【摘要】：目的1.分析垂體柄中斷綜合征(pituitary stalk interruption syndrome,PSIS)惑者臨床特征。2.分析PSIS患者垂體柄損傷程度對臨床特征及激素水平的影響。3.探討影響垂體生長發(fā)育的基因PROKR2、PROK2、HESX1、LHX3、LHX4、 OTX2、SOX3、PROP1、POU1F1外顯子突變與垂體柄中斷綜合征(PSIS)的相關(guān)性。4.探討PSIS患者與正常人PROKR2、HESX1、LHX3、LHX4、OTX2、SOX3、 PROP1基因改變頻數(shù)差異。方法1.回顧性分析我科2001年以來收治的114例PSIS患者的臨床特征、生化檢查、內(nèi)分泌實(shí)驗(yàn)、影像學(xué)特征。2.回顧性的分析了自2001年來我科收治的89例年齡大于14歲的男性PSIS患者的病歷資料,按照垂體MRI垂體柄缺失程度,將其分成垂體柄纖細(xì)組(n=17,Group1)和垂體柄中斷組(n=72, Group 2),比較兩組患者臨床癥狀及激素分泌水平等的差異。3.采用聚合酶鏈反應(yīng)和基因測序方法對59例PSIS患者基因組DNA之PROKR2、PROK2、HESX1、LHX3、LHX4、OTX2、SOX3、PROP1、POU1F1基因外顯子進(jìn)行測序分析。4.選取100例同種族的健康人做對照,對發(fā)現(xiàn)的7個基因12個外顯子改變處片段進(jìn)行測序,比較PSIS患者組與對照組間變異率的差異。結(jié)果1.114例患者,男女比例8.5:1,平均年齡21.1±6.1歲。其中臀先露占自然分娩出生的89.9%(89/99例),身材矮小率71.8%(89/114例),骨齡延遲6.13±5.14歲,第二性征普遍發(fā)育不良。生長激素缺乏、性腺功能低下、腎上腺功能低下、甲狀腺功能低下的比例分別是：100%、94%、84.2%、74.6%,高泌乳素血癥比例為28.1%。存在3種以上垂體激素異常的患者占92.1%(105/114例)。58例成年男性患者中,53例臀位生產(chǎn)患者與5例頭位生產(chǎn)患者比較,身高、陰莖牽長、睪丸容積、垂體前葉高度、興奮試驗(yàn)結(jié)果差異均無統(tǒng)計學(xué)意義(氏0.05)。2.(1)臨床特點(diǎn)比較：Group 1組的身高、陰莖牽長、睪丸容積、垂體高度等指標(biāo)均大于Group 2(P0.05)。臀位生產(chǎn)率、合并先天性畸形／疾病率兩組無統(tǒng)計學(xué)差異。(2)激素水平比較：Group1的GH峰值、ACTH峰值、LH峰值均大于Group 2(P0.05)。兩組TSH值無統(tǒng)計學(xué)差異。(3)垂體前葉高度Group 1大于Group2(P0.05)。3PROKR2單核苷酸改變6例,其中5例位于第2外顯子c.991GA,1例位于第2外顯子c.1057CT;HESX1單核苷酸改變1例,位于第1外顯子c.142AT;LHX3單核苷酸改變1例,位于第2外顯子c.806CT;LHX4單核苷酸改變62例次,其中10例次位于第1外顯子c.63TC,1例次位于第3外顯子c.450CT,51例次位于第6外顯子c.983AG:OTX2單核苷酸改變1例,位于第1外顯子c.1123TC;SOX3單核苷酸改變6例,其中4例位于第1外顯子c.157GA,2例位于c.1131GA;PROP1單核苷酸改變56例次,其中46側(cè)位于第1外顯子c.27TC,10例位于第3外顯子c.424GA：未發(fā)現(xiàn)PROK2、POU1F1基因外顯子改變。4.PSIS患者組與對照組PROKR2、HESX1、LHX3、LHX4、OTX2、SOX3、 PROP1基因外顯子改變頻數(shù)變異率差異均無統(tǒng)計學(xué)意義(P0.05)。結(jié)論1.中國的PSIS患者的臨床表現(xiàn)、癥狀、激素缺乏程度嚴(yán)重：出生方式不同的患者病情嚴(yán)重程度無顯著差異。2.垂體柄缺如的PSIS患者較垂體柄纖細(xì)者無論臨床表現(xiàn)、激素指標(biāo)以及腺垂體發(fā)育均更差。3.(1)暫不能確定PROKR2、HESX1、LHX3、LHX4、OTX2、SOX3、PROP1基因外顯子改變是否是引起PSIS的有意義突變。4.PSIS患者PROKR2、HESX1、LHX3、LHX4、OTX2、SOX3、PROP1基因12處外顯子改變頻數(shù)與正常人無差異。
[Abstract]:Objective 1. To analyze the clinical features of pituitary stalk interruption syndrome (PSIS). To analyze the effect of PSIS on the clinical features and hormone levels in patients with PSIS. The relationship between the mutation of PROKR2, PROK2, HESX1, LHX3, LHX4, OTX2, SOX3, PROP1, POU1F1 and PSIS was discussed. The frequency difference of PROKR2, HESX1, LHX3, LHX4, OTX2, SOX3 and PROP1 in patients with PSIS was studied. Method 1. The clinical characteristics, biochemical examination, endocrine and imaging features of 114 patients with PSIS in our hospital since 2001 were analyzed retrospectively. A retrospective analysis of the medical records of 89 male PSIS patients with an age of more than 14 years in our department since 2001 was retrospectively analyzed. According to the extent of the pituitary stalk of the pituitary, it was divided into the fine group of the pituitary stalk (n = 17, Group1) and the pituitary stalk interruption group (n = 72, Group 2). The differences of the clinical symptoms and the level of hormone secretion in the two groups were compared. The exons of PROKR2, PROK2, HESX1, LHX3, LHX4, OTX2, SOX3, PROP1 and POU1F1 were sequenced by polymerase chain reaction and gene sequencing. A control group of 100 healthy controls of the same race was selected, and 12 exons of the 7 genes were sequenced, and the variation of the variation rate between the PSIS group and the control group was compared. Results 1.114 patients, the ratio of male to female was 8.5:1, the mean age was 21.1 to 6.1 years. Among them, 89.9% (89/99), 71.8% (89/114), 6.13 and 5.14 years of age, and the second sign of generalized dysplasia. Growth hormone deficiency, hypogonadism, hypofunction of the adrenal gland and low thyroid function were 100%,94%, 84.2%, 74.6%, and the proportion of hyperprolactinemia was 28.1%, respectively. There were more than 3 patients with abnormal pituitary hormone (92.1%) (105/114). Of the 58 adult male patients,53 cases of hip-position production were compared with 5 patients with head-position production, and the height, length of the penis, the volume of the testis, the height of the anterior lobe and the height of the anterior lobe of the pituitary, and the difference of the results of the excitation test were not statistically significant (No. 0.05). (1) The characteristics of the group were: the height of Group 1, the length of the penis, the volume of the testis and the height of the pituitary were greater than that of Group 2 (P0.05). There was no statistical difference between the two groups. (2) The levels of GH, ACTH and LH in Group1 were higher than that of Group 2 (P0.05). There was no statistical difference between the two groups of TSH values. (3) The height Group 1 of the anterior pituitary was greater than that of Group2 (P0.05).3 PROKR2 single-nucleonic acid was changed in 6 cases,5 of which were located in the second exon c.991 GA, one in the second exon c.1057 CT, and one case of the HESX1 single-nucleonic acid, which was located at the second exon c. 806CT; Of the 62 cases of LHX4,10 of them were located in the first exon c. 63TC, one in the third exon c.450 CT, and 51 in the 6th exon c.983 AG: OTX2 single-nucleonic acid change in 1 case, located in the first exon c.1123 TC, and the SOX3 single-nucleonic acid was changed in 6 cases. Of these,4 were located in exon 1, c. 157GA,2 in c.1131 GA, and 56 in proP1, which were located in exon 1, c. 27TC and 10 in exon 3, c. 424GA: no PROK2, POU1F1 gene exon changes were found.4. PSIS patient group and control group PROKR2, HESX1, LHX3, LHX4, OTX2, SOX3, There was no significant difference in the frequency variation of the exon of PROP1 gene (P0.05). Conclusion 1. The clinical manifestations, symptoms and hormone deficiency of PSIS patients in China were serious: there was no significant difference in the severity of the patients with different birth methods. Compared with the pituitary stalk, the pituitary stalk in the PSIS patients with PSIS is worse regardless of the clinical manifestation, the hormone index and the development of the pituitary gland. (1) The change of exon of PROKR2, HESX1, LHX3, LHX4, OTX2, SOX3 and PROP1 in PROKR2, HESX1, LHX3, LHX4, OTX2, SOX3 and PROP1 could not be determined.
【學(xué)位授予單位】：中國人民解放軍醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R584

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