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中华妇幼临床医学杂志(电子版) ›› 2020, Vol. 16 ›› Issue (02) : 188 -195. doi: 10.3877/cma.j.issn.1673-5250.2020.02.010

所属专题： 文献；

论著

先天性类脂性肾上腺皮质增生症的临床及基因突变特点并文献复习
李国红1, 陈晓波1,†(), 宋福英1, 董倩1   
  1. 1. 首都儿科研究所附属儿童医院内分泌科，北京　100020
  • 收稿日期:2019-10-10 修回日期:2020-01-04 出版日期:2020-04-01
  • 通信作者: 陈晓波

Clinical and gene mutation characteristics of congenital lipoid adrenal hyperplasia and literature review

Guohong Li1, Xiaobo Chen1,†(), Fuying Song1, Qian Dong1   

  1. 1. Department of Endocrinology, Children′s Hospital, Capital Institute of Pediatrics, Beijing 100020, China
  • Received:2019-10-10 Revised:2020-01-04 Published:2020-04-01
  • Corresponding author: Xiaobo Chen
  • About author:
    Corresponding author: Chen Xiaobo, Email:
  • Supported by:
    Capital Health Development and Research Special Project of Beijing Municipal Health and Family Commission(Shoufa 2018-1-2101)
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引用本文：

李国红, 陈晓波, 宋福英, 董倩. 先天性类脂性肾上腺皮质增生症的临床及基因突变特点并文献复习[J]. 中华妇幼临床医学杂志(电子版), 2020, 16(02): 188-195.

Guohong Li, Xiaobo Chen, Fuying Song, Qian Dong. Clinical and gene mutation characteristics of congenital lipoid adrenal hyperplasia and literature review[J]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2020, 16(02): 188-195.

目的

探讨儿童先天性类脂性肾上腺皮质增生症(CLAH)的临床及类固醇激素合成急性调节蛋白(StAR)基因突变特点。

方法

选择2018年7月至2019年5月，于首都儿科研究所附属儿童医院接受治疗的3例CLAH患儿为研究对象。回顾性分析其临床病例资料，包括临床表现、家系基因检测结果、治疗和随访结果等。以"先天性类脂性肾上腺皮脂增生症""肾上腺皮质增生""StAR基因""congenital lipoid adrenal hyperplasia""congenital adrenal hyperplasia""StAR"等为中、英文关键词，在PubMed数据库、中国医知网、中国生物医学文献服务系统(SinoMed)、中国知网和万方数据库中，检索有关类CLAH及StAR基因突变相关文献，检索时间设定为各数据库建库至2019年5月1日。本研究经首都儿科研究所附属儿童医院伦理委员会批准(审批文号：SHERLL2020006)，基因检测均征得患儿家属知情同意，并与其签署知情同意书。

结果

3例患儿的临床StAR基因突变特点如下。①临床表现：均在婴儿期起病，有皮肤色素沉，呕吐，体重不增等肾上腺功能不全症状。②实验室检查结果：均有低血钠、高血钾及低血糖，皮质醇水平显著降低，促肾上腺皮质激素(ACTH)水平明显升高。③肾上腺增强CT检查结果：均提示可见双侧肾上腺显著增生，表现为低密度影(类似液体密度)。④染色体核型分析结果：患儿1、3为46，XY，表现为女性外阴外观。⑤高通量测序结果：均发生StAR基因的纯合突变，突变位点分别位于c.772C>T，c.707_708delinsCTT和c.229G>A。本研究文献检索结果显示，国内文献曾报道23例CLAH患儿，均经StAR基因突变检测而被确诊，结合本研究3例，共计26例CLAH患儿纳入本研究。StAR基因的纯合突变中，突变位点位于c.772C>T(p.Q258X)为23.1%(12/52)，c.707_708delAG ins CTT(p.K236Tfs*47)为15.4%(8/52)，c.229G>A(p.Q77X)所占比例为15.4%(8/52)。

结论

CLAH为先天性肾上腺皮质增生症(CAH)的罕见类型，常在婴儿期起病，可表现为水、电解质紊乱，男性女性化，可伴有梗阻性黄疸。StAR基因的纯合突变位点位于p.Q258X，这可能是中国人群StAR热点突变。临床医师应注意对具有上述临床症状患儿的CLAH鉴别诊断，基因检测有助于CLAH的诊断，并可为该病的遗传咨询提供参考依据。

关键词: 先天性类脂性肾上腺皮质增生症, 肾上腺皮质增生, 基因测定, StAR基因, 高通量核苷酸测序, 儿童
Objective

To explore the clinical features of congenital lipoid adrenal hyperplasia (CLAH) and the characteristics of steroidogenic acute regulatory protein(StAR) gene mutations.

Methods

From July 2018 to May 2019, three children with CLAH who were treated in the children′s Hospital, Capital Institute of Pediatrics were selected into this study. The clinical data were analyzed retrospectively. Including the clinical manifestations, family genetic testing results, treatment and follow-up results were analyzed and so on. In addition, with " congenital lipoid adrenal hyperplasia" " adrenal hyperplasia" " StAR gene" " congenital adrenal hyperplasia" and " StAR" as Chinese and English key words, the literatures related to lipoid adrenal hyperplasia and steroid hormone synthesis acute regulatory protein (StAR) gene mutation were searched in PubMed database, China Medical Knowledge Infrastructure, Chinese Biomedical Literature Service System (SinoMed), China Knowledge Infrastructure and Wanfang database from database establishment to May 1, 2019. The study was approved by the ethics committee of Children′s Hospital, Capital Institute of Pediatrics (Approval No. SHERLL2020006), and the genetic testing was conducted with the informed consent of the family members of these three children.

Results

The characteristics of clinical StAR gene mutation in three children were as follows. ①Clinical manifestations: All three children had onset in infancy with clinical manifestations of adrenal insufficiency such as skin pigmentation, vomiting, and no weight gain. ②Laboratory results: Laboratory examination results of 3 children with CLAH showed low sodium, high potassium and hypoglycemia, significantly decreased cortisol levels, and significantly increased adrenocorticotropic hormone (ACTH) levels. ③ Adrenaline enhanced CT examination results: The enhanced CT findings of adrenal gland showed significant hyperplasia of bilateral adrenal glands, showing hypodense shadow (fluid-like). ④Chromosome karyotype analysis results: The karyotype of patient No.1 and patient No.3 was 46, XY, female vulva appearance. ⑤ High-throughput sequencing test results: Homozygous mutation of StAR gene was detected by high-throughput sequencing test of 3 children, and the mutation sites were located at c. 772C>T, c. 707_708delinsCTT and c. 229G>A, respectively. According to the results of literature retrieval, 23 cases of children with CLAH due to the StAR gene mutation diagnosed by genetic testing have been reported in China, which was a total of 26 cases when combined with the 3 cases included in this study. Among them, c. 772C>T (p.Q258X) accounted for 23.1%(12/52), c. 707_708delAG ins CTT (p.K236Tfs*47) accounted for 15.4% (8/52), c. 229G>A (p.Q77X) accounted for 15.4%(8/52).

Conclusions

CLAH is a rare type of congenital adrenal hyperplasia (CAH), which often onsets in infancy. It can be characterized by electrolyte disorder and male feminization, along with obstructive jaundice. The homozygous mutation site of StAR gene is located at p. Q258X, this could be a StAR hotspot mutation in Chinese population. Clinicians should pay attention to the differential diagnosis of CLAH. Genetic testing is helpful for the diagnosis of CLAH, and can provide reference for genetic consultation of CLAH.

Key words: Congenital lipoid adrenal hyperplasia, Adrenal hyperplasia, Genetic testing, StAR gene, High-throughput nucleotide sequencing, Child
表1 3例CLAH患儿实验室检查结果
患儿编号(No.) 血Na＋(mol/L) 血K＋(mol/L) 血Cl－(mol/L) 雌二醇(pmol/L) LH(IU/L) FSH(IU/L) 睾酮(nmol/L) 血糖(mmol/L)
1 129 7.15 93 <18.35 1.98 2.31 <0.087 2.03
2 125 6.30 92 <18.35 1.67 2.25 <0.087 1.90
3 123 7.25 89 <18.35 1.02 2.52 <0.087 2.60
正常参考范围 135～145 3.50～5.50 96～106 卵泡期：45.40～854.00 卵泡期：2.40～12.60 卵泡期：3.50～12.50 <0.087 3.90～6.10
? ? ? 排卵期：151.00～1 461.00 排卵期：14.00～95.60 排卵期：4.70～21.50 ? ?
? ? ? 黄体期：81.90～1 251.00 黄体期：1.00～11.40 黄体期：1.70～7.70 ? ?
患儿编号(No.) 皮质醇(ug/dL) a 17-羟孕酮(ng/mL) 孕酮(nmol/L) PRA(pg/mL) Ang Ⅰ(ng/mL) Ang Ⅱ(pg/mL) 醛固酮(pg/mL)
1 0.72 0.12 0.16 11 2.80 396 238
2 1.12 0.28 0.13 41 7.00 291 230
3 0.83 0.56 0.40 67 11.00 456 249
正常参考范围 6.20～19.40 0.15～1.10 卵泡期：1.18～2.84 7～19 0.07～1.51 15～97 60～174
? ? ? 排卵期：0.38～38.10 ? ? ? ?
? ? ? 黄体期：5.82～75.90 ? ? ? ?
图1 患儿1(女性，3个月12 d龄)肾上腺增强CT检查结果显示双侧肾上腺增生(图1A：轴位；图1B：冠状位)
图2 患儿1(女性，3个月12 d龄)及其父母StAR基因高通量测序法测序图(图2A：患儿1 StAR基因chr8：38001877存在c.772C>T纯合突变；图2B：患儿1母亲StAR基因chr8：38001877存在c.772C>T杂合突变；图2C：患儿1父亲StAR基因chr8：38001877存在c.772C>T杂合突变)
图3 患儿2(女性，5个月龄)及其母亲StAR基因高通量测序法测序图(图3A：患儿2 StAR基因chr8：38002776存在c.707_708delins CTT纯合突变；图3B：患儿2母亲StAR基因chr8：38002776存在c.707_708delins CTT杂合突变)
图4 患儿3(女性，1个月19 d龄) StAR基因高通量测序法测序图(StAR基因chr8：38005795存在c.229C>T纯合突变)
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