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Purpose: Von Hippel-Lindau (VHL) disease is an autosomal-dominantly inherited tumor predisposition syndrome. One of the most common tumors are central nervous system (CNS) hemangioblastomas. Recommendations on the initiation and continuation of the screening and surveillance program for CNS tumors in pediatric VHL patients are based on small case series and thus low evidence level. To derive more robust screening recommendations, we report on the largest monocentric pediatric cohort of VHL patients., Methods: We performed a retrospective analysis on a pediatric cohort of 99 VHL patients consulted at our VHL center from 1992 to 2023. Clinical, surgical, genetic, and imaging data were collected and statistically analyzed., Results: 42 patients (50% male) developed CNS hemangioblastomas, of whom 18 patients (56% male) underwent hemangioblastoma surgery (mean age at first surgery: 14.9 ± 1.9 years; range 10.2-17). The first asymptomatic patient was operated on at the age of 13.2 years due to tumor progress. Truncating VHL mutation carriers had a significantly higher manifestation rate (HR = 3.7, 95% CI: 1.9-7.4, p < 0.0001) and surgery rate (HR = 3.3, 95% CI: 1.2-8.9, p = 0.02) compared with missense mutation carriers., Conclusion: We recommend starting MRI imaging at the age of 12 years with examination intervals every (1-) 2 years depending on CNS involvement. Special attention should be paid to patients with truncating variants. Affected families should be educated regularly on potential tumor-associated symptoms to enable timely MRI imaging and eventually intervention, as CNS hemangioblastoma may develop before screening begins., German Clinical Trials Register Registration Number: DRKS00029553, date of registration 08/16/2022, retrospectively registered., (© 2024. The Author(s).)

Kidney cysts are characterized by an abnormal tubular geometry that may result from loss of orientation and random cell divisions during renal development. Since cystic kidney disease is caused by mutations of ciliary proteins and cilia act as flow sensors in the kidney, we examined three polarized events in Madin Darby Canine Kidney cells under flow: cell division, cell migration, and centriole movement. We found that the mitotic orientation of dividing cells was not affected by flow and was randomly distributed in relation to the direction of the flow. Flow did not alter the direction and speed of cell migration in a wound-healing assay. However, flow resulted in increased motility of centrioles and biased centrioles to move along the axis of the flow. This effect was lost after flow-induced calcium signaling was abolished by a mutant polycystin 2. Our findings suggest that the cilium may translate fluid flow into altered centriole movements to provide tubular epithelial cells with the spatial orientation required to establish and/or maintain a normal tubular geometry.

Primary cilia have been shown to play an important role in embryonic development as well as in postnatal life. Dysfunctional cilia are associated with situs inversus, retinal abnormalities, impaired mucociliary clearance, infertility, hydrocephalus, and congenital renal cysts. In autosomal dominant polycystic kidney disease, mutations of the ciliary proteins polycystin1 or the transient receptor potential (TRP) channel family protein polycystin2 (TRPP2) cause progressive cyst formation and destruction of the kidney. Primary cilia act as flow sensors and respond to flow-mediated bending with a prolonged intracellular calcium increase, which appears to require an intact polycystin protein complex. We have established a novel flow chamber system, which allows us to study renal epithelial cells by live cell imaging. We show that MDCK cells respond to flow by a delayed increase in intracellular calcium and that this response requires these cells to be ciliated. We show that a novel interactor of TRPP2, kidney injury molecule-1 (Kim1), which is expressed at low levels in the normal kidney and upregulated after ischemia, in renal cell cancer and in PKD is targeted to primary cilia when stably expressed in MDCK cells. We demonstrate that expression of tyrosine mutant Kim1, lacking a conserved tyrosine in the intracellular tail, abolishes the calcium increase in response to flow in a dominant negative manner. These results establish Kim1 as a novel regulatory molecule of flow-induced calcium signaling.