The HFE Cys282Tyr mutation as a necessary but not sufficient cause of clinical hereditary hemochromatosis.

It is not unusual for a disease to be considered rare when first described and to prove to be much more prevalent as the medical profession becomes aware of its existence. This seemed to be the case with hereditary hemochromatosis. But now the perception that hemochromatosis is a common disease has undergone a sudden reversal. Although everyone does not yet agree, the data that have accumulated in the past year provide compelling evidence that the actual disease, as contrasted with the genotype or biochemical phenotype, is quite rare after all. In this perspective I will review how an exaggerated impression of the clinical penetrance of the Cys282Tyr mutation of HFE developed, consider some of the factors that may be important in determining whether a person with HFE mutations develops the clinical stigmata of hemochromatosis, and suggest what further studies are needed to better understand the low penetrance of the HFE mutations.