Pathophysiology and management of glaucoma associated with phakomatoses.

The phakomatoses, encephalotrigeminal angiomatosis (ETA; Sturge-Weber Syndrome), neurofibromatosis type 1 (NF1 or von Recklinghausen disease), Von Hippel-Lindau (VHL) disease, tuberous sclerosis (TSC), oculodermal melanocytosis (ODM), and phakomatosis pigmentovascularis are a group of neurocutaneous disorders that have characteristic systemic and ocular manifestations. Through many different mechanisms, they may cause glaucomatous damage of the optic nerve and subsequent vision loss varying from mild to severe. Glaucoma commonly affects patients with ETA (43-72%), orbito-facial NF1 (23-50%), and ODM (10%). Rarely, it may present as neovascular glaucoma in VHL and TSC. In ETA, glaucoma typically occurs ipsilateral to the port-wine stain, which is caused by a mutation in the GNAQ gene. Specifically, mechanical malformation of the anterior chamber angle and elevated episcleral venous pressure has been implicated as causes of glaucoma in ETA. In NF1, which is caused by a mutation in the NF1 tumor suppressor gene, glaucoma commonly occurs ipsilateral to lid plexiform neurofibromas. Histological studies of eyes with NF1 have revealed direct anterior chamber infiltration by neurofibromas, secondary angle closure, fibrovascularization, and developmental angle abnormalities as mechanisms of glaucoma. Lastly, phakomatosis pigmentovascularis is a rare combination of ODM and port-wine stain. Affected patients are at very high risk of developing glaucoma. Despite the many different mechanisms of glaucomatous damage, management follows similar principles as that for congenital glaucoma and primary open angle glaucoma. First-line therapy is topical intraocular pressure-lowering eye drops. Surgical management, including goniotomy, trabeculotomy, trabeculectomy, and tube shunt placement may be required for more severe cases.

Von Hippel-Lindau Disease.

Phakomatoses (phakoma = birthmark) are a group of diseases or syndromes that have hamartomas (tumorous malformations composed of tissues normally present at the location where they develop) of the skin, brain, and eye (oculoneurocutaneous syndromes).

von Hippel-Lindau development in children and adolescents.

The autosomal dominant von Hippel-Lindau disease (vHL) is associated with a lifelong risk of tumor development, especially retinal and CNS hemangioblastomas, pheochromocytoma, and renal cell carcinoma. Knowledge of paediatric vHL development is limited, and current surveillance guidelines are based on expert opinions. We aimed to describe the course of vHL development in children and adolescents, focusing on age at first manifestation, manifestation frequencies, and types. The prevalence of vHL diagnosis as well as manifestations in childhood were evaluated based on 99 patients, who had started surveillance before 18 years: 37 Danish patients from the national vHL research database and 62 international patients reported in 15 articles. Overall, 70% (69 of 99) developed manifestations before 18 years (median age at first manifestation: 12 years (range: 6-17 years)). Thirty per cent (30 of 99) had developed more than one manifestation type; the most frequent were retinal (34%) and CNS (30%) hemangioblastomas. Among the 37 Danish patients, 85% (97 of 116) of their tumors were asymptomatic. Vision outcome is significantly improved in hemangioblastomas that are treated while still asymptomatic. We agree with current guidelines that retinal surveillance be performed from birth. The patients had their first CNS hemangioblastomas at the median ages of 13-14 years (range: 6-17 years). Further, 11% (4 of 37) of the Danish patients had CNS surgery in their teenage years. Although the cohort is too small to make definite conclusions about specific initiation ages, regular CNS surveillance from vHL patients' teenage years seems clinically relevant.

PARS PLANA VITRECTOMY IN ADVANCED CASES OF VON HIPPEL-LINDAU EYE DISEASE.

PURPOSE: To investigate spectrum of patients with Von Hippel-Lindau disease (VHL) that required pars plana vitrectomy and evaluate anatomical and functional outcomes of surgery. METHODS: Twenty-three patients who underwent surgery for advanced VHL eye disease were assessed by genetic tests, diagnostic tests for systemic lesions, and clinical eye examination. The vitrectomized eyes were divided into two groups: with or without retinotomy (group R vs. NR). Functional and anatomical outcome was analyzed and compared between the groups. RESULTS: All patients had central nervous system hemangioblastomas and 57% had other systemic tumors. Point germline mutations, large partial deletions, and complete vhl gene deletions were found in 64%, 27%, and 9% of patients, accordingly. Destruction of hemangioblastomas by retinotomy, laser, or cryotherapy and anatomical attachment of the retina were achieved in all eyes. Preoperative mean distance best-corrected visual acuity was logarithm of the minimum angle of resolution 2.66 (20/9,140) in group R and 1.76 (20/1,150) in group NR (P < 0.05). At 6 months postoperatively, distance best-corrected visual acuity improved in 20 eyes (83%). After over 24 months postoperatively, distance best-corrected visual acuity remained better than preoperatively in 36% in the R group and in 70% in the NR group of eyes. During 24 months postoperatively in 17 eyes, new retinal capillary hemangiomas developed. The mean number of new retinal capillary hemangiomas per eye was higher in group R than in group NR (3.14 vs. 0.70; P < 0.01). In group R, number of new retinal capillary hemangioblastoma was higher in retinal segments where retinotomy was performed (n = 29) than in other areas (n = 13) (P < 0.01). CONCLUSION: Advanced VHL eye disease correlates with occurrence of central nervous system and systemic lesions. Spectrum of vhl gene mutation in the patients corresponds to that of the general VHL population. Pars plana vitrectomy in advanced VHL eye disease can improve or preserve visual function, but postoperative progression of ocular VHL disease can be accelerated in cases where retinotomy is performed.

Terson's Syndrome in a Patient with von Hippel-Lindau Disease.

PURPOSE: Terson's syndrome is a condition where a preretinal hemorrhage forms as a result of increased intracranial pressure. The elevated intracranial pressure is thought to be transmitted through the veins and the optic nerve sheath to the optic disc and retina, causing the thin capillary walls to rupture. The authors present a unique case of Terson's syndrome in a patient who underwent recent surgical management for cerebellar hemangioblastomas related to von Hippel-Lindau disease. CASE REPORT: A 17-year-old African American female patient with a history of von Hippel-Lindau disease presented with pain in her right eye. She had recently undergone surgery to remove cerebellar hemangioblastomas. Preliminary fundus imaging was performed, but before formal ophthalmic testing could be conducted, the patient seized and was taken directly to the emergency room. When the patient returned for a formal evaluation 3 weeks later, a new preretinal "boat-shaped" hemorrhage was now present. Additionally, reports from the emergency room suggested that she had bled into the cavity where the previous cerebellar resection had taken place. This hemorrhage likely led to an increase in intracranial pressure, causing a Terson's-like event. CONCLUSIONS: A Terson's event may be caused by high intracranial pressure secondary to the surgical removal of von Hippel-Lindau syndrome-associated cerebellar tumors and should be included as a possible complication of surgical management.

MicroRNAs in the pathogenesis of cystic kidney disease.

PURPOSE OF REVIEW: Cystic kidney diseases are common renal disorders characterized by the formation of fluid-filled epithelial cysts in the kidneys. The progressive growth and expansion of the renal cysts replace existing renal tissue within the renal parenchyma, leading to reduced renal function. While several genes have been identified in association with inherited causes of cystic kidney disease, the molecular mechanisms that regulate these genes in the context of post-transcriptional regulation are still poorly understood. There is increasing evidence that microRNA (miRNA) dysregulation is associated with the pathogenesis of cystic kidney disease. RECENT FINDINGS: In this review, recent studies that implicate dysregulation of miRNA expression in cystogenesis will be discussed. The relationship of specific miRNAs, such as the miR-17∼92 cluster and cystic kidney disease, miR-92a and von Hippel-Lindau syndrome, and alterations in LIN28-LET7 expression in Wilms tumor will be explored. SUMMARY: At present, there are no specific treatments available for patients with cystic kidney disease. Understanding and identifying specific miRNAs involved in the pathogenesis of these disorders may have the potential to lead to the development of novel therapies and biomarkers.

Perioperative management of pheochromocytoma and catecholamine-induced dilated cardiomyopathy in a pediatric patient.

Dilated cardiomyopathy resulting from pheochromocytoma-mediated catecholamine excess poses a unique challenge to heart failure management. Although early screening of patients with familial neoplastic syndromes at risk for pheochromocytoma may facilitate early resection, the resultant manifestations of prolonged catecholamine excess among patients with undiagnosed pheochromocytoma may lead to myocardial fibrosis with both systolic and diastolic dysfunction. Furthermore, the hemodynamic effects of catecholamine excess exacerbate the risks of perioperative hemodynamic instability in the setting of such myocardial depression. This report describes an approach to the perioperative care of a child who had pheochromocytoma and catecholamine-induced cardiomyopathy with ventricular dysfunction refractory to medical management.

Tubular deficiency of von Hippel-Lindau attenuates renal disease progression in anti-GBM glomerulonephritis.

In many kidney diseases, the original insult primarily involves the glomerulus and may then pass onto the tubulointerstitium. Several hypotheses link glomerular disease to tubular injury; perhaps the foremost hypothesis involves chronic tubular hypoxia. The reported effects of hypoxia and consecutive stabilization of hypoxia-inducible factors (HIFs), however, are controversial. Hypoxia induces interstitial fibrosis but also has beneficial effects on renal disease progression when HIF is activated pharmacologically. To analyze the impact of HIF on tubulointerstitial disease development in primary glomerular disease, transgenic von Hippel Lindau (VHL)-knockout mice were generated and null expression was induced before the onset of autoimmune IgG-mediated anti-glomerular basement membrane glomerulonephritis (GN). Tubular VHL knockout and, thus, local HIF-α stabilization increased renal production of vascular endothelial growth factor, tumor growth factor-ß(1), and platelet-derived growth factor-B, resulting in augmented formation of capillaries and interstitial matrix, and conversion of fibroblasts to myofibroblasts. Within the glomerular disease, VHL knockout reduced the glomerular damage and attenuated tubulointerstitial injury. Likewise, proteinuria, plasma urea concentration, and tubulointerstitial matrix were decreased in VHL knockout with GN. These findings shown that tubular HIF-α stabilization in glomerular disease is beneficial for disease outcome. In comparison with VHL knockout alone, GN is a much stronger activator of fibrosis such that stimuli other than hypoxia may be considered important for renal disease progression.

Longitudinal analysis of retinal hemangioblastomatosis and visual function in ocular von Hippel-Lindau disease.

OBJECTIVE: Characterization of the structural and functional progression of ocular von Hippel-Lindau (VHL) disease and analysis of patient factors influencing disease progression. DESIGN: Retrospective analysis of a case series from a longitudinal, observational study. PARTICIPANTS: Two hundred forty-nine participants with clinically defined systemic VHL disease and more than 2 years of ophthalmic follow-up. METHODS: Standardized scoring of ocular phenotype and systemic characteristics was performed at each study visit and was analyzed longitudinally to determine progression of ocular VHL disease. MAIN OUTCOME MEASURES: Measures evaluated include: visual acuity, features of ocular VHL disease (presence, location, number, and extent of retinal capillary hemangioblastomas [RCHs]), germline mutation in the VHL gene, demographics (age, gender, age at onset of ocular disease), and patient characteristics (smoking status, body mass index). RESULTS: Most participants demonstrated relative anatomic and functional stability in ocular VHL disease status over a mean follow-up of 8.2 ± 4.0 years. Approximately three quarters (73%) of participants without ocular VHL disease at baseline remained disease free at the end of follow-up. Among eyes with ocular VHL disease at baseline, 88% did not demonstrate RCHs in a new retinal location, 70% remained stable in RCH number, and 79% remained stable in the extent of RCH involvement. Mean visual acuity for all study eyes (n = 498) decreased by 5.1 ± 0.6 letters across follow-up, with 16.1% of study eyes decreasing by more than 10 letters in visual acuity. Among eyes affected at baseline, greater vision loss was associated with the presence of juxtapapillary RCHs, development of RCH in a new location, and increase in peripheral RCH number and extent. Younger baseline age, younger age at onset of ocular VHL disease, involvement of the fellow eye with ocular VHL disease, and missense or protein-truncating germline mutations were associated significantly with increased anatomic involvement and functional deterioration. CONCLUSIONS: Patients with ocular VHL disease maintain relative anatomic and functional stability, with only a minority demonstrating marked anatomic progression and vision loss. Systemic and ocular risk factors for anatomic progression and vision loss can help practitioners identify patients with a higher risk profile for counseling, closer follow-up, and proactive treatment. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

von Hippel-Lindau disease: surveillance strategy for endolymphatic sac tumors.

PURPOSE: : Up to 16% of patients with the hereditary von Hippel-Lindau disease develop endolymphatic sac tumors of the inner ear. Early diagnosis and treatment of endolymphatic sac tumors can prevent audiovestibular morbidity, but optimal endolymphatic sac tumor surveillance strategy has yet to be determined. We aimed to evaluate endolymphatic sac tumor surveillance to determine the best surveillance strategy. METHODS: : In a national prospective study, 40 VHL mutation carriers were interviewed about audiovestibular symptoms and had audiological examinations and magnetic resonance imaging of the inner ear. Further, we performed a meta-analysis including all reported endolymphatic sac tumor von Hippel-Lindau disease cases in the literature (N = 140 with 156 endolymphatic sac tumors). RESULTS: : In the prospective study, endolymphatic sac tumors were suspected based on audiovestibular symptoms, audiometry, and magnetic resonance imaging in 34%, 30%, and 12.5% of subjects, respectively. In total, more than 90% of radiologically diagnosed endolymphatic sac tumors were associated with abnormal audiometric findings. No endolymphatic sac tumor genotype-phenotype correlations were found. CONCLUSION: : We recommend annual audiometry as a first-line endolymphatic sac tumor screening tool, and in countries where periodic surveillance magnetic resonance imaging of the central nervous system is performed, specific images of the inner ear should be included. Audiometric abnormalities in patients with von Hippel-Lindau disease without magnetic resonance imaging-visible endolymphatic sac tumors could be due to microscopic endolymphatic sac tumors. Determination of audiometric endolymphatic sac tumor characteristics could further target screening and improve endolymphatic sac tumor diagnosis.

The hypoxia response pathway and ß-cell function.

ß-cells sense glucose and secrete appropriate amounts of insulin by coupling glucose uptake and glycolysis with quantitative ATP production via mitochondrial oxidative pathways. Therefore, oxidative phosphorylation is essential for normal ß-cell function. Multiple cell types adapt to hypoxia by inducing a transcriptional programme coordinated by the transcription factor hypoxia-inducible factor (HIF). HIF activity is regulated by the von Hippel-Lindau (Vhl) protein, which targets the HIFα subunit for proteasomal degradation in the presence of oxygen. Several recent studies have shown that Vhl deletion in ß-cells results in Hif1α activation, impaired glucose-stimulated insulin secretion (GSIS) and glucose intolerance. This was found to be because of alterations in ß-cell gene expression inducing a switch from aerobic glucose metabolism to anaerobic glycolysis, thus disrupting the GSIS triggering pathway. Situations in which islets may become hypoxic are discussed, in particular islet transplantation which has been reported to cause islet hypoxia because of an inadequate blood supply post-transplant. Aside from this principal role for HIF in negatively regulating ß-cell glucose sensing, other aspects of hypoxia signalling are discussed including ß-cell differentiation, development and vascularization. In conclusion, recent studies clearly show that hypoxia response mechanisms can negatively impact on glucose sensing mechanisms in the ß-cell and this has the potential to impair ß-cell function in a number of physiological and clinical situations.

Adult renal cystic disease: a genetic, biological, and developmental primer.

Renal cystic diseases in adults are a heterogeneous group of disorders characterized by the presence of multiple cysts in the kidneys. These diseases may be categorized as hereditary, acquired, or developmental on the basis of their pathogenesis. Hereditary conditions include autosomal dominant polycystic kidney disease, medullary cystic kidney disease, von Hippel-Lindau disease, and tuberous sclerosis. Acquired conditions include cystic kidney disease, which develops in patients with end-stage renal disease. Developmental cystic diseases of the adult kidney include localized renal cystic disease, multicystic dysplastic kidney, and medullary sponge kidney. In recent years, many molecular and cellular mechanisms involved in the pathogenesis of renal cystic diseases have been identified. Hereditary renal cystic diseases are characterized by genetic mutations that lead to defects in the structure and function of the primary cilia of renal tubular epithelial cells, abnormal proliferation of tubular epithelium, and increased fluid secretion, all of which ultimately result in the development of renal cysts. A better understanding of these pathophysiologic mechanisms is now providing the basis for the development of more targeted therapeutic drugs for some of these disorders. Cross-sectional imaging provides useful information for diagnosis, surveillance, prognostication, and evaluation of treatment response in renal cystic diseases.

Clinical characteristics of renal cell carcinoma in Korean patients with von Hippel-Lindau disease compared to sporadic bilateral or multifocal renal cell carcinoma.

This study was done to analyze the clinical characteristics of renal cell carcinoma (RCC) in Korean patients with von Hippel-Lindau (VHL) disease. Between January 1996 and July 2008, 1,514 patients were diagnosed with RCC and 24 patients were diagnosed with VHL disease at our institute. We analyzed the clinical characteristics of the 24 patients diagnosed with VHL. The mean age of patients with VHL was 39.2+/-12.6 yr; the mean age of patients with both VHL and RCC was 42.5+/-10.3 yr. Among the 24 patients with VHL, 7 patients had retinal angiomas, 11 had RCC, 16 had renal lesions, 18 had pancreatic lesions and 21 had cerebellar hemangioblastomas. There was no significant difference between survival rates of patients with VHL alone and those with VHL and RCC. However, cancer-specific survival rates were significantly different between patients with both VHL and RCC and patients with sporadic bilateral or multifocal RCC. In our Korean study, the incidence of RCC in patients with VHL disease is 45.8% and the incidence of VHL disease in patients with RCC is 0.73%. Due to the low overall incidence of VHL in Korea, extended multi-institutional studies are needed to establish the true characteristics of VHL disease.

The ubiquitin-proteasome system in kidney physiology and disease.

Intracellular proteins continuously turn over by degradation and synthesis in all organ tissues. Owing to its irreversible nature, protein degradation is a highly selective process to avoid irreparable breakdown of cellular constituents, thereby disrupting cellular stability, integrity and signalling. The majority of intracellular proteins are degraded by the ubiquitin-proteasome system (UPS), a multi-enzyme process that involves the covalent conjugation of ubiquitin to a substrate protein and its recognition and degradation by the core multicomponent proteolytic complex of the UPS, the proteasome. In addition to labelling misfolded, damaged, aggregation-prone and intact but unneeded proteins for proteasomal degradation, ubiquitylation regulates a multitude of cellular processes, such as transcription, translation, endocytosis, and receptor activity and subcellular localization. In addition, the proteasome generates peptides for antigen presentation in the immune system and for further degradation by peptidases to provide amino acids for protein biosynthesis and gluconeogenesis. Alterations of the UPS or of protein substrates that render them more or less susceptible to degradation are responsible for disorders associated with renal cell dysfunction. In this Review, we provide insight into the elegant and complex nature of UPS-mediated proteostasis and focus on its established and potential roles in renal cell physiology and pathophysiology.

Renal cell carcinoma.

PURPOSE OF REVIEW: The recent contributions to renal cell carcinoma in the fields of molecular biology and the expanded use of molecularly targeted agents will be reviewed. This study is intended to update prognostic and therapeutic decision-making data and provide perspective on advances in understanding the molecular biology of this disease. RECENT FINDINGS: Updates to the currently used prognostic algorithms for renal cell carcinoma are needed, and recently verified prognostic nomograms will be discussed. This comes in the wake of numerous advances in the use of molecularly targeted drugs, which will be reviewed. Finally, advancements in understanding the biology of renal cell carcinoma include the discovery of von Hippel-Lindau associated mechanisms involved in renal cyst formation and renewed appreciation for the influence of this pathway on the tumor cell glucose utilization profile. SUMMARY: Renal cell carcinoma continues to evolve swiftly with the approval of new agents and the maturation of clinical trials to provide relevant structure to treatment decisions. This study will give an overview of the latest concepts in the epidemiology and biology of renal cell carcinoma and provide current surgical and systemic updates for managing renal cell carcinoma.

Clinical course of retrobulbar hemangioblastomas in von Hippel-Lindau disease.

OBJECTIVE: To report clinical findings of rare retrobulbar optic nerve hemangioblastomas associated with von Hippel-Lindau disease (VHL). DESIGN: Retrospective observational case series. PARTICIPANTS: Nine patients with VHL. METHODS: The clinical course and magnetic resonance imaging findings of patients with VHL and hemangioblastomas affecting the anterior visual pathway from the intraorbital optic nerve to the optic chiasm are reviewed. MAIN OUTCOME MEASURE: Clinical course of retrobulbar optic nerve hemangioblastomas. RESULTS: The mean age of VHL diagnosis was 24+/-14 years, and mean follow-up was 5+/-4 years. All had other CNS lesions and retinal hemangioblastomas. Approximately 50% (5/9) had a previous enucleation or had visual acuity loss (4/9), some due to other VHL ocular complications. Four patients underwent surgical resection of an intracranial hemangioblastoma. Growth patterns and pathology are similar to those of other hemangioblastomas in the CNS. CONCLUSIONS: Although these lesions are rare, patients with VHL who present with signs of optic neuropathy should be evaluated for anterior visual pathway hemangioblastomas impinging on the optic nerve from the orbit to the chiasm. On neuroimaging, the hemangioblastomas may demonstrate chiasmal or optic tract edema, associated cysts, and T(2) flow voids. Lesions may remain radiologically and clinically stable, evolve radiographically with no visual or neurological progression, or progress clinically and radiographically. Patients at risk for visual loss should be considered for surgical resection. Close coordination among neuroradiology, neurosurgery, and ophthalmology patient care teams is advised for optimal management of these patients.

Surgical management of cerebellar hemangioblastomas in patients with von Hippel-Lindau disease.

OBJECT: Despite the frequency of cerebellar hemangioblastomas in von Hippel-Lindau (VHL) disease, their optimum contemporary management has not been defined, and is made complex because of the multiple, progressive, and protean nature of the tumors found in patients with this disorder. To examine modern management and outcomes of cerebellar hemangioblastomas in VHL disease, the authors reviewed findings in patients with this disease who underwent resection of cerebellar hemangioblastomas. METHODS: Consecutive patients with VHL disease who underwent surgery for cerebellar hemangioblastoma(s) at the National Institutes of Health were included. Eighty consecutive patients (44 female and 36 male patients) underwent 126 operations for removal of 164 cerebellar hemangioblastomas (age at surgery 37.8+/-10.3 years, follow-up duration 96.0+/-60.3 months). Serial clinical examinations, imaging studies, and operative records were analyzed. RESULTS: Symptoms and signs included headache (94 operations; 75%), ataxia (55%), dysmetria (29%), and hydrocephalus (28%). Although the primary objective of surgery was resection of the hemangioblastoma considered responsible for symptoms (136 of the hemangioblastomas [83%]), 28 additional hemangioblastomas (17%) were removed during the same surgeries. Tumors associated with symptoms were larger (diameter 1.8+/-1.9 cm; volume 2.8+/-3.4 cm3; p<0.05) and more likely to be associated with peritumoral edema or peritumoral cysts (100% associated with edema and/or cyst; p<0.05) than asymptomatic tumors (diameter 1.1+/-0.9 cm; volume 0.7+/-0.4 cm3; 18%). More tumors were located in the posterior (74%) compared with the anterior (26%) half of the cerebellum (p<0.05). Three months after resection, symptom improvement/stabilization had occurred following 124 of the operations (98%). Preoperative hydrocephalus resolved after tumor removal in 33 cases (94%) and did not require cerebrospinal fluid diversion. Long-term imaging follow-up (61.5+/-15.0 months) revealed no recurrences. CONCLUSIONS: Symptoms and signs caused by cerebellar hemangioblastomas in VHL disease are associated with edema and peritumoral cyst formation/propagation and are treated safely and effectively with resection. Cerebrospinal fluid diversion is rarely necessary after complete tumor removal in patients with preoperative hydrocephalus. Cerebellar hemangioblastomas are preferentially distributed in the posterior half of the cerebellum, as they are in the brainstem and spinal cord. Tumor recurrence is avoided by meticulous extracapsular resection.

An Advanced Well-differentiated Pancreatic Neuroendocrine Carcinoma (NET-G3) Associated with Von Hippel-Lindau Disease.

A 45-year old woman who underwent several surgeries for tumors associated with von Hippel-Lindau disease (VHL) was referred to our hospital due to a pancreatic tumor and liver tumors. She was diagnosed with pancreatic neuroendocrine tumor (NET) with a Ki67 index of 40% based on the examination of a biopsy specimen of the liver tumors. She was treated with everolimus for 6 months and sunitinib for 6 weeks as first- and second-line therapies. She survived for 13 months. At autopsy the diagnosis of pancreatic neuroendocrine tumor (NET)-G3 was confirmed. We herein report an aggressive clinical course of VHL-related NET G3. The further accumulation of cases is required to reach a consensus on treatment for this disease.

Von Hippel angioma.

We report a three year follow up of a 35-year-old Indian gentleman who presented with sudden, painless blurring of left (L) eye vision with initial visual acuity (VA) of 6/60. Fundoscopy revealed (L) vitreous haemorrhage and subsequently confirmed a (L) inferotemporal capillary haemangioma. The adjacent area of capillary haemangioma was treated with barricade argon laser photocoagulation to prevent progression of exudative retinal detachment inferiorly. Subsequent follow up showed mild regression of capillary haemangioma with maintenance of (L) eye vision at 6/9.