Abstract
Short stature is a frequent disorder in the pediatric population and can be caused by multiple factors. In the last few years, the introduction of Next Generation Sequencing (NGS) in the molecular diagnostic workflow led to the discovery of mutations in novel genes causing short stature including heterozygous mutations in ACAN gene. It encodes for aggrecan, a primary proteoglycan component specific for the structure of the cartilage growth plate, articular and intervertebral disc. We report a novel ACAN heterozygous pathogenic variant in a family with idiopathic short stature, early-onset osteoarthritis and osteoarthritis dissecans (SSOAOD). We also performed a literature review summarizing the clinical characteristic of ACAN's patients. The probands are two Caucasian sisters with a family history of short stature and osteoarthritis dissecans. They showed dysmorphic features such as mild midface hypoplasia, brachydactyly and broad thumbs, especially the great toes. The same phenotype was presented in the mother who had had short stature and suffered from intervertebral disc disease. DNA sequencing identified a heterozygous pathogenic variation (c.4390delG p.Val1464Ter) in the sisters, with a maternal inheritance. The nonsense mutation, located on exon 12, results in premature truncation and presumed loss of protein function. In terms of treatment, our patients underwent recombinant human growth hormone replacement therapy, associated with gonadotropin releasing hormone therapy, in order to block early growth cessation and therefore reach a better final height. Our case suggests that SSOAOD ACAN related should be considered in the differential diagnosis of children with autosomal dominant short stature and family history of joints disease.
Highlights
Short stature is defined as a height of at least two standard deviations below the average observed in age and sex control population (Hauer et al, 2017)
A targeted Next Generation Sequencing (NGS) panel containing 67 genes involved in syndromic and non-syndromic short stature detected in both sibs the presence of a heterozygous pathogenic variation in exon 12, namely c.4390delG that causes the changing of the reading frame from GTA encoding Valine at position 464 to stop codon (p.Val1464Ter)
We report a novel heterozygous mutation in ACAN (c.4390delG; p.Val1464Ter), located in exon 12, in a family with short stature associated with early-onset osteoarthritis and osteoarthritis dissecans (SSOAOD)
Summary
Short stature is defined as a height of at least two standard deviations below the average observed in age and sex control population (Hauer et al, 2017). ACAN is located on chromosome 15q26 and consists of 19 exons, ranging in size from 77 to 4224 bp It encodes for aggrecan, a primary proteoglycan component specific for the structure of the cartilage growth plate, articular and intervertebral disc (Uchida et al, 2020). ACAN biallelic mutations are related to spondyloepimetaphyseal dysplasia, aggrecan type (SEMD, OMIM#612813) (Tompson et al, 2009), while mutations at the heterozygous state can cause spondyloepiphyseal dysplasia, Kimberley type (SEDK, OMIM#608361) (Gleghorn et al, 2005), short stature associated with or without accelerated bone age (BA), early-onset osteoarthritis (OA) and/or osteoarthritis dissecans (SSOAOD, OMIM#165800) and various idiopathic short stature phenotypes (Stattin et al, 2010; Quintos et al, 2015; Tatsi et al, 2017; Van der Steen et al, 2017)
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