【摘要】：目的:結(jié)節(jié)性硬化癥(Tuberous sclerosis complex TSC )是單基因常染色體顯性遺傳病,發(fā)病機(jī)制是基因缺陷導(dǎo)致mTOR信號(hào)通路過度活化,雷帕霉素靶蛋白(mTOR )通路在衰老過程中起重要作用,抑制mTOR通路可以改善與年齡有關(guān)的疾病如:認(rèn)知能力下降、癌癥、老年癡呆癥、腎和心臟疾病等。雷帕霉素(Rapamycin)能特異性抑制mTOR信號(hào)通路,是延緩衰老和治療衰老相關(guān)疾病的潛在性藥物,同時(shí)也是結(jié)節(jié)性硬化癥(Tuberous sclerosis complex TSC)的分子靶向治療藥物。對(duì)于雷帕霉素安全性的研究多集中在器官移植及癌癥患者中,本研究主要通過回顧性調(diào)查研究及觀察性研究,對(duì)TSC兒童體格發(fā)育狀態(tài)進(jìn)行調(diào)查,以及對(duì)長(zhǎng)期服用雷帕霉素治療的TSC兒童與健康兒童的體格發(fā)育情況、TSC兒童服藥前后生化指標(biāo)、血常規(guī)及藥物副反應(yīng)進(jìn)行比較,從而評(píng)價(jià)雷帕霉素的療效、安全性及對(duì)兒童體格發(fā)育的影響。第一部分結(jié)節(jié)性硬化癥兒童體格發(fā)育狀態(tài)調(diào)查方法:收集2012年10月-2016年10月在我院兒科門診確診為結(jié)節(jié)性硬化癥未服用雷帕霉素的學(xué)齡前期患兒體格發(fā)育(身高、體重)的情況行回顧性調(diào)查研究。所收集的體格生長(zhǎng)指標(biāo):身高、體重、體塊指數(shù)與國(guó)家衛(wèi)計(jì)委網(wǎng)站發(fā)表的《中國(guó)7歲以下兒童生長(zhǎng)發(fā)育參照標(biāo)準(zhǔn)》進(jìn)行比較,從而了解TSC患兒體格生長(zhǎng)情況。結(jié)果:入組295例學(xué)齡前期TSC兒童,嬰幼兒占研究人群的74.24%。在研究的病例中癲癇發(fā)生率為89.83%,顱內(nèi)病變者(皮層鈣化+室管膜下結(jié)節(jié)+ SEGA)占72.88%,智力障礙者占72.54%,心臟橫紋肌瘤的發(fā)生率占13.9%,腎臟錯(cuò)構(gòu)瘤發(fā)生率為7.46%。在入組的患兒中身高在正常范圍的占91.86%,身高高于同年齡同性別正常兒童X+2SD的占4.75%,低于同年齡同性別正常兒童X-2SD的占3.39%。體重在正常范圍的占94.24%,體重高于同年齡同性別正常兒童X+2SD的占5.7% (男童體重高于X+2SD的占5.41%,女童體重高于X+2SD的占5.04%),年齡大于3歲10人,小于3歲的7人。無體重低于同年齡同性別正常兒童X-2SD的患兒。BMI在正常范圍的占83.39%,高于X+2SD的患兒占14.24% (男童10.9%,女童17.99%),低于X-2SD的占2.37%。在合并腎臟病變的患兒中BMI高于正常的比例是31.03%。結(jié)論:在我們研究的七歲以下TSC患兒中癲癇的發(fā)生率稍高于文獻(xiàn)報(bào)道,顱內(nèi)病變及智力障礙者明顯高于文獻(xiàn)報(bào)道,腎臟錯(cuò)構(gòu)瘤的發(fā)生率明顯低于文獻(xiàn)報(bào)道�；純荷砀呱L(zhǎng)與同年齡同性別正常兒童大致相同。體重生長(zhǎng)與同年齡同性別兒童大致正常,BMI高于正常的TSC患兒較正常同齡兒偏高,且女童比例高于男童。在TSC合并癲癇、心臟病變、顱內(nèi)病變的患兒中其身高、體重、BMI分布無明顯差異,但合并腎臟病變的患兒中BMI高于正常的比例偏高。第二部分雷帕霉素治療后的療效、安全性及對(duì)其體格發(fā)育的影響研究方法:本研究是回顧性的開放性臨床試驗(yàn)。病例來自2014年9月到2016年12月在我院門診就診的結(jié)節(jié)性硬化癥兒童,根據(jù)納入和排除標(biāo)準(zhǔn)納入病人,入組后給予雷帕霉素治療。測(cè)量用藥前身高、體重、生化、血常規(guī)及隨訪治療后1年、2年后患兒身高、體重、生化、血常規(guī)及藥物副反應(yīng)情況,分析雷帕霉素的療效、安全性及對(duì)其體格發(fā)育情況的影響。結(jié)果:我們?nèi)虢M的122名TSC兒童用藥前身高在正常范圍的110人,占總?cè)藬?shù)的90.16%,高于同年齡同性別正常兒童x+2SD的為9人,占總?cè)藬?shù)的7.38%,低于同性別童年齡正常兒童身高的均值x-2SD的3人,占總?cè)藬?shù)的2.46%。應(yīng)用雷帕霉素治療1年后,TSC兒童身高在正常范圍的115人,占總?cè)藬?shù)的94.26%,高于同年齡同性別正常兒童x+2SD的為7人,占總?cè)藬?shù)的5.74%,無低于x-2SD的患兒;體重評(píng)價(jià):TSC兒童用藥前體重在正常范圍的114人,占總?cè)藬?shù)的93.44%,高于同年齡同性別正常兒童x+2SD的為8人,占總?cè)藬?shù)的6.56%,無低于x-2SD的患兒。應(yīng)用雷帕霉素治療1年后,TSC兒童體重在正常范圍的116人,占總?cè)藬?shù)的95.08%,高于同年齡同性別正常兒童x+2SD的為6人,占總?cè)藬?shù)的4.92%,無低于x-2SD的患兒。身體勻稱度評(píng)價(jià):體塊指數(shù)(BMI) : TSC兒童用藥前BMI在正常范圍的99人,占總?cè)藬?shù)的81.15%,高于同年齡同性別正常兒童x+2SD的為21人,占總?cè)藬?shù)的17.21%,低于同年齡同性別正常兒童x-2SD的為2人,占總?cè)藬?shù)的1.64%。應(yīng)用雷帕霉素治療1年后,TSC兒童BMI在正常范圍的99人,占總?cè)藬?shù)的81.15%,高于同年齡同性別正常兒童x+2SD的為20人,占總?cè)藬?shù)的16.39%,低于同年齡同性別正常兒童x-2SD的為3人,占總?cè)藬?shù)的2.46%。生長(zhǎng)速率評(píng)價(jià):所有入組患兒身高年生長(zhǎng)速率在正常范圍的109人,占總?cè)藬?shù)的89.34%。22名TSC患兒用藥1、2年后自身前后對(duì)照年生長(zhǎng)速率比較:其中8人年生長(zhǎng)速率減慢,14人年生長(zhǎng)速率增加。應(yīng)用雷帕霉素治療過程中我們觀察到的藥物副作用主要有脂質(zhì)代謝異常:總膽固醇升高8人(5.46-6.95mmo/L),占6.56%,其中5人在治療3個(gè)月內(nèi)升高;低密度脂蛋白升高13人(3.47-4.5 mmo/L),占10.66%,其中有6人在治療3個(gè)月內(nèi)發(fā)現(xiàn)升高;高密度脂蛋白增高22人(1.61-2.4mmol/L),占18.03%,其中14人在治療半年后升高;甘油三脂增高1人(1.82mmol/L),占0.82%;其余副作用有:食欲減退(3.28%)、口腔潰瘍(5.74%)、肝功能異常(4.92%),均為1-2級(jí)副反應(yīng),均為一過性,給予對(duì)癥治療后可恢復(fù)正常。無血小板減少癥和中性粒細(xì)胞減少癥的發(fā)生、無血糖異常及腎功能損害。應(yīng)用雷帕霉素治療1年前后對(duì)療效進(jìn)行評(píng)價(jià)分析:癲癇、心臟橫紋肌瘤、心肌或腱索強(qiáng)回聲、色素脫失斑、鯊魚皮樣斑、腎臟多發(fā)結(jié)節(jié)治療前后的改變有統(tǒng)計(jì)學(xué)意義,余癥狀無統(tǒng)計(jì)學(xué)意義。結(jié)論:在TSC兒童中長(zhǎng)期應(yīng)用雷帕霉素可使患兒癲癇、心臟病變、色素脫失斑、鯊魚皮樣斑、腎臟多發(fā)結(jié)節(jié)的癥狀減輕,且對(duì)身高、體重、體塊指數(shù)、身高年增長(zhǎng)速率均無影響,無骨髓抑制、腎功能異常、血糖異常的發(fā)生。在我們的研究中發(fā)現(xiàn)應(yīng)用雷帕霉素治療后有脂質(zhì)代謝異常的副作用,其中主要以總膽固醇、低密度脂蛋白膽固醇、高密度脂蛋白膽固醇增高為主。在總膽固醇及低密度脂蛋白膽固醇升高的患兒中52.38%的患兒在治療早期即出現(xiàn)升高,隨著治療時(shí)間的延長(zhǎng)無累積效應(yīng)。63.64%應(yīng)雷帕霉素治療的TSC患兒高密度脂蛋白膽固醇升高發(fā)生在治療半年以上。其余的藥物副反應(yīng)多為一過性,對(duì)癥治療后可恢復(fù)正常,在嬰幼兒中有一過性肝功能損害,無持續(xù)肝功能損害的發(fā)生。在嬰幼兒中應(yīng)用雷帕霉素治療,需密切監(jiān)測(cè)肝功能、血脂及其他副作用的發(fā)生。
[Abstract]:Objective: Tuberous sclerosis complex TSC (TSC) is a monogenic autosomal dominant inherited disease. The pathogenesis of TSC is overactivation of mTOR signaling pathway caused by genetic defects. Rapamycin target protein (mTOR) pathway plays an important role in the aging process. Inhibiting the mTOR pathway can improve age-related diseases such as cognitive impairment. Rapamycin can specifically inhibit the mTOR signaling pathway. Rapamycin is a potential drug for delaying aging and treating aging-related diseases. It is also a molecular targeted drug for tuberculosis sclerosis complex TSC. Concentrated on organ transplantation and cancer patients, this study investigated the physical development of TSC children through retrospective and observational studies, as well as the physical development of TSC children and healthy children treated with rapamycin for a long time, biochemical indicators of TSC children before and after taking drugs, blood routine and side effects of drugs. To evaluate the efficacy, safety and impact of rapamycin on physical development in children. Part I: Investigation of physical development in children with tuberous sclerosis Methods: Physical development (height, weight) of preschool children with tuberous sclerosis diagnosed in our pediatric clinic from October 2012 to October 2016 was collected. Results: 295 preschool TSC children were enrolled and 74.24% of them were infants. The incidence of epilepsy was 89.83%. Intracranial lesions (cortical calcification + subependymal nodules + SEGA) accounted for 72.88%. Mental retardation accounted for 72.54%. Cardiac rhabdomyoma accounted for 13.9%. Renal hamartoma accounted for 7.46%. Among the children enrolled in the study, 91.86% were in the normal range and the height was higher than that of the same age and sex. Children with X+2SD accounted for 4.75%, 3.39% were lower than normal children of the same age. 94.24% were in normal weight, 5.7% were higher than normal children of the same age (5.41% were in boys'weight higher than X+2SD, 5.04% were in girls' weight higher than X+2SD), 10 were older than 3 years old, 7 were younger than 3 years old. The incidence of epilepsy was slightly higher in children under 7 years of age with TSC than in those under 7 years of age. It was reported that the incidence of renal hamartoma was significantly lower in children with intracranial lesions and mental retardation than in the literature. The height growth of the children was roughly the same as that of normal children of the same age and sex. There was no significant difference in height, weight and BMI distribution among children with TSC complicated with epilepsy, heart disease and intracranial lesions, but the proportion of children with renal lesions with BMI higher than normal was higher. Open clinical trial. The cases were from children with tuberculous sclerosis who were admitted to our outpatient clinic from September 2014 to December 2016. According to inclusion and exclusion criteria, the patients were treated with rapamycin. The height, weight, biochemistry, blood routine and follow-up were measured before treatment. The height, weight, biochemistry, blood routine and blood routine of the children were measured after 1 year and 2 years of treatment. The side effects of rapamycin were analyzed, and the effects of rapamycin on the efficacy, safety and physical development were analyzed. Results: Among the 122 TSC children, 110 (90.16%) were in normal height, 9 (7.38%) were higher than that of the normal children of the same age, and 9 (7.38%) were lower than that of the normal children of the same sex. One year after rapamycin treatment, 115 (94.26%) of the TSC children were in the normal range, 7 (5.74%) were higher than that of the same age and sex normal children (x+2SD), and no lower than that of the x-2SD children. 114, accounting for 93.44% of the total, 8, accounting for 6.56% of the total, were higher than normal children of the same age and sex x + 2SD, and none was lower than x-2SD. Body mass index (BMI): Before treatment, 99 children with TSC had BMI in the normal range, accounting for 81.15% of the total, 21 children with higher BMI than those with same age and normal sex, accounting for 17.21% of the total, and 2 children with lower BMI than those with same age and normal sex, accounting for 1.64% of the total. One year after treatment, 99 children with TSC had BMI in the normal range, accounting for 81.15% of the total, which was higher than 20 children of the same age with normal sex, accounting for 16.39% of the total, and 3 children of the same age with normal sex, accounting for 2.46% of the total. Comparing the annual growth rate of 22 children with TSC before and after 1 or 2 years of treatment, the annual growth rate of 8 children slowed down and that of 14 children increased. Five patients were elevated within 3 months of treatment, 13 patients (3.47-4.5 mmo/L) had elevated LDL, accounting for 10.66%. Six of them had elevated HDL, 22 (1.61-2.4 mmol/L) had elevated HDL, accounting for 18.03%. Fourteen of them had elevated HDL after half a year of treatment, one (1.82 mmol/L) had elevated triglycerides, accounting for 0.82%. The other side effects were: loss of appetite (1.61-2.4 mmol/L). 3.28%, oral ulcer (5.74%) and abnormal liver function (4.92%) were all grade 1-2 side effects, which were transient and could be recovered after symptomatic treatment. Myoma, myocardial or chordae tendineae strong echo, depigmentation plaque, shark skin-like plaque, renal multiple nodules before and after treatment had statistical significance, the remaining symptoms were not statistically significant. Conclusion: Long-term use of rapamycin in children with TSC can alleviate the symptoms of epilepsy, heart disease, depigmentation plaque, shark skin-like plaque, renal multiple nodules, and There was no effect on height, body weight, body mass index, annual growth rate of height, no bone marrow suppression, renal dysfunction, and abnormal blood glucose. In our study, we found that lipid metabolism was abnormal after rapamycin treatment, and the main side effects were total cholesterol, low density lipoprotein cholesterol and high density lipoprotein cholesterol. MAIN. Among the children with elevated total cholesterol and low density lipoprotein cholesterol, 52.38% had elevated HDL cholesterol at the early stage of treatment. There was no cumulative effect with the prolongation of treatment time. 63.64% of TSC patients treated with rapamycin had elevated HDL cholesterol more than half a year after treatment. After treatment, the symptoms can be restored to normal, and there is a transient liver function damage in infants, without the occurrence of persistent liver function damage.
【學(xué)位授予單位】：中國(guó)人民解放軍醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R725.9

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9 楊澤紅;張昌華;;貴州省侗族7歲以下兒童體格發(fā)育現(xiàn)狀[A];新世紀(jì)全國(guó)首屆小兒綜合研究學(xué)術(shù)會(huì)議論文匯編[C];2001年

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