本文選題：垂體柄阻斷綜合征 + 垂體轉(zhuǎn)錄因子�。� 參考：《山東大學(xué)》2014年博士論文

【摘要】：研究背景 垂體柄阻斷綜合征(PSIS)是因垂體柄結(jié)構(gòu)異常(如斷裂缺失或明顯變細(xì))導(dǎo)致垂體功能減退的臨床綜合癥候群,常伴有垂體前葉發(fā)育不良、垂體后葉異位或缺如等垂體結(jié)構(gòu)異常,可導(dǎo)致一種或多種垂體激素缺乏。若同時(shí)有兩種或以上垂體激素缺乏時(shí)稱(chēng)為多種垂體激素缺乏癥(MPHD)。目前病因尚不明確,相關(guān)研究提示某些垂體發(fā)育相關(guān)轉(zhuǎn)錄因子發(fā)生基因變異可能導(dǎo)致PSIS的發(fā)生,如LHX4基因變異可直接導(dǎo)致神經(jīng)結(jié)構(gòu)異常,如垂體柄缺失,垂體后葉異位,垂體前葉發(fā)育不良,胼胝體損傷等；HESX1基因變異表現(xiàn)出類(lèi)似視中隔發(fā)育不良癥狀并伴有垂體發(fā)育不良、垂體柄損傷；OTX2基因變異可表現(xiàn)為垂體結(jié)構(gòu)異常伴或不伴眼部畸形。還有研究表明：基因變異多與近親婚配相關(guān),表現(xiàn)為垂體柄完整,垂體源性激素缺乏；而圍產(chǎn)期的損傷,如胎位異常(如臀位或立位產(chǎn)、橫位產(chǎn))、缺氧缺血窒息、產(chǎn)傷等,則與垂體柄纖細(xì)/阻斷、垂體后葉異位、下丘腦源性的激素缺乏密切相關(guān)。 目前對(duì)該類(lèi)疾病的診斷以依賴(lài)內(nèi)分泌激素的檢查及垂體核磁共振顯示垂體柄結(jié)構(gòu)異常為依據(jù)。但由于垂體結(jié)構(gòu)及功能的特殊性及垂體相關(guān)內(nèi)分泌激素與生長(zhǎng)發(fā)育的密切相關(guān)性,不同垂體激素的缺乏可能發(fā)生在患者生長(zhǎng)發(fā)育的各個(gè)時(shí)期。對(duì)于兒童及青少年時(shí)期發(fā)病的PSIS患者來(lái)說(shuō),如何及時(shí)發(fā)現(xiàn)不同年齡患者不同程度的垂體功能損傷,如何合理安排內(nèi)分泌激素替代治療的順序,并結(jié)合患者年齡、疾病程度制定個(gè)體化治療方案,保證正常生長(zhǎng)及青春期發(fā)育,如何對(duì)預(yù)后進(jìn)行預(yù)測(cè)評(píng)估仍有爭(zhēng)議。特別是合并有促性腺激素缺乏的PSIS患者,性激素替代治療的時(shí)機(jī)及對(duì)其他激素替代治療的影響仍無(wú)定論。 本研究擬通過(guò)系統(tǒng)回顧、對(duì)照分析等方法對(duì)臨床確診的72例PSIS兒童及青少年的不同病因、不同臨床表現(xiàn)及治療方案等進(jìn)行統(tǒng)計(jì)分析,以期明確PSIS發(fā)生的主要病因,探討個(gè)體化的激素替代治療方案,并尋找可能影響或改善預(yù)后的因素。 研究目的 1.通過(guò)對(duì)已確診的PSIS兒童及青少年開(kāi)展病史調(diào)查及垂體相關(guān)轉(zhuǎn)錄因子的基因變異檢測(cè),分析比較異常出生史、基因變異等致病因素導(dǎo)致PSIS發(fā)生的比例及特點(diǎn)。 2.將已確診的PSIS兒童及青少年按照不同病因、垂體形態(tài)學(xué)指標(biāo)、起始治療年齡等指標(biāo)分別分組,并對(duì)缺乏的垂體激素水平、替代治療的藥物劑量及治療后受損的垂體激素恢復(fù)程度等指標(biāo)進(jìn)行跟蹤隨訪(fǎng)及統(tǒng)計(jì)分析,探討上述指標(biāo)對(duì)患者臨床表現(xiàn)、治療方案的影響,為指導(dǎo)評(píng)估PSIS兒童及青少年患者的預(yù)后提供理論支持。研究方法 研究對(duì)象選取： 觀察組(PSIS組)：2010年10月～2013年10月在山東省立醫(yī)院兒科內(nèi)分泌專(zhuān)業(yè)組就診的72例PSIS患者,男65例,女7例。 對(duì)照組：來(lái)山東省立醫(yī)院門(mén)診查體的4-24歲的正常兒童、青少年及成人共60例,男49例,女11例,年齡與性別比例與觀察組無(wú)顯著性差異。 對(duì)上述研究對(duì)象進(jìn)行以下研究分析： 1.確診PSIS患者的病因分析： 建立確診PSIS患者的診療檔案,記錄PSIS患者出生史資料,統(tǒng)計(jì)胎位異常伴或不伴缺氧窒息史、胎位正常伴或不伴缺氧窒息史的發(fā)生率。同時(shí)篩查HESX1、LHX4、OTX2等垂體轉(zhuǎn)錄因子的基因。比較圍產(chǎn)期因素、垂體基因變異因素導(dǎo)致PSIS發(fā)生的比例差異。 2.不同病因、不同垂體形態(tài)對(duì)PSIS患者臨床表現(xiàn)型的影響： 2.1按照圍產(chǎn)期損傷、垂體基因變異等病因不同分組,統(tǒng)計(jì)分析不同病因所致PSIS患者在垂體損傷程度、伴或不伴垂體外器官／結(jié)構(gòu)發(fā)育異常、垂體激素缺乏種類(lèi)及程度等臨床表現(xiàn)方面的差異 2.2按照核磁共振顯示垂體柄變細(xì)、斷裂／缺失等形態(tài)學(xué)指標(biāo)不同分組,統(tǒng)計(jì)其他垂體結(jié)構(gòu)異常的發(fā)生率(包括垂體前葉發(fā)育不良,垂體后葉異位、分裂、缺失等)、垂體激素缺乏種類(lèi)及程度等臨床表現(xiàn)方面的差異,并對(duì)上述患者進(jìn)行隨訪(fǎng)觀察并以對(duì)照組激素水平為參照,分析激素替代治療藥物劑量及療效的差異。 3.分析經(jīng)激素替代治療后已達(dá)終身高PSIS患者的療效影響因素： 選取入組后經(jīng)激素替代治療已隨訪(fǎng)至達(dá)終身高的PSIS患者,依據(jù)其是否達(dá)到正常同性別同年齡組正常身高／遺傳靶身高分組,比較其致病因素、垂體形態(tài)學(xué)指標(biāo)、激素替代治療劑量及療程等因素的差異,通過(guò)對(duì)比分析,得出可能影響PSIS患者預(yù)后的因素 4.合并有低促性腺激素性性發(fā)育不良(HH)的PSIS患者促性腺激素替代治療方案探討 選取合并有HH的男性PSIS患者,分別按照垂體形態(tài)、開(kāi)始促性腺激素替代治療的年齡分組,分階段給予促性腺激素替代治療：絨促性素(HCG)準(zhǔn)備期；HCG+尿促性素(HMG)聯(lián)合治療期。分別比較治療前后,及不同治療期垂體-性腺激素水平、第二性征發(fā)育水平,并與對(duì)照組比較,得出可能影響促性腺激素替代治療療效的因素,制定個(gè)體化促性腺激素替代治療方案。 研究結(jié)果 1.確診PSIS患者的病因分析 72例PSIS患者中男65例,女7例,男性顯著多于女性(p0.01)。其中有臀位產(chǎn)史(含足先露)者59例,頭位難產(chǎn)有缺氧窒息史者4例,早產(chǎn)剖宮產(chǎn)1例,頭位產(chǎn)且出生史無(wú)異常者6例,出生史不詳2例。臀位產(chǎn)與頭位產(chǎn)史之間存在顯著性差異(P0.001)。 72例PSIS患者中合并有垂體外器官／結(jié)構(gòu)異常者2例,1例合并視神經(jīng)萎縮,1例合并透明隔缺如。共22例患者及直系親屬(含上述2例合并有垂體外器官／結(jié)構(gòu)異�；颊�)行垂體發(fā)育相關(guān)轉(zhuǎn)錄因子HESX1、LHX4、OTX2基因變異篩查,僅有5例患者檢測(cè)到LHX4基因的變異位點(diǎn),但均未見(jiàn)致病性突變位點(diǎn)或大片段基因缺失。 2.不同病因、不同垂體形態(tài)對(duì)PSIS患者臨床表現(xiàn)型的影響 檢測(cè)到LHX4基因變異的5例患者中,2例為垂體柄部分阻斷,3例為垂體柄完全阻斷,其中pPSIS2例患者中有1例患者合并有視神經(jīng)萎縮。垂體的前葉高度、后葉異位發(fā)生率、垂體激素缺乏種類(lèi)數(shù)與LHX4基因突變發(fā)生的位點(diǎn)之間無(wú)明顯相關(guān)性。 垂體區(qū)域核磁共振顯示,垂體柄完全阻斷組PSIS患者38例,垂體柄部分阻斷組患者34例。其中垂體柄完全阻斷組患者的垂體前葉高度明顯縮小(P0.01),垂體后葉異位的發(fā)生率顯著高于垂體柄部分阻斷組(P0.01)。另外,垂體柄完全阻斷組患兒生長(zhǎng)激素軸、垂體-甲狀腺軸、垂體-腎上腺軸激素水平均低于垂體柄部分阻斷組、對(duì)照組(P均0.01)。但除IGF-1及FT4外(P0.01,0.05),垂體柄部分阻斷組患兒的其他垂體-靶腺激素水平與對(duì)照組相比無(wú)顯著差異。 經(jīng)相關(guān)激素替代治療后,垂體柄完全阻斷組及部分阻斷組患者的垂體激素水平均可升至正常,與對(duì)照組無(wú)差異,但垂體柄完全阻斷組合并促甲狀腺激素缺乏患者的左旋甲狀腺素鈉劑量顯著高于垂體柄部分阻斷組(P0.05),合并促腎上腺皮質(zhì)激素激素缺乏患者的氫化可的松劑量略高于垂體柄部分阻斷組,但無(wú)統(tǒng)計(jì)學(xué)差異。 3.分析經(jīng)激素替代治療后已達(dá)終身高PSIS患者的療效影響因素 PSIS患者中共有17例經(jīng)激素替代治療后達(dá)到終身高,其中達(dá)到正常同性別同年齡組正常身高/遺傳靶身高者12例(女性1例)。達(dá)到終身高后的身高標(biāo)準(zhǔn)差積分(FH-SDS)與rhGH治療總療程呈顯著正相關(guān)(P均0.05)；與開(kāi)始治療年齡(CA治療前)、垂體激素缺乏種類(lèi)數(shù)呈顯著負(fù)相關(guān)(P均0.05),與垂體柄形態(tài)分類(lèi)、垂體前葉高度、開(kāi)始治療時(shí)的骨齡等因素均無(wú)顯著相關(guān)性。rhGH治療的總療程與治療前遺傳靶身高與實(shí)際身高的差距(distance to TH=SDS靶身高-SDS治療前)呈顯著正相關(guān)(P0.05)；達(dá)到終身高后的總身高獲益(total height gain=SDS終身高-SDS治療前)與CA治療前(P0.05)、BA治療前(P0.01)均呈顯著負(fù)相關(guān),與rhGH治療的總療程呈顯著正相關(guān)(P0.001)。與同性別正常同齡人比較FH-SDS-1的達(dá)標(biāo)組PSIS患者共6例,5例在10歲前開(kāi)始治療 4.合并有低促性腺激素性性發(fā)育不良(HH)的PSIS患者促性腺激素替代治療方案探討 合并有低促性腺激素性性發(fā)育不良(HH)的男性PSIS患者共38例(年齡均大于14歲),按照垂體柄形態(tài)分組后發(fā)現(xiàn)與垂體柄部分阻斷組相比,垂體柄完全阻斷組患者的睪酮水平顯著降低,余垂體-性腺激素水平無(wú)顯著差異。按照開(kāi)始促性腺激素替代治療年齡分為2觀察組：青少年組(14-18歲,共25例),成年組(18-24歲,共13例),并分別匹配同年齡段對(duì)照組。治療前兩觀察組促性腺激素水平均無(wú)統(tǒng)計(jì)學(xué)差異,第二性征方面除陰莖長(zhǎng)度外兩觀察組亦無(wú)顯著差異,均落后于同年齡對(duì)照組。HCG單一治療期,青少年組睪酮升高水平顯著優(yōu)于成年組(P0.01),青少年組治療1月后睪酮水平可接近同年齡對(duì)照組,成年組接受HCG治療3個(gè)月仍低于同年齡對(duì)照組(P0.01)。HCG+HMG聯(lián)合治療6月,青少年組睪酮水平已超過(guò)同年齡對(duì)照組(P0.01),成年組睪酮水平接近同年齡對(duì)照組。經(jīng)過(guò)促性腺激素替代治療后,兩觀察組患者睪丸體積、陰莖長(zhǎng)度均較治療前顯著增加(P0.01),青少年組tanner分期、陰莖長(zhǎng)度接近同年齡對(duì)照組,但兩組PSIS患者睪丸體積仍落后于同年齡對(duì)照組。 研究結(jié)論 1、導(dǎo)致PSIS發(fā)病的因素中,圍產(chǎn)期損傷為主要因素,特別是臀位/站位產(chǎn),基因突變多發(fā)生于頭位產(chǎn)患兒。 2、下丘腦-垂體區(qū)核磁共振顯示的垂體柄的受損程度及其他垂體結(jié)構(gòu)異常與垂體分泌功能損傷相關(guān),可用于評(píng)估PSIS患者垂體功能損傷程度。垂體柄完全斷裂合并垂體后葉異位對(duì)多種垂體激素缺乏有預(yù)測(cè)價(jià)值。 3、PSIS患者接受激素替代治療的療效與開(kāi)始治療的年齡密切相關(guān),特別是身高收益和性激素水平的改善,因此對(duì)于兒童及青少年時(shí)期發(fā)病的PSIS患者應(yīng)及時(shí)診斷,早期干預(yù)。
[Abstract]:Background of the study

The pituitary stalk blocking syndrome ( PSIS ) is a clinical comprehensive syndrome caused by abnormal pituitary stalk structure ( such as loss of fracture or obvious thinning ) , which is often accompanied by abnormal pituitary gland dysplasia , pituitary posterior leaflet ectopic or abnormal pituitary structure , which can lead to one or more pituitary hormones deficiency .
The HESX1 gene mutation showed similar symptoms of septal dysplasia with pituitary dysplasia and pituitary stalk injury .
The OTX2 gene mutation can be characterized by abnormal pituitary structure with or without eye deformity .
In the perinatal period , such as abnormal fetal position ( such as breech position or vertical position , lateral position ) , hypoxia ischemia asphyxia , and injury , it is closely related to the pituitary stalk ' s fine / blocking , posterior pituitary , hypothalamic source sex hormone deficiency .

The diagnosis of this kind of disease is based on the examination of endocrine hormone and the abnormal pituitary stalk structure . However , due to the particularity of the structure and function of the pituitary and the relation of pituitary - related endocrine hormone to the growth and development of pituitary stalk , the deficiency of different pituitary hormones may occur in various stages of the growth and development of the patient .

In order to clarify the main cause of PSIS , explore the main cause of PSIS , explore the individualized hormone replacement therapy , and find the factors which may influence or improve the prognosis .

Purpose of study

1 . Through the investigation of medical history and gene mutation detection of pituitary - related transcription factors in confirmed PSIS children and adolescents , the proportion and characteristics of PSIS caused by abnormal birth history and genetic variation were analyzed .

2 . The patients and adolescents diagnosed PSIS were grouped according to the indexes of different etiologies , pituitary morphological indexes and initial treatment age , and follow - up and statistical analysis were carried out on the deficiency of pituitary hormone level , the dosage of alternative therapy and the degree of recovery of pituitary hormone after treatment . The effects of these indexes on the clinical manifestation and treatment plan of patients were discussed , and the theoretical support was provided to guide the assessment of the prognosis of PSIS children and adolescents .

Study Object Selection :

Observation group ( PSIS group ) : From October 2010 to October 2013 , 72 patients with PSIS , 65 male and 7 female , were treated in the pediatric endocrine professional group of Shandong Provincial Hospital .

In the control group , there were 60 cases of normal children , adolescents and adults from 4 to 24 years old from the outpatient clinic of Shandong Provincial Hospital . There were 49 males and 11 females . There was no significant difference between age and sex ratio and observation group .

The following studies were conducted on the above study subjects :

1 . Etiological analysis of confirmed PSIS patients :

To establish the diagnosis and treatment records of PSIS patients , record the birth history data of PSIS patients , statistical fetal position abnormalities with or without the history of hypoxia asphyxia , fetal position normal with or without the incidence of hypoxic asphyxia . Meanwhile , the genes of pituitary transcription factors such as HESX1 , LHX4 and OTX2 were screened .

2 . Effects of different etiologies and forms on clinical manifestation of PSIS patients :

2.1 According to different subgroups of perinatal injury , pituitary gene mutation and so on , the differences of clinical manifestation of PSIS patients with different etiologies were analyzed , including the degree of pituitary injury , the abnormal pituitary organs / structure development , the type and degree of pituitary hormone deficiency and so on .

2.2 According to different groups of morphological indexes such as thinning , fracture / deletion of pituitary stalk , the incidence of other abnormal pituitary structure abnormalities ( including anterior pituitary dysplasia , posterior pituitary , division , deletion , etc . ) , pituitary hormones deficiency type and degree were analyzed , and the patients were followed up and observed with the control group hormone level , and the difference of the therapeutic effect of hormone replacement therapy was analyzed .

3 . Analysis of the effects of hormone replacement therapy on the efficacy of life - long PSIS patients :

Patients with PSIS who had been followed up for a long life were treated with hormone replacement therapy after enrollment . Based on whether they reached the height of normal height / genetic target in the same age group , the differences of pathogenic factors , pituitary morphological indexes , hormone replacement therapy dosage and treatment course were compared , and the factors which could affect the prognosis of PSIS patients were obtained by comparative analysis .

4 . Study on the Treatment of Gonadotropin in Patients with PSIS Combined with Low Gonadotropic Hypoplastic ( HH )

Male PSIS patients with HH were selected according to the pituitary morphology , the age group of gonadotrophin replacement therapy was started , and gonadotrophin replacement therapy was given in different stages : chorionic gonadotropin ( HCG ) preparation period ;
HCG + urotropin ( HMG ) combined treatment period . Compared with the control group , the factors that might affect the curative effect of gonadotrophin replacement therapy were compared with the control group .

Results of the study

1 . Etiological analysis of patients with confirmed PSIS

Among 72 patients with PSIS , there were 65 males and 7 females , there were significantly more males than females ( P 0.01 ) . Among them , there were 59 patients with breech delivery history ( including forefoot exposed ) , 4 premature cesarean section , 6 premature cesarean section , 6 premature cesarean section , and no abnormal birth history . There was a significant difference between breech delivery and head position history ( P0.001 ) .

In 72 patients with PSIS , there were 2 cases with pituitary external organs / structure abnormality , 1 case with optic atrophy and 1 case with clear septal defect . A total of 22 patients and immediate family members ( including 2 patients with pituitary external organs / structural abnormalities ) were screened for pituitary development related transcription factors HESX1 , LHX4 , OTX2 gene mutation , only 5 patients had detected the mutation sites of LHX4 gene , but none of them were found to be pathogenic mutation site or large fragment gene deletion .

2 . Effects of different etiologies and forms on clinical manifestation of PSIS patients

Of the 5 patients who detected the mutation of LHX4 gene , 2 cases were blocked by the pituitary stalk and 3 cases were completely blocked by the pituitary stalk . Among them , 1 patient had optic nerve atrophy in 1 patient . There was no significant correlation between the number of anterior lobe height and posterior leaflet ectopic incidence , the number of pituitary hormones and the locus of LHX4 gene mutation .

In addition , the pituitary - pituitary - thyroid axis and pituitary - adrenal axis hormone levels were significantly higher than those in the control group ( P0.01 ) . However , the pituitary - pituitary - thyroid axis and pituitary - adrenal axis hormone levels were significantly lower than those in the control group ( P0.01 ) , but the other pituitary - target gland hormone levels were not significantly different from those in the control group except for IGF - 1 and FT4 ( P0.01 , 0.05 ) .

After the hormone replacement therapy , the pituitary hormone levels in the complete block group and the partial occlusion group were higher than those in the control group ( P0.05 ) .

3 . Analysis of the factors influencing the efficacy of hormone replacement therapy in patients with PSIS

In patients with PSIS , there were 17 cases ( 1 case of female ) who reached the height of normal height / genetic target after hormone replacement therapy ( P < 0.05 ) .
There was a significant negative correlation between the number of pituitary hormones ( P < 0.05 ) , the morphology of pituitary stalk , the height of anterior pituitary , and the age of bone age at the beginning of treatment ( P0.05 ) .
The total height gain ( total height gain = SDS lifetime high - SDS treatment before treatment ) was significantly correlated with the treatment before CA ( P0.05 ) , before BA treatment ( P0.01 ) .

4 . Study on the Treatment of Gonadotropin in Patients with PSIS Combined with Low Gonadotropic Hypoplastic ( HH )

There were 38 cases of male PSIS patients with low gonadotropic hypogonadotropic dysplasia ( HH ) ( older than 14 years old ) . Compared with the control group , there was no significant difference in the levels of testosterone between the two groups ( P 0.01 ) . The levels of testosterone in the group of adolescents were significantly higher than those in the control group ( P0.01 ) .

Conclusions of the study

1 . Among the factors leading to the pathogenesis of PSIS , perinatal injury is the main factor , especially breech position / position , and the mutation of gene mutation occurs in the head position .

2 . The degree of damage of pituitary stalk and other pituitary structure abnormalities in the hypothalamus - pituitary region were correlated with the function of pituitary secretory function , which could be used to evaluate the degree of pituitary dysfunction in PSIS patients .

3 . The effect of hormone replacement therapy in patients with PSIS is closely related to the age of starting treatment , especially the improvement of height and sex hormone levels . Therefore , patients with PSIS should be diagnosed early and early intervention for children and adolescents .
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R725.8

【參考文獻(xiàn)】

相關(guān)期刊論文 前1條

1 潘琦偉;朱惠娟;龔鳳英;李乃適;張濤;白剛;潘慧;曾現(xiàn)偉;;兒童青少年垂體柄中斷綜合征的鞍區(qū)磁共振影像特征[J];中國(guó)醫(yī)學(xué)科學(xué)院學(xué)報(bào);2011年01期

，

本文編號(hào)：2019240