Cystic Kidney Disease Research Articles

Development of an Interactive Dashboard for OSSE Rare Disease Registries.

The Open Source Registry System for Rare Diseases (OSSE), a web-based tool to create rare disease patient registries, currently offers no possibility to view aggregated registry data within the system. Here, we present the development and implementation of a dashboard for the registry of the German NEOCYST (Network for early onset cystic kidney diseases) consortium. Based on user requirements from NEOCYST, we developed a general dashboard for all OSSE registries, which was extended with NEOCYST-specific statistics. The dashboard now allows users to gain a quick overview of key data, such as patient counts or the availability of biospecimens. This work represents a first prototypical approach for an OSSE dashboard, demonstrated in an existing rare disease registry, to be further evaluated and enhanced in the future.

Potential Therapeutic Effects of Long-Term Stem Cell Administration: Impact on the Gene Profile and Kidney Function of PKD/Mhm (Cy/+) Rats.

Cystic kidney disease (CKD) is a heterogeneous group of genetic disorders and one of the most common causes of end-stage renal disease. Here, we investigate the potential effects of long-term human stem cell treatment on kidney function and the gene expression profile of PKD/Mhm (Cy/+) rats. Human adipose-derived stromal cells (ASC) and human skin-derived ABCB5+ stromal cells (2 × 106) were infused intravenously or intraperitoneally monthly, over 6 months. Additionally, ASC and ABCB5+-derived conditioned media were administrated intraperitoneally. The gene expression profile results showed a significant reprogramming of metabolism-related pathways along with downregulation of the cAMP, NF-kB and apoptosis pathways. During the experimental period, we measured the principal renal parameters as well as renal function using an innovative non-invasive transcutaneous device. All together, these analyses show a moderate amelioration of renal function in the ABCB5+ and ASC-treated groups. Additionally, ABCB5+ and ASC-derived conditioned media treatments lead to milder but still promising improvements. Even though further analyses have to be performed, the preliminary results obtained in this study can lay the foundations for a novel therapeutic approach with the application of cell-based therapy in CKD.

MO046: Exome sequencing of Israeli Druze individuals on dialysis reveals common as well as population- specific monogenic etiologies in ∼30%

Abstract BACKGROUND AND AIMS Genetic etiologies are estimated to affect ∼10% of adults with advanced CKD. However, significant population disparities in genetic kidney disease exist and population-based screening are lacking especially among minority groups. The Druze population is a middle-eastern minority with high rates of end-stage renal disease (ESRD) and consanguinity, which suggests high rates of population-specific monogenic CKD etiologies. We therefore hypothesized that by exome sequencing we will identify a unique distribution of monogenic ESRD causes as compared with prior studies and that important ramifications for clinical practice may ensue. METHOD We initiated a national multicenter study of all Israeli dialysis units in order to provide comprehensive evidence for ESRD's genetic basis (Israeli ESRD Genetic Consortium Cohort). Specifically, during 2020, we recruited 97% (n = 94) of Israeli Druze individuals on dialysis from 12 different hospitals and community-based units. We conducted exome sequencing and diagnostic analysis for all patients. We assessed the diagnostic yield of genetic analysis and its relation to baseline clinical phenotypes. RESULTS Overall, the cohort consists of 94 individuals from 91 different families with first-degree consanguinity rate of 28%. Participants mean age was 62 years (ranging from 18 to 88 years). Most common primary clinical diagnoses were diabetic kidney disease, nephropathy of unknown origin, glomerular or cystic kidney disease, together encompassing 90% of all cases. None had previous molecular diagnosis. Using exome sequencing, we identified a genetic etiology in 27 out of 94 (28.7%) participants. We identified WDR19 (NPHP13) homozygous mutation c.878G > A (p.C293Y) as the most common genetic diagnosis (5.3%). Follow-up clinical characterization revealed that all affected individuals exhibited non-syndromic adulthood-onset ESRD, supporting a profound mutation-dependent phenotypic heterogeneity and weak pre-exome phenotypic specificity. Other prevalent genetic diagnoses included type IV collagen, PKD1, PKD2 and UMOD mutations as well as monogenic forms of diabetes and hyperlipidemia. Molecular diagnosis corresponded to the pre-exome clinical diagnosis in only one-third of the participants. CONCLUSION Exome sequencing in Druze with ESRD yields a genetic diagnosis in just <30% of cases with WDR19 mutation being the most prevalent single-gene etiology. These results, which remarkably inform clinical management, emphasize the importance of revealing population-specific mutations given the underutilization of genetic testing, particularly among adult minorities.

MO059: Trajectory Analysis of the Kidney Organoid Proteome Extends its Modelling Potential of Disease

Abstract BACKGROUND AND AIMS Kidney organoids are a valuable and innovative model to understand genetic diseases, kidney development and transcriptomic dynamics. However, their proteome has not been analyzed so far. It is unclear how their proteome changes during differentiation, and if more complex disease processes such as inflammatory tissue responses could be modelled with this approach. METHOD Here, we used proteomics to compare organoids with existing model systems such as native glomeruli and cultured cells. We characterize the trajectory of organoid differentiation and delineate innate immune responses in organoids to expand its scope as a model system in nephrology. We also compared our proteomics with bulk and single cell transcriptomic data. RESULTS Genes involved in podocytopathies and cystic kidney diseases were abundantly expressed on protein level, distinguishing organoids from almost every available cell culture model. On their pathway to terminal differentiation, organoids developed increased deposition of extracellular matrix. Single cell transcriptomic analysis suggests that most changes locate to podocytes and early podocyte progenitors. This matrix deposition is different from commonly used animal models of glomerular disease. A novel signaling system discovered was the TNFα system, a system also available in podocytes. Incubation of organoids with high concentrations of TNFα led to an activation of NF-kB signaling, and secretion of cytokines and complement components, alongside with extracellular matrix components. CONCLUSION Interestingly, this signaling system directly links inflammatory signaling, production of cytokines and complement, and production of extracellular matrix. Thus, we provide a repository of human kidney organoid proteins that revealed the potential to model pathophysiological pathways beyond genetic diseases.

Acquired Cystic Kidney Disease: A Hidden Complication in Children on Chronic Hemodialysis.

ObjectiveTo determine the frequency of acquired cystic kidney disease (ACKD) in children on chronic hemodialysis.Material and methodsIn this single-center cross-sectional study, 150 children were included who were on chronic hemodialysis for six months. Ultrasound was done to see the renal cysts. Cystic changes that could not fulfill the criteria for ACKD were also noted and analyzed.ResultsThe mean age was 14.5 ± 3.5 years, of these 63 (42%) were males. Acquired cysts were detected in 53 (35%) of the patient and 18 patients (12%) had solitary cysts. The distribution of these entities was similar across all age groups. The underlying etiologies in the descending order were unknown 64 (43%), stone disease 31 (21%), each of the congenital anomalies of the kidney and urinary tract, and glomerulonephritis 23 (15%), and others nine (6%). A higher frequency of ACKD was detected in the children on renal replacement therapy for more than two years (33 out of 53 children, 63% with a p-value of 0.004).ConclusionThe ACKD was found in one-third of our hemodialysis children and its frequency increases with the duration of hemodialysis. This percentage may not reflect the true prevalence as there is a lack of consensus on the definition of ACKD. Periodic assessment of chronic kidney disease patients for the development of ACKD especially on chronic hemodialysis is required to reduce the morbidity.

A Comprehensive Immune Cell Atlas of Cystic Kidney Disease Reveals the Involvement of Adaptive Immune Cells in Injury-Mediated Cyst Progression in Mice.

Inducible disruption of cilia-related genes in adult mice results in slowly progressive cystic disease, which can be greatly accelerated by renal injury. To identify in an unbiased manner modifier cells that may be influencing the differential rate of cyst growth in injured versus non-injured cilia mutant kidneys at a time of similar cyst severity, we generated a single-cell atlas of cystic kidney disease. We conducted RNA-seq on 79,355 cells from control mice and adult-induced conditional Ift88 mice (hereafter referred to as cilia mutant mice) that were harvested approximately 7 months post-induction or 8 weeks post 30-minute unilateral ischemia reperfusion injury. Analyses of single-cell RNA-seq data of CD45+ immune cells revealed that adaptive immune cells differed more in cluster composition, cell proportion, and gene expression than cells of myeloid origin when comparing cystic models with one another and with non-cystic controls. Surprisingly, genetic deletion of adaptive immune cells significantly reduced injury-accelerated cystic disease but had no effect on cyst growth in non-injured cilia mutant mice, independent of the rate of cyst growth or underlying genetic mutation. Using NicheNet, we identified a list of candidate cell types and ligands that were enriched in injured cilia mutant mice compared with aged cilia mutant mice and non-cystic controls that may be responsible for the observed dependence on adaptive immune cells during injury-accelerated cystic disease. Collectively, these data highlight the diversity of immune cell involvement in cystic kidney disease.

Kidney stone formation in a novel murine model of polycystic kidney disease.

Individuals with autosomal dominant polycystic kidney disease have a higher incidence of stone formation than the general population. However, there are no cystic animal models known to develop stones. Cystic mice compound heterozygous for hypomorphic Pkd1V and Pkd1RC alleles develop cystic kidneys within a few weeks of birth but live beyond 20 wk of age, allowing for the study of cystic comorbidities including stone formation. Cystic Pkd1V/RC mice were euthanized at 3, 13, or 26 wk of age, and their kidneys were analyzed by microcomputed tomography (µCT) for stone formation. Mice had occasional mineral aggregates that could be detected by µCT analysis at 3 wk of age. At 13 or 26 wk of age, numerous white masses were visible beneath the kidney surface. µCT analysis confirmed the masses to be large mineral stone deposits throughout the renal cortex, with mineral content increasing with age. Staining of histological sections with alizarin red and von Kossa suggested that the stone deposits were composed primarily of calcium and phosphate. Microdissection confirmed stones localized within cyst lumens. Analysis of individual stones by µCT and infrared spectroscopy confirmed apatite mineral composition. Urinalysis revealed elevated levels of phosphate and citrate at 3 wk of age and lower pH and elevated levels of calcium and citrate at 13 wk of age, suggesting altered phosphate and calcium homeostasis as a potential cause of mineralization and renal stone formation. This is the first animal model exhibiting overt kidney stone formation in the context of cystic kidney disease.NEW & NOTEWORTHY Compound heterozygous Pkd1V/RC mice were found to form calcium phosphate-containing stones within cysts of the renal cortex by 13 wk of age. This is the first polycystic kidney disease animal model exhibiting spontaneous stone formation. A growing body of evidence suggests a link between renal stone formation and cystic kidney disease. This mouse model may be useful for studying the interplay between stone and cyst formation and the functional role of polycystins in mineral homeostasis.

370 Clinical Utility of Targeted Whole Exome Sequencing in a Cystic Kidney Disease Clinic

370 Clinical Utility of Targeted Whole Exome Sequencing in a Cystic Kidney Disease Clinic

Multi-omics studies reveal genes critical for AKI and ferroptosis

Family-based linkage studies, more recently combined with exome sequencing, have identified coding regions that explain the development of cystic kidney diseases and nephrotic syndrome, as well as other rare kidney diseases; however, common adult-onset kidney diseases, including hypertensive and diabetic nephropathy, are multifactorial. These diseases show more complex inheritance patterns and less involvement of each causative region compared with the pure and rare genetic diseases, thus requiring a different approach to study them.

Primary URECs: a source to better understand the pathology of renal tubular epithelia in pediatric hereditary cystic kidney diseases

BackgroundIn pediatric hereditary cystic kidney diseases, epithelial cell defects mostly result from rare, autosomal recessively inherited pathogenic variants in genes encoding proteins of the cilia-centrosome complex. Consequences of individual gene variants on epithelial function are often difficult to predict and can furthermore depend on the patient’s genetic background. Here, we studied urine-derived renal tubular epithelial cells (URECs) from genetically determined, pediatric cohorts of different hereditary cystic kidney diseases, comprising autosomal recessive polycystic kidney disease, nephronophthisis (NPH) and the Bardet Biedl syndrome (BBS). UREC characteristics and behavior in epithelial function-related 3D cell culture were compared in order to identify gene and variant-specific properties and to determine aspects of epithelial (cell) dysfunction.ResultsUREC preparations from patients (19) and healthy controls (39) were studied in a qualitative and quantitative manner using primary cells cultured for up-to 21 days. In patients with biallelic pathogenic variants in PKHD1 or NPHP genes, we were able to receive satisfactory amounts of URECs of reproducible quality. In BBS patients, UREC yield was lower and more dependent on the individual genotype. In contrast, in UREC preparations derived from healthy controls, no predictable and satisfactory outcome could be established. Considering cell proliferation, tubular origin and epithelial properties in 2D/3D culture conditions, we observed distinct and reproducible epithelial properties of URECs. In particular, the cells from patients carrying PKHD1 variants were characterized by a high incidence of defective morphogenesis of monolayered spheroids—a property proposed to be suitable for corrective intervention. Furthermore, we explored different ways to generate reference cell lines for both—patients and healthy controls—in order to eliminate restrictions in cell number and availability of primary URECs.ConclusionsEx vivo 3D cell culture of primary URECs represents a valuable, non-invasive source to evaluate epithelial cell function in kidney diseases and as such helps to elucidate the functional consequences of rare genetic disorders. In combination with genetically defined control cell lines to be generated in the future, the cultivation of primary URECs could become a relevant tool for testing personalized treatment of epithelial dysfunction in patients with hereditary cystic kidney disease.

EP351: Next-generation sequencing panels for cystic kidney disease with improvements for sequencing and alignment challenges

Inherited cystic kidney disease (CKD) is a heterogeneous group of conditions and is one of the most common causes of end stage kidney disease (ESKD). Identification of CKD can occur prenatally, in childhood, or in adulthood; it can be unilateral or bilateral in nature and can be non-syndromic or syndromic. Identifying the underlying molecular etiology of CKD can have implications for many aspects of clinical management, including refining the classification of the disease and enabling evaluation of previously unrecognized extra-renal features when a syndromic etiology is found.

Genetic Etiologies, Diagnosis, and Management of Neonatal Cystic Kidney Disease.

Fetal kidney development is a complex and carefully orchestrated process. The proper formation of kidney tissue involves many transcription factors and signaling pathways. Pathogenic variants in the genes that encodethese factors and proteins can result in neonatal cystic kidney disease. Advancements in genomic sequencing have allowed us to identify many of these variants and better understand the genetic underpinnings for an increasing number of presentations of childhood kidney disorders. This review discusses the genes essential in kidney development, particularly those involved in the structure and function of primary cilia, and implications of gene identification for prognostication and management of cystic kidney disorders.

Antibody responses to 2 doses of mRNA COVID-19 vaccine in pediatric patients with kidney diseases

Antibody responses to 2 doses of mRNA COVID-19 vaccine in pediatric patients with kidney diseases

Detection of DZIP1L mutations by whole-exome sequencing in consanguineous families with polycystic kidney disease

BackgroundAutosomal recessive polycystic kidney disease is a cystic kidney disease with early onset and clinically characterized by enlarged echogenic kidneys, hypertension, varying degrees of kidney dysfunction, and liver fibrosis. It is most frequently caused by sequence variants in the PKHD1 gene, encoding fibrocystin. In more rare cases, sequence variants in DZIP1L are seen, encoding the basal body protein DAZ interacting protein 1-like protein (DZIP1L). So far, only four different DZIP1L variants have been reported.MethodsFour children from three consanguineous families presenting with polycystic kidney disease were selected for targeted or untargeted exome sequencing.ResultsWe identified two different, previously not reported homozygous DZIP1L sequence variants: c.193 T > C; p.(Cys65Arg), and c.216C > G; p.(Cys72Trp). Functional analyses of the c.216C > G; p.(Cys72Trp) variant indicated mislocalization of mutant DZIP1L.ConclusionsIn line with published data, our results suggest a critical role of the N-terminal domain for proper protein function. Although patients with PKHD1-associated autosomal recessive polycystic kidney disease often have liver abnormalities, none of the present four patients showed any clinically relevant liver involvement. Our data demonstrate the power and efficiency of next-generation sequencing-based approaches. While DZIP1L-related polycystic kidney disease certainly represents a rare form of the disease, our results emphasize the importance of including DZIP1L in multigene panels and in the data analysis of whole-exome sequencing for cystic kidney diseases.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Multiregion sequencing of sarcomatoid renal cell carcinoma arising from autosomal dominant polycystic kidney disease.

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is an inherited cystic kidney disease associated with a spectrum of various renal and extrarenal manifestations, including increased risk of kidney cancers. Here, we present the initial molecular description of sarcomatoid renal cell carcinoma (sRCC) arising in the setting of ADPKD.MethodsMultiregion whole‐exome sequencing and whole transcriptomic sequencing were used to examine intratumoral molecular heterogeneity among histologically‐distinct spindle (sarcomatoid), epithelioid, or biphasic compartments within the tumor and compared with the non‐malignant ADPKD component.ResultsSpindle and biphasic components harbored several overlapping driver gene mutations, but do not share any with the epithelioid component. Mutations in ATM, CTNNB1, and NF2 were present only in the biphasic and spindle components, while mutations in BID, FLT3, ARID1B, and SMARCA2 were present only in the epithelioid component. We observed dichotomous evolutionary pathways in the development of epithelioid and spindle compartments, involving early mutations in TP53 and ATM/CTNNB1/NF2 respectively. Wnt, PI3K‐mTOR, and MAPK signaling pathways, known key mechanisms involved in ADPKD development, featured prominently in the sarcomatoid component.ConclusionThis highlights that common pro‐oncogenic signals are present between ADPKD and sRCC providing insights into their shared pathobiology.

POS-486 SECONDARY POLYCYTHEMIA IN NEPHROTIC SYNDROME – AN UNCOMMON ASSOCIATION

Polycythaemia is defined as haemoglobin (Hb) of over16.5 g/dL in men and 16 g/dL in women or haematocrit of over 49% in men and 48% in women (WHO 2017). Primary polycythaemiais caused by erythropoietin (EPO) receptor mutations or Janus Kinase 2 (JAK2) mutations. Secondary polycythaemia is occasionally seen with renal diseases such as cystic kidney disease, tumours, renal artery stenosis and after renal transplantation. Polycythaemia associated with Nephrotic Syndrome (NS) is very rare. This association was first described by Emmanuel DA and Wenzel FJ in 1962. Here, we describe four patients with NS who had polycythaemia at presentation.Heavy protienuria leading to renal interstitial oedema causing hypoxia and increased EPO production and high serum IL8 and increased stability of IL8 mRNA(in minimal change disease) are thought to cause secondary polycythaemia in NS. The resolution of polycythaemia following reduction in proteinuria further strengthens the causation.The exact pathogenesis remains to be elucidated. This is a retrospective observational study conducted in NU Hospitals, Bengaluru, India.There were four patients with NS and polycythaemia, between February 2015 to May 2021. All patients with NSwere subjected to biochemical investigations and ultrasonography (USG) of the abdomen after a detailed history and physical examination as per our hospital protocol. Coagulation profile and blood grouping were done prior to renal biopsy. Percutaneous renal biopsy was done under real-time USG guidance. The tissue obtained was sent for Light microscopic examination, Immunofluorescence microscopy and Electron microscopy. In view of the polycythaemia, all these patients underwent a Chest X Ray, arterial blood gas (ABG) analysis, serum EPO and serum JAK2 mutation studies. All four patients in our study were men. Mean age was 32.25 ± 11.70 years. Mean Hb was 18.75 ± 1.22 g/dL. Mean hematocrit was 54.67 ± 6.5 %. Mean proteinuria at onset was 7.62 ± 7.45 grams/day. Mean serum creatinine at the onset was 1.30 ± 0.58 mg/dL. None had splenomegaly. All had normal total white cell and platelet count. None were smokers. ABG was normal in all. All patients had normal serum EPO levels (mean 3.4±1.64 mU/ml) and negative JAK2 mutation analysis. The etiology of NS was minimal change disease (MCD), primary membranous nephropathy (MGN), primary focal segmental glomerulosclerosis (FSGS) and IgA nephropathy in each one of them. PLA2R antibodies were positive in the serum and renal tissue of the patient with MGN.Immunosuppression was initiated in all patients except the patient with IgA nephropathy who had significant chronicity. Three out of four patients had resolution of polycythemia in parallel with remission of NS.The patient with MCD was detected to have polycythaemia during a relapse. This study highlights polycythaemia as an unusual complication of NS.Most cases of NS and polycythemia documented in the literature correspond to FSGS, mainly associated with polycythaemia vera. There are case reports of secondary polycythaemia associated with primary FSGS, MGN and MCD. We didn't do IL8 and IL11 assay in our patients. To the best of our knowledge ours is probably the largest case series of polycythaemia associated with NS.

POS-434 The Protective Effect of UMOD Single Nucleotide Polymorphisms (SNPs) rs12917707 on the Risk of Kidney Failure

Common genetic variations have important roles in the development and progression of chronic kidney disease (CKD), but so far most single-nucleotide polymorphisms (SNPs) described tend to have a small effect size. Uromodulin or Tamm-Horsfall, is the most abundant urinary protein in physiological conditions. Rare mutations in its encoding gene UMOD cause a Mendelian Medullary cystic kidney disease type 2 presenting in childhood. Common variants of UMOD are implicated in GFR trait in the general population.

POS-816 DE NOVO KIDNEY ALLOGRAFT RENAL CELL CARCINOMA: A RARE UNSALVAGEABLE CAUSE OF ALLOGRAFT LOSS IN A VERY LATE POST-TRANSPLANT PERIOD

Renal cell carcinoma (RCC) is a common malignancy in end-stage kidney disease (ESKD) from acquired cystic kidney disease (ACKD). With a net state of immunosuppression, kidney transplant recipients (KTR) are even at higher risk for RCC; however, RCC in the kidney allograft is uncommon unless it results from donor-derived disease. We report a case of old-aged woman with kidney allograft masses at the very late post-transplant period. Explanted transplant allograft revealed RCC.

Activation of Notch3 in Renal Tubular Cells Leads to Progressive Cystic Kidney Disease.

Background: Polycystic kidney disease (PKD) is a genetic disorder affecting millions of people worldwide that is characterized by fluid-filled cysts and leads to end-stage renal disease (ESRD). The hallmarks of PKD are proliferation and dedifferentiation of tubular epithelial cells, cellular processes known to be regulated by Notch signaling. Methods: We found increased Notch3 expression in human PKD and renal cell carcinoma biopsies. To obtain insight into the underlying mechanisms and the functional consequences of this abnormal expression, we developed a transgenic mouse model with conditional overexpression of the intracellular Notch3 (ICN3) domain specifically in renal tubules. We evaluated the alterations in renal function (creatininemia, BUN) and structure (cysts, fibrosis, inflammation) and measured the expression of several genes involved in Notch signaling and the mechanisms of inflammation, proliferation, dedifferentiation, fibrosis, injury, apoptosis and regeneration. Results: After one month of ICN3 overexpression, kidneys were larger with tubules grossly enlarged in diameter, with cell hypertrophy and hyperplasia, exclusively in the outer stripe of the outer medulla. After three months, mice developed numerous cysts in proximal and distal tubules. The cysts had variable sizes and were lined with a single- or multilayered, flattened, cuboid or columnar epithelium. This resulted in epithelial hyperplasia, which was observed as protrusions into the cystic lumen in some of the renal cysts. The pre-cystic and cystic epithelium showed increased expression of cytoskeletal filaments and markers of epithelial injury and dedifferentiation. Additionally, the epithelium showed increased proliferation with an aberrant orientation of the mitotic spindle. These phenotypic tubular alterations led to progressive interstitial inflammation and fibrosis. Conclusions: In summary, Notch3 signaling promoted tubular cell proliferation, the alignment of cell division, dedifferentiation and hyperplasia, leading to cystic kidney diseases and pre-neoplastic lesions.

Von Hippel-Lindau; A 47-year-old woman with renal cell carcinoma and multiorgan involvement

Von Hippel-Lindau (VHL) is a rare autosomal dominant genetic disease. Affected individuals manifest clinically with tumors involving multiple organs including hemangioblastoma of the central nervous system and retina, cystic kidney disease, renal cell carcinoma (RCC), pheochromocytoma, and pancreatic neuroendocrine tumors. Its diagnosis is based on genetic testing and clinical criteria in suspected patients. Treatment principles are to save organs and periodic surveillance for in-time tumor detection and appropriate follow-ups. This case report presents a 47-year-old woman with five years history of abdominal pain alongside long-standing headaches and progressive hearing loss. On imaging, multiple suspicious tumors throughout her body were detected and she proceeded to surgical resection. She was finally diagnosed with RCC, central nervous system tumor hemangioblastoma, and pancreatic cyst. The patient underwent a right-sided nephrectomy and Sunitinib therapy. She is continuing therapy and currently does not have any sign of metastasis. Due to her constellation of tumors VHL disease was suspected. Although she did not have any positive family history, the VHL diagnosis was conducted based on clinical criteria. The case emphasized the importance of timely recognition and evaluation of suspected cases and evidence base surveillance. Physician familiarity with the underestimated disease is of paramount importance.