Case analysis and literature review of 3 children with short stature with <i>ACAN</i> gene mutation

Abstract

Abstract:

Objective:To analyze the clinical features and genetic changes of 3 children in short stature withACANgene mutation.Methods:The clinical data, laboratory examinations, and genetic testing results of 3 children withACANgene mutations diagnosed with short stature at our pediatric endocrine disease clinic from 2018 to 2020 were collected, and the literature was reviewed for analysis and summary.Results:All the three children had a short family history, and their clinical manifestations were short stature. One patient had a slight limitation of the flexion activity of the thoracolumbar spine, and no other system abnormalities were found. Among them, the oldest of the 3 children was 5 years and 1 month, and the bone age was roughly consistent with or slightly advanced than the actual age, and the peak growth hormone challenge in 2 cases was less than 10 μg/L. The variations in the ACAN gene are c.G1877A and c.7360, respectively_ 7361del and c.7038_ 7039insCGGTGT, case 1 and case 2 are novel mutations that have not been reported in major databases. After the application of recombinant human growth hormone, the height of all three children improved. Reviewing the literature at home and abroad, we found that there were 120 children and 216 relatives reported at present. Among them, there were 80 ACAN gene variants related to short stature registered in HGMD, of which short stature was the most important clinical manifestation, followed by skeletal dysplasia.Conclusions:Mutations of ACAN gene mainly lead to short stature and skeletal dysplasia in children, and their clinical bone phenotypes are diverse, which can also only be manifested as short stature. For children with short stature, especially those with short stature family history, no matter whether they have skeletal abnormalities, they should be alert to this gene mutation.

Key words:ACANgene,Short stature,Idiopathic short stature

CLC Number:

R596
R446

LI Yanxiao, LU Wenli, WANG Xinqiong, CHEN Ye, XIAO Yuan, DONG Zhiya, MA Xiaoyu. Case analysis and literature review of 3 children with short stature withACANgene mutation[J]. Journal of Diagnostics Concepts & Practice, 2023, 22(05): 448-453.

Figures/Tables7

Table 1

Clinical characteristics and gene phenotype of three patients with ACAN gene mutations

Indice	Patient 1	Patient 2	Patient 3
Gender	Male	Female	Male
Age	5 years and 1 month	4 years and 1 month	5 years
Height（cm）	103.3（-2.0 SD）	94.0（-2.52 SD）	101.2(-2.39 SD)
Weight（kg）	18.0	14.6	17.6
BMI（kg/m²）	16.9	16.5	17.2
Bone age（y)	5.75	4	5.5
IGF-1（ng/mL）	162	90	99
GH peak（μg/L）	8.35	12.1	8.9
Gene mutations	c.G1877A	c.7360_7361del	c.7038_7039insCGGTGT
Protein	p. W626	p. E2454fs	p. Arg2349_Glu2350insCysArg
ACMG	Seaked	Seaked	Unknown
Origin	Father	Mather	Mather

Table 1

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Table 2

Summary of the clinical characteristics and proportion of patients with ACAN gene mutations in the past years of literature review

Reference	Mutations	S	He/N	Ha/F	J	OA/OD	V	BA
Reference	Mutations	S	He/N	Ha/F	J	OA/OD	V	delayed	advanced
[ 10 ]	74	12/74	34/74	24/74	8/74	20/74	20/74	22/45	23/45
[ 11 ]	1	0/1	1	1/1	0/1	0/1	1/1	0/1	1/1
[ 12 ]	2	1/2	0/2	0/1	0/1	0/2	0/2	1/2	1/2
[ 13 ]	1	0/1	1/1	0/1	0/1	0/1	0/1	1/1	0/1
[ 14 ]	2	0/2	2/2	2/2	2/2	2/2	0/2	2/2	0/2
[ 10 ]	2	1/2	1/2	1/2	1/2	1/2	1/2	1/2	1/2
[ 15 ]	5	4/5	1/5	0/5	0/5	0/5	4/5	4/5	1/5
[ 16 ]	13	/	/	/	/	/	/	5/13	7/13
[ 17 ]	7	2/7	4/7	5/7	0/7	0/7	3/7	6/7	1/7

Table 2

References20

[1]	李晓静, 罗飞宏, 裴舟, 等. 1496例矮小症病因分析及基于IGF-1水平生长激素缺乏症诊断预测模型的建立[J].临床儿科杂志,2012,30(12):1110-1115.
	LI X J, LUO F H, PEI Z, et al. Analyzing the etiology of 1496 children with short stature and establishing the predict model of growth hormone deficiency using IGF-1 levels[J].J Clin Pediatr,2012,30(12):1110-1115.
[2]	武苏, 汪素美, 朱子阳, 等. 2132例矮小症患儿病因及骨龄分析[J].临床儿科杂志,2015(8):730-733.
	WU S, WANG S M, ZHU Z Y, et al. Etiology and bone age of 2132 children with short stature[J].J Clin Pediatr,2015(8):730-733.
[3]	COHEN P, ROGOL A D, DEAL C L, et al. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Pediatric Endocrinology Workshop[J].J Clin Endocrinol Metab,2008,93(11):4210-4217. doi:10.1210/jc.2008-0509 URL
[4]	CHEN W W, LIU H X, LIU J, et al. Etiology and genetic diagnosis of short stature in children[J].Zhongguo Dang Dai Er Ke Za Zhi,2019,21(4):381-386. Chinese.
[5]	韩晓伟, 董治亚, 张婉玉, 等. 矮小症病因及临床特征分析[J].临床儿科杂志,2019,37(1):39-42.
	HAN X W, DONG Z Y, ZHANG W Y, et al. Analysis of the etiology and clinical characteristics of short stature[J].J Clin Pediatr,2019,37(1):39-42.
[6]	NIA H T, ORTIZ C, GRODZINSKY A. Aggrecan: approaches to study biophysical and biomechanical properties[J].Methods Mol Biol,2022,2303:209-226. doi:10.1007/978-1-0716-1398-6_17pmid:34626381
[7]	LAUING K L, CORTES M, DOMOWICZ M S, et al. Aggrecan is required for growth plate cytoarchitecture and differentiation[J].Dev Biol,2014,396(2):224-236. doi:10.1016/j.ydbio.2014.10.005pmid:25446537
[8]	STAVBER L, HOVNIK T, KOTNIK P, et al. High frequency of pathogenic ACAN variants including an intragenic deletion in selected individuals with short stature[J].Eur J Endocrinol,2020,182(3):243-253. doi:10.1530/EJE-19-0771pmid:31841439
[9]	ROUGHLEY P J, MORT J S. The role of aggrecan in normal and osteoarthritic cartilage[J].Exp Orthop,2014,1(1):8.
[10]	WEI M, YING Y, LI Z, et al. Identification of novel ACAN mutations in two Chinese families and genotype-phenotype correlation in patients with 74 pathogenic ACAN variations[J].Mol Genet Genomic Med,2021,9(11): e1823. doi:10.1002/mgg3.v9.11 URL
[11]	UCHIDA N, SHIBATA H, NISHIMURA G, et al. A novel mutation in theACANgene in a family with autosomal dominant short stature and intervertebral disc disease[J].Hum Genome Var,2020,7(1):44. doi:10.1038/s41439-020-00132-8
[12]	赵莉莉, 朱一琳, 袁珂, 等. 重组人生长激素改善ACAN基因变异致家族性矮小的疗效观察及文献复习[J].临床儿科杂志,2021,39(1):59-64.
	ZHAO L L, ZHU Y L, YUAN K, et al. Efficacy of recombinant human growth hormtherapy in familial short stature withACANgene variants and review of literature[J].J Clin Pediatr,2021,39(1):59-64.
[13]	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[J].临床医学进展,2021,11(04):1537-1543.
	Ma JY, Wang YY, Li T. Gene Mutation and its clinical observation of short stature caused byACANgene mutation[J]Advances in Clinical Medicine,2021,11(04):1537-1543. doi:10.12677/ACM.2021.114220 URL
[14]	MANCIOPPI V, PRODAM F, MELLONE S, et al. Retrospective diagnosis of a novel acan pathogenic variant in a family with short stature: a case report and review of the literature[J].Front Genet,2021,12:708864. doi:10.3389/fgene.2021.708864 URL
[15]	王晓艳, 谢蓉蓉, 吴海瑛, 等. 五个 ACAN基因变异致身材矮小家系的临床及遗传学分析[J].中华医学遗传学杂志,2021,38(10):942-946.
	WANG X Y, XIE R R, WU H Y, et al. Clinical and analysis of five Chinese pedigrees affected with short stature due to variants ofACANgene[J].Chin J Med Genet,2021,38(10):942-946.
[16]	LIN L, LI M, LUO J, et al. A High Proportion of novel ACAN mutations and their prevalence in a large cohort of chinese short stature children[J].J Clin Endocrinol Metab,2021,106(7):e2711-e2719. doi:10.1210/clinem/dgab088pmid:33606014
[17]	SUN J, JIANG L, LIU G, et al. Evaluation of growth hormone therapy in seven chinese children with familial short stature caused by novel ACAN variants[J].Front Pediatr,2022,10:819074. doi:10.3389/fped.2022.819074 URL
[18]	GKOUROGIANNI A, ANDREW M, TYZINSKI L, et al. Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations[J].J Clin Endocrinol Metab,2017,102(2):460-469. doi:10.1210/jc.2016-3313pmid:27870580
[19]	GIBSON B G, BRIGGS M D. The aggrecanopathies: an evolving phe- notypic spectrum of human genetic skeletal diseases[J].Orphanet J Rare Dis,2016,11(1):86. doi:10.1186/s13023-016-0459-2 URL
[20]	WU S, WANG C, CAO Q, et al. The Spectrum ofACANgene mutations in a selected Chinese cohort of short stature: genotype-phenotype correlation[J].Front Genet,2022,13:891040. doi:10.3389/fgene.2022.891040 URL

Case analysis and literature review of 3 children with short stature withACANgene mutation

RichHTML

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

Figures/Tables7

References20

Related Articles2

Recommended Articles

Metrics

Comments

[1]	ZHANG Juanjuan, HE Qinyu, YANG Yuanyan, DONG Zhiya, XIAO Yuan, CHEN Lifen, ZHANG Caiping.Lamb-Shaffer syndrome presenting as short stature with delays in motor and language acquisition: a case report and literature review[J]. Journal of Diagnostics Concepts & Practice, 2022, 21(03): 336-342.
[2]	LI Lin, AN Jingjing, WANG Junqi, WANG Xinqiong, DONG Zhiya.The structure of gut microbiome in idiopathic short stature profiled by 16S rRNA second generation sequencing sequencing[J]. Journal of Diagnostics Concepts & Practice, 2021, 20(02): 149-154.