Von Hippel-Lindau disease

Jennifer Baccon MD PhD (Dr. Baccon of Penn State University has no relevant financial relationships to disclose.)
Javad Towfighi MD (Dr. Towfighi of Penn State University has no relevant financial relationships to disclose.)
Harvey B Sarnat MD FRCPC MS, editor. (Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.)
Originally released February 28, 1996; last updated July 24, 2016; expires July 24, 2019

This article includes discussion of von Hippel-Lindau disease, VHL disease, and von Hippel-Lindau syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

The authors review the diverse systemic manifestations of von Hippel-Lindau disease. They provide historical context as well as current methods employed in the diagnosis and treatment of this disorder. Classic physical and radiographic manifestations are illustrated in a clinical vignette. There is special focus on the current debate about whether pregnancy alters hemangioblastoma progression. New recommendations for management of pancreatic lesions and for pheochromocytoma surveillance are reviewed.

Key points

 

• Von Hippel-Lindau disease is an autosomal dominant hereditary multisystem tumor syndrome with marked intra-and interfamilial variability.

 

• 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.

 

• There is correlation between the type of gene mutation and its phenotypic expression, particularly for pheochromocytoma and renal cell carcinoma.

 

• 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.

 

• 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

Panas and Remy were first to describe retinal hemangioblastoma, using the descriptive term “retinal angiomatosis” (Panas and Remy 1879). Other investigators interpreted the retinal lesions as vascular malformations, including Collins, who was the first to recognize the inherited nature of this disorder (Collins 1894). Von Hippel was the first to document the progressive nature of the retinal lesions (von Hippel 1904).

The history of hemangioblastoma of the cerebellum was initiated by Hughlings Jackson in 1872 (Jackson 1872). Several authors subsequently noted an association between cerebellar cysts and small cysts of the pancreas and kidneys (Pye-Smith 1885; von Hippel 1911). 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 (Tresling 1920). 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 (Lindau 1926). The term "von Hippel-Lindau disease" was first used in 1936 (Davison 1936) and has been in common use since the 1970s (Maher et al 2011). Melmon and Rosen reviewed the literature on the disease and suggested the clinical diagnostic criteria (Melmon and Rosen 1964). Möller described the heredity of the disease as an autosomal dominant trait (Möller 1929). In 1988, Seizinger and colleagues demonstrated the responsible gene at short arm of chromosome 3 (Seizinger et al 1988). Latif and colleagues showed that the abnormal gene of von Hippel-Lindau disease behaves as a tumor suppressor gene (Latif et al 1993). These molecular genetic findings established the definitive criteria for the disease to confirm the diagnostic viability of the clinical criteria (Stolle et al 1998).

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