Late-Onset Manifestations of Von Hippel-Lindau Syndrome: A Case Report.

Von Hippel-Lindau (VHL) syndrome is characterized by a range of tumors including phaeochromocytomas, pancreatic adenomas, cerebellar haemangioblastomas, and renal cell carcinomas. A 50-year-old male presented with a three-week history of headache. Additionally, the patient exhibited signs of hypertension. Ultrasonography (USG) abdomen and pelvis showed a solid mass lesion in the left adrenal gland, iso-echoic to the renal cortex. On contrast-enhanced computed tomography (CECT) of the brain, a well-defined solid cystic lesion was seen in the left posterior cerebellar hemisphere. Small nodular enhancing lesions were seen in the right cerebellar hemisphere. On further imaging with MRI brain contrast, the lesions in the cerebellum were diagnosed as multifocal hemangioblastomas. Laboratory investigations revealed elevated urinary metanephrines and normetanephrine, suggesting pheochromocytoma. Based on radiological and biochemical investigations, with the features of cerebellar haemangioblastomas and pheochromocytoma, a diagnosis of VHL syndrome was made.

Discovering a novel genetic variant in 11 family members who had isolated pheochromocytoma linked to von Hippel-Lindau (VHL) syndrome, aligning with the type 2c phenotype.

INTRODUCTION: Von Hippel-Lindau disease (e.g. VHL) is an autosomal dominant multi-organ cancer syndrome caused by a mutation in the VHL tumour suppressor gene. In this study, we introduce a novel genetic variant found in 11 family members diagnosed initially with isolated Pheochromocytoma. Subsequent findings revealed its association with VHL syndrome and corresponds to the Type 2 C phenotype. METHODS: The VHL gene was amplified through the utilisation of the polymerase chain reaction (PCR). PCR fragments were sequenced using bidirectional Sanger sequencing, using BigDye™ Terminator v3.1 Cycle Sequencing Kit, running on the 3500 genetic analyser. Results were assembled and analysed Using Software SeqA and chromas pro. RESULTS: A heterozygous in-frame duplication of three nucleotides, specifically ATG, c.377_379dup; p.Asp126dup in exon 2, was identified in all the patients tested within the pedigree. CONCLUSION: In this study, we disclose the identification of a novel genetic variant in a Jordanian family, affecting eleven family members with pheochromocytoma associated with VHL disease. This finding underscores the importance of screening family members and contemplating genetic testing for individuals newly diagnosed with pheochromocytoma and could enhance our comprehension of the potential adverse consequences associated with VHL germline mutations.

Goal: To study a novel gene change in a family with Von Hippel-Lindau (e.g. VHL) syndrome, which increases cancer chances.Participants: 11 family members with Pheochromocytoma, a tumour linked to VHL.Methods:Used PCR to copy the VHL gene.Analysed the gene using Sanger sequencing.Findings:Found a novel gene change in all family members. This change, called an in-frame duplication, affects a protein.It's in a specific part of the gene.Conclusion:Stressing the importance of genetic testing for Pheochromocytoma patients to grasp VHL mutation risks.

Insulinoma Unmasked Post Sleeve Gastrectomy With Incidental Renal Cell Carcinoma: A Rare Case.

Insulinoma is a functional pancreatic neuroendocrine tumor (pNET). Usually benign and solitary, these tumors present with recurrent episodes of hypoglycemia due to insulin hypersecretion. It's a rare cause of post bariatric surgery hypoglycemia and hence poses a diagnostic challenge. Here, we report the first case of a 53-year-old male with insulinoma unmasked post sleeve gastrectomy with incidental renal cell carcinoma (RCC). He presented with symptoms of Whipple's triad after two months of sleeve gastrectomy done for morbid obesity. On further inquiry, the patient gave a history of an asymptomatic peripancreatic neuroendocrine tumor (NET) for the past 11 years. With a suspicion of insulinoma, biochemical workup followed by non-invasive imaging like GA-68 DOTA and CT triphasic abdomen scan was done to guide the diagnosis of an insulinoma which also detected a second primary tumor in the right kidney, likely to be a malignant RCC. Following pancreatic mass excision with radical nephrectomy for right renal mass, histopathology (HPE) and immunohistochemistry (IHC) confirmed the diagnosis of an insulinoma and a right renal clear cell carcinoma. The patient was discharged with no further episodes of hypoglycemia. Hence, persistent hypoglycemia post bariatric surgery could be an indication of a hidden insulinoma and this possibility of synchronous tumors should be kept in mind when dealing with rare tumors like insulinoma.

Computed tomography-guided percutaneous cryoablation of hereditary adrenal pheochromocytoma in three patients.

OBJECTIVES: Pheochromocytomas (PHEO) are neuroendocrine tumors rarely diagnosed in children. We are reporting on the management challenges of three adolescent patients who present with hereditary PHEO. CASE PRESENTATION: The index patient and his male sibling presented with bilateral PHEO, while a third patient presented with a unilateral PHEO, all associated with von Hippel-Lindau (VHL) syndrome. The patients were treated with computed tomography (CT)-guided percutaneous cryoablation (CRA) of the adrenal lesions, with varying degrees of success. CONCLUSIONS: CT-guided percutaneous CRA of hereditary PHEO has not been reported in the pediatric population and may represent a novel treatment strategy that reduces the risk of intraprocedural complications and adrenal insufficiency (AI).

Von-Hipple Lindau syndrome with family history: a case report and seventeen years follow-up study.

Background: Von-Hipple Lindau syndrome is an uncommon autosomal dominant disorder. 17 years ago we diagnosed a young woman with VHL syndrome validated by Sanger sequencing, her family members were genetically tested as well, and 187 healthy people were randomly selected for VHL genetic testing as controls. We analyze the clinical and genetic characteristics of VHL syndrome in a Chinese lineage and with 17-year follow-up. Case presentation: A woman was finally diagnosed with VHL syndrome due to the detection of a missense mutation c.353T > C in exon 2 of the short arm of chromosome 3, which resulted in a leucine substitution at amino acid 118 of the encoded protein by a proline, which may be thought the main cause of the disease. The same mutation was observed in two other family members, their clinical symptoms are not entirely identical. However, this mutation was not found in other family members or 187 healthy controls. She clinically presented with central nervous system hemangioblastomas, clear renal cell carcinoma, and pancreatic neuroendocrine neoplasms, despite the multi-organ involvement and several relapses during the disease, the patients survive well for she was treated with aggressive surgery early in the course of the plaguing symptoms, whereas patients who are not aggressively treated have a poorer prognosis. Conclusion: The clinical presentation of VHL syndrome is atypical, and early identification and treatment of VHL syndrome is possible by genetic testing techniques. Multiple relapses occurred during the course of the disease, but early diagnosis and aggressive treatment allowed the patients to survive well.

Diversities of Mechanism in Patients with VHL Syndrome and diabetes: A Report of Two Cases and Literature Review.

Background: Von Hippel-Lindau (VHL) syndrome is characterized by tumorous lesions affecting multiple organs. Pancreatic involvement in VHL syndrome can present as endocrine tumors and pancreatic cysts, which can interfere with both exocrine and endocrine functions of the pancreas. Diabetes is an uncommon complication of VHL syndrome. Purpose: This study aims to summarize the various mechanisms of diabetes in VHL syndrome by reporting two cases and conducting a literature review. Methods: We analyzed the clinical and imaging data of two patients with VHL syndrome and diabetes. Additionally, we reviewed the existing literature to explore the clinical diversities and management strategies for VHL syndrome complicated with diabetes. Results: The first patient presented with liver metastasis of pancreatic neuroendocrine tumor and multiple pheochromocytoma. After surgery, the patient's diabetic control improved, as evidenced by a significant reduction in insulin dosage. This indicates a potential insulin resistance due to elevated metanephrine levels prior to surgery and partial insulin deficiency caused by distal pancreatectomy. The second patient had multiple hemangioblastomas, as well as multiple pancreatic cysts and positive pancreatic islet autoantibodies. Diabetes in this case may be attributed to pancreatic lesions and the coexistence of autoimmune insulitis. A literature review of other patients with VHL combined with diabetes revealed multiple mechanisms, including increased catecholamine levels, pancreatic lesions, surgical removal of pancreatic tissue, endocrine treatment, and possibly the coexistence of autoimmune insulitis. Conclusion: VHL syndrome complicated with diabetes involves diverse mechanisms.

Prognostic Factors of Spinal Intramedullary Hemangioblastoma : Analysis of Surgical Outcomes and Tumor Characteristics.

Objective: Spinal intramedullary hemangioblastoma is a rare and highly vascularized benign tumor. The characteristics of the tumor, its corresponding location, and surgical outcomes remain unknown. The purpose of this study was to identify risk factors and strategies for neurologic deterioration following hemangioblastoma surgery. Methods: A comprehensive retrospective analysis was undertaken to evaluate patients who underwent surgical intervention for intramedullary hemangioblastoma at our institution from 1993 to 2022. Patients with at least one year of follow-up data were included. The analysis covered patient demographics, pre- and post-operative Modified McCormick Scale (MMCS), tumor location, and tumor size. Results: This study included 25 cases. One-year after surgery, neurological deterioration was observed in 5 (20.0%) cases, and neurological improvement was found in 9 (36.0%) cases. Five cases were ventrally located, and twelve cases were dorsally located. Ventrally located cases were larger in tumor axial size (p = 0.029) than dorsal location tumors, resulting in poorer follow-up MMCS and a higher prevalence of von Hippel-Lindau syndrome (VHL) (p = 0.042). Three of them were confirmed to be supplied by the anterior spinal artery. In the case of dorsally located cases, there was no neurologic deterioration. Conclusion: In intramedullary spinal cord hemangioblastomas, cases located ventrally had a higher incidence of neurological deterioration following surgery than those located dorsally or in intramedullary extramedullary cases. Ventrally located hemangioblastomas were larger than those in other locations. They were mainly supplied by the anterior spinal artery in VHL patients.

Optic nerve haemangioblastoma in association with von Hippel-Lindau syndrome: case report and literature review.

Optic nerve haemangioblastoma (ONH) is an uncommon, benign, non-meningothelial, mesenchymal tumour of unclear origin. Most are associated with von Hippel-Lindau (VHL) syndrome (71%), and only 40 cases have been reported in the medical literature. Most of the patients develop non-specific visual symptoms, including decreased visual acuity and/or loss of visual fields, exophthalmos, trigeminal neuralgia, and retroorbital pain. Optic nerve sheath meningioma and optic nerve glioma are among the differential diagnoses that may be considered in this location. Contrast-enhanced MRI is considered an optimal diagnostic tool, which helps to determine some characteristics that guide towards an adequate diagnosis and treatment. We present a 42-year-old patient with a history of VHL syndrome in whom a cerebellar lesion and optic nerve lesions were evidenced, and we did a review of the literature and case analysis.

New Prospects on Neuroimaging in Von Hippel Lindau Disease-A Narrative Review.

(1) Background: Hemangiomas in Von Hippel-Lindau (VHL) syndrome patients are typically benign but pose threats due to their vital locations involving the central nervous system and the retina. An MRI is currently recommended as the gold standard for tumors associated with VHL in the head region. This narrative review aims to comprehensively outline current standards and recent findings related to imaging of retinal and CNS hemangiomas in Von Hippel-Lindau syndrome. (2) Material and Methods: A review in adherence to PRISMA guidelines using the search string "Von Hippel-Lindau hemangioblastoma imaging" was conducted on PUBMED and SCOPUS databases. (3) Results: After reviewing 455 titles and abstracts, 20 publications fulfilling the inclusion criteria were analyzed. The analysis included studies describing MRI, CT, optical coherence tomography, and PET/CT. (4) Conclusion: While MRI remains the gold standard for diagnosing head tumors in Von Hippel-Lindau syndrome, various PET/CT methods show promise as alternative imaging modalities.

Therapeutic Targeting of Hypoxia-Inducible Factors in Cancer.

In the realm of cancer therapeutics, targeting the hypoxia-inducible factor (HIF) pathway has emerged as a promising strategy. This study delves into the intricate web of HIF-associated mechanisms, exploring avenues for future anticancer therapies. Framing the investigation within the broader context of cancer progression and hypoxia response, this article aims to decipher the pivotal role played by HIF in regulating genes influencing angiogenesis, cell proliferation, and glucose metabolism. Employing diverse approaches such as HIF inhibitors, anti-angiogenic therapies, and hypoxia-activated prodrugs, the research methodologically intervenes at different nodes of the HIF pathway. Findings showcase the efficacy of agents like EZN-2968, Minnelide, and Acriflavine in modulating HIF-1α protein synthesis and destabilizing HIF-1, providing preliminary proof of HIF-1α mRNA modulation and antitumor activity. However, challenges, including toxicity, necessitate continued exploration and development, as exemplified by ongoing clinical trials. This article concludes by emphasizing the potential of targeted HIF therapies in disrupting cancer-related signaling pathways.

The von Hippel-Lindau protein forms fibrillar amyloid assemblies that are mitigated by the anti-amyloid molecule Purpurin.

The von Hippel-Lindau protein (pVHL) is a tumor suppressor involved in oxygen regulation via dynamic nucleocytoplasmic shuttling. It plays a crucial role in cell survival by degrading hypoxia-inducible factors (HIFs). Mutations in the VHL gene cause angiogenic tumors, characterized as VHL syndrome. However, aggressive tumors involving wild-type pVHL have also been described but the underlying mechanism remains to be revealed. We have previously shown that pVHL possesses several short amyloid-forming motifs, making it aggregation-prone. In this study, using a series of biophysical assays, we demonstrated that a pVHL-derived fragment (pVHL104-140) that harbors the nuclear export motif and HIF binding site, forms amyloid-like fibrillar structures in vitro by following secondary-nucleation-based kinetics. The peptide also formed amyloids at acidic pH that mimics the tumor microenvironment. We, subsequently, validated the amyloid formation by pVHL in vitro. Using the Curli-dependent amyloid generator (C-DAG) expression system, we confirmed the amyloidogenesis of pVHL in bacterial cells. The pVHL amyloids are an attractive target for therapeutics of the VHL syndrome. Accordingly, we demonstrated in vitro that Purpurin is a potent inhibitor of pVHL fibrillation. The amyloidogenic behavior of wild-type pVHL and its inhibition provide novel insights into the molecular underpinning of the VHL syndrome and its possible treatment.

Outcome of Multiple Retinal Capillary Hemangioma Following Focal Laser and Intravitreal Bevacizumab Injection: A Case Report.

Retinal hemangioma has posed a therapeutic problem for ophthalmologists for almost a decade. The location of hemangioma in the retina is an important factor in determining the treatment options as well as the size of the tumor, clarity of media, and secondary features of the mass. A 22-year-old male presented to vitreoretina clinic at a tertiary eye hospital, with a history of sudden decrease of vision in the left eye for 1 year associated with mild ocular pains. Physical and systemic examination revealed no positive findings. On ocular examination, the visual acuity was 6/6 in the right eye and perception of light in the left eye, and there was no improvement with best correction. Anterior segment examination in both eyes was essentially normal. Dilated funduscopy revealed a well-circumscribed and elevated vascular orange reddish mass in the juxtapapillary area, temporal to the disc with dilated tortuous feeder blood vessels measuring 6.4 × 3.0 mm in the right eye and vitreous hemorrhage with tractional retinal detachment in the left eye. The small solitary lesion in the right eye was treated with focal laser. This was followed by intravitreal bevacizumab avastin 1.25 mg in 0.05 mL in the same eye, monthly three doses, with the aim of targeting the bigger lesion at the juxtapapillary area to reduce the risk of visual loss. Patient also had pars plana vitrectomy, endolaser photocoagulation, and silicon oil in the left eye. There was complete resolution of the tumor, which was not measurable after third dose of intravitreal avastin. Patient vision remained 6/6, and there was no recurrence at the last follow-up visit 3 years after treatment. Antivascular endothelial growth factors like avastin are effective in the treatment of retinal capillary hemangioma, thereby inducing complete tumor resolution as well as maintaining good vision in the early stages of the disease before complication occurs, as it is evident in this case study.

Hemangioblastoma of the medulla oblongata that caused isolated fourth ventricle after stereotactic radiosurgery: A case report.

Isolated fourth ventricle is a rare complication following shunt insertion of the lateral ventricles for hydrocephalus. The present report describes a rare case of a hemangioblastoma of the medulla oblongata that caused isolated fourth ventricle due to intraventricular deposition of fibrin. A 34-year-old man presented with headache a month before admission. Magnetic resonance imaging indicated multiple tumors in the medulla oblongata and the bilateral cerebellar hemisphere with surrounding edema, and the patient was diagnosed with hemangioblastoma. The patient began to develop progressive headache and nausea after stereotactic radiosurgery, and computed tomography showed obstructive hydrocephalus. Endoscopic third ventriculostomy was performed, and the intraoperative view of this showed that the walls of the lateral and third ventricles were covered with a white membrane-like substance. Endoscopic third ventriculostomy and then ventriculoperitoneal shunt did not improve the hydrocephalus. The patient's consciousness deteriorated due to isolated fourth ventricle and upward herniation. The patient underwent posterior fossa craniotomy and the tumor in the medulla oblongata was removed via a telovelar approach. Intraoperatively, the fourth ventricle was filled with a white membrane-like substance, which was surgically removed and pathologically diagnosed as fibrin. The patient's consciousness and obstructive hydrocephalus improved after surgery. The present case suggests that isolated fourth ventricle may occur after VP shunt placement for the hydrocephalus with hyperproteinorachia.

Case report: Sympathetic ophthalmia after vitrectomies in a patient with Von Hippel-Lindau syndrome.

Background: Sympathetic ophthalmia (SO) is a rare but sight-threatening uveitis, and most observations have been made after typical manifestations occur. This report focuses on the choroidal changes detected by multimodal imaging at the presymptomatic stage of SO, which is implicated in the early recognition of SO. Case presentation: A 21-year-old woman suffered from decreased vision in the right eye and was diagnosed with retinal capillary hemangioblastomas associated with Von Hippel-Lindau syndrome. The patient underwent two 23-G pars plana vitrectomies (PPVs), soon after which typical signs of SO manifested. SO resolved quickly after the oral administration of prednisone and remained stable during the follow-up of more than 1 year. The retrospective analysis revealed preexisting bilaterally increased choroidal thickness, dots of flow void on the choroid, and choriocapillaris en-face slabs in optical coherence tomography angiography (OCTA) after the first PPV, which were all reversed by corticosteroid treatment. Conclusion: The case report highlights the involvement of the choroid and choriocapillaris at the presymptomatic stage of SO after the first inciting event. Abnormally thickened choroid and flow void dots suggested that SO had started and an ensuing surgery would run the risk of exacerbating SO. OCTA scanning of both eyes should be ordered routinely for patients with a history of trauma or intraocular surgeries, especially before the next surgical intervention. The report also suggests that non-human leukocyte antigen gene variation may also regulate the progression of SO, which requires further laboratory investigations.

[Hereditary renal tumor syndromes.] / Örökletes vesetumor-szindrómák.

Kidney tumors may develop in association with hereditary tumor syndromes. The clinical presentation of these disorders is various, and in some cases, the renal tumor is the first manifestation of the syndrome. Thus, pathologists need to be aware of the gross and histological signs that may suggest the possibility of a tumor syndrome. In this paper, we summarize and illustrate the characteristics of kidney tumors, genetic background along with the extrarenal manifestations in the following diseases: Von Hippel-Lindau syndrome, hereditary papillary renal cell carcinoma syndrome, hereditary leiomyomatosis and renal cell carcinoma syndrome, Birt-Hogg-Dubé syndrome, tuberous sclerosis, hereditary paraganglioma and pheochromocytoma syndrome, and inherited BAP1 tumor syndrome. At the end of the manuscript, we discuss the tumor syndromes with increased risk of Wilms tumors. Such patients require a holistic approach and multidisciplinary care. Our work aims to make those involved in the diagnosis and treatment of kidney tumors aware of these rare diseases that require life-long surveillance. Orv Hetil. 2023; 164(10): 363-375.

[A Surgically Treated Depression]. / Eine chirurgisch behandelte Depression.

A Surgically Treated Depression Abstract. We present a 64-year-old patient with an unclear deterioration of her general condition due to a suspected depression. Despite antidepressive treatment, her condition further deteriorated. The CT/MRI of the skull showed a cerebellar tumor as well as a hydrocephalus obstructivus. Together with tumor staging, the histology, which revealed a hemangioblastoma, led to the diagnosis of VHL syndrome. Patients with VHL syndrome and their families should be included in a screening program, unless molecular genetic testing has ruled out the disease.

How 'eye' helped in von Hippel-Lindau syndrome.

BACKGROUND: Von Hippel-Lindau syndrome is a rare autosomal dominantly inherited multisystemic oncologic syndrome, presenting predominantly with angiomatosis in embryologically similar neurologic tissue such as retina, cerebellum and adrenals. Retinal hemangioblastomas are the hallmark ophthalmic finding. In this case report, we describe the importance of timely diagnosis, thorough systemic examination and treatment of bilaterally asymmetrical retinal hemangioblastomas in a young adult male. CASE PRESENTATION: A 31-year-old male presented with painless diminution of vision in both eyes, associated with eyestrain and headache. Multiple asymmetric retinal lesions and dilated feeder vessels were noted on ophthalmoscopic examination and confirmed by fluorescein angiography to be retinal hemangioblastomas. Comprehensive systemic examination revealed cerebellar hemangioblastomas and multiple pancreatic and renal cysts. Treatment of retinal lesions was done by combination therapy of argon laser photocoagulation and cryopexy, which lead to a good visual outcome. Subsequently, neurosurgical resection of cerebellar hemangioblastoma proved to be lifesaving for the patient. CONCLUSION: RHBs are the earliest, easiest and the most frequently detected manifestation of VHL. Identification of ocular manifestations play a pivotal role in early diagnosis and timely intervention in VHL syndrome, thereby significantly reducing associated morbidity and mortality. Therefore, an ophthalmologist's role is crucial in the management of these potentially deadly tumours.

Indications for genetic study in gastro-entero-pancreatic and thoracic neuroendocrine tumors.

Gastro-entero-pancreatic (GEP-NET) and thoracic neuroendocrine tumours (NETs) are one of the most heritable groups of neoplasms in the body, being multiple endocrine neoplasia syndrome type 1 (MEN1), the genetic syndrome most frequently associated with this type of tumours. Moreover, Von Hippel Lindau syndrome, tuberous sclerosis, type 4 multiple neoplasia syndrome, and type 1 neurofibromatosis are associated with an increased risk of developing GEP-NETs. Another important aspect in GEP-NETs and thoracic NETs is the knowledge of the molecular background since the molecular profile of these tumours may have implications in the prognosis and in the response to specific treatments. This review summarizes the main indications for performing a genetic study in patients with GEP-NETs and thoracic NETs, and the methods used to carry it out. Moreover, it offers a description of the main hereditary syndromes associated with these NETs and their molecular background, as well as the clinical implications of the molecular profile.

Anesthetic Challenge in a Parturient With Von Hippel-Lindau Disease.

Von Hippel-Lindau (VHL) syndrome is a rare autosomal dominant disease with incomplete penetrance and variable expression. The features of cerebellar and spinal tumors, pheochromocytomas, and increased intracranial pressure complicate the anesthetic management of such patients. This report describes the anesthetic management of a parturient with VHL disease and highlights the importance of proper surveillance, vigilant management, and individualized treatment plans from a multidisciplinary team.

A Case Report of Von Hippel-Lindau Syndrome with Hypertension and Diabetes as the First Manifestation / 罕见病研究

Von Hippel-Lindau (VHL) syndrome, also known as cerebral retinal angiomatosis, is a kind of neuroendocrine tumor. The incidence rate is high, and the heredity is very high, which can involve the retina, central nervous system, various organs and various tissue parts. This paper reports a case of VHL syndrome with hypertension and diabetes as the main manifestations, in order to improve the understanding of the disease and reduce misdiagnosis and missed diagnosis.