von Hippel–Lindau disease (VHL) is an autosomal dominant inherited genetic disorder caused by a germline mutation of chromosome 3 (VHL gene). Patients affected with VHL develop multiple central nervous system (CNS) lesions, including retinal and craniospinal hemangioblastomas, as well as endolymphatic sac tumors (ELSTs). Visceral VHL-associated lesions frequently include renal cell carcinomas, renal cysts, pheochromocytomas, extra-adrenal paragangliomas, pancreatic microcystic adenomas, pancreatic cysts, and pancreatic neuroendocrine tumors, as well as cystadenomas of the epididymis and broad ligament (1–3) (Figure 1). VHL has an incidence of approximately 1 in 36,000–39,000 live births (4, 5). Penetrance is nearly complete and most (over 90%) patients display evidence of the disease by the age of 65 years (6).

Treatment of VHL is complex due to the multisystem involvement, the location of tumors, and the immense variability of symptoms that can be produced related to various tumor locations and systems involved. Recent studies have elucidated new germline-based targets for treatment. Existing treatments include combinations of chemotherapy, radiation therapy, and surgical resection. We describe the current personalized management of the CNS manifestations of VHL and the potential putative therapeutics that are based on germline mutation types.

Mutations in the VHL gene lead to the development of the manifestations of VHL. The VHL gene is located on the short arm of chromosome 3 (3p) and is a tumor suppressor gene (8). Germline mutations of VHL account for more than 95% of the patients affected by VHL (5% have somatic inactivation of the VHL gene in sporadically occurring hemangioblastomas and renal cell carcinomas) (9). VHL patients inherit a VHL germline mutation from the VHL-affected parent and a normal (wild-type) gene from the non-affected parent. Tumorigenesis occurs when the wild-type VHL allele is inactivated (loss of heterozygosity) in certain susceptible target organs that include the viscera (kidneys, pancreas, adrenal glands, and adnexal organs), as well as the CNS (7).

The VHL gene encodes VHL protein (pVHL), a protein that is part of the E3 ubiquitin ligase, which is involved in proteasomal degradation. It targets hypoxia inducible factor (HIF)-1/2α (10) transcription factors that are activated in hypoxic conditions to upregulate genes, including vascular endothelial growth factor (VEGF), transcription growth factor (TGF), erythropoietin (EPO), EPO receptor, transferrin, and angiopoietin (11). These factors are involved in angiogenesis, erythropoiesis, cell proliferation, and/or tumorigenesis/metastasis. HIF-2α is a known oncogene that contributes to cell proliferation and tumorigenesis (11). pVHL participates in degradation of HIF-1/2-α by binding the transcription factors to the proteasome complex (Figure 2). When the VHL gene is mutated and its function is reduced/lost, HIF-1/2α is upregulated (even in the absence of hypoxic conditions) due to its reduced degradation by the VHL ubiquitin–proteasome complex (7).

Multiple VHL germline mutations have been discovered, ranging from deletions to missense mutations. Germline VHL missense mutations are the most common and underlie 60–70% of all VHL-associated mutations (4). Recent studies have shown that the proteins translated from the missense mutated VHL gene are highly unstable and rapidly degraded (10), but retain the functional capacity of wild-type protein. Consequently, treatment strategies that extend the half-life of pVHL in this circumstance could lead to normalization (reversal) of VHL-related pathobiologic features.

Endolymphatic sac tumors are vascular, low-grade papillary adenocarcinomas affecting up to 11% of VHL patients. Mean age of diagnosis is 22 years, and bilateral ELSTs are found in approximately 30% of patients with VHL (17). The majority of the patients had associated audiovestibular symptoms, including sensorineural hearing loss (84% of ears), tinnitus (73%), and vertigo (68%) that did not correlate with tumor size (18). The audiovestibular findings associated with ELSTs are thought to be due to intralabyrinthine hemorrhage, endolymphatic hydrops, and/or direct invasion of the otic capsule by tumor (19). Sudden hearing loss (43%) has been correlated with intralabyrinthine hemorrhage. Gradual hearing loss (47%) is most often related to endolymphatic hydrops.

Regular screening of VHL patients for ELSTs is recommended, with surgical intervention in selected patients before morbidity develops. Surgery is curative for completely excised tumors. Kim and colleagues found that hearing was stabilized postoperatively in 90% of patients after ELST resection (18). Current indications for ELST resection in VHL patients include imaging evidence of an ELST with serviceable hearing (and/or audiovestibular signs/symptoms), evidence of ELST-associated intralabyrinthine hemorrhage, ELST-associated hydrops, or mass effect by the ELST (19, 20). Contrast-enhanced delayed FLAIR MRI has been found to be an efficacious, non-invasive method of detecting ELST-associated hydrops (21). The role of adjuvant therapy, including chemotherapy, fractionated radiotherapy, or stereotactic radiosurgery, is not established.

Recent investigations into the pathogenesis of VHL tumors have revealed new potential targets for treatment. Metelo and colleagues (22) studied VHL models in zebrafish using vhl^−/− embryos. Treatment with HIF-2α inhibitors decreased expression of HIF-2α targeted genes. The effect was dose dependent in these studies. It improved new angiogenic sprouting that was seen in vhl^−/− embryos and returned abnormal cardiac function to baseline, suggesting that HIF-2α could lead to potential targeted treatments for systemic VHL tumors.

The most frequent mutations in VHL are missense mutations. VHL patients that harbor a missense germline mutation have a quantitative reduction of missense mutant VHL protein (pVHL), but still maintain physiologic pVHL mRNA expression. Recent data indicate that mutant pVHL is highly unstable and is quickly degraded after translation. Interestingly, missense mutant pVHL retains its E3 ligase function, including HIF degradation. The premature pVHL degradation is due to misfolding and imbalance of chaperonin binding (23).

Histone deacetylase inhibitors (HDACis) can modulate the pVHL degradation pathway by inhibiting the HDAC6–Hsp90 chaperone axis, stabilizing pVHL, and restoring activity comparable to wild-type protein in vitro and in mouse VHL models. HDACi-mediated stabilization of missense pVHL significantly attenuates the growth of mouse VHL tumors (23). These findings provide direct insight into the pathobiology of VHL-associated tumors and elucidate a new treatment paradigm for personalized therapy in those individuals with missense VHL mutations.

von Hippel–Lindau disease is a complex and progressive process involving multisystem tumor formation. Individuals afflicted with VHL disease require a personalized approach for therapy, as tumors are neither uniform in their locations nor identical in their symptomatology. Currently, successful systemic treatments are lacking. The first choice of therapy for hemangioblastomas and ELSTs is surgery, and the decision to proceed with surgery is personalized to the individual. Surgery is reserved for hemangioblastomas based on symptom development and progression in tumor or cyst size. Surgery for ELSTs can also be based upon symptomatology, but indications also include radiographic findings of ELSTs and serviceable hearing. Care is taken to tailor the exact treatment to each individual patient and their tumor burden.

Recent studies revealed missense mutations in the VHL gene actually allow for transcription of the protein, albeit an unstable one that is rapidly degraded due to misfolding and chaperonin binding. The protein is then unable to function and degrade its target, HIF-2α as part of the proteasome. HDACis interfere with chaperonin pathways and, in result, stabilize the protein and allow return to function in vitro and in VHL mouse models. This offers a unique opportunity for a new treatment modality that in theory would be able to treat the underlying mechanism of tumorigenesis and affect the whole body, multiple systems, and possibly all of the differing tumor types in the body.

Further investigation and Phase I clinical trials would need to be conducted to assess the feasibility of developing HDACis as possible treatments. Currently, vorinostat, an HDACi, is undergoing Phase I trials for VHL patients with hemangioblastomas and missense mutations, trial #NCT02108002. With the potential of new therapies on the horizon, this could permit further treatment of the complex manifestations of VHL disease tailored to the individuals with this most common VHL germline mutation.

von Hippel–Lindau disease is a complex disorder, and patients develop a wide constellation of symptoms related to the varying locations and types of tumors present. Currently, therapies are tailored toward the individual tumors and patient findings. Discovery of pVHL stabilization with use of HDACis in missense mutated pVHL provides a potential for new treatment directed toward the underlying mechanisms of tumorigenesis that could further tailor therapy toward the individual with VHL and offer a uniform treatment for various tumors associated with the disease.

All three authors participated in the research, composition, drafting, and editing of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.