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Hereditary Multiple Exostoses: New Insights into Pathogenesis, Clinical Complications, and Potential Treatments

  • Rare Bone Diseases (C Langman and E Shore, Section Editors)
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Abstract

Purpose of Review

Hereditary multiple exostoses (HME) is a complex musculoskeletal pediatric disorder characterized by osteochondromas that form next to the growth plates of many skeletal elements, including long bones, ribs, and vertebrae. Due to its intricacies and unresolved issues, HME continues to pose major challenges to both clinicians and biomedical researchers. The purpose of this review is to describe and analyze recent advances in this field and point to possible targets and strategies for future biologically based therapeutic intervention.

Recent Findings

Most HME cases are linked to loss-of-function mutations in EXT1 or EXT2 that encode glycosyltransferases responsible for heparan sulfate (HS) synthesis, leading to HS deficiency. Recent genomic inquiries have extended those findings but have yet to provide a definitive genotype-phenotype correlation. Clinical studies emphasize that in addition to the well-known skeletal problems caused by osteochondromas, HME patients can experience, and suffer from, other symptoms and health complications such as chronic pain and nerve impingement. Laboratory work has produced novel insights into alterations in cellular and molecular mechanisms instigated by HS deficiency and subtending onset and growth of osteochondroma and how such changes could be targeted toward therapeutic ends.

Summary

HME is a rare and orphan disease and, as such, is being studied only by a handful of clinical and basic investigators. Despite this limitation, significant advances have been made in the last few years, and the future bodes well for deciphering more thoroughly its pathogenesis and, in turn, identifying the most effective treatment for osteochondroma prevention.

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Acknowledgements

The original studies in the author’s laboratory upon which this review is based were supported by the NIAMS grant R01AR06175. The author expresses his gratitude to the many colleagues participating in those studies, to collaborators providing reagents and mouse lines, and to Dr. E. Koyama in particular for contribution to Fig. 1 model. Due to the concise nature of this review, not all relevant and deserving literature and authors could be cited. The author would like to acknowledge the passionate efforts of the Multiple Hereditary Exostoses Research Foundation (http://www.mherf.org/), a private nonprofit organization dedicated to the support of families and patients with HME and to advocating HME public awareness and biomedical research.

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  1. Translational Research Program in Pediatric Orthopaedics, Abramson Research Center, 902D, Division of Orthopaedic Surgery, Department of Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA

    Maurizio Pacifici

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Correspondence to Maurizio Pacifici.

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M. Pacifici declares that he is part of a patent application on heparanase as a putative therapeutic target in HME.

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All studies involving laboratory animals or human subjects were performed after approval by the appropriate institutional review boards. When required, written informed consent was obtained from all participants.

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This article is part of the Topical Collection on Rare Bone Diseases

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Pacifici, M. Hereditary Multiple Exostoses: New Insights into Pathogenesis, Clinical Complications, and Potential Treatments. Curr Osteoporos Rep 15, 142–152 (2017). https://doi.org/10.1007/s11914-017-0355-2

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