Diagnosis and treatment of Von Hippel‑Lindau syndrome: A case series

Introduction

Von Hippel-Lindau (VHL) syndrome is an inherited multisystem disorder caused by mutations in the VHL tumor suppressor gene located at chromosome 3p25-26(1). The incidence of VHL disease is ~1 in 36,000 live births with a penetrance >90% (2). This syndrome is characterized by a predisposition to develop both benign and malignant tumors in multiple organs, including hemangioblastomas of the brain/spinal cord/retina, renal cell carcinomas (RCCs), pheochromocytomas (PhCs), pancreatic neuroendocrine tumors and endolymphatic sac tumors (ELSTs).

The VHL gene serves a pivotal role in regulating critical cellular processes. The VHL protein plays a central role in cellular oxygen sensing and hypoxic adaptation through the erythropoietin-VHL-hypoxia-inducible factor (HIF) signaling axis, while also participating in multiple HIF-independent pathways (3). Notably, deficient VHL gene function results in dysregulated homeostasis of HIFs, causing pathological accumulation of these transcription factors that ultimately drive transcriptional programs, which promote neoplastic proliferation and angiogenesis (4). Current pharmacotherapeutic research primarily targets HIF cascade proteins and functional restoration of mutated VHL proteins (2).

VHL syndrome exhibits marked heterogeneity in clinical manifestations with a variable age of onset, thus mandating the lifelong clinical monitoring of patients. The combination of early genetic diagnosis and periodic tumor surveillance is pivotal for optimizing therapeutic outcomes in affected individuals (5). The present study retrospectively reviewed the clinical data of four patients diagnosed with VHL syndrome at Hebei General Hospital (Shijiazhuang, China), aiming to summarize their clinical features and therapeutic management.

Case report

Case 1

A 34-year-old man presented with posterior neck pain persisting for 14 weeks, which had worsened over the preceding week. The patient was admitted to Hebei General Hospital in October 2010. A neurological examination revealed clear consciousness and intact cranial nerve function. Muscle strength was graded 4+ in the right limbs and grade 4 in the left limbs (6). The medical history of the patient included bilateral adrenal PhCs diagnosed in 2005, for which they underwent laparoscopic pheochromocytoma resection to manage hypertension. There was no history of infectious diseases or hereditary conditions. Cranial magnetic resonance imaging (MRI) demonstrated a space-occupying lesion in the left cerebellar hemisphere, along with multiple areas of abnormal enhancement in the cerebellar vermis, right cerebellar tonsils and right cerebellar hemisphere (data not shown). The findings were consistent with various hemangioblastomas. The patient underwent intracranial tumor resection on October 2010, with postoperative pathology confirming hemangioblastoma (Fig. 1A and C-L) and the following pathological results: Hematoxylin and eosin staining showed that the tumor tissue exhibited nested and alveolar growth patterns, composed of large tumor cells with vacuolated, lipid-rich cytoplasm. Marked nuclear pleomorphism was observed, featuring atypical nuclei with hyperchromasia. Mitotic figures were rare. The tumor cell nests were surrounded by abundant capillary networks involving predominantly thin-walled vessels, with some showing characteristic highly branched ‘staghorn’ morphology. Immunohistochemical findings were as follows: CD34(+++; strong diffuse positivity); solute carrier family 2 facilitated glucose transporter member 1(+); vimentin(+++; strong diffuse positivity); epithelial membrane antigen(-), effectively ruling out angiomatous meningioma; Ki-67 (<5% positive), supporting the diagnosis of hemangioblastoma; glial fibrillary acidic protein(-), excluding diffuse astrocytoma; pan-cytokeratin(-); CD10(-); and paired box protein Pax-8(-), excluding metastatic carcinoma and metastatic renal cell carcinoma (7). The patient's symptoms improved after surgery and they were subsequently discharged.

Figure 1 Postoperative pathological images of case 1. (A and C.L) Postoperative pathological images taken in October 2010 (x100 total magnification). Pathological results: Left cerebellar hemisphere hemangioblastoma. (B) Postoperative pathological image taken in March 2014 (x200 total magnification). Pathological results: (A.C) Hematoxylin and eosin staining showing that the tumor tissue demonstrates nested and alveolar growth patterns, composed of large tumor cells with vacuolated, lipid.rich cytoplasm. Marked nuclear pleomorphism is observed, featuring atypical nuclei with hyperchromasia. Mitotic figures are rare. The tumor cell nests are surrounded by abundant capillary networks, predominantly thin.walled vessels with some showing characteristic highly branched 'staghorn' morphology. Immunohistochemical findings: (D) CD34(+++; strong diffuse positivity). (E) Solute carrier family 2 facilitated glucose transporter member 1(+). (F) Vimentin(+++; strong diffuse positivity). (G) Epithelial membrane antigen(.), effectively ruling out angiomatous meningioma. (H) Ki.67 (<5% positive), supporting the diagnosis of hemangioblastoma. (I) Glial fibrillary acidic protein(.), excluding diffuse astrocytoma. (J) Pan.cytokeratin (.). (K) CD10(.). (L) Paired box protein Pax.8(.), excluding metastatic carcinoma and metastatic renal cell carcinoma.

In March 2014, the patient was re-admitted to the Department of Neurosurgery due to gait instability persisting for >2 months. Neurological examination revealed no notable deficits. Cranial MRI demonstrated multiple small nodules within the cerebellum and a cystic-solid mass in the cerebellar vermis, exerting pressure on the fourth ventricle and resulting in mild supratentorial hydrocephalus (data not shown). Intracranial surgery was performed 7 days after readmission, and postoperative histopathology confirmed a capillary hemangioblastoma (Fig. 1B). Tissue sections were cut from formalin-fixed, paraffin-embedded tissue blocks at a 4-µm thickness. Sections were deparaffinized in xylene and rehydrated through graded ethanol. Heat-induced epitope retrieval was performed in citrate buffer (pH 6.0) for 5 min. Sections were treated with 3% hydrogen peroxide in methanol for 30 min to quench endogenous peroxidase activity. Sections were incubated overnight at 4˚C in a humidified chamber with anti-HIF-1α (1:200 dilution; GeneTex, Inc.) and anti-PKM2 (1:400 dilution; Cell Signaling Technology, Inc.). After washing with PBS, immunostaining was performed using the SP detection kit (Beijing Zhongshan Jinqiao Biotechnology Co., Ltd.) according to the manufacturer's instructions. Nuclei were counterstained with hematoxylin. Parallel staining omitting primary antibodies was included for each experiment. The patient was discharged in a stable condition following clinical improvement.

Abdominal ultrasound revealed a hypoechoic area in the pancreas (data not shown), whereas the adrenal glands and kidneys appeared normal. A pancreatic neuroendocrine tumor measuring 2.1x2.4 cm was identified in January 2018. Surgical intervention was deferred as there was no marked tumor growth during follow-up. Intracranial surgery was performed 4 days after admission and a postoperative histopathological examination was completed. Tissues were fixed in 10% neutral buffered formalin at room temperature (20-25˚C) for 24 h before being sectioned to 4-µm thick. Hematoxylin and eosin staining was performed using hematoxylin for 5 min at room temperature and using eosin for 2 min at room temperature. Results were examined using an Olympus BX53 microscope (Olympus Corporation) and confirmed the diagnosis of hemangioblastoma (Fig. 1A) (8). The patient experienced symptomatic improvement following the procedure, owing to a clinically notable resolution of gait disturbance.

Follow-up evaluations showed that the patient underwent a pancreatic and adrenal MRI in October 2018. Imaging revealed multiple abnormal signal intensities within the pancreas (Fig. 2A and B), suggestive of neuroendocrine tumors. An additional lesion in the pancreatic body was consistent with a pancreatic cyst. Multiple signal abnormalities in the left adrenal gland indicated PhC (Fig. 2C-E), and an abnormal signal intensity at the lower pole of the right kidney was consistent with a renal cyst. A contrast-enhanced cranial MRI performed in February 2019, showed nodular enhancement in both cerebellar hemispheres, raising concern for recurrence of VHL-associated lesions (Fig. 2F-H). Based on the presence of cerebellar hemangioblastomas, pancreatic neuroendocrine tumors, adrenal PhC and a renal cyst, a diagnosis of VHL syndrome was strongly suspected. As of May 2025, patient 1 was alive; their parents and son were also alive at this time and showed no signs of VHL syndrome-related symptoms.

Figure 2 Imaging of case 1. Images (A.E) were acquired in January 2018, while images (F.H) were obtained in February 2019. (A) Lipid compression sequence on T2WI (the arrow indicates a pancreatic cyst). (B) T1WI fat suppression-enhanced sequence (the arrow indicates a pancreatic cyst). (C) Diffusion.weighted imaging sequence, showing adrenal PhC (thin arrow) and neurofibroma of the foramen (thick arrow). (D) T1WI fat suppression.enhanced sequence, showing adrenal PhC (thin arrow) and neurofibroma of the foramen (thick arrow). (E) T1WI fat suppression sequence, showing adrenal PhC (thin arrow) and pancreatic neuroendocrine tumor (thick arrow). (F.H) T1WI enhancement, with arrows pointing to the different hemangioblastomas. WI, weighted imaging.

Case 2

A 45-year-old woman presented with a 2-year history of paresthesia in the left hand and left lower limb, which had progressively worsened over the past 6 months. The patient was admitted to Hebei General Hospital in October 2019. Neurological examination revealed a positive Hoffmann's sign on the left side, with no other significant abnormalities.

In 2012, the patient underwent a choledochojejunostomy due to bile duct obstruction caused by multiple pancreatic cysts. The patient had also experienced elevated blood glucose levels for >2 years. There was no reported family history of infectious or hereditary diseases. A contrast-enhanced brain and cervical spine MRI revealed abnormal signal intensities in the cerebellar vermis, dorsal medulla oblongata and dorsal spinal cord at the C5-6 level (Fig. 3A and B). Numerous tortuous flow-void vascular structures were observed, consistent with multiple central nervous system hemangioblastoma (CNS-H) tumors (Fig. 3). Abdominal ultrasound demonstrated pancreatic thickening with multiple anechoic cystic areas and calcifications (data not shown). A diagnosis of VHL syndrome was considered based on the presence of numerous CNS-H tumors found in the cerebellum, brainstem and spinal cord, in conjunction with a history of pancreatic cysts. As of May 2025, the patient was lost to follow-up. No health status information is available regarding the parents or children of the patient.

Figure 3 Imaging of case 2. The MRI examination was performed in November 2019. (A and B) Sagittal plane of T2-weighted imaging sequence, showing multiple abnormal signal intensities (arrows) in the cerebellum vermis and spinal cord. (C) T1WI enhanced sequence, showing multiple hemangioblastomas of the CNS with syringomyelia. (D and E) T1WI enhanced sequences showing multiple hemangioblastomas of the CNS. CNS, central nervous system; T1WI, T1-weighted imaging.

Case 3

A 30-year-old woman was admitted to Hebei General Hospital in May 2018, with a complaint of a fever persisting for >20 days. Neurological examination revealed no evident abnormalities. The medical history of the patient included surgical resection of brain tumors in 2012 and 2014, with postoperative pathology confirming hemangioblastomas. There was no reported family history of infectious or hereditary diseases. Renal computed tomography (CT) revealed bilateral renal masses suggestive of RCC, cysts in the upper poles of both kidneys, multiple pancreatic cysts and a hemangioblastoma at the L2-3 vertebral level (Fig. 4). In this case, the largest of the bilateral renal cell carcinomas was found to be 9.3x5.4x6.8 cm in 2018. During a follow-up examination in July 2019 after treatment, the tumor lesion was found to be significantly smaller than before. Based on the presence of CNS-H, RCC, renal cysts and pancreatic cysts, a diagnosis of VHL syndrome was suspected. As of May 2025, the patient was confirmed deceased. It was also reported that the father of the patient had succumbed (without a known history of VHL syndrome), while their mother, who was suspected to have VHL syndrome, was alive at this time. The patient had a son who showed no evidence of VHL-related manifestations.

Figure 4 Imaging of case 3. The CT scan was performed in May 2018. (A-D) Non-contrast CT images, demonstrating multiple lesions in both kidneys and the pancreas. The specific types of lesions require further evaluation with contrast-enhanced CT scans. (E and F) Arterial phases of enhanced CT scanning. (G and H) Venous phases of enhanced CT scanning. (I and J) Delayed period of enhanced CT scanning. The scans indicate renal cell carcinoma (thick white short arrows), a renal cyst (thin white long arrows) and a pancreatic cyst (red arrows). CT, computed tomography.

Case 4

A 50-year-old woman with a 12-year history of intermittent headaches and dizziness was admitted to Hebei General Hospital in March 2019. Neurological examination revealed no notable abnormalities. The medical history of the patient included brain tumor resection 12 years earlier, with postoperative pathology confirming hemangioblastoma. In April 2018, the patient experienced tumor recurrence and underwent a second surgical resection (Fig. 5A-Q), which again confirmed hemangioblastoma. There was no family history of infectious or hereditary diseases. Contrast-enhanced chest and abdominal CT scans revealed a pancreatic mass, a cyst in the pancreatic tail, bilateral adrenal PhC (Fig. 5R) and radiologic features highly suggestive of bilateral RCC (Fig. 5S and T).

Figure 5 Imaging of case 4. (A-Q) MRI was performed on March 11, 2019, and (R-T) CT scans were obtained on March 15, 2019. (A-D) Sagittal, coronal and cross-sectional images enhanced by lipid pressure on T1WI. The images show meningeal metastasis of the hemangioblastoma. (E and F) T1WI cross-sectional plain scans. (G and H) T2-weighted imaging cross-sections. (I and J) Cross-sections of fluid-attenuated inversion recovery sequence. (K-Q) T1WI enhanced scanning. (E-Q) Multiple hemangioblastomas in the bilateral cerebellar hemispheres and vermis. (R) CT-enhanced scan showing adrenal pheochromocytoma (arrow). (S) CT-enhanced scan showing renal cell carcinoma (arrow). (T) CT-enhanced scan showing the renal cyst (arrow). CT, computed tomography; T1WI, T1-weighted imaging.

Thoracic spine MRI (Fig. 5A-C) with contrast showed abnormal enhancement of the posterior spinal cord at the T3 level and the T12-L1 intervertebral space, raising suspicion for meningeal metastases of hemangioblastoma. A diagnosis of VHL syndrome was established based on the presence of multiple hemangioblastomas in the cerebellum and thoracic spinal cord, along with RCC, pancreatic cysts and adrenal PhC. This patient was diagnosed with a non-functioning pheochromocytoma due to the absence of hypertensive manifestations, and therefore no specific treatment was administered. As of May 2025, the patient was in good health. Both parents and two daughters were physically healthy with no clinical manifestations related to VHL syndrome at this time.

Literature review

VHL syndrome is a rare autosomal dominant disorder characterized by the development of tumors and cysts across multiple organ systems. The syndrome results from mutations in the VHL gene, which is a tumor suppressor gene, located on chromosome 3p25-p26(1). The estimated incidence of VHL syndrome ranges from 1 in 36,000-45,500 individuals (9). Mutations in the VHL gene lead to dysregulation of the HIF pathways, resulting in the upregulation of vascular endothelial growth factor (VEGF) and platelet-derived growth factor-β, both of which are implicated in tumorigenesis (10). Genetic alterations in the VHL gene can be identified in 39-75% of familial cases, whereas 25-61% of cases occur sporadically, without a family history (11). The present study diverges from previous research by not only cataloging tumor heterogeneity across patients with VHL syndrome, but also longitudinally tracking treatment response statistics for each therapeutic intervention in individual patients, with a median follow-up period of ~8 years.

Clinical diagnosis and classification

VHL syndrome is characterized by the development of tumors across multiple organ systems, specifically CNS-H, retinal hemangioblastoma (RH), RCC, PhC and ELST, among others. Diagnosis is based on both clinical assessment and genetic analysis. The most widely accepted clinical diagnostic criteria, proposed by Maher et al (12), include: i) The presence of any one of the characteristic tumor types in a patient with a positive family history; ii) in the absence of a family history, a diagnosis may be established when a patient presents with either two or more hemangioblastomas, or a single hemangioblastoma in combination with a related visceral tumor. Genetic testing [sequence analysis and gene-targeted deletion/duplication analysis (1)] remains the definitive method for diagnosis (13). Genetic testing should be promptly pursued to confirm the diagnosis in patients with a strong clinical suspicion but inconclusive findings.

Classification

VHL syndrome is classified internationally into two types (14), based on the presence or absence of PhC (Table I).

Table I Classification of VHL syndrome.

Table I

Classification of VHL syndrome.

Type	Characteristics
Type 1	No pheochromocytoma
1A	Renal cancer (case 3)
1B	No renal cancer (case 2)
Type 2	Pheochromocytoma
2A	No renal cancer + tumors of other organs (case 1)
2B	Renal cancer (case 4)
2C	Only pheochromocytoma

Pathological features of VHL syndrome in organs

VHL syndrome demonstrates diverse clinical manifestations and can involve multiple organs, either concurrently or sequentially over time. The interval between the onset of lesions in different organs may range from several years to decades. For example, in the cases described in the present study, the intervals were 5 years in case 1, 7 years in case 2, 6 years in case 3 and 11 years in case 4 (Table II).

Table II Clinical data and affected organs.

Table II

Clinical data and affected organs.

				CNS hemangioblastoma
Case	Sex	Age at first onset, years	Chief complaint	Head	Spinal cord	Retina	Pancreas	Kidney
1	Male	29	Posterior neck pain	Cerebellum	L1	No	Pancreatic neuroendocrine tumor, pancreatic cyst	Left adrenal pheochromocytoma, right renal cysts
2	Female	38	Paresthesia in the left hand and left lower limb	Medulla oblongata	C5-6	No	Multiple pancreatic cysts	No
3	Female	24	Fever	Cerebellar hemisphere and medulla oblongata	L2-3	No	Multiple pancreatic cysts	Bilateral renal cysts, bilateral RCC
4	Female	38	Intermittent headache and dizziness	Cerebellar hemisphere and vermis	T3, T12-L1	No	Pancreatic cyst	Bilateral RCC, bilateral adrenal pheochromocytoma

[i] CNS, central nervous system; RCC, renal cell carcinoma.

CNS-H

CNS-H is the most frequent tumor associated with VHL syndrome and represents the leading cause of mortality in affected patients. Onset typically occurs between 20 and 30 years of age. CNS-H predominantly arises in the cerebellum (44-72%), spinal cord (13-50%) and brainstem (10-25%), with rare involvement of the optic pathway, choroid plexus, anterior pituitary and infundibulum (~1%) (15). Clinical manifestations are variable and may include headache, dizziness, balance disturbances, limb pain, weakness, numbness and aspiration pneumonia (16). Early symptoms are often nonspecific, making differential diagnosis challenging; for instance, in case 2, the patient underwent ulnar nerve decompression due to an initial misdiagnosis of hand numbness attributed to ulnar nerve compression. Surgical resection remains the standard treatment for large or symptomatic CNS-H tumors (17). Radiotherapy is increasingly employed for lesions that are small, deep-seated, multifocal or otherwise unsuitable for surgery (18). Recurrence is common following initial treatment, necessitating regular monitoring. Given that 5-38% of CNS-H cases are linked to VHL syndrome (19), thorough family history assessment and prompt screening of other organ systems are critical upon CNS-H detection. Genetic testing facilitates early diagnosis and management of VHL syndrome when clinically indicated.

In the present study, cases 1, 3 and 4 underwent surgical removal of intracranial tumors at initial presentation; however, tumor recurrence was observed 4, 2 and 11 years postoperatively, respectively. Case 2 did not receive surgery due to the complexity of the lesion.

RH

RH is the second most prevalent tumor linked to VHL syndrome worldwide, occurring in ~73% of cases (20). However, the incidence among Chinese patients is markedly lower, at ~22% (21), possibly reflecting variations associated with ethnicity or genetics. RH is usually diagnosed at ~25 years of age, with most patients presenting between 10 and 40 years of age (22). Bilateral involvement occurs in 50-60% of cases (23). Early-stage RH is generally asymptomatic, but as the disease advances, patients may experience visual deterioration, potentially leading to blindness. Consequently, early detection and timely intervention are vital to preserve vision. The primary treatment method involves tumor ablation through laser photocoagulation or cryotherapy (24). When ablative therapies are ineffective or unsuitable, intravitreal injections of anti-VEGF agents serve as an alternative option (25).

Pancreatic disease

Pancreatic lesions develop in ~60% of patients with VHL syndrome, including simple cysts, serous cystadenomas and neuroendocrine tumors (26). Among these, multiple cysts are the most common, with a subset developing into pancreatic neuroendocrine tumors (27). At initial diagnosis, pancreatic lesions constitute the only abdominal finding in ~12% of patients with VHL syndrome (28). Clinically, >90% of patients remain asymptomatic; however, hyperglycemia may arise if insulin secretion is disrupted. Tumors that compress the pancreatic or bile ducts can lead to obstructive jaundice and gastrointestinal symptoms, such as diarrhea and constipation. Simple cysts and serous cystadenomas generally have a benign course and warrant regular surveillance. Neuroendocrine tumors, which carry a risk of metastasis, require management tailored to tumor size, growth dynamics and specific gene mutations (29).

In case 2, a choledochojejunostomy was performed to relieve bile duct obstruction which was caused by compression from pancreatic cysts. The patient developed elevated blood glucose levels 2 years after the cysts were identified, suggesting a potential link between cyst compression and hyperglycemia. For patients with VHL syndrome, regular blood sugar monitoring is advisable following the detection of pancreatic cysts. If hyperglycemia occurs and other causes are excluded, addressing the pancreatic cyst may help achieve improved glucose control. In case 1, a pancreatic neuroendocrine tumor measuring 2.1x2.4 cm was identified in January 2018. Surgical intervention was deferred as there was no marked tumor growth during follow-up, however close observation was maintained. The remaining two cases had multiple asymptomatic pancreatic cysts that did not require specific treatment, although continued monitoring was recommended.

Kidney lesions

Approximately two-thirds of patients with VHL syndrome develop renal cysts or RCC. Although renal cysts are benign, they carry the risk of progressing to cancer, necessitating careful surveillance (12). RCC is the second most common cause of mortality among patients with VHL syndrome and typically manifests between the ages of 20 and 50 years. It often presents as multiple bilateral lesions, which grow slowly and metastasize late (30). Early disease stages are usually asymptomatic, while advanced stages may cause symptoms such as lower back pain and hematuria. For tumors <3 cm, regular monitoring is advised (31). The diagnosis primarily relies on imaging modalities including ultrasonography, CT and MRI (4). Notably, 68Ga-NY104 PET/CT has demonstrated marked diagnostic value for imaging metastatic RCC, while its application in primary RCC requires further clinical validation (32). Tumors >3 cm are generally managed with nephron-sparing surgery. Breakthroughs in targeted therapies, particularly HIF and VEGF inhibitors, have provided novel therapeutic options for advanced or metastatic RCC (33).

In case 1, the patient had a solitary renal cyst without any clinical symptoms; therefore, no treatment was administered. Case 3 was diagnosed with bilateral RCC in 2018, with the largest tumor measuring 9.3x5.4x6.8 cm. Following treatment, a marked reduction in tumor size was observed during the follow-up examination in July 2019. Case 4 presented with kidney cancer involving a tumor <3 cm in diameter, and thus, no further treatment was deemed necessary.

PhC

PhC occurs in 10-20% of patients with VHL syndrome, with >90% of cases arising in the adrenal glands. Rare cases involve locations such as the carotid sinus, vagus nerve or abdominal aorta (34). The average age of onset is 34 years. Adrenal PhC can be unilateral or bilateral, with ~44% of cases affecting both adrenal glands. These tumors may be either functional or non-functional. Functional pheochromocytomas demonstrate overproduction of catecholamines (epinephrine, norepinephrine and dopamine), clinically presenting with characteristic symptom clusters: Sudden-onset high blood pressure, rapid heartbeat, profuse sweating, severe headaches and shaking tremor. Hypertension is the most common clinical manifestation (4). Surgical removal remains the primary treatment for PhC, although there is a recurrence risk, underscoring the importance of regular follow-up (35).

Case 1 underwent surgery for bilateral adrenal PhC in 2005 and initially recovered well; however, a recurrence of the left adrenal PhC was detected in 2018. Histologically, bilateral PhC associated with VHL syndrome is indistinguishable from solitary PhC. In young patients with hypertension and bilateral adrenal PhC, VHL syndrome should be suspected. In case 4, PhC was considered non-functional due to the absence of hypertension, thus no treatment was initiated. However, close surveillance was maintained, with plans to address adrenal PhC before any other surgical interventions to reduce intraoperative risks.

Other lesions of VHL syndrome

Bilateral epididymal papillary cystadenomas occur in approximately one-half of all male patients with VHL syndrome, usually presenting as painless scrotal masses. These lesions typically do not impact fertility. Female patients may develop cystadenomas of the broad ligament, which are generally asymptomatic and do not require specific treatment (2).

None of the four cases in the current study showed involvement of the reproductive system.

Discussion

VHL syndrome is a rare disorder affecting multiple organs, and its diagnosis can be challenging due to the variability in which organs are involved and the order of their appearance. When VHL syndrome is clinically suspected, a thorough examination and detailed family history review are essential. Screening and monitoring family members, especially offspring, is recommended after diagnosis. Advances in the study of the VHL gene have introduced new diagnostic tools and treatment options. Genetic testing allows for the identification of specific mutations and helps to assess the risk of tumor development across various organs, facilitating focused surveillance. Currently, surgery remains the primary treatment, although tumor recurrence after surgery is common. Insights into VHL gene mutations affecting the VEGF signaling pathway have spurred progress in targeted drug therapies, such as belzutifan (HIF-2 inhibitor) (36), tivozanib (VEGF receptor tyrosine kinase inhibitor) (37) and bevacizumab (anti-VEGF monoclonal antibody) (38).

With ongoing advancements in molecular biology, gene therapy presents a promising option for managing VHL syndrome in the future. The critical research trajectory in this disease domain hinges on establishing a translational pipeline where clinicians can: i) Systematically correlate clinical-radiographic phenotypes with genetic suspicion indices: Germline VHL mutations are classified into distinct subtypes, each associated with specific clinical manifestations of the syndrome (4); and ii) implement tiered molecular diagnostics as per the American College of Medical Genetics and Genomics guidelines (39). The primary clinical implication of the present study lies in its capacity to alert clinicians to consider VHL syndrome, a heritable syndrome of tumor predisposition, in the differential diagnosis when evaluating patients with multisystem tumors, particularly those demonstrating atypical organ involvement patterns.

The primary limitations of the current study include: A restricted cohort size (n=4), and the absence of novel clinical manifestations or previously undocumented organ involvement patterns in VHL syndrome. We subsequently aim to establish a longitudinal VHL registry to systematically expand the sample size and comprehensively characterize its phenotypic evolution, with the ultimate goal of identifying potential genotype-phenotype associations and emerging disease patterns.

Acknowledgements

Not applicable.

Funding

Funding: No funding was received.

Availability of data and materials

The data generated in the present study may be requested from the corresponding author.

Authors' contributions

SD prepared the initial draft of the manuscript and participated in patient data analysis and medical history follow-up. HC handled data collection for the study, providing the patient's clinical history and medical records, and participated in both data acquisition and analysis. RD contributed to revising and refining the manuscript, and participated in both data analysis and interpretation. YB and DJ contributed to data acquisition and data analysis, and the evaluation of treatment recommendations. TP and YW contributed to data analysis and interpretation. SD and HC confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

All studies involving human participants were reviewed and approved by the Hebei General Hospital Ethics Committee (Shijiazhuang, China; approval no. 2024-LW-150) and were conducted following the ethical principles outlined in the 1964 Declaration of Helsinki and its subsequent amendments.

Patient consent for publication

Patient identities were anonymized throughout data collection and analysis. All personal identifiers were either removed or encrypted, including names, addresses, social security numbers and hospital ID numbers. The data were then aggregated and analyzed to ensure that individual patients could not be re-identified. A waiver of patient consent for publication was approved by the Hebei General Hospital Ethics Committee.

Competing interests

The authors declare that they have no competing interests.

References