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.

Keywords: EXT1 gene; EXT2 gene; HME diagnostics; HME molecular backround; HME therapeutic strategies; diaphyseal aclasis; hereditary multiple exostoses (HME); multiple osteochondromas (MO).

FIGURE 1

The radiography showing two different types of exostoses. Pictures (a,b) present sessile, mound shape osteochondromas, while (c,d) show pedunculated exostoses.

FIGURE 2

The hereditary multiple exostoses (HMEs) localization in the human skeleton.

FIGURE 3

Pie charts showing the percentage of mutation types found in the EXT1 and EXT2 genes in patients affected with hereditary multiple exostoses (HMEs). Data were obtained from Human Gene Mutation Database (HGMD v.2021.1; accessed on 25^th of May).

FIGURE 4

A bar graph showing mutational discrepancies in the EXT1 and EXT2 among different cohorts of patients affected with hereditary multiple exostoses (HMEs) and reported in the medical literature. The following cohorts were included: Brazilian, Chinese, Italian, Japanese, Polish, Saudi Arabic, Spanish and United Kingdom (UK) populations.

FIGURE 5

This figure shows the schematic formation of exostoses. In the growth plate, one can observe a proliferation zone of chondrocytes responsible for bone elongation. During this process, cells from the upper layers proliferate, while cells from the lower layers undergo apoptosis and then calcify. As a result of mutations in the EXT1 and EXT2 genes, chondrocytes with shortened heparan sulfate (HS) chains appear in this area. If the cell is located in the middle column, it can be rescued by the neighboring cells whith normal length HS chains. In this case, exostoses do not form. Conversely, if the cell is present in the outer columns, it escapes from a normal differentiation process. The cell loses its polarity but still keeps its proliferation potential. Then, the cell starts to translocate to lower layers of chondrocytes and grabs some non-mutated cells with it too. In the last stage, the cells form exostoses.