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© 2002 Nature Publishing Group The study of human hereditary cancer syndromes, including syndromes that are relatively rare, has often provided important insights into common, non-hered- itary malignancies. Moreover, the genes that are linked to hereditary cancer syndromes are almost invariably important in fundamental cellular processes such as cell division, apoptosis and DNA repair. These princi- ples are illustrated well by recent studies of the von Hippel–Lindau (VHL) hereditary cancer syndrome. The gene ( VHL ) that, when mutated in the germ line, causes this syndrome is also frequently inactivated in clear-cell carcinoma of the kidney, which affects approximately 30,000 people in the United States every year. Moreover, studies of the VHL gene product, pVHL, have helped to elucidate how mammalian cells sense and respond to changes in oxygen availability. Careful clinical observations made almost a century ago, in conjunction with recent advances in molecular biology, have given rise to a more detailed understand- ing of the mammalian oxygen-sensing pathway and the potential role of this pathway in cancer, heart attacks and stroke . Clinical description The first reports of patients who (it is now known) had VHL disease were published in the medical litera- ture approximately 100 years ago. Treacher Collins and, later, Eugene von Hippel described families in which individuals developed angiomas — blood- vessel tumours of the retina 1,2 (FIG. 1a,b). Later, the neuropathologist Arvind Lindau reported that such patients were also at high risk of developing blood- vessel tumours of the brain (especially the cerebel- lum) and spinal cord, known as haemangioblastomas 3 (FIG. 1c). Retinal angiomas are histologically indistin- guishable from haemangioblastomas, and so are also sometimes referred to as haemangioblastomas 4 .The vascular nature of these tumours is easiest to appreci- ate following injection of a contrast agent such as flu- orescein (FIG.1b). A variety of other tumours have been associated with VHL disease, including clear-cell car- cinoma of the kidney (FIG. 1d), PHAEOCHROMOCYTOMA , endolymphatic-sac tumours and islet-cell tumours of the pancreas 5 . In addition, visceral cysts (especially of the pancreas and kidney) are also common. VHL disease affects approximately 1 in 35,000 indi- viduals, and transmission of the disease seems to occur in an autosomal-dominant manner (see below). Symptoms typically develop in the second, third and fourth decades of life. Retinal haemangioblastomas can usually be treated with LASER PHOTOCOAGULATION if detected early, but they can cause significant problems, including RETINAL DETACHMENT and blindness, if they are undiag- nosed or neglected. Lesions involving the optic nerve or MACULA are particularly problematic, as these areas are not amenable to laser or surgical intervention.
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