先天性肾上腺皮质增生症21-羟化酶缺陷35例临床分析
发布时间：2018-08-25 15:14
【摘要】：目的总结分析21-羟化酶缺乏症(21-hydroxylase deficiency,21-OHD)患者的临床表现和基因特点,以提高临床医师对该症的诊治水平。方法(1)、收集被诊断为21-羟化酶缺乏症患者的临床资料,包括临床表现、体格检查、实验室检查等;(2)、应用Sanger测序联合MLPA技术对CYP21A2基因外显子及外显子侧翼20bp区域进行检测;(3)、糖皮质激素替代治疗和随访,监测可能出现的并发症;(4)、统计学分析。结果(1)、共纳入21-羟化酶缺乏症患者35例,其中男性患儿15例(43%,15/35),女性患儿20例(57%,20/35);失盐型患儿20例(57%,20/35),单纯男性患儿15例(43%,15/35)。失盐型患儿就诊原因以呕吐、腹泻最为常见(占50%,10/20),平均诊断年龄4.91±13.24月龄。单纯男性化型患儿就诊原因以外生殖器异常最常见(占100%,15/15),平均诊断年龄56.53±38.06月龄。(2)、35例患儿均行血清17-OHP、雄烯二酮、孕酮、睾酮检测,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)睾酮增高。33例行血清ACTH与皮质醇检测,其中30例(90%,30/33)ACTH升高,17例(51%,17/33)皮质醇降低。(3)、应用Sanger测序联合MLPA技术对25例患儿CYP21A2基因外显子及外显子侧翼20bp区域进行检测,23例检测出CYP21A2基因突变,2例检测结果阴性,检测阳性率为92%。25例患儿CYP21A2基因Sanger测序共检测出13种点突变,包括9种错义突变(p.I173N、E6 cluster、p.R357W、p.V282L、p.R484P、p.Arg436Cys、p.Ser494Asn、p.Asp184Glu、p.Arg357Trp);2种缺失突变(p.G111Vfs*21、p.L308Ffs*6);1种无义突变(p.Q319X)和1种剪接位点突变(I2G)。其中以I2G(38%)、p.I173N(14%)最常见。其中5例Sanger测序仅发现CYP21A2基因一个突变点和3例未能发现突变点。对上述8例患儿采用MLPA技术进行CYP21A2基因检测。共检出3种大片段缺失(第1号、第3号外显子缺失;4号外显子缺失;1-7号外显子缺失)。仍有2例MLPA技术检测结果阴性。(4)、本研究中4例21-OHD患儿并发中枢性性早熟(Central precocious puberty,CPP),诊断21-羟化酶缺乏症的年龄平均为4.4±2.31岁,诊断中枢性性早熟的年龄平均为6.61±1.14岁,骨龄平均为11.25±0.5岁。结论(1)、呕吐、腹泻是失盐型21-OHD患儿最常见的就诊原因,也是该型患者并发肾上腺危象的常见诱因,因其无特异性,易导致诊断延误。(2)、类固醇激素在21-OHD的诊断中敏感性依次为:17羟孕酮=雄烯二酮孕酮皮质醇睾酮。(3)、延迟诊治和不规律治疗可能是21-OHD患儿并发CPP的重要原因,尤其当患儿骨龄提前至11-12岁龄时,需警惕CPP发生的可能。(4)、CYP21A2基因Sanger测序联合MLPA技术是一种简便、可靠的基因检测手段,可同时检出基因点突变和大片段缺失,对本组病人检出率高达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 卤13.24 months. Genital abnormality was the most common cause in simple masculine type (100% 15 / 15). The average diagnostic age was 56.53 卤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 卤2. 31 years, the average age of diagnosis of central precocious puberty was 6. 61 卤1. 14 years, and the average age of bone age was 11. 25 卤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.
【学位授予单位】：广西医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：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 卤13.24 months. Genital abnormality was the most common cause in simple masculine type (100% 15 / 15). The average diagnostic age was 56.53 卤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 卤2. 31 years, the average age of diagnosis of central precocious puberty was 6. 61 卤1. 14 years, and the average age of bone age was 11. 25 卤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.
【学位授予单位】：广西医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R725.8
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