The lack of additional mutations in our H63D homozygotes suggests that this genotype could be the primary cause of iron overload in these patients. Despite our results, we cannot entirely discount the possibility that one or more genetic modifier factor exists, simply because we were unable to find it, although there was a precedent in the HFE gene. Genetic modifier factors have been described for C282Y mutations in the HFE gene, but at the present time they have never been reported in H63D homozygotes.
Hb E-Saskatoon [beta22(B4)Glu-->Lys] does not cause any clinical symptoms in the heterozygous state. The homozygous state shows moderate phenotype expression. It has also been detected in association with beta-thalassemia. We present the first case of Hb E-Saskatoon associated with Hb Lepore-Baltimore. This unusual combination of mutations does not aggravate the clinical picture, as only microcytosis and hypochromia have been observed. Hb E-Saskatoon can only be correctly characterized by ion exchange high performance liquid chromatography (HPLC) or by DNA sequencing.
Hereditary hemochromatosis (HH) is an autosomal recessive disease caused by a defective iron absorption. C282Y is the most frequent HFE gene mutation causing HH in Northern European populations and their descendants. However, two other mutations, H63D and S65C, have been described as pathogenic changes. In this study, we have tried to evaluate the frequency of these three mutations in our community. Eighty-three patients with clinical and/or biochemical features of hemochromatosis and 150 controls were screened for H63D, S65C, and C282Y mutations using a PCR-restriction fragment length polymorphism (RFLP)-based strategy. In contrast to previous studies, 7% of the patients were homozygous for C282Y mutation. The remaining patients were 20% H63D homozygous, 10% H63D/C282Y compound heterozygous, 1% H63D/S65C compound heterozygous, 22% H63D heterozygous, 2% C282Y heterozygous, 2% S65C heterozygous, and 36% of patients lacked any of the three mutations studied, despite the fact that they showed clinical/biochemical features of hemochromatosis. We observed a high frequency of the H63D mutation in both the control group and patients, whereas the main genotypes implicated in HH in our series were H63D homozygous and H63D/C282Y compound heterozygous. We propose that the H63D mutation be analyzed in HH patients from our geographic area. Moreover, further studies are needed to elucidate the role of this mutation in the development of HH and the genetic, environmental or other factors that affect the genotype-phenotype correlation between H63D and hemochromatosis.
SUMMARY Worldwide, iron deficiency (ID) is the leading risk factor for disability and mortality, affecting both developing and developed countries with major consequences for human health as well as social and economic development. ID results from any situation in which dietary iron intake does not balance iron demands because of increased iron requirements, limited external supply and/or increased blood loss. In absolute ID, ferritin stores are progressively diminished; the supply of iron to transferrin is compromised, and as a consequence transferrin saturation is decreased. In functional ID (FID), iron stores cannot be mobilized as fast as necessary from the repleted macrophages of the reticuloendothelial system to the bone marrow. This condition is typical of the anemia of chronic diseases (ACD) because of inflammation‐induced increased hepcidin levels. Both absolute and functional ID may evolve to ID anemia (IDA). The diagnosis of ACD + IDA remains challenging. In addition to a soluble transferrin receptor (sTfR)/log ferritin ratio > 2, there are several important hematological indices that may help in the diagnosis of absolute ID in ACD, such as the reticulocyte hemoglobin content and the percentage of hypochromic red blood cells. In this paper we review the causes of ID, the different laboratory tests available and how to combine them to establish a correct diagnosis of ID, FID, IDA, ACD and ACD + IDA.
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