Clinical penetrance: Clinicians do not encounter many cases of full-blown hemochromatosis. Our at tempts to obtain samples from patients with iron overload who manifested diabetes, cirrhosis, cardiomyopathy, and darkening of the skin from our own clinic and from major centers in which many patients with hemochromatosis are treated have met with very little success.
Most of the many patients that have been diagnosed as having hemochromatosis have been diagnosed on the basis of biochemical changes and non-specific systems, such as fatigue and arthropathy. Neither common clinical experience²¹̛ ²² nor autopsy series²¹ ̛ ²³ ⁻²⁵ suggest that hemochromatosis is a common cause of death. However, it has been a common belief that milder symptoms are, in contrast, very common in patients homozygous for the C282Y mutation, and it has been suggested that most of the homozygous males will develop symptoms by the time they are 40 year of age.²⁶ This impression that a mild phenotype exists (and the accompanying assumption that these leads to the more severe phenotype if not treated)has been based largely on uncontrolled observations in which the patients being assessed and the physician performing the assessment knew the diagnosis and could well have been influenced by it.