Variable phenotypic presentation of iron overload in H63D homozygotes: aregenetic modifiers the cause?

Background-First considered as a polymorphism of the HFE gene, the H63D mut ation is now widely recognised as a haemochromatosis associated allele. But few H63D homozygotes with clinical manifestations of hereditary haemochrom atosis (HH) have been reported. Concurrently, an increasing number of genes have been shown to interact with HFE in iron metabolism. Aims-To describe the clinical expression of iron overload (IO) associated w ith H63D homozygosity, and search for potential genetic modifiers (within t he HFE or other genes) that could explain the variability of the phenotypes . Patients and methods-We retrospectively analysed the clinical phenotype o f 56 H63D homozygotes referred for a personal or family history of IO. For each subject we examined intragenic HFE haplotypes and transferrin receptor (TfR) gene polymorphisms and searched for the Y250X mutation on the TFR2 g ene. Additionally, we sequenced the HFE gene of H63D homozygotes with HH. Results-Fifty of 56 subjects had biological and/or clinical abnormalities o f iron metabolism. Up to two thirds of patients (n=34) had no acquired caus e of IO. Among these, 12 had a phenotypic diagnosis of HH. In the iron load ed group there was a strong prevalence of male patients. No correlation was found between the potential genetic modifiers and phenotypes. No additiona l mutation of HFE was identified. Conclusion-The variable phenotypes associated with H63D homozygosity do not appear to be linked to other HFE mutations, to the TFR2 Y250X mutation, or to HFE or TfR gene intragenic polymorphisms. The exact role of H63D homozy gosity in IO and HH needs to be further investigated in unselected populati ons.