Hereditary Multiple Exostoses: a review of clinical appearance and metabolic pattern

Abstract

SummaryHereditary multiple exostoses (HME) is an inherited genetic condition characterized by the presence of multiple exostoses (osteochondromas). MHE is a relatively rare autosomal dominant disorder, mainly caused by loss of function mutations in two genes: exostosin-1 (EXT1) and exostosin-2 (EXT2). These genes are linked to heparan sulfate (HS) synthesis, but the specific molecular mechanism leading to the disruption of the cartilage structure and the consequent exostoses formation is still not resolved. The aim of this paper is to encounter the main aspects of HME reviewing the literature, in order to improve clinical features and evolution, and the metabolic-pathogenetic mechanisms underlying. Although MHE may be asymptomatic, a wide spectrum of clinical manifestations is found in paediatric patients with this disorder. Pain is experienced by the majority of patients, even restricted motion of the joint is often encountered. Sometimes exostoses can interfere with normal development of the growth plate, giving rise to limb deformities, low stature and scoliosis. Other many neurovascular and associated disorders can lead to surgery. The most feared complication is the malignant transformation of an existing osteochondroma into a secondary peripheral chondrosarcoma, during adulthood. The therapeutic approach to HME is substantially surgical, whereas the medical one is still at an experimental level. In conclusion, HME is a complex disease where the paediatrician, the geneticist and the orthopaedic surgeon play an interchangeable role in diagnosis, research and therapy. We are waiting for new studies able to explain better the role of HS in signal transduction, because it plays a role in other bone and cartilage diseases (in particular malignant degeneration) as well as in skeletal embryology.

A de novo mutation in the EXT2 gene associated with osteochondromatosis in a litter of American Staffordshire Terriers

“…Most of these presumptive deleterious variants are nonsense, frameshift, or splice site variants that are predicted to result in loss of or diminished protein function. In the majority of inherited cases, the condition is dominantly inherited, such that only 1 defective allele copy is necessary to trigger the disease . Approximately 10% of human patients have a de novo mutation, as we have documented in this litter of dogs …”

“…This heterozygous mutation was uniquely present in all affected littermates, yet absent in all family members available for testing, a population of unaffected, unrelated American Staffordshire terriers, a population of unrelated dogs of other breeds, and the most recently available public canine SNP database. This mutation also is predicted to introduce a stop codon in a protein‐coding portion of a gene that has been strongly implicated in osteochondromatosis in humans …”

“…In humans, osteochondromatosis, also referred to as multiple cartilaginous exostoses or hereditary multiple exostoses, is a relatively rare condition that is strongly associated with mutations in the genes EXT1 or EXT2. Mutations in these genes have been described in between 70 and 94% of patients with osteochondromatosis, with about 2/3 of the mutations being in EXT1, however this proportion can vary widely by population subgroups . An international mutation database for osteochondromatosis in humans has documented 432 unique variants in EXT1, and 223 unique variants in EXT2 that have been associated with the disease .…”

“…Because both EXT1 and EXT2 are required for heparan sulfate synthesis, heterozygous mutations in either gene results in systemic deficiency of these molecules in approximately 50% of patients with osteochondromatosis . The exact mechanism by which mutations in EXT1 and EXT2 cause osteochondromatosis is unknown, however 2 theories have been advanced: haploinsufficiency and loss‐of‐heterozygosity (LOH) . The first model suggests that the lower gene dosage associated with a heterozygous mutation causes insufficient amounts of heparan sulfate, and results in an environment in which osteochondromas can proliferate .…”

“…The condition has been reported in people, horses, dogs, and cats, although the condition in cats appears to differ from that in other species, occurring after skeletal maturity . It is inherited as an autosomal dominant trait in people, with >90% of cases being associated with a loss of function mutation in exostosin 1 or 2 (EXT1 or EXT2) . Both of these genes encode glycosyltransferases important in the generation heparan sulfate .…”