Hereditary hemochromatosis causes iron overload and is associated with a variety 
of genetic and phenotypic conditions. Early diagnosis is important so that 
effective treatment can be administered and the risk of tissue damage avoided. 
Most patients are homozygous for the c.845G>A (p.C282Y) mutation in the HFE 
gene; however, rare forms of genetic iron overload must be diagnosed using a 
specific genetic analysis. We studied the genotype of 5 patients who had 
hyperferritinemia and an iron overload phenotype, but not classic mutations in 
the HFE gene. Two patients were undergoing phlebotomy and had no iron overload, 
1 with metabolic syndrome and no phlebotomy had mild iron overload, and 2 
patients had severe iron overload despite phlebotomy. The patients' first-degree 
relatives also underwent the analysis. We found 5 not previously published 
mutations: c.-408_-406delCAA in HFE, c.1118G>A (p.G373D), c.1473G>A (p.E491E) 
and c.2085G>C (p.S695S) in TFR2; and c.-428_-427GG>TT in SLC40A1. Moreover, we 
found 3 previously published mutations: c.221C>T (p.R71X) in HFE; c.1127C>A 
(p.A376D) in TFR2; and c.539T>C (p.I180T) in SLC40A1. Four patients were double 
heterozygous or compound heterozygous for the mutations mentioned above, and the 
patient with metabolic syndrome was heterozygous for a mutation in the TFR2 
gene. Our findings show that hereditary hemochromatosis is clinically and 
genetically heterogeneous and that acquired factors may modify or determine the 
phenotype.