Data_Sheet_1_Evaluation of Growth Hormone Therapy in Seven Chinese Children With Familial Short Stature Caused by Novel ACAN Variants.docx

ObjectiveACAN gene variants are an important cause of familial short stature (FSS). Appropriate growth-promoting therapies effectively improve the patient height. Here, we report a therapeutic assessment of cases of seven families of FSS patients with heterozygous ACAN variants. Our findings provide a valuable theoretical basis for the clinical diagnosis and treatment of this disease.
MethodsFrom December 2020 to June 2021, 32 FSS patients were examined in Tianjin Medical University General Hospital (Tianjin, China) by whole-exome sequencing to determine whether ACAN variants were present. Their clinical data were summarized and scrupulously analyzed.
ResultsWe found seven novel heterozygous ACAN variants: c.1051 + 2T > A, c.313T > C (p.S105P), c.2660C > G (p.S887X), c.2153C > A (p. T718K), c.7243delG (p.D2415Tfs*4), c.2911G > T (p.G971X), c.758-7T > C. All seven patients had proportionate short stature and mild skeletal dysplasia. Endocrine examination results were normal. Only one of the patients had an advanced bone age (1.1 years older than chronological age), whereas the other patients had normal bone ages. All of them had a family history of short stature, with or without osteoarthritis or intervertebral disc disease. All seven patients accepted treatment with recombinant human growth hormone (rhGH) and were regularly followed up. One patient did not come at the follow-up visit. The height of the remaining six patients before and after the treatment was −2.89 ± 0.68 SDS, −1.91 ± 0.93 SDS, respectively, with a treatment course of 1.85 ± 1.91 years. A good therapeutic response was observed in all of them.
ConclusionsIn this study, seven novel heterozygous variants in ACAN were discovered, which expanded the spectrum of the already established ACAN pathogenic variants. In FSS cohort, the proportion of ACAN variants accounted was large. The treatment with rhGH effectively increased the patient height, but further studies with longer follow-up periods and more extensive observations are required to elucidate the long-term effect.

研究目的：聚集蛋白聚糖基因（ACAN）变异是家族性矮小症（familial short stature, FSS）的重要病因，恰当的促生长治疗可有效改善患者身高。本研究针对7个携带杂合型ACAN变异的FSS患者家系开展治疗评估，研究结果为该疾病的临床诊疗提供了极具价值的理论依据。
研究方法：2020年12月至2021年6月，本研究于中国天津医科大学总医院纳入32例FSS患者，通过全外显子组测序检测其是否携带ACAN变异，并对所有患者的临床资料进行汇总与细致分析。
研究结果：本研究共检出7种全新的杂合型ACAN变异，具体为c.1051 + 2T > A、c.313T > C (p.S105P)、c.2660C > G (p.S887X)、c.2153C > A (p.T718K)、c.7243delG (p.D2415Tfs*4)、c.2911G > T (p.G971X)、c.758-7T > C。7例患者均表现为匀称性矮小伴轻度骨骼发育不良，内分泌检查结果均未见异常。仅1例患者骨龄超前（较实际年龄大1.1岁），其余患者骨龄均正常。所有患者均有矮小症家族史，部分合并骨关节炎或椎间盘疾病。7例患者均接受重组人生长激素（recombinant human growth hormone, rhGH）治疗并定期随访，其中1例患者失访。剩余6例患者治疗前、后的身高分别为-2.89±0.68标准差评分（standard deviation score, SDS）、-1.91±0.93 SDS，治疗时长为1.85±1.91年，所有患者均获得良好的治疗应答。
研究结论：本研究共检出7种全新的ACAN杂合型变异，扩充了已报道的ACAN致病性变异谱。在FSS队列中，ACAN变异的占比颇高。重组人生长激素治疗可有效提升患者身高，但仍需开展更长随访周期、更大样本量的研究以明确其长期疗效。