Dermatology

Von Hippel-Lindau syndrome (retinocerebral angiomatosis)

Von Hippel-Lindau syndrome (retinocerebral angiomatosis) ICD-9 759.6

Are You Confident of the Diagnosis?

What you should be alert for in the history

Von Hippel-Lindau syndrome (VHLS) is a genetic disorder with autosomal dominant inheritance. Symptoms usually begin in childhood or early adolescence and there is usually a family history.

Mutations in the Von Hippel-Lindau (VHL) gene (3p25) impart increased susceptibility to a variety of tumors, benign and malignant. CNS hemangioblastomas are the most common lesions, with symptoms including headache, numbness, dizziness, pain, weakness, ataxia and incontinence.

Retinal hemangiomas cause a painless loss of visual acuity/field and sudden visual loss/changes with hemorrhage. Other tumors include: renal cell carcinomas, renal cysts, pheochromocytomas (symptoms include headache and sweating), pancreatic islet cell tumors (which are usually asymptomatic with abdominal pain, diarrhea, hypoglycemic symptoms) and endolymphatic sac tumors (symptoms include hearing loss (permanent), tinnitus, vertigo, ear fullness, facial weakness).

There are two major subtypes:

  • VHL Type 1 - low pheochromocytoma risk; due to whole or partial gene deletion of nonsense mutation

  • VHL Type 2 - high pheochromocytoma risk; due to missense mutation

Characteristic findings on physical examination

Patients have a normal general appearance. Clinical findings will depend on the location of the various tumors. CNS hemangioblastomas most frequently occur in the cerebellum and spinal cord and cause numbness, weakness, sensory deficits, ataxia, dysmetria and nystagmus.

Retinal hemangiomas can be identified by a vascular retinal mass on fundoscopic or slit lamp examination. Renal cell carcinomas and renal cysts are rarely detectable on physical examination unless the lesion is of considerable size. 30% of patients with pheochromocytomas can be asymptomatic. Patients present with hypertension and tachycardia. Pancreatic islet cell tumors are rarely detectable on physical examination although there is possible vital sign instability with hypoglycemia. Endolymphatic sac tumors can be identified by decreased hearing and facial paresis.

Expected results of diagnostic studies

There is usually a family history of VHLS. Genetic screening can be used to identify mutations in the VHL gene, but up to 20% of patients with clinical VHLS will have non-detectable mutations. Laboratory findings show positive for urinary metanephrines, elevated pancreatic enzymes and hypoglycemia. MRI is the imaging modality of choice for the various tumors/cysts.

Diagnosis confirmation

VHLS needs to be differentiated from:

  • Multiple endocrine neoplasia syndromes (MEN) - distinct tumor pattern; lack of VHL mutation

  • Tuberous sclerosis - mental retardation and skin angiofibromas are usually present; different tumor profile; lack of VHL mutation

  • Neurofibromatosis - CN 8 nerve sheath tumor instead of endolymphatic sac tumor; lack of VHL mutation

  • Pheochromocytoma - more narrow tumor scope; lack of VHL mutation

  • Polycystic kidney disease - lack of various tumors; lack of VHL mutation

Who is at Risk for Developing this Disease?

There is autosomal dominant mutation in the VHL gene. 20% of cases arise de novo. The disease affects 1 in 36,000 live births.

What is the Cause of the Disease?

Etiology

VHLS is caused by loss of function mutations in the VHL gene.

Pathophysiology

The VHL protein (pVHL) is involved in a variety of cellular functions including:

  • Cell cycle control: Lack of pVHL leaves Cyclin D1 unbound and free to act to promote proliferation.

  • Polyubiquitination: Lack of this cellular process allows for the accumulation of proteins that would otherwise be degraded.

  • Regulation of hypoxia-inducible factors (HIFs): Lack of pVHL results in accumulations of HIFs that then activate various pro-survival mechanisms including angiogenesis.

  • Regulation of hypoxia-inducible genes: Lack of pVHL results in activation of genes associated with hypoxia (VEGF, PDGF, EPO) that then activate various pro-survival mechanisms including angiogenesis and increased red blood cell production.

  • Interaction with the extracellular matrix: Lack of pVHL results in loss of extracellular adhesion and communication with subsequent loss of differentiation in favor of proliferation.

Systemic Implications and Complications

With CNS hemangioblastomas, there is a risk for potential intracranial hemorrhage and increased intracranial pressures. Poor motor control can lead to falls. Retinal hemangiomas can cause a risk of hemorrhage, acute glaucoma, and sudden vision loss. Renal cell carcinomas and renal cysts can cause a risk of progressive renal failure and tumor metastasis.

With pheochromocytomas there is a risk for hypertensive crisis. With pancreatic islet cell tumors there is a risk for significant hypoglycemia, dehydration from persistent diarrhea and tumor metastasis. Endolymphatic sac tumors bring the risk of permanent hearing loss and increased fall risk due to dysequilibrium.

There are also implications for life decisions concerning childbearing.

Treatment Options

A multidisciplinary approach is key, including offering genetic counseling to patients. Surveillance for the various tumor types with the relevant laboratory work-up and imaging is necessary.

The following treatment options are particular to the tumor:

  • CNS hemangioblastomas

  • Monitoring for signs of increased intracranial pressure

  • Management of neurologic symptoms (weakness, falls, etc.)

  • Surgical resection

Retinal hemangiomas

  • Monitoring for signs of hemorrhage, acute glaucoma, and sudden visual changes

  • Laser photocoagulation or cryotherapy for peripheral retinal lesions

Renal cell carcinomas and renal cysts

  • Medical management of renal insufficiency

  • Possible role for anti-VEGF therapies (currently under investigation, e.g. bevacizumab)

  • Surgical resection with partial nephrectomy

Pheochromocytomas

  • Medical management of hypertension

  • Surgical resection

Pancreatic islet cell tumors

  • Medical management of hypoglycemia, GI symptoms, pain

  • Surgical resection

  • Monitoring for evidence of recurrence

Endolymphatic sac tumors

  • Medical management of hearing loss, vertigo

  • Surgical resection

Optimal Therapeutic Approach for this Disease

A multidisciplinary approach is key, especially including genetic counseling. Patients need to be monitored for signs of worsening CNS/sensory symptoms and evidence of tumor recurrence, etc. Medical management of associated signs/symptoms is required with surgical interventions when indicated.

Patient Management

A multidisciplinary approach is key, especially including genetic counseling. Patients need to be monitored for signs of worsening CNS/sensory symptoms and evidence of tumor recurrence, etc. Medical management of associated signs/symptoms is required with surgical interventions when indicated.

Unusual Clinical Scenarios to Consider in Patient Management

Endolymphatic sac papillary carcinoma is a rare malignancy associated with VHLS.

What is the Evidence?

Barontini, M, Dahia, PL. "VHL disease". Best Pract Res Clin Endocrinol Metab. vol. 24. 2010. pp. 401-13.

(An excellent and up-to-date review of VHL focusing on the basic science aspects of the disease and how new insights can translate into clinical interventions.)

Defendi, GL. "von Hippel-Lindau disease".

(A basic review on the clinical features and management of VHL.)
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