1. Introduction
Hereditary Multiple Exostoses (HME) is a rare orphan autosomal-dominant pediatric disorder with a prevalence of about 1:50 000 (Wicklund et al., 1995; Schmale et al., 1994). The disease is estimated to occur more frequently in males (male-to-female ratio,1.5:1) (D’Arienzo et al., 2019). HME is characterized by the formation of osteochondromas (non-malignant cartilage-capped bony tumors) or exostoses within the perichondrium next to the growth plates of long bones, ribs, hip and vertebrae in very young and adolescent patients (Ryckx et al., 2013). Osteochondromas can turn into chondrosarcomas or osteosarcomas that can be life threatening in about 2% of the patients (Porter DE and Simpson AHRW,1999; Porter et al., 2004). The current clinical treatment of HME is commonly to resect the symptomatic chondrosarcomas or osteochondromas and to ameliorate the associated skeletal defects. The etiological treatment is not yet available as the evidence on etiological diagnosis of HME is limited.
The identification of likely pathogenic genes associated with HME was reported in the past. Wu et al. reported that the majority of the studied patients carried mutations in the exostosin-1 (EXT1 ) and exostosin-2 (EXT2 ) genes (Wu et al., 1994; Wuyts et al., 1996).EXT1 consists of 11 exons and spans about 312kb at 8q24 (Ludecke et al.,1997), while EXT2 comprises 16 exons and is located at 11p11.2, spanning about 150kb (Clines et al.,1997). It is known that the genes belong to the EXT multigene family, are ubiquitously expressed and act as tumor suppressors. The proteins encoded byEXT family genes are involved in the adhesion and/or polymerization of heparin sulfate (HS) chains at HS proteoglycans (HSPG’s) (Lind et al.,1998; McCormick et al., 1998; Busse et al.,2007). To date, over 650 mutations in EXT1 and EXT2 have been reported, most of which are nonsense, frameshift, or splice site, resulting in the synthesis of truncated EXT proteins with no suppression activity (Jennes et al., 2009; Ciavarella et al., 2013).
In this study, we identified a novel frameshift insertion mutation in the proband, which is absent both in Clinvar or Human Genome database and current clinical reports. The novel frameshift insertion mutation found in the proband was also confirmed in the affected individuals but not in the unaffected individuals; Further, the Polyphen and SIFT analysis were used to evaluate the effect of the frameshift insertion mutation, with a support result of obtaining a dysfunctional protein from the mutated gene. Therefore, we concluded that the genetic variation caused by the frameshift insertion mutation could be associated with the pathogenicity of HME in this pedigree. The finding could be used as a new support on prenatal diagnosis for preventing the birth defect incidence of HME.