Choroidal neovascularization and angioid streaks in pseudoxanthoma elasticum

AIM: To report a case of pseudoxanthoma elasticum (PXE) in a 48 year old woman that presented with bilateral blurry vision. METHODS: A case report RESULTS: A 48-year-old woman presented with bilateral blurry vision and right eye metamorphopsia. The patient had a history of angioid streaks in the left eye ten years ago for which she had received laser surgery and had poor residual vision. Visual acuity was 20/60 in the right eye and count fingers at 6 feet in the left. Fundus examination showed subretinal hemorrhage and macular thickening on the right and a disciform macular scar with focal atrophic pigment epithelial lesions on the left. Both eyes had angioid streaks and peau d’orange pigmentary pattern of the retina. External examination showed several, yellow skin papules and plaques on the lateral and posterior neck, as well as prominent mental creases. Pathologic examination of skin biopsy confirmed the diagnosis of PXE, showing calcium deposition and fragmented, clumped elastic fibers in the deep reticular dermis. She responded well to intravitreal bevacizumab injections and visual acuity improved to 20/25 OD. Preventative care was emphasized and the patient was referred to cardiology, gastroenterology and human genetics for counseling. CONCLUSION: PXE is a multisystem disorder affecting the dermatologic, ocular, and cardiovascular systems. Ophthalmic findings of angioid streaks and choroidal neovascularization in the presence of stereotypical skin changes and prominent mental creases should prompt evaluation for PXE.

Anti-vascular endothelial growth factor treatment for choroidal neovascularization secondary to angioid streaks in pseudoxanthoma elasticum： a case report and systemic review

The present study reports a case of a patient with choroidal neovascularization(CNV)associated with pseudoxanthoma elasticum(PXE).We observed the functional and anatomical improvement of the patient treated with intravitreal vascular endothelial growth factor(VEGF)inhibitor bevacizumab.The study also systematically searched the database for similar cases to provide a literature review.Data concerning the clinical features,treatment strategies and outcomes were extracted and analyzed.Retrospective interventional case report and systematic literature review.A 56-year-old healthy Chinese woman with CNV secondary to PXE was reported.Examinations included best corrected visual acuity(BCVA),biomicroscopy,optical coherence tomography(OCT),fluorescein and indocyanine green angiography and digital fundus photography.The patient managed with intravitreal anti-vascular endothelial growth factor(anti-VEGF)injections(bevacizumab 1.25 mg/0.05 m L).The Cochrane Library,Pub Med,OVID,and Up To Date databases were searched using the term pseudoxanthoma elasticum or Gr?nblad-Strandberg syndrome with the limits English.Articles that predated the databases were gathered from current references.Fundus examination revealed angioid streaks bilaterally and CNV in left eye(LE).After the patient underwent three intravitreal injections of bevacizumab,the LE showed absorption of the subretinal fluid and shrinkage of the CNV.Visual acuity(VA)was improved in her treated LE.Bevacizumab treatment was well tolerated with no adverse events reported.Approximately ten articles about 45 patients(49 eyes)describing CNV secondary to angioid streaks in PXE treated with anti-VEGF were found in the literature search.In the present case,bevacizumab of an initial three injection loading dose,achieved maintenance of visual function in the treatment of CNV associated with angioid streaks in PXE.Literature articles concluded that the intravitreal application of anti-VEGF is highly efficient for improving and stabilizing the lesion as well as the eyesight.So we believe that anti-VEGF therapy can be a great choice of treatment for CNV secondary to angioid streaks related PXE.

弹性纤维性假黄瘤一例及基因检测分析

患者,女,28岁。颈部、双肘窝皮疹无痒痛20余年。提取患者外周血DNA行全外显子基因检查可检测到ABCC6基因突变,对其变异进行一代测序验证,检出c.4404-1G>A和c.3703C>T:p.R1235W均为杂合变异。根据皮肤损害及基因检查,诊断考虑弹性纤维性假黄瘤。治疗上颈部皮下结节给予手术治疗,术后随诊6个月未复发。

弹性纤维性假黄瘤一例

患者,女,12岁。颈前、胸腹部弥漫性黄色斑丘疹3个月。皮损组织病理示真皮层内见灶状分布的纤维组织,免疫组化示CD163(+),Ki-67(约1%+)。特殊染色:Van Gieson染色(+),弹力纤维染色(±),网织纤维染色(-)。行全外显子组高通量测序,基因检测结果为ABCC6基因发生c.2312del半合子突变,患者父母及家属均无相关症状,未进行基因检测,突变来源未知。结合患者临床表现及基因结果,诊断为弹性纤维性假黄瘤,未予治疗,目前密切随访中。

Angioid Streaks in Psuedoxanthoma Elasticum

Pseudoxanthoma elasticum (PXE) is a hereditary disorder that affects primarily the elastic tissues of skin, eyes and blood vessels. Its estimated prevalence is thought to be 1:25,000 - 100,000. PXE patients also carry an increased risk for cardiovascular and gastrointestinal diseases. Early diagnosis can play a crucial role in preventing early loss of vision and systemic complications in these patients however despite having characteristic clinical features;it is still to a large extent being under-diagnosed. Here we present two cases of PXE with reduced vision.

弹性纤维假黄瘤研究进展

弹性纤维假黄瘤(PXE)是一种罕见的以结缔组织异位钙化为特征的遗传性疾病,主要累及皮肤、视网膜、心血管等多种器官和系统,特征性的病理改变为真皮弹性纤维异常钙化和碎裂。其发病主要与ABCC6基因突变有关,ABCC6参与维持血清无机焦磷酸(PPi)的稳态,PPi是异位钙化的主要抑制剂,PPi缺乏可导致异位钙化的发生。PXE的临床表现具有高度异质性,典型皮损为淡黄色扁平丘疹、斑块,后期可表现为皮肤松弛、皱缩等症状,眼部、心血管等并发症则严重影响患者的健康及生活质量。PXE治疗包括改善症状、系统性抗异位钙化、基因治疗等方面。本文就PXE临床表现、发病机制及诊断治疗的研究进展进行综述。

Kidney Stones Are Prevalent in Individuals with Pseudoxanthoma Elasticum, a Genetic Ectopic Mineralization Disorder

Objective:Pseudoxanthoma elasticum(PXE)is a rare genetic disorder caused by loss-of-function mutations in the ABCC6 gene.While PXE is characterized by ectopic mineralization of connective tissues clinically affecting the skin,eyes,and cardiovascular system,kidney stones were reported in some individuals with PXE.The aim of this study is to determine whether kidney stones are an incidental finding or a frequent manifestation of PXE.Methods:We first investigated the genetic basis of two siblings diagnosed with PXE.The younger patient presented with recurrent kidney stones since 8 years old.Secondly,to address whether kidney stones are associated with PXE,the prevalence of kidney stones in a survey cohort of 563 respondents with PXE was compared to that of a general U.S.population survey,National Health and Nutrition Examination Survey,with 28,629 participants.Results:Genetic analysis in both patients identified compound heterozygous mutations in ABCC6,c.2787+1G>T,and c.3774_3775insC.The analysis of participants 20 years old and older revealed that 23.4%of PXE patients had previously had a kidney stone,a significant increase compared to 9.2%in the general population(P<0.01).In addition,17.8%of PXE patients reported their first kidney stone episode before age of 18 years old.Conclusions:PXE correlates with an increased risk of developing kidney stones with considerable morbidity and health-care cost.

弹性纤维性假黄瘤1例

报告1例颈部弹性纤维性假黄瘤。患者女,41岁。颈部多发性肤色或淡黄色扁平丘疹40余年,偶觉瘙痒。组织病理学检查示真皮网状层中部有多量波纹状、扭曲、断裂或不规则形状的深嗜碱性纤维成分。诊断为弹性纤维性假黄瘤。

弹性纤维假黄瘤ABCC6基因突变检测

目的对弹性纤维假黄瘤患者的ABCC6基因突变进行检测,为进一步开展基因诊断和基因治疗奠定基础。方法采用聚合酶链反应扩增患者和健康对照个体ABCC6基因的全部外显子,直接测序法进行DNA测序,100例无亲缘关系的正常人作为对照。结果在1例散发患者中检测到1个错义突变(3940C→T),导致其编码蛋白第1314位精氨酸变成色氨酸(R1314W)。其他无亲缘关系的正常对照均未发现该突变。结论该错义突变可影响基因转录和翻译产物,是ABCC6基因的特异性突变。

儿童弹性纤维假黄瘤

报告1例儿童弹性纤维假黄瘤。患儿男,9岁。颈部及腹部丘疹3年。皮肤科检查:颈部及腹部可见成片密集分布的淡黄色粟粒至米粒大丘疹,呈网状排列。皮损组织病理检查:真皮上部和中部可见弹性纤维变性、断裂,排列不规则,呈团块状或颗粒状改变。弹性纤维Verhoeff-Van Gleson染色:真皮可见大量弹性纤维变性、断裂、卷曲,呈碎片或颗粒状。诊断:弹性纤维假黄瘤。

弹性假黄瘤样真皮乳头层弹性纤维溶解症国内首例报告

报告国内首次发现的弹性假黄瘤样真皮乳头层弹性纤维溶解症1例。患者女,38岁。因多发性肌炎10月余,颈部起黄色斑丘疹2月就诊。双侧颈部、锁骨上方有数十个绿豆至黄豆大淡黄色柔软丘疹或斑块,呈鹅卵石样。临床及实验室检查符合多发性肌炎,无眼及心血管改变。组织病理检查以韦杰尔特染液染色,可见真皮乳头层弹力纤维完全消失,真皮网状层内弹性组织轻度减少,von-kossa染色未见钙化。透射电镜真皮乳头层内弹力纤维消失,在真皮网状层上部可见大量未成熟的弹力纤维,胶原纤维结构正常。

儿童弹性纤维性假黄瘤

报告1例幼儿期发病的弹性纤维性假黄瘤。患儿男,8岁。因发现腹部丘疹、斑块5年余,加重1年入院。否认家族遗传病史。体格检查:系统查体未见明显异常。皮肤科检查:双侧颈部、腋窝、胸腹部及腹股沟可见密集融合的黄色扁平丘疹及斑块,下腹部皮肤松弛。腹部B超示肾脏多发性钙化。上腹部皮损组织病理学检查:真皮中层弹性纤维嗜碱性变、断裂。诊断:弹性纤维性假黄瘤。

无明显外伤史的脉络膜破裂:1例病例报道并文献复习

脉络膜破裂大部分是由撞击引起的对冲伤,冲击力通过玻璃体传导眼底引起,因此一般脉络膜破裂会有比较明确的外伤或者钝挫伤病史。本文将报告1例16岁体校男生在无明显外伤史出现多发性脉络膜破裂伤,通过查阅文献发现有文献报道在隐匿性假性黄色瘤(pseudoxanthoma elasticum,PXE)疾病中可在无明显外伤或轻微外伤出现脉络膜破裂,并根据文献复习考虑本病例为隐匿性PXE可能。

视网膜血管样条纹15例报告

对15例视网膜血管样条纹的临床所见及其条纹特征予以描述，就其形态划为矢状、环孤状和网状．并对血管样纹发生机理、组织病理学所见等进行了讨论。

From variome to phenome:Pathogenesis,diagnosis and management of ectopic mineralization disorders

Ectopic mineralization- inappropriate biomineralization in soft tissues- is a frequent finding in physiological aging processes and several common disorders, which can be associated with significant morbidity and mortality. Further, pathologic mineralization is seen in several rare genetic disorders, which often present life-threatening phenotypes. These disorders are classified based on the mechanisms through which the mineralization occurs: metastatic or dystrophic calcification or ectopic ossification. Underlying mechanisms have been extensively studied, which resulted in several hypotheses regarding the etiology of mineralization in the extracellular matrix of soft tissue. These hypotheses include intracellular and extracellular mechanisms, such as the formation of matrix vesicles, aberrant osteogenic and chondrogenic signaling, apoptosis and oxidative stress. Though coherence between the different findings is not always clear, current insights have led to improvement of the diagnosis and management of ectopic mineralization patients, thus translating pathogenetic knowledge(variome) to the phenotype(phenome). In this review, we will focus on the clinical presentation, pathogenesis and management of primary genetic soft tissue mineralization disorders. As examples of dystrophic calcification disorders Pseudoxanthoma elasticum, Generalized arterial calcification of infancy, Keutel syndrome, Idiopathic basal ganglia calcification and Arterial calcification due to CD73(NT5E) deficiency will be discussed. Hyperphosphatemic familial tumoral calcinosis will be reviewed as an example of mineralization disorders caused by metastatic calcification.

Comprehensive validation of a diagnostic strategy for sequencing genes with one or multiple pseudogenes using pseudoxanthoma elasticum as a model

Pseudogenes are frequently encountered noncoding sequences with a high sequence similarity to their protein-coding paralogue.For this reason,their presence is often considered troublesome in molecular diagnostics.In pseudoxanthoma elasticum(PXE),a disease predominantly caused by mutations in ATPbinding cassette family C member 6(ABCC6),the presence of two pseudogenes complicates the analysis of sequence data.With whole-exome sequencing(WES)becoming the standard of care in molecular diagnostics,we wanted to evaluate whether this technique is as reliable as gene-specific targeted enrichment analysis for the analysis of ABCC6.We established a PCR-based targeted enrichment and next-generation sequencing testing approach and demonstrated that the ABCC6-specific enrichment combined with the applied mapping algorithm overcomes the complication of ABCC6 pseudogene aspecificities,contrary to WES.We propose a time-and cost-efficient diagnostic strategy for comprehensive and accurate molecular genetic testing of PXE,which is highly automatable.

弹性假黄瘤的脉络膜新生血管和血管样条纹症(英文)

目的:报告1例表现为双眼视力模糊的48岁女子患弹性假黄瘤病(pseudoxanthoma elasticum,PXE)的病例。方法:病例报告。结果:患者,女,48岁,双眼视力模糊,右眼视物变形。10a前因左眼患血管样条纹症接受激光手术,残余视力较差。右眼视力为20/60,左眼6英尺数指。眼底检查可见视网膜下出血和右侧黄斑增厚及左侧椭圆形黄斑瘢痕伴病灶萎缩性色素上皮病变。双眼有血管样条纹和橙色视网膜色素图案。外部检查发现颈部侧面和后面有几处黄色皮肤丘疹和斑块,以及明显的颏皱褶。皮肤切片病理检查证实了PXE的诊断,显示有网状真皮层深层的钙沉积和成碎片的成丛的弹性纤维。患者对玻璃体内注射贝伐单抗反应良好,右眼视力提高到20/25。强调预防保健的重要性,建议患者求助于心脏病学、胃肠病学和人类遗传学咨询服务。结论:PXE是一个累及多系统的疾病,它影响着皮肤、眼和心血管系统。在固有的皮肤变化和明显的颏皱褶的存在下,血管样条纹症和脉络膜新生血管的眼科发现能提高PXE的评估。

Cutaneous Manifestations of Sickle Cell Disease

Sickle cell disease is an inherited erythrocyte disorder affecting multiple organ systems. As individuals are living well into middle age due to advances in diagnosis and treatment, further disease-related complications are being recognized. This article reviews the cutaneous manifestations of sickle cell disease including leg ulcers and acquired pseudoxanthoma elasticum.

Atherogenic Diet Accelerates Ectopic Mineralization in a Mouse Model of Pseudoxanthoma Elasticum

Objective:Pseudoxanthoma elasticum(PXE)is a multisystem heritable disorder caused by mutations in the Abcc6 gene.The disease is characterized by ectopic mineralization of the skin,eyes,and arterial blood vessels.Previous studies have suggested that cardiovascular complications in patients with PXE are caused in part by premature atherosclerosis.The aim of this study is to determine the effect of an atherogenic diet on ectopic mineralization.Methods:We used Abcc6^(tm1JfK)mice(Abcc6^(-/-)mice)as an established preclinical model of PXE.The offspring at age of 4 weeks were divided into two groups and fed the standard control laboratory diet(control group)and the atherogenic diet.Serum lipid profiles and bile acids were measured,and steatosis and tissue mineralization were evaluated by histopathologic analysis and chemical calcium quantification assay,respectively.Results:After 50-58 weeks of feeding an atherogenic diet,the concentrations of total cholesterol,low-density lipoprotein/very-low-density lipoprotein cholesterol,and bile acids were significantly higher in the Abcc6^(-/-)mice on the atherogenic diet(180.9±14.8 g/L,145.9±12.9 g/L,and 9.7±1.4μmol/L,respectively)than in Abcc6^(-/-)mice on a control diet(85.2±4.8 g/L,25.1±5.5 g/L,and 3.3±0.5μmol/L,respectively)(P<0.001).Hypercholesterolemia was accompanied by extensive lipid accumulation in the liver and aorta,a characteristic feature of steatosis.The direct calcium assay demonstrated significantly increased mineralization of the muzzle skin containing the dermal sheath of vibrissae(57.2±4.4μmol Ca/gram tissue on the atherogenic diet and 43.9±2.2μmol Ca/gram tissue on control diet;P<0.01),a reproducible biomarker of the ectopic mineralization process in these mice.An increased frequency of mineralization was also observed in the kidneys and eyes of mice on the atherogenic diet(P<0.01).Conclusion:These observations suggest that the atherogenic diet caused hypercholesterolemia and accelerated ectopic mineralization in the Abcc6^(-/-)mice.Our findings have clinical implications for patients with PXE,a currently intractable disorder with considerable morbidity and occasional mortality.

弹性假黄色瘤一例ABCC6基因突变分析

目的：报告1例弹性假黄色瘤，并检测ABCC6基因突变情况。方法分析1例弹性假黄色瘤先证者的临床资料，并收集其父母、儿子及100例无亲缘关系的健康对照的外周血，提取基因组DNA，PCR扩增ABCC6基因编码区31个外显子，并进行DNA直接测序与ABCC6编码蛋白质功能预测。结果先证者父母及儿子表型均正常。基因突变分析显示，先证者存在ABCC6基因c.373G〉A（p.E125K）和c.3703C〉T （p.R1235W）的复合杂合突变，先证者母亲为c.3703C〉T（p.R1235W）杂合突变携带者，先证者父亲和儿子为c.373G〉A（p.E125K）杂合突变携带者，而100例无亲缘关系的健康对照均未检测到该两种突变。物种间序列比对分析发现，ABCC6编码蛋白质第125位谷氨酸和第1235位精氨酸为进化高度保守的序列，SIFT和Polyphen-2软件预测c.373G〉A（p.E125K）和c.3703C〉T（p.R1235W）突变为有害变异位点。结论 ABCC6基因c.373G〉A（p.E125K）和c.3703C〉T（p.R1235W）的复合杂合突变可能是该例弹性假黄色瘤患者发病的原因。