ESPE Abstracts

Objective: To explore the clinical manifestations and genetic characteristics of 10 patients with ACAN variants presented as short stature, and analyze the efficacy of recombinant human growth hormone (rhGH) and/or combined with gonadotropin-releasing hormone agonist (GnRHa) in some patients with premature thelarche.

Methods: We reviewed clinical data of 10 patients with ACAN variants. Genetic testing was performed on probands and their parents. Exome capture and T-A cloning were performed on two variants. We summarized the clinical characteristics of 126 Chinese patients with ACAN variants. Nine patients were treated with rhGH alone and/or combined with GnRHa.

Result: Ten patients were admitted to hospital for "growth delay" at the age of (8.2±1.4) years. All of them presented with proportionate short stature, eight had flat nasal bridge, four each had bossing forehead and scoliosis, three were midface hypoplasia, two with brachydactyly, one had short neck, pigeon breast and another had cubitus valgus. There were three patients had central precocious puberty (CPP), three had early puberty, one had incomplete precocious puberty, five had advanced bone age, two had growth hormone deficiency. Eight ACAN variants (c.1_2delAT, c.7276G>A, c.488G>A, c.5185del, c.1429+1G>C, c.2831dupT, c.6337delG, c.3127_3642del) were detected in ten patients. Among them, seven were new variants. Exon capture showed c.1429+1G>C results in ACAN protein (Val465Glyfs*13) frameshift. T-A cloning showed one patient had 515bp deletion in exon 12 (c.3127_3642del), the same variant point had not found in the parents, which was a de novo variant. Compared with Europe and the United States, short fingers, short neck, broad toes, mid-face hypoplasia and early-onset osteoarthritis were less frequently in Chinese patients. Five patients were treated with rhGH alone for (0.55±0.11) years, the height standard deviation score (HtSDS) increased from (-2.35±0.42) to (-1.85±0.45). Two patients of CPP/early puberty were treated with rhGH combined with GnRHa for 2.5 years and 0.75 years, respectively. Two patients progressed significantly in bone yage, and were combined with GnRHa at 0.25 and 1.0 years of rhGH therapy. Combined treatment was (1.42±0.99) years, HtSDS increased from (-2.43±0.31) to (-1.84±0.44).

Conclusion: Seven novel variants were reported for the first time. ACAN variants should be considered in patients presented with short stature, premature thelarche, advanced bone age, and with or without special facial features. Diagnosis was comfirmed by genetic testing.. rhGH and/or combined with GnRHa can improve the height of patients with ACAN variants.