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.

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.

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.

Clinical and Genetic Investigation of a Multi-generational Chinese Family Afflicted with Von Hippel-Lindau Disease

Background：Von Hippel-Lindau （VHL） disease is a hereditary tumor disorder caused by mutations or deletions of the VHL gene.Few studies have documented the clinical phenotype and genetic basis of the occurrence of VHL disease in China.This study armed to present clinical and genetic analyses of VHL within a five-generation VHL family from Northwestern China,and summarize the VHL mutations and clinical characteristics of Chinese families with VHL according to previous studies.Methods：An epidemiological investigation of family members was done to collect the general information.A retrospective study of clinical VHL cases was launched to collect the relative clinical data.Genetic linkage and haplotype analysis were used to make sure the linkage of VHL to disease in this family.The VHL gene screening was performed by directly analyzing DNA sequence output.At last,we summarized the VHL gene mutation in China by the literature review.Results：A five-generation North-western Chinese family afflicted with VHL disease was traced in this research.The family consisted of 38 living family members,of whom nine were affected.The individuals afflicted with VHL exhibited multi-organ tumors that included pheochromocytomas （8）,central nervous system hemangioblastomas （3）,pancreatic endocrine tumors （2）,pancreatic cysts （3）,renal cysts （4）,and paragangliomas （2）.A linkage analysis resulted in a high maximal LOD score of 8.26 （theta =0.0） for the marker D3S1263,which is in the same chromosome region as VHL.Sequence analysis resulted in the identification of a functional C〉T transition mutation （c.499 C〉T,p.R167W） located in exon 3 of the 16th codon of VHL.All affected individuals shared this mutation,whereas the unaffected family members and an additional 100 unrelated healthy individuals did not.To date,49 mutations have been associated with this disease in Chinese populations.The most frequent VHL mutations in China are p.S65 W,p.N78 S,p.R161Q and p.R167 W.Conclusions：The results supported the notion that the genomic sequence that corresponds to the 167th residue of VHL is a mutational hotspot.Further research is needed to clarify the molecular role of VHL in the development of organ-specific tumors.

Imaging manifestations of von Hippel-Lindau disease: a report of 3 casesImaging manifestations of von Hippel-Lindau disease: a report of 3 cases

Von Hippel-Lindau (VHL) disease is an autosomal dominant here ditary familial neoplasm syndrome characte rized by development of a variety of benign and malignant tumors in multiple organ systems,such as the brain,kidney,pancreas,adrenalgland,and epididymis,with aprev a lence of one in 39000- 53000.1 4 Hallmarks of the condition in clude retinal angiomas,hem angioblastomas of the cerebellum and the spinal cord,renal cell carcinoma and cysts,and pheochrom ocytomas.In this article,we report imaging findings in three cases of VHLdisease.

Genetic characterization and protein stability analysis of a Chinese family with Von Hippel-Lindau disease

Background Von HippeI-Lindau disease （VHL）,a heritable autosomal dominant disease characterized by neoplasia in multiple organ systems,has rarely been reported in Asia.We genetically investigated a unique Chinese family with VHL disease and performed an analysis of the VHL protein stability.Methods Genomic deoxyribonucleic acid （DNA） extracted from peripheral blood was amplified by polymerase chain reaction （PCR） to three exons of the VHL gene in 9 members of the Chinese family with VHL disease.PCR products were directly sequenced.We estimated the effects of VHL gene mutation on the stability of pVHL,which is indicated by the free energy difference between the wild-type and the mutant protein （△△G）.Results The Chinese family was classified as VHL type 1.Three family members,including two patients and a carrier,had a T to G heterozygotic missense mutation at nucleotide 515 of the VHL gene exon 1.This missense mutation resulted in the transition from leucine to arginine in amino acid 101 of the VHL protein.There was low stability of the VHL protein （the △△G was 12.71 kcal/mol） caused by this missense mutation.Conclusions We first reported a family with this VHL gene mutation in Asia.This missense mutation is predicted to significantly reduce the stability of the VHL protein and contribute to the development of the renal cell carcinoma （RCC） phenotype displayed by this family.The genetic characterization and protein stability analysis of families with VHL disease are important for early diagnosis and prevention of the disease being passed on to their offspring.

Management of solid renal tumour associated with von Hippel-Lindau disease

Von Hippel-Lindau （VHL） disease is a rare autosomal dominant disorder caused by germ line mutations of the VHL tumour suppressor gene. it predisposes affected individuals to develop a variety of neoplasms, including haemangioblastomas of the central nervous system, retinal angiomas, renal cell carcinomas （RCCs）, pheochromocytomas and cysts of the kidneys and epididymis. Germ line VHL mutations have been found in all VHL disease families. RCC occurs in 25% to 45% of patients with VHL disease and is one of the leading causes of death.

Genetic study of a large Chinese kindred with von Hippel-Lindau disease

Background Von Hippel-Lindau (VHL) disease is a heraditary cancer syndrome caused by germline mutations of the VHL tumor on the suppressor gene. This study was to show the clinical characteristics of a large Chinese kindred with von Hippel-Lindau disease and to evaluate the role of the genetic test of VHL disease in the diagnosis of VHL disease and clinical screening of members of the VHL disease family.Methods DNA extracted from peripheral blood was amplified by PCR to three exons of the VHL gene in 27 members of a large kindred with VHL disease. PCR products were directly sequenced. The involvements of multi-organs in the kindred with VHL disease were confirmed by history taking and radiography.Results Of 47 members in the four generations of the kindred, 18 members were diagnosed as having VHL desease. Clinical manifestations of 18 patients included: central nervous system (CNS) hemangioblastoma (5), renal cell carcinoma and CNS hemangioblastoma (3), renal cell carcinoma and retinal angioma (3), renal cell carcinoma and multiple pancreatic cysts (1), renal cell carcinoma and retinal angioma and multiple pancreatic cysts (2), renal cell carcinoma and CNS hemangioblastomas and multiple pancreatic cysts (1), and multiple pancreatic cysts and multiple renal cysts (1), multiple pancreatic cysts (2). The common lesions of the 18 patients were renal cell carcinoma (55.6%), CNS hemangioblastoma (50.0%), retinal angioma (27.8%), and multiple pancreatic cysts (38.9%). Among the 27 members who volunteered for genetic analysis, 15 members including 9 affected family patients and 2 asymptomatic patients and 4 carriers, who are still alive, presented a codon 78 from Asn to Ser change at nucleotide 446 (A→G) in exon 1. Four members were carriers with the same VHL gene mutation. Two asymptomatic patients were initially diagnosed by genetic testing and subsequently confirmed radiologically and surgically. Members without gene mutation had no clinical evidence of VHL disease.Conclusions The large Chinese kindred with VHL disease was classified as type Ⅰ. The main characteristics in the kindred were higher incidence of renal cell carcinoma and lower incidence of retinal angioma. Genetic test plays an important role in early detecting asymptomatic patients and the carriers in clinical screening of members of the families with VHL disease. It is also important to prevent the transmission of VHL disease to their offsprings in the kindred.

Von Hippel-Lindau protein and respiratory diseases

Von Hippel-Lindau protein(p VHL) was first identified as a tumor suppressor gene as mutations in the VHL gene predispose individuals to systemic benign or malignant tumors and cysts in many organs, including renal cell carcinoma of the clear-cell type and hemangioblastoma. Although p VHL is best known to act as a component of ubiquitin protein ligase for the proteasomal degradation of hypoxia inducible factor(HIF)-α, p VHL also interacts with extracellular matrix proteins and cytoskeleton, regulating extracellular matrix assembly, cell signaling, and many other cellular functions. Recent studies suggest that p VHL contributes to many lung diseases, including pulmonary arterial hypertension, lung cancer, pulmonary fibrosis, and acute respiratory distress syndrome. Mutation or loss of function of p VHL activates HIF and induced expression of vascular endothelial growth factor, endothelin-1, and Fox M1, leading to pulmonary arterial hypertension. Loss of p VHL in lung cancer cells promotes epithelial-mesenchymal transition and cancer migration and invasion while decreasing lung cancer cell proliferation and colonization. In patients of idiopathic pulmonary fibrosis, elevated expression of p VHL induces expression of fibronectin/integrin α5β1/focal adhesion kinase signaling, resulting in fibroproliferation and fi-brosis. In alveolar epithelial cells, p VHL mediates Na, K-ATPase degradation in an HIF independent pathway, causing decreased edema clearance during hypoxia. These studies suggest that p VHL plays key roles in the pathogenesis of many lung diseases, and further investigations are warranted to elucidate the underlying molecular mechanisms.

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

AIM 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.METHODS Consecutive 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: V W F : R C o/V W F : A g, V W F : C B/V W F : A g, V W F : A g/ADAMTS13 act, and ADAMTS13act/ADAMTS13:Ag. RESULTS Compared 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 ADAMTS13 act 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). CONCLUSION Complex 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.

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。

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 typeⅠ(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’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’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.

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。