Diagnosis and management of pancreatic neuroendocrine tumor in von Hippel-Lindau disease

The pancreatic manifestations seen in patients with von Hippel-Lindau(VHL) disease are subdivided into 2 categories:pancreatic neuroendocrine tumors(NET),and cystic lesions,including simple cyst and serous cystadenoma.The VHL-associated cystic lesions are generally asymptomatic and do not require any treatment,unless they are indistinguishable from other cystic tumor types with malignant potential.Because pancreatic NET in VHL disease are non-functioning and have malignant potential,it is of clinical importance to find and diagnose these as early as possible.It will be recommended that comprehensive surveillance using dynamic computed tomography for abdominal manifestations,including pancreatic NET,should start from the age of 15 years in VHL patients.Unlike sporadic non-functioning NET without VHL disease,in which surgical resection is generally recommended,VHL patients at lower metastatic risk of pancreatic NET should be spared the risks of operative resection.

Spontaneous intramural duodenal hematoma in type 2B von Willebrand disease

Intramural duodenal hematoma is a rare cause of a proximal gastrointestinal tract obstruction.Presentation of intramural duodenal hematoma most often occurs following blunt abdominal trauma in children,but spontaneous non-traumatic cases have been linked to anticoagulant therapy,pancreatitis,malignancy,vasculitis and endoscopy.We report an unusual case of spontaneous intramural duodenal hematoma presenting as an intestinal obstruction associated with acute pancreatitis in a patient with established von Willebrand disease,type 2B.The patient presented with abrupt onset of abdominal pain,nausea,and vomiting.Computed tomography imaging identified an intramural duodenal mass consistent with blood measuring 4.7 cm×8.7 cm in the second portion of the duodenum abutting on the head of the pancreas.Serum lipase was 3828 units/L.Patient was managed conservatively with bowel rest,continuous nasogastric decompression,total parenteral nutrition,recombinant factorⅧ(humateP)and transfusion.Symptoms resolved over the course of the hospitalization.This case highlights an important complication of an inherited coagulopathy.

Levels and activities of von Willebrand factor and metalloproteinase with thrombospondin type-1 motif, number 13 in inflammatory bowel diseases

To evaluate the levels of von Willebrand factor (VWF) and metalloproteinase with thrombospondin type-1 motif, number 13 (ADAMTS13) in inflammatory bowel disease (IBD) and correlate them with the disease activity. METHODSConsecutive patients with IBD aged 18 years or older were enrolled in the study. Forty-seven patients with ulcerative colitis (UC), 38 with Crohn’s disease (CD), and 50 healthy controls were included. The white blood cell count, haematocrit, platelet count, fibrinogen, partial activated thromboplastin time, C-reactive protein, albumin, VWF antigen level (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), VWF collagen-binding activity (VWF:CB), and ADAMTS13 antigen level (ADAMTS13:Ag) and activity (ADAMTS13act) were measured. The following ratios were assessed: VWF:RCo/VWF:Ag, VWF:CB/VWF:Ag, VWF:Ag/ADAMTS13act, and ADAMTS13act/ADAMTS13:Ag. RESULTSCompared to controls, the odds ratio (OR) of an elevated VWF: Ag > 150% was 8.7 (95%CI: 2.7-28.1) in the UC group and 16.2 (95%CI: 4.8-54.0) in the CD group. VWF:CB was lower in UC patients, and active CD was associated with a higher VWF: RCo (+38%). The ORs of VWF:CB/VWF:Ag < 0.7 (a marker of acquired von Willebrand syndrome) in the UC and CD groups were 11.9 (95%CI: 4.4-32.4) and 13.3 (95%CI: 4.6-38.1), respectively. Active UC was associated with lower ADAMTS13:Ag (-23%) and ADAMTS13act (-20%) compared to UC in remission. Patients with active CD had a 15% lower ADAMTS13act than controls. The activity of UC, but not that of CD, was inversely correlated with ADAMTS13:Ag (r = -0.76) and ADAMTS13act (r = -0.81). CONCLUSIONComplex VWF-ADAMTS13-mediated mechanisms disturb haemostasis in IBD. A reduced WVF:CB is a risk factor for bleeding, while a lower ADAMTS13 level combined with an elevated VWF:Ag could predispose one to thrombosis.

Changing insights in the diagnosis and classification of autosomal recessive and dominant von Willebrand diseases 1980-2015

The European Clinical Laboratory and Molecular(ECLM) criteria define 10 distinct Willebrand diseases(VWD) recessive type 3, severe 1, 2C and 2N; dominant VWD type 1 secretion/clearance defect, 2A, 2B, 2E, 2M and 2D; and mild type 1 VWD(usually carriers of recessive VWD). Recessive severe 1 and 2C VWD are characterized by secretion and multimerization defects caused by mutations in the D1-D2 domain. Recessive 2N VWD is a mild hemophilia due to D'-FVIII-von Willebrand factor(VWF) binding site mutations. Dominant 2E VWD caused by heterozygous missense mutations in the D3 domain is featured by a secretion-clearancemultimerization VWF defect. Dominant VWD type 2M due to loss of function mutations in the A1 domain is characterized by decreased ristocetin-induced platelet aggregation and VWF RCo, normal VWF multimers and VWF CB, a poor response of VWF RCo and good response of VWF CB to desmopressin(DDAVP). Dominant VWD type 2A induced by heterozygous mutations in the A2 domain results in hypersensitivity of VWF for proteolysis by ADAMTS13 into VWF degradationproducts, resulting in loss of large VWF multimers with triplet structure of each individual VWF band. Dominant VWD type 2B due to a gain of function mutation in the A1 domain is featured by spontaneous interaction between platelet glycoprotein Ib(GPIb) and mutated VWF A1 followed by increased proteolysis with loss of large VWF multimers and presence of each VWF band. A new category of dominant VWD type 1 secretion or clearance defect due to mutations in the D3 domain or D4-C1-C5 domains consists of two groups Those with normal or smeary pattern of VWF multimers.

von Willebrand Factor and von Willebrand Disease

von Willebrand factor (vWF) is an important compound in the human plasma. which is synthesized by endotlrelial cells and also by megakaryocytes. The gene for vWF is located near the tip of the short arm of chromosome 12, being approximately 180 kb in length and consisting of 52 exons separated by 51 introns. The mature vWF subunit consists of 2 050 amino acid residues with molecular weight of about 250 ku. In plasma vWF appears as various multimers. vWF has two well-characterized functions.

Neurofibromatosis Type 1 or Von Recklinghausen Disease: About Three Cases to the National Hospital of Niamey and Literature Review

We report three cases of neurofibromatosis type 1 disease with literature review, collected in the department of neurology and internal medicine from National Hospital of Niamey (HNN). Two of them were men and the first signs were noted by the mother at the birth in 2 cases. Only one case of consanguinity was observed. Clinically, light brown spots on the skin, neurofibromas, Lisch nodules were constantly observed. Histopathological’s exam confirmed neurofibromas. Moreover, cutaneous and ophthalmological manifestations lead to the diagnostic. Two cases of orthopedic complications were observed: one scoliosis and one Congenital dysplasia of the long bones. There was no specific treatment. Neurofibromatosis type 1 or von Recklinghausen’s disease is the most frequent phacomatosis and its diagnosis is usually composed of a set of clinical criteria of the National Institute Health (Bethesda, 1988).

Small bowel volvulus as a complication of von Recklinghausen's disease:A case report

We report the case of a 25-year-old male with Neurofibromatosis type&#x02005;I&#x02005;(NF-1), who presented at the time of admission with clinical findings of an acute abdomen caused by a mechanical obstruction. Computerized tomography showed a volvulus of the terminal ileum with mesenteric swirling as the cause of the patient&#x02019;s symptoms. Consecutive exploratory laparotomy confirmed the diagnosis and 70 cm of the small intestine was resected due to an affection of the mesentery by multiple neurofibromas. The gastrointestinal tract is affected in approximately 10% of patients with NF-1, however the mesentery is almost always spared. Here we describe the unique case of a patient with a volvulus caused by mesenteric manifestation of von Recklinghausen&#x02019;s disease, emphasizing the role of surgery in a team of multidisciplinary specialists to treat this multiorganic disease.

Autoimmune Diseases and Acquired Von Willebrand Disease in Two Cases of Progeria

Ammar A., a 23-year-old male patient, who lives in Babylon, Haswa District, and his mother describes symptoms of growth retardation, skin changes, hair changes early graying and alopecia. These manifestation started early during his childhood period. There is canseguanity between the patient’s mother & father also one of the patient’s sister has similar illness and one male brother died few months following his birth. We admit the patient to hospital due acute pulmonary infection in Jan 2009, which is controlled after a course of antibiotic and after 5 months he develops generalised mucocuteneous bullous eruption which shows partial response to oral prednisolone 2 mg/Kg. The patient has normal IQ and he is in the secondary school and he has normal blood picture and the only abnormal biochemical abnormalities is mild hyperlipidemia Serum cholestrol of 5.8 mmol/L and Serum Triglyceride of 260 mg/dl. Ammar’s Sister Qawthar A., who has a similar phenotypic manifestations, presented skin vitiligo and hepatosplenomegaly associated with sever anemia and jaundice and her presentation suggestive of autoimmune haemolytic anemia improved following blood transfusion, corticosteroid and azothioprim. In February 2014 Ammer presented with multiple and diffuse cuteneous ecchymymosis with markedly prolonged PTT and slightly proloned bleeding time highly consistent with acquired Von Willebrand’s disease. In conclusion premature aging is a predisposing factor for disturbed immunity and development of autoimmune diseases.

Ileocolic Intussusception Prolapsing from the Rectum in von Recklinghausen's Disease

Intussusception is a paediatric condition that rarely presents in adults. We report an exceptional case of ileocolic intussusception prolapsing from the rectum in an adult with Von Recklinghausen′s disease. A 31-year-old man with von Recklinghausen′s disease presented to emergency department with a history of severe abdominal pain, vomits and rectal bleeding. Abdominal computed tomography showed intestinal obstruction probably due to a sigmoidorectal intussusception. Ileum, appendix, cecum and ascending colon were found to be intussuscepting through transverse, descending and sigmoid colon and prolapsing from the rectum during an emergent laparotomy. A right hemicolectomy was performed. An anatomical pathology examination revealed a neurofibroma of the appendix as lead point for intussusception. Intussusception in adults requires early surgical resection regardless of the nature of the initial case. Neurofibroma of the appendix is very rare;although it is benign, prompt resection is recommended because of a high risk of appendicitis and malignant transformation.

Genome-Wide Analysis of von Willebrand Factor A Gene Family in Rice for Its Role in Imparting Biotic Stress Resistance with Emphasis on Rice Blast Disease

von Willebrand factor A(vWA)genes are well characterized in humans except for few BONZAI genes,but the vWA genes are least explored in plants.Considering the novelty and vital role of vWA genes,this study aimed at characterization of vWA superfamily in rice.Rice genome was found to have 40 vWA genes distributed across all the 12 chromosomes,and 20 of the 40 vWA genes were unique while the remaining shared large fragment similarities with each other,indicating gene duplication.In addition to vWA domain,vWA proteins possess other different motifs or domains,such as ubiquitin interacting motif in protein degradation pathway,and RING finger in protein-protein interaction.Expression analysis of vWA genes in available expression data suggested that they probably function in biotic and abiotic stress responses including hormonal response and signaling.The frequency of transposon elements in the entire 3K rice germplasm was negligible except for 9 vWA genes,indicating the importance of these genes in rice.Structural and functional diversities showed that the vWA genes in a blast-resistant rice variety Tetep had huge variations compared to blast-susceptible rice varieties HP2216 and Nipponbare.qRT-PCR analysis of vWA genes in Magnaporthe oryzae infected rice tissues indicated OsvWA9,OsvWA36,OsvWA37 and OsvWA18 as the optimal candidate genes for disease resistance.This is the first attempt to characterize vWA gene family in plant species.

Multidisciplinary management of patients diagnosed with von Hippel-Lindau disease: A practical review of the literature for clinicians

Objective:The aim of the current review is to summarize the available evidence to aid clinicians in the surveillance,treatment and follow-up of the different primary tumors developed by patients diagnosed with von Hippel-Lindau(VHL)syndrome.Methods:A non-systematic narrative review of original articles,meta-analyses,and random-ized trials was conducted,including articles in the pre-clinical setting to support relevant find-ings.Results:VHL disease is the most common rare hereditary disorder associated with clear cell renal cell carcinoma.Affected individuals inherit a germline mutation in one VHL allele,and any somatic event that disrupt the other allele can trigger mutations,chromosomal rearrange-ments,or epigenetic regulations leading to oncogenesis.From a clinical perspective,patients continuously develop multiple primary tumors.Conclusion:Because VHL is considered a rare disease,very limited evidence is available for diagnosis,surveillance,active treatment with local or systemic therapy and follow-up.

Von Hippel-Lindau病的遗传学及其相关治疗研究进展

Von Hippel-Lindau病(VHL病)是VHL基因变异导致的遗传肿瘤综合征。VHL病相关肿瘤常为多发,其常规治疗方法为手术,但术后易复发。VHL基因具有缺氧诱导因子(HIF)依赖及HIF非依赖的肿瘤抑制作用,关于VHL病遗传学机制的研究为该病的治疗奠定了基础。近年来针对VHL病遗传学机制靶向药物的出现,为该病的治疗提供了新的思路,作用于缺氧诱导通路的小分子靶向药物,如belzutifan、酪氨酸激酶抑制剂,在临床试验中对VHL病的治疗展示了良好的应用前景。本文对VHL病遗传学机制及相关治疗进展进行总结。针对VHL病靶向药物更深入的临床研究将会为该病患者提供更多的治疗选择。

Comprehensive treatment of von Hippel-Lindau disease:A case report

von Hippel-Lindau(VHL)disease is a rare autosomal dominant multiorgan disease characterized by several benign and malignant tumors rich in vascular,as well as cysts in other organs.A great clinical treatment strategy is significantly warranted for good prognosis of patients with VHL disease.Herein,we reported a case of a 45-year-old woman diagnosed with VHL disease with spinal hemangioblastoma(HB)and clear cell renal cell carcinoma(ccRCC).Four years after the resection of the right kidney,a recurrent RCC in the right kidney and a malignant lesion in the left kidney were observed.This patient was started on sorafenib(800 mg,daily)and tislelizumab(200 mg per 3 weeks).After 6 months of treatment,the size of renal cell carcinoma was dramatically reduced and renal function improved.More importantly,she achieved partial response during the whole treatment.Microscopically,intramedullary masses resection was done and the HB in T4-5 thoracic spinal was removed.Neurologic symptoms such as numbness and pain were remarkably alleviated.Additionally,tislelizumab-induced elevation in liver transaminase levels and hypothyroidism were revered by hepatoprotector and levothyroxine,respectively.In short,comprehensive treatment strategies may benefit patients with VHL disease,especially with HB and ccRCC.

Reduced-size liver transplantation for glycogen storage disease

BACKGROUND: Glycogen storage disease (GSD) is an inherited metabolic disorder in which the concentration and/or structure of glycogen in tissues is abnormal. Essentially, abnormalities in all known enzymes involved in the synthesis or degradation of glycogen and glucose have been found to cause some type of GSD. Liver and muscle have abundant quantities of glycogen and are the most common and seriously affected tissues. This study was to assess reduced-size liver transplantation for the treatment of GSD. METHODS: The clinical data from one case of GSD type I with hepatic adenoma was retrospectively analyzed. The clinical manifestations were hepatomegaly, delayed puberty, growth retardation, sexual immaturity, hypoglycemia, and lactic acidosis, which made the young female patient eligible for reduced-size liver transplantation. RESULTS: The patient recovered uneventfully with satisfactory outcome, including 12 cm growth in height and 5 kg increase in weight during 16 months after successful reduced-size liver transplantation. She has been living a normal life for 4 years so far. CONCLUSIONS: Reduced-size liver transplantation is an effective treatment for GSD with hepatomegaly and hepatic adenoma. Delayed puberty, growth retardation, hypoglycemia and lactic acidosis can be cured by surgery.

Von Hippel-Lindau病的CT及MRI影像学特点

目的:分析Von Hippel-Lindau(VHL)病的CT及MRI影像学特点。方法:回顾性分析7例经基因检测证实的VHL病患者的临床资料及CT、MRI影像学特点。结果:7例患者中,CNS血管母细胞瘤6例(小脑单发2例,腰髓单发1例,脑及脊髓多发3例),MRI表现为实性或囊实性病灶,前者增强后实性结节明显强化,后者呈典型“大囊小结节”伴结节明显强化。视网膜母细胞瘤1例,20年前已手术切除。7例患者腹部均有一个或多个内脏病变,其中胰腺多发囊肿7例,胰腺肿瘤1例,肾透明细胞癌6例(均为多发),肾脏多发囊肿4例,肾上腺嗜铬细胞瘤3例,双侧睾丸肿瘤1例。结论:VHL病累及全身多个器官,影像表现多样,以血管母细胞瘤、胰腺多发囊肿及肾细胞癌最常见,熟悉其影像表现对早期诊断、早期治疗及延长患者生命具有重要意义。

非透析2型糖尿病肾病患者病情严重程度的影响因素分析

目的:探讨非透析2型糖尿病肾病(DKD)患者病情严重程度的影响因素。方法:选取2020年1月—2022年3月海军安庆医院收治的86例非透析2型DKD患者为研究对象,收集患者性别,年龄,体质量指数(BMI),糖尿病病程,高血压分级,入院第2天总胆固醇(TC)、甘油三酯(TG)、空腹血糖、糖化血红蛋白(HbA1c)、尿白蛋白肌酐比值(UACR)、估算肾小球滤过率(eGFR)以及血清超敏C反应蛋白(hs-CRP)、同型半胱氨酸(Hcy)、血管性血友病因子(vWF)水平等资料。根据eGFR对研究对象进行分组,eGFR≥60 m L/(m i n·1.73 m^(2))为A组,eGFR 30~<60 mL/(min·1.73 m^(2))为B组,eGFR<30 mL/(min·1.73 m^(2))为C组,采用多因素Logistc回归分析非透析2型DKD患者病情严重程度的危险因素。结果:单因素分析结果显示,三组受试者间性别、年龄、BMI、高血压分级、TC、TG比较,差异无统计学意义(P>0.05),而糖尿病病程、空腹血糖、HbA1c、UACR以及血清hs-CRP、Hcy、vWF水平比较,差异具有统计学意义(P<0.05);多因素logistic回归分析结果显示,年龄[OR=1.022,95%CI:(1.011,1.033),P<0.001]、糖尿病病程[OR=1.315,95%CI:(1.082,1.591),P=0.013]、高血压分级[OR=1.091,95%CI:(0.994,1.218),P=0.030]、UACR[OR=1.085,95%CI:(1.003,1.162),P=0.022],以及血清hs-CRP[OR=1.031,95%CI:(1.011,1.057),P=0.017]、Hcy[OR=1.018,95%CI:(0.913,1.149),P<0.001]、vWF[OR=1.016,95%CI:(1.011,1.023),P<0.001]水平是非透析2型DKD患者eGFR低的影响因素。结论:非透析2型DKD患者病情严重程度与年龄、糖尿病病程、高血压分级、UACR以及血清hs-CRP、Hcy、vWF水平密切相关。

1例c.1117C>T/c.7288-9T>G复合杂合突变所致血管性血友病家系的发病机制分析

目的探讨1例血管性血友病(vWD)家系的诊断及发病机制。方法家系收集。收集北京大学第一医院就诊的先证者及其家系成员(共4人),检测活化部分凝血活酶时间(APTT)、血管性血友病因子抗原(vWF:Ag)和活性(vWF:Ac)、凝血因子Ⅷ活性(FⅧ:C)、vWF瑞斯托霉素辅因子(vWF:RCo),进行瑞斯托霉素诱导血小板聚集试验(RIPA)、vWF胶原结合(vWF:CB)试验,对先证者及其家系成员进行诊断。提取先证者及其家系成员外周血基因组DNA,进行全外显子测序,分析vWF基因突变,采用生物信息分析工具进行基因突变位点致病性分析,探讨先证者发病机制。结果先证者(Ⅲ_(1))的APTT轻度延长、FⅧ:C正常、vWF:Ag、vWF:Ac、vWF:RCo和vWF:CB明显减低,1.0 mg/mL和1.25 mg/mL的RIPA无明显聚集;父亲(Ⅱ_(3))的APTT、FⅧ:C、vWF:Ag、vWF:Ac和vWF:CB均正常,vWF:RCo轻度减低;母亲(Ⅱ_(4))的APTT、FⅧ:C、vWF:Ag、vWF:RCo和vWF:CB均正常,vWF:Ac明显减低;哥哥(Ⅲ_(2))的APTT、FⅧ:C均正常,vWF:Ag、vWF:Ac、vWF:RCo及vWF:CB均不同程度减低;父亲(Ⅱ_(3))、母亲(Ⅱ_(4))和哥哥(Ⅲ_(2))的1.0 mg/mL RIPA均无明显聚集。基因分析显示先证者(Ⅲ_(1))存在vWF基因c.7288-9T>G和c.1117C>T复合杂合突变,其父亲(Ⅱ_(3))存在vWF基因c.7288-9T>G杂合突变;母亲(Ⅱ_(4))和哥哥(Ⅲ_(2))存在vWF基因c.1117C>T杂合突变。结论先证者为2A型vWD,其vWF基因c.1117C>T和c.7288-9T>G杂合突变可能是导致该先证者发病的原因。

Von Hippel-Lindau综合征的影像学特征

目的分析Von Hippel-lindau(VHL)综合征的CT及MRI表现,探讨其影像学特征。方法回顾性分析经病理证实的9例VHL综合征患者资料,对其CT及MR表现进行系统性分析。结果 9例患者影像学检查均有一处或多处神经系统的血管母细胞瘤,其中3例病变单发于脊髓,2例单发于小脑,4例脊髓与小脑同时发现病变;2例视网膜多发动脉瘤;2例内淋巴囊瘤;8例有胰腺、肝或肾的多发肿瘤和囊肿;4例具有家族遗传史。结论 VHL综合征可累及多个器官,影像及临床表现复杂多样,熟悉掌握其影像学表现有利于疾病的诊断。

KL-6、IL-17与CTD-ILD的相关性研究

目的比较KL-6、IL-17在CTD-ILD与CTD中表达水平的差异,探讨KL-6、IL-17在CTD-ILD中的诊断价值,并分析KL-6、IL-17与肺弥散功能的相关性,为CTD-ILD的诊断和病情严重程度的评估提供依据。方法选取2022年9月1日至2024年01月31日就诊于昆明市第一人民医院的患者。总共收集结缔组织病合并间质性肺疾病患者30例,纳为实验组,即CTD-ILD组;总共收集结缔组织病患者39例,纳为对照组,即CTD组。采用ELISA双夹心抗体法检测KL-6、IL-17,将收集数据进行相关性分析。结果(1)CTDILD组的血清KL-6、IL-17高于CTD组,差异有统计学意义(P<0.05)。(2)KL-6与DLCO%pred之间存在负相关关系(P<0.05),IL-17与DLCO%pred不存在相关关系。(3)通过绘制受试者工作特性曲线(ROC)显示:KL-6、IL-17对诊断CTD-ILD的AUC分别为0.902、0.656。结论KL-6、IL-17可作为诊断CTD-ILD的指标,其中,KL-6的诊断价值高于IL-17。KL-6可作为评价肺弥散功能严重程度的指标;而IL-17不能作为评价肺弥散功能严重程度的指标。

von Hippel-Lindau综合征的CT及MRI表现

目的 von Hippel-Lindau(VHL)综合征是一组罕见的多器官受累的常染色体显性遗传性疾病,临床表现复杂、易误诊。本文探讨VHL综合征的临床特点、CT及MRI特征,提高对本病的早期诊断和综合治疗水平。资料与方法回顾性分析5例VHL综合征患者的临床资料、CT及MRI表现,随访治疗后的结局。结果 5例VHL综合征患者中,小脑血管网织细胞瘤4例,其中1例合并脑干多发血管网织细胞瘤,颈髓多发血管网织细胞瘤1例,典型MRI表现为多发囊实性混杂信号,强化MRI呈实质部明显强化。肾透明细胞癌3例,典型CT表现为等或稍低密度肿块,强化CT可见肿块呈欠均匀强化。双侧附睾囊腺瘤1例,超声示双侧附睾囊实性肿物,实质部分回声不均匀且血流丰富。出院后随访至2015年1月,格拉斯哥预后评分恢复良好3例,死亡2例,均死于肾癌。结论 VHL综合征患者预后较差,肾癌为主要死亡原因。早期应对高度怀疑或已诊断为VHL综合征的患者行VHL基因检测分析并仔细询问其家族史,早期治疗、长期随访及定期影像学检查有助于改善患者预后。