儿童Hutchinson-Gilford早老症六例分析

目的 对6例中国儿童早老症的临床特征进行总结,并对部分患儿的致病基因携带情况进行分析。方法 选取6例儿童早老症患儿为研究对象,对其临床资料进行总结,并对其中4例患儿家系进行致病基因测序分析。分别留取研究对象的EDTA抗凝血3 ml,用DNA提取试剂盒提取基因组DNA,然后运用一代测序技术对患儿家系进行核纤层蛋白A/C(LMNA)基因测序,并将测序结果与正常结果比对,寻找致病性突变位点。结果 6例早老症患儿均具有典型的临床表现,如严重生长迟缓、特殊皮肤表现、典型颅面表现等,符合文献报道的儿童早老症临床特征。基因测序结果显示,2例患儿携带LMNA c．1824 C>T(p.G608G)经典杂合突变,另外2例分别携带LMNA IVS8-4 C>A、c.1968＋2T>C非经典型突变,其中IVS8-4 C>A突变尚未见文献报道。结论 在中国儿童中,LMNA经典杂合突变和非经典突变均可导致早老症的发生。儿童早老症患儿具有典型的临床表现,临床容易诊断。致病基因测序发现LMNA突变,可进一步明确诊断。     

早老症一例追踪观察及临床分析

早老症 ,又称Hutchinson Guilford综合征 (Hutchinson Guilfordprogeriasyndrome ,HGPS) ,是与自然老化不同的一种局部性老化性疾病 ,临床比较少见 ,国内报道仅十余例。本组于 1998年 11月门诊诊治一例并跟踪观察 ,现报道如下。临床资料1.患者女性 ,2 7岁 ,工人。出生体重 3 .5kg。三岁后生长发育迟缓 ,脱发明显 ,5岁全秃。 8个月出牙 ,10岁换牙。智力发育正常 ,生活可自理。曾多次就诊 ,均诊为垂体性侏儒症 ,未行特殊处理。 15岁月经来潮 ,每次持续 3～ 4天 ,不规律 ,量少 ,需以人工周期维持。 2 4岁结婚 ,婚后夫妻感情尚好 ,4个月后闭…     

早老症的分子机制

儿童早老症（Hutchinson Giford Progeria Syndrome,HGPS）是由于基因突变导致的疾病,它的发病率很低,大概是八百万分之一,患者出生的早期就开始出现衰老的容貌。     

早老症合并高血压和冠心病（附一例尸检报告）

早老症在文献中极为少见。本文报道１例早老症及其尸检资料。患儿男性，１２岁。自出生４～５个月起，即出现头发脱落、毛发稀少、皮肤变薄以及色素沉着等特征。以后随年龄增长，逐渐呈现老年人面貌。５岁时，发现有高血压和冠心病，并常有心绞痛发作。临床诊浙早老症合并高血压和冠心病。尸检见全身广泛动脉粥样硬化及冠状动脉粥样硬化和心肌梗塞。     

酷似系统性硬化症的成人早老症一例

成人早老症(progeria of adult)又名Werner综合征(Wemer syndrome，WS)，是一种罕见的常染色体隐性遗传性疾病，以特征性的鸟形、面具形脸，身材矮小，幼年即出现早老特征，硬皮病样皮肤损害和内分泌代谢异常为特点，极易误诊为系统性硬化症(systemic scleroderma，SSc)。我们曾诊治1例WS病例，误诊为SSc长达20余年，现报告如下。     

早老蛋白的结构,功能及其与阿尔茨海默病的关系

近几年来的研究发现，位于１４号染色体上的早老蛋白１基因及１号染色体上的早老蛋白２基因与早发性家族性阿尔茨海默病有关。早老蛋白１和早老蛋白２是含７个跨膜结构的整合蛋白，参与Ｎｏｔｃｈ信息传递及细胞凋亡。早老蛋白基因突变导致β－淀粉样蛋白（Ａβ４２）增多，从而引起家族性阿尔茨海默病。本文着重就早老蛋白的研究进展与家族性阿尔茨海默病的关系加以综述。     

散发性迟发型痴呆与遗传基因早老蛋白1的多态性分析

对２０１４例６０岁以上老年人行痴呆流行病学调查。筛选出散发性迟发型痴呆（ＡＤ）患者３２例,血管性痴呆（ＶＤ）患者２１例,非痴呆（ＮＤ）３２例。取其外周血抗凝,用酚,氯仿法提取ＤＮＡ,应用聚合酶链反应－限制性片段长度多态性分析（ＰＣＲ－ＲＦＬＰ）技术对遗传基因早老蛋白１（ＰＳ１）的多态性进行分析。     

核纤层蛋白病一例并文献复习

目的 探讨核纤层蛋白病的诊断及治疗方法,提高对核纤层蛋白病的认识.方法 结合1例核纤层蛋白病患者的临床资料和文献复习,详细分析该病的组织起源、临床病理特点、分型、诊断、罄别诊断、治疗及预后等,完善患者各系统筛查以评估皮肤、骨骼、骨骼肌、心肌、神经和脂肪组织的受累情况.结果 各系统筛查结果提示患者多组织(皮肤、骨骼、骨骼肌、脂肪、神经)发育不良/加速退行性变伴左卵巢良性浆液性囊腺瘤.其临床表现复杂,重叠了Charcot-Marie-Tooth病、Emery-Dreffuss肌营养不良、Dunnigan型家族性部分性脂肪萎缩、脂肪萎缩性糖尿病并下颌骨肢端发育不良症、非典型Werner综合征的表现,临床诊断为(新型)核纤层蛋白病.结论 核纤层蛋白病罕见,极易误诊,应予基因筛查以明确其分子病因.     

厚皮指症20例临床病理分析及六例随访

目的 提高对厚皮指症临床特点、鉴别诊断和预后的认识.方法 分析20例厚皮指症的临床资料并随访6例患者.结果 本组患者男性17例,女性3例,平均发病年龄(15±2)岁.主要表现为隐匿出现的手近端指间(PIP)关节两侧无症状性的质硬肿胀.患者发病前均有强迫性掰动挤压PIP关节发出弹响的习惯.生化检验均为正常,类风湿因子和抗核抗体为阴性.X线和磁共振成像(MRI)可以见到受累PIP关节周围的软组织肿胀及增厚,但骨结构和关节无异常.肿胀组织病理显示:表皮角化过度,轻度表皮增生,真皮层明显增厚,其内聚集着较多弯曲的粗糙胶原纤维束.尽管其中8例患者停止掰动挤压手指关节已达3~22年,但是其PIP关节肿胀仍未减轻.结论 厚皮指症是一种多数累及手指PlP关节的浅表性、良性、手指纤维瘤性皮肤病,不同于幼年类风湿关节炎及指节垫.     

Model of human aging: Recent findings on Werner’s and Hutchinson-Gilford progeria syndromes

The molecular mechanisms involved in human aging are complicated. Two progeria syndromes, Werner’s syndrome (WS) and Hutchinson-Gilford progeria syndrome (HGPS), characterized by clinical features mimicking physiological aging at an early age, provide insights into the mechanisms of natural aging. Based on recent findings on WS and HGPS, we suggest a model of human aging. Human aging can be triggered by two main mechanisms, telomere shortening and DNA damage. In telomere-dependent aging, telomere shortening and dysfunction may lead to DNA damage responses which induce cellular senescence. In DNA damage-initiated aging, DNA damage accumulates, along with DNA repair deficiencies, resulting in genomic instability and accelerated cellular senescence. In addition, aging due to both mechanisms (DNA damage and telomere shortening) is strongly dependent on p53 status. These two mechanisms can also act cooperatively to increase the overall level of genomic instability, triggering the onset of human aging phenotypes.     

Age-dependent loss of MMP-3 in Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, progressive segmental premature aging disease that includes scleroderma-like skin, progressive joint contracture, and atherosclerosis. Affected individuals die prematurely of heart attacks or strokes. Extracellular matrix dysregulation is implicated as a factor in disease progression. We analyzed messenger RNA and protein levels for matrix metalloproteinases (MMPs)-2,-3, and -9 in HGPS primary human dermal fibroblasts using real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and gelatin zymography. MMP-3 messenger RNA and protein levels decreased significantly with increasing donor age in HGPS fibroblasts but not in controls. MMP-2 messenger RNA also showed a donor age-dependent decrease in HGPS fibroblasts, but levels of secreted protein were unchanged. MMP-9 was similar in HGPS and control cultures. The decreased MMP-3 may represent a shift in the inherent extracellular matrix-degrading proteolytic balance in favor of matrix deposition in HGPS. This metalloproteinase has the potential to serve as a biomarker of therapeutic efficacy when assessing treatments for HGPS.     

Hyaluronuria in a case of progeria. (Hutchinson-Gilford syndrome)

A classic case of progeria (Hutchinson-Gilford syndrome) in a 9-year-old Japanese boy is presented. The characteristic clinical features in this patient were similar to those reported in the literature. The total amount of acid glycosaminoglycans excreted in the urine was within the normal range, but there was an increase in hyaluronic acid excretion. The hyaluronuria was a novel finding in progeria, providing a common linkage with the hyaluronuria found in Werner's syndrome.     

Mechanisms of premature vascular aging in children with Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford progeria syndrome is a rare, segmental premature aging syndrome of accelerated atherosclerosis and early death from myocardial infarction or stroke. This study sought to establish comprehensive characterization of the fatal vasculopathy in Hutchinson-Gilford progeria syndrome and its relevance to normal aging. We performed cardiovascular assessments at a single clinical site on the largest prospectively studied cohort to date. Carotid-femoral pulse wave velocity was dramatically elevated (mean: 13.00±3.83 m/s). Carotid duplex ultrasound echobrightness, assessed in predefined tissue sites as a measure of arterial wall density, was significantly greater than age- and sex-matched controls in the intima-media (P<0.02), near adventitia (P<0.003), and deep adventitia (P<0.01), as was internal carotid artery mean flow velocity (P<0.0001). Ankle-brachial indices were abnormal in 78% of patients. Effective disease treatments may be heralded by normalizing trends of these noninvasive cardiovascular measures. The data demonstrate that, along with peripheral vascular occlusive disease, accelerated vascular stiffening is an early and pervasive mechanism of vascular disease in Hutchinson-Gilford progeria syndrome. There is considerable overlap with cardiovascular changes of normal aging, which reinforces the view that defining mechanisms of cardiovascular disease in Hutchinson-Gilford progeria syndrome provides a unique opportunity to isolate a subset of factors influencing cardiovascular disease in the general aging population.     

Progeria of stem cells: stem cell exhaustion in Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, fatal genetic disorder that is characterized by segmental accelerated aging. The major causal mutation associated with HGPS triggers abnormal messenger RNA splicing of the lamin A gene leading to changes in the nuclear architecture. To date, two models have been proposed to explain how mutations in the lamin A gene could lead to HGPS, structural fragility and altered gene expression. We favor a compatible model that links HGPS to stem cell-driven tissue regeneration. In this model, nuclear fragility of lamin A-deficient cells increases apoptotic cell death to levels that exhaust tissues' ability for stem cell-driven regeneration. Tissue-specific differences in cell death or regenerative potential, or both, result in the tissue-specific segmental aging pattern seen in HGPS. We propose that the pattern of aging-related conditions present or absent in HGPS can provide insight into the genetic and environmental factors that contribute to normal aging.     

A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model

Hutchinson-Gilford progeria syndrome (HGPS) is the most dramatic form of human premature aging. Death occurs at a mean age of 13 years, usually from heart attack or stroke. Almost all cases of HGPS are caused by a de novo point mutation in the lamin A (LMNA) gene that results in production of a mutant lamin A protein termed progerin. This protein is permanently modified by a lipid farnesyl group, and acts as a dominant negative, disrupting nuclear structure. Treatment with farnesyltransferase inhibitors (FTIs) has been shown to prevent and even reverse this nuclear abnormality in cultured HGPS fibroblasts. We have previously created a mouse model of HGPS that shows progressive loss of vascular smooth muscle cells in the media of the large arteries, in a pattern that is strikingly similar to the cardiovascular disease seen in patients with HGPS. Here we show that the dose-dependent administration of the FTI tipifarnib (R115777, Zarnestra) to this HGPS mouse model can significantly prevent both the onset of the cardiovascular phenotype as well as the late progression of existing cardiovascular disease. These observations provide encouraging evidence for the current clinical trial of FTIs for this rare and devastating disease.     

Aging of Hutchinson-Gilford progeria syndrome fibroblasts is characterised by hyperproliferation and increased apoptosis

Hutchinson-Gilford progeria syndrome is a rare genetic disorder that mimics certain aspects of aging prematurely. Recent work has revealed that mutations in the lamin A gene are a cause of the disease. We show here that cellular aging of Hutchinson-Gilford progeria syndrome fibroblasts is characterised by a period of hyperproliferation and terminates with a large increase in the rate of apoptosis. The occurrence of cells with abnormal nuclear morphology reported by others is shown to be a result of cell division since the fraction of these abnormalities increases with cellular age. Similarly, the proportion of cells with an abnormal or absent A-type lamina increases with age. These data provide clues as to the cellular basis for premature aging in HGPS and support the view that cellular senescence and tissue homeostasis are important factors in the normal aging process.