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.
Highlights
Hereditary multiple exostoses (HMEs) syndrome, known as multiple osteochondromas, hereditary deforming chondrodysplasia, multiple cartilaginous exostoses, or diaphyseal aclasis, was first described in a French family by Alexis Boyer in 1814 (Hennekam, 1991)
The most severe complication of HME is a sporadic malignant transformation into chondrosarcoma (CHS), which risk depends on age, sex, genotype, and anatomical distribution of exostoses (Stieber and Dormans, 2005; Czajka and DiCaprio, 2015)
The study performed among Brazilian, Italian, Polish, Spanish, and United Kingdom HME cohorts suggested that pathogenic variants more often localize in the EXT1 gene rather than in EXT2 gene (Figure 4) (Lonie et al, 2006; Sarrión et al, 2013; Jamsheer et al, 2014; Santos et al, 2018; Fusco et al, 2019)
Summary
Hereditary multiple exostoses (HMEs) syndrome, 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. 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 Golgiassociated glycosyltransferases, responsible for heparan sulfate biosynthesis. Some of the patients with HMEs do not carry pathogenic variants in those genes, the presence of somatic mutations, deep intronic variants, or another genes/loci is suggested.
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