van der Steen Manouk, Pfundt Rolph, Maas Stephan J W H, Bakker-van Waarde Willie M, Odink Roelof J, Hokken-Koelega Anita C S
Dutch Growth Research Foundation, 3001 KB Rotterdam, The Netherlands.
Erasmus University Medical Center-Sophia Children's Hospital, 3015 GJ Rotterdam, The Netherlands.
J Clin Endocrinol Metab. 2017 May 1;102(5):1458-1467. doi: 10.1210/jc.2016-2941.
Some children born small for gestational age (SGA) show advanced bone age (BA) maturation during growth hormone (GH) treatment. ACAN gene mutations have been described in children with short stature and advanced BA.
To determine the presence of ACAN gene mutations in short SGA children with advanced BA and assess the response to GH treatment.
BA assessment in 290 GH-treated SGA children. ACAN sequencing in 29 children with advanced BA ≥0.5 years compared with calendar age.
Four of 29 SGA children with advanced BA had an ACAN gene mutation (13.8%). Mutations were related to additional characteristics: midface hypoplasia (P = 0.003), joint problems (P = 0.010), and broad great toes (P = 0.003). Children with one or fewer additional characteristic had no mutation. Of children with two additional characteristics, 50% had a mutation. Of children with three additional characteristics, 100% had a mutation. All GH-treated children with a mutation received gonadotropin-releasing hormone analog (GnRHa) treatment for 2 years from onset of puberty. At adult height, one girl was 5 cm taller than her mother and one boy was 8 cm taller than his father with the same ACAN gene mutation.
This study expands the differential diagnosis of genetic variants in children born SGA and proposes a clinical scoring system for identifying subjects most likely to have an ACAN gene mutation. ACAN sequencing should be considered in children born SGA with persistent short stature, advanced BA, and midface hypoplasia, joint problems, or broad great toes. Our findings suggest that children with an ACAN gene mutation benefit from GH treatment with 2 years of GnRHa.
一些小于胎龄儿（SGA）在生长激素（GH）治疗期间显示骨龄（BA）成熟提前。身材矮小且骨龄提前的儿童中已发现ACAN基因突变。
确定骨龄提前的矮小SGA儿童中ACAN基因突变的存在情况，并评估对GH治疗的反应。
对290例接受GH治疗的SGA儿童进行骨龄评估。对29例骨龄比实际年龄提前≥0.5岁的儿童进行ACAN基因测序。
29例骨龄提前的SGA儿童中有4例存在ACAN基因突变（13.8%）。突变与其他特征相关：面中部发育不全（P = 0.003）、关节问题（P = 0.010）和大脚趾宽阔（P = 0.003）。具有一个或更少其他特征的儿童没有突变。具有两个其他特征的儿童中，50%有突变。具有三个其他特征的儿童中，100%有突变。所有携带突变的接受GH治疗的儿童从青春期开始接受促性腺激素释放激素类似物（GnRHa）治疗2年。在成人身高时，一名携带相同ACAN基因突变的女孩比她母亲高5厘米，一名男孩比他父亲高8厘米。
本研究扩展了SGA出生儿童遗传变异的鉴别诊断，并提出了一种临床评分系统，用于识别最可能存在ACAN基因突变的受试者。对于出生时为SGA、持续身材矮小、骨龄提前且有面中部发育不全、关节问题或大脚趾宽阔的儿童，应考虑进行ACAN基因测序。我们的研究结果表明，携带ACAN基因突变的儿童从接受2年GnRHa的GH治疗中获益。
