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Von Hippel-Lindau disease

Von Hippel-Lindau disease (VHL) is a rare inherited genetic condition involving the abnormal growth of tumors in parts of the body which are particularly rich in blood supply. more...

VACTERL association
Van der Woude syndrome
Van Goethem syndrome
Varicella Zoster
Variegate porphyria
Vasovagal syncope
VATER association
Velocardiofacial syndrome
Ventricular septal defect
Viral hemorrhagic fever
Vitamin B12 Deficiency
VLCAD deficiency
Von Gierke disease
Von Hippel-Lindau disease
Von Recklinghausen disease
Von Willebrand disease


Features of VHL are:

  • angiomatosis - little knots of capillaries in various organs. These tend to be cavernous hemangiomas, which are sharply defined, sponge-like tumors composed of large, dilated, cavernous vascular spaces.
  • hemangioblastomas - tumors of the central nervous system (CNS, especially the cerebellum). These tumors, whether benign (usual) or malignant (rarer), may cause problems, for example angiomas in the brain or spinal cord may press on nerve or brain tissue. As an angioma grows, the walls of the blood vessels may weaken and leak, causing damage to surrounding tissues. Blood leakage from angiomas in the retina can interfere with vision. Cysts may also grow around angiomas.
  • pheochromocytoma - tumors of the adrenal medulla that often produce catecholamines
  • renal cell carcinoma - in some forms

Untreated, VHL may result in blindness and permanent brain damage, death is usually caused by complications of malignant tumors in the brain or kidney.


There are various subtypes (see OMIM):

  • Type 1 (angiomatosis without pheochromocytoma)
  • Type 2 (angiomatosis with pheochromocytoma)
    • Type 2A (with renal cell carcinoma)
    • Type 2B (without renal cell carcinoma)
    • Type 2C (only pheochromocytoma and no angiomatosis or renal cell carcinoma)


The disease is caused by mutations of the VHL gene on the short arm of the third chromosome (3p26-p25). The resultant protein is produced in two forms, an 18 kDa and a 30 kDa protein that functions as a tumor suppressor gene. The main action of the VHL protein is thought to be its E3 ubiquitin ligase activity that results in specific target proteins being 'marked' for degradation. The most researched of these targets is hypoxia inducible factor 1a (HIF1a), a transcription factor that induces the expression of a number of angiogenesis related factors. It stands to reason that the loss of VHL protein activity results in an increased amount of HIF1a, and thus increased levels of angiongenic factors. In turn, this leads to unregulated blood vessel growth, one of the prerequesites of a tumour.

VHL is an autosomal dominant disorder, but there is a wide variation in the age of onset of the disease, the organ system affected and the severity of effect. Most people with von Hippel-Lindau syndrome inherit an altered copy of the gene from one parent. In about 20 percent of cases, however, the altered gene is the result of a new mutation that occurred during the formation of reproductive cells (eggs or sperm) or early in fetal development.

As long as one copy of the VHL gene is producing functional VHL protein in each cell, tumors do not form. If a mutation occurs in the second copy of the VHL gene during a person's lifetime, the cell will have no working copies of the gene and will produce no functional VHL protein. A lack of this protein allows tumors characteristic of von Hippel-Lindau syndrome to develop.


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Obstructing lesions of the endolymphatic sac and duct mimicking Meniere's disease
From Ear, Nose & Throat Journal, 11/1/04 by Ryan C. Cmejrek


In this retrospective case series and literature review, we demonstrate that temporal bone lesions that obstruct the endolymphatic sac or duct can cause symptoms of Meniere's disease. This finding is likely attributable to endolymphatic hydrops; initially, such cases typically masquerade as Meniere's disease. Between July 1995 and April 2002, a total of 379 patients were treated for an initial diagnosis of Meniere's disease at our institution. Among this group, 3 patients were found to have an obstructing lesion of the endolymphatic sac or duct that we felt was causally related to their Meniere's-like symptomatology. We reviewed these cases and noted the similarities in each patient's presentation, including a common pathophysiology. On imaging studies, each patient had a different pathologic lesion that involved the endolymphatic sac or duct: patient 1 had a jugular megabulb, and she was ultimately treated with vestibular nerve section; patient 2 had a cholesterol granuloma, which was treated with surgical excision; patient 3 had an endolymphatic sac tumor that was treated with surgical excision. As has been suggested in previous reports, not all cases of Meniere's disease are idiopathic. We conclude that obstruction of the endolymphatic sac or vestibular aqueduct by a mass lesion or vascular anomaly can lead to vestibulocochlear pathology that mimics Meniere's disease.


Meniere's disease is defined as the idiopathic syndrome of endolymphatic hydrops that results in hearing loss, tinnitus, and episodic vertigo, and aural fullness. (1) However, there is continuing controversy in the literature regarding the underlying pathophysiology of Meniere's disease, and most authors agree that not all cases are idiopathic. Recent reports have suggested many possible etiologies, including autoimmune disease, (2) viral infection, (3) allergy, (4) and otosclerosis. (5) In any event, impaired absorption or overproduction of endolymph is presumed to cause endolymphatic hydrops and associated Meniere's symptomatology. Similarly, vascular compression of the endolymphatic sac and duct has been shown to be associated with Meniere's symptomatology in the presence of anatomic variants such as jugular megabulb (6) and an anomalous vein of the vestibular aqueduct. (7)

Between July 1995 and April 2002, a total of 379 patients had been seen in the otology--neurotology clinic with a diagnosis of Meniere's disease. In addition to the typical medical and audiologic workup that was administered to all patients, those with unilateral hearing loss underwent imaging studies in order to rule out retrocochlear disease.

In this article, we describe the cases of 3 patients who initially presented with fluctuating sensorineural hearing loss, tinnitus, episodic vertigo, and aural fullness and who were initially diagnosed with Meniere's disease. Further evaluation and diagnostic imaging revealed that each had a mass lesion of the temporal bone that had obstructed the endolymphatic system. Patients 1 and 2 exhibited compression and erosion of the endolymphatic sac and duct by a jugular megabulb and a cholesterol granuloma, respectively. Patient 3 had two endolymphatic sac tumors that led to an internal obstruction of the sac bilaterally.

We propose that any abnormal space-occupying lesion of the temporal bone has the potential to cause endolymphatic hydrops by obstructing the endolymphatic duct or sac.

Case reports

Patient 1. A 35-year-old woman presented with a 9-year history of Meniere's disease; she had a right-sided sensorineural hearing loss that had been sudden in onset and slowly progressive over the years. The hearing loss was accompanied by fluctuating nonpulsatile tinnitus, episodes of vertigo that initially occurred a few times monthly, and aural fullness. Her symptoms had begun during a pregnancy, and they were presumed to be of viral etiology. She had sought intervention when her episodes of vertigo began to occur almost daily. An audiogram showed essentially normal hearing in the left ear and a sloping mild-to-profound sensorineural hearing loss in the right ear (figure 1, A). Her speech discrimination score on the right was 0%. Magnetic resonance imaging (MRI) was negative for retrocochlear pathology.


After 3 years of conservative medical therapy (a low-salt diet and a diuretic), the patient returned with worsening vertigo and drop attacks. Findings on electronystagmography were normal. However, computed tomography (CT) of the temporal bones detected an enlargement of the right jugular bulb with encroachment on the endolymphatic sac and duct (figure 1, B). The patient underwent an endolymphatic shunt procedure, but her vertigo actually worsened and was unresponsive to gentamicin therapy delivered to the middle ear. Labyrinthectomy was recommended, but the patient was hesitant to sacrifice the slight degree of auditory perception that remained in her right ear. Instead, she underwent a middle fossa vestibular nerve section. At the 4-year follow-up, she remained free of disabling vertigo.

Patient 2. A 45-year-old woman presented with a diagnosis of Meniere's disease and a long history of fluctuating hearing loss and tinnitus on the left. She reported a 7-year history of episodic vertigo that had worsened over the preceding 3 years; she also complained that sound was distorted. She sought an otologic evaluation when she began to experience an increasing feeling of pressure and pain deep in her left ear.

An audiogram revealed a mild high-frequency sensorineural hearing loss on the right and a mild-to-moderate low-frequency sensorineural hearing loss on the left (figure 2, A). MRI detected a complex mass on the left petrous bone that extended to the posterior fossa and obstructed the endolymphatic sac (figure 2, B). A slight dural erosion was noted, but the internal auditory canal and cochlea were not involved. Electrocochleography revealed a summating-potential to action-potential (SWAP) ratio of 0.56 on the left and 0.15 on the right, findings that are consistent with endolymphatic hydrops of the left ear.


The patient underwent a transtemporal resection of the lesion and dural reconstruction. The mass was not only locally invasive, it had invaded the endolymphatic sac and duct, as well. Final pathology was consistent with a cholesterol granuloma. Postoperatively, the patient's hearing declined slightly, but her vertigo had completely resolved.

Patient 3. A 37-year-old woman with von Hippel-Lindau disease presented with a diagnosis of Meniere's disease that manifested as hearing loss and tinnitus on the left over several years and a recent increase in the frequency of vertigo attacks to one a day. These symptoms had been unresponsive to diet, diuretics, and other medications. The patient had no other medical problems related to her von Hippel-Lindau disease, and she was taking no medications. Findings on physical examination were significant only for a Weber test that lateralized to the right ear at 512 Hz. An audiogram showed an upsloping sensorineural hearing loss in the left ear (figure 3, A). Her speech discrimination score on the left was 72%. MRI detected a left temporal bone lesion posterior to the posterior semicircular canal and a similar, smaller lesion on the right (figure 3, B). (8)


The patient underwent a left mastoidectomy and exploration of the left endolymphatic sac with tumor resection and preservation of the labyrinth and dura. Final pathology was consistent with an endolymphatic sac tumor (previously known as an aggressive papillary tumor). Postoperatively, her vertigo resolved and her hearing improved. Although electronystagmography 6 months postoperatively showed a residual peripheral deficit on the left, the vertigo remained absent.

Over the course of 3 years, the patient's speech discrimination score fell to 0% in the left ear despite the absence of tumor regrowth on imaging studies. Electrocochleography showed an increase in the SWAP ratio in both ears (right: 0.48; left: 0.53), and she began noticing a fluctuation in the hearing in her right ear and a return of the vertigo. There was also a subtle increase in the size of her right-sided endolymphatic sac tumor. She elected to continue medical management.

A noteworthy aspect of this case is that it was included in an earlier series describing hearing preservation surgery in von Hippel-Lindau disease-related endolymphatic sac tumors. (8) Since that report was written, new electrocochleographic data presented herein further support the hypothesis that the affected ears are indeed hydropic.


The role of endolymphatic hydrops in Meniere's disease has been a topic of much discussion in the otolaryngology literature since it was first described by Hallpike and Cairns in 1938. (9) To date, the most reliable animal model of hydrops has been the guinea pig, the model initially described by Kimura and Schuknecht. (10) However, studies of endolymphatic duct obstruction in primates have not as strongly supported its role as a principal inciting pathologic entity in Meniere's disease in humans. (11,12) The limitations of detecting hydrops in living patients has made it difficult to definitively establish a cause-and-effect relationship between endolymphatic obstruction, Meniere's disease, and its proposed histopathologic correlate, endolymphatic hydrops.

Our findings, combined with those of Jahrsdoerfer et al (6) and Hosseinzadeh et al, (7) support the concept that obstruction of the endolymphatic sac and duct by a number of causes (e.g., a tumor, vascular anomaly, or internal sac disease) can produce symptomatic Meniere's-like disease, likely via the production of endolymphatic hydrops, as has been seen in the guinea pig. (10) This concept is supported by the presence of the electrocochleographic abnormalities in 2 of our patients and the relief of their vertigo symptoms by surgical decompression or VIIIth nerve section.

Our findings and those of temporal bone histologic studies support the concept that even microscopic violation of the endolymphatic duct can potentially incite hydrops. (13,14) Yoon et al were able to show that endolymphatic hydrops and otosclerotic obstruction of the vestibular aqueduct can coexist. (13) Rizvi and Gibbin demonstrated that vestibular aqueduct obstruction secondary to fracture-induced ossification also has the potential to produce hydrops. (14) These findings support the concept that any disturbance of longitudinal outflow of endolymph can lead to the development of endolymphatic hydrops and Meniere's symptomatology.

The cause of idiopathic Meniere's disease in the absence of obvious endolymphatic sac or duct obstruction remains unclear. Data on the underabsorption or overproduction of endolymphatic fluid are still being accumulated. Clinical data presented in our report and others (6,7,10) indicate that sac and duct malfunction by reason of gross obstruction appears to be an important contributing cause of hydrops production in some cases. Hence, the evidence indicates that a variety of lesions that cause obstruction of the endolymphatic sac by external or internal luminal obstruction can lead to clinical Meniere's disease symptomatology.

Our 3 case reports provide further evidence to support the idea that endolymphatic hydrops represents the final common pathway in the production of Meniere's symptomatology. However, they also underscore the fact that Meniere's disease is a diagnosis of exclusion. Careful physical and radiologic assessment of each patient is warranted even when classic Meniere's disease seems to be the most likely diagnosis. Further research into the underlying mechanisms of endolymphatic hydrops will likely lead to refinement of our current understanding of the link between hydrops and Meniere's disease in the coming years.


(1.) Committee on Hearing and Equilibrium guidelines for the diagnosis and evaluation of therapy in Meniere's disease. American Academy of Otolaryngology-Head and Neck Foundation, Inc. Otolaryngol Head Neck Surg 1995;113:181-5.

(2.) Boulassel MR, Tomasi JP, Deggouj N, Gersdorff M. COCH5B2 is a target antigen of anti-inner ear antibodies in autoimmune inner ear diseases. Otol Neurotol 2001;22:614-18.

(3.) Takahash K, Aono T, Shichinohe M, et al. Herpesvirus DNA in peripheral blood mononuclear cells of some patients with Meniere's disease. Microbiol Immunol 2001;45:635-8.

(4.) Noell CA, Roland PS, Mabry RL, Shoup AG. Inhalant allergy and Meniere's disease. Use of electrocochleography and intranasal allergen challenge as investigational tools. Otolaryngol Head Neck Surg 2001;125:346-50.

(5.) Franklin DJ, Pollak A, Fisch U. Meniere's symptoms resulting from bilateral otosclerotic occlusion of the endolymphatic duct: An analysis of a causal relationship between otosclerosis and Meniere's disease. Am J Otol 1990;11:135-40.

(6.) Jahrsdoerfer RA, Cail WS, Cantrell RW. Endolymphatic duct obstruction from a jugular bulb diverticulum. Ann Otol Rhinol Laryngol 1981;90(6 Pt 1):619-23.

(7.) Hosseinzadeh M, Hilinski JM, Turner WJ, Harris JR Meniere disease caused by an anomalous vein of the vestibular aqueduct. Arch Otolaryngol Head Neck Surg 1998;124:695-8.

(8.) Megerian CA, Haynes DS, Poe DS, et al. Hearing preservation surgery for small endolymphatic sac tumors in patients with von Hippel-Lindau syndrome. Otol Neurotol 2002;23:378-87.

(9.) Hallpike CS, Cairns H. Observations on the pathology of Meniere's syndrome. J Laryngol Otol 1938;53:625-55.

(10.)Kimura RS, Schuknecht HF. Membranous hydrops in the inner ear of the guinea pig after obliteration of the endolymphatic sac. Pract Otorhinolaryngol 1965;27:343-54.

(11.) Sub KW, Cody DT. Obliteration of vestibular and cochlear aqueducts in animals. Trans Sect Otolaryngol Am Acad Opthalmol Otolaryngol 1977;84:359-79.

(12.) Swart JG, Schuknecht HF. Long-term effects of destruction of the endolymphatic sac in a primate species. Laryngoscope 1988;98: 1183-9.

(13.) Yoon TH, Paparella MM, Schachern PA. Otosclerosis involving the vestibular aqueduct and Meniere's disease. Otolaryngol Head Neck Surg 1990;103:107-12.

(14.) Rizvi SS, Gibbin KP. Effect of transverse temporal bone fracture on the fluid compartment of the inner ear. Ann Otol Rhinol Laryngol 1979;88(Pt 1):741-8.

From the Department of Otolaryngology--Head and Neck Surgery, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland.

Reprint requests: Cliff A. Megerian, MD, Department of Otolaryngology-Head and Neck Surgery, University Hospitals of Cleveland, 11100 Euclid Ave., Cleveland, OH 44106. Phone: (216) 844-5500; fax: (216) 844-5727; e-mail:

Originally presented at the Middle Section meeting of the Triological Society; Jan. 17-19, 2003; Indianapolis.

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