Hereditary Multiple Exostoses—A Review of the Molecular Background, Diagnostics, and Potential Therapeutic Strategies

Abstract

Hereditary multiple exostoses (HMEs) syndrome, also known as multiple osteochondromas, represents a rare and severe human skeletal disorder. The disease is characterized by multiple benign cartilage-capped bony outgrowths, termed exostoses or osteochondromas, that locate most commonly in the juxta-epiphyseal portions of long bones. Affected individuals usually complain of persistent pain caused by the pressure on neighboring tissues, disturbance of blood circulation, or rarely by spinal cord compression. However, the most severe complication of this condition is malignant transformation into chondrosarcoma, occurring in up to 3.9% of HMEs patients. The disease results mainly from heterozygous loss-of-function alterations in the EXT1 or EXT2 genes, encoding Golgi-associated glycosyltransferases, responsible for heparan sulfate biosynthesis. Some of the patients with HMEs do not carry pathogenic variants in those genes, hence the presence of somatic mutations, deep intronic variants, or another genes/loci is suggested. This review presents the systematic analysis of current cellular and molecular concepts of HMEs along with clinical characteristics, clinical and molecular diagnostic methods, differential diagnosis, and potential treatment options.

Structure of the human heparan sulfate polymerase complex EXT1-EXT2

“…Mutations in either the EXT1 or EXT2 gene in humans are associated with hereditary multiple exostoses, a skeletal disorder characterized by formation of osteochondromas 37 . We compiled a list of all known single amino acid patient mutations linked to a loss-of-function of EXT1 and EXT2 and mapped them onto the complex structure.…”

Clinical survey of a pedigree with hereditary multiple exostoses and identification of EXT‑2 gene deletion mutation

“…For example, Inubushi et al ( 16 ) reported a connection between increased BMP signaling and osteochondromagenesis, which serves an essential role in skeletal development by regulating chondrocyte proliferation and differentiation; they also suggest that treatment with a BMP inhibitor may be effective in patients with HME, which showed promising results in their study conducted on mouse models. Bukowska-Olech et al ( 12 ) hypothesized that heparanase, an enzyme that cleaves the heparan sulfate (HS) chains and stimulates chondrogenesis, is physiologically found only in the hypertrophic zone and perichondrium, and its wider distribution and increased activity possibly served a role in the development of osteochondromas.…”

“…Although several risk factors and pathogenic mechanisms have been hypothesized, it is most frequently suggested that mutations in exostosin glycosyltransferase 1 (EXT-1) and EXT-2 , genes with autosomal dominant inheritance, are the most likely responsible factors for HME ( 2 , 12 ), having been detected in 28–65% and in 21–61% of the affected patients, respectively ( 1 ). EXT-1 is located on chromosome 8q24,11-q24.13 and EXT-2 on chromosome 11p11-12 ( 11 ); both encode glycosyltransferases and serve vital roles in the synthesis of HS.…”

“…Therefore, heterozygous mutations of the EXT-1 or EXT-2 gene lead to an HS deficiency of ~50%, which is inadequate for giving rise to osteochondroma formation in patients with HME ( 11 ). An increasing number of mutations of EXT-1 and EXT-2 have been observed ( 12 , 17 ). In Guo et al ( 18 ), a novel heterozygous splice mutation (c.1284+2del) in EXT-1 was identified in a three-generation family with HME.…”

Structure of the human heparan sulfate polymerase complex EXT1-EXT2

“…Mutations in either the ext1 or ext2 gene in humans are associated with hereditary multiple exostoses, a skeletal disorder characterized by formation of osteochondromas 36 . We compiled a list of all known single amino acid patient mutations linked to a loss-of-function of EXT1 and EXT2 and mapped them onto the complex structure.…”