【摘要】：目的總結(jié)分析21-羥化酶缺乏癥(21-hydroxylase deficiency,21-OHD)患者的臨床表現(xiàn)和基因特點,以提高臨床醫(yī)師對該癥的診治水平。方法(1)、收集被診斷為21-羥化酶缺乏癥患者的臨床資料,包括臨床表現(xiàn)、體格檢查、實驗室檢查等;(2)、應(yīng)用Sanger測序聯(lián)合MLPA技術(shù)對CYP21A2基因外顯子及外顯子側(cè)翼20bp區(qū)域進行檢測;(3)、糖皮質(zhì)激素替代治療和隨訪,監(jiān)測可能出現(xiàn)的并發(fā)癥;(4)、統(tǒng)計學分析。結(jié)果(1)、共納入21-羥化酶缺乏癥患者35例,其中男性患兒15例(43%,15/35),女性患兒20例(57%,20/35);失鹽型患兒20例(57%,20/35),單純男性患兒15例(43%,15/35)。失鹽型患兒就診原因以嘔吐、腹瀉最為常見(占50%,10/20),平均診斷年齡4.91±13.24月齡。單純男性化型患兒就診原因以外生殖器異常最常見(占100%,15/15),平均診斷年齡56.53±38.06月齡。(2)、35例患兒均行血清17-OHP、雄烯二酮、孕酮、睪酮檢測,35例(100%)17-OHP、雄烯二酮均增高,31例(88%,31/35)孕酮增高,17例(48%,17/35)睪酮增高。33例行血清ACTH與皮質(zhì)醇檢測,其中30例(90%,30/33)ACTH升高,17例(51%,17/33)皮質(zhì)醇降低。(3)、應(yīng)用Sanger測序聯(lián)合MLPA技術(shù)對25例患兒CYP21A2基因外顯子及外顯子側(cè)翼20bp區(qū)域進行檢測,23例檢測出CYP21A2基因突變,2例檢測結(jié)果陰性,檢測陽性率為92%。25例患兒CYP21A2基因Sanger測序共檢測出13種點突變,包括9種錯義突變(p.I173N、E6 cluster、p.R357W、p.V282L、p.R484P、p.Arg436Cys、p.Ser494Asn、p.Asp184Glu、p.Arg357Trp);2種缺失突變(p.G111Vfs*21、p.L308Ffs*6);1種無義突變(p.Q319X)和1種剪接位點突變(I2G)。其中以I2G(38%)、p.I173N(14%)最常見。其中5例Sanger測序僅發(fā)現(xiàn)CYP21A2基因一個突變點和3例未能發(fā)現(xiàn)突變點。對上述8例患兒采用MLPA技術(shù)進行CYP21A2基因檢測。共檢出3種大片段缺失(第1號、第3號外顯子缺失;4號外顯子缺失;1-7號外顯子缺失)。仍有2例MLPA技術(shù)檢測結(jié)果陰性。(4)、本研究中4例21-OHD患兒并發(fā)中樞性性早熟(Central precocious puberty,CPP),診斷21-羥化酶缺乏癥的年齡平均為4.4±2.31歲,診斷中樞性性早熟的年齡平均為6.61±1.14歲,骨齡平均為11.25±0.5歲。結(jié)論(1)、嘔吐、腹瀉是失鹽型21-OHD患兒最常見的就診原因,也是該型患者并發(fā)腎上腺危象的常見誘因,因其無特異性,易導致診斷延誤。(2)、類固醇激素在21-OHD的診斷中敏感性依次為:17羥孕酮=雄烯二酮孕酮皮質(zhì)醇睪酮。(3)、延遲診治和不規(guī)律治療可能是21-OHD患兒并發(fā)CPP的重要原因,尤其當患兒骨齡提前至11-12歲齡時,需警惕CPP發(fā)生的可能。(4)、CYP21A2基因Sanger測序聯(lián)合MLPA技術(shù)是一種簡便、可靠的基因檢測手段,可同時檢出基因點突變和大片段缺失,對本組病人檢出率高達92%。
[Abstract]:Objective to summarize and analyze the clinical manifestations and gene characteristics of 21-hydroxylase deficiency (21-hydroxylase deficiency,21-OHD) patients in order to improve the diagnosis and treatment of 21-hydroxylase deficiency (21-hydroxylase deficiency,21-OHD). Methods (1) the clinical data, including clinical manifestation, physical examination, were collected in patients with 21-hydroxylase deficiency. (2) Sanger sequencing combined with MLPA technique was used to detect exon and 20bp region of CYP21A2 gene; (3) glucocorticoid replacement therapy and follow-up were used to monitor possible complications; (4) statistical analysis. Results (1) A total of 35 patients with 21-hydroxylase deficiency were included, including 15 male (43 / 15 / 35), 20 female (57 / 20 / 35), 20 salt loss (57 / 20 / 35) and 15 male (43 / 15 / 35). Vomiting and diarrhea were the most common causes (50 / 10 / 20), with an average diagnostic age of 4.91 鹵13.24 months. Genital abnormality was the most common cause in simple masculine type (100% 15 / 15). The average diagnostic age was 56.53 鹵38.06 months. (2) Serum 17-OHP, androstenedione, progesterone were performed in 35 children. Testosterone was detected in 35 cases (100%), androstenedione in 31 cases (88 / 31 / 35), progesterone in 17 cases (48 / 17 / 35). Serum ACTH and cortisol were detected in 33 cases. Among them, 30 cases (90 / 33) of ACTH increased and 17 cases (51 / 17 / 33) of cortisol decreased. (3) Sanger sequencing combined with MLPA technique was used to detect CYP21A2 gene exon and 20bp region of exon flanking in 25 children. The results of CYP21A2 gene mutation in 2 cases were negative in 2 cases. A total of 13 point mutations were detected by Sanger sequencing of the CYP21A2 gene in 92.25 children, including 9 missense mutations (p. I173Nfs5 cluster,p.R357W,p.V282L,p.R484P,p.Arg436Cys,p.Ser494Asn,p.Asp184Glu,p.Arg357Trp) and 2 deletions (p.G111VfsSX 21p. L308Ffsfsfsl6), one nonsense mutation (p.Q319X) and one splice site mutation (I2G). Among them, I 2G (38%) p. I 173N (14%) was the most common. Only one mutation point of CYP21A2 gene was found in 5 cases of Sanger sequencing and no mutation point was found in 3 cases. The MLPA technique was used to detect the CYP21A2 gene in the 8 children mentioned above. A total of 3 large fragment deletions were detected (exon 1, exon 3, exon 1-7, exon 4, exon 1-7). In this study, 4 cases of 21-OHD complicated with central precocious puberty (Central precocious puberty,CPP), the average age of diagnosis of 21-hydroxylase deficiency was 4.4 鹵2. 31 years, the average age of diagnosis of central precocious puberty was 6. 61 鹵1. 14 years, and the average age of bone age was 11. 25 鹵0. 5 years. Conclusion (1) vomiting and diarrhea are the most common causes of 21-OHD and the common inducement of adrenal crisis, because they are not specific. The sensitivity of steroid hormone in the diagnosis of 21-OHD is: 17 hydroxyprogesterone = androstenedione progesterone cortisol testosterone. (3) delayed diagnosis and treatment and irregular treatment may be the important causes of CPP in children with 21-OHD. Especially when the bone age of children reaches 11-12 years of age, we should be aware of the possibility of CPP. (4) Sanger sequencing of CYP21A2 gene combined with MLPA technique is a simple and reliable method for gene detection, which can detect both point mutations and large deletions of genes. The detection rate of this group of patients was as high as 92.
【學位授予單位】：廣西醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R725.8

【參考文獻】

中國期刊全文數(shù)據(jù)庫 前10條

1 崔西春;王志芳;范應(yīng)中;李瀘平;張勝利;姚浩宇;李福凱;王家祥;;女性假兩性畸形內(nèi)外科聯(lián)合治療經(jīng)驗探討[J];醫(yī)學與哲學(B);2016年12期

2 楊綠綠;畢丹東;梁世山;林鵬程;蔡志明;鐘桂梅;;102例性早熟女童性器官發(fā)育及血清激素水平分析[J];中外醫(yī)療;2016年23期

3 鞏純秀;;腎上腺危象處理[J];中國實用兒科雜志;2016年06期

4 葉軍;王華;鄒卉;許爭峰;;先天性腎上腺皮質(zhì)增生癥新生兒篩查共識[J];中華兒科雜志;2016年06期

5 張令暉;胡菊萍;胡蜀紅;嚴兆丹;劉夢江;;失鹽型類固醇21-羥化酶缺乏癥64例臨床分析[J];華中科技大學學報(醫(yī)學版);2015年06期

6 張育才;任玉倩;;兒童腎上腺危象的早期識別與治療[J];中國小兒急救醫(yī)學;2015年10期

7 楊洋;周曉玉;周曉光;;21-羥化酶缺乏先天性腎上腺皮質(zhì)增生癥52例臨床分析[J];中國當代兒科雜志;2015年06期

8 梁玲;辛穎;;47例先天性腎上腺皮質(zhì)增生癥的臨床特點及診治分析[J];中國優(yōu)生與遺傳雜志;2014年01期

9 蘇U，

本文編號：2203277