本文關(guān)鍵詞：尿道下裂表型不一致的同卵雙胞胎的外顯子組測(cè)序研究及尿道下裂術(shù)后尿瘺的整形外科修復(fù)　出處：《北京協(xié)和醫(yī)學(xué)院》2017年博士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 尿道下裂 尿瘺 危險(xiǎn)因素 同卵雙胞胎 外顯子組測(cè)序

【摘要】：第一部分:尿道下裂表型不一致的同卵雙胞胎的外顯子組測(cè)序研究背景與目的尿道下裂是常見(jiàn)的泌尿生殖系統(tǒng)畸形之一,但大多數(shù)患者無(wú)法找到明確的病因。目前的研究提示多種環(huán)境及遺傳因素均與尿道下裂發(fā)病相關(guān),復(fù)雜多樣的致病機(jī)制為尿道下裂的病因?qū)W研究帶來(lái)困難。本中心收治了兩名尿道下裂患者,其各自的同卵雙胞胎兄弟泌尿生殖系統(tǒng)發(fā)育完全正常,導(dǎo)致兩者表型差異的可能原因之一是患者基因在受精卵分裂為兩個(gè)獨(dú)立胚胎后發(fā)生了突變。本研究通過(guò)應(yīng)用外顯子組測(cè)序技術(shù)對(duì)此假設(shè)進(jìn)行驗(yàn)證,以期為尿道下裂的分子遺傳致病機(jī)制研究提供線索。方法從兩對(duì)尿道下裂表型不一致的同卵雙胞胎的外周血提取DNA樣品,經(jīng)外顯子組測(cè)序后,通過(guò)嚴(yán)格的生物信息學(xué)篩選得出可疑的致病變異,并通過(guò)Sanger測(cè)序進(jìn)行驗(yàn)證。結(jié)果4個(gè)SNV和4個(gè)InDel通過(guò)篩選成為可疑變異,其中1個(gè)InDel為兩名患者所共有,但經(jīng)Sanger測(cè)序驗(yàn)證后均為陰性結(jié)果。結(jié)論本研究未能在外顯子組找到可能導(dǎo)致兩對(duì)同卵雙胞胎尿道下裂表型不一致的基因變異,表觀遺傳差異等其他的分子遺傳致病機(jī)制或可能為潛在的原因。第二部分:尿道下裂術(shù)后尿瘺的整形外科修復(fù)背景尿道皮膚瘺(簡(jiǎn)稱“尿瘺”)是尿道下裂術(shù)后最為常見(jiàn)的并發(fā)癥之一。尿瘺復(fù)雜的臨床表現(xiàn)為手術(shù)方法的選擇帶來(lái)困難,尿痿直徑、位置、個(gè)數(shù)及其他并發(fā)癥情況均可對(duì)手術(shù)方法的選擇產(chǎn)生影響,并可能成為影響手術(shù)結(jié)果的危險(xiǎn)因素。如何合理地根據(jù)各種臨床表現(xiàn)選擇修復(fù)方式是尿瘺治療的難點(diǎn),目前臨床上仍主要依賴手術(shù)醫(yī)師的個(gè)人經(jīng)驗(yàn)進(jìn)行判斷,既往相關(guān)研究在樣本量或研究方法上存在一定局限,亟待補(bǔ)充系統(tǒng)性的回顧及總結(jié)。第一節(jié)尿瘺的整形外科修復(fù)策略目的通過(guò)回顧本中心接診的尿道下裂術(shù)后尿瘺患者的相關(guān)臨床資料,總結(jié)本中心在選擇手術(shù)方法上的經(jīng)驗(yàn)及策略,并提出尿瘺手術(shù)路徑圖。方法回顧性分析2005年1月至2015年12月因尿道下裂術(shù)后尿瘺而接受手術(shù)修復(fù)的患者,統(tǒng)計(jì)包括患者年齡、初始尿道下裂類型、瘺口直徑、位置、個(gè)數(shù)、除尿瘺外其他并發(fā)癥的類型、所采取的手術(shù)方法及治療結(jié)果等多項(xiàng)參數(shù),通過(guò)手術(shù)路徑圖的方式對(duì)修復(fù)策略進(jìn)行總結(jié)。結(jié)果排除41名失訪患者后,共有232名患者納入研究。118例患者(50.9%)初始的尿道下裂類型為近端型,123例患者(53.0%)有至少一個(gè)直徑大于或等于2mm的瘺口,74例患者(31.9%)存在多個(gè)瘺口,98例患者(42.2%)除尿瘺外存在其他并發(fā)癥。177名患者(76.3%)在隨訪期間內(nèi)無(wú)尿道相關(guān)并發(fā)癥。結(jié)論處理尿道下裂術(shù)后尿瘺時(shí),應(yīng)綜合瘺口直徑、位置、個(gè)數(shù)、局部組織條件及合并并發(fā)癥類型后個(gè)性化地采用相應(yīng)的手術(shù)方式進(jìn)行修復(fù)。對(duì)于單純尿瘺的患者,無(wú)張力地關(guān)閉瘺口及應(yīng)用血運(yùn)良好的組織多層次地覆蓋是修復(fù)成功的關(guān)鍵。對(duì)于合并陰莖彎曲、尿道中段狹窄及近端異位尿道外口的病例,應(yīng)考慮分期重做尿道下裂的可能性。研究中提出的手術(shù)路徑圖可為尿瘺手術(shù)的規(guī)范化治療提供參考。第二節(jié)尿瘺修復(fù)術(shù)的危險(xiǎn)因素分析目的應(yīng)用合適的統(tǒng)計(jì)學(xué)分析方法對(duì)本中心接受尿瘺修復(fù)術(shù)的患者的臨床資料進(jìn)行回顧分析,探討影響尿瘺修復(fù)術(shù)成功率的潛在危險(xiǎn)因素。方法回顧性分析2005年1月至2015年12月因尿道下裂術(shù)后出現(xiàn)尿瘺而接受修復(fù)術(shù)的患者,以隨訪期內(nèi)無(wú)復(fù)瘺或其他尿道相關(guān)不良事件為手術(shù)成功的定義,統(tǒng)計(jì)分析患者年齡、瘺口直徑、瘺口位置、瘺口個(gè)數(shù)、尿瘺修復(fù)次數(shù)、是否合并其他并發(fā)癥及是否存在術(shù)后感染與尿瘺修復(fù)術(shù)成功率的關(guān)系。結(jié)果排除55例行分期手術(shù)重建尿道的患者及33例失訪患者后,共185例患者納入研究,147例患者(79.5%)手術(shù)取得成功。在單因素分析中,瘺口直徑(p=0.012)、尿瘺修復(fù)次數(shù)(p=0.008)與術(shù)后感染(p=0.044)與尿瘺修復(fù)術(shù)的成功率相關(guān)。多因素非條件Logistic回歸分析顯示,瘺口直徑(校正OR=2.42,p=0.030)與尿瘺修復(fù)次數(shù)(校正OR=3.09,p=0.008)是尿瘺修復(fù)術(shù)的兩個(gè)獨(dú)立危險(xiǎn)因素,進(jìn)一步的分析提示兩個(gè)危險(xiǎn)因素間不存在混雜、效應(yīng)修飾作用或交互作用。結(jié)論本研究提示,瘺口直徑和修復(fù)次數(shù)是尿瘺修復(fù)術(shù)的兩個(gè)獨(dú)立的危險(xiǎn)因素,當(dāng)瘺口直徑大于或等于2mm時(shí),手術(shù)失敗的風(fēng)險(xiǎn)相對(duì)提高了 2.42倍;當(dāng)患者多次接受尿瘺修復(fù)術(shù)時(shí),該風(fēng)險(xiǎn)提高了 3.09倍;但當(dāng)兩個(gè)危險(xiǎn)因素同時(shí)存在時(shí),該風(fēng)險(xiǎn)的上升并不顯著。臨床上在處理相關(guān)病例時(shí),應(yīng)更為謹(jǐn)慎并注意采取相應(yīng)的保護(hù)措施。
[Abstract]:The first part: identical twins hypospadias phenotype inconsistent genome sequencing research background and purpose of hypospadias deformity of the urogenital system is common, but most patients are unable to find a clear etiology. The present study suggests that many environmental and genetic factors were associated with hypospadias, difficult pathogenesis is complicated the etiology of hypospadias. We treated two patients with hypospadias, the identical twin of the genitourinary system development is completely normal, leading to both phenotypic differences can be one of the reasons is that patients with gene in zygote is divided into two independent embryos after mutation. In this study, through the application of explicit this sub group sequencing hypothesis verification, in order to provide clues for the study of molecular genetic pathogenesis of hypospadias. Methods from two for hypospadias Discordant monozygotic twins with peripheral blood samples of DNA isolated by exome sequencing, biological information through strict screening the suspicious pathogenic mutation, which was verified by Sanger sequencing. The results of 4 SNV and 4 InDel by screening become suspicious variation, of which 1 InDel two in total, but by Sanger after sequencing showed negative results. Conclusion this study failed to find exomes may lead to two pairs of monozygotic twins discordant for hypospadias genetic mutation, epigenetic differences and other molecular genetic pathogenesis or may be potential reasons. The second part: the urethra hypospadias fistula plastic surgery repair background urethrocutaneous fistula ("fistula") is after hypospadias surgery is one of the most common complications. Clinical manifestations of urinary fistula complicated difficult for the choice of surgical methods, urinary fistula The diameter, location, impact number and other complications can be the operation method choice, and may be the risk factors affecting the surgical results. How to reasonably according to various clinical manifestations of choice of repair of urinary fistula treatment is difficult, there are still mainly depends on the surgeon's personal experience through judgment, previous relevant research in the quantity of samples or research methods there are certain limitations, to supplement the review and summarization system. The first section of plastic surgery to repair strategy by reviewing the admissions center of urinary fistula after hypospadias repair of urinary fistula were related to clinical data, summarize the experience and strategy in the choice of surgical methods on the center, and put forward the operation path of urinary fistula figure. Methods a retrospective analysis from January 2005 to December 2015 because of urinary fistula after hypospadias underwent surgical repair of patients, including patients with early age statistics. Only the type of hypospadias, fistula diameter, location, number, type and other complications except for urinary fistula, a number of parameters to the surgical methods and results of treatment, to repair strategy summed up through the operation path graph. The results excluding the 41 patients lost to follow-up, a total of 232 patients were included in the study.118 patients (50.9%) the initial type of hypospadias were proximal type, 123 patients (53%) had at least one diameter greater than or equal to 2mm fistula, 74 patients (31.9%) there are multiple fistula, 98 patients (42.2%) in the presence of other fistula complications in.177 patients (76.3%) no urethral related complications during the follow-up period. Conclusion the treatment of postoperative urinary fistula, fistula diameter should be comprehensive, position, number, condition and complication of local tissue after using personalized type of surgical repair for simple urinary fistula patients, no one To close the fistula and the application of good blood supply organization multi-level coverage is the key to the successful repair. For patients with penile curvature, mid urethral stricture and proximal ectopic urethral orifice cases, should consider the possibility to redo the staging of hypospadias. Provide reference for the standardized treatment of surgical path for urinary fistula surgical repair of the second section. The risk factors of urinary fistula were retrospectively analyzed clinical data were analyzed using appropriate statistical analysis methods to the center for repair of urinary fistula, the potential risk factors of urinary fistula repair success rate. Methods: a retrospective analysis of patients from January 2005 to December 2015 due to urinary fistula occurred after hypospadias surgery received repair, in the follow-up period no other urethral fistula or related adverse event was the definition of success, statistical analysis of the age of patients, the diameter of the fistula, The location of fistula, fistula number, urinary fistula repair times, if combined with other complications and whether postoperative infection rate and urinary fistula repair. Results 55 cases excluded surgical staging of urethral reconstruction and 33 patients lost to follow-up patients, a total of 185 patients were included in the study, 147 patients (79.5%) surgery success. In univariate analysis, the fistula diameter (p=0.012), urinary fistula repair times (p=0.008) and postoperative infection (p=0.044) associated with urinary fistula repair success rate. Non conditional Logistic regression analysis showed that the diameter of fistula (adjusted OR=2.42, p=0.030) and OR=3.09 (the number of fistula repair correction. P=0.008) is the two independent risk factors of urinary fistula repair, further analysis showed that two risk factors do not exist between hybrid, modified the effect or interaction. Conclusion this study indicates that the diameter of fistula and urinary fistula repair repair times is two Independent risk factors, when the diameter is greater than or equal to 2mm, the relative risk of surgical failure is increased by 2.42 times; when the patient repeatedly accepted repair of urinary fistula, the risk increased by 3.09 times; but when the two risk factors existing at the same time, the increased risk is not significant. In the clinical treatment cases, should be more cautious and take corresponding measures to protect them.

【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R699.6

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2 滕志海;重組人表皮生長(zhǎng)因子凝膠在尿道下裂術(shù)后尿瘺中的應(yīng)用效果觀察[D];河北醫(yī)科大學(xué);2014年

3 阿布都熱扎克·木塔力甫;尿道下裂術(shù)后尿瘺兩種手術(shù)方法對(duì)比觀察（附43例）[D];新疆醫(yī)科大學(xué);2008年

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