先天性类脂质性肾上腺皮质增生症临床特点及StAR基因突变分析

谢婷; 郑纪鹏; 黄永兰; 樊春; 吴冬燕; 谭敏沂; 李秀珍; 程静; 刘丽

doi:10.7499/j.issn.1008-8830.2015.05.012

PDF(1359 KB)

HTML

中国当代儿科杂志 ›› 2015, Vol. 17 ›› Issue (5) : 472-476. DOI: 10.7499/j.issn.1008-8830.2015.05.012

论著·临床研究

先天性类脂质性肾上腺皮质增生症临床特点及StAR基因突变分析

谢婷, 郑纪鹏, 黄永兰, 樊春, 吴冬燕, 谭敏沂, 李秀珍, 程静, 刘丽

作者信息 +

Clinical features and StAR gene mutations in children with congenital lipoid adrenal hyperplasia

XIE Ting, ZHENG Ji-Peng, HUANG Yong-Lan, FAN Chun, WU Dong-Yan, TAN Min-Yi, LI Xiu-Zhen, CHENG Jing, LIU Li

Author information +

文章历史 +

摘要

该文回顾性分析2例先天性类脂质性肾上腺皮质增生症(LCAH)患儿的临床表现、类固醇激素谱及影像学检查结果, 采用DNA直接测序法及限制性片段长度多态性(RFLP)技术对类固醇生成急性调节蛋白(StAR)基因突变进行分析。2例患儿均为46, XX女性, 确诊年龄分别为4个月及2岁4个月。婴儿早期出现皮肤色素沉着、生长迟缓、低钠血症等肾上腺皮质功能低下表现, 血ACTH显著增高, 皮质醇正常或降低, 各类雄性激素均未见增高。肾上腺超声提示双侧肾上腺增大或正常, 经氢化可的松及9α-氟氢可的松替代治疗后生长发育正常。StAR基因突变分析显示患儿1为p.Q258X纯合已知无义突变; 患儿2为p.E123K/IVS4+2T>A复合杂合突变, 且为新突变, 其父母分别为新突变IVS4+2T>A及p.E123K的携带者。保守性分析及PolyPhen-2软件预测提示p.E123K为致病性突变。RFLP分析显示患儿2及其父亲的PCR扩增产物经酶切后同时出现670、423、247 bp 3条条带, 而其母亲及50例正常对照仅出现423和247 bp两条条带, 提示IVS4+2T>A突变改变氨基酸酶切位点。对于婴儿早期发生的肾上腺皮质功能低下的女性表型患儿应警惕LCAH, 类固醇激素谱、核型分析及肾上腺超声有助诊断, 确诊依赖StAR基因突变分析。

Abstract

This article reported the clinical manifestations, steroid profiles and adrenal ultrasound findings in two unrelated Chinese girls with lipoid congenital adrenal hyperplasia (LCAH). Direct DNA sequencing and restriction fragment length polymorphism (RFLP) analysis were used to identify the mutations of steroidogenic acute regulatory protein (StAR) gene. The two patients with 46,XX karyotype, presented hyperpigmentation, growth retardation, and hyponatremia. Steroid profiles analysis revealed elevated plasma adrenocorticotrophic hormone levels, decreased or normal serum cortisol levels and low levels of androgens. Ultrasound examinations revealed that enlarged adrenals in patient 1 and normal adrenals in patient 2. Direct DNA sequencing of StAR gene showed a reported homozygous for c.772C>T(p.Q258X) in patient 1. Compound heterozygous for c.367G>A(p.E123K) and IVS4+2T>A (both novel mutations) were found in patient 2, inherited from her mother and father respectively. The amino acid of mutant position of the novel p.E123K was highly conserved in ten different species and was predicted to have impacts on the structure and function of StAR protein by the PolyPhen-2 prediction software. RFLP analysis revealed three bands (670, 423 and 247 bp) in patient 2 and her father and two bands (423 and 247 bp) in her mother and 50 controls. It is concluded that LCAH should be considered in girls with early onset of adrenal insufficiency and that steroid profiles, karyotype analysis, adrenal ultrasound and StAR gene analysis may be helpful for the definite diagnosis of LCAH.

导出引用

谢婷, 郑纪鹏, 黄永兰, 樊春, 吴冬燕, 谭敏沂, 李秀珍, 程静, 刘丽. 先天性类脂质性肾上腺皮质增生症临床特点及StAR基因突变分析[J]. 中国当代儿科杂志. 2015, 17(5): 472-476 https://doi.org/10.7499/j.issn.1008-8830.2015.05.012

XIE Ting, ZHENG Ji-Peng, HUANG Yong-Lan, FAN Chun, WU Dong-Yan, TAN Min-Yi, LI Xiu-Zhen, CHENG Jing, LIU Li. Clinical features and StAR gene mutations in children with congenital lipoid adrenal hyperplasia[J]. Chinese Journal of Contemporary Pediatrics. 2015, 17(5): 472-476 https://doi.org/10.7499/j.issn.1008-8830.2015.05.012

参考文献

[1] 邱文娟, 叶军, 韩蓓, 等. 先天性类脂质性肾上腺增生症分子遗传学分析[J].中华儿科杂志, 2004, 42(8): 585-588.
[2] Eiden-Plach A, Nguyen HH, Schneider U, et al. Alu Sx repeat-induced homozygous deletion of the StAR gene causes lipoidcongenital adrenal hyperplasia[J]. J Steroid Biochem Mol Biol, 2012, 130(1-2): 1-6.
[3] Gonzalez AA, Reyes ML, Carvajal CA, et al. Congenital lipoid adrenal hyperplasia caused by a novel splicing mutation in the gene for the steroidogenic acute regulatory protein[J]. J Clin Endocrinol Metab, 2004, 89(2): 946-951.
[4] Chen X, Baker BY, Abduljabbar MA, et al. A geneticisolate of congenital lipoid adrenal hyperplasia with atypical clinical findings[J]. J ClinEndocrinol Metab, 2005, 90(2): 835-840.
[5] Baker BY, Lin L, Kim CJ, et al. Nonclassic congenitallipoid adrenal hyperplasia: a new disorder of the steroidogenic acute regulatory protein with very late presentation and normal male genitalia[J]. J Clin Endocrinol Metab, 2006, 91(12): 4781-4785.
[6] Sahakitrungruang T, Soccio RE, Lang-Muritano M, et al. Clinical, genetic, and functional characterization of four patients carrying partial loss-of-function mutations in the steroidogenic acute regulatory protein (StAR)[J]. J Clin Endocrinol Metab, 2010, 95(7): 3352-3359.
[7] Fluck CE, Pandey AV, Dick B, et al. Characterization of novel StAR (steroidogenic acute regulatory protein) mutations causing non-classic lipoid adrenal hyperplasia[J]. PLoS One, 2011, 6(5): e20178.
[8] Camats N, Pandey AV, Fernandez-Cancio M, et al. STAR splicing mutations cause the severe phenotype of lipoidcongenital adrenal hyperplasia: insights from a novel splicemutation and review of reported cases[J]. Clin Endocrinol (Oxf), 2014, 80(2): 191-199.
[9] King SR, Bhangoo A, Stocco DM. Functional and physiological consequences of StAR deficiency: role in lipoid congenital adrenal hyperplasia[J]. Endocr Dev, 2011, 20: 47-53.
[10] Lekarev O, Mallet D, Yuen T, et al. Congenital lipoid adrenal hyperplasia (a rare form of adrenal insufficiency and ambiguous genitalia) caused by a novel mutation of the steroidogenic acute regulatory protein gene[J]. Eur J Pediatr, 2012, 171(5): 787-793.
[11] 肖园, 杨军, 张惠杰, 等. 先天性肾上腺发育不良家系中DAX-1新突变的发现[J]. 中华儿科杂志, 2007, 45(12): 937-941.
[12] Hashemipour M, Ghasemi M, Hovsepian S. A case of congenital lipoid adrenal hyperplasia[J]. Int J Prev Med, 2012, 3(7): 510-514.