垂体柄中断综合征患者临床特征与基因分析

发布时间：2019-06-15 15:45

【摘要】：目的1.分析垂体柄中断综合征(pituitary stalk interruption syndrome,PSIS)惑者临床特征。2.分析PSIS患者垂体柄损伤程度对临床特征及激素水平的影响。3.探讨影响垂体生长发育的基因PROKR2、PROK2、HESX1、LHX3、LHX4、 OTX2、SOX3、PROP1、POU1F1外显子突变与垂体柄中断综合征(PSIS)的相关性。4.探讨PSIS患者与正常人PROKR2、HESX1、LHX3、LHX4、OTX2、SOX3、 PROP1基因改变频数差异。方法1.回顾性分析我科2001年以来收治的114例PSIS患者的临床特征、生化检查、内分泌实验、影像学特征。2.回顾性的分析了自2001年来我科收治的89例年龄大于14岁的男性PSIS患者的病历资料,按照垂体MRI垂体柄缺失程度,将其分成垂体柄纤细组(n=17,Group1)和垂体柄中断组(n=72, Group 2),比较两组患者临床症状及激素分泌水平等的差异。3.采用聚合酶链反应和基因测序方法对59例PSIS患者基因组DNA之PROKR2、PROK2、HESX1、LHX3、LHX4、OTX2、SOX3、PROP1、POU1F1基因外显子进行测序分析。4.选取100例同种族的健康人做对照,对发现的7个基因12个外显子改变处片段进行测序,比较PSIS患者组与对照组间变异率的差异。结果1.114例患者,男女比例8.5:1,平均年龄21.1±6.1岁。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),骨龄延迟6.13±5.14岁,第二性征普遍发育不良。生长激素缺乏、性腺功能低下、肾上腺功能低下、甲状腺功能低下的比例分别是：100%、94%、84.2%、74.6%,高泌乳素血症比例为28.1%。存在3种以上垂体激素异常的患者占92.1%(105/114例)。58例成年男性患者中,53例臀位生产患者与5例头位生产患者比较,身高、阴茎牵长、睾丸容积、垂体前叶高度、兴奋试验结果差异均无统计学意义(氏0.05)。2.(1)临床特点比较：Group 1组的身高、阴茎牵长、睾丸容积、垂体高度等指标均大于Group 2(P0.05)。臀位生产率、合并先天性畸形／疾病率两组无统计学差异。(2)激素水平比较：Group1的GH峰值、ACTH峰值、LH峰值均大于Group 2(P0.05)。两组TSH值无统计学差异。(3)垂体前叶高度Group 1大于Group2(P0.05)。3PROKR2单核苷酸改变6例,其中5例位于第2外显子c.991GA,1例位于第2外显子c.1057CT;HESX1单核苷酸改变1例,位于第1外显子c.142AT;LHX3单核苷酸改变1例,位于第2外显子c.806CT;LHX4单核苷酸改变62例次,其中10例次位于第1外显子c.63TC,1例次位于第3外显子c.450CT,51例次位于第6外显子c.983AG:OTX2单核苷酸改变1例,位于第1外显子c.1123TC;SOX3单核苷酸改变6例,其中4例位于第1外显子c.157GA,2例位于c.1131GA;PROP1单核苷酸改变56例次,其中46侧位于第1外显子c.27TC,10例位于第3外显子c.424GA：未发现PROK2、POU1F1基因外显子改变。4.PSIS患者组与对照组PROKR2、HESX1、LHX3、LHX4、OTX2、SOX3、 PROP1基因外显子改变频数变异率差异均无统计学意义(P0.05)。结论1.中国的PSIS患者的临床表现、症状、激素缺乏程度严重：出生方式不同的患者病情严重程度无显著差异。2.垂体柄缺如的PSIS患者较垂体柄纤细者无论临床表现、激素指标以及腺垂体发育均更差。3.(1)暂不能确定PROKR2、HESX1、LHX3、LHX4、OTX2、SOX3、PROP1基因外显子改变是否是引起PSIS的有意义突变。4.PSIS患者PROKR2、HESX1、LHX3、LHX4、OTX2、SOX3、PROP1基因12处外显子改变频数与正常人无差异。
[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.
【学位授予单位】：中国人民解放军医学院
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R584

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