育龄期21-羟化酶缺乏症误诊为多囊卵巢综合征二例并文献复习

doi:10.12280/gjszjk.20210611

摘要/Abstract

摘要：

21-羟化酶缺乏症（21-hydroxylase deficiency,21-OHD）是先天性肾上腺皮质增生症最常见的一种,部分21-OHD患者的临床症状不典型,容易漏诊、误诊。报道2例因月经紊乱、不孕及高雄激素血症就诊而误诊为多囊卵巢综合征（polycystic ovary syndrome,PCOS）的21-OHD患者的临床资料,基因测序显示1例携带c.374G>A（p.Arg125His）和c.518T>A（p.Ile173Asn）杂合错义突变,明确了突变基因来自患者父母;另1例携带c.518T>A（p.Ile173Asn）纯合错义突变,因亲属未检测故未明确突变来源。给予地塞米松口服治疗,2例患者均恢复规律月经,高雄激素血症临床症状得到改善,其中1例成功妊娠并分娩。育龄期女性如以不孕、高雄激素血症表现就诊,诊断为PCOS而治疗效果不佳时,应考虑21-OHD,进一步行17-羟孕酮测定、促肾上腺皮质激素兴奋试验和基因突变检测可明确诊断。

关键词: 类固醇21-羟化酶, 雄激素增多症, 肾上腺增生,先天性, 多囊卵巢综合征, 基因, 突变,误义, 21-羟化酶缺乏症

Abstract:

21-hydroxylase deficiency (21-OHD) is one of the most common congenital adrenal hyperplasia. The clinical symptom in part of patients with 21-OHD is atypical, so that 21-OHD is easy to be misdiagnosed or missed diagnosis. In this paper, we report 2 cases of 21-OHD that was misdiagnosed as polycystic ovary syndrome (PCOS) due to menstrual disorder, infertility and hyperandrogenemia. Sanger sequencing showed that one patient carried c.374G>A (p.Arg125His) and c.518T>A (p.Ile173Asn) heterozygous missense mutations, confirming that the mutant gene came from her parents. Another patient carried homozygous missense mutation of c.518T>A (p.Ile173Asn), and the source of mutation was not clear because her relatives were not detected. With the treatment of oral dexamethasone, 2 patients were restored the regular menstruation, and improved the symptoms of hyperandrogenism. One patient got successful pregnancy and childbirth. When women of childbearing age with infertility and hyperandrogenemia were diagnosed as PCOS, and the treatment effect is not good, 21-OHD should be considered. The combination of 17-OHP assay, ACTH excitation test and gene mutation test will be helpful for the definite diagnosis and differential diagnosis.

Key words: Steroid 21-hydroxylase, Hyperandrogenism, Adrenal hyperplasia, congenital, Polycystic ovary syndrome, Genes, Mutation, missense, 21-hydroxylase deficiency

迟学秀, 郭宝强, 于姗, 何东华. 育龄期21-羟化酶缺乏症误诊为多囊卵巢综合征二例并文献复习[J]. 国际生殖健康/计划生育, 2022, 41(4): 289-293.

CHI Xue-xiu, GUO Bao-qiang, YU Shan, HE Dong-hua. Two Cases of 21-Hydroxylase Deficiency in Reproductive Age Misdiagnosed as Polycystic Ovary Syndrome and Literature Review[J]. Journal of International Reproductive Health/Family Planning, 2022, 41(4): 289-293.

图/表 4

参考文献 18

[1]	Merke DP, Auchus RJ. Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency[J]. N Engl J Med, 2020, 383(13):1248-1261. doi: 10.1056/NEJMra1909786. doi: 10.1056/NEJMra1909786 URL
[2]	Speiser PW, Arlt W, Auchus RJ, et al. Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline[J]. J Clin Endocrinol Metab, 2018, 103(11):4043-4088. doi: 10.1210/jc.2018-01865. doi: 10.1210/jc.2018-01865 URL
[3]	Hannah-Shmouni F, Morissette R, Sinaii N, et al. Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians[J]. Genet Med, 2017, 19(11):1276-1279. doi: 10.1038/gim.2017.46. doi: 10.1038/gim.2017.46 pmid: 28541281
[4]	El-Maouche D, Arlt W, Merke DP. Congenital adrenal hyperplasia[J]. Lancet, 2017, 390(10108):2194-2210. doi: 10.1016/S0140-6736(17)31431-9. doi: S0140-6736(17)31431-9 pmid: 28576284
[5]	Hannah-Shmouni F, Chen W, Merke DP. Genetics of Congenital Adrenal Hyperplasia[J]. Endocrinol Metab Clin North Am, 2017, 46(2):435-458. doi: 10.1016/j.ecl.2017.01.008. doi: 10.1016/j.ecl.2017.01.008 URL
[6]	Livadas S, Dracopoulou M, Dastamani A, et al. The spectrum of clinical, hormonal and molecular findings in 280 individuals with nonclassical congenital adrenal hyperplasia caused by mutations of the CYP21A2 gene[J]. Clin Endocrinol(Oxf), 2015, 82(4):543-549. doi: 10.1111/cen.12543. doi: 10.1111/cen.12543 URL
[7]	聂敏, 崔铭萱, 茅江峰, 等. 孕酮对21-羟化酶缺陷症的诊断价值初步探讨[J]. 中华医学杂志, 2016, 96(48):3866-3869. doi: 10.3760/cma.j.issn.0376-2491.2016.48.003. doi: 10.3760/cma.j.issn.0376-2491.2016.48.003
[8]	曾丽婷, 韩兵, 刘炳丽, 等. 33例成人单纯男性化型21-羟化酶缺陷症的临床特点与基因型研究[J]. 中华内科杂志, 2019, 58(6):428-434. doi: 10.3760/cma.j.issn.0578-1426.2019.06.006. doi: 10.3760/cma.j.issn.0578-1426.2019.06.006
[9]	董步连, 缑灵山, 杨丽, 等. 徐州地区21-羟化酶缺乏症患儿遗传学及临床表型分析[J]. 徐州医科大学学报, 2020, 40(12):859-863. doi: 10.3969/j.issn.2096-3882.2020.12.001. doi: 10.3969/j.issn.2096-3882.2020.12.001
[10]	舒剑波, 张新杰, 徐晓薇, 等. 21-羟化酶缺乏症CYP21A2基因突变及表型分析[J]. 中华内分泌代谢杂志, 2019, 35(1):21-25. doi: 10.3760/cma.j.issn.1000-6699.2019.01.004. doi: 10.3760/cma.j.issn.1000-6699.2019.01.004
[11]	Haider S, Islam B, D′Atri V, et al. Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia[J]. Proc Natl Acad Sci U S A, 2013, 110(7):2605-2610. doi: 10.1073/pnas.1221133110. doi: 10.1073/pnas.1221133110 URL
[12]	Usui T, Nishisho K, Kaji M, et al. Three novel mutations in Japanese patients with 21-hydroxylase deficiency[J]. Horm Res, 2004, 61(3):126-132. doi: 10.1159/000075587. doi: 10.1159/000075587
[13]	Chiou SH, Hu MC, Chung BC. A missense mutation at Ile172--Asn or Arg356--Trp causes steroid 21-hydroxylase deficiency[J]. J Biol Chem, 1990, 265(6):3549-3552. pmid: 2303461
[14]	丁颖, 田秦杰, 卢琳. 孕酮在非经典型21羟化酶缺乏症和多囊卵巢综合征鉴别诊断中的作用[J]. 生殖医学杂志, 2010, 19(4):309-312. doi: 10.3969/j.issn.1004-3845.2010.04.005. doi: 10.3969/j.issn.1004-3845.2010.04.005
[15]	王胜男, 夏艳洁, 许莉军, 等. 非经典型21-羟化酶缺陷症与多囊卵巢综合征的鉴别诊断分析[J]. 中华内分泌代谢杂志, 2020, 36(4):288-293. doi: 10.3760/cma.j.cn311282-20190822-00337. doi: 10.3760/cma.j.cn311282-20190822-00337
[16]	陈晓波, 高亢. 21-羟化酶缺乏症诊治新进展[J]. 中华实用儿科临床杂志, 2019, 34(20):1526-1530. doi: 10.3760/cma.j.issn.2095-428X.2019.20.002. doi: 10.3760/cma.j.issn.2095-428X.2019.20.002
[17]	Glintborg D, Hermann AP, Brusgaard K, et al. Significantly higher adrenocorticotropin-stimulated cortisol and 17-hydroxyprogesterone levels in 337 consecutive, premenopausal, caucasian, hirsute patients compared with healthy controls[J]. J Clin Endocrinol Metab, 2005, 90(3):1347-1353. doi: 10.1210/jc.2004-1214. doi: 10.1210/jc.2004-1214 URL
[18]	刘绿. 21-羟化酶缺乏症的药物治疗及研究进展[D]. 重庆: 重庆医科大学, 2020.

检测时间	T（nmol/L）	P（nmol/L）	FSH（U/L）	LH（U/L）	E₂（pmol/L）	ACTH（pmol/L）	17-OHP（nmol/L）	AD（nmol/L）	DHEAs（μmol/L）
2020-06-16	3.42	15.27	6.19	15.62	338.11	4.72	62.42	28.00	13.23
2020-07-20	0.33	3.80	4.90	7.60	2 138.54	5.10	-	-	-
2020-08-31	0.22	126.20	6.62	6.13	588.90	4.56	21.82	10.62	4.70
2021-07-26	0.09	1.17	8.17	3.40	274.10	0.23	20.60	6.25	3.14
参考范围	0.29~1.67	卵泡期0~0.9	卵泡期3.4~21.6	卵泡期1.8~11.8	卵泡期282.17~336.72	1.44~12.72	卵泡期0.15~3.09	1.04~11.45	2.57~8.84

检测时间	T（nmol/L）	P（nmol/L）	FSH（U/L）	LH（U/L）	E₂（pmol/L）	ACTH（pmol/L）	17-OHP（nmol/L）	AD（nmol/L）	DHEAs（μmol/L）
2020-06-16	3.42	15.27	6.19	15.62	338.11	4.72	62.42	28.00	13.23
2020-07-20	0.33	3.80	4.90	7.60	2 138.54	5.10	-	-	-
2020-08-31	0.22	126.20	6.62	6.13	588.90	4.56	21.82	10.62	4.70
2021-07-26	0.09	1.17	8.17	3.40	274.10	0.23	20.60	6.25	3.14
参考范围	0.29~1.67	卵泡期0~0.9	卵泡期3.4~21.6	卵泡期1.8~11.8	卵泡期282.17~336.72	1.44~12.72	卵泡期0.15~3.09	1.04~11.45	2.57~8.84

检测时间	T（nmol/L）	P（nmol/L）	FSH（U/L）	LH（U/L）	E₂（pmol/L）	ACTH（pmol/L）	17-OHP（nmol/L）	AD（nmol/L）	DHEAs（μmol/L）
2020-08-17	8.52	45.99	9.99	4.98	764.21	12.64	554.34	>34.7	6.85
2020-09-04	0.09	3.80	6.12	3.56	2 138.54	3.12	321.94	25.33	5.26
2020-10-20	1.51	35.21	4.90	7.60	588.90	3.18	-	-	-
2021-01-08	0.68	7.61	2.78	2.88	5 903.18	10.42	67.57	8.33	2.32
参考范围	0.29~1.67	卵泡期0~0.9	卵泡期3.4~21.6	卵泡期1.8~11.8	卵泡期282.17~336.72	1.44~12.72	卵泡期0.15~3.09	1.04~11.45	2.57~8.84

检测时间	T（nmol/L）	P（nmol/L）	FSH（U/L）	LH（U/L）	E₂（pmol/L）	ACTH（pmol/L）	17-OHP（nmol/L）	AD（nmol/L）	DHEAs（μmol/L）
2020-08-17	8.52	45.99	9.99	4.98	764.21	12.64	554.34	>34.7	6.85
2020-09-04	0.09	3.80	6.12	3.56	2 138.54	3.12	321.94	25.33	5.26
2020-10-20	1.51	35.21	4.90	7.60	588.90	3.18	-	-	-
2021-01-08	0.68	7.61	2.78	2.88	5 903.18	10.42	67.57	8.33	2.32
参考范围	0.29~1.67	卵泡期0~0.9	卵泡期3.4~21.6	卵泡期1.8~11.8	卵泡期282.17~336.72	1.44~12.72	卵泡期0.15~3.09	1.04~11.45	2.57~8.84