogenetic protein signaling as revealed by Smad1/5/8 phosphorylation. It also stimulated cell migration and proliferation. Interfering with HS function both with the chemical antagonist Surfen or treatment with bacterial heparitinase up-regulated endogenous heparanase gene expression, suggesting a counterintuitive feedback mechanism that would result in further HS reduction and increased signaling. Thus, we tested a potent heparanase inhibitor (SST0001), which strongly inhibited chondrogenesis. Our data clearly indicate that heparanase is able to stimulate chondrogenesis, bone morphogenetic protein signaling, cell migration, and cell proliferation in chondrogenic cells. These properties may allow heparanase to play a role in Exostosis genesis and pathogenesis, thus making it a conceivable therapeutic target in hereditary multiple exostoses.
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heparan sulfate in skeletal development growth and pathology the case of hereditary multiple exostoses
Developmental Dynamics, 2013Co-Authors: Julianne Huegel, Motomi Enomotoiwamoto, Federica Sgariglia, Eiki Koyama, John P. Dormans, Maurizio PacificiAbstract:Heparan sulfate (HS) is an essential component of cell surface and matrix-associated proteoglycans (HSPGs). Due to their sulfation patterns, the HS chains interact with numerous signaling proteins and regulate their distribution and activity on target cells. Many of these proteins, including bone morphogenetic protein family members, are expressed in the growth plate of developing skeletal elements, and several skeletal phenotypes are caused by mutations in HS-synthesizing and modifying enzymes. The disease we discuss here is Hereditary Multiple Exostoses (HME), a disorder caused by mutations in HS synthesizing enzymes EXT1 and EXT2, leading to HS deficiency. The exostoses are benign cartilaginous-bony outgrowths, form next to growth plates, can cause growth retardation and deformities, chronic pain and impaired motion, and progress to malignancy in 2-5% of patients. We describe recent advancements on HME pathogenesis and Exostosis formation deriving from studies that have determined distribution, activities and roles of signaling proteins in wild type and HS-deficient cells and tissues. Aberrant distribution of signaling factors combined with aberrant responsiveness of target cells to those same factors appear to be a major culprit in Exostosis formation. Insights from these studies suggest plausible and cogent ideas about how HME could be treated in the future.
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compound heterozygous loss of ext1 and ext2 is sufficient for formation of multiple exostoses in mouse ribs and long bones
Bone, 2011Co-Authors: Manuela Schuksz, Daniel E Wells, Christina Mundy, Yu Yamaguchi, Eiki Koyama, Maurizio Pacifici, Jeffrey D EskoAbstract:Multiple Hereditary Exostoses (MHE) syndrome is caused by haploinsufficiency in Golgi-associated heparan sulfate polymerases EXT1 or EXT2 and is characterized by formation of exostoses next to growing long bones and other skeletal elements. Recent mouse studies have indicated that formation of stereotypic exostoses requires a complete loss of Ext expression, suggesting that a similar local loss of EXT function may underlie Exostosis formation in patients. To further test this possibility and gain greater insights into pathogenic mechanisms, we created heterozygous Ext1+/− and compound Ext1+/−/Ext2+/− mice. Like Ext2+/− mice described previously (Stickens et al. Development 132:5055), Ext1+/− mice displayed rib-associated Exostosis-like outgrowths only. However, compound heterozygous mice had nearly twice as many outgrowths and, more importantly, displayed stereotypic growth plate-like exostoses along their long bones. Ext1+/−Ext2+/− exostoses contained very low levels of immuno-detectable heparan sulfate, and Ext1+/−Ext2+/− chondrocytes, endothelial cells and fibroblasts in vitro produced shortened heparan sulfate chains compared to controls and responded less vigorously to exogenous factors such as FGF-18. We also found that rib outgrowths formed in Ext1f/+Col2Cre and Ext1f/+Dermo1Cre mice, suggesting that ectopic skeletal tissue can be induced by conditional Ext ablation in local chondrogenic and/or perichondrial cells. The study indicates that formation of stereotypic exostoses requires a significant, but not complete, loss of Ext expression and that Exostosis incidence and phenotype are intimately sensitive to, and inversely related to, Ext expression. The data also indicate that the nature and organization of ectopic tissue may be influenced by site-specific anatomical cues and mechanisms.
Jacqueline T. Hecht - One of the best experts on this subject based on the ideXlab platform.
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differentiation induced loss of heparan sulfate in human Exostosis derived chondrocytes
Differentiation, 2005Co-Authors: Richard Haynes, William G. Cole, Jacqueline T. Hecht, Elizabeth Hayes, Robert J Long, Mary C Farachcarson, Daniel D CarsonAbstract:An Exostosis or osteochondroma is an aberrant bony growth occurring next to the growth plate either as an isolated growth abnormality or as part of the Hereditary Multiple Exostosis (HME) syndrome. Mutations in either exostosin 1 (EXT1) or exostosin 2 (EXT2) gene cause the HME syndrome and also some isolated osteochondromas. The EXT1 and EXT2 genes are glycosyltransferases that function as hetero-oligomers in the Golgi to add repeating glycosaminoglycans (GAGs) to heparan sulfate (HS) chains. Previously, we demonstrated that HS is markedly diminished in the Exostosis cartilage cap and that the HS proteoglycan, perlecan, has an abnormal distribution in these caps. The present studies were undertaken to evaluate which chondrocyte-specific functions are associated with diminished HS synthesis in human chondrocytes harboring either EXT1 or EXT2 mutations. Systematic evaluation of Exostosis cartilage caps and chondrocytes, both in vitro and in vivo, suggests that chondrocyte-specific cell functions account for diminished HS levels. In addition, we provide evidence that perichondrial cells give rise to chondrocytes that clonally expand and develop into an Exostosis. Undifferentiated EXT chondrocytes synthesized amounts of HS similar to control chondrocytes; however, EXT chondrocytes displayed very poor survival in vitro under conditions that promote normal chondrocyte differentiation with high efficiency. Collectively, these observations suggest that loss of one copy of either the EXT1 or EXT2 gene product compromises the perichondrial chondrocytes' ability to differentiate normally and to survive in a differentiated state in vitro. In vivo, these compromised responses may lead to abnormal chondrocyte growth, perhaps from a perichondrial stem cell reserve.
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reevaluation of a genetic model for the development of Exostosis in hereditary multiple Exostosis
American Journal of Medical Genetics, 2002Co-Authors: Catherine Rhoades Hall, Richard Haynes, William G. Cole, Jacqueline T. HechtAbstract:EXT1 and EXT2 are genes that have been shown to cause hereditary multiple Exostosis (HME), a syndrome marked by the formation of bony growths juxtaposed to the growth plate. These genes are members of a growing family of proteins with glycosyltransferase activity required for the synthesis of heparan sulfate chains. This protein activity is predicted to play a role in the expression of proteoglycans on the cell surface and in the extracellular matrix. We and others have previously suggested that a two-hit mutational model applies to the development of an Exostosis where a germline mutation coupled with a somatic mutation results in the loss of EXT1 or EXT2 function and subsequent tumor formation. We report the direct sequencing and loss of heterozygosity (LOH) analysis of 12 exostoses from 10 HME families, 4 solitary exostoses, and their corresponding constitutional DNA. Of the 16 exostoses screened, we find only one solitary case in which two somatic mutations, a deletion and an LOH, are present. This provides limited support for the two-hit hypothesis involving the EXT1 and EXT2 genes for the development of an Exostosis. Alternative models are developed based on the functional significance of EXT proteins in heparan sulfate biosynthesis. © 2002 Wiley-Liss, Inc.
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Heparan sulfate abnormalities in Exostosis growth plates
Bone, 2002Co-Authors: Jacqueline T. Hecht, Catherine Rhoades Hall, Richard Haynes, Mark B Snuggs, E. Hayes, William G. ColeAbstract:Abstract Hereditary multiple exostoses (HME), a condition associated with development and growth of bony exostoses at the ends of the long bones, is caused by germline mutations in the EXT genes. EXT1 and EXT2 function as glycosyltransferases that participate in the biosynthesis of heparan sulfate (HS) to modify proteoglycans. HS proteoglycans, synthesized by chondrocytes and secreted to the extracellular matrix of the growth plate, play critical roles in growth plate signaling and remodeling. As part of studies to delineate the mechanism(s) by which an Exostosis develops, we have systematically evaluated four growth plates from two HME and two solitary exostoses. Mutational events were correlated with the presence/absence and distribution of HS and the normally abundant proteoglycan, perlecan (PLN). DNA from the HME exostoses demonstrated heterozygous germline EXT1 or EXT2 mutations, and DNA from one solitary Exostosis demonstrated a somatic EXT1 mutation. No loss of heterozygosity was observed in any of these samples. The chondrocyte zones of four Exostosis growth plates showed absence of HS, as well as diminished and abnormal distribution of PLN. These results indicate that, although multiple mutational events do not occur in the EXT1 or EXT2 genes, a complete loss of HS was found in the Exostosis growth plates. This functional knockout of the Exostosis chondrocytes’ ability to synthesize HS chains further supports the observations of cytoskeletal abnormalities and chondrocyte disorganization associated with abnormal cell signaling.
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Heparan sulfate abnormalities in Exostosis growth plates.
Bone, 2002Co-Authors: Jacqueline T. Hecht, Catherine Rhoades Hall, Richard Haynes, Mark B Snuggs, E. Hayes, William G. ColeAbstract:Abstract Hereditary multiple exostoses (HME), a condition associated with development and growth of bony exostoses at the ends of the long bones, is caused by germline mutations in the EXT genes. EXT1 and EXT2 function as glycosyltransferases that participate in the biosynthesis of heparan sulfate (HS) to modify proteoglycans. HS proteoglycans, synthesized by chondrocytes and secreted to the extracellular matrix of the growth plate, play critical roles in growth plate signaling and remodeling. As part of studies to delineate the mechanism(s) by which an Exostosis develops, we have systematically evaluated four growth plates from two HME and two solitary exostoses. Mutational events were correlated with the presence/absence and distribution of HS and the normally abundant proteoglycan, perlecan (PLN). DNA from the HME exostoses demonstrated heterozygous germline EXT1 or EXT2 mutations, and DNA from one solitary Exostosis demonstrated a somatic EXT1 mutation. No loss of heterozygosity was observed in any of these samples. The chondrocyte zones of four Exostosis growth plates showed absence of HS, as well as diminished and abnormal distribution of PLN. These results indicate that, although multiple mutational events do not occur in the EXT1 or EXT2 genes, a complete loss of HS was found in the Exostosis growth plates. This functional knockout of the Exostosis chondrocytes’ ability to synthesize HS chains further supports the observations of cytoskeletal abnormalities and chondrocyte disorganization associated with abnormal cell signaling.
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natural history study of hereditary multiple exostoses
American Journal of Medical Genetics, 1995Co-Authors: C L Wicklund, R M Pauli, David E Johnston, Jacqueline T. HechtAbstract:Hereditary multiple Exostosis (EXT) is an autosomal dominant disorder in which the clinical hallmark is the growth of bony protuberances from long bones and which can cause a variety of orthopedic deformities. This study sought to further delineate the natural history of EXT. In addition, since previous studies have suggested that there are deviations from Mendelelian expectations in EXT, including incomplete penetrance and a skewed sex ratio, we attempted to confirm or refute these suggestions. Both portions of the study were carried out through retrospective review of 43 affected probands and 137 of their affected relatives. Data are presented concerning frequency and severity of complications of EXT including short stature, sequelae of exostoses, occurrence of malignant degeneration of exostoses, and problems in pregnancy and delivery of affected females. Only 2.8% of the total affected population had experienced Exostosis-related malignancy, an estimate which is considerably less than earlier reports would suggest. Penetrance was 100%. There was an excess of males within the entire affected population (104:76) and within identified probands (28:15). However, the male to female ratio was unskewed in nuclear families (probands, affected sibs, and parents). The excess of males appears to be related to males having more severe and more frequent complications of EXT than having any primary genetic origin. © 1995 Wiley-Liss, Inc.
Harry P W Kozakewich - One of the best experts on this subject based on the ideXlab platform.
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distinct chromosomal rearrangements in subungual dupuytren Exostosis and bizarre parosteal osteochondromatous proliferation nora lesion
The American Journal of Surgical Pathology, 2004Co-Authors: Eduardo Zambrano, Vânia Nose, Antonio R Perezatayde, Mark C Gebhardt, Timothy M Hresko, Paul K Kleinman, Kathleen E Richkind, Harry P W KozakewichAbstract:Background: Proliferative lesions ofthe bone surface, such as subungual ( Dupuytren) Exostosis and bizarre parosteal osteochondromatous proliferation (BPOP, Nora lesion) are currently classified as reactive, proliferative processes that mimic primary neoplasms of bone. Methods: Cytogenetic analysis was performed on 3 subungual exostoses of the great toe and 2 BPOP lesions of the radius and ulna. Results: A balanced translocation t(X;6) was identified in all cases of subungual exostoses. The chromosomal rearrangements observed in I case of BPOP differed from those seen in subungual Exostosis. Conclusions: The presence of chromosomal abnormalities in subungual Exostosis and BPOP suggests that these lesions are neoplastic, with a different molecular pathogenesis, and that each is a distinct clinicopathologic entity.
Fabio Ferri-de-barros - One of the best experts on this subject based on the ideXlab platform.
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Subungual Exostosis of the Toes: A Systematic Review
Clinical Orthopaedics and Related Research®, 2014Co-Authors: Mark P. Dacambra, Sumit K. Gupta, Fabio Ferri-de-barrosAbstract:Background Subungual Exostosis is a relatively common benign bone tumor that occurs in the distal phalanges of the toes and can be a source of pain and nail deformity. There is controversy about the treatment of these lesions and there are few studies that have synthesized what is known and provided meaningful information on treatment. Questions/purposes We performed a systematic review to address the following questions: (1) What is the best surgical approach for excising these lesions? (2) What is the age range, sex distribution, and presenting symptoms of subungual exostoses and which toe is most frequently affected? (3) What complications arise from treatment? Methods Two authors independently searched multiple databases (Medline, 1950–May 2013; Cochrane EBM database, and EMBASE, 1980–May 2013 provided by OVID; ACP Journal Club, 2003–May 2013; CINAHL by EBSCO, 1937–May 2013; and PubMed by NLM, 1940–May 2013), and key words were chosen to achieve a broad search strategy. We included studies on the management of toe exostoses with > 10 cases and we excluded studies that reported on upper extremity exostoses or osteochondromas. Demographic and treatment data were collected from each article by two independent authors and collated. A total of 124 abstracts were screened, and 116 articles were reviewed in full, of which 13 met the inclusion criteria. Results Complete marginal excision through a fish mouth incision protecting the nail led to a recurrence rate of 4% and satisfactory clinical results, defined as no requirement for postoperative intervention and a satisfactory clinical appearance in 73%. Most studies provided incomplete descriptions of specific surgical techniques used. Fifty-five percent of the patients were younger than 18 years of age. A history of toe trauma before diagnosis was present in approximately 30% of the cases. Delayed diagnosis occurred in approximately 10% of the cases and onychodystrophy occurred in more than 10%. Conclusions There is weak evidence to guide management of subungual Exostosis. Adequate wound management postexcision aiming to minimize disruption to the nail bed and matrix may prevent onychodystrophy, which is a common complication of treatment.