ESPE Abstracts

Objective: To explore the genotypes and phenotypes of 19 patients with ACAN variants presented as short stature with or without premature thelarche and abnormal intellectual development. Then the therapeutic response to recombinant human growth hormone (rhGH) and/or gonadotropin-releasing hormone agonist (GnRHa) were analysed.

Methods: We reviewed clinical data of 19 patients with ACAN variants. Genetic testing was performed on probands and their parents. The minigene splicing assay and T/A cloning were performed for three splice variants and one deletion variant of ACAN gene. 15 patients were treated with rhGH alone and/or combined with GnRHa. Then, we summarized the clinical characteristics of 126 Chinese patients with ACAN variants.

Result: 19 patients all had proportionate short stature (-1.97~-4.64 SD), among them, 15 patients presented with mild facial dysmorphism and skeletal abnormalities (frontal bossing, low-set ears, flat nasal bridge, high-arched palate, short neck, brachydactyly, mild scoliosis, and O-shaped legs). Notably, four patients had central precocious puberty, three patients had early puberty, and one patient had incomplete precocious puberty. Four males had global developmental delay/intelligence disability. 15 ACAN variants were identified in 19 patients (c.488G>A, c.5185del, c.2897_2953del, c.1429+1G>C, c.1052-1G>A, c.1605-2A>C, c.2831dupT, c.6337delG, c.1_2delAT, c.3127_3642del, c.7211_7214del, c.7276G>A, c.7153G>A，c.6723_6727dup, c.4962_4963delTG). Exon capture showed c.1429+1G>C, c.1052-1G>A, c.1605-2A>C result in ACAN protein changes (p. Val465Glyfs*13, p.Gly351_Gly476del, p.Tyr536Glyfs*9), respectively. 15 individuals received rhGH therapy for 0.5~4.8 years, and the height standard deviation score (HtSDS) increased from (-2~-3.33) to (-0.51~-2.20). Due to advanced bone age, six patients were given rhGH combined with GnRHa therapy, and HtSDS increased by 0.49~1.27. Compared with Europe and the United States, short fingers, short neck, broad toes, mid-face hypoplasia and early-onset osteoarthritis were less frequent in Chinese patients.

Conclusion: We identified 15 ACAN variants, 13 of which are novel. ACAN gene variants may be associated with central precocious puberty and global developmental delay/intellectual disability. This study expands the genotypic and phenotypic spectrum of ACAN -related short stature. rhGH and/or combined with GnRHa can improve the height of patients with ACAN variants.

Keywords: ACAN, short stature, precocious puberty, global developmental delay/intellectual disability, rhGH, GnRHa