AR、SRD5A2基因突变与46,XY性腺发育不良相关性研究
发布时间：2018-09-07 20:00
【摘要】：第一部分 38例46,XY性发育异常AR、SRD5A2基因突变分析 目的：分析46,XY性发育异常与AR、SRD5A2基因突变相关性。 方法：自2011.1至2013.1共搜集我院38例46,XY性发育不良患儿,采外周静脉血,提取DNA,利用PCR扩增目的基因后,采用Sanger测序法进行测序。对患儿AR、SRD5A2基因全编码序列检测,应用seqMan7.1、MutationSurveyor3.97软件对上述测序结果进行分析。以50例健康体检有生育能力的成年男性做为对照。 结果：(1)、38例46,XYDSD患儿中,发现16例(占42.1%)存在基因突变,其中尿道下裂合并小阴茎占31.6%,女性外阴表现者(男性假两性畸形)占7.9%。并发现两例来自同一家系的患儿同时存在AR (p.Q557R)、SRD5A2(p.R227Q)基因突变。(2)、AR基因1-8外显子发现6处点突变,发现一新发突变(p.Q557R)；突变病例7例(占18.4%),2例来自于同一家系在2号外显子存在错义突变p.Q557R；2例不同血缘患儿在7号外显子错义突变分别为p.R856H、p.R841L;2例不同血缘患儿在8号外显子存在错义突变分别为：p.A871V、p.V890M;还有一例为位于8号外显子中性突变p.S889S;(3)、SRD5A2基因突变病例为11例(占28.9%),1例为移码突变P.C222Vfs225X,4例为复合型突变(3例p.G203S/p.R227Q,1例p.R227Q/p.A228V),6例单个错义突变4例为p.R227Q,1例为p.A228V,1例为p.L20P。其中RC222Vfs225X、复合突变p.R227Q/p.A228V未报道过。(4)50例正常对照测序分析未发现AR基因存在：Q557R、R856H、 R841L、A871V、V890M、p.S889S; SRD5A2基因未发现存在：A228V、L20P、 R227Q、G203S位点突变及P.C222Vfs225X。(5)38例46,XYDSDAR基因1号外显子CAG(n=18-31),GGC(n=13-18);CAG平均重复数目为：23.13,GGC平均重复数目为：16.74。(6)SRD5A2基因1号外显子L89V、281+15TC在患儿和正常对照组均存在。 结论：1.男性两性畸形、尿道下裂合并小阴茎患儿应首选AR基因、SRD5A2基因突变检测。2.SRD5A2基因c.680GA,p.R227Q可能是中国人群的热点突变。3.关于基因型与临床表型的分析仍需进一步扩大样本进行分析。4.对于AR基因两个氨基酸重复序列长度是否影响雄激素受体活性仍不清楚。 第二部分 双氢睾酮凝胶治疗23例男童小阴茎疗效及安全性分析 目的：探索性研究双氢睾酮凝胶治疗男童小阴茎治疗疗效与安全性分析,提供小阴茎治疗方案。 方法：以前瞻性自身对照研究方法,对上述存在小阴茎抚养为男性的患儿,经知情同意后,局部给予涂抹双氢睾酮凝胶(0.1-0.3mg/kg/d),疗程3-6月。用Feldman方法测量阴茎延伸长度,睾丸模型子比较测量睾丸体积,G-P骨龄图谱评测骨龄,监测治疗前(0月),治疗后1月、3月、6月血常规、生化、性激素,并监测血清双氢睾酮浓度,观察治疗期间的不良反应。 结果：23例患儿入选,用药治疗平均年龄：4.07+3.4岁。未治疗前(0月)23例患儿阴茎长度为：1.68±0.6cm,PL标准差分值(SDS)的变化(△PL-SDS)为-1.13±0.47cm；1月时22人随访,阴茎长度为2.2±0.66cm,△PL-SDS为-0.54±0.53cm,0月与1月阴茎长度相比,p=0.0031,有统计学意义；3月时19人随访,阴茎长度为2.53±0.58cm,△PL-SDS为-0.28±0.75cm；0月与3月阴茎长度相比,p0.001,有显著统计学意义。6月时12人随访,阴茎长度为3±0.7cm；△PL-SDS为0.24±0.52cm。0月与6月阴茎长度相比,p0.001,有显著统计学意义。治疗1月时平均阴茎长度增长为：0.58cm,治疗3月时阴茎长度增长为：1.02cm,治疗6月时阴茎长度增长为：1.5cm。目前结束用药18例,(66.7%)12/18例PL达标(2.5s)给予停药,2/18例可完善手术,4/18改善撒尿姿势,2/18例未达标。治疗后1月、3月、6月血肝肾功能、血常规、性激素、身高、体重较用药前无统计学意义(P0.05),治疗前后骨龄无统计学意义(P0.05)。用药后监测血清双氢睾酮浓度维持于TunerⅡ-Ⅲ水平。20例患儿用药局部皮肤颜色变暗。 结论：1、双氢睾酮凝胶局部应用治疗小阴茎,有效促进阴茎生长。2、有局部皮肤色素沉着,无明显全身不良反应。
[Abstract]:Part one
Mutation analysis of AR and SRD5A2 gene in 38 cases of 46 and XY sexual dysplasia
Objective: to analyze the correlation between 46, XY sex development abnormality and AR and SRD5A2 gene mutation.
Methods: DNA was extracted from peripheral venous blood of 38 children with XY sexual dysplasia from 2011.1 to 2013.1. After amplifying the target gene by PCR, Sanger sequencing method was used for sequencing. Healthy adults with fertility were used as controls.
Results: (1) Among 38 children with XYDSD, 16 (42.1%) had gene mutations, including hypospadias with penis (31.6%) and female vulva (7.9%). A new mutation was found in exon 7 (p.Q557R), 7 (18.4%) cases, 2 (p.Q557R) from the same family, 2 (p.R856H, p.R841L) in exon 7, and 2 (p.A871V, p.V890M) in exon 8 from different kinship. There was also a neutral mutation in exon 8 p.S889S; (3) SRD5A2 gene mutation in 11 cases (28.9%), a frameshift mutation in 1 case (P.C222Vfs225X), a compound mutation in 4 cases (3 cases p.G203S/p.R227Q, 1 case p.R227Q/p.A228V), a single missense mutation in 4 cases (p.R227Q, 1 case p.A228V, 1 case p.L20P). 27Q/p.A228V was not reported. (4) No AR gene was found in 50 normal controls: Q557R, R856H, R841L, A871V, V890M, p.S889S; SRD5A2 gene was not found: A228V, L20P, R227Q, G203S mutation and P.C222Vfs225X. (5) 38 cases 46, XYDSDAR gene exon 1 CAG (n = 18-31), GGC (n = 13-18). The average number of GGC repeats was 16.74. (6) Exon 1 L89V and 281 + 15TC of SRD5A2 gene were found in both children and normal controls.
Conclusion: 1. AR gene should be the first choice for children with male hermaphroditism and hypospadias complicated with penis. 2. SRD5A2 gene mutation detection. 2. SRD5A2 gene C. 680GA, P. R227Q may be a hotspot mutation in Chinese population. 3. Genotype and clinical phenotype analysis still need to be further expanded sample analysis. 4. For AR gene two amino acid repeat sequence length. Whether androgen affects the activity of androgen receptor remains unclear.
The second part
Efficacy and safety of dihydrotestosterone gel in treatment of 23 cases of small penis in boys
Objective: To explore the efficacy and safety of dihydrotestosterone gel in the treatment of small penis in boys, and to provide a treatment plan for small penis.
METHODS: A prospective self-controlled study was conducted in the above-mentioned children with small penis who were raised as males. After informed consent, dihydrotestosterone gel (0.1-0.3 mg/kg/d) was applied locally for 3-6 months. Penile elongation was measured by Feldman method, testicular volume was measured by comparing testicular models, and bone age was measured by G-P bone age map. Blood routine, biochemical, sex hormone, serum dihydrotestosterone concentration were monitored before treatment (10 months), 1 month, 3 months and 6 months after treatment, and adverse reactions were observed.
Results: Twenty-three children were enrolled in the study. The average age of treatment was 4.07+3.4 years. Before treatment (October), the penile length of 23 children was 1.68+0.6 cm, the change of PL standard deviation value (SDS) was - 1.13+0.47 cm; during January, 22 patients were followed up, and the penile length was 2.2+0.66 cm, Delta PL-SDS was - 0.54+0.53 cm. Compared with the penile length in October and January, the change of PL-SDS was - 0.0031, P = 0.0031, P = 0.0031. There was statistical significance; 19 patients were followed up in March, the penis length was 2.53 + 0.58 cm, Delta PL-SDS was - 0.28 + 0.75 cm; in October and March, the penis length was p0.001, there was significant statistical significance. The average length of penis increased by 0.58 cm at month, 1.02 cm at month 3 and 1.5 cm at month 6. Blood routine, sex hormone, height and weight had no statistical significance (P 0.05), and bone age had no statistical significance (P 0.05) before and after treatment.
CONCLUSION: 1. Dihydrotestosterone gel can effectively promote penile growth in local application. 2. It has local skin pigmentation without obvious systemic adverse reactions.
【学位授予单位】：复旦大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R725.8
本文编号：2229271
[Abstract]:Part one
Mutation analysis of AR and SRD5A2 gene in 38 cases of 46 and XY sexual dysplasia
Objective: to analyze the correlation between 46, XY sex development abnormality and AR and SRD5A2 gene mutation.
Methods: DNA was extracted from peripheral venous blood of 38 children with XY sexual dysplasia from 2011.1 to 2013.1. After amplifying the target gene by PCR, Sanger sequencing method was used for sequencing. Healthy adults with fertility were used as controls.
Results: (1) Among 38 children with XYDSD, 16 (42.1%) had gene mutations, including hypospadias with penis (31.6%) and female vulva (7.9%). A new mutation was found in exon 7 (p.Q557R), 7 (18.4%) cases, 2 (p.Q557R) from the same family, 2 (p.R856H, p.R841L) in exon 7, and 2 (p.A871V, p.V890M) in exon 8 from different kinship. There was also a neutral mutation in exon 8 p.S889S; (3) SRD5A2 gene mutation in 11 cases (28.9%), a frameshift mutation in 1 case (P.C222Vfs225X), a compound mutation in 4 cases (3 cases p.G203S/p.R227Q, 1 case p.R227Q/p.A228V), a single missense mutation in 4 cases (p.R227Q, 1 case p.A228V, 1 case p.L20P). 27Q/p.A228V was not reported. (4) No AR gene was found in 50 normal controls: Q557R, R856H, R841L, A871V, V890M, p.S889S; SRD5A2 gene was not found: A228V, L20P, R227Q, G203S mutation and P.C222Vfs225X. (5) 38 cases 46, XYDSDAR gene exon 1 CAG (n = 18-31), GGC (n = 13-18). The average number of GGC repeats was 16.74. (6) Exon 1 L89V and 281 + 15TC of SRD5A2 gene were found in both children and normal controls.
Conclusion: 1. AR gene should be the first choice for children with male hermaphroditism and hypospadias complicated with penis. 2. SRD5A2 gene mutation detection. 2. SRD5A2 gene C. 680GA, P. R227Q may be a hotspot mutation in Chinese population. 3. Genotype and clinical phenotype analysis still need to be further expanded sample analysis. 4. For AR gene two amino acid repeat sequence length. Whether androgen affects the activity of androgen receptor remains unclear.
The second part
Efficacy and safety of dihydrotestosterone gel in treatment of 23 cases of small penis in boys
Objective: To explore the efficacy and safety of dihydrotestosterone gel in the treatment of small penis in boys, and to provide a treatment plan for small penis.
METHODS: A prospective self-controlled study was conducted in the above-mentioned children with small penis who were raised as males. After informed consent, dihydrotestosterone gel (0.1-0.3 mg/kg/d) was applied locally for 3-6 months. Penile elongation was measured by Feldman method, testicular volume was measured by comparing testicular models, and bone age was measured by G-P bone age map. Blood routine, biochemical, sex hormone, serum dihydrotestosterone concentration were monitored before treatment (10 months), 1 month, 3 months and 6 months after treatment, and adverse reactions were observed.
Results: Twenty-three children were enrolled in the study. The average age of treatment was 4.07+3.4 years. Before treatment (October), the penile length of 23 children was 1.68+0.6 cm, the change of PL standard deviation value (SDS) was - 1.13+0.47 cm; during January, 22 patients were followed up, and the penile length was 2.2+0.66 cm, Delta PL-SDS was - 0.54+0.53 cm. Compared with the penile length in October and January, the change of PL-SDS was - 0.0031, P = 0.0031, P = 0.0031. There was statistical significance; 19 patients were followed up in March, the penis length was 2.53 + 0.58 cm, Delta PL-SDS was - 0.28 + 0.75 cm; in October and March, the penis length was p0.001, there was significant statistical significance. The average length of penis increased by 0.58 cm at month, 1.02 cm at month 3 and 1.5 cm at month 6. Blood routine, sex hormone, height and weight had no statistical significance (P 0.05), and bone age had no statistical significance (P 0.05) before and after treatment.
CONCLUSION: 1. Dihydrotestosterone gel can effectively promote penile growth in local application. 2. It has local skin pigmentation without obvious systemic adverse reactions.
【学位授予单位】：复旦大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R725.8
【参考文献】
相关期刊论文 前1条
1 佟明;金艳阳;李刚;刘四明;吉春冬;;睾酮5-α还原酶Ⅱ基因V89L多态性与前列腺癌预后关系的研究[J];中华男科学杂志;2010年11期
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