Von Hippel–Lindau Disease

Overview

Von Hippel–Lindau (VHL) disease is a rare, inherited multisystem disorder characterized by the development of both benign and malignant tumors and cysts in various organs. It most commonly affects the brain, spinal cord, eyes, kidneys, adrenal glands, pancreas, and inner ear. VHL is caused by mutations in the VHL tumor suppressor gene and follows an autosomal dominant inheritance pattern. If left untreated, VHL-associated tumors can cause serious complications, including neurological damage and cancer, particularly clear cell renal cell carcinoma (ccRCC).

Causes

VHL disease is caused by mutations in the VHL gene, located on chromosome 3p25-26. This gene produces a protein involved in regulating cell growth and controlling responses to hypoxia (low oxygen levels). When the gene is mutated, abnormal cell growth occurs, leading to tumor development. Key causes and risk factors include:

• Inherited mutations: In about 80% of cases, the mutation is inherited from a parent

• De novo mutations: In approximately 20% of cases, the mutation occurs spontaneously without family history

• Autosomal dominant inheritance: Each child of an affected parent has a 50% chance of inheriting the mutation

Symptoms

Symptoms of VHL vary widely depending on the location and type of tumor or cyst. Common manifestations include:

• CNS hemangioblastomas: Benign vascular tumors in the brain or spinal cord causing headaches, balance issues, or weakness

• Retinal hemangioblastomas: Tumors in the eye that may lead to vision loss if untreated

• Renal cell carcinoma: Often bilateral and multifocal, potentially leading to kidney failure or metastasis

• Pheochromocytomas: Tumors of the adrenal glands that cause hypertension, palpitations, and sweating

• Pancreatic cysts and neuroendocrine tumors: Often asymptomatic but may cause abdominal discomfort or become malignant

• Endolymphatic sac tumors: Affect the inner ear, leading to hearing loss and balance issues

• Epididymal or broad ligament cystadenomas: Typically benign and asymptomatic

Diagnosis

Diagnosis of VHL disease involves clinical evaluation, imaging studies, and genetic testing. The key steps include:

• Family and medical history: Assessing for characteristic tumors or a known VHL mutation

• MRI or CT scans: Imaging of the brain, spine, kidneys, pancreas, and adrenal glands to detect tumors or cysts

• Ophthalmologic examination: To identify retinal hemangioblastomas

• Biochemical tests: For catecholamines and metanephrines to detect pheochromocytomas

• Genetic testing: Confirmation of VHL gene mutation, which is essential for diagnosis and family screening

Treatment

There is no cure for VHL, but treatment focuses on early detection and surgical management of tumors to prevent complications. Management strategies include:

• Regular surveillance: Lifelong monitoring with periodic imaging and blood tests to detect tumors early

• Surgical removal: Indicated for symptomatic CNS hemangioblastomas, renal tumors >3 cm, and adrenal pheochromocytomas

• Laser photocoagulation or cryotherapy: For retinal hemangioblastomas

• Targeted therapy: Agents like tyrosine kinase inhibitors (e.g., sunitinib, pazopanib) for advanced renal cell carcinoma

• Radiotherapy or stereotactic radiosurgery: In select cases where surgery is not feasible

• Genetic counseling: For patients and family members to guide testing and reproductive planning

Prognosis

The prognosis of VHL depends on the type and location of the tumors, as well as how early they are detected and managed. With regular surveillance and timely intervention, many individuals with VHL can maintain a good quality of life and normal lifespan. However, untreated or aggressive tumors, especially renal cell carcinoma and CNS hemangioblastomas, can lead to significant morbidity and mortality. Early genetic diagnosis and coordinated care from a multidisciplinary team are critical for improving outcomes in VHL patients.