Von Hippel Lindau Disease
What is Von Hippel Lindau Disease
Von Hippel Lindau disease is an autosomal-dominant disorder with high penetrance, characterized by development of benign and malignant tumors in multiple organ systems, particularly the central nervous system and the kidneys. Its incidence ranges from 1:36,000 to 1:53,000. Von Hippel Lindau disease has been divided into two categories: type 1 is characterized by the absence of pheochromocytomas, and type 2 by the presence of these tumors (7% to 20% of families)
Genetics in Von Hippel Lindau Disease
Von Hippel-Lindau disease is caused by a single gene, a tumor suppressor gene located on the short arm of chromosome 3 (3p25-26). The Von Hippel Lindau protein binds and suppresses the activity of elongin, a protein that activates the transcription of mRNA. Up to one fourth of subjects diagnosed with Von Hippel Lindau disease may not have a family history of the disease. As in TSC, somatic mosaicism has been shown to occur in Von Hippel Lindau disease. Parents of patients without a family history can have a mutation in only some of their cells and tissues with mild or no clinical abnormalities, whereas their offspring may have the mutated gene in all cells because of a germ cell mutation in the parent. As with other tumor suppressor genes, the development of tumors depends on a second, somatic mutation in the homologous VHL allele.
Clinical Features of Von Hippel Lindau Disease
Central nervous system, eyes, kidneys, adrenal glands, pancreas, and epididymis are commonly affected in Von Hippel-Lindau disease. Central nervous system involvement is an important cause of morbidity and mortality in these patients. The typical lesions are hemangioblastomas arising from the cerebellum, the spinal cord, or the brainstem. Supratentorial localization of hemangioblastomas is rare. Although these are benign tumors, they may cause symptoms depending on their size, site, and growth rate. They tend to recur even after radical resection.
Retinal hemangioblastomas develop in more than one half of all the cases. They may be multiple and bilateral. In the early stage, they appear as red dots, resembling microaneurysms of diabetic retinopathy. They may grow and cause blindness owing to retinal detachment and hemorrhage. Therefore, regular ophthalmologic examination is important for the early detection and treatment of these tumors.
The characteristic renal lesions in Von Hippel-Lindau disease are cysts and carcinomas. Renal cysts, which may be multiple and bilateral, are present in 50% to 70% of patients. They may be misdiagnosed as ADPKD. Renal cell carcinoma (RCC) is an important cause of morbidity and mortality, being responsible for up to 50% of the deaths due to VHL disease. The penetrance of RCC is high; it develops in up to 77% of all patients with Von Hippel-Lindau disease by 60 years of age. In contrast to the general population, it occurs at a younger age (mean age, 44 years) and is often multiple and bilateral. Local recurrence after nephron-sparing surgery is common, necessitating repeated surgeries. ESRD eventually develops in approximately 25% of patients because of extensive resections or bilateral nephrectomies and rarely because of polycystic kidney disease.
Pheochromocytomas cluster within certain families ( Von Hippel-Lindau disease type 2). They occur at a younger age than the sporadic cases and may be multiple, bilateral, and extra-adrenal. They may cause intermittent or sustained hypertension or remain quiescent. Patients with Von Hippel-Lindau disease should be screened for pheochromocytomas before renal angiography or any surgical procedure because of the risk of hypertensive crisis.
Pancreatic cysts and serous cyst adenomas are found in approximately 30% of patients with Von Hippel-Lindau disease. Cysts are often multiple and may completely replace the gland. Although cysts are mostly asymptomatic, complications such as biliary obstruction and pain may occur because of their space-occupying effects. Pancreatic islet cell tumors occur rarely, as do adenocarcinomas of the pancreas and Vater's ampulla.
Epididymal lesions are found in 10% to 60% of male patients. These are cystadenomas that may be unilateral or bilateral. Cysts and angiomas may also be detected in the liver, spleen, and lung. Endolymphatic sac tumors may occur in approximately 10% of cases . These tumors are frequently bilateral and may cause hearing loss by local invasion.
Diagnosis of Von Hippel Lindau Disease
In patients with a family history of hemangioblastomas of the retina or the central nervous system, the finding of a single retinal or cerebellar hemangioblastoma or a visceral lesion (i.e., RCC, pancreatic cyst or tumor, pheochromocytoma, papillary cystadenocarcinoma of the epididymis) is sufficient for the diagnosis of Von Hippel-Lindau disease. In patients with no family history, two or more hemangioblastomas or one hemangioblastoma and a visceral lesion are necessary for the diagnosis. Direct mutation analysis of individual patients and families is now possible as well, with a mutation detection rate of 80% to 100% reported.
Von Hippel-Lindau disease should be considered in the differential diagnosis of ADPKD. The diagnosis of ADPKD can be made with the findings of bilateral enlarged kidneys and the positive family history. Among extrarenal findings, hepatic cysts are common and pancreatic cysts are rare in ADPKD. On the other hand, in Von Hippel-Lindau disease, hepatic cysts are rare but pancreatic cysts are common. Von Hippel-Lindau disease should be suspected in a patient who has multiple pancreatic cysts without any hepatic cysts.