This article reviews the diverse systemic manifestations of von Hippel-Lindau disease and discusses the historical context of the disease as well as current methods employed in the diagnosis and treatment of the disorder. Classic physical and radiographic manifestations are illustrated in a clinical vignette. New recommendations for the management of pancreatic lesions and for pheochromocytoma surveillance are reviewed.
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• Von Hippel-Lindau disease is an autosomal dominant hereditary multisystem tumor syndrome with marked intra-and interfamilial variability.
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• The tumors are highly vascular and mostly consist of hemangioblastomas of the CNS and retina, renal cell carcinoma, endolymphatic sac tumor of inner ear, and adrenal pheochromocytoma.
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• There is correlation between the type of gene mutation and its phenotypic expression, particularly for pheochromocytoma and renal cell carcinoma.
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• Molecular diagnostic testing for the von Hippel-Lindau gene (VHL gene) is available and can be performed on asymptomatic high-risk individuals and in high-risk pregnancies in the early prenatal period.
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• Management mainly consists of excision of malignant lesions (eg, renal tumors) and surgical removal or ablation of symptomatic benign lesions (eg, hemangioblastomas), which are followed closely for possible recurrence or development of new lesions.
Historical note and terminology
Collins was the first investigator to recognize the inherited nature of what was called “retinal angiomatosis,” which we now call retinal hemangioblastoma (09). Von Hippel was the first to document the progressive nature of the retinal lesions (65).
The history of hemangioblastoma of the cerebellum was initiated by Hughlings Jackson (24). Several authors subsequently noted an association between cerebellar cysts and small cysts of the pancreas and kidneys (53; 66). These associated lesions later became known as the von Hippel-Lindau complex.
Tresling described the first family with an association between retinal and cerebellar tumors (63). Lindau combined, as a single entity, the clinical-pathological hemangioblastic alterations of the retina, cerebellum, spinal cord, and lesions of the pancreas, kidneys, adrenal medulla, liver, and epididymis (32). The term "von Hippel-Lindau disease" was first used in 1936 (13) and has been in common use since the 1970s (36). Melmon and Rosen reviewed the literature on the disease and suggested the clinical diagnostic criteria (41). In 1988, Seizinger and colleagues demonstrated the responsible gene at short arm of chromosome 3 (58). Latif and colleagues showed that the abnormal gene of von Hippel-Lindau disease behaves as a tumor suppressor gene (31). These molecular genetic findings established the definitive criteria for the disease to confirm the diagnostic viability of the clinical criteria (62).