目的:分析ACAN基因变异与矮身材的关系,观察重组人生长激素(rhGH)的疗效与安全性。方法:回顾分析一例ACAN基因变异的矮身材患儿的临床资料,检索相关文献,总结ACAN基因变异与矮身材的关系,观察rhGH的疗效与安全性。结果:患儿为5岁7个月的女孩,矮身材,身高104.7 cm (−2.22 SD),其父亲身高175 cm (+0.42 SD),母亲身高163 cm (+0.47 SD),家族中均无矮身材者;无特殊面容及骨骼畸形,无第二性征发育;骨龄示7岁;基因测序示ACAN基因存在杂合变异c534C > G (p.N178K),其父母该位点均无变异,其为自发突变。予rhGH 50 ug∙kg
−1∙d
−1治疗,身高第一年增长7.8 cm (112.5 cm, −1.58 SD),后予rhGH 60 ug∙kg
−1∙d
−1治疗8个月,身高增长4.9 cm (117.4 cm, −1.28 SD),身高由−2.22SD追至−1.28 SD;骨龄进展2.5岁。结论:骨龄提前的矮身材患儿应考虑存在ACAN基因突变;应用rhGH治疗身高明显改善。
Objective: To analyze the relationship between ACAN gene variation and short stature and observe the efficacy and safety of recombinant human growth hormone (rhGH). Methods: Review the clinical data of a case of idiopathic short stature with ACAN gene mutation and search the relevant literatures to summarize the relationship between ACAN gene mutation and short stature, and observe the efficacy and safety of recombinant human growth hormone. Results: The patient was a 5-year and 7 months old girl with a short stature of 104.7 cm (−2.22 SD). She had short stature and was 104.7 cm (−2.22 SD) in height. Her father was 175 cm (+0.42 SD) in height and her mother was 163 cm (+0.47 SD) in height .There was no short stature in her family. There was no special face and skeletal deformity and secondary sexual development. Her bone age was 7 years. The gene sequencing revealed a heterozygous variation (c534c > G (p.n178k)) in ACAN gene, which was spontaneous mutation. And there was no mutation in this locus of the ACAN gene in her parents. Her height increased by 7.8 cm (112.5 cm, −1.28 SD) in the first year of treatment with rhGH (50 ug∙kg
−1∙d
−1) and the height increased by 4.9 cm (117.4 cm, −1.28SD) after 8 months of treatment with rhGH (60 ug∙kg
−1∙d
−1). Her height recovered from −2.22 SD to −1.28 SD and her bone age progressed by 2.5 years. Conclusion: The ACAN gene mutation should be considered in children with advanced bone age and the height can be improved significantly by rhGH.
ACAN基因,矮身材,骨龄提前,生长激素, ACAN Gene Short Stature Advanced Bone Age Growth Hormone摘要
目的:分析ACAN基因变异与矮身材的关系,观察重组人生长激素(rhGH)的疗效与安全性。方法:回顾分析一例ACAN基因变异的矮身材患儿的临床资料,检索相关文献,总结ACAN基因变异与矮身材的关系,观察rhGH的疗效与安全性。结果:患儿为5岁7个月的女孩,矮身材,身高104.7 cm (−2.22 SD),其父亲身高175 cm (+0.42 SD),母亲身高163 cm (+0.47 SD),家族中均无矮身材者;无特殊面容及骨骼畸形,无第二性征发育;骨龄示7岁;基因测序示ACAN基因存在杂合变异c534C > G (p.N178K),其父母该位点均无变异,其为自发突变。予rhGH 50 ug∙kg−1∙d−1治疗,身高第一年增长7.8 cm (112.5 cm, −1.58 SD),后予rhGH 60 ug∙kg−1∙d−1治疗8个月,身高增长4.9 cm (117.4 cm, −1.28 SD),身高由−2.22SD追至−1.28 SD;骨龄进展2.5岁。结论:骨龄提前的矮身材患儿应考虑存在ACAN基因突变;应用rhGH治疗身高明显改善。
关键词
ACAN基因,矮身材,骨龄提前,生长激素
Gene Mutation and Its Clinical Observation of Short Stature Caused by ACAN Gene Mutation
Jianying Ma1, Yuanyuan Wang2, Tang Li3*
1Department of Pediatrics, Qingdao Hiser Hospital Affiliated to Qingdao University, Qingdao Shandong
2Department of Pediatrics, Maternal and Children Health Hospital, Weifang Shandong
3Department of Endocrinology, Women and Children’s Hospital Affiliated to Qingdao University, Qingdao Shandong
Objective: To analyze the relationship between ACAN gene variation and short stature and observe the efficacy and safety of recombinant human growth hormone (rhGH). Methods: Review the clinical data of a case of idiopathic short stature with ACAN gene mutation and search the relevant literatures to summarize the relationship between ACAN gene mutation and short stature, and observe the efficacy and safety of recombinant human growth hormone. Results: The patient was a 5-year and 7 months old girl with a short stature of 104.7 cm (−2.22 SD). She had short stature and was 104.7 cm (−2.22 SD) in height. Her father was 175 cm (+0.42 SD) in height and her mother was 163 cm (+0.47 SD) in height .There was no short stature in her family. There was no special face and skeletal deformity and secondary sexual development. Her bone age was 7 years. The gene sequencing revealed a heterozygous variation (c534c > G (p.n178k)) in ACAN gene, which was spontaneous mutation. And there was no mutation in this locus of the ACAN gene in her parents. Her height increased by 7.8 cm (112.5 cm, −1.28 SD) in the first year of treatment with rhGH (50 ug∙kg−1∙d−1) and the height increased by 4.9 cm (117.4 cm, −1.28SD) after 8 months of treatment with rhGH (60 ug∙kg−1∙d−1). Her height recovered from −2.22 SD to −1.28 SD and her bone age progressed by 2.5 years. Conclusion: The ACAN gene mutation should be considered in children with advanced bone age and the height can be improved significantly by rhGH.
Keywords:ACAN Gene, Short Stature, Advanced Bone Age, Growth Hormone
患儿来自于山东省青岛市妇女儿童医院内分泌科。女,5岁7月,因生长缓慢就诊。患儿系G1P1,足月剖宫产分娩,无缺氧窒息史,出生时身长50 cm,体重3.25 Kg。1岁始父母发现生长速度较同龄儿童慢。该患儿自幼身体健康,无心肺及肾脏等慢性疾病;智力发育正常,性格开朗,家庭和睦;其父身高175 cm (+0.42 SD),母身高163 cm (+0.47 SD),家族中无矮身材者。查体身高104.7 cm (−2.22 SD),体重20.5 kg,双乳B1期,女性幼稚外阴,PH1期,无特殊面容及骨骼畸形。实验室检查血常规,尿常规,肝肾功能电解质,甲状腺功能,皮质醇,ACTH,17-OH孕酮,性激素及血尿串联质谱均无异常。染色体46,XX。骨龄提前,7岁。子宫卵巢彩超、下丘脑垂体核磁共振及脊柱X线未发现异常。生长激素(GH)激发试验口服可乐定GH峰值为10.26 ng/ml,静脉注射胰岛素GH峰值为8.53 ng/ml,胰岛素样生长因子-1为196.8 ug/l。经家属知情同意给予高通量全外显子基因检测,基因测序证实该患儿第15号染色体外显子处存在ACAN基因杂合变异c534C > G (p.N178K),即编码区第534号核苷酸由胞嘧啶变异为鸟嘌呤,导致第178号氨基酸由天冬酰胺变异为赖氨酸,为错义突变。根据ACMG指南,该变异初步判定为致病性变异(Likely pathogenic),经家系验证分析,受检人之父该位点无变异,受检人之母该位点无变异,此变异为自发突变(见图1)。在正常人群数据库中的频率为阴性,为低频变异。人类基因变异数据库(HGMD)未有该位点的相关性报道,该突变为国内外首次报道。生物信息学蛋白功能预测软件PolyPhen-2预测为有害。诊断为:矮身材(ACAN基因变异)。
诊断后给予长春金赛公司重组人生长激素(rhGH) 50 ug∙kg−1∙d−1皮下注射一年,身高增长7.8 cm (112.5 cm, −1.58 SD)。但后期生长速度明显减缓,于第13个月增加rhGH用量至60 ug∙kg−1∙d−1治疗8个月,身高增长4.9 cm (117.4 cm, −1.28 SD)。目前年龄7岁3个月,身高117.4 cm (−1.28 SD),体重24.8 Kg,骨龄片示9.5岁。患儿经rhGH治疗20个月,身高由−2.22 SD追至−1.28 SD (见图2),骨龄增加2.5岁(见图3)。随访中未发现第二性征发育,各项检查指标在正常范围,继续随访中。
马建英,王媛媛,李 堂. ACAN基因变异致矮身材基因改变与临床观察Gene Mutation and Its Clinical Observation of Short Stature Caused by ACAN Gene Mutation[J]. 临床医学进展, 2021, 11(04): 1537-1543. https://doi.org/10.12677/ACM.2021.114220
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