Genetics, Pathophysiology, and Current Challenges in Von Hippel–Lindau Disease Therapeutics

This review article focuses on von Hippel–Lindau (VHL) disease, a rare genetic disorder characterized by the development of tumors and cysts throughout the body. It discusses the following aspects of the disease. Genetics: VHL disease is caused by mutations in the VHL tumor suppressor gene located on chromosome 3. These mutations can be inherited or occur spontaneously. This article details the different types of mutations and their associated clinical features. Pathophysiology: The underlying cause of VHL disease is the loss of function of the VHL protein (pVHL). This protein normally regulates hypoxia-inducible factors (HIFs), which are involved in cell growth and survival. When pVHL is dysfunctional, HIF levels become elevated, leading to uncontrolled cell growth and tumor formation. Clinical Manifestations: VHL disease can affect various organs, including the brain, spinal cord, retina, kidneys, pancreas, and adrenal glands. Symptoms depend on the location and size of the tumors. Diagnosis: Diagnosis of VHL disease involves a combination of clinical criteria, imaging studies, and genetic testing. Treatment: Treatment options for VHL disease depend on the type and location of the tumors. Surgery is the mainstay of treatment, but other options like radiation therapy may also be used. Challenges: This article highlights the challenges in VHL disease management, including the lack of effective therapies for some tumor types and the need for better methods to monitor disease progression. In conclusion, we emphasize the importance of ongoing research to develop new and improved treatments for VHL disease.


Introduction
von Hippel-Lindau (VHL) disease is a rare, autosomal dominant genetic disorder characterized by the development of multiple tumors and cysts throughout the body, resulting from germline mutations or deletions in the VHL tumor suppressor gene located on chromosome three [1].VHL affects approximately 1 in 36,000 individuals globally [2].While the condition can start at any age, the median age of onset is 26 years, with a high penetrance of disease manifestations by age 65 for 97% of the cases [3].
The clinical spectrum of VHL is broad, encompassing benign and malignant tumors involving the central nervous system, retina, kidneys, adrenal glands, pancreas, and other organs [4].Hemangioblastomas, highly vascular tumors that can arise in the central nervous system, retina, and other locations, are a hallmark of VHL [5].While most VHL-associated tumors are benign, they can cause significant morbidity due to their location and size.Notably, VHL patients are at increased risk for developing clear cell renal cell carcinoma and pheochromocytoma [6,7].
The underlying pathophysiology of VHL involves dysregulation of the hypoxiainducible factor (HIF) pathway [7,8].The VHL protein is a critical component of the E3 ubiquitin ligase complex that targets HIF for degradation under normoxic conditions.In the absence of functional VHL, HIF is stabilized, leading to aberrant activation of genes involved in angiogenesis, erythropoiesis, and glucose metabolism [3,9].
Differential diagnosis of VHL can be challenging due to the overlap of clinical features with other genetic and sporadic conditions.To establish a definitive diagnosis, genetic testing to identify pathogenic variants in the VHL gene is essential [10-13] ( Richards et al., 2015).

Von Hippel-Lindau (VHL) Disease: Highlights
VHL disease is a multiorgan neoplastic syndrome with autosomal dominant transmission, complete penetrance, and variable expression caused by mutations in the VHL gene.Although VHL disease is hereditary in many cases, new mutations cause up to 20% of the cases [14].Pathogenic variants in the VHL gene predispose individuals to tumors and cysts in many organ systems.These include brain and spinal cord hemangioblastoma, renal cell carcinoma (RCC), retinal hemangioblastoma (RH), pheochromocytoma, epididymal and broad ligament cystadenomas, endolymphatic sac tumor, pancreatic neuroendocrine tumors, and renal and pancreatic cysts [4,15].

History
Observations relating to VHL disease first appeared in the 19th century.For example, in 1879, Panas and Rémy illustrated a retinal hemangioblastoma for the first time.Subsequently, von Hippel contributed to the description of the disease through clinical data obtained from a patient with multiple retinal lesions that appeared over several years.From all her observations, von Hippel concluded that the primary retinal lesion was a hemangioblastoma.Later, in 1926, Lindau published a monograph.In this document, he brought together into one coherent entity the retinal, cerebral, and visceral components of this disease.Lindau designated "central nervous system angiomatosis" as this disease entity because he believed that visceral concomitants did not manifest by symptoms.Finally, 'Lindau's disease' was defined as an association of cerebellar hemangioblastoma with one or more lesions: retinal hemangioblastoma (the "von Hippel tumor"), spinal cord hemangioblastoma, pancreatic cysts, renal and epididymal abnormalities, and the existence of at least one other family member with the disease [16].This term changed to the 'von Hippel-Lindau (VHL)' disease in the 1970s.In 1988, a report explained the linkage of the VHL gene to chromosome 3 [17], and, in 1993, a research group identified the VHL tumor suppressor gene [1].

Etiology
von Hippel-Lindau (VHL) syndrome is a syndrome associated with functional inactivation of the von Hippel-Lindau protein (pVHL) [18].The von Hippel-Lindau protein (pVHL) is a tumor suppressor mainly known for its role as a regulator of hypoxia-inducible factor (HIF) activity [19].The homonymous VHL gene codifies the pVHL protein, localizes on chromosome 3p25, and is expressed in fetal and adult tissues [20].On the other hand, VHL-related tumor development follows Knudson's 'two-hit model' of tumorigenesis [21]: Patients with VHL are born with a germline mutation in one copy of their VHL gene in all cells (first hit or event).Somatic mutation in the other copy of the VHL gene (second hit or event) initiates tumor development in a particular cell [22,23].

Epidemiology
The disease reports penetrance of > 80% by age 60 and an approaching 100% by age 75.The prevalence of VHL disease is between 1 in 39,000 and 1 in 91,000 individuals in different regional populations [24,25].Most are >20 years old and are prone to selection bias due to the inclusion of clinically affected patients with VHL disease diagnosed before genetic testing was available.For example, VHL disease had a birth incidence of 1 in 36,000 live births in eastern England, and prevalences of 1 in 39,000 individuals in southwestern Germany and 1 in 53,000 individuals in eastern England [26,27].However, in Denmark, in an unselected cohort of all known Danish carriers of a disease-causing variant, VHL prevalence is estimated at 1 in 46,900 individuals and an incidence of 1 in 27,300 live births [28].

Pathophysiology
von Hippel-Lindau (VHL) syndrome is a rare hereditary cancer characterized by the development of benign or malignant tumors in specific topographic locations.In this sense, central nervous system hemangioblastoma and clear cell renal cell carcinoma (RCC) are the most frequently tumors [4].
Tumorigenesis in VHL syndrome is linked to the loss of function of the VHL tumor suppressor protein in cell differentiation [29] where hypoxia-inducible factors (HIF1 and HIF2) are activated and accumulate in the cell [30,31].The consequences of this up-regulation include transcriptional activation of genes containing hypoxia-responsive elements [32,33].However, it remains unclear why the loss of VHL function and subsequent HIF activation lead to tumorigenesis.Tumorigenesis is associated with the PI3K/Akt signaling pathway, and this pathway is also associated with HIF activation and deactivation of tumor suppressors.Further research is needed in this area associated with VHL [34].The PI3K/AKT signaling pathway is a critical regulator of various cellular processes, including metabolism, growth, and survival; it has a significant role in cancer biology, and is associated with HIF activation and the deactivation of tumor suppressors.
HIF Activation: The PI3K/AKT pathway can activate hypoxia-inducible factor 1 alpha (HIF1α) even under normoxic conditions (normal oxygen levels) [34].This occurs through several mechanisms.Increased Stability: PI3K/AKT signaling can inhibit the prolyl hydroxylases (PHDs) that normally target HIF1α for degradation.When PHDs are inhibited, HIF1α becomes more stable and accumulates in the cell, leading to its activation and subsequent transcription of target genes involved in angiogenesis, metabolism, and cell survival [35].Transcriptional Regulation: Activated AKT can also enhance the transcription of HIF1α by promoting its translation and increasing its mRNA levels, further contributing to its accumulation and activity in cancer cells [36].Deactivation of Tumor Suppressors: The PI3K/AKT pathway is known to negatively regulate several tumor suppressor proteins, which can lead to enhanced tumorigenesis.PTEN (Phosphatase and Tensin Homolog): PTEN is a well-known tumor suppressor that negatively regulates the PI3K/AKT pathway.Loss of PTEN function leads to increased AKT activity, promoting cell survival and proliferation while inhibiting apoptosis.This loss of PTEN is common in various cancers, including breast cancer [37].p53: The tumor suppressor p53, which is crucial for DNA repair and apoptosis, can also be inhibited by the PI3K/AKT pathway.AKT can phosphorylate and inactivate p53, leading to reduced apoptosis and enhanced cell survival, contributing to cancer progression [38].FoxO Transcription Factors: AKT can phosphorylate FoxO transcription factors, leading to their exclusion from the nucleus and subsequent degradation.FoxOs are involved in the regulation of genes that promote cell cycle arrest and apoptosis, so their inactivation by AKT promotes tumor growth and survival [39].In summary, the PI3K/AKT signaling pathway promotes the activation of HIF1α, which supports tumor growth and survival, while simultaneously deactivating key tumor suppressors like PTEN and p53, facilitating cancer progression and resistance to therapies.
Another explanation of why the loss of VHL function and subsequent HIF activation lead to tumorigenesis suggests that the 'second hit' would cause loss of pivotal VHL function during organ development, leading to maldeveloped structures that represent prerequisites for tumor formation [40].

VHL Gene and Protein
In 1988, Seizinger and colleagues mapped the VHL gene.The findings showed that the VHL gene is located on the short arm of chromosome 3 in the 3p 25-25 region (Figure 1).Moreover, the VHL gene has 14,500 base pairs of genomic DNA, and 852 nucleotides with three exons that can generate two mRNAs through a process that causes the loss of exon 2. This gene is conserved in rodents, flies, and worms [41,42].HIF1α, which supports tumor growth and survival, while simultaneously deactivating key tumor suppressors like PTEN and p53, facilitating cancer progression and resistance to therapies.Another explanation of why the loss of VHL function and subsequent HIF activation lead to tumorigenesis suggests that the 'second hit' would cause loss of pivotal VHL function during organ development, leading to maldeveloped structures that represent prerequisites for tumor formation [40].

VHL Gene and Protein
In 1988, Seizinger and colleagues mapped the VHL gene.The findings showed that the VHL gene is located on the short arm of chromosome 3 in the 3p 25-25 region (Figure 1).Moreover, the VHL gene has 14,500 base pairs of genomic DNA, and 852 nucleotides with three exons that can generate two mRNAs through a process that causes the loss of exon 2. This gene is conserved in rodents, flies, and worms [41,42].The VHL gene consists of three exons with the capacity to generate two mRNA transcripts.The mRNA1 transcript is composed of exons 1, 2, and 3, and the mRNA2 transcript is composed of exons 1 and 3 (Figure 2).The mRNA1 transcript encodes two pVHL proteins.When translation occurs, the complete protein from 1 to 213 amino acids with a molecular mass of 24~30 kDa, also known as pVHL30, and a small peptide from 54 to 213 amino acids is translated through an alternative start codon at codon 54 with a molecular mass of 18~19 kDa, also known as pVHL19.Both proteins (pVHL30 and pVHL19) are localized in the cytoplasm and cell nucleus, respectively [43,44].The structure of the pVHL protein has two domains: the β domain that ranges from 63 to 155 aa and the α domain that includes amino acids 156 to 193, as shown in Figure 3. On the other hand, the protein pVHL30 contains an acidic domain located in amino acids 1-54, absent from the pVHL19 protein.The function of pVHL30 is present in several events.For example, protein degradation via the proteasome is the most studied, and in addition to both isoforms, it appears to maintain tumor suppression activity [45].The VHL gene consists of three exons with the capacity to generate two mRNA transcripts.The mRNA1 transcript is composed of exons 1, 2, and 3, and the mRNA2 transcript is composed of exons 1 and 3 (Figure 2).The mRNA1 transcript encodes two pVHL proteins.When translation occurs, the complete protein from 1 to 213 amino acids with a molecular mass of 24~30 kDa, also known as pVHL30, and a small peptide from 54 to 213 amino acids is translated through an alternative start codon at codon 54 with a molecular mass of 18~19 kDa, also known as pVHL19.Both proteins (pVHL30 and pVHL19) are localized in the cytoplasm and cell nucleus, respectively [43,44].
to therapies.
Another explanation of why the loss of VHL function and subsequent HIF activation lead to tumorigenesis suggests that the 'second hit' would cause loss of pivotal VHL function during organ development, leading to maldeveloped structures that represent prerequisites for tumor formation [40].

VHL Gene and Protein
In 1988, Seizinger and colleagues mapped the VHL gene.The findings showed that the VHL gene is located on the short arm of chromosome 3 in the 3p 25-25 region (Figure 1).Moreover, the VHL gene has 14,500 base pairs of genomic DNA, and 852 nucleotides with three exons that can generate two mRNAs through a process that causes the loss of exon 2. This gene is conserved in rodents, flies, and worms [41,42].The VHL gene consists of three exons with the capacity to generate two mRNA transcripts.The mRNA1 transcript is composed of exons 1, 2, and 3, and the mRNA2 transcript is composed of exons 1 and 3 (Figure 2).The mRNA1 transcript encodes two pVHL proteins.When translation occurs, the complete protein from 1 to 213 amino acids with a molecular mass of 24~30 kDa, also known as pVHL30, and a small peptide from 54 to 213 amino acids is translated through an alternative start codon at codon 54 with a molecular mass of 18~19 kDa, also known as pVHL19.Both proteins (pVHL30 and pVHL19) are localized in the cytoplasm and cell nucleus, respectively [43,44].The structure of the pVHL protein has two domains: the β domain that ranges from 63 to 155 aa and the α domain that includes amino acids 156 to 193, as shown in Figure 3. On the other hand, the protein pVHL30 contains an acidic domain located in amino acids 1-54, absent from the pVHL19 protein.The function of pVHL30 is present in several events.For example, protein degradation via the proteasome is the most studied, and in addition to both isoforms, it appears to maintain tumor suppression activity [45].The structure of the pVHL protein has two domains: the β domain that ranges from 63 to 155 aa and the α domain that includes amino acids 156 to 193, as shown in Figure 3. On the other hand, the protein pVHL30 contains an acidic domain located in amino acids 1-54, absent from the pVHL19 protein.The function of pVHL30 is present in several events.For example, protein degradation via the proteasome is the most studied, and in addition to both isoforms, it appears to maintain tumor suppression activity [45].

Inheritance
VHL disease is autosomal dominant; that is, it is transmitted from parents to children.However, the disease can occur sporadically.The mutation is inherited when one parent has the VHL gene altered (mutated), so each child has a 50% chance of inheriting it.Consistent with the dominant inheritance pattern, it is enough to have an altered gene to develop the disease.Thus, an affected parent (who therefore has a mutated gene and a normal one) could pass on the mutated gene to his offspring, who in turn will develop the disease despite having the other normal gene (see Figure 4) [46].VHL disease is also autosomal, which means that men and women can suffer from it equally (Figure 4).People with parents, brothers, or sisters with VHL have a 50% risk of disease.If the person has an uncle, cousin, or grandparent with VHL, they are also at risk for developing VHL.Moreover, the presence of the disease in individuals without family background has been reported, therefore it is necessarily a differential diagnosis for each individual [47].

Mutations
In VHL gene mutation carriers, the development of the disease begins with the loss or inactivation of the wild-type allele.Cytogenetic abnormalities, mutations, or

Inheritance
VHL disease is autosomal dominant; that is, it is transmitted from parents to children.However, the disease can occur sporadically.The mutation is inherited when one parent has the VHL gene altered (mutated), so each child has a 50% chance of inheriting it.Consistent with the dominant inheritance pattern, it is enough to have an altered gene to develop the disease.Thus, an affected parent (who therefore has a mutated gene and a normal one) could pass on the mutated gene to his offspring, who in turn will develop the disease despite having the other normal gene (see Figure 4) [46].VHL disease is also autosomal, which means that men and women can suffer from it equally (Figure 4).People with parents, brothers, or sisters with VHL have a 50% risk of disease.If the person has an uncle, cousin, or grandparent with VHL, they are also at risk for developing VHL.Moreover, the presence of the disease in individuals without family background has been reported, therefore it is necessarily a differential diagnosis for each individual [47].

Inheritance
VHL disease is autosomal dominant; that is, it is transmitted from parents to children.However, the disease can occur sporadically.The mutation is inherited when one parent has the VHL gene altered (mutated), so each child has a 50% chance of inheriting it.Consistent with the dominant inheritance pattern, it is enough to have an altered gene to develop the disease.Thus, an affected parent (who therefore has a mutated gene and a normal one) could pass on the mutated gene to his offspring, who in turn will develop the disease despite having the other normal gene (see Figure 4) [46].VHL disease is also autosomal, which means that men and women can suffer from it equally (Figure 4).People with parents, brothers, or sisters with VHL have a 50% risk of disease.If the person has an uncle, cousin, or grandparent with VHL, they are also at risk for developing VHL.Moreover, the presence of the disease in individuals without family background has been reported, therefore it is necessarily a differential diagnosis for each individual [47].

Mutations
In VHL gene mutation carriers, the development of the disease begins with the loss or inactivation of the wild-type allele.Cytogenetic abnormalities, mutations, or

Mutations
In VHL gene mutation carriers, the development of the disease begins with the loss or inactivation of the wild-type allele.Cytogenetic abnormalities, mutations, or hypermethylation cause inactivation of the remaining 'healthy' allele (Figure 5).Currently, it is unknown why the second event occurs in some tissues and not in others [48].On the other hand, some studies show that patients develop retinal hemangioblastoma with complete deletion of the VHL gene less frequently than those with a single amino acid substitution in the VHL gene.In addition, there were no differences between patients with a truncated variant and those with a single amino acid substitution [49,50].
Diagnostics 2024, 14, x FOR PEER REVIEW hypermethylation cause inactivation of the remaining 'healthy' allele (Figure 5 rently, it is unknown why the second event occurs in some tissues and not in othe On the other hand, some studies show that patients develop retinal hemangiobl with complete deletion of the VHL gene less frequently than those with a single acid substitution in the VHL gene.In addition, there were no differences between p with a truncated variant and those with a single amino acid substitution [49,50].Germline VHL mutations cause different protein defects that result in the heterogeneity of VHL disease.For example, type 1 VHL disease (without pheochr toma) is associated with mutations that cause the complete unraveling of the protei ture (missense mutations in the hydrophobic core of the VHL protein, protein-tru mutations, and partial gene deletions).On the other hand, VHL disease type 2 (wit ochromocytoma) is associated with missense mutations at pVHL protein bindin causing local defects [51].Table 1 shows several examples of the relationship betw type of VHL disease and some mutations.Germline VHL mutations cause different protein defects that result in the clinical heterogeneity of VHL disease.For example, type 1 VHL disease (without pheochromocytoma) is associated with mutations that cause the complete unraveling of the protein structure (missense mutations in the hydrophobic core of the VHL protein, protein-truncating mutations, and partial gene deletions).On the other hand, VHL disease type 2 (with phaeochromocytoma) is associated with missense mutations at pVHL protein binding sites, causing local defects [51].Table 1 shows several examples of the relationship between the type of VHL disease and some mutations.[52].Database was revised in 30 September 2021.

Manifestations, Diagnosis, and Treatment of VHL Disease
Symptoms of VHL disease vary among patients and depend on the size and location of the tumors.On the other hand, diagnosis can be made based on specific clinical criteria (signs, symptoms, and imaging), or when molecular genetic testing reveals a change in the VHL gene.Finally, treatment depends on the location and size of the tumors and usually involves surgical removal of the tumors.Radiation therapy may be used in some cases (Table 2).

Manifestations, Diagnosis, and Treatment of VHL Disease
Symptoms of VHL disease vary among patients and depend on the size and location of the tumors.On the other hand, diagnosis can be made based on specific clinical criteria (signs, symptoms, and imaging), or when molecular genetic testing reveals a change in the VHL gene.Finally, treatment depends on the location and size of the tumors and usually involves surgical removal of the tumors.Radiation therapy may be used in some cases (Table 2).

Manifestations, Diagnosis, and Treatment of VHL Disease
Symptoms of VHL disease vary among patients and depend on the size and location of the tumors.On the other hand, diagnosis can be made based on specific clinical criteria (signs, symptoms, and imaging), or when molecular genetic testing reveals a change in the VHL gene.Finally, treatment depends on the location and size of the tumors and usually involves surgical removal of the tumors.Radiation therapy may be used in some cases (Table 2).

Molecular Basis of VHL Disease
The best known pVHL function is the regulation of hypoxia-inducible factor-alpha (HIF-α) protein levels through degradation under normoxic conditions [115].The interaction between pVHL and HIF-α requires the hydroxylation dependent on prolyl-4 hydroxylase domain enzymes (PHD1, -2 and -3) of at least one of two specific proline residues of HIF-α [116].Subsequently, HIF-α is ubiquitylated and degraded via the proteasome.Under hypoxic conditions or in the presence of mutant pVHL [60,117], the pVHL complex cannot recognize HIF-α, then HIF-α accumulates in the cytoplasm.In the cytoplasm, HIFα forms a heterodimer with HIF-β.Subsequently, the heterodimer translocates to the nucleus with the transcriptional coactivator p300, where it binds to response elements (HRE) [118] and promotes the transcription of many genes involved in angiogenesis, glucose metabolism, cell survival, and tumor progression [9] (Figure 7).
mTOR is a serine/threonine protein kinase.mTOR nucleates two different complexes, mTORC1 and mTORC2 [120].mTORC1 is composed of mTOR, the regulatory associated protein of mTOR (RAPTOR), and the protein mammalian lethal with sec-teen protein 8 [121].Some mTORC1 substrates are S6 kinase 1 (S6K1) and the eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1).Finally, phosphorylation of S6K1 and 4E-BP1 by mTORC1 stimulates protein translation [122].Targeting the PI3K/Akt/mTOR pathways is a promising strategy in cancer, and possible in VHL treatment due to their central role in tumor biology, potential to overcome resistance, and ability to enhance the effectiveness of existing therapies [123].[111]

Molecular Basis of VHL Disease
The best known pVHL function is the regulation of hypoxia-inducible factor-alpha (HIF-α) protein levels through degradation under normoxic conditions [115].The interaction between pVHL and HIF-α requires the hydroxylation dependent on prolyl-4 hydroxylase domain enzymes (PHD1, -2 and -3) of at least one of two specific proline residues of HIF-α [116].Subsequently, HIF-α is ubiquitylated and degraded via the proteasome.Under hypoxic conditions or in the presence of mutant pVHL [60,117], the pVHL complex cannot recognize HIF-α, then HIF-α accumulates in the cytoplasm.In the cytoplasm, HIFα forms a heterodimer with HIF-β.Subsequently, the heterodimer translocates to the nucleus with the transcriptional coactivator p300, where it binds to response elements (HRE) [118] and promotes the transcription of many genes involved in angiogenesis, glucose metabolism, cell survival, and tumor progression [9] (Figure 7).
mTOR is a serine/threonine protein kinase.mTOR nucleates two different complexes, mTORC1 and mTORC2 [120].mTORC1 is composed of mTOR, the regulatory associated protein of mTOR (RAPTOR), and the protein mammalian lethal with sec-teen protein 8 [121].Some mTORC1 substrates are S6 kinase 1 (S6K1) and the eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1).Finally, phosphorylation of S6K1 and 4E-BP1 by mTORC1 stimulates protein translation [122].Targeting the PI3K/Akt/mTOR pathways is a promising strategy in cancer, and possible in VHL treatment due to their central role in tumor biology, potential to overcome resistance, and ability to enhance the effectiveness of existing therapies [123].
In response to hypoxia, the regulation of mTORC1 involves the protein regulated in

Molecular Basis of VHL Disease
The best known pVHL function is the regulation of hypoxia-inducible factor-alpha (HIF-α) protein levels through degradation under normoxic conditions [115].The interaction between pVHL and HIF-α requires the hydroxylation dependent on prolyl-4 hydroxylase domain enzymes (PHD1, -2 and -3) of at least one of two specific proline residues of HIF-α [116].Subsequently, HIF-α is ubiquitylated and degraded via the proteasome.Under hypoxic conditions or in the presence of mutant pVHL [60,117], the pVHL complex cannot recognize HIF-α, then HIF-α accumulates in the cytoplasm.In the cytoplasm, HIF-α forms a heterodimer with HIF-β.Subsequently, the heterodimer translocates to the nucleus with the transcriptional coactivator p300, where it binds to response elements (HRE) [118] and promotes the transcription of many genes involved in angiogenesis, glucose metabolism, cell survival, and tumor progression [9] (Figure 7).However, the pathogenesis of clear cell renal cell carcinomas (ccRCCs) implies mTOR complex 1 (mTORC1).For example, reports show that mTORC1 activates in 60% to 85% of ccRCCs [119].
mTOR is a serine/threonine protein kinase.mTOR nucleates two different complexes, mTORC1 and mTORC2 [120].mTORC1 is composed of mTOR, the regulatory associated protein of mTOR (RAPTOR), and the protein mammalian lethal with sec-teen protein 8 [121].Some mTORC1 substrates are S6 kinase 1 (S6K1) and the eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1).Finally, phosphorylation of S6K1 and 4E-BP1 by mTORC1 stimulates protein translation [122].Targeting the PI3K/Akt/mTOR pathways is a promising strategy in cancer, and possible in VHL treatment due to their central role in tumor biology, potential to overcome resistance, and ability to enhance the effectiveness of existing therapies [123].
In response to hypoxia, the regulation of mTORC1 involves the protein regulated in development and the DNA damage response 1 (REDD1).In this condition, HIF binds to a response element in the REDD1 promoter for induction, and therefore negatively regulates mTORC1 [124] (Figure 7a right).Paradoxically, mTORC1 is broadly activated in ccRCCs, pVHL-inactivated, HIF-activated, and up-regulated REDD1.These findings suggest that other mechanisms favor tumors to escape growth suppressor signals resulting from pVHL loss and up-regulation of REDD1 [125] (Figure 7b left).
Another HIF-dependent mechanism that activates mTORC1 is the down-regulation of the mTOR inhibitor, the DEP domain-containing mTOR-interacting protein (DEPTOR).DEPTOR is significantly down-regulated in pVHL-deficient ccRCC tumors and cell lines.In this tumor type, DEPTOR is transcriptionally suppressed by both HIF-1 and HIF-2, mediated by the HIF target gene, BHLHe40 [126] (Figure 7b left).
Finally, a study revealed a new mechanism for the deregulation of mTORC1 in ccRCC.The report showed that pVHL represses the regulatory-associated protein of mTOR (RAP-TOR), inhibiting mTORC1 signaling.Therefore, the loss of pVHL function in ccRCC is consistent with the hyperactivation of mTORC1 signaling.This mechanism describes a novel pVHL-mediated regulation of mTORC1 by targeted ubiquitination and degradation independent of HIF [127] (Figure 7b right).
pVHL is a critical tumor suppressor in ccRCCs.On the other hand, most patients with ccRCC are drug-resistant to therapies.Although targeted therapies that inhibit angiogenesis and mTOR pathways can lead to initial tumor control, most patients develop resistance [128][129][130].Therefore, the identification of additional pVHL substrates could improve therapeutic options for ccRCC.Next, we review some pVHL substrates and possible therapeutic targets in ccRCCs.
Most reports on pVHL/HIF transcriptional activation have focused on HIF-bound promoters.However, evidence suggests distal enhancer elements in pVHL/HIF transcriptional control.In this sense, a study identified a master regulator crucial for the pathogenesis of ccRCC, ZNF395.pVHL loss stabilizes HIF2α occupancy in tumor-specific gained enhancers.HIF2α recruits histone acetyltransferase p300 to maintain H3K27 acetylation, up-regulating the expression of ccRCC-specific genes such as ZNF395.ZNF395 has a functional role in ccRCC tumorigenesis in vitro and in vivo [131] (Figure 8a-1).
A genome-wide in vitro expression strategy to identify proteins that bind to pVHL when hydroxylated determined that zinc fingers and homeoboxes 2 (ZHX2) are a novel pVHL substrate transcription factor.Analysis of tumors from ccRCC patients and pVHL loss-of-function mutations confirmed pVHL loss usually increases the abundance and nuclear levels of ZHX2 in ccRCC tumors.Mechanically, this study revealed that ZHX2 could promote NF-kB activation and carcinogenesis of ccRCC [132].Another study showed the downstream signaling pathway of ZHX2.ZHX2 facilitated proliferation and migration in ccRCC cell lines by activating the MEK1/ERK1/2 signaling pathway.Furthermore, ZHX2 overexpression could induce Sunitinib resistance by activating autophagy through the MAPK/ERK signal pathway [133] (Figure 8a-2 up).
Regarding SNC hemangioblastomas, the analysis of tissues with mutations in the expressions of VHL gene showed the JAK2 and STAT3.The results of this study indicate that pVHL binds to JAK2 and STAT3 and mediates its ubiquitination.Furthermore, the study suggests that hemangioblast progenitor cells can differentiate into neoplastic cells by activating the JAK-STAT signaling pathway [138] (Figure 8b-1).Another novel genome-wide in vitro expression strategy coupled with a GST-binding screen for pVHL substrates identified Scm-like with four malignant brain tumor domains 1 (SFMBT1) as a direct target of pVHL.In renal tumors compared to adjacent normal tissue, the levels of SFMBT1 are high.On the other hand, the functional characterization of SFMBT1 showed that it promotes ccRCC cell proliferation, anchorage-independent growth, and tumor xenograft growth.The analysis also identified sphingosine kinase 1 (SPHK1).SPHK1 is an SFMBT1 target gene that contributes to the oncogenic phenotype of renal tumors [134].SFMBT1 and its downstream target gene SPHK1 could represent a new therapeutic strategy for patients with ccRCC treatment (Figure 8a-2 below).
Finally, mRNA expression levels of both transcription factors (ZHX2 and SFMBT1) in a tissue microarray constructed using 97 ccRCC samples showed an association with overall survival (OS) and disease-free survival (DFS) analyses.In this sense, survival analysis demonstrated that poor clinical outcomes in patients with ccRCC were associated with combined high expression levels of SFBMT1 and ZHX2.These results suggest that the co-expression of these two targets could be a promising biomarker for predicting the outcome of patients with ccRCC [135].
However, a study describes the pathologic angiogenic phenotype of pVHL missense mutations in ccRCC.In this case, the SUMO Enhancer (RSUME) sumoylates pVHL mutants.This post-translational modification promotes HIF-2α stabilization and leads to enhanced VEGF action.Therefore, it promotes more vascularized tumors.Regarding pathology, RSUME levels are higher in tumor patients with pVHL mutations and are associated with a poor prognosis in RCC tumors.These findings suggest that RSUME could be a biomarker of the outcomes of renal cell carcinoma [136] (Figure 8a-3).
Regarding SNC hemangioblastomas, the analysis of tissues with mutations in the expressions of VHL gene showed the JAK2 and STAT3.The results of this study indicate that pVHL binds to JAK2 and STAT3 and mediates its ubiquitination.Furthermore, the study suggests that hemangioblast progenitor cells can differentiate into neoplastic cells by activating the JAK-STAT signaling pathway [138] (Figure 8b-1).

Animal Models for the Study of VHL
Current animal models for VHL disease can partially capture the disease by showing the involvement of a particular organ; therefore, much work is still needed to develop a model that exhibits several of the clinical manifestations (Table 3).Other manifestations of VHL disease, such as tumors of the endolymphatic sac, middle ear, pheochromocytoma, cerebellar, and cervical hemangioblastomas, are not seen in almost any of the models.Additionally, phenotypes not associated with VHL disease can also arise from the product of the mutated VHL protein [139,140].
The first animal model for VHL disease led to the development of an aberrant placenta, and thus was lethal to the embryo.Mice died in utero at embryonic days 10.5 and 12.5 [141].However, the use of conditional VHL knockouts in mice has been shown to be an effective approach to delineate the role of VHL in individual organ systems.
Eyes.To date, there is still no adequate model to study the CNS and retinal hemangioblastomas.A zebrafish model expressing retinal neovascularization from vascular leakage, edema, and retinal detachment has been developed [142].Studies have shown an increase in VEGF and CXCR4A in the CNS in these zebrafish.In fact, this model manifests certain aspects of age-related macular degeneration, diabetic retinopathy, and some cases of VHL [143].However, zebrafish do not develop hemangioblastomas; van Rooijen and colleagues were able to use this zebrafish model to demonstrate inhibition of angiogenesis through the administration of VEGF receptor tyrosine kinase inhibition.Kidney.CCRCC is a malignant kidney neoplasm that arises sporadically or is inherited through inactivation of VHL.Rankin et al. were the first group to successfully create a model that generated renal microcysts and macrocysts with similar morphological and molecular characteristics found in VHL-associated kidney disease [144].Using Cre-loxP, they eliminated VHL expression from the proximal tubule using the phosphoenolpyruvate carboxykinase (PEPCK) promoter to drive Cre expression.Other groups have managed to obtain phenotypes that manifest acute nephritis with hematuria, proteinuria, and renal failure; characteristic features of pauci-immune RPGN (glomerulonephritis crescent) with prominent segmental fibrin deposition and fibrinoid necrosis [145].
Pancreas.Shen et al. produced a model using the insulin promoter factor 1 (Pdx) promoter to drive Cre expression.Survivors secondary to incomplete penetrance expressed highly vascularized cysts and microcystic adenomas, eliminating VHL expression throughout the pancreas [146].
Reproductive system.Ksp1.3-Cre mice were crossed with Vhlh fl / fl mice and Pten fl / fl mice.The modified mice were then bred to generate a mouse model with dual VHL and Pten deficiencies specific for genital tract epithelium.These mice were able to recapitulate clear cell cystadenoma of the genital tract. in both males and females [147].
Liver.A mouse model in which VHL was acutely inactivated in utero exhibited embryonic lethality with liver necrosis and vascular defects [148].A mouse model that conditionally inactivated VHL in hepatocytes led to hepatic hemangiomas [149].Similarly, another model that conditionally inactivated VHL in a mosaic pattern in multiple organs showed liver hemangiomas, as well as angiectasias in the pancreas, heart, lung, and kidney [150].Some other models showed growth deficiency, angiectasias, hemangiomas, endothelial cell proliferation, severe liver steatosis (accumulation of neutral fat in hepatocytes), and inflammatory cell infiltration [144].
In recent years, various animal models have been proposed in which the main objective is the inactivation of the VHL gene product in various organs (Table 3).In these models, the mechanisms associated with HIF and its link with tumorigenesis.However, these models are generally considered incapable of recapitulation of the most common characteristics of human VHL disease.To date, there are no models that develop retinal hemangioblastomas, the most common clinical manifestation of the disease [151].

Biomarkers in VHL Disease
Biomarkers for VHL disease are scarce.However, some studies propose several.For example, monitoring plasma levels of HIF-dependent molecules would allow monitoring of disease activity in VHL patients [101].Although a report confirmed that elevated plasma VEGF levels are associated with an increased risk of dying from ccRCC, plasma VEGF levels are also significantly increased in tumors without VHL alteration.It suggests that VHL-independent mechanisms are involved in up-regulation of VEGF in ccRCC [152].On the other hand, in serum from patients with VHL, no correlation was found between VEGF levels and the presence of manifestations of VHL disease [153].Finally, in another study, the presence of abnormalities in VHL did not correlate with overall survival (OS), disease-specific survival (DSS), and progression or recurrence-free survival (PFS), and the expression of VEGF had no prognostic value.However, this study showed an association with a poorer prognosis in patients with no expression of VHL and HIF1-α expression and patients with overexpression of ERK5 [154].
The remarkable phenotypic heterogeneity in organ involvement and tumor onset age between and within VHL families has not allowed reliable markers to predict the age-related tumor risks in VHL patients.In this sense, the information shown in Table 4 is a compilation of several molecules proposed as biomarkers.The samples are mainly renal tissues.The recruited subjects are patients with VHL disease with ccRCC, while some patients have VHL disease with hemangioblastoma or pancreatic lesions.The heterogeneity of the disease concerning clinical and molecular issues manifests itself in the diversity of the molecules described in the table.Last, several molecules are prognostic biomarkers, which means those that indicate the probability of a change in a future clinical event, disease recurrence, or progression in an identified population [155].

■
The expression of FGD5-AS1 was significantly lower in ccRCC than in adjacent normal tissues, and increased FGD5-AS1 was associated with longer OS and DFS. [162]

SFMBT1 and ZHX2
Tumor tissues and adjacent normal tissues • 97 patients with ccRCC.

■
High levels of SFBMT1 and ZHX2 expression were associated with poor clinical outcomes in patients with ccRCC. [135] 89 Zrbevacizumab Imaging The main limitation of these studies is the relatively small number of patients, but they provide an approximation to standard clinical and pathological data that are still essential in the development of biomarker panels for von Hippel-Lindau disease in addition to the molecular mechanisms that underlie this disease.Table 4 resumes the current principal biomarkers for VHL as follows: A study involving 300 patients with von Hippel-Lindau (VHL) disease and 92 healthy family controls found that VHL patients exhibited significantly shorter telomere lengths, which were associated with increased risks of various VHL-related tumors, indicating that telomere length could serve as a biomarker for VHL risk [156].In metastatic renal cell carcinoma (mRCC) patients, tumors with double c-Myc/HIF-2α-positive staining were linked to worse outcomes with sunitinib treatment [157].SERPINH1 was identified as a potential prognostic marker for disease-free survival (DFS) in patients with clear cell renal cell carcinoma (ccRCC) [158].Positive PD-L1 expression in ccRCC correlated with more aggressive disease in both sporadic and hereditary VHL-associated cases [159].High lamin B1 expression was found to be an unfavorable prognostic marker in primary RCC [160].Low expression of CTLA-4 and PD-1, along with a low fraction of immune cells, was associated with poor survival in high-risk kidney cancer patients [161].Reduced expression of lncRNA FGD5-AS1 in ccRCC was linked to shorter overall survival (OS) and DFS [162].High levels of SFMBT1 and ZHX2 were associated with poor outcomes in ccRCC [135].In imaging studies, 89Zr-bevacizumab PET showed potential in visualizing VHL disease manifestations, though it could not predict lesion behavior [163], and 68Gallium-DOTATATE PET/CT demonstrated higher detection rates in pancreatic lesions associated with VHL compared to CT and MRI [164].

Effect of Regional Populations on VHL Disease
While the genetic basis of VHL disease remains consistent across populations, the prevalence and specific manifestations can vary regionally.Several factors contribute to these differences: Founder effects: In isolated populations, specific VHL gene mutations may be more prevalent due to a shared common ancestor.This can lead to variations in disease phenotype and severity [165].
Genetic background: Different genetic backgrounds can modify the expression and penetrance of VHL disease.Polymorphisms in genes interacting with VHL or genes involved in tumorigenesis pathways may influence disease progression [166].
Environmental factors: Exposure to certain environmental factors, such as diet, lifestyle, and toxins, may interact with genetic susceptibility to VHL disease, leading to variations in disease presentation [167].
Healthcare access and practices: Differences in healthcare access and practices can impact the early detection, diagnosis, and management of VHL disease, leading to variations in disease outcomes [168].
It is essential to consider these regional differences when studying VHL disease to develop targeted prevention, early detection, and treatment strategies.

Targeted Therapy in VHL Disease
Clinical research on VHL disease is summarized in the next table (Table 5) As follows: A series of clinical trials investigating various therapeutic agents for conditions related to von Hippel-Lindau (VHL) disease and renal cell carcinoma (RCC) yielded mixed outcomes.Sunitinib trials (NCT00673816 and NCT00330564) were terminated due to slow recruitment and adverse events, with some limited efficacy in RCC lesions [169,170].The combination of ranibizumab and E10030 (NCT02859441) showed a limited effect on VHL-associated retinal hemangiomas but maintained a reasonable safety profile [171].Neovastat (Protocol CT/AE-941/002 and III) demonstrated a survival benefit and good tolerability in RCC patients, especially in a higher dose group [172,173].Propranolol (EudraCT 2014-003671-30) showed promise in stabilizing retinal hemangioblastomas in VHL patients with minimal adverse effects [174].However, sorafenib (EudraCT 2007-002132-29) showed no response in CNS hemangioblastomas over six months [175].Pazopanib (NCT01436227) and belzutifan (NCT03401788) were associated with tumor size reduction and disease stabilization in VHL-related conditions [176][177][178].Other trials, such as those involving PT2385, dovitinib, ranibizumab, vorinostat, and vandetanib, showed varying degrees of efficacy and tolerability, with some requiring further exploration to optimize their clinical benefits [179][180][181].Finally, tyrosine kinase inhibitors (TKIs) demonstrated partial responses in VHL-related tumors, particularly RCC and pancreatic lesions, with acceptable side effects in a study by the Medical Ethics Committee of Peking University [182].Intravitreous injections of ranibizumab (0.5 mg) and E10030 (1.5 mg) were administered unilaterally and each received 9 injections prior to week 52 and were followed for 104 weeks.
One participant manifested mild episodic ocular hypertension in the study eye.The change in BCVA in the study eye at week 52 for the three participants was -5, -   For sunitinib, a dosage of 50 mg/day was administered orally for 28 days, followed by a 14-day break per cycle for several cycles.For sorafenib, a dose of 800 mg/day divided into two doses was administered orally.For axitinib, a dose of 10 mg/day divided into two doses was administered orally.For pazopanib, a dose of 800 mg/day was administered orally.
A partial response was observed in eleven (31%) of thirty-six renal cell carcinomas, four (27%) of fifteen pancreatic lesions, and one (20%) of five central nervous system (CNS) hemangioblastomas.The mean tumor size decreased significantly for renal cell carcinomas (p = 0.0001), renal cysts (p = 0.027), and pancreatic lesions (p = 0.003) after TKI therapy.Finally, the side effects were acceptable.

Discussion
The current review provides a comprehensive overview of von Hippel-Lindau (VHL) disease, a rare genetic disorder characterized by multiple organ neoplastic syndrome.The disease is caused by deletions or mutations in the VHL gene [183], resulting in the development of cysts and tumors in various organs, including the brain, spine, eyes, kidneys, pancreas, adrenal glands, inner ears, reproductive tract, liver, and lungs [108].The prevalence of VHL disease is estimated to be between 1 in 39,000 and 1 in 91,000 individuals in different regional populations [24,25].The penetrance of the disease is high, with a significant risk of developing clinical manifestations throughout life, emphasizing the importance of thoroughly understanding the underlying genetics and pathophysiology.Here, we discuss the etiology, epidemiology, pathophysiology, genetics, clinical manifestations, diagnosis, and current treatments, as well as the molecular aspects of the disease.VHL is inherited in an autosomal dominant manner and is associated with mutations in the VHL gene.It discusses the role of von Hippel-Lindau protein (pVHL) as a tumor suppressor known for regulating hypoxia-inducible factor (HIF) activity [19].We provide insights into the inheritance pattern, mutations, and animal models used to study this disease, emphasizing the need for more comprehensive models that capture the diverse clinical manifestations of the disease.Furthermore, this review explores the biomarkers for VHL disease (Table 4).We discuss the proposed biomarkers for VHL disease that include monitoring plasma levels of HIF-dependent molecules, such as VEGF, which may allow for the monitoring of disease activity in VHL patients.However, it is important to note that elevated plasma VEGF levels are also significantly increased in tumors without VHL alteration, suggesting the involvement of VHL-independent mechanisms in up-regulating VEGF in clear cell renal cell carcinoma (ccRCC) [101,152,153,184].Additionally, studies have shown that the presence of abnormalities in VHL does not correlate with overall survival, disease-specific survival, and progression or recurrence-free survival.Telomere length is another potential biomarker for risk assessment in VHL patients.Shorter blood telomers are reported in VHL patients [156].The limitations of using blood telomere length as a biomarker for VHL disease include the relatively small number of patients studied, which may impact the generalizability of the findings.Additionally, the heterogeneity of the disease in terms of clinical and molecular aspects may affect the reliability of telomere length as a predictive marker for age-related tumor risks in VHL patients.Furthermore, it is argued that while shorter blood telomere length is associated with higher age-related risks of VHL-associated central nervous system hemangioblastomas, renal cell carcinoma, pancreatic cysts, and neuroendocrine tumors, the correlation may not be consistent across all patients with VHL disease.Therefore, the use of blood telomere length as a biomarker for VHL disease may have limitations in accurately predicting tumor risks and disease progression in all individuals with VHL.
Therefore, while these biomarkers show promise, further research is needed to establish their reliability and clinical utility in predicting tumor risks and disease progression in VHL patients.
The identification of mutations in the VHL gene has been crucial for the diagnosis and management of VHL [185].Mutations in this gene have been observed to predispose affected individuals to develop a variety of tumors.Understanding how these mutations lead to tumor formation is critical for the development of more specific and effective therapeutic approaches.
In terms of pathophysiology, it has been demonstrated that the inactivation of the wildtype allele of the VHL gene is an initial event in the development of the disease, followed by the loss of function of the second allele, triggering tumorigenesis.This "two-hit" model proposed by Knudson has been fundamental in understanding tumor progression in VHL and has led to deeper investigations into the molecular mechanisms involved in this disease.
Furthermore, the review highlights the importance of clinical heterogeneity in VHL, with significant variations in disease presentation even within the same family.This underscores the need for an individualized approach in the diagnosis and management of patients with VHL, considering both genetic and clinical aspects.
The current review discusses the various manifestations of VHL disease, such as retinal hemangioblastomas, renal cell carcinomas, pheochromocytomas, and pancreatic cysts, and the corresponding diagnostic modalities and treatments.Furthermore, it sheds light on the molecular basis of VHL disease, elucidating the role of the pVHL protein in regulating hypoxia-inducible factor-alpha (HIF-α) protein levels through degradation under normoxic conditions.It also explores the association between VHL loss and the activation of the mTOR pathway [119], highlighting the significance of various pVHL substrates, such as ZNF395, ZHX2, SFMBT1, RSUME, and TBK1, in the pathogenesis of clear cell renal cell carcinomas [136][137][138].
Ongoing research in the genetics and pathophysiology of von Hippel-Lindau disease is crucial for improving early diagnosis, clinical management, and the development of more effective therapies.Understanding the underlying molecular mechanisms of VHL will not only expand our knowledge of this disease but also open up new opportunities for more precise and personalized therapeutic interventions in the future.

Conclusions
The genetic basis of VHL disease, characterized by mutations in the VHL gene, plays a central role in predisposing individuals to a spectrum of tumors and cysts in various organs.Further research into the genetic mechanisms underlying VHL is essential for advancing diagnostic and therapeutic strategies.
The pathophysiology of VHL syndrome, involving the loss of function of the VHL tumor suppressor protein and subsequent activation of hypoxia-inducible factors, provides valuable insights into the molecular pathways driving tumorigenesis in this condition.Understanding these pathways is crucial for developing targeted therapies.
The clinical heterogeneity observed in VHL underscores the need for personalized approaches to diagnosis and management.Tailoring treatment strategies to individual patients based on their genetic and clinical profiles can optimize outcomes and quality of life.
Advances in the understanding of VHL disease at the genetic and molecular levels hold promise for the development of more effective and personalized therapeutic interventions.Targeted therapies that address the specific molecular alterations in VHL-associated tumors could revolutionize treatment outcomes.
Future Directions: Continued research into the genetics, pathophysiology, and clinical management of VHL disease is essential for improving patient outcomes and quality of life.Collaborative efforts across disciplines, including genetics, oncology, and molecular biology, will be crucial for advancing our understanding of VHL and translating this knowledge into innovative therapeutic approaches.
The present review delves into the intricate interplay of genetics, pathophysiology, and clinical manifestations of VHL disease.By elucidating the role of the VHL tumor suppressor gene, the dysregulation of the hypoxia-inducible factor (HIF) pathway, and the diverse clinical presentations, this work provides a comprehensive overview of the disease.While significant strides have been made in understanding the underlying mechanisms of VHL disease, challenges persist in developing effective therapies for all tumor types.Furthermore, the influence of regional factors, such as founder effects, genetic background, environmental exposures, and healthcare disparities, underscores the need for specific approaches to prevention, early detection, and treatment.Continued research is imperative to unravel the complexities of VHL disease, identify novel therapeutic targets, and improve the quality of life for affected individuals.A multidisciplinary approach, encompassing genetics, pathology, clinical research, and patient care, is essential to advancing our understanding and management of this debilitating condition ultimately improving outcomes for individuals affected by this complex genetic syndrome.

Figure 6 .
Figure 6.Major pVHL mutations associated with development of tumorigenesis in VHL disease.VHL protein has a beta, alpha, beta domain.Two isoforms are known according to the molecular weight of pVHL30 and pVHL18/19, and both proteins are tumor suppressors.Created with BioRender.com.https://app.biorender.com/illustrations/61eb579664332600a3d2a456(accessed on 5 October 2021).

Figure 6 .
Figure 6.Major pVHL mutations associated with development of tumorigenesis in VHL disease.VHL protein has a beta, alpha, beta domain.Two isoforms are known according to the molecular weight of pVHL30 and pVHL18/19, and both proteins are tumor suppressors.Created with BioRender.com.https://app.biorender.com/illustrations/61eb579664332600a3d2a456(accessed on 5 October 2021).

Table 1 .
Clinical classification of VHL and associated mutations.

Table 2 .
Summary of the lesions, symptoms, diagnosis, imaging, and treatment of VHL patients.

/Frequency in Patients by Age Symptoms Diagnosis (MR, Magnetic Resonance; CT, Computed Tomography) Imagen Treatment and Management Refs.
Diagnostics 2024, 14, x FOR PEER REVIEW 9 of 34

Table 2 .
Summary of the lesions, symptoms, diagnosis, imaging, and treatment of VHL patients.

Table 2 .
Summary of the lesions, symptoms, diagnosis, imaging, and treatment of VHL patients.

/Frequency in Patients by Age Symptoms Diagnosis (MR, Magnetic Resonance; CT, Computed Tomography) Imagen Treatment and Management Refs.
[113,114]

Table 3 .
Animal models for von Hippel-Lindau disease.

Table 5 .
Clinical trials for von Hippel-Lindau disease.