垂体柄中断综合征的临床特点及病因学研究
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摘要
背景：
垂体柄中断综合征（Pituitary Stalk Interruption Syndrome, PSIS）是指垂体柄纤细或缺如导致下丘脑分泌的促激素释放激素不能通过垂体柄运送到垂体所致的一系列临床症候群。PSIS是内分泌系统的罕见疾病，国外及国内分别于1987年及2005年才首次报道该疾病。因此，对其临床特点的认识尚不充分，导致部分患者漏诊、误诊。PSIS的病因尚不明确。目前的研究认为基因突变可能是该病的原因。HESX1、LHX4、OTX2和SOX3基因被认为与该病的发生相关，是研究的热点。各种族之间遗传背景存在差异，中国尚无PSIS患者的病因学分析数据，中国人种HESX1、LHX4、OTX2和SOX3基因外显子区域变异情况是否有新的特点尚不明了。国外研究显示，PSIS患者HESX1、LHX4、OTX2和SOX3基因外显子区域突变率低，难以完全解释该疾病。已有部分个案报道发现PSIS患者存在拷贝数变异。拷贝数变异（Copy Number Variations, CNVs）是指与参考序列相比，基因组中≥1kb的DNA片段插入、缺失和/或扩增，及其互相组合衍生出的复杂染色体结构变异。CNVs于2004年首次被发现，是目前遗传学研究中的另一热点。拷贝数变异是否与PSIS的发病相关尚不明了，亟需较大规模的研究验证二者间的关系。研究证实仅有1.5%的核苷酸序列参与蛋白编码，基因上存在大量的非编码区域（UntranslatedRegions, UTRs）。这些UTRs在基因表达的调控中扮演了重要角色。已发现非编码区突变可致疾病的发生。HESX1及LHX4与垂体发育相关，存在致垂体柄中断综合征的可能性。已有报道在垂体柄中断综合征患者中检出了上述两基因外显子区域的异常，但仅有极低比例的患者合并上述异常。而HESX1及LHX4基因非编码区保守度较高，具备影响基因功能的条件，有可能是垂体柄中断综合征的病因。但目前尚无非编码区与垂体柄中断综合征间关系的研究。
目的：
总结PSIS患者的临床特点，明确中国PSIS患者中HESX1、LHX4、OTX2和SOX3基因外显子区域变异情况，明确拷贝数变异与PSIS间的关系，明确HESX1及LHX4基因非编码区异常与垂体柄中断综合征间的关系。为从临床特点及病因学两方面更深入、全面地认识该疾病，从而实现早诊断、早治疗，并进一步提供遗传学咨询、产前诊断、基因治疗提供基础数据。
方法：
1、回顾性分析58例PSIS患者及46例生长激素缺乏合并正常垂体柄（GrowthHormone Deficiency but A Normal Pituitary Stalk, NPS）患者的临床资料，包括近亲结婚、家族史、围产期事件、合并畸形情况、青春期发育情况、骨龄、人体测量学指标、激素基础及负荷后分泌情况、垂体MRI等。
2、运用PCR及自动测序技术对33例PSIS患者行HESX1、LHX4、OTX2及SOX3基因外显子测序分析。针对PSIS患者中变异率较高的LHX4基因外显子1及外显子6，选取200例同种族的健康对照行测序分析，比较两组间变异率的差异。运用SIFT和polyphen-2软件对HESX1基因突变进行功能预测。
3、选取9例垂体柄中断综合征患者为研究对象。对其中的5例采用AffymetrixGenome-Wide Human Mapping SNP6.0Array芯片平台、4例采用Illumina HumanOmni5M芯片平台在全基因组范围内进行拷贝数检测。对检测出的可疑拷贝数变异区域采用qPCR方法进行验证。
4、选取36例留取了DNA标本的垂体柄中断综合征患者为研究对象。采用PCR及直接测序的方法对HESX1基因5’、3’非编码区及LHX4基因3’非编码区进行测序分析。
结果：
1、PSIS及NPS患者的性别比、近亲结婚率、家族史、围产期事件率（除臀位生产率外）、畸形率、人体测量学指标无显著性差异。两组患者的GH缺乏率均为100%，ACTH缺乏率分别为77.6%和23.9%，TSH缺乏率分别为43.1%和10.9%，LH/FSH缺乏率分别为94.2%和47.4%，多种垂体激素缺乏率分别为93.1%和41.3%。PSIS患者垂体前叶激素释放的储备功能更差。两组患者的垂体后叶功能均基本正常。PSIS患者垂体前叶萎缩、垂体柄异常、垂体后叶异位的比例分别为98.3%、100%和91.4%。NPS患者上述比例分别为54.3%、0和0。
2、在1例患者中检出1种新的HESX1基因杂合错义突变（c.142A>T,p.Thr48Ser）。HESX1蛋白变异位点T48高度保守，但并未位于eh1、HRPW和同源结构域这几个关键结构区域。SIFT软件对于HESX1基因突变的评分为0.76，属于―可耐受变异‖；polyphen-2软件的评分为0.001，属于―良性变异‖。分别在7、1、31例患者中检出3种LHX4基因杂合多态性（c.63T>C, p.Gly21Gly; c.450C>T,p.Asn150Asn; c.983A>G, p.Asn328Ser），其中c.63T>C, p.Gly21Gly及c.983A>G,p.Asn328Ser的发生率在PSIS患者及正常对照组中无显著性差异。在1例患者中检出1种新的SOX3基因半合子多态性(c.157G>C, p.Val53Leu)。所有的患者中均未检出OTX2基因外显子区域异常。
3、 Xq21.31-Xq21.32区域检出了较为集中的拷贝数扩增区。其中90,864,846-90,969,300区域的拷贝数变异为8例患者共有，为非常见拷贝数变异，位于PCDH11X基因上游，经鉴定为可疑目标区域。对其中的两个位点进行了qPCR检测，相对定量值均<1.3。考虑与该区域位于X及Y染色体的同源区段有关。
4、36例垂体柄中断综合征患者中未检出HESX1基因非编码区异常。2例患者检出LHX4基因3’非编码区杂合异常（c.26C>T）。该变异位点低度保守，并未位于K-Box（KB）及多腺苷酸化信号（Polyadenylation Signal, PAS）区域。
结论：
1、PSIS患者主要表现为不同程度的垂体前叶功能低下及垂体形态学异常。与NPS患者相比，PSIS患者的垂体前叶激素缺乏更重，垂体形态学异常比例更高。生长激素缺乏患者早期垂体MRI检查明确垂体柄情况具有重要意义。
2、中国PSIS患者中各检出HESX1及SOX3基因外显子区域一种新的变异形式。中国PSIS患者HESX1、LHX4、OTX2及SOX3基因外显子的突变率低。PSIS的病因仍有待进一步探索。
3、垂体柄中断综合征病因复杂。拷贝数变异与垂体柄中断综合征关系的研究仍任重道远。
4、暂未发现HESX1及LHX4基因非编码区变异与垂体柄中断综合征相关。可能有其它因素参与了垂体柄中断综合征的发病。
Background:
Pituitary stalk interruption syndrome (PSIS) is characterized by a thin or absentpituitary stalk, leading to the obstruction of the transport of the hormones secreted bythe hypothalamus to the pituitary, and subsequently resulting in a cluster ofmanifestations. PSIS is a rare disease, and it was firstly reported in1987and2005in theforeign country and in China respectively. So the recognition of the disease wasinsufficient, resulting in missed diagnosis and misdiagnosis. To date, a goodunderstanding of the pathogenesis of PSIS remains elusive. Recent studies have focusedon genetic mutations in PSIS, especially in those genes involved in pituitarydevelopment and growth hormone secretion. HESX1, LHX4, OTX2and SOX3wereconsidered as the candidate genes and were the research hotspot. The geneticbackground was different between ethnic groups, and there was no genetic analysis inChinese PSIS patients. As a result, the characteristic of variations in the exons ofHESX1, LHX4, OTX2and SOX3in Chinese PSIS patients was not clear. It is reportedthat the mutation rates in the exons of HESX1, LHX4, OTX2and SOX3were low inPSIS, so these gene mutations can hardly be the cause. Some case reports have foundcopy number variations(CNVs) in PSIS patients, suggesting CNVs may be the cause.Copy number variations is defined as a DNA segment that is1kb or larger and presentat variable copy number in comparison with a reference genome, including insertion,microdeletion or microduplication, and complex structural variations of the genomicregion deriving from the combination of the disorders mentioned above. CNVs wasfirstly reported in2004, and now it is a hotspot in genetic research. It is not determinedwhether there are some associations between CNVs and PSIS, and large sample studiesare needed. It is confirmed that only a small fraction(about1.5%) of the genetic material codes for protein, and the rest fraction are untrsanslated regions(UTRs), which playimportant roles in the regulation of gene expression. Mutations in the UTRs are thecause of certain diseases. HESX1and LHX4are the key genes in the development ofpituitary, and it has been confirmed in studies in PSIS patients that HESX1and LHX4variations can cause pituitary stalk interruption syndrome. However, mutations can befound only in a small fractions of PSIS patients in the exons of HESX1and LHX4. TheUTRs of HESX1and LHX4are highly conserved and mutations in this regions canpossibly be associated with PSIS. Until now, there is no report on the relationshipbetweeen UTRs and pitutitary stalk interruption syndrome.
Objectives:
We characterized the clinical features of PSIS, detected the variations in exons ofHESX1, LHX4, OTX2and SOX3in Chinese PSIS patients, explored the relationshipbetween copy number variations and pituitary stalk interruption syndrome, anddetermined the associations of variations in the untranslated regions of HESX1andLHX4and the disease, with the hope that a better and more comprehensive recognitionof pituitary stalk interruption syndrome can be got, and subsequently earlier diagnosisand treatment can be achieved, and meanwhile fundamental data of genetic consultation,prenatal diagnosis and genetic therapy can be obtained.
Methods:
1. Clinical data of58patients with PSIS and46patients with GH deficiency but anormal pituitary stalk (NPS) were retrospectively analysed, including consanguineousparents, family history, perinatal history, associated malformations, pubertal status, boneage, anthropometry measurements, basal and peak hormone levels and pituitary MRIs.
2. HESX1, LHX4, OTX2and SOX3polymorphisms were screened in33PSISpatients by PCR and direct sequence analysis. Exon1and6of LHX4, the most variablesites of PSIS patients, were also screened in200normal, healthy, ethnically-matchedcontrols. To predict the protein function affected by an amino acid substitution inHESX1, we performed in silico analysis using SIFT and polyphen-2web software.
3.9patients with pituitary stalk interruption syndrome were studied. Copy number variations were detected by Affymetrix Genome-Wide Human Mapping SNP6.0Arrayin5patients and Illumina Human Omni5M Arrays in the other4patients. QuantitativeRT-PCR (qPCR) was used to verify the microarray results.
4.36patients with pituitary stalk interruption syndrome whose DNA werepreserved were chose as the objectives. PCR and direct sequencing analysis wereperformed to detect the5’ and3’ untranslated regions of HESX1and the3’ untranslatedregion of LHX4.
Results:
1. Both PSIS and NPS patients were similar in terms of gender ratio,consanguineous parents, familial history, perinatal events (except for breechpresentation), malformation, and anthropometry measurements. Deficiency of GH was100%in both PSIS and NPS groups. Other deficiency rates for PSIS and NPS groupswere: ACTH,77.6%and23.9%; TSH,43.1%and10.9%; LH/FSH,94.2%and47.4%;and combined pituitary hormone,93.1%and41.3%, respectively. GH, ACTH, and LHlevels increased after pharmacological stimulation in NPS patients, but not in PSISpatients. In PSIS and NPS patients, the percentages of anterior pituitary hypoplasia were98.3%and54.3%, pituitary stalk abnormality were100%and0%, and ectopicneurohypophysis were91.4%and0%.
2. A novel heterozygous sequence variant (c.142A>T, p.Thr48Ser) was found inHESX1in one PSIS patient. T48in the amino acid sequence encoded by HESX1is ahighly conserved residue. However, it was not located in eh1, HRPW or homeodomain,specific domains of HESX1protein. The score obtained for the new substitution(p.Thr48Ser in HESX1) from SIFT software was0.76, which placed the rare sequencevariant in the―tolerant‖class. By applying polyphen-2software, this rare sequencevariant was predicted to be benign with a score of0.001.3polymorphisms (c.63T>C,p.Gly21Gly; c.450C>T, p.Asn150Asn; and c.983A>G, p.Asn328Ser) were detected inLHX4in7,1, and31PSIS patients, respectively. c.63T>C, p.Gly21Gly and c.983A>G,p.Asn328Ser were also found in the control, with almost the same variation rates asPSIS patients. We also found a novel hemizygous polymorphism (c.157G>C, p.Val53Leu) in SOX3in one PSIS patient. No OTX2abnormality was detected in PSISpatients.
3. Intensive copy number variation regions were detected in Xq21.31-Xq21.32.The90,864,846-90,969,300region, located at the upstream of the PCDH11X gene, wasfound to have copy number gain in8patients, which was not a common copy numbervariation, and was identified as the object region. The relative copy numbers of the twosites in the region tested by qPCR were all below1.3. The cause of the inconsistentresults may be that the region was located in a major X/Y block of homology.
4. No variation was detected in the5’ and3’ untranslated regions of HESX1in the36patients.2patients suffered from a variation in the3’ untranslated region of LHX4（c.26C>T）. The altered locus was not highly conserved, and was not located in theK-Box or polyadenylation signal regions.
Conclusions:
1. PSIS patients often exhibited different degrees of anterior pituitary hormonedeficiencies and pituitary morphology abnormalities. Compared with NPS, PSISpatients had more severe basal anterior pituitary hormone deficiency, lower anteriorpituitary hormone secretion potential, and higher probability of abnormal pituitarymorphology. An earlier performance of pituitary MRI to determine the status of thepituitary stalk in patients with growth hormone deficiency is of great importance.
2. A novel variation was detected in HESX1and SOX3in Chinese PSIS patientsrespectively. The mutation rates in the exons of HESX1, LHX4, OTX2and SOX3inChinese PSIS patients were low. Further studies are needed to define the cause of PSIS.
3. The pathogenesis of pituitary stalk interruption syndrome remains elusive.Further studies are needed to define the relationship between copy number variationsand pituitary stalk interruption syndrome.
4. No association between variations in the untranslated regions of HESX1andLHX4and pituitary stalk interruption syndrome was found in the present study. Furtherstudies are needed.
垂体柄中断综合征（Pituitary Stalk Interruption Syndrome, PSIS）是指垂体柄纤细或缺如导致下丘脑分泌的促激素释放激素不能通过垂体柄运送到垂体所致的一系列临床症候群。PSIS是内分泌系统的罕见疾病，国外及国内分别于1987年及2005年才首次报道该疾病。因此，对其临床特点的认识尚不充分，导致部分患者漏诊、误诊。PSIS的病因尚不明确。目前的研究认为基因突变可能是该病的原因。HESX1、LHX4、OTX2和SOX3基因被认为与该病的发生相关，是研究的热点。各种族之间遗传背景存在差异，中国尚无PSIS患者的病因学分析数据，中国人种HESX1、LHX4、OTX2和SOX3基因外显子区域变异情况是否有新的特点尚不明了。国外研究显示，PSIS患者HESX1、LHX4、OTX2和SOX3基因外显子区域突变率低，难以完全解释该疾病。已有部分个案报道发现PSIS患者存在拷贝数变异。拷贝数变异（Copy Number Variations, CNVs）是指与参考序列相比，基因组中≥1kb的DNA片段插入、缺失和/或扩增，及其互相组合衍生出的复杂染色体结构变异。CNVs于2004年首次被发现，是目前遗传学研究中的另一热点。拷贝数变异是否与PSIS的发病相关尚不明了，亟需较大规模的研究验证二者间的关系。研究证实仅有1.5%的核苷酸序列参与蛋白编码，基因上存在大量的非编码区域（UntranslatedRegions, UTRs）。这些UTRs在基因表达的调控中扮演了重要角色。已发现非编码区突变可致疾病的发生。HESX1及LHX4与垂体发育相关，存在致垂体柄中断综合征的可能性。已有报道在垂体柄中断综合征患者中检出了上述两基因外显子区域的异常，但仅有极低比例的患者合并上述异常。而HESX1及LHX4基因非编码区保守度较高，具备影响基因功能的条件，有可能是垂体柄中断综合征的病因。但目前尚无非编码区与垂体柄中断综合征间关系的研究。
目的：
总结PSIS患者的临床特点，明确中国PSIS患者中HESX1、LHX4、OTX2和SOX3基因外显子区域变异情况，明确拷贝数变异与PSIS间的关系，明确HESX1及LHX4基因非编码区异常与垂体柄中断综合征间的关系。为从临床特点及病因学两方面更深入、全面地认识该疾病，从而实现早诊断、早治疗，并进一步提供遗传学咨询、产前诊断、基因治疗提供基础数据。
方法：
1、回顾性分析58例PSIS患者及46例生长激素缺乏合并正常垂体柄（GrowthHormone Deficiency but A Normal Pituitary Stalk, NPS）患者的临床资料，包括近亲结婚、家族史、围产期事件、合并畸形情况、青春期发育情况、骨龄、人体测量学指标、激素基础及负荷后分泌情况、垂体MRI等。
2、运用PCR及自动测序技术对33例PSIS患者行HESX1、LHX4、OTX2及SOX3基因外显子测序分析。针对PSIS患者中变异率较高的LHX4基因外显子1及外显子6，选取200例同种族的健康对照行测序分析，比较两组间变异率的差异。运用SIFT和polyphen-2软件对HESX1基因突变进行功能预测。
3、选取9例垂体柄中断综合征患者为研究对象。对其中的5例采用AffymetrixGenome-Wide Human Mapping SNP6.0Array芯片平台、4例采用Illumina HumanOmni5M芯片平台在全基因组范围内进行拷贝数检测。对检测出的可疑拷贝数变异区域采用qPCR方法进行验证。
4、选取36例留取了DNA标本的垂体柄中断综合征患者为研究对象。采用PCR及直接测序的方法对HESX1基因5’、3’非编码区及LHX4基因3’非编码区进行测序分析。
结果：
1、PSIS及NPS患者的性别比、近亲结婚率、家族史、围产期事件率（除臀位生产率外）、畸形率、人体测量学指标无显著性差异。两组患者的GH缺乏率均为100%，ACTH缺乏率分别为77.6%和23.9%，TSH缺乏率分别为43.1%和10.9%，LH/FSH缺乏率分别为94.2%和47.4%，多种垂体激素缺乏率分别为93.1%和41.3%。PSIS患者垂体前叶激素释放的储备功能更差。两组患者的垂体后叶功能均基本正常。PSIS患者垂体前叶萎缩、垂体柄异常、垂体后叶异位的比例分别为98.3%、100%和91.4%。NPS患者上述比例分别为54.3%、0和0。
2、在1例患者中检出1种新的HESX1基因杂合错义突变（c.142A>T,p.Thr48Ser）。HESX1蛋白变异位点T48高度保守，但并未位于eh1、HRPW和同源结构域这几个关键结构区域。SIFT软件对于HESX1基因突变的评分为0.76，属于―可耐受变异‖；polyphen-2软件的评分为0.001，属于―良性变异‖。分别在7、1、31例患者中检出3种LHX4基因杂合多态性（c.63T>C, p.Gly21Gly; c.450C>T,p.Asn150Asn; c.983A>G, p.Asn328Ser），其中c.63T>C, p.Gly21Gly及c.983A>G,p.Asn328Ser的发生率在PSIS患者及正常对照组中无显著性差异。在1例患者中检出1种新的SOX3基因半合子多态性(c.157G>C, p.Val53Leu)。所有的患者中均未检出OTX2基因外显子区域异常。
3、 Xq21.31-Xq21.32区域检出了较为集中的拷贝数扩增区。其中90,864,846-90,969,300区域的拷贝数变异为8例患者共有，为非常见拷贝数变异，位于PCDH11X基因上游，经鉴定为可疑目标区域。对其中的两个位点进行了qPCR检测，相对定量值均<1.3。考虑与该区域位于X及Y染色体的同源区段有关。
4、36例垂体柄中断综合征患者中未检出HESX1基因非编码区异常。2例患者检出LHX4基因3’非编码区杂合异常（c.26C>T）。该变异位点低度保守，并未位于K-Box（KB）及多腺苷酸化信号（Polyadenylation Signal, PAS）区域。
结论：
1、PSIS患者主要表现为不同程度的垂体前叶功能低下及垂体形态学异常。与NPS患者相比，PSIS患者的垂体前叶激素缺乏更重，垂体形态学异常比例更高。生长激素缺乏患者早期垂体MRI检查明确垂体柄情况具有重要意义。
2、中国PSIS患者中各检出HESX1及SOX3基因外显子区域一种新的变异形式。中国PSIS患者HESX1、LHX4、OTX2及SOX3基因外显子的突变率低。PSIS的病因仍有待进一步探索。
3、垂体柄中断综合征病因复杂。拷贝数变异与垂体柄中断综合征关系的研究仍任重道远。
4、暂未发现HESX1及LHX4基因非编码区变异与垂体柄中断综合征相关。可能有其它因素参与了垂体柄中断综合征的发病。
Background:
Pituitary stalk interruption syndrome (PSIS) is characterized by a thin or absentpituitary stalk, leading to the obstruction of the transport of the hormones secreted bythe hypothalamus to the pituitary, and subsequently resulting in a cluster ofmanifestations. PSIS is a rare disease, and it was firstly reported in1987and2005in theforeign country and in China respectively. So the recognition of the disease wasinsufficient, resulting in missed diagnosis and misdiagnosis. To date, a goodunderstanding of the pathogenesis of PSIS remains elusive. Recent studies have focusedon genetic mutations in PSIS, especially in those genes involved in pituitarydevelopment and growth hormone secretion. HESX1, LHX4, OTX2and SOX3wereconsidered as the candidate genes and were the research hotspot. The geneticbackground was different between ethnic groups, and there was no genetic analysis inChinese PSIS patients. As a result, the characteristic of variations in the exons ofHESX1, LHX4, OTX2and SOX3in Chinese PSIS patients was not clear. It is reportedthat the mutation rates in the exons of HESX1, LHX4, OTX2and SOX3were low inPSIS, so these gene mutations can hardly be the cause. Some case reports have foundcopy number variations(CNVs) in PSIS patients, suggesting CNVs may be the cause.Copy number variations is defined as a DNA segment that is1kb or larger and presentat variable copy number in comparison with a reference genome, including insertion,microdeletion or microduplication, and complex structural variations of the genomicregion deriving from the combination of the disorders mentioned above. CNVs wasfirstly reported in2004, and now it is a hotspot in genetic research. It is not determinedwhether there are some associations between CNVs and PSIS, and large sample studiesare needed. It is confirmed that only a small fraction(about1.5%) of the genetic material codes for protein, and the rest fraction are untrsanslated regions(UTRs), which playimportant roles in the regulation of gene expression. Mutations in the UTRs are thecause of certain diseases. HESX1and LHX4are the key genes in the development ofpituitary, and it has been confirmed in studies in PSIS patients that HESX1and LHX4variations can cause pituitary stalk interruption syndrome. However, mutations can befound only in a small fractions of PSIS patients in the exons of HESX1and LHX4. TheUTRs of HESX1and LHX4are highly conserved and mutations in this regions canpossibly be associated with PSIS. Until now, there is no report on the relationshipbetweeen UTRs and pitutitary stalk interruption syndrome.
Objectives:
We characterized the clinical features of PSIS, detected the variations in exons ofHESX1, LHX4, OTX2and SOX3in Chinese PSIS patients, explored the relationshipbetween copy number variations and pituitary stalk interruption syndrome, anddetermined the associations of variations in the untranslated regions of HESX1andLHX4and the disease, with the hope that a better and more comprehensive recognitionof pituitary stalk interruption syndrome can be got, and subsequently earlier diagnosisand treatment can be achieved, and meanwhile fundamental data of genetic consultation,prenatal diagnosis and genetic therapy can be obtained.
Methods:
1. Clinical data of58patients with PSIS and46patients with GH deficiency but anormal pituitary stalk (NPS) were retrospectively analysed, including consanguineousparents, family history, perinatal history, associated malformations, pubertal status, boneage, anthropometry measurements, basal and peak hormone levels and pituitary MRIs.
2. HESX1, LHX4, OTX2and SOX3polymorphisms were screened in33PSISpatients by PCR and direct sequence analysis. Exon1and6of LHX4, the most variablesites of PSIS patients, were also screened in200normal, healthy, ethnically-matchedcontrols. To predict the protein function affected by an amino acid substitution inHESX1, we performed in silico analysis using SIFT and polyphen-2web software.
3.9patients with pituitary stalk interruption syndrome were studied. Copy number variations were detected by Affymetrix Genome-Wide Human Mapping SNP6.0Arrayin5patients and Illumina Human Omni5M Arrays in the other4patients. QuantitativeRT-PCR (qPCR) was used to verify the microarray results.
4.36patients with pituitary stalk interruption syndrome whose DNA werepreserved were chose as the objectives. PCR and direct sequencing analysis wereperformed to detect the5’ and3’ untranslated regions of HESX1and the3’ untranslatedregion of LHX4.
Results:
1. Both PSIS and NPS patients were similar in terms of gender ratio,consanguineous parents, familial history, perinatal events (except for breechpresentation), malformation, and anthropometry measurements. Deficiency of GH was100%in both PSIS and NPS groups. Other deficiency rates for PSIS and NPS groupswere: ACTH,77.6%and23.9%; TSH,43.1%and10.9%; LH/FSH,94.2%and47.4%;and combined pituitary hormone,93.1%and41.3%, respectively. GH, ACTH, and LHlevels increased after pharmacological stimulation in NPS patients, but not in PSISpatients. In PSIS and NPS patients, the percentages of anterior pituitary hypoplasia were98.3%and54.3%, pituitary stalk abnormality were100%and0%, and ectopicneurohypophysis were91.4%and0%.
2. A novel heterozygous sequence variant (c.142A>T, p.Thr48Ser) was found inHESX1in one PSIS patient. T48in the amino acid sequence encoded by HESX1is ahighly conserved residue. However, it was not located in eh1, HRPW or homeodomain,specific domains of HESX1protein. The score obtained for the new substitution(p.Thr48Ser in HESX1) from SIFT software was0.76, which placed the rare sequencevariant in the―tolerant‖class. By applying polyphen-2software, this rare sequencevariant was predicted to be benign with a score of0.001.3polymorphisms (c.63T>C,p.Gly21Gly; c.450C>T, p.Asn150Asn; and c.983A>G, p.Asn328Ser) were detected inLHX4in7,1, and31PSIS patients, respectively. c.63T>C, p.Gly21Gly and c.983A>G,p.Asn328Ser were also found in the control, with almost the same variation rates asPSIS patients. We also found a novel hemizygous polymorphism (c.157G>C, p.Val53Leu) in SOX3in one PSIS patient. No OTX2abnormality was detected in PSISpatients.
3. Intensive copy number variation regions were detected in Xq21.31-Xq21.32.The90,864,846-90,969,300region, located at the upstream of the PCDH11X gene, wasfound to have copy number gain in8patients, which was not a common copy numbervariation, and was identified as the object region. The relative copy numbers of the twosites in the region tested by qPCR were all below1.3. The cause of the inconsistentresults may be that the region was located in a major X/Y block of homology.
4. No variation was detected in the5’ and3’ untranslated regions of HESX1in the36patients.2patients suffered from a variation in the3’ untranslated region of LHX4（c.26C>T）. The altered locus was not highly conserved, and was not located in theK-Box or polyadenylation signal regions.
Conclusions:
1. PSIS patients often exhibited different degrees of anterior pituitary hormonedeficiencies and pituitary morphology abnormalities. Compared with NPS, PSISpatients had more severe basal anterior pituitary hormone deficiency, lower anteriorpituitary hormone secretion potential, and higher probability of abnormal pituitarymorphology. An earlier performance of pituitary MRI to determine the status of thepituitary stalk in patients with growth hormone deficiency is of great importance.
2. A novel variation was detected in HESX1and SOX3in Chinese PSIS patientsrespectively. The mutation rates in the exons of HESX1, LHX4, OTX2and SOX3inChinese PSIS patients were low. Further studies are needed to define the cause of PSIS.
3. The pathogenesis of pituitary stalk interruption syndrome remains elusive.Further studies are needed to define the relationship between copy number variationsand pituitary stalk interruption syndrome.
4. No association between variations in the untranslated regions of HESX1andLHX4and pituitary stalk interruption syndrome was found in the present study. Furtherstudies are needed.
引文
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2. Fujisawa I, Kikuchi K, Nishimura K, et al. Transection of the pituitary stalk:development of an ectopic posterior lobe assessed with MR imaging. Radiology1987;165:487-9.
3. Tauber M, Chevrel J, Diene G, et al. Long-term evolution of endocrine disordersand effect of GH therapy in35patients with pituitary stalk interruption syndrome. HormRes2005;64:266-73.
4. Pinto G, Netchine I, Sobrier ML, Brunelle F, Souberbielle JC, Brauner R. Pituitarystalk interruption syndrome: a clinical-biological-genetic assessment of its pathogenesis.J Clin Endocrinol Metab1997;82:3450-4.
5. Reynaud R, Albarel F, Saveanu A, et al. Pituitary stalk interruption syndrome in83patients: novel HESX1mutation and severe hormonal prognosis in malformative forms.European Journal of Endocrinology2011;164:457-65.
6. Reynaud R, Gueydan M, Saveanu A, et al. Genetic screening of combined pituitaryhormone deficiency: experience in195patients. J Clin Endocrinol Metab2006;91:3329-36.
7. Arrigo T, Wasniewska M, De Luca F, et al. Congenital adenohypophysis aplasia:clinical features and analysis of the transcriptional factors for embryonic pituitarydevelopment. J Endocrinol Invest2006;29:208-13.
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1. Reynaud R, Albarel F, Saveanu A, et al. Pituitary stalk interruption syndrome in83patients: novel HESX1mutation and severe hormonal prognosis in malformative forms.European Journal of Endocrinology2011;164:457-65.
2. Reynaud R, Jayakody SA, Monnier C, et al. PROKR2variants in multiplehypopituitarism with pituitary stalk interruption. J Clin Endocrinol Metab2012;97:E1068-73.
3. Yang Y, Guo QH, Wang BA, et al. Pituitary stalk interruption syndrome in58Chinese patients: clinical features and genetic analysis. Clin Endocrinol (Oxf)2012.
4. Castinetti F, Saveanu A, Reynaud R, et al. A novel dysfunctional LHX4mutationwith high phenotypical variability in patients with hypopituitarism. J Clin EndocrinolMetab2008;93:2790-9.
5. Qian X, Shu A, Qin W, et al. A novel insertion mutation in the FOXL2gene isdetected in a big Chinese family with blepharophimosis-ptosis-epicanthus inversus.Mutation research2004;554:19-22.
6. Beffagna G, Occhi G, Nava A, et al. Regulatory mutations in transforming growthfactor-beta3gene cause arrhythmogenic right ventricular cardiomyopathy type1.Cardiovascular research2005;65:366-73.
7. Damjanovich K, Langa C, Blanco FJ, et al.5'UTR mutations of ENG causehereditary hemorrhagic telangiectasia. Orphanet J Rare Dis2011;6:85.
8. Tauber M, Chevrel J, Diene G, et al. Long-term evolution of endocrine disordersand effect of GH therapy in35patients with pituitary stalk interruption syndrome. HormRes2005;64:266-73.
9. Pinto G, Netchine I, Sobrier ML, Brunelle F, Souberbielle JC, Brauner R. Pituitarystalk interruption syndrome: a clinical-biological-genetic assessment of its pathogenesis.J Clin Endocrinol Metab1997;82:3450-4.
10. Reynaud R, Gueydan M, Saveanu A, et al. Genetic screening of combined pituitaryhormone deficiency: experience in195patients. J Clin Endocrinol Metab2006;91:3329-36.
11. Dattani MT. Growth hormone deficiency and combined pituitary hormonedeficiency: does the genotype matter? Clin Endocrinol (Oxf)2005;63:121-30.
12. Melo ME, Marui S, Carvalho LR, et al. Hormonal, pituitary magnetic resonance,LHX4and HESX1evaluation in patients with hypopituitarism and ectopic posteriorpituitary lobe. Clin Endocrinol (Oxf)2007;66:95-102.
13. Ashkenazi-Hoffnung L, Lebenthal Y, Wyatt AW, et al. A novel loss-of-functionmutation in OTX2in a patient with anophthalmia and isolated growth hormonedeficiency. Hum Genet2010;127:721-9.
14. Woods KS, Cundall M, Turton J, et al. Over-and underdosage of SOX3isassociated with infundibular hypoplasia and hypopituitarism. Am J Hum Genet2005;76:833-49.
15. Dateki S, Fukami M, Uematsu A, et al. Mutation and gene copy number analyses ofsix pituitary transcription factor genes in71patients with combined pituitary hormonedeficiency: identification of a single patient with LHX4deletion. J Clin EndocrinolMetab2010;95:4043-7.
16. El Chehadeh-Djebbar S, Callier P, Masurel-Paulet A, et al.17q21.31microdeletionin a patient with pituitary stalk interruption syndrome. Eur J Med Genet2011;54:369-73.
17. Mignone F, Gissi C, Liuni S, Pesole G. Untranslated regions of mRNAs. GenomeBiol2002;3:REVIEWS0004.
18. Pickering BM, Willis AE. The implications of structured5' untranslated regions ontranslation and disease. Seminars in cell&developmental biology2005;16:39-47.
19. de Moor CH, Meijer H, Lissenden S. Mechanisms of translational control by the3'UTR in development and differentiation. Seminars in cell&developmental biology2005;16:49-58.
1. El Chehadeh-Djebbar S, Callier P, Masurel-Paulet A, et al.17q21.31microdeletionin a patient with pituitary stalk interruption syndrome. Eur J Med Genet2011;54:369-73.
2. Fujisawa I, Kikuchi K, Nishimura K, et al. Transection of the pituitary stalk:development of an ectopic posterior lobe assessed with MR imaging. Radiology1987;165:487-9.
3.赵明,王晓,张忠军.垂体柄中断综合征一例.中华内分泌代谢杂志2005:280-77.
4. Tauber M, Chevrel J, Diene G, et al. Long-term evolution of endocrine disordersand effect of GH therapy in35patients with pituitary stalk interruption syndrome. HormRes2005;64:266-73.
5. Pinto G, Netchine I, Sobrier ML, Brunelle F, Souberbielle JC, Brauner R. Pituitarystalk interruption syndrome: a clinical-biological-genetic assessment of its pathogenesis.J Clin Endocrinol Metab1997;82:3450-4.
6. Reynaud R, Albarel F, Saveanu A, et al. Pituitary stalk interruption syndrome in83patients: novel HESX1mutation and severe hormonal prognosis in malformative forms.European Journal of Endocrinology2011;164:457-65.
7. Reynaud R, Gueydan M, Saveanu A, et al. Genetic screening of combined pituitaryhormone deficiency: experience in195patients. J Clin Endocrinol Metab2006;91:3329-36.
8. Dattani MT. Growth hormone deficiency and combined pituitary hormonedeficiency: does the genotype matter? Clin Endocrinol (Oxf)2005;63:121-30.
9. Melo ME, Marui S, Carvalho LR, et al. Hormonal, pituitary magnetic resonance,LHX4and HESX1evaluation in patients with hypopituitarism and ectopic posteriorpituitary lobe. Clin Endocrinol (Oxf)2007;66:95-102.
10. Ashkenazi-Hoffnung L, Lebenthal Y, Wyatt AW, et al. A novel loss-of-functionmutation in OTX2in a patient with anophthalmia and isolated growth hormonedeficiency. Hum Genet2010;127:721-9.
11. Woods KS, Cundall M, Turton J, et al. Over-and underdosage of SOX3isassociated with infundibular hypoplasia and hypopituitarism. Am J Hum Genet2005;76:833-49.
12. Castinetti F, Saveanu A, Reynaud R, et al. A novel dysfunctional LHX4mutationwith high phenotypical variability in patients with hypopituitarism. J Clin EndocrinolMetab2008;93:2790-9.
13. Yang Y, Guo QH, Wang BA, et al. Pituitary stalk interruption syndrome in58Chinese patients: clinical features and genetic analysis. Clin Endocrinol (Oxf)2012.
14. Hester SD, Reid L, Nowak N, et al. Comparison of comparative genomichybridization technologies across microarray platforms. J Biomol Tech2009;20:135-51.
15. Henrichsen CN, Chaignat E, Reymond A. Copy number variants, diseases and geneexpression. Hum Mol Genet2009;18:R1-8.
16. Dateki S, Fukami M, Uematsu A, et al. Mutation and gene copy number analyses ofsix pituitary transcription factor genes in71patients with combined pituitary hormonedeficiency: identification of a single patient with LHX4deletion. J Clin EndocrinolMetab2010;95:4043-7.
1. Pinto G, Netchine I, Sobrier ML, Brunelle F, Souberbielle JC, Brauner R. Pituitarystalk interruption syndrome: a clinical-biological-genetic assessment of its pathogenesis.J Clin Endocrinol Metab1997;82:3450-4.
2. Fernandez-Rodriguez E, Quinteiro C, Barreiro J, et al. Pituitary stalkdysgenesis-induced hypopituitarism in adult patients: prevalence, evolution of hormonedysfunction and genetic analysis. Neuroendocrinology2011;93:181-8.
3. Argyropoulou M, Perignon F, Brauner R, Brunelle F. Magnetic-resonance-imagingin the diagnosis of growth-hormone deficiency. Journal of Pediatrics1992;120:886-91.
4. Fujisawa I, Kikuchi K, Nishimura K, et al. Transection of the pituitary stalk:development of an ectopic posterior lobe assessed with MR imaging. Radiology1987;165:487-9.
5.赵明,王晓,张忠军.垂体柄中断综合征一例.中华内分泌代谢杂志2005:280-77.
6. El Chehadeh-Djebbar S, Callier P, Masurel-Paulet A, et al.17q21.31microdeletionin a patient with pituitary stalk interruption syndrome. Eur J Med Genet2011;54:369-73.
7. Rocha MG, Marchisotti FG, Osorio MG, et al. High prevalence of pituitarymagnetic resonance abnormalities and gene mutations in a cohort of Brazilian childrenwith growth hormone deficiency and response to treatment. J Pediatr Endocrinol Metab2008;21:673-80.
8. Maghnie M, Larizza D, Triulzi F, Sampaolo P, Scotti G, Severi F. Hypopituitarismand stalk agenesis: a congenital syndrome worsened by breech delivery? Horm Res1991;35:104-8.
9. Albrechtsen S, Rasmussen S, Dalaker K, Irgens LM. The occurrence of breechpresentation in Norway1967-1994. Acta Obstet Gynecol Scand1998;77:410-5.
10. Reynaud R, Albarel F, Saveanu A, et al. Pituitary stalk interruption syndrome in83patients: novel HESX1mutation and severe hormonal prognosis in malformative forms.European Journal of Endocrinology2011;164:457-65.
11. Tauber M, Chevrel J, Diene G, et al. Long-term evolution of endocrine disordersand effect of GH therapy in35patients with pituitary stalk interruption syndrome. HormRes2005;64:266-73.
12. Simon D, Hadjiathanasiou C, Garel C, Czernichow P, Leger J. Phenotypicvariability in children with growth hormone deficiency associated with posteriorpituitary ectopia. Clinical Endocrinology2006;64:416-22.
13. Dattani MT. Growth hormone deficiency and combined pituitary hormonedeficiency: does the genotype matter? Clin Endocrinol (Oxf)2005;63:121-30.
14. Kim SS, Kim Y, Shin YL, Kim GH, Kim TU, Yoo HW. Clinical characteristics andmolecular analysis of PIT1, PROP1,LHX3, and HESX1in combined pituitary hormonedeficiency patients with abnormal pituitary MR imaging. Horm Res2003;60:277-83.
15. Reynaud R, Gueydan M, Saveanu A, et al. Genetic screening of combined pituitaryhormone deficiency: experience in195patients. J Clin Endocrinol Metab2006;91:3329-36.
16. Rainbow LA, Rees SA, Shaikh MG, et al. Mutation analysis of POUF-1, PROP-1and HESX-1show low frequency of mutations in children with sporadic forms ofcombined pituitary hormone deficiency and septo-optic dysplasia. Clin Endocrinol (Oxf)2005;62:163-8.
17. Voutetakis A, Maniati-Christidi M, Kanaka-Gantenbein C, et al. Prolonged jaundiceand hypothyroidism as the presenting symptoms in a neonate with a novel Prop1genemutation (Q83X). Eur J Endocrinol2004;150:257-64.
18. Melo ME, Marui S, Carvalho LR, et al. Hormonal, pituitary magnetic resonance,LHX4and HESX1evaluation in patients with hypopituitarism and ectopic posteriorpituitary lobe. Clin Endocrinol (Oxf)2007;66:95-102.
19. Castinetti F, Saveanu A, Reynaud R, et al. A novel dysfunctional LHX4mutationwith high phenotypical variability in patients with hypopituitarism. J Clin EndocrinolMetab2008;93:2790-9.
20. Ragge NK, Brown AG, Poloschek CM, et al. Heterozygous mutations of OTX2cause severe ocular malformations. Am J Hum Genet2005;76:1008-22.
21. Dateki S, Kosaka K, Hasegawa K, et al. Heterozygous orthodenticle homeobox2mutations are associated with variable pituitary phenotype. J Clin Endocrinol Metab2010;95:756-64.
22. Ashkenazi-Hoffnung L, Lebenthal Y, Wyatt AW, et al. A novel loss-of-functionmutation in OTX2in a patient with anophthalmia and isolated growth hormonedeficiency. Hum Genet2010;127:721-9.
23. Laumonnier F, Ronce N, Hamel BC, et al. Transcription factor SOX3is involved inX-linked mental retardation with growth hormone deficiency. Am J Hum Genet2002;71:1450-5.
24. Woods KS, Cundall M, Turton J, et al. Over-and underdosage of SOX3isassociated with infundibular hypoplasia and hypopituitarism. Am J Hum Genet2005;76:833-49.
25. Alatzoglou KS, Turton JP, Kelberman D, et al. Expanding the spectrum ofmutations in GH1and GHRHR: genetic screening in a large cohort of patients withcongenital isolated growth hormone deficiency. J Clin Endocrinol Metab2009;94:3191-9.
26. Osorio MG, Marui S, Jorge AA, et al. Pituitary magnetic resonance imaging andfunction in patients with growth hormone deficiency with and without mutations inGHRH-R, GH-1, or PROP-1genes. J Clin Endocrinol Metab2002;87:5076-84.
27. Arrigo T, Wasniewska M, De Luca F, et al. Congenital adenohypophysis aplasia:clinical features and analysis of the transcriptional factors for embryonic pituitarydevelopment. J Endocrinol Invest2006;29:208-13.
28. Scully KM, Rosenfeld MG. Pituitary development: regulatory codes in mammalianorganogenesis. Science2002;295:2231-5.
29. Reynaud R, Jayakody SA, Monnier C, et al. PROKR2variants in multiplehypopituitarism with pituitary stalk interruption. J Clin Endocrinol Metab2012;97:E1068-73.
30. Louvel M, Marcu M, Trivin C, Souberbielle JC, Brauner R. Diagnosis of growthhormone (GH) deficiency: comparison of pituitary stalk interruption syndrome andtransient GH deficiency. BMC Pediatr2009;9:29.
31. Coutant R, Rouleau S, Despert F, Magontier N, Loisel D, Limal JM. Growth andadult height in GH-treated children with nonacquired GH deficiency and idiopathicshort stature: the influence of pituitary magnetic resonance imaging findings. J ClinEndocrinol Metab2001;86:4649-54.
32. Chen S, Leger J, Garel C, Hassan M, Czernichow P. Growth hormone deficiencywith ectopic neurohypophysis: anatomical variations and relationship between thevisibility of the pituitary stalk asserted by magnetic resonance imaging and anteriorpituitary function. J Clin Endocrinol Metab1999;84:2408-13.
33. Marcu M, Trivin C, Souberbielle JC, Brauner R. Factors influencing the growthhormone peak and plasma insulin-like growth factor I in young adults with pituitarystalk interruption syndrome. BMC Endocr Disord2008;8:7.
34. Rottembourg D, Linglart A, Adamsbaum C, et al. Gonadotrophic status inadolescents with pituitary stalk interruption syndrome. Clin Endocrinol (Oxf)2008;69:105-11.
35. Trivin C, Gluckman E, Leblanc T, Cousin MN, Soulier J, Brauner R. Factors andmarkers of growth hormone secretion and gonadal function in Fanconi anemia. GrowthHorm IGF Res2007;17:122-9.
36.郭清华,陆菊明,窦京涛,吕朝晖,母义明.垂体柄中断综合征五例分析并文献复习.中华内分泌代谢杂志2008;24.
37. Abernethy LJ. Imaging of the pituitary in children with growth disorders. Eur JRadiol1998;26:102-8.
38. Maghnie M, Genovese E, Villa A, Spagnolo L, Campan R, Severi F. Dynamic MRIin the congenital agenesis of the neural pituitary stalk syndrome: The role of theVascular pituitary stalk in predicting residual anterior pituitary function. ClinicalEndocrinology1996;45:281-90.
39. Main KM, Schmidt IM, Skakkebaek NE. A possible role for reproductive hormonesin newborn boys: progressive hypogonadism without the postnatal testosterone peak. JClin Endocrinol Metab2000;85:4905-7.
40. Main KM, Schmidt IM, Toppari J, Skakkebaek NE. Early postnatal treatment ofhypogonadotropic hypogonadism with recombinant human FSH and LH. Eur JEndocrinol2002;146:75-9.
41. Guyda HJ. Four decades of growth hormone therapy for short children: what havewe achieved? J Clin Endocrinol Metab1999;84:4307-16.
42. Zenaty D, Garel C, Limoni C, Czernichow P, Leger J. Presence of magneticresonance imaging abnormalities of the hypothalamic-pituitary axis is a significantdeterminant of the first3years growth response to human growth hormone treatment inprepubertal children with nonacquired growth hormone deficiency. Clin Endocrinol(Oxf)2003;58:647-52.
43. Bright GM, Julius JR, Lima J, Blethen SL. Growth hormone stimulation test resultsas predictors of recombinant human growth hormone treatment outcomes: preliminaryanalysis of the national cooperative growth study database. Pediatrics1999;104:1028-31.
44. Van den Broeck J, Arends N, Hokken-Koelega A. Growth response to recombinanthuman growth hormone (GH) in children with idiopathic growth retardation by level ofmaximum GH peak during GH stimulation tests. Horm Res2000;53:267-73.
45. de Ridder MA, Stijnen T, Hokken-Koelega AC. Prediction of adult height ingrowth-hormone-treated children with growth hormone deficiency. J Clin EndocrinolMetab2007;92:925-31.
46. Loche S, Cambiaso P, Merola B, et al. The effect of Hexarelin ongrowth-hormone(GH) secretion in patients with GH deficiency. Journal of ClinicalEndocrinology&Metabolism1995;80:2692-6.
2. Fernandez-Rodriguez E, Quinteiro C, Barreiro J, et al. Pituitary stalkdysgenesis-induced hypopituitarism in adult patients: prevalence, evolution of hormonedysfunction and genetic analysis. Neuroendocrinology2011;93:181-8.
3. Argyropoulou M, Perignon F, Brauner R, Brunelle F. Magnetic-resonance-imagingin the diagnosis of growth-hormone deficiency. Journal of Pediatrics1992;120:886-91.
4. El Chehadeh-Djebbar S, Callier P, Masurel-Paulet A, et al.17q21.31microdeletionin a patient with pituitary stalk interruption syndrome. Eur J Med Genet2011;54:369-73.
5. Fujisawa I, Kikuchi K, Nishimura K, et al. Transection of the pituitary stalk:development of an ectopic posterior lobe assessed with MR imaging. Radiology1987;165:487-9.
6.赵明,王晓,张忠军.垂体柄中断综合征一例.中华内分泌代谢杂志2005:280-77.
7. Rocha MG, Marchisotti FG, Osorio MG, et al. High prevalence of pituitarymagnetic resonance abnormalities and gene mutations in a cohort of Brazilian childrenwith growth hormone deficiency and response to treatment. J Pediatr Endocrinol Metab2008;21:673-80.
8. Tauber M, Chevrel J, Diene G, et al. Long-term evolution of endocrine disordersand effect of GH therapy in35patients with pituitary stalk interruption syndrome. HormRes2005;64:266-73.
9. Guyda HJ. Four decades of growth hormone therapy for short children: what havewe achieved? J Clin Endocrinol Metab1999;84:4307-16.
10. Coutant R, Rouleau S, Despert F, Magontier N, Loisel D, Limal JM. Growth andadult height in GH-treated children with nonacquired GH deficiency and idiopathicshort stature: the influence of pituitary magnetic resonance imaging findings. J ClinEndocrinol Metab2001;86:4649-54.
11. Louvel M, Marcu M, Trivin C, Souberbielle JC, Brauner R. Diagnosis of growthhormone (GH) deficiency: comparison of pituitary stalk interruption syndrome andtransient GH deficiency. BMC Pediatr2009;9:29.
12. Reynaud R, Albarel F, Saveanu A, et al. Pituitary stalk interruption syndrome in83patients: novel HESX1mutation and severe hormonal prognosis in malformative forms.European Journal of Endocrinology2011;164:457-65.
13. Reynaud R, Gueydan M, Saveanu A, et al. Genetic screening of combined pituitaryhormone deficiency: experience in195patients. J Clin Endocrinol Metab2006;91:3329-36.
14. Arrigo T, Wasniewska M, De Luca F, et al. Congenital adenohypophysis aplasia:clinical features and analysis of the transcriptional factors for embryonic pituitarydevelopment. J Endocrinol Invest2006;29:208-13.
15. Dattani MT. Growth hormone deficiency and combined pituitary hormonedeficiency: does the genotype matter? Clin Endocrinol (Oxf)2005;63:121-30.
16. Melo ME, Marui S, Carvalho LR, et al. Hormonal, pituitary magnetic resonance,LHX4and HESX1evaluation in patients with hypopituitarism and ectopic posteriorpituitary lobe. Clin Endocrinol (Oxf)2007;66:95-102.
17. Ashkenazi-Hoffnung L, Lebenthal Y, Wyatt AW, et al. A novel loss-of-functionmutation in OTX2in a patient with anophthalmia and isolated growth hormonedeficiency. Hum Genet2010;127:721-9.
18. Woods KS, Cundall M, Turton J, et al. Over-and underdosage of SOX3isassociated with infundibular hypoplasia and hypopituitarism. Am J Hum Genet2005;76:833-49.
19. Castinetti F, Saveanu A, Reynaud R, et al. A novel dysfunctional LHX4mutationwith high phenotypical variability in patients with hypopituitarism. J Clin EndocrinolMetab2008;93:2790-9.
20. Redon R, Ishikawa S, Fitch KR, et al. Global variation in copy number in thehuman genome. Nature2006;444:444-54.
21.孙玉琳,刘飞,赵晓航.拷贝数变异的全基因组关联分析. Progress inBiochemistry and Biophysics2009;36:968-77.
22. Oldridge DA, Banerjee S, Setlur SR, Sboner A, Demichelis F. Optimizing copynumber variation analysis using genome-wide short sequence oligonucleotide arrays.Nucleic acids research2010;38:3275-86.
23. Sebat J, Lakshmi B, Troge J, et al. Large-scale copy number polymorphism in thehuman genome. Science2004;305:525-8.
24. Iafrate AJ, Feuk L, Rivera MN, et al. Detection of large-scale variation in thehuman genome. Nat Genet2004;36:949-51.
25. Dateki S, Fukami M, Uematsu A, et al. Mutation and gene copy number analyses ofsix pituitary transcription factor genes in71patients with combined pituitary hormonedeficiency: identification of a single patient with LHX4deletion. J Clin EndocrinolMetab2010;95:4043-7.
26. Yang Y, Guo QH, Wang BA, et al. Pituitary stalk interruption syndrome in58Chinese patients: clinical features and genetic analysis. Clin Endocrinol (Oxf)2012.
27. Mignone F, Gissi C, Liuni S, Pesole G. Untranslated regions of mRNAs. GenomeBiol2002;3:REVIEWS0004.
28. Pickering BM, Willis AE. The implications of structured5' untranslated regions ontranslation and disease. Seminars in cell&developmental biology2005;16:39-47.
29. de Moor CH, Meijer H, Lissenden S. Mechanisms of translational control by the3'UTR in development and differentiation. Seminars in cell&developmental biology2005;16:49-58.
30. Qian X, Shu A, Qin W, et al. A novel insertion mutation in the FOXL2gene isdetected in a big Chinese family with blepharophimosis-ptosis-epicanthus inversus.Mutation research2004;554:19-22.
31. Beffagna G, Occhi G, Nava A, et al. Regulatory mutations in transforming growthfactor-beta3gene cause arrhythmogenic right ventricular cardiomyopathy type1.Cardiovascular research2005;65:366-73.
32. Damjanovich K, Langa C, Blanco FJ, et al.5'UTR mutations of ENG causehereditary hemorrhagic telangiectasia. Orphanet J Rare Dis2011;6:85.
1. Fujisawa I, Kikuchi K, Nishimura K, et al. Transection of the pituitary stalk:development of an ectopic posterior lobe assessed with MR imaging. Radiology1987;165:487-9.
2. El Chehadeh-Djebbar S, Callier P, Masurel-Paulet A, et al.17q21.31microdeletionin a patient with pituitary stalk interruption syndrome. Eur J Med Genet2011;54:369-73.
3. Tauber M, Chevrel J, Diene G, et al. Long-term evolution of endocrine disordersand effect of GH therapy in35patients with pituitary stalk interruption syndrome. HormRes2005;64:266-73.
4. Pinto G, Netchine I, Sobrier ML, Brunelle F, Souberbielle JC, Brauner R. Pituitarystalk interruption syndrome: a clinical-biological-genetic assessment of its pathogenesis.J Clin Endocrinol Metab1997;82:3450-4.
5. Trivin C, Gluckman E, Leblanc T, Cousin MN, Soulier J, Brauner R. Factors andmarkers of growth hormone secretion and gonadal function in Fanconi anemia. GrowthHorm IGF Res2007;17:122-9.
6. Simon D, Hadjiathanasiou C, Garel C, Czernichow P, Leger J. Phenotypicvariability in children with growth hormone deficiency associated with posteriorpituitary ectopia. Clinical Endocrinology2006;64:416-22.
7. Gascoin-Lachambre G, Brauner R, Duche L, Chalumeau M. Pituitary stalkinterruption syndrome: diagnostic delay and sensitivity of the auxological criteria of thegrowth hormone research society. PLoS One2011;6:e16367.
8. Chen S, Leger J, Garel C, Hassan M, Czernichow P. Growth hormone deficiencywith ectopic neurohypophysis: anatomical variations and relationship between thevisibility of the pituitary stalk asserted by magnetic resonance imaging and anteriorpituitary function. J Clin Endocrinol Metab1999;84:2408-13.
9. Maghnie M, Genovese E, Villa A, Spagnolo L, Campan R, Severi F. Dynamic MRIin the congenital agenesis of the neural pituitary stalk syndrome: The role of theVascular pituitary stalk in predicting residual anterior pituitary function. ClinicalEndocrinology1996;45:281-90.
10.赵明,王晓,张忠军.垂体柄中断综合征一例.中华内分泌代谢杂志2005:280-77.
11. Wang GL, Fu JF, Wang CL, Liang L. Clinical analysis of13cases with growthhormone deficiency combined with pituitary stalk interruption. Zhonghua Er Ke Za Zhi2010;48:305-7.
12. Rocha MG, Marchisotti FG, Osorio MG, et al. High prevalence of pituitarymagnetic resonance abnormalities and gene mutations in a cohort of Brazilian childrenwith growth hormone deficiency and response to treatment. J Pediatr Endocrinol Metab2008;21:673-80.
13. Argyropoulou M, Perignon F, Brauner R, Brunelle F. Magnetic-resonance-imagingin the diagnosis of growth-hormone deficiency. Journal of Pediatrics1992;120:886-91.
14. Li H, Ji CY, Zong XN, Zhang YQ. Height and weight standardized growth chartsfor Chinese children and adolescents aged0to18years. Zhonghua Er Ke Za Zhi2009;47:487-92.
15. Fok T, Hon K, So HK, et al. Normative data of penile length for term Chinesenewborns. Neonatology2005;87:242-5.
16. Greulich WW, Pyle SI. Radiographic atlas of skeletal development of the hand andwrist. The American Journal of the Medical Sciences1959;238:393.
17. Kabir AA, Steinmann WC, Myers L, et al. Unnecessary cesarean delivery inLouisiana: An analysis of birth certificate data. American journal of obstetrics andgynecology2004;190:10-9.
18. Reynaud R, Albarel F, Saveanu A, et al. Pituitary stalk interruption syndrome in83patients: novel HESX1mutation and severe hormonal prognosis in malformative forms.European Journal of Endocrinology2011;164:457-65.
19. Fernandez-Rodriguez E, Quinteiro C, Barreiro J, et al. Pituitary stalkdysgenesis-induced hypopituitarism in adult patients: prevalence, evolution of hormonedysfunction and genetic analysis. Neuroendocrinology2011;93:181-8.
20. Consensus guidelines for the diagnosis and treatment of growth hormone (GH)deficiency in childhood and adolescence: summary statement of the GH ResearchSociety. GH Research Society. J Clin Endocrinol Metab2000;85:3990-3.
21. Louvel M, Marcu M, Trivin C, Souberbielle JC, Brauner R. Diagnosis of growthhormone (GH) deficiency: comparison of pituitary stalk interruption syndrome andtransient GH deficiency. BMC Pediatr2009;9:29.
22. Coutant R, Rouleau S, Despert F, Magontier N, Loisel D, Limal JM. Growth andadult height in GH-treated children with nonacquired GH deficiency and idiopathicshort stature: the influence of pituitary magnetic resonance imaging findings. J ClinEndocrinol Metab2001;86:4649-54.
23. Rottembourg D, Linglart A, Adamsbaum C, et al. Gonadotrophic status inadolescents with pituitary stalk interruption syndrome. Clin Endocrinol (Oxf)2008;69:105-11.
24. Marcu M, Trivin C, Souberbielle JC, Brauner R. Factors influencing the growthhormone peak and plasma insulin-like growth factor I in young adults with pituitarystalk interruption syndrome. BMC Endocr Disord2008;8:7.
1. El Chehadeh-Djebbar S, Callier P, Masurel-Paulet A, et al.17q21.31microdeletionin a patient with pituitary stalk interruption syndrome. Eur J Med Genet2011;54:369-73.
2. Fujisawa I, Kikuchi K, Nishimura K, et al. Transection of the pituitary stalk:development of an ectopic posterior lobe assessed with MR imaging. Radiology1987;165:487-9.
3. Tauber M, Chevrel J, Diene G, et al. Long-term evolution of endocrine disordersand effect of GH therapy in35patients with pituitary stalk interruption syndrome. HormRes2005;64:266-73.
4. Pinto G, Netchine I, Sobrier ML, Brunelle F, Souberbielle JC, Brauner R. Pituitarystalk interruption syndrome: a clinical-biological-genetic assessment of its pathogenesis.J Clin Endocrinol Metab1997;82:3450-4.
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4. Tauber M, Chevrel J, Diene G, et al. Long-term evolution of endocrine disordersand effect of GH therapy in35patients with pituitary stalk interruption syndrome. HormRes2005;64:266-73.
5. Pinto G, Netchine I, Sobrier ML, Brunelle F, Souberbielle JC, Brauner R. Pituitarystalk interruption syndrome: a clinical-biological-genetic assessment of its pathogenesis.J Clin Endocrinol Metab1997;82:3450-4.
6. Reynaud R, Albarel F, Saveanu A, et al. Pituitary stalk interruption syndrome in83patients: novel HESX1mutation and severe hormonal prognosis in malformative forms.European Journal of Endocrinology2011;164:457-65.
7. Reynaud R, Gueydan M, Saveanu A, et al. Genetic screening of combined pituitaryhormone deficiency: experience in195patients. J Clin Endocrinol Metab2006;91:3329-36.
8. Dattani MT. Growth hormone deficiency and combined pituitary hormonedeficiency: does the genotype matter? Clin Endocrinol (Oxf)2005;63:121-30.
9. Melo ME, Marui S, Carvalho LR, et al. Hormonal, pituitary magnetic resonance,LHX4and HESX1evaluation in patients with hypopituitarism and ectopic posteriorpituitary lobe. Clin Endocrinol (Oxf)2007;66:95-102.
10. Ashkenazi-Hoffnung L, Lebenthal Y, Wyatt AW, et al. A novel loss-of-functionmutation in OTX2in a patient with anophthalmia and isolated growth hormonedeficiency. Hum Genet2010;127:721-9.
11. Woods KS, Cundall M, Turton J, et al. Over-and underdosage of SOX3isassociated with infundibular hypoplasia and hypopituitarism. Am J Hum Genet2005;76:833-49.
12. Castinetti F, Saveanu A, Reynaud R, et al. A novel dysfunctional LHX4mutationwith high phenotypical variability in patients with hypopituitarism. J Clin EndocrinolMetab2008;93:2790-9.
13. Yang Y, Guo QH, Wang BA, et al. Pituitary stalk interruption syndrome in58Chinese patients: clinical features and genetic analysis. Clin Endocrinol (Oxf)2012.
14. Hester SD, Reid L, Nowak N, et al. Comparison of comparative genomichybridization technologies across microarray platforms. J Biomol Tech2009;20:135-51.
15. Henrichsen CN, Chaignat E, Reymond A. Copy number variants, diseases and geneexpression. Hum Mol Genet2009;18:R1-8.
16. Dateki S, Fukami M, Uematsu A, et al. Mutation and gene copy number analyses ofsix pituitary transcription factor genes in71patients with combined pituitary hormonedeficiency: identification of a single patient with LHX4deletion. J Clin EndocrinolMetab2010;95:4043-7.
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