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

doi:10.3877/cma.j.issn.1673-5250.2020.02.010

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	?	?	?	?

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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