垂体柄阻断综合征儿童及青少年的病因、诊疗与预后评估

发布时间：2018-06-14 22:41

本文选题：垂体柄阻断综合征 + 垂体转录因子　；参考：《山东大学》2014年博士论文

【摘要】：研究背景垂体柄阻断综合征(PSIS)是因垂体柄结构异常(如断裂缺失或明显变细)导致垂体功能减退的临床综合症候群,常伴有垂体前叶发育不良、垂体后叶异位或缺如等垂体结构异常,可导致一种或多种垂体激素缺乏。若同时有两种或以上垂体激素缺乏时称为多种垂体激素缺乏症(MPHD)。目前病因尚不明确,相关研究提示某些垂体发育相关转录因子发生基因变异可能导致PSIS的发生,如LHX4基因变异可直接导致神经结构异常,如垂体柄缺失,垂体后叶异位,垂体前叶发育不良,胼胝体损伤等；HESX1基因变异表现出类似视中隔发育不良症状并伴有垂体发育不良、垂体柄损伤；OTX2基因变异可表现为垂体结构异常伴或不伴眼部畸形。还有研究表明：基因变异多与近亲婚配相关,表现为垂体柄完整,垂体源性激素缺乏；而围产期的损伤,如胎位异常(如臀位或立位产、横位产)、缺氧缺血窒息、产伤等,则与垂体柄纤细/阻断、垂体后叶异位、下丘脑源性的激素缺乏密切相关。目前对该类疾病的诊断以依赖内分泌激素的检查及垂体核磁共振显示垂体柄结构异常为依据。但由于垂体结构及功能的特殊性及垂体相关内分泌激素与生长发育的密切相关性,不同垂体激素的缺乏可能发生在患者生长发育的各个时期。对于儿童及青少年时期发病的PSIS患者来说,如何及时发现不同年龄患者不同程度的垂体功能损伤,如何合理安排内分泌激素替代治疗的顺序,并结合患者年龄、疾病程度制定个体化治疗方案,保证正常生长及青春期发育,如何对预后进行预测评估仍有争议。特别是合并有促性腺激素缺乏的PSIS患者,性激素替代治疗的时机及对其他激素替代治疗的影响仍无定论。本研究拟通过系统回顾、对照分析等方法对临床确诊的72例PSIS儿童及青少年的不同病因、不同临床表现及治疗方案等进行统计分析,以期明确PSIS发生的主要病因,探讨个体化的激素替代治疗方案,并寻找可能影响或改善预后的因素。研究目的 1.通过对已确诊的PSIS儿童及青少年开展病史调查及垂体相关转录因子的基因变异检测,分析比较异常出生史、基因变异等致病因素导致PSIS发生的比例及特点。 2.将已确诊的PSIS儿童及青少年按照不同病因、垂体形态学指标、起始治疗年龄等指标分别分组,并对缺乏的垂体激素水平、替代治疗的药物剂量及治疗后受损的垂体激素恢复程度等指标进行跟踪随访及统计分析,探讨上述指标对患者临床表现、治疗方案的影响,为指导评估PSIS儿童及青少年患者的预后提供理论支持。研究方法研究对象选取：观察组(PSIS组)：2010年10月～2013年10月在山东省立医院儿科内分泌专业组就诊的72例PSIS患者,男65例,女7例。对照组：来山东省立医院门诊查体的4-24岁的正常儿童、青少年及成人共60例,男49例,女11例,年龄与性别比例与观察组无显著性差异。对上述研究对象进行以下研究分析： 1.确诊PSIS患者的病因分析：建立确诊PSIS患者的诊疗档案,记录PSIS患者出生史资料,统计胎位异常伴或不伴缺氧窒息史、胎位正常伴或不伴缺氧窒息史的发生率。同时筛查HESX1、LHX4、OTX2等垂体转录因子的基因。比较围产期因素、垂体基因变异因素导致PSIS发生的比例差异。 2.不同病因、不同垂体形态对PSIS患者临床表现型的影响： 2.1按照围产期损伤、垂体基因变异等病因不同分组,统计分析不同病因所致PSIS患者在垂体损伤程度、伴或不伴垂体外器官／结构发育异常、垂体激素缺乏种类及程度等临床表现方面的差异 2.2按照核磁共振显示垂体柄变细、断裂／缺失等形态学指标不同分组,统计其他垂体结构异常的发生率(包括垂体前叶发育不良,垂体后叶异位、分裂、缺失等)、垂体激素缺乏种类及程度等临床表现方面的差异,并对上述患者进行随访观察并以对照组激素水平为参照,分析激素替代治疗药物剂量及疗效的差异。 3.分析经激素替代治疗后已达终身高PSIS患者的疗效影响因素：选取入组后经激素替代治疗已随访至达终身高的PSIS患者,依据其是否达到正常同性别同年龄组正常身高／遗传靶身高分组,比较其致病因素、垂体形态学指标、激素替代治疗剂量及疗程等因素的差异,通过对比分析,得出可能影响PSIS患者预后的因素 4.合并有低促性腺激素性性发育不良(HH)的PSIS患者促性腺激素替代治疗方案探讨选取合并有HH的男性PSIS患者,分别按照垂体形态、开始促性腺激素替代治疗的年龄分组,分阶段给予促性腺激素替代治疗：绒促性素(HCG)准备期；HCG+尿促性素(HMG)联合治疗期。分别比较治疗前后,及不同治疗期垂体-性腺激素水平、第二性征发育水平,并与对照组比较,得出可能影响促性腺激素替代治疗疗效的因素,制定个体化促性腺激素替代治疗方案。研究结果 1.确诊PSIS患者的病因分析 72例PSIS患者中男65例,女7例,男性显著多于女性(p0.01)。其中有臀位产史(含足先露)者59例,头位难产有缺氧窒息史者4例,早产剖宫产1例,头位产且出生史无异常者6例,出生史不详2例。臀位产与头位产史之间存在显著性差异(P0.001)。 72例PSIS患者中合并有垂体外器官／结构异常者2例,1例合并视神经萎缩,1例合并透明隔缺如。共22例患者及直系亲属(含上述2例合并有垂体外器官／结构异常患者)行垂体发育相关转录因子HESX1、LHX4、OTX2基因变异筛查,仅有5例患者检测到LHX4基因的变异位点,但均未见致病性突变位点或大片段基因缺失。 2.不同病因、不同垂体形态对PSIS患者临床表现型的影响检测到LHX4基因变异的5例患者中,2例为垂体柄部分阻断,3例为垂体柄完全阻断,其中pPSIS2例患者中有1例患者合并有视神经萎缩。垂体的前叶高度、后叶异位发生率、垂体激素缺乏种类数与LHX4基因突变发生的位点之间无明显相关性。垂体区域核磁共振显示,垂体柄完全阻断组PSIS患者38例,垂体柄部分阻断组患者34例。其中垂体柄完全阻断组患者的垂体前叶高度明显缩小(P0.01),垂体后叶异位的发生率显著高于垂体柄部分阻断组(P0.01)。另外,垂体柄完全阻断组患儿生长激素轴、垂体-甲状腺轴、垂体-肾上腺轴激素水平均低于垂体柄部分阻断组、对照组(P均0.01)。但除IGF-1及FT4外(P0.01,0.05),垂体柄部分阻断组患儿的其他垂体-靶腺激素水平与对照组相比无显著差异。经相关激素替代治疗后,垂体柄完全阻断组及部分阻断组患者的垂体激素水平均可升至正常,与对照组无差异,但垂体柄完全阻断组合并促甲状腺激素缺乏患者的左旋甲状腺素钠剂量显著高于垂体柄部分阻断组(P0.05),合并促肾上腺皮质激素激素缺乏患者的氢化可的松剂量略高于垂体柄部分阻断组,但无统计学差异。 3.分析经激素替代治疗后已达终身高PSIS患者的疗效影响因素 PSIS患者中共有17例经激素替代治疗后达到终身高,其中达到正常同性别同年龄组正常身高/遗传靶身高者12例(女性1例)。达到终身高后的身高标准差积分(FH-SDS)与rhGH治疗总疗程呈显著正相关(P均0.05)；与开始治疗年龄(CA治疗前)、垂体激素缺乏种类数呈显著负相关(P均0.05),与垂体柄形态分类、垂体前叶高度、开始治疗时的骨龄等因素均无显著相关性。rhGH治疗的总疗程与治疗前遗传靶身高与实际身高的差距(distance to TH=SDS靶身高-SDS治疗前)呈显著正相关(P0.05)；达到终身高后的总身高获益(total height gain=SDS终身高-SDS治疗前)与CA治疗前(P0.05)、BA治疗前(P0.01)均呈显著负相关,与rhGH治疗的总疗程呈显著正相关(P0.001)。与同性别正常同龄人比较FH-SDS-1的达标组PSIS患者共6例,5例在10岁前开始治疗 4.合并有低促性腺激素性性发育不良(HH)的PSIS患者促性腺激素替代治疗方案探讨合并有低促性腺激素性性发育不良(HH)的男性PSIS患者共38例(年龄均大于14岁),按照垂体柄形态分组后发现与垂体柄部分阻断组相比,垂体柄完全阻断组患者的睾酮水平显著降低,余垂体-性腺激素水平无显著差异。按照开始促性腺激素替代治疗年龄分为2观察组：青少年组(14-18岁,共25例),成年组(18-24岁,共13例),并分别匹配同年龄段对照组。治疗前两观察组促性腺激素水平均无统计学差异,第二性征方面除阴茎长度外两观察组亦无显著差异,均落后于同年龄对照组。HCG单一治疗期,青少年组睾酮升高水平显著优于成年组(P0.01),青少年组治疗1月后睾酮水平可接近同年龄对照组,成年组接受HCG治疗3个月仍低于同年龄对照组(P0.01)。HCG+HMG联合治疗6月,青少年组睾酮水平已超过同年龄对照组(P0.01),成年组睾酮水平接近同年龄对照组。经过促性腺激素替代治疗后,两观察组患者睾丸体积、阴茎长度均较治疗前显著增加(P0.01),青少年组tanner分期、阴茎长度接近同年龄对照组,但两组PSIS患者睾丸体积仍落后于同年龄对照组。研究结论 1、导致PSIS发病的因素中,围产期损伤为主要因素,特别是臀位/站位产,基因突变多发生于头位产患儿。 2、下丘脑-垂体区核磁共振显示的垂体柄的受损程度及其他垂体结构异常与垂体分泌功能损伤相关,可用于评估PSIS患者垂体功能损伤程度。垂体柄完全断裂合并垂体后叶异位对多种垂体激素缺乏有预测价值。 3、PSIS患者接受激素替代治疗的疗效与开始治疗的年龄密切相关,特别是身高收益和性激素水平的改善,因此对于儿童及青少年时期发病的PSIS患者应及时诊断,早期干预。
[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 .
【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R725.8

【参考文献】