AR、SRD5A2基因突變與46,XY性腺發(fā)育不良相關(guān)性研究
發(fā)布時(shí)間：2018-09-07 20:00
【摘要】：第一部分 38例46,XY性發(fā)育異常AR、SRD5A2基因突變分析 目的：分析46,XY性發(fā)育異常與AR、SRD5A2基因突變相關(guān)性。 方法：自2011.1至2013.1共搜集我院38例46,XY性發(fā)育不良患兒,采外周靜脈血,提取DNA,利用PCR擴(kuò)增目的基因后,采用Sanger測(cè)序法進(jìn)行測(cè)序。對(duì)患兒AR、SRD5A2基因全編碼序列檢測(cè),應(yīng)用seqMan7.1、MutationSurveyor3.97軟件對(duì)上述測(cè)序結(jié)果進(jìn)行分析。以50例健康體檢有生育能力的成年男性做為對(duì)照。 結(jié)果：(1)、38例46,XYDSD患兒中,發(fā)現(xiàn)16例(占42.1%)存在基因突變,其中尿道下裂合并小陰莖占31.6%,女性外陰表現(xiàn)者(男性假兩性畸形)占7.9%。并發(fā)現(xiàn)兩例來自同一家系的患兒同時(shí)存在AR (p.Q557R)、SRD5A2(p.R227Q)基因突變。(2)、AR基因1-8外顯子發(fā)現(xiàn)6處點(diǎn)突變,發(fā)現(xiàn)一新發(fā)突變(p.Q557R)；突變病例7例(占18.4%),2例來自于同一家系在2號(hào)外顯子存在錯(cuò)義突變p.Q557R；2例不同血緣患兒在7號(hào)外顯子錯(cuò)義突變分別為p.R856H、p.R841L;2例不同血緣患兒在8號(hào)外顯子存在錯(cuò)義突變分別為：p.A871V、p.V890M;還有一例為位于8號(hào)外顯子中性突變p.S889S;(3)、SRD5A2基因突變病例為11例(占28.9%),1例為移碼突變P.C222Vfs225X,4例為復(fù)合型突變(3例p.G203S/p.R227Q,1例p.R227Q/p.A228V),6例單個(gè)錯(cuò)義突變4例為p.R227Q,1例為p.A228V,1例為p.L20P。其中RC222Vfs225X、復(fù)合突變p.R227Q/p.A228V未報(bào)道過。(4)50例正常對(duì)照測(cè)序分析未發(fā)現(xiàn)AR基因存在：Q557R、R856H、 R841L、A871V、V890M、p.S889S; SRD5A2基因未發(fā)現(xiàn)存在：A228V、L20P、 R227Q、G203S位點(diǎn)突變及P.C222Vfs225X。(5)38例46,XYDSDAR基因1號(hào)外顯子CAG(n=18-31),GGC(n=13-18);CAG平均重復(fù)數(shù)目為：23.13,GGC平均重復(fù)數(shù)目為：16.74。(6)SRD5A2基因1號(hào)外顯子L89V、281+15TC在患兒和正常對(duì)照組均存在。 結(jié)論：1.男性兩性畸形、尿道下裂合并小陰莖患兒應(yīng)首選AR基因、SRD5A2基因突變檢測(cè)。2.SRD5A2基因c.680GA,p.R227Q可能是中國人群的熱點(diǎn)突變。3.關(guān)于基因型與臨床表型的分析仍需進(jìn)一步擴(kuò)大樣本進(jìn)行分析。4.對(duì)于AR基因兩個(gè)氨基酸重復(fù)序列長(zhǎng)度是否影響雄激素受體活性仍不清楚。 第二部分 雙氫睪酮凝膠治療23例男童小陰莖療效及安全性分析 目的：探索性研究雙氫睪酮凝膠治療男童小陰莖治療療效與安全性分析,提供小陰莖治療方案。 方法：以前瞻性自身對(duì)照研究方法,對(duì)上述存在小陰莖撫養(yǎng)為男性的患兒,經(jīng)知情同意后,局部給予涂抹雙氫睪酮凝膠(0.1-0.3mg/kg/d),療程3-6月。用Feldman方法測(cè)量陰莖延伸長(zhǎng)度,睪丸模型子比較測(cè)量睪丸體積,G-P骨齡圖譜評(píng)測(cè)骨齡,監(jiān)測(cè)治療前(0月),治療后1月、3月、6月血常規(guī)、生化、性激素,并監(jiān)測(cè)血清雙氫睪酮濃度,觀察治療期間的不良反應(yīng)。 結(jié)果：23例患兒入選,用藥治療平均年齡：4.07+3.4歲。未治療前(0月)23例患兒陰莖長(zhǎng)度為：1.68±0.6cm,PL標(biāo)準(zhǔn)差分值(SDS)的變化(△PL-SDS)為-1.13±0.47cm；1月時(shí)22人隨訪,陰莖長(zhǎng)度為2.2±0.66cm,△PL-SDS為-0.54±0.53cm,0月與1月陰莖長(zhǎng)度相比,p=0.0031,有統(tǒng)計(jì)學(xué)意義；3月時(shí)19人隨訪,陰莖長(zhǎng)度為2.53±0.58cm,△PL-SDS為-0.28±0.75cm；0月與3月陰莖長(zhǎng)度相比,p0.001,有顯著統(tǒng)計(jì)學(xué)意義。6月時(shí)12人隨訪,陰莖長(zhǎng)度為3±0.7cm；△PL-SDS為0.24±0.52cm。0月與6月陰莖長(zhǎng)度相比,p0.001,有顯著統(tǒng)計(jì)學(xué)意義。治療1月時(shí)平均陰莖長(zhǎng)度增長(zhǎng)為：0.58cm,治療3月時(shí)陰莖長(zhǎng)度增長(zhǎng)為：1.02cm,治療6月時(shí)陰莖長(zhǎng)度增長(zhǎng)為：1.5cm。目前結(jié)束用藥18例,(66.7%)12/18例PL達(dá)標(biāo)(2.5s)給予停藥,2/18例可完善手術(shù),4/18改善撒尿姿勢(shì),2/18例未達(dá)標(biāo)。治療后1月、3月、6月血肝腎功能、血常規(guī)、性激素、身高、體重較用藥前無統(tǒng)計(jì)學(xué)意義(P0.05),治療前后骨齡無統(tǒng)計(jì)學(xué)意義(P0.05)。用藥后監(jiān)測(cè)血清雙氫睪酮濃度維持于TunerⅡ-Ⅲ水平。20例患兒用藥局部皮膚顏色變暗。 結(jié)論：1、雙氫睪酮凝膠局部應(yīng)用治療小陰莖,有效促進(jìn)陰莖生長(zhǎng)。2、有局部皮膚色素沉著,無明顯全身不良反應(yīng)。
[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.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2013
【分類號(hào)】：R725.8
本文編號(hào)：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.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2013
【分類號(hào)】：R725.8
【參考文獻(xiàn)】
相關(guān)期刊論文 前1條
1 佟明;金艷陽;李剛;劉四明;吉春冬;;睪酮5-α還原酶Ⅱ基因V89L多態(tài)性與前列腺癌預(yù)后關(guān)系的研究[J];中華男科學(xué)雜志;2010年11期
，本文編號(hào)：2229271
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