背景:身材矮小同源异型盒(SHOX)基因的致病突变是儿童身材矮小的主要遗传原因之一,发病率为1/1000~1/2000,主要临床表现为身材矮小和(或)肢体骨骼异常。SHOX基因突变主要是调控序列基因的大量缺失,而外显子突变相对罕见。外显子5突变的致病率仅为1/50000~1/100000。本研究回顾1例SHOX基因第5外显子突变患儿的临床资料,分析其临床表型,发病机制,诊断,结合国内外相关文献对SHOX基因突变的治疗及预后进行分析。
方法:患者为8岁女孩,身高105.2cm(-4.31标准偏差)。她坐的身高/身高比率为56.8%(>55.5%),她表现出高拱形腭,牙列不规则,小颌畸形,短手指,和正常的生长激素刺激测试。进行全外显子组测序,和Sanger测序用于站点验证。测序结果显示SHOX基因第5外显子存在c.577G>A的杂合突变,继承自父亲。先证者的临床症状与SHOX基因突变相关的身材矮小特发性家族性表型一致。父亲,爷爷,叔叔,先证者的姐妹都有c.577G>A杂合突变。因此,临床诊断为SHOX基因缺陷引起的儿童身材矮小。SHOX:c.577G>A突变可能是该家族中家族性特发性身材矮小的遗传病因,这种新的突变丰富了SHOX基因的突变谱。
结论:这是世界上首例由SHOX基因第5外显子c.577G>A位点突变引起的家族性特发性侏儒症。这种新的突变丰富了SHOX基因的突变谱。强调基因检测很重要,包括SHOX基因,对家族性特发性身材矮小的患者,及时给予SHOX基因突变引起身材矮小的个体生长激素治疗,以提高其成年身高。
BACKGROUND: The pathogenic mutation of short stature homeobox (SHOX) gene is one of the main genetic causes of short stature in children, with an incidence rate of 1/1000~1/2000 and the main clinical manifestations are short stature and (or) limb skeletal abnormalities. SHOX gene mutations are mostly large deletions of regulatory sequence genes, while exon mutations are relatively rare. The pathogenic rate of mutations occurring in exon 5 is only 1/50 000~1/100 000. This study reviewed the clinical data of a child with SHOX gene mutation in exon 5, and analyzed the clinical phenotype, pathogenesis, diagnosis, treatment and prognosis of SHOX gene mutation in combination with relevant literature at home and abroad.
METHODS: The patient was an 8-year-old girl with a height of 105.2 cm (-4.31 standard deviations). Her sitting height/height ratio was 56.8% (>55.5%), and she exhibited high-arched palate, irregular dentition, micrognathia, short fingers, and a normal growth hormone stimulation test. Whole-exome sequencing was performed, and Sanger sequencing was used for site validation. The sequencing results revealed a heterozygous mutation of c.577G > A in exon 5 of the SHOX gene, inherited from the father. The clinical symptoms of the proband were consistent with the phenotype of short stature idiopathic familial associated with SHOX gene mutations. The father, grandfather, uncle, and sister of the proband all had the c.577G > A heterozygous mutation. Therefore, the clinical diagnosis was childhood short stature caused by SHOX gene defects. The SHOX: c.577G > A mutation is likely to be the genetic etiology of familial idiopathic short stature in this family, and this novel mutation enriches the mutation spectrum of the SHOX gene.
CONCLUSIONS: This is the first case report of familial idiopathic dwarfism caused by mutation at the c.577G > A locus of exon 5 of SHOX gene in the world. This novel mutation enriches the mutation spectrum of the SHOX gene. It is important to emphasize genetic testing, including the SHOX gene, in patients with familial idiopathic short stature and to provide timely growth hormone therapy to individuals with short stature caused by SHOX gene mutations in order to improve their adult height.