IMPE Abstracts

Background: Aggrecan (encoded by ACAN gene) is a significant proteoglycan that is an important component of the cartilage extracellular matrix, and plays a vital role in cartilage and bone morphogenesis. Pathogenic ACAN gene loss‐of‐function variants have been associated with various short stature and bone dysplasia.

Objective: We observed the clinical and genetic characteristics of fourteen patients with ACAN variants, as well as efficacy of recombinant human growth hormone (rhGH) alone or in Combination with gonadotropin-releasing hormone agonist (GnRHa) in some patients.

Methods: We reviewed with short stature patients admitted to our department between June 2016 and September 2022. The ACAN variations were detected using whole-exome sequencing, and their clinical characteristics were meticulously analyzed.

Result: In fourteen Chinese short stature patients, eleven ACAN heterozygous variants (p.Glu2426Lys, p.lle1729Tyrfs*24, p.Ser968_Ala986del, p.Arg163His, p.Val465Glyfs*13, p.Glu945Argfs*484, p.Ala2113fsTer17, p.?，p.Ala1043_Ala1214del, p.Asn2404Serfs*14, p.Glu2385Lys) were identified. All patients had proportionate short stature, some had mild facial dysmorphism and skeletal abnormalities (frontal bossing, flat nasal bridge, short neck, brachydactyly, mild scoliosis). Additionally, three females in our study had central precocious puberty, while three males had global developmental delay/intelligence disability. Six individuals received rhGH and/or GnRHa therapy.

Conclusion: We identified eleven ACAN heterozygous variants, nine of which were novel. Our findings broaden the phenotypic and genotypic spectrum of ACAN-related short stature.

Keywords: ACAN, short stature, global developmental delay/intellectual disability, central precocious puberty, therapy