Hemochromatosis type 3 was the first non-HFE form of hemochromatosis for which a molecular diagnosis was made. As HFE hemochromatosis had already been described and the elucidation of juvenile hemochromatosis was well under way the disorder was described as the third type of hemochromatosis identified or hemochromatosis type 3. It is an autosomal recessive disorder and two abnormal copies of the mutation are required to produce the disorder. In 2000 the transferrin receptor 2 (TfR2) gene on chromosome 7q22 was identified as the cause. Transferrin receptor 2 is similar to transferrin receptor 1 which is the predominant form of transferrin receptor, but the two receptors function differently in body tissues. Comparison of the two forms of transferrin receptor helped elucidate TfR2 hemochromatosis.
The first paper describing TfR2 hemochromatosis identified two copies of the Y250X nonsense mutation in six patients from two unrelated Sicilian families. Further mutations have since been identified. Most of the patients who have been identified are Italians. However cases have been reported in French and Japanese patients. Hemochromatosis type 3 is considered a rare disorder. Less than 30 cases were reported up to 2004. The description of Japanese patients is important as hemochromatosis of any form is an unusual disorder in Asians. This is in contrast to hemochromatosis which is described as a common disorder of Caucasians.
How TfR2 fits into iron metabolism has yet to be clearly defined. There is evidence that TfR2 acts as a liver sensor for circulating iron. It may have a significant role in HAMP expression. HAMP has a limited role in the liver while TfR2 appears to have an important role. HAMP mutations may cause juvenile hemochromatosis. This close linking of HAMP and TfR2 may in part explain why TfR2 hemochromatosis is more severe than hemochromatosis type 1.
The cases described so far suggest that TfR2 hemochromatosis or hemochromatosis type 3 is intermediate in severity between hemochromatosis type 1 or HFE related hemochromatosis and hemochromatosis type 2 or juvenile hemochromatosis. The onset of TfR2 hemochromatosis is more rapid than HFE related hemochromatosis. Age at diagnosis of hemochromatosis type 3 is significantly lower than for hemochromatosis type 1. Cases are frequently detected before the age of 30 years. There is a more equal sex ratio in cases of hemochromatosis type 3 than hemochromatosis type 1. Enough cases have probably not been described to decide if the sex ratio is equal in hemochromatosis type 3. While not as severe as juvenile hemochromatosis, hemochromatosis type 3 may present with hypogonadism. Other presentations recorded have been arthralgia, skin pigmentation, diabetes, heart failure and cirrhosis.
Despite the description of young patients with TfR2 hemochromatosis the disorder is different and distinct from juvenile hemochromatosis. The level of iron loading is not as high and the disorder is not as rapidly progressive as juvenile hemochromatosis.
There is a description of an Italian brother and sister with compound heterozygosity for C282Y/H63D and two copies of the TfR2 mutation Q137X. These siblings presented with a disorder similar to juvenile hemochromatosis.