Genotype-Phenotype Heterogeneity in Von Hippel-Lindau Disease: A Single-Center Multidisciplinary Study

Genotype-Phenotype Heterogeneity in Von Hippel-Lindau Disease: A Single-Center Multidisciplinary Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Genotype-Phenotype Heterogeneity in Von Hippel-Lindau Disease: A Single-Center Multidisciplinary Study Ali Duru, Alp Peker, Feyza Altunbaş Yalabık, Duygu Gamze Aracı, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8660830/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction: Von Hippel-Lindau (VHL) disease is an autosomal dominant familial cancer syndrome caused by germline mutations in the VHL tumor suppressor gene, leading to various neoplasms including hemangioblastomas, renal cell carcinoma (RCC), and pheochromocytomas. This study evaluates the clinical, radiological, and genetic profiles of two unrelated families: family A, in whom genotype–phenotype correlations were systematically analyzed, and family B, characterized by a novel de novo pathogenic variant. Methods Patients suspected of VHL were analyzed using exome sequencing and targeted family testing. Variants were interpreted according to ACMG/AMP 2015 guidelines and interpreted in line with the ClinGen recommendations for the VHL gene. Clinical follow-ups included multidisciplinary evaluations including detailed ophthalmologic screenings. Results The study primarily focuses on Family A, where 21 members carry the c.499C > T (p.Arg167Trp) variant. This variant revealed remarkable phenotypic heterogeneity, as family members presented with clinical manifestations consistent with multiple VHL subtypes across the established disease spectrum. In reported cases in the literature, pheochromocytoma is the most frequent manifestation (72%), whereas RCC is the least common (4.5%). In Family B, the study identified a novel frameshift mutation, c.449_462dup (p.Val155IlefsTer9), which has not been previously reported. Notably, this patient also carried a pathogenic BRCA2 variant, representing a rare case of Multilocus Inherited Neoplasia Allele Syndrome (MINAS). Furthermore, the administration of belzutifan, a HIF-2α inhibitor, showed promising results in stabilizing renal cystic lesions in the Family B proband. Conclusion Our findings highlight that even identical mutations, such as c.499C > T, can result in a wide spectrum of clinical outcomes, likely due to genetic, epigenetic, or environmental modifiers. The identification of novel variants and MINAS cases emphasizes the need for comprehensive genetic screening. Lifelong, multidisciplinary surveillance remains critical for the early detection and management of VHL-associated lesions to prevent morbidity. Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Von Hippel-Lindau (VHL) disease (OMIM: 193300) is an autosomal dominant inherited familial cancer syndrome that causes central nervous system hemangioblastomas, retinal hemangioblastomas, pancreatic neuroendocrine tumors, pancreatic cysts, endolymphatic sac tumors, broad ligament cystadenomas, and epididymal cystadenomas. The incidence of VHL disease is estimated to be varying up to 1/36,000-91000 individuals [ 1 ]. In 80% of VHL cases, a germline VHL mutation is identified, while de novo germline VHL variants are found in 20% of cases [ 2 ]. Somatic VHL variants have been observed in isolated clear cell renal cell carcinomas (ccRCC) and central nervous system hemangioblastomas (CNSHB) [ 3 , 4 ]. The diagnosis of VHL disease is made based on clinical findings and germline genetic testing. Pathogenic variants in the VHL gene can be detected with ~ 85% sensitivity using sequence analysis and ~ 10% sensitivity with deletion/duplication analysis [ 1 , 3 ]. The VHL gene is a tumor suppressor gene located on the short arm of chromosome 3 (3p25.3), a highly conserved region. It contains three exons, and due to an alternative translation initiation codon at codon 54, two forms of the VHL protein (pVHL) are synthesized: the larger form, pVHL30 (30kDA), with 213 amino acids, and the smaller form, pVHL19 (19kDA), with 160 amino acids. Both forms play roles in the same tumor-suppressing mechanism [ 5 ]. The chemical structure of pVHL includes two important subunits. The first is the HIF binding region between amino acids 91–113, which contains beta-sheet structures. The second is the Elongin C binding region between amino acids 157–170, containing an alpha-helix domain. Under normoxic conditions, this region forms a complex with Elongin C and Elongin B, resulting in the formation of the VBC complex. This complex interacts with Cul2, facilitating HIF degradation through the proteasome-dependent ubiquitin ligase E3 function. In cases of VHL dysfunction or hypoxic conditions, HIF degradation is impaired, leading to increased transcription of genes involved in angiogenesis, such as VEGF, TGFB, TGFα, and PDGF. Tumor development in VHL disease is thought to follow Knudson's two-hit model. Initially, one allele is inactivated due to a germline VHL mutation, while the second allele is inactivated by a somatic mutation, deletion, or promoter hypermethylation, leading to tumor formation [ 6 ]. Clinically, VHL disease is divided into two main types: Type 1, which does not include pheochromocytoma, and Type 2, which carries a high risk for pheochromocytoma and is further subdivided into three subgroups. Type 2A is associated with a low risk of ccRCC, Type 2B with a high risk of ccRCC, and Type 2C involves only pheochromocytoma. The phenotype presented by patients can vary in multitudes, and differ due to genomic characteristics. Pathogenic missense variants that disrupt HIF regulation generally lead to VHL type 1, while those that don't affect HIF regulation are linked to VHL type 2 [ 7 ]. Variants associated with pheochromocytoma but low renal cell carcinoma risk (VHL types 2A/2C) likely retain HIF1α regulation, while those causing both pheochromocytoma and renal cell carcinoma (VHL type 2B) do not. Mutated pVHL may also alter apoptosis in sympatho-adrenal precursor cells. Defining families of multiple patients are needed when evaluating a newly diagnosed person. Here, in this study we present 32 patients of the VHL disease. We define their phenotypical characteristics, pathological and radiological features. We observe clinical anamnesis data, cancer types and diagnosis ages, and treatment regimens they’ve received. We identify a large family consisting of multiple patients with the variant c.499C > T, which confers multiple cancer types relating the variant with type 2 VHL disease, and we further dive into genotype-phenotype correlations regarding this genetic variant. Materials and Method This study included individuals clinically suspected of having Von Hippel–Lindau (VHL) disease, who were referred for exome sequencing at the Medical Genetics clinic of Akdeniz University Hospital. The primary cohort consisted of index cases with clinical features suggestive of VHL, such as retinal hemangioblastomas, central nervous system hemangioblastomas, renal cell carcinoma, or pheochromocytoma. After identification of candidate variants in index cases, targeted testing was extended to available family members (parents, siblings, children) to assess inheritance and segregation patterns. All participants or their legal guardians provided written informed consent prior to genetic testing. The study protocol was reviewed and approved by the Akdeniz University Medicine Faculty Ethical Committee (Decision number 03.01.2025/no:11). Sample Collection and DNA Extraction Peripheral blood samples (5–10 mL) were collected in EDTA tubes from all index cases and available relatives. Genomic DNA was extracted using the QIAamp DNA Blood Mini Kit (Qiagen, Hilden, Germany) following the manufacturer’s instructions. DNA purity and concentration were evaluated using NanoDrop 2000 (Thermo Fisher Scientific) and Qubit 4.0 fluorometer (Invitrogen). Library Preparation and Target Enrichment Genomic DNA (100–200 ng) was used for library preparation with the Illumina DNA Prep with Enrichment kit (Illumina, San Diego, CA, USA). The exonic regions of the genome, including flanking intronic sequences (~ 20 bp), were captured using the Illumina Exome Panel. Library fragment size and quality were assessed using the Agilent 2100 Bioanalyzer, and libraries were quantified using a Qubit fluorometer. Next-Generation Sequencing Sequencing was performed on the Illumina NovaSeq 6000 platform using 150 bp paired-end reads. Each sample achieved a mean target coverage of ≥ 100×, with at least 95% of the targeted regions covered at ≥ 20×. Bioinformatics and Variant Analysis Raw sequencing data were processed following the GATK Best Practices. Reads were aligned to the human reference genome GRCh38 using BWA-MEM. Variant calling was performed using GATK HaplotypeCaller, and variants were annotated with ANNOVAR. Population frequency data (gnomAD), pathogenicity prediction tools (SIFT, PolyPhen-2, MutationTaster, CADD), and disease-specific databases (ClinVar, HGMD, OMIM) were used for interpretation. Special attention was given to the analysis of the VHL (NM_000551.4) gene, and variants were prioritized based on their clinical relevance, zygosity, and co-segregation with disease phenotype. Known hotspot variants previously associated with VHL syndrome were flagged for clinical relevance. Family Member Evaluation Following the identification of potentially pathogenic variants in index cases, targeted sequencing (via Sanger or NGS-based validation) was performed in available family members to determine inheritance patterns (e.g., de novo, autosomal dominant transmission) and to assess genotype-phenotype correlations within families. Variant Classification and Reporting All variants were classified according to the ACMG/AMP guidelines. Variants considered pathogenic or likely pathogenic were confirmed via Sanger sequencing. Final clinical reports were issued by a multidisciplinary team and included interpretation, inheritance information, and genetic counseling recommendations. All patients encompassing pathogenic variants in the VHL gene, were referred to ophthalmologic examination to rule out retinal lesions, and to ENT specialists for hearing assessment. Biochemical screening with 24-hour urine metanephrines was initiated, if not previously done. Multidisciplinary follow-up is ongoing on all patients. Results Overall, there are 32 patients in this study, with ages ranging from 2 to 47. The large family case we present in this study involves 31 patients with 21 of them shown to be carrying the variant of c.499C > T (p.Arg167Trp) in the VHL gene. The remaining one patient in this study, from a different family with a different founding variant, was added due to their specific treatment regimen preferred. Table 1 Clinical features of patients with VHL syndrome in Family A Patient Diagnosis Age Pheochromocytoma CNC. Hemangioma Retinal Angioma RCC PNET Pancreatic/Renal Cysts Other lesions I-2 - N/A N/A N/A N/A N/A N/A esophageal cancer II-2 - N/A N/A N/A N/A N/A N/A N/A II-4 47 No Yes N/A Yes N/A No No II-7 41 Yes Yes N/A No No No No III-3 40 No No No No No Yes (pancreatic) No III-5 35 N/A N/A N/A N/A N/A N/A N/A III-7 31 Yes Yes No No Yes No Yes (Liver hemangioma) III-9 29 N/A N/A N/A N/A N/A N/A N/A III-11 37 N/A N/A N/A N/A N/A N/A N/A III-13 - Yes No N/A No Yes No No III-14 42 N/A N/A N/A N/A Yes N/A N/A III-18 - N/A N/A Yes N/A N/A N/A N/A III-21 20 No No No No No No Left Surrenal Adenoma III-23 23 Yes No No No No No No III-24 14 No No No No No No No III-26 30 No Yes No No No Yes (pancreatic) No III-27 30 N/A N/A N/A N/A N/A N/A N/A IV-6 6 N/A N/A N/A N/A N/A N/A N/A IV-8 3 N/A N/A N/A N/A N/A N/A N/A IV-12 4 No No No No No No No IV-13 4 No No Yes No No No No IV-15 5 No No No No No No No IV-16 3 No No No No No No No IV-20 29 Yes Yes N/A N/A N/A N/A N/A IV-25 29 No No No No No No No IV-27 9 No No No No No No No IV-28 5 No No No No No No No IV-29 7 No No No No No No No IV-30 2 No No No No No No No IV-31 4 No No No No No No No V-3 4 N/A N/A N/A N/A N/A N/A N/A RCC : renal cell carcinoma PNET: pancreatic neuroendocrine tumor N/A: Not available In the Family A, 8 of the 21 members carrying the c.499C > T variant, were observed to have cancer both ranging in cancer types to the first diagnosis age, meanwhile, the rest have not yet been diagnosed with any. The clinical outcomes of patients carrying the same variant vary in utmost differences since one patient is diagnosed with 8 different types of VHL related cancers until the age of 32, meanwhile, another member is seen to be free of VHL related cancers at the age of 37, with all the cautionary tests including MRi testing evaluated. In Family A, the most frequently observed manifestations of von Hippel-Lindau (VHL) disease were pheochromocytoma, central nervous system (CNS) hemangiomas, and pancreatic neuroendocrine tumors (PNET). CNS hemangiomas, likely corresponding to hemangioblastomas, were confirmed in five patients (II-4, II-7, III-7, III-26, IV-20). Pheochromocytomas were similarly observed in five patients (II-7, III-7, III-13, III-23, IV-20), while PNETs were documented in three individuals (III-7, III-13, III-14). Renal cell carcinoma (RCC) was identified in one patient (II-4), and retinal angiomas were confirmed in two patients (III-18, IV-13). A notable feature in this family is the high prevalence of pheochromocytoma. The co-occurrence of pheochromocytoma and CNS hemangioma in patients II-7 and IV-20 suggests a pattern consistent with VHL Type 2, which is characterized by an elevated risk of pheochromocytoma. Pancreatic involvement was also significant, encompassing both PNETs (three patients) and benign pancreatic cysts (two patients: III-3, III-26). The expression of VHL-related lesions was observed to be age-dependent. Younger family members, particularly those in generations IV and V, were frequently reported as negative for all lesions (e.g., IV-6 at 6 years and V-3 at 4 years). This highlights the importance of age-dependent penetrance in VHL disease and underscores the need for ongoing surveillance in at-risk individuals. In addition to classic VHL-associated lesions, some atypical findings were noted, including esophageal cancer in patient I-2 and a left adrenal adenoma in patient III-21. While these may represent incidental findings, their potential association with VHL gene dysfunction warrants further investigation. Several limitations of the dataset should be acknowledged. A substantial proportion of entries were marked as "N/A," particularly for retinal angiomas, PNETs, and pancreatic cysts, indicating that not all patients underwent comprehensive diagnostic imaging. Consequently, the true prevalence of certain lesions may be underestimated. Finally, the age at diagnosis is an important consideration; older patients (e.g., II-4, diagnosed at 47 years) may present with a cumulative burden of lesions over their lifetime, in contrast to younger patients whose clinical profiles may be incomplete. Proband of family B, was a young adult male with a suspected diagnosis of von Hippel-Lindau (VHL) disease, referred for genetic evaluation. He had a history of bilateral retinal hemangioblastomas previously treated with laser photocoagulation. Family history was remarkable for VHL in his mother, sister, and maternal aunt, with additional reports of various malignancies, including breast cancer, lung cancer, and lymphoma among other relatives. Radiological work-up revealed multiple complex cystic renal lesions bilaterally, several of which demonstrated features consistent with Bosniak type 4 cystic renal cell carcinoma (RCC). The patient underwent cryoablation for two RCC lesions in the right kidney. Follow-up imaging confirmed no residual enhancement. Additionally, multiple subcentimeter pancreatic cysts were observed, consistent with benign VHL-associated pancreatic lesions. The patient has no other significant past surgical history and reports allergic rhinitis triggered by dust and pollen. He denies tobacco use but consumes alcohol socially. No consanguinity was reported between parents, and there is no known family history of additional genetic disorders. A promising result in proband B was that renal cyst progression had drastically diminished with the use of Belzutifan, an oral HIF-2α inhibitor approved for the treatment of von Hippel–Lindau (VHL) disease–associated tumors, targeting the hypoxia signaling pathway to suppress tumor growth [ 8 ]. Genetic testing detected the c.449_462dup variant, a 14-nucleotide duplication, occurring in the VHL gene in proband of family B. This duplication results in a frameshift mutation designated as p.Val155IlefsTer9. The frameshift is predicted to alter the reading frame from codon 155, where valine is replaced by isoleucine, and introduces a premature termination codon (Ter) at the ninth amino acid position downstream of the frameshift. This premature stop codon is likely to result in a truncated VHL protein. This variant has not been previously reported in the literature. This loss of function variant is classified as likely pathogenic according to the ACMG/AMP 2015 guidelines and interpreted in line with the ClinGen recommendations for the VHL gene [ 9 ] Furthermore, a truncating BRCA2 variant, c.1507A > T (p.Lys503; NM_000059.4), was also detected in the proband. This loss of function variant introduces a premature termination codon, was evaluated as a pathogenic variant. The pathology specimens of patients who had tumor resection operations done by surgical departments of Akdeniz University Hospital, were analysed by the medical pathology specialists of the hospital. Section (a), shown in figure, demonstrates a pheochromocytoma from the patient III-7, proband of family A, with Von Hippel–Lindau disease. The tumor exhibits the characteristic Zellballen architecture composed of nests of polygonal cells with granular cytoplasm, separated by delicate fibrovascular stroma. Immunohistochemical staining for chromogranin A shows strong diffuse cytoplasmic positivity, confirming the neuroendocrine nature of the tumor, consistent with a VHL-associated pheochromocytoma. Section (b) demonstrates a renal biopsy from the patient III-2, proband of Family B, with Von Hippel–Lindau (VHL) disease, showing characteristic features of clear cell renal cell carcinoma (ccRCC). Histologically, the tumor is composed of nests and clusters of neoplastic cells with abundant clear cytoplasm and intervening delicate fibrovascular septa. These findings are consistent with the typical morphology of ccRCC, which is the most frequent renal manifestation in VHL syndrome due to dysregulation of the HIF signaling pathway. Immunohistochemical staining was performed using carbonic anhydrase IX (CAIX), a highly sensitive and specific marker for ccRCC. The tumor cells show strong membranous staining in a characteristic box-like pattern, supporting the diagnosis of clear cell RCC. This staining pattern, along with the histomorphological features and clinical context, confirms the diagnosis of VHL-associated ccRCC. Ophthalmology screening of the patients revealed OCT features demonstrating marked structural alterations of the macula, from the proband of family A, characterized by prominent intraretinal cystic spaces and disruption of the outer retinal layers (Fig. 3 ). These cystic changes likely represent secondary macular edema arising in the context of chronic retinal involvement associated with VHL-related vascular lesions. The accompanying irregularities at the level of the RPE and outer retina, together with the central atrophic appearance on fundus imaging, suggest longstanding damage from prior exudation or sequelae of regressed retinal capillary hemangiomas. Overall, the imaging findings are consistent with chronic VHL-associated macular remodeling, combining central chorioretinal atrophy with secondary intraretinal cystic degeneration. Discussion -Review of the Literature: The c.499C > T (p.R167W) variant of the VHL gene has been associated with multiple types of Von Hippel-Lindau (VHL) disease in different case studies. This variant has been linked to VHL Type I, Type IIA, Type IIB, and Type IIC in several different studies [ 10 ]. The variant was observed in multiple cases, each exhibiting different clinical manifestations of VHL, including pheochromocytomas, hemangioblastomas, endolymphatic sac tumors and retinal capillary hemangioblastomas [ 10 , 11 , 12 , 13 ]. One study investigated a five-generation family in China and found that individuals carrying the c.499C > T mutation exhibited a variety of VHL-related tumors. The study classified patients into Type I (without pheochromocytomas), Type IIA (with pheochromocytomas but low risk of renal cell carcinoma), and Type IIC (pheochromocytomas only phenotype) [ 10 ]. Another case report documented a 34-year-old male patient with multiple retinal capillary hemangioblastomas (RCHs) and a family history of VHL, where genetic testing confirmed the presence of the c.499C > T mutation [ 11 ]. Additionally, a separate case reported a young male patient with bilateral pheochromocytomas leading to acute myocardial infarction, also found to carry the c.499C > T variant [ 12 ]. Table 2 Shows publications in the literature that recorded families or individuals identified to have the c.499C > T variant. Phenotypes associated with VHL were listed together with the number of patients exhibiting each feature among those carrying the identified variant. Zhang et. al [ 10 ] Guo et. al [ 11 ] Bachurska et. al [ 12 ] Su et. al [ 13 ] Hasani-Ranjbar et. al [ 14 ] Chen et. al [ 15 ] Duru et. al Total Systolic Blood pressure > 180 mmHg (1/9) N/A (0/1) N/A (0/1) (0/1) N/A (1/12) Cerebellar Hemangioblastoma (3/9) (1/1) (0/1) N/A (0/3) (1/1) (5/10) (11/25) Retinal Angioma N/A N/A N/A N/A (2/3) N/A (2/8) (4/11) Pancreatic endocrine tumors (2/9) (0/1) (0/1) N/A (0/3) (1/1) (3/9) (6/24) Pancreatic cysts (3/9) (0/1) (0/1) N/A (0/3) (0/1) (2/9) (5/24) Renal cell cancer (0/9) N/A (0/1) N/A (0/3) (0/1) (1/8) (1/22) Renal cysts (4/9) (0/1) (0/1) N/A (0/3) (0/1) (0/9) (4/24) Pheochromocytoma (7/9) (1/1) (1/1) N/A (3/3) (1/1) (5/10) (18/25) Paraganglioma (2/9) (0/1) (0/1) N/A (0/3) (1/1) N/A (3/15) Endolymphatic sac tumor N/A N/A N/A (1/1) (0/3) N/A N/A (1/4) VHL phenotypes I (1) IIA (4) IIC (4) IIA (1) IIC (1) I (1) IIA (3) IIB (1) I (3) IIA (1) IIB (3) IIC (1) I (5) IIA (9) IIB (4) IIC (6) Patients who exhibited features of VHL, both in our cohort and in the literature, were selected for discussion in this table. In our cohort, only eight patients had sufficient clinical information to allow classification into VHL subtypes. Many pediatric patients were found to carry the c.499C > T variant through segregation analysis, but they had only undergone baseline evaluations appropriate for their ages. Additionally, several patients lacked detailed anamnesis, preventing reliable classification. Ultimately, eight well-documented patients from Family A were classified according to their VHL type: patients II-4, III-3, and III-26 as type 1; patient IV-20 as type 2A; patients II-7, III-7, and III-13 as type 2B; and patient III-23 as type 2C. This demonstrates that the c.499C > T variant presents a highly variable clinical spectrum, even among members of the same family. Overall, including the literature review, patients carrying the c.499C > T variant comprise 5 type 1, 9 type 2A, 4 type 2B, and 6 type 2C cases, further highlighting the phenotypic variability associated with this mutation (Table 2 ). This variability suggests that the c.499C > T variant does not strictly dictate a single clinical outcome, but rather interacts with additional genetic, epigenetic, or environmental factors to shape the individual phenotype. For clinicians and genetic counselors, this means that carriers of c.499C > T require comprehensive and long-term surveillance, even if initial evaluations are unremarkable, as different VHL-associated tumors may manifest at different ages. The review of the available literature also reveals that most reported VHL cases with pathogenic variants, including those involving the c.499C > T allele, did not undergo dedicated audiologic evaluation or targeted imaging of the temporal bone to assess for endolymphatic sac tumors (ELST). Given that ELSTs may remain asymptomatic in early stages and can lead to irreversible sensorineural hearing loss if not detected promptly, this gap represents a clinically important oversight. We therefore recommend that all patients carrying pathogenic VHL alleles receive systematic hearing assessments, including formal audiometry as part of their baseline and longitudinal surveillance. Incorporating standardized otologic evaluation into routine VHL follow-up protocols may improve early detection of ELSTs and prevent avoidable morbidity. -The c.499C > T variant: Together, these instances highlight the significant clinical variability linked to the VHL gene's c.499C > T variant. The difficulty of determining precise genotype-phenotype associations in VHL syndrome is highlighted by the wide range of phenotypes. The fact that several clinical subtypes (Type I, IIA, and IIC) can result from the same pathogenic mutation supports the idea that altering genetic, epigenetic, or environmental factors might affect how a disease manifests. The idea that the penetrance and expressivity of VHL mutations are extremely variable is further supported by the variability shown in instances that appear to be isolated but have similar variants. Even among carriers of the same variant, our results highlight the need for tailored clinical surveillance and counseling approaches for VHL patients. When evaluating the “Total” column in Table 2 , the most frequently observed phenotypes of Von Hippel-Lindau (VHL) syndrome among patients carrying the c.499C > T (p.R167W) variant are summarized below, ranked from most to least common, with corresponding frequencies and percentages: pheochromocytoma was present in 18 of 25 patients (72%), cerebellar hemangioblastoma in 11 of 25 patients (44%), retinal angioma in 4 of 11 patients (36.4%), pancreatic neuroendocrine tumors in 6 of 24 patients (25%), endolymphatic sac tumors in 1 of 4 patients (25%), pancreatic cysts in 5 of 24 patients (20.8%), paraganglioma in 3 of 15 patients (20%), renal cysts in 4 of 24 patients (16.7%), systolic blood pressure exceeding 180 mmHg in 1 of 12 patients (8.3%), and renal cell carcinoma (RCC) in 1 of 22 patients (4.5%) (Fig. 4 ). Among the various manifestations, pheochromocytoma was the most frequently observed phenotype in patients carrying the c.499C > T (p.R167W) VHL variant, present in 72% of cases. This high frequency may be related to the specific effect of this missense mutation on the VHL protein, which could preferentially disrupt pathways involved in adrenal chromaffin cell proliferation and tumorigenesis. The predominance of pheochromocytoma in this patient group underscores the importance of careful clinical surveillance, including regular biochemical and imaging assessments, to ensure timely detection and management. Given the potential for life-threatening complications such as hypertensive crises, clinicians should maintain a high index of suspicion for pheochromocytoma in carriers of the c.499C > T variant, even in the absence of overt symptoms. Also, amongst all features, RCC is the least commonly observed in patients carrying the c.499C > T allele, and several factors may explain this finding. Incomplete or variable penetrance of VHL manifestations can result in organ-specific differences, meaning that some carriers may develop CNS or adrenal lesions without significant renal involvement. However, age-dependent penetrance is likely to play a role, since RCC in VHL often manifests later in life, and some patients may not yet have developed detectable renal tumors at the time of reporting. These factors underscore the importance of regular, comprehensive renal surveillance even in patients with missense VHL variants that appear to confer a lower RCC risk. The tumor spectrum observed in Family A further exemplifies the phenotypic diversity characteristic of VHL syndrome. While retinal angiomas and pheochromocytomas were the most frequently encountered manifestations, a variety of less commonly reported VHL-associated lesions, such as liver and pancreatic hemangioblastomas, cerebellar and spinal cord hemangioblastomas, and pancreatic cancer, were also present. Interestingly, adrenal hemangiomas and multiple pancreatic cysts were noted in some individuals, expanding the phenotypic landscape linked to the c.499C > T variant. Of particular significance is the absence of renal cell carcinoma and baseline hypertension in any family members, despite these features being commonly reported in other VHL cohorts. This absence may reflect the influence of protective modifying factors against renal involvement in this specific family. -Regarding Follow-ups and Treatment; In family B, the proband’s clinical course highlights the emerging role of targeted therapies in the management of VHL-associated neoplasms, particularly the use of belzutifan. As an oral HIF-2α inhibitor, belzutifan has demonstrated efficacy in reducing tumor burden by interfering with the hypoxia-inducible pathway, a central mechanism in VHL tumorigenesis [ 8 ]. In this case, belzutifan use was associated with a marked stabilization of renal cystic lesions, suggesting potential disease-modifying benefits beyond surgical intervention. This pharmacologic approach is especially relevant for patients with multifocal or bilateral renal involvement, where repeated surgical interventions may pose cumulative risks to renal function. In recent years, other novel agents such as tyrosine kinase inhibitors (e.g., sunitinib, pazopanib) and mTOR inhibitors (e.g., everolimus) have also been explored in Renal cell carcinoma, particularly for patients with advanced or inoperable tumors; however, these treatments often come with broader toxicity profiles and are not VHL-specific [ 16 ]. Belzutifan, by contrast, offers a more targeted and tolerable alternative, positioning it as a frontline option in the evolving landscape of VHL management. This case underscores the importance of integrating molecularly guided therapies into the care of VHL patients, particularly those with progressive or high-risk lesions. Over the course of time, from when belzutifan use for VHL patients had been approved by FDA, in patients with VHL-associated RCC, belzutifan has demonstrated objective response rates around 49% and durable tumor control, significantly delaying or even avoiding the need for nephron-sparing surgery—a critical advantage given the multifocal nature of renal lesions in VHL [ 17 ]. The drug has also shown strong activity in extra-renal manifestations: response rates in pancreatic neuroendocrine tumors have reached up to 91%, highlighting its efficacy in traditionally hard-to-treat organs [ 17 , 8 ]. Promising outcomes have likewise been reported in CNS hemangioblastomas, with tumor shrinkage and neurological improvement attributed to reduced edema and mass effect [ 18 , 8 ]. Additionally, belzutifan has shown efficacy in treating retinal hemangioblastomas, leading to lesion regression and stabilization or improvement in visual acuity, thereby offering a less invasive alternative to local therapies such as laser photocoagulation or enucleation [ 18 ]. Another important point to consider in the clinical management of proband B, was that he was observed to be a carrier of a pathogenic variant in the BRCA2 gene. This condition, which may explain the death of the individual designated as I-4 in the pedigree (Fig. 1 ) due to breast cancer, suggests that the proband B is a carrier of two distinct cancer-related genetic conditions and represents a case of multilocus inherited neoplasia allele syndrome (MINAS) [ 19 ]. To our knowledge, this represents the first reported case of multilocus inherited neoplasia allele syndrome involving the concomitant presence of pathogenic germline variants in VHL and BRCA2, thereby expanding the molecular spectrum of MINAS and underscoring the importance of comprehensive multigene testing in hereditary cancer predisposition syndromes. In patients with known or suspected VHL, increased retinal vein tortuosity (as seen in Fig. 3 a and 3 b) is a finding that may represent early microvascular involvement preceding the development of retinal hemangioblastomas. Although not diagnostic on its own, this vascular change reflects underlying angiogenic activity and is thought to be associated with a phenotype in which CNS hemangioblastomas are more likely to emerge. Accordingly, new or progressive tortuosity should prompt intensified ophthalmologic surveillance and may serve as an indication to schedule for cranial and spinal MRI, particularly in patients who are overdue for imaging or have not yet undergone baseline CNS evaluation [ 20 ]. In such patients with suspected microvascular changes, macular OCT alone might be insufficient; OCT imaging should also be performed directly over the suspected lesion. In particular, when peripapillary involvement is a concern, peripapillary OCT is required to ensure accurate assessment of early structural changes and lesion-related retinal alterations [ 21 ]. Conclusion Presenting large VHL family cases in the literature helps in establishing genotype-phenotype correlations and identifying mutation hotspots like codon 167. These studies provide valuable insight into the penetrance, variability, and clinical spectrum of VHL disease, allowing for better genetic counseling and risk assessment for affected families. In conclusion, the c.499C > T (p.R167W) variant is within a known hotspot in VHL disease, associated with multiple subtypes and a range of clinical manifestations. By documenting large family cases and detailed case reports, the literature aids in refining clinical management strategies and improving early diagnosis, ultimately reducing life-threatening complications. There are many VHL families in which a family member presents with no cancer history, however, carries the same pathogenic variant as the other members. For such members, a deeper investigation might lead to better understanding of cancer formation and progression. Many cancer-related genes express proteins which unite with multiple others to form a protein complex that maintains a role in cell cycle processes, erroneous DNA reparations, cell division or death. It is important to evaluate the clinical history of hereditary cancer patients, considering the operational function of the protein or the protein complex involved in the cancer formation. The wide range in expressivity and penetrance differences in VHL disease suggests there should be made larger studies on mechanism related genes, expressions and genome wide associations (GWAS) regarding people who carry known pathogenic hereditary cancer gene variants. Since the people who have pathogenic variants in the VHL gene are almost definitely predestined to experience cancer until their 40’, it is feasable to suggest that VHL is a model gene to investigate such a hypothesis’. It is yet to be discovered if there are changes in, especially, DNA repair genes which potentially ameliorate the clinical presentation of such cases. Certain VHL gene variants appear to show specific tendencies toward particular disease manifestations. For example, some missense variants, such as c.499C > T, may predispose carriers to pheochromocytomas, while other variants are more strongly associated with CNS or renal lesions. Recognizing these genotype-phenotype correlations can help guide targeted surveillance and early intervention in affected patients. Declarations Competing Interests: There are no conflicts of interest of any authors of this manuscript. Funding: This study did not receive any specific funding. Ethical Approval: Ethical approval was not required for this study because it reports a single clinical case evaluated as part of routine diagnostic testing. All procedures were performed in accordance with institutional and national ethical standards and the Declaration of Helsinki. Written informed consent for genetic testing and publication of anonymized clinical and genetic data was obtained from the patient. Acknowledgements: The literature review of clinical features in patients observed to carry the c.499C>T variant, was made via PRISMA guidelines. We thank our working group in the laboratory, and our patients, and the families, for consistently adhering to clinical follow-up and segregation analyses. 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Buckley M, Terwagne C, Ganner A, Cubitt L, Brewer R, Kim DK, Kajba CM, Forrester N, Dace P, De Jonghe J, Shepherd STC, Sawyer C, McEwen M, Diederichs S, Neumann-Haefelin E, Turajlic S, Ivakine EA, Findlay GM. Saturation genome editing maps the functional spectrum of pathogenic VHL alleles. Nat Genet. 2024 Jul;56(7):1446-1455. doi: 10.1038/s41588-024-01800-z. Epub 2024 Jul 5. PMID: 38969834; PMCID: PMC11250436. Shankar GM, Taylor-Weiner A, Lelic N, Jones RT, Kim JC, Francis JM, Abedalthagafi M, Borges LF, Coumans JV, Curry WT, Nahed BV, Shin JH, Paek SH, Park SH, Stewart C, Lawrence MS, Cibulskis K, Thorner AR, Van Hummelen P, Stemmer-Rachamimov AO, Batchelor TT, Carter SL, Hoang MP, Santagata S, Louis DN, Barker FG, Meyerson M, Getz G, Brastianos PK, Cahill DP. Sporadic hemangioblastomas are characterized by cryptic VHL inactivation. Acta Neuropathol Commun. 2014 Dec 24;2:167. doi: 10.1186/s40478-014-0167-x. PMID: 25589003; PMCID: PMC4297409. 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Mutation screening of VHL gene in a family with malignant bilateral pheochromocytoma: from isolated familial pheochromocytoma to von Hippel-Lindau disease. Fam Cancer. 2009;8(4):465-71. doi: 10.1007/s10689-009-9266-4. Epub 2009 Aug 1. PMID: 19649731. Chen Y, Zhou N, He X, Su Y, Xu J, Tang H, Guo D. The truth behind multiple neuroendocrine tumors: Von Hippel-Lindau syndrome and its diagnostic challenges-A case report and literature review. Sci Prog. 2025 Oct-Dec;108(4):368504251400811. doi: 10.1177/00368504251400811. Epub 2025 Nov 21. PMID: 41269879; PMCID: PMC12639212. Calvo E, Schmidinger M, Heng DY, Grünwald V, Escudier B. Improvement in survival end points of patients with metastatic renal cell carcinoma through sequential targeted therapy. Cancer Treat Rev. 2016 Nov;50:109-117. doi: 10.1016/j.ctrv.2016.09.002. Epub 2016 Sep 10. PMID: 27664394. Arevalo A, Patel N, Muraki P, Ohtake S, Bratslavsky G, Clark C, Mann J, Iliopoulos O, Jonasch E, Srinivasan R, Shuch B. Understanding the Impact of Belzutifan on Treatment Strategies for Patients with VHL. J Kidney Cancer VHL. 2022 Sep 28;9(3):41-46. doi: 10.15586/jkcvhl.v9i3.245. PMID: 36310638; PMCID: PMC9551368. Dameron CM, Maja AK, Mehra D, Batra NN. Belzutifan as the Primary Treatment of Bilateral Juxtapapillary Retinal Hemangioblastoma in a Patient With Von Hippel-Lindau Disease. J Vitreoretin Dis. 2024 Dec 31:24741264241309684. doi: 10.1177/24741264241309684. Epub ahead of print. PMID: 39744647; PMCID: PMC11686499. Yuen J, Zhou S, Caeser R, Venkatramani M, Bte Ishak DN, Li ST, Zhang Z, Chiang J, Chan SH, Ngeow J. Multi-locus inherited neoplasia alleles syndromes in cancer: implications for clinical practice. Eur J Hum Genet. 2025 Mar;33(3):289-296. doi: 10.1038/s41431-025-01785-1. Epub 2025 Jan 23. PMID: 39843919; PMCID: PMC11894078. Senthamizh T, Tripathy K. Retinal Vascular Anomalies (VHL, Cavernous Hemangioma, Wyburn-Mason) [Updated 2024 May 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK603735/ Pilotto E, Nacci EB, De Mojà G, Ferrara AM, Parrozzani R, Londei D, Zovato S, Midena E. Structural and microvascular changes of the peripapillary retinal nerve fiber layer in Von Hippel-Lindau disease: an OCT and OCT angiography study. Sci Rep. 2021 Jan 8;11(1):25. doi: 10.1038/s41598-020-79652-w. PMID: 33420143; PMCID: PMC7794312. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8660830","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":593409439,"identity":"341afc04-6fd5-4a6f-8119-266d1b6cde5a","order_by":0,"name":"Ali Duru","email":"","orcid":"","institution":"Akdeniz University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ali","middleName":"","lastName":"Duru","suffix":""},{"id":593409441,"identity":"7fd060a2-77d8-489d-887d-d7e6b3c2e737","order_by":1,"name":"Alp Peker","email":"","orcid":"","institution":"Akdeniz University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Alp","middleName":"","lastName":"Peker","suffix":""},{"id":593409445,"identity":"e024263d-6506-4200-9b16-ff6a88f80064","order_by":2,"name":"Feyza Altunbaş Yalabık","email":"","orcid":"","institution":"Akdeniz University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Feyza","middleName":"Altunbaş","lastName":"Yalabık","suffix":""},{"id":593409447,"identity":"4174c186-7577-4a27-bb11-0bd2fcac3a6f","order_by":3,"name":"Duygu Gamze Aracı","email":"","orcid":"","institution":"Akdeniz University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Duygu","middleName":"Gamze","lastName":"Aracı","suffix":""},{"id":593409451,"identity":"99434ab1-39df-466c-b166-4fabaf8b9bac","order_by":4,"name":"Mert Coşkun","email":"","orcid":"","institution":"Akdeniz University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mert","middleName":"","lastName":"Coşkun","suffix":""},{"id":593409454,"identity":"037f58c6-873e-4240-87d1-61badfafe85f","order_by":5,"name":"Aslı Toylu","email":"","orcid":"","institution":"Akdeniz University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Aslı","middleName":"","lastName":"Toylu","suffix":""},{"id":593409456,"identity":"8385b5b4-533d-4243-b2aa-eca2414597d2","order_by":6,"name":"Büşra Altınbilek Yavuz","email":"","orcid":"","institution":"Akdeniz University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Büşra","middleName":"Altınbilek","lastName":"Yavuz","suffix":""},{"id":593409457,"identity":"f24e340e-5f10-4675-8946-5f0488c2ece6","order_by":7,"name":"Bahar Akkaya","email":"","orcid":"","institution":"Akdeniz University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Bahar","middleName":"","lastName":"Akkaya","suffix":""},{"id":593409460,"identity":"ae4a790d-40e1-4c63-853f-bf258a4fd59a","order_by":8,"name":"Mehmet Erkan Doğan","email":"","orcid":"","institution":"Akdeniz University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mehmet","middleName":"Erkan","lastName":"Doğan","suffix":""},{"id":593409463,"identity":"19726967-6a72-4301-808f-2bba7051e201","order_by":9,"name":"Özden Altıok Clark","email":"","orcid":"","institution":"Akdeniz University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Özden","middleName":"Altıok","lastName":"Clark","suffix":""},{"id":593409466,"identity":"c19b22f1-6874-443a-9299-aaeda1be0ef2","order_by":10,"name":"Sezin Yakut Uzuner","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7ElEQVRIiWNgGAWjYHACZiC2YZBgSGAAIQaGA0RpSUhD0cLYQISWwxAtDMRokZ+R/NiY98d5ecn25GMPHvxhkOO7kcD+uAKPFoMbacbJPAm3DWfzPEs3SOBhMJa8kcDYeAafFokE48NALYzzJHLMJBIkGBI3gLTgc5n8jPTPQC3n7OdJ5H+TSDBgqCeoheFGDshhBxJnS+SwSSQkMCQYENJicOZNseGctOTkmT3PgA47IGE488zDxpl4HdaevlnijY2d7Yzjyc8kf/yxkec7nnzgI16HCSSgcCWAmFBM8h/ALz8KRsEoGAWjgAEAft5QZy8XMrwAAAAASUVORK5CYII=","orcid":"","institution":"Akdeniz University Hospital","correspondingAuthor":true,"prefix":"","firstName":"Sezin","middleName":"Yakut","lastName":"Uzuner","suffix":""}],"badges":[],"createdAt":"2026-01-21 14:09:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8660830/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8660830/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103175962,"identity":"9fb97c9c-b45f-4e01-9b13-c1d9ee3ba8d2","added_by":"auto","created_at":"2026-02-22 16:29:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":635160,"visible":true,"origin":"","legend":"\u003cp\u003eTwo separate families represented with their pedigrees in this figure with the founding variant identified. For each family, the proband was evaluated first and forwarded to genetic testing. Then, various family members were forwarded after initial identification of the proband’s variant. Several individuals in all families were not forwarded to VHL gene testing, however, they were clinically diagnosed with VHL. These individuals were shown with a filled quadrant shape, as shown in the figure.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8660830/v1/fdce05f093b51e1bf30a71ab.png"},{"id":103504491,"identity":"04ce1143-c836-45aa-9600-1efd95559957","added_by":"auto","created_at":"2026-02-26 13:20:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":353881,"visible":true,"origin":"","legend":"\u003cp\u003eHistological sections from the patients. (a) Pheochromacytoma specimen from patient III-7, (b) Renal cell carcinoma specimen from patient III-2.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8660830/v1/ac29fb6e8642446e07d9aa0a.png"},{"id":103504904,"identity":"dedee41e-8457-42db-b622-74c39e9ac829","added_by":"auto","created_at":"2026-02-26 13:22:02","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":616923,"visible":true,"origin":"","legend":"\u003cp\u003eInfrared fundus visuals and OCT images of patients, III-19 (family A), III-2 (family B), and IV-13 (family A) respectively, presenting notable tortuosity in retinal veins, vascular malformations in III-19-A and III-2-B (a,b), and visible retinal angioma around the optic disc in patient IV-13-A (c).\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8660830/v1/63864c47e899f10c3fdfd0f1.png"},{"id":103175964,"identity":"6ecd2a27-354c-40b9-bac3-5404d5388106","added_by":"auto","created_at":"2026-02-22 16:29:04","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":36117,"visible":true,"origin":"","legend":"\u003cp\u003ePhenotypes observed in all patients, in the literature and our cohort, and the percentages observed.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8660830/v1/479ef0392b9059de08ba043e.png"},{"id":105034841,"identity":"b4b87a50-246b-4426-b271-a1340afe9041","added_by":"auto","created_at":"2026-03-20 07:24:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2458755,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8660830/v1/53a5db46-132a-400a-b752-f58e3677a12b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Genotype-Phenotype Heterogeneity in Von Hippel-Lindau Disease: A Single-Center Multidisciplinary Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eVon Hippel-Lindau (VHL) disease (OMIM: 193300) is an autosomal dominant inherited familial cancer syndrome that causes central nervous system hemangioblastomas, retinal hemangioblastomas, pancreatic neuroendocrine tumors, pancreatic cysts, endolymphatic sac tumors, broad ligament cystadenomas, and epididymal cystadenomas. The incidence of VHL disease is estimated to be varying up to 1/36,000-91000 individuals [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In 80% of VHL cases, a germline VHL mutation is identified, while de novo germline VHL variants are found in 20% of cases [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Somatic VHL variants have been observed in isolated clear cell renal cell carcinomas (ccRCC) and central nervous system hemangioblastomas (CNSHB) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe diagnosis of VHL disease is made based on clinical findings and germline genetic testing. Pathogenic variants in the VHL gene can be detected with ~\u0026thinsp;85% sensitivity using sequence analysis and ~\u0026thinsp;10% sensitivity with deletion/duplication analysis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The VHL gene is a tumor suppressor gene located on the short arm of chromosome 3 (3p25.3), a highly conserved region. It contains three exons, and due to an alternative translation initiation codon at codon 54, two forms of the VHL protein (pVHL) are synthesized: the larger form, pVHL30 (30kDA), with 213 amino acids, and the smaller form, pVHL19 (19kDA), with 160 amino acids. Both forms play roles in the same tumor-suppressing mechanism [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe chemical structure of pVHL includes two important subunits. The first is the HIF binding region between amino acids 91\u0026ndash;113, which contains beta-sheet structures. The second is the Elongin C binding region between amino acids 157\u0026ndash;170, containing an alpha-helix domain. Under normoxic conditions, this region forms a complex with Elongin C and Elongin B, resulting in the formation of the VBC complex. This complex interacts with Cul2, facilitating HIF degradation through the proteasome-dependent ubiquitin ligase E3 function. In cases of VHL dysfunction or hypoxic conditions, HIF degradation is impaired, leading to increased transcription of genes involved in angiogenesis, such as VEGF, TGFB, TGFα, and PDGF.\u003c/p\u003e \u003cp\u003eTumor development in VHL disease is thought to follow Knudson's two-hit model. Initially, one allele is inactivated due to a germline VHL mutation, while the second allele is inactivated by a somatic mutation, deletion, or promoter hypermethylation, leading to tumor formation [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eClinically, VHL disease is divided into two main types: Type 1, which does not include pheochromocytoma, and Type 2, which carries a high risk for pheochromocytoma and is further subdivided into three subgroups. Type 2A is associated with a low risk of ccRCC, Type 2B with a high risk of ccRCC, and Type 2C involves only pheochromocytoma. The phenotype presented by patients can vary in multitudes, and differ due to genomic characteristics. Pathogenic missense variants that disrupt HIF regulation generally lead to VHL type 1, while those that don't affect HIF regulation are linked to VHL type 2 [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Variants associated with pheochromocytoma but low renal cell carcinoma risk (VHL types 2A/2C) likely retain HIF1α regulation, while those causing both pheochromocytoma and renal cell carcinoma (VHL type 2B) do not. Mutated pVHL may also alter apoptosis in sympatho-adrenal precursor cells. Defining families of multiple patients are needed when evaluating a newly diagnosed person.\u003c/p\u003e \u003cp\u003eHere, in this study we present 32 patients of the VHL disease. We define their phenotypical characteristics, pathological and radiological features. We observe clinical anamnesis data, cancer types and diagnosis ages, and treatment regimens they\u0026rsquo;ve received. We identify a large family consisting of multiple patients with the variant c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T, which confers multiple cancer types relating the variant with type 2 VHL disease, and we further dive into genotype-phenotype correlations regarding this genetic variant.\u003c/p\u003e"},{"header":"Materials and Method","content":"\u003cp\u003eThis study included individuals clinically suspected of having Von Hippel\u0026ndash;Lindau (VHL) disease, who were referred for exome sequencing at the Medical Genetics clinic of Akdeniz University Hospital. The primary cohort consisted of index cases with clinical features suggestive of VHL, such as retinal hemangioblastomas, central nervous system hemangioblastomas, renal cell carcinoma, or pheochromocytoma. After identification of candidate variants in index cases, targeted testing was extended to available family members (parents, siblings, children) to assess inheritance and segregation patterns. All participants or their legal guardians provided written informed consent prior to genetic testing. The study protocol was reviewed and approved by the Akdeniz University Medicine Faculty Ethical Committee (Decision number 03.01.2025/no:11).\u003c/p\u003e \u003cp\u003eSample Collection and DNA Extraction\u003c/p\u003e \u003cp\u003ePeripheral blood samples (5\u0026ndash;10 mL) were collected in EDTA tubes from all index cases and available relatives. Genomic DNA was extracted using the QIAamp DNA Blood Mini Kit (Qiagen, Hilden, Germany) following the manufacturer\u0026rsquo;s instructions. DNA purity and concentration were evaluated using NanoDrop 2000 (Thermo Fisher Scientific) and Qubit 4.0 fluorometer (Invitrogen).\u003c/p\u003e \u003cp\u003eLibrary Preparation and Target Enrichment\u003c/p\u003e \u003cp\u003eGenomic DNA (100\u0026ndash;200 ng) was used for library preparation with the Illumina DNA Prep with Enrichment kit (Illumina, San Diego, CA, USA). The exonic regions of the genome, including flanking intronic sequences (~\u0026thinsp;20 bp), were captured using the Illumina Exome Panel. Library fragment size and quality were assessed using the Agilent 2100 Bioanalyzer, and libraries were quantified using a Qubit fluorometer.\u003c/p\u003e \u003cp\u003eNext-Generation Sequencing\u003c/p\u003e \u003cp\u003eSequencing was performed on the Illumina NovaSeq 6000 platform using 150 bp paired-end reads. Each sample achieved a mean target coverage of \u0026ge;\u0026thinsp;100\u0026times;, with at least 95% of the targeted regions covered at \u0026ge;\u0026thinsp;20\u0026times;.\u003c/p\u003e \u003cp\u003eBioinformatics and Variant Analysis\u003c/p\u003e \u003cp\u003eRaw sequencing data were processed following the GATK Best Practices. Reads were aligned to the human reference genome GRCh38 using BWA-MEM. Variant calling was performed using GATK HaplotypeCaller, and variants were annotated with ANNOVAR. Population frequency data (gnomAD), pathogenicity prediction tools (SIFT, PolyPhen-2, MutationTaster, CADD), and disease-specific databases (ClinVar, HGMD, OMIM) were used for interpretation.\u003c/p\u003e \u003cp\u003eSpecial attention was given to the analysis of the VHL (NM_000551.4) gene, and variants were prioritized based on their clinical relevance, zygosity, and co-segregation with disease phenotype. Known hotspot variants previously associated with VHL syndrome were flagged for clinical relevance.\u003c/p\u003e \u003cp\u003eFamily Member Evaluation\u003c/p\u003e \u003cp\u003eFollowing the identification of potentially pathogenic variants in index cases, targeted sequencing (via Sanger or NGS-based validation) was performed in available family members to determine inheritance patterns (e.g., de novo, autosomal dominant transmission) and to assess genotype-phenotype correlations within families.\u003c/p\u003e \u003cp\u003eVariant Classification and Reporting\u003c/p\u003e \u003cp\u003e All variants were classified according to the ACMG/AMP guidelines. Variants considered pathogenic or likely pathogenic were confirmed via Sanger sequencing. Final clinical reports were issued by a multidisciplinary team and included interpretation, inheritance information, and genetic counseling recommendations.\u003c/p\u003e \u003cp\u003eAll patients encompassing pathogenic variants in the VHL gene, were referred to ophthalmologic examination to rule out retinal lesions, and to ENT specialists for hearing assessment. Biochemical screening with 24-hour urine metanephrines was initiated, if not previously done. Multidisciplinary follow-up is ongoing on all patients.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eOverall, there are 32 patients in this study, with ages ranging from 2 to 47. The large family case we present in this study involves 31 patients with 21 of them shown to be carrying the variant of c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg167Trp) in the VHL gene. The remaining one patient in this study, from a different family with a different founding variant, was added due to their specific treatment regimen preferred.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical features of patients with VHL syndrome in Family A\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDiagnosis Age\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePheochromocytoma\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCNC. Hemangioma\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRetinal Angioma\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRCC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePNET\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePancreatic/Renal Cysts\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eOther lesions\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI-2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eesophageal cancer\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eII-2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eII-4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eII-7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII-3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYes (pancreatic)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII-5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII-7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eYes (Liver hemangioma)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII-9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII-11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII-13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII-14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII-18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII-21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eLeft Surrenal Adenoma\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII-23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII-24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII-26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYes (pancreatic)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII-27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV-6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV-12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV-13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV-15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV-16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV-20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV-25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV-27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV-28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV-29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV-30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV-31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eV-3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eRCC\u003c/em\u003e: renal cell carcinoma \u003cem\u003ePNET: pancreatic neuroendocrine tumor N/A: Not available\u003c/em\u003e\u003c/p\u003e \u003cp\u003eIn the Family A, 8 of the 21 members carrying the c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T variant, were observed to have cancer both ranging in cancer types to the first diagnosis age, meanwhile, the rest have not yet been diagnosed with any. The clinical outcomes of patients carrying the same variant vary in utmost differences since one patient is diagnosed with 8 different types of VHL related cancers until the age of 32, meanwhile, another member is seen to be free of VHL related cancers at the age of 37, with all the cautionary tests including MRi testing evaluated.\u003c/p\u003e \u003cp\u003eIn Family A, the most frequently observed manifestations of von Hippel-Lindau (VHL) disease were pheochromocytoma, central nervous system (CNS) hemangiomas, and pancreatic neuroendocrine tumors (PNET). CNS hemangiomas, likely corresponding to hemangioblastomas, were confirmed in five patients (II-4, II-7, III-7, III-26, IV-20). Pheochromocytomas were similarly observed in five patients (II-7, III-7, III-13, III-23, IV-20), while PNETs were documented in three individuals (III-7, III-13, III-14). Renal cell carcinoma (RCC) was identified in one patient (II-4), and retinal angiomas were confirmed in two patients (III-18, IV-13).\u003c/p\u003e \u003cp\u003eA notable feature in this family is the high prevalence of pheochromocytoma. The co-occurrence of pheochromocytoma and CNS hemangioma in patients II-7 and IV-20 suggests a pattern consistent with VHL Type 2, which is characterized by an elevated risk of pheochromocytoma. Pancreatic involvement was also significant, encompassing both PNETs (three patients) and benign pancreatic cysts (two patients: III-3, III-26). The expression of VHL-related lesions was observed to be age-dependent. Younger family members, particularly those in generations IV and V, were frequently reported as negative for all lesions (e.g., IV-6 at 6 years and V-3 at 4 years). This highlights the importance of age-dependent penetrance in VHL disease and underscores the need for ongoing surveillance in at-risk individuals.\u003c/p\u003e \u003cp\u003eIn addition to classic VHL-associated lesions, some atypical findings were noted, including esophageal cancer in patient I-2 and a left adrenal adenoma in patient III-21. While these may represent incidental findings, their potential association with VHL gene dysfunction warrants further investigation.\u003c/p\u003e \u003cp\u003eSeveral limitations of the dataset should be acknowledged. A substantial proportion of entries were marked as \"N/A,\" particularly for retinal angiomas, PNETs, and pancreatic cysts, indicating that not all patients underwent comprehensive diagnostic imaging. Consequently, the true prevalence of certain lesions may be underestimated. Finally, the age at diagnosis is an important consideration; older patients (e.g., II-4, diagnosed at 47 years) may present with a cumulative burden of lesions over their lifetime, in contrast to younger patients whose clinical profiles may be incomplete.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eProband of family B, was a young adult male with a suspected diagnosis of von Hippel-Lindau (VHL) disease, referred for genetic evaluation. He had a history of bilateral retinal hemangioblastomas previously treated with laser photocoagulation. Family history was remarkable for VHL in his mother, sister, and maternal aunt, with additional reports of various malignancies, including breast cancer, lung cancer, and lymphoma among other relatives. Radiological work-up revealed multiple complex cystic renal lesions bilaterally, several of which demonstrated features consistent with Bosniak type 4 cystic renal cell carcinoma (RCC). The patient underwent cryoablation for two RCC lesions in the right kidney. Follow-up imaging confirmed no residual enhancement. Additionally, multiple subcentimeter pancreatic cysts were observed, consistent with benign VHL-associated pancreatic lesions. The patient has no other significant past surgical history and reports allergic rhinitis triggered by dust and pollen. He denies tobacco use but consumes alcohol socially. No consanguinity was reported between parents, and there is no known family history of additional genetic disorders. A promising result in proband B was that renal cyst progression had drastically diminished with the use of Belzutifan, an oral HIF-2α inhibitor approved for the treatment of von Hippel\u0026ndash;Lindau (VHL) disease\u0026ndash;associated tumors, targeting the hypoxia signaling pathway to suppress tumor growth [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGenetic testing detected the c.449_462dup variant, a 14-nucleotide duplication, occurring in the VHL gene in proband of family B. This duplication results in a frameshift mutation designated as p.Val155IlefsTer9. The frameshift is predicted to alter the reading frame from codon 155, where valine is replaced by isoleucine, and introduces a premature termination codon (Ter) at the ninth amino acid position downstream of the frameshift. This premature stop codon is likely to result in a truncated VHL protein. This variant has not been previously reported in the literature. This loss of function variant is classified as likely pathogenic according to the ACMG/AMP 2015 guidelines and interpreted in line with the ClinGen recommendations for the \u003cem\u003eVHL\u003c/em\u003e gene [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] Furthermore, a truncating BRCA2 variant, c.1507A\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Lys503; NM_000059.4), was also detected in the proband. This loss of function variant introduces a premature termination codon, was evaluated as a pathogenic variant.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe pathology specimens of patients who had tumor resection operations done by surgical departments of Akdeniz University Hospital, were analysed by the medical pathology specialists of the hospital. Section (a), shown in figure, demonstrates a pheochromocytoma from the patient III-7, proband of family A, with Von Hippel\u0026ndash;Lindau disease. The tumor exhibits the characteristic Zellballen architecture composed of nests of polygonal cells with granular cytoplasm, separated by delicate fibrovascular stroma. Immunohistochemical staining for chromogranin A shows strong diffuse cytoplasmic positivity, confirming the neuroendocrine nature of the tumor, consistent with a VHL-associated pheochromocytoma.\u003c/p\u003e \u003cp\u003eSection (b) demonstrates a renal biopsy from the patient III-2, proband of Family B, with Von Hippel\u0026ndash;Lindau (VHL) disease, showing characteristic features of clear cell renal cell carcinoma (ccRCC). Histologically, the tumor is composed of nests and clusters of neoplastic cells with abundant clear cytoplasm and intervening delicate fibrovascular septa. These findings are consistent with the typical morphology of ccRCC, which is the most frequent renal manifestation in VHL syndrome due to dysregulation of the HIF signaling pathway. Immunohistochemical staining was performed using carbonic anhydrase IX (CAIX), a highly sensitive and specific marker for ccRCC. The tumor cells show strong membranous staining in a characteristic box-like pattern, supporting the diagnosis of clear cell RCC. This staining pattern, along with the histomorphological features and clinical context, confirms the diagnosis of VHL-associated ccRCC.\u003c/p\u003e \u003cp\u003eOphthalmology screening of the patients revealed OCT features demonstrating marked structural alterations of the macula, from the proband of family A, characterized by prominent intraretinal cystic spaces and disruption of the outer retinal layers (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). These cystic changes likely represent secondary macular edema arising in the context of chronic retinal involvement associated with VHL-related vascular lesions. The accompanying irregularities at the level of the RPE and outer retina, together with the central atrophic appearance on fundus imaging, suggest longstanding damage from prior exudation or sequelae of regressed retinal capillary hemangiomas. Overall, the imaging findings are consistent with chronic VHL-associated macular remodeling, combining central chorioretinal atrophy with secondary intraretinal cystic degeneration.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e-Review of the Literature:\u003c/h2\u003e \u003cp\u003eThe c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.R167W) variant of the VHL gene has been associated with multiple types of Von Hippel-Lindau (VHL) disease in different case studies. This variant has been linked to VHL Type I, Type IIA, Type IIB, and Type IIC in several different studies [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The variant was observed in multiple cases, each exhibiting different clinical manifestations of VHL, including pheochromocytomas, hemangioblastomas, endolymphatic sac tumors and retinal capillary hemangioblastomas [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOne study investigated a five-generation family in China and found that individuals carrying the c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T mutation exhibited a variety of VHL-related tumors. The study classified patients into Type I (without pheochromocytomas), Type IIA (with pheochromocytomas but low risk of renal cell carcinoma), and Type IIC (pheochromocytomas only phenotype) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Another case report documented a 34-year-old male patient with multiple retinal capillary hemangioblastomas (RCHs) and a family history of VHL, where genetic testing confirmed the presence of the c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T mutation [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Additionally, a separate case reported a young male patient with bilateral pheochromocytomas leading to acute myocardial infarction, also found to carry the c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T variant [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eShows publications in the literature that recorded families or individuals identified to have the c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T variant. Phenotypes associated with VHL were listed together with the number of patients exhibiting each feature among those carrying the identified variant.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eZhang et. al [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGuo et. al [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBachurska et. al [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSu et. al [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHasani-Ranjbar et. al [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eChen et. al [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDuru et. al\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystolic Blood pressure\u0026thinsp;\u0026gt;\u0026thinsp;180 mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(1/9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(0/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(0/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(0/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(1/12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCerebellar Hemangioblastoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(3/9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(1/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(0/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(0/3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(1/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(5/10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(11/25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRetinal Angioma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(2/3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(2/8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(4/11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePancreatic endocrine tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(2/9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(0/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(0/3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(1/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(3/9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(6/24)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePancreatic cysts\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(3/9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(0/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(0/3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(0/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(2/9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(5/24)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal cell cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(0/9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(0/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(0/3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(0/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(1/8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(1/22)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal cysts\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(4/9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(0/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(0/3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(0/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0/9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(4/24)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePheochromocytoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(7/9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(1/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(1/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(3/3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(1/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(5/10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(18/25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParaganglioma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(2/9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(0/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(0/3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(1/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(3/15)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndolymphatic sac tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(1/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(0/3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(1/4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eVHL\u003c/em\u003e phenotypes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eI (1)\u003c/p\u003e \u003cp\u003eIIA (4)\u003c/p\u003e \u003cp\u003eIIC (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIIA (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIIC (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eI (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIIA (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIIB (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eI (3)\u003c/p\u003e \u003cp\u003eIIA (1)\u003c/p\u003e \u003cp\u003eIIB (3)\u003c/p\u003e \u003cp\u003eIIC (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eI (5)\u003c/p\u003e \u003cp\u003eIIA (9)\u003c/p\u003e \u003cp\u003eIIB (4)\u003c/p\u003e \u003cp\u003eIIC (6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePatients who exhibited features of VHL, both in our cohort and in the literature, were selected for discussion in this table. In our cohort, only eight patients had sufficient clinical information to allow classification into VHL subtypes. Many pediatric patients were found to carry the c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T variant through segregation analysis, but they had only undergone baseline evaluations appropriate for their ages. Additionally, several patients lacked detailed anamnesis, preventing reliable classification. Ultimately, eight well-documented patients from Family A were classified according to their VHL type: patients II-4, III-3, and III-26 as type 1; patient IV-20 as type 2A; patients II-7, III-7, and III-13 as type 2B; and patient III-23 as type 2C. This demonstrates that the c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T variant presents a highly variable clinical spectrum, even among members of the same family.\u003c/p\u003e \u003cp\u003eOverall, including the literature review, patients carrying the c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T variant comprise 5 type 1, 9 type 2A, 4 type 2B, and 6 type 2C cases, further highlighting the phenotypic variability associated with this mutation (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). This variability suggests that the c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T variant does not strictly dictate a single clinical outcome, but rather interacts with additional genetic, epigenetic, or environmental factors to shape the individual phenotype. For clinicians and genetic counselors, this means that carriers of c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T require comprehensive and long-term surveillance, even if initial evaluations are unremarkable, as different VHL-associated tumors may manifest at different ages.\u003c/p\u003e \u003cp\u003eThe review of the available literature also reveals that most reported VHL cases with pathogenic variants, including those involving the c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T allele, did not undergo dedicated audiologic evaluation or targeted imaging of the temporal bone to assess for endolymphatic sac tumors (ELST). Given that ELSTs may remain asymptomatic in early stages and can lead to irreversible sensorineural hearing loss if not detected promptly, this gap represents a clinically important oversight. We therefore recommend that all patients carrying pathogenic VHL alleles receive systematic hearing assessments, including formal audiometry as part of their baseline and longitudinal surveillance. Incorporating standardized otologic evaluation into routine VHL follow-up protocols may improve early detection of ELSTs and prevent avoidable morbidity.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003e-The c.499C \u003e T variant:\u003c/h3\u003e\n\u003cp\u003eTogether, these instances highlight the significant clinical variability linked to the VHL gene's c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T variant. The difficulty of determining precise genotype-phenotype associations in VHL syndrome is highlighted by the wide range of phenotypes. The fact that several clinical subtypes (Type I, IIA, and IIC) can result from the same pathogenic mutation supports the idea that altering genetic, epigenetic, or environmental factors might affect how a disease manifests. The idea that the penetrance and expressivity of VHL mutations are extremely variable is further supported by the variability shown in instances that appear to be isolated but have similar variants. Even among carriers of the same variant, our results highlight the need for tailored clinical surveillance and counseling approaches for VHL patients.\u003c/p\u003e \u003cp\u003eWhen evaluating the \u0026ldquo;Total\u0026rdquo; column in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, the most frequently observed phenotypes of Von Hippel-Lindau (VHL) syndrome among patients carrying the c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.R167W) variant are summarized below, ranked from most to least common, with corresponding frequencies and percentages: pheochromocytoma was present in 18 of 25 patients (72%), cerebellar hemangioblastoma in 11 of 25 patients (44%), retinal angioma in 4 of 11 patients (36.4%), pancreatic neuroendocrine tumors in 6 of 24 patients (25%), endolymphatic sac tumors in 1 of 4 patients (25%), pancreatic cysts in 5 of 24 patients (20.8%), paraganglioma in 3 of 15 patients (20%), renal cysts in 4 of 24 patients (16.7%), systolic blood pressure exceeding 180 mmHg in 1 of 12 patients (8.3%), and renal cell carcinoma (RCC) in 1 of 22 patients (4.5%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAmong the various manifestations, pheochromocytoma was the most frequently observed phenotype in patients carrying the c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.R167W) VHL variant, present in 72% of cases. This high frequency may be related to the specific effect of this missense mutation on the VHL protein, which could preferentially disrupt pathways involved in adrenal chromaffin cell proliferation and tumorigenesis. The predominance of pheochromocytoma in this patient group underscores the importance of careful clinical surveillance, including regular biochemical and imaging assessments, to ensure timely detection and management. Given the potential for life-threatening complications such as hypertensive crises, clinicians should maintain a high index of suspicion for pheochromocytoma in carriers of the c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T variant, even in the absence of overt symptoms.\u003c/p\u003e \u003cp\u003eAlso, amongst all features, RCC is the least commonly observed in patients carrying the c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T allele, and several factors may explain this finding. Incomplete or variable penetrance of VHL manifestations can result in organ-specific differences, meaning that some carriers may develop CNS or adrenal lesions without significant renal involvement. However, age-dependent penetrance is likely to play a role, since RCC in VHL often manifests later in life, and some patients may not yet have developed detectable renal tumors at the time of reporting. These factors underscore the importance of regular, comprehensive renal surveillance even in patients with missense VHL variants that appear to confer a lower RCC risk.\u003c/p\u003e \u003cp\u003eThe tumor spectrum observed in Family A further exemplifies the phenotypic diversity characteristic of VHL syndrome. While retinal angiomas and pheochromocytomas were the most frequently encountered manifestations, a variety of less commonly reported VHL-associated lesions, such as liver and pancreatic hemangioblastomas, cerebellar and spinal cord hemangioblastomas, and pancreatic cancer, were also present. Interestingly, adrenal hemangiomas and multiple pancreatic cysts were noted in some individuals, expanding the phenotypic landscape linked to the c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T variant. Of particular significance is the absence of renal cell carcinoma and baseline hypertension in any family members, despite these features being commonly reported in other VHL cohorts. This absence may reflect the influence of protective modifying factors against renal involvement in this specific family.\u003c/p\u003e \u003cp\u003e \u003cb\u003e-Regarding Follow-ups and Treatment;\u003c/b\u003e \u003c/p\u003e \u003cp\u003eIn family B, the proband\u0026rsquo;s clinical course highlights the emerging role of targeted therapies in the management of VHL-associated neoplasms, particularly the use of belzutifan. As an oral HIF-2α inhibitor, belzutifan has demonstrated efficacy in reducing tumor burden by interfering with the hypoxia-inducible pathway, a central mechanism in VHL tumorigenesis [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In this case, belzutifan use was associated with a marked stabilization of renal cystic lesions, suggesting potential disease-modifying benefits beyond surgical intervention. This pharmacologic approach is especially relevant for patients with multifocal or bilateral renal involvement, where repeated surgical interventions may pose cumulative risks to renal function. In recent years, other novel agents such as tyrosine kinase inhibitors (e.g., sunitinib, pazopanib) and mTOR inhibitors (e.g., everolimus) have also been explored in Renal cell carcinoma, particularly for patients with advanced or inoperable tumors; however, these treatments often come with broader toxicity profiles and are not VHL-specific [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Belzutifan, by contrast, offers a more targeted and tolerable alternative, positioning it as a frontline option in the evolving landscape of VHL management. This case underscores the importance of integrating molecularly guided therapies into the care of VHL patients, particularly those with progressive or high-risk lesions.\u003c/p\u003e \u003cp\u003eOver the course of time, from when belzutifan use for VHL patients had been approved by FDA, in patients with VHL-associated RCC, belzutifan has demonstrated objective response rates around 49% and durable tumor control, significantly delaying or even avoiding the need for nephron-sparing surgery\u0026mdash;a critical advantage given the multifocal nature of renal lesions in VHL [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The drug has also shown strong activity in extra-renal manifestations: response rates in pancreatic neuroendocrine tumors have reached up to 91%, highlighting its efficacy in traditionally hard-to-treat organs [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Promising outcomes have likewise been reported in CNS hemangioblastomas, with tumor shrinkage and neurological improvement attributed to reduced edema and mass effect [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Additionally, belzutifan has shown efficacy in treating retinal hemangioblastomas, leading to lesion regression and stabilization or improvement in visual acuity, thereby offering a less invasive alternative to local therapies such as laser photocoagulation or enucleation [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAnother important point to consider in the clinical management of proband B, was that he was observed to be a carrier of a pathogenic variant in the \u003cem\u003eBRCA2\u003c/em\u003e gene. This condition, which may explain the death of the individual designated as I-4 in the pedigree (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) due to breast cancer, suggests that the proband B is a carrier of two distinct cancer-related genetic conditions and represents a case of multilocus inherited neoplasia allele syndrome (MINAS) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. To our knowledge, this represents the first reported case of multilocus inherited neoplasia allele syndrome involving the concomitant presence of pathogenic germline variants in VHL and BRCA2, thereby expanding the molecular spectrum of MINAS and underscoring the importance of comprehensive multigene testing in hereditary cancer predisposition syndromes.\u003c/p\u003e \u003cp\u003eIn patients with known or suspected VHL, increased retinal vein tortuosity (as seen in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb) is a finding that may represent early microvascular involvement preceding the development of retinal hemangioblastomas. Although not diagnostic on its own, this vascular change reflects underlying angiogenic activity and is thought to be associated with a phenotype in which CNS hemangioblastomas are more likely to emerge. Accordingly, new or progressive tortuosity should prompt intensified ophthalmologic surveillance and may serve as an indication to schedule for cranial and spinal MRI, particularly in patients who are overdue for imaging or have not yet undergone baseline CNS evaluation [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In such patients with suspected microvascular changes, macular OCT alone might be insufficient; OCT imaging should also be performed directly over the suspected lesion. In particular, when peripapillary involvement is a concern, peripapillary OCT is required to ensure accurate assessment of early structural changes and lesion-related retinal alterations [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePresenting large VHL family cases in the literature helps in establishing genotype-phenotype correlations and identifying mutation hotspots like codon 167. These studies provide valuable insight into the penetrance, variability, and clinical spectrum of VHL disease, allowing for better genetic counseling and risk assessment for affected families.\u003c/p\u003e \u003cp\u003eIn conclusion, the c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.R167W) variant is within a known hotspot in VHL disease, associated with multiple subtypes and a range of clinical manifestations. By documenting large family cases and detailed case reports, the literature aids in refining clinical management strategies and improving early diagnosis, ultimately reducing life-threatening complications.\u003c/p\u003e \u003cp\u003eThere are many VHL families in which a family member presents with no cancer history, however, carries the same pathogenic variant as the other members. For such members, a deeper investigation might lead to better understanding of cancer formation and progression. Many cancer-related genes express proteins which unite with multiple others to form a protein complex that maintains a role in cell cycle processes, erroneous DNA reparations, cell division or death. It is important to evaluate the clinical history of hereditary cancer patients, considering the operational function of the protein or the protein complex involved in the cancer formation. The wide range in expressivity and penetrance differences in VHL disease suggests there should be made larger studies on mechanism related genes, expressions and genome wide associations (GWAS) regarding people who carry known pathogenic hereditary cancer gene variants. Since the people who have pathogenic variants in the VHL gene are almost definitely predestined to experience cancer until their 40\u0026rsquo;, it is feasable to suggest that VHL is a model gene to investigate such a hypothesis\u0026rsquo;. It is yet to be discovered if there are changes in, especially, DNA repair genes which potentially ameliorate the clinical presentation of such cases.\u003c/p\u003e \u003cp\u003eCertain VHL gene variants appear to show specific tendencies toward particular disease manifestations. For example, some missense variants, such as c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T, may predispose carriers to pheochromocytomas, while other variants are more strongly associated with CNS or renal lesions. Recognizing these genotype-phenotype correlations can help guide targeted surveillance and early intervention in affected patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere are no conflicts of interest of any authors of this manuscript.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study did not receive any specific funding.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eEthical Approval:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval was not required for this study because it reports a single clinical case evaluated as part of routine diagnostic testing. All procedures were performed in accordance with institutional and national ethical standards and the Declaration of Helsinki. Written informed consent for genetic testing and publication of anonymized clinical and genetic data was obtained from the patient.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe literature review of clinical features in patients observed to carry the c.499C\u0026gt;T variant, was made via PRISMA guidelines. We thank our working group in the laboratory, and our patients, and the families, for consistently adhering to clinical follow-up and segregation analyses.\u003c/p\u003e\n\n"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eLouise M Binderup M, Smerdel M, Borgwadt L, Beck Nielsen SS, Madsen MG, Møller HU, Kiilgaard JF, Friis-Hansen L, Harbud V, Cortnum S, Owen H, Gimsing S, Friis Juhl HA, Munthe S, Geilswijk M, Rasmussen ÅK, Møldrup U, Graumann O, Donskov F, Grønbæk H, Stausbøl-Grøn B, Schaffalitzky de Muckadell O, Knigge U, Dam G, Wadt KA, Bøgeskov L, Bagi P, Lund L, Stochholm K, Ousager LB, Sunde L. von Hippel-Lindau disease: Updated guideline for diagnosis and surveillance. Eur J Med Genet. 2022 Aug;65(8):104538. doi: 10.1016/j.ejmg.2022.104538. Epub 2022 Jun 13. PMID: 35709961. \u003c/li\u003e\n \u003cli\u003eBond E, Yashar B, Else T, Osborne J, Marvin M. Disclosure of genetic risk to dating partners among young adults with von Hippel-Lindau disease. 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PMID: 40909814; PMCID: PMC12407605.\u003c/li\u003e\n \u003cli\u003eZhang J, Ma J, Du X, Wu D, Ai H, Bai J, Dong S, Yang Q, Qu K, Lyu Y, Valenzuela RK, Liu C. Clinical and genetic investigation of a multi-generational Chinese family afflicted with Von Hippel-Lindau disease. Chin Med J (Engl). 2015 Jan 5;128(1):32-8. doi: 10.4103/0366-6999.147802. PMID: 25563310; PMCID: PMC4837816. \u003c/li\u003e\n \u003cli\u003eGuo J, Du L, Zhou P, Guo X, Dai F, Jin X. Combined therapy guided by multimodal imaging of fifteen retinal capillary hemangioblastomas in a monocular Von Hippel- Lindau syndrome case report. BMC Ophthalmol. 2022 May 6;22(1):205. doi: 10.1186/s12886-022-02409-8. PMID: 35524216; PMCID: PMC9074324. \u003c/li\u003e\n \u003cli\u003eBachurska S, Staykov D, Belovezhdov V, Sasano H, Gulinac M, Stefanov C, Neumann HP. Bilateral pheochromocytoma/intra-adrenal paraganglioma in von Hippel-Lindau patient causing acute myocardial infarction. Pol J Pathol. 2014 Mar;65(1):78-82. doi: 10.5114/pjp.2014.42675. PMID: 25119015.\u003c/li\u003e\n \u003cli\u003eSu Y, Shen WD, Wang CC, Han WJ, Liu J, Hou ZH, Song ZG, Huang DL, Han DY, Yang SM. [Endolymphatic sac tumor with von Hippel-Lindau disease: report of two cases with testing of von Hippel-Lindau gene]. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2013 Nov;48(11):913-8. Chinese. PMID: 24444636. \u003c/li\u003e\n \u003cli\u003eHasani-Ranjbar S, Amoli MM, Ebrahim-Habibi A, Haghpanah V, Hejazi M, Soltani A, Larijani B. Mutation screening of VHL gene in a family with malignant bilateral pheochromocytoma: from isolated familial pheochromocytoma to von Hippel-Lindau disease. Fam Cancer. 2009;8(4):465-71. doi: 10.1007/s10689-009-9266-4. Epub 2009 Aug 1. PMID: 19649731.\u003c/li\u003e\n \u003cli\u003eChen Y, Zhou N, He X, Su Y, Xu J, Tang H, Guo D. 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Available from: https://www.ncbi.nlm.nih.gov/books/NBK603735/\u003c/li\u003e\n \u003cli\u003ePilotto E, Nacci EB, De Mojà G, Ferrara AM, Parrozzani R, Londei D, Zovato S, Midena E. Structural and microvascular changes of the peripapillary retinal nerve fiber layer in Von Hippel-Lindau disease: an OCT and OCT angiography study. Sci Rep. 2021 Jan 8;11(1):25. doi: 10.1038/s41598-020-79652-w. PMID: 33420143; PMCID: PMC7794312.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8660830/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8660830/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction:\u003c/h2\u003e \u003cp\u003eVon Hippel-Lindau (VHL) disease is an autosomal dominant familial cancer syndrome caused by germline mutations in the \u003cem\u003eVHL\u003c/em\u003e tumor suppressor gene, leading to various neoplasms including hemangioblastomas, renal cell carcinoma (RCC), and pheochromocytomas. This study evaluates the clinical, radiological, and genetic profiles of two unrelated families: family A, in whom genotype\u0026ndash;phenotype correlations were systematically analyzed, and family B, characterized by a novel de novo pathogenic variant.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003ePatients suspected of VHL were analyzed using exome sequencing and targeted family testing. Variants were interpreted according to ACMG/AMP 2015 guidelines and interpreted in line with the ClinGen recommendations for the \u003cem\u003eVHL\u003c/em\u003e gene. Clinical follow-ups included multidisciplinary evaluations including detailed ophthalmologic screenings.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe study primarily focuses on Family A, where 21 members carry the c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg167Trp) variant. This variant revealed remarkable phenotypic heterogeneity, as family members presented with clinical manifestations consistent with multiple VHL subtypes across the established disease spectrum. In reported cases in the literature, pheochromocytoma is the most frequent manifestation (72%), whereas RCC is the least common (4.5%). In Family B, the study identified a novel frameshift mutation, c.449_462dup (p.Val155IlefsTer9), which has not been previously reported. Notably, this patient also carried a pathogenic BRCA2 variant, representing a rare case of Multilocus Inherited Neoplasia Allele Syndrome (MINAS). Furthermore, the administration of belzutifan, a HIF-2α inhibitor, showed promising results in stabilizing renal cystic lesions in the Family B proband.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOur findings highlight that even identical mutations, such as c.499C\u0026thinsp;\u0026gt;\u0026thinsp;T, can result in a wide spectrum of clinical outcomes, likely due to genetic, epigenetic, or environmental modifiers. The identification of novel variants and MINAS cases emphasizes the need for comprehensive genetic screening. Lifelong, multidisciplinary surveillance remains critical for the early detection and management of VHL-associated lesions to prevent morbidity.\u003c/p\u003e","manuscriptTitle":"Genotype-Phenotype Heterogeneity in Von Hippel-Lindau Disease: A Single-Center Multidisciplinary Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-22 16:29:00","doi":"10.21203/rs.3.rs-8660830/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"30ecdf4e-0752-4ed2-953d-a9c7ff4f51c5","owner":[],"postedDate":"February 22nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-19T04:55:34+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-22 16:29:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8660830","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8660830","identity":"rs-8660830","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}