先天性腎上腺皮質(zhì)增生癥21-羥化酶缺陷35例臨床分析
發(fā)布時(shí)間：2018-08-25 15:14
【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(diǎn),以提高臨床醫(yī)師對(duì)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(shí)驗(yàn)室檢查等;(2)、應(yīng)用Sanger測(cè)序聯(lián)合MLPA技術(shù)對(duì)CYP21A2基因外顯子及外顯子側(cè)翼20bp區(qū)域進(jìn)行檢測(cè);(3)、糖皮質(zhì)激素替代治療和隨訪,監(jiān)測(cè)可能出現(xiàn)的并發(fā)癥;(4)、統(tǒng)計(jì)學(xué)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(cè),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(cè),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(cè)序聯(lián)合MLPA技術(shù)對(duì)25例患兒CYP21A2基因外顯子及外顯子側(cè)翼20bp區(qū)域進(jìn)行檢測(cè),23例檢測(cè)出CYP21A2基因突變,2例檢測(cè)結(jié)果陰性,檢測(cè)陽(yáng)性率為92%。25例患兒CYP21A2基因Sanger測(cè)序共檢測(cè)出13種點(diǎn)突變,包括9種錯(cuò)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(wú)義突變(p.Q319X)和1種剪接位點(diǎn)突變(I2G)。其中以I2G(38%)、p.I173N(14%)最常見。其中5例Sanger測(cè)序僅發(fā)現(xiàn)CYP21A2基因一個(gè)突變點(diǎn)和3例未能發(fā)現(xiàn)突變點(diǎn)。對(duì)上述8例患兒采用MLPA技術(shù)進(jìn)行CYP21A2基因檢測(cè)。共檢出3種大片段缺失(第1號(hào)、第3號(hào)外顯子缺失;4號(hào)外顯子缺失;1-7號(hào)外顯子缺失)。仍有2例MLPA技術(shù)檢測(cè)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(wú)特異性,易導(dǎo)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(dāng)患兒骨齡提前至11-12歲齡時(shí),需警惕CPP發(fā)生的可能。(4)、CYP21A2基因Sanger測(cè)序聯(lián)合MLPA技術(shù)是一種簡(jiǎn)便、可靠的基因檢測(cè)手段,可同時(shí)檢出基因點(diǎn)突變和大片段缺失,對(duì)本組病人檢出率高達(dá)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(xué)位授予單位】：廣西醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R725.8
[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(xué)位授予單位】：廣西醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R725.8
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