Hereditary hyperferritinemia-cataract syndrome (HHCS) is an autosomal dominant disorder characterized by increased serum L-ferritin levels and bilateral cataracts, in the absence of iron overload (OMIM #600886) (Fig. 17.1). Under physiological conditions, regulation of ferritin synthesis is finely controlled at the translational level by iron availability. This is achieved by the high-affinity interaction of non-coding stem-loop structures located in the untranslated regions (UTRs) of L- and H-ferritin mRNAs known as iron-responsive elements (IREs) with cytoplasmic mRNA-binding proteins. A single non-coding IRE is located on the 5′ UTR of the genes that encode L- and H-ferritin. Binding of IRPs to IREs normally represses translation of their corresponding cis genes. Heterogeneous mutations in the IRE of L-ferritin reduce the binding affinity of IRPs to IREs and thereby diminish the negative control of L-ferritin (but not H-ferritin) synthesis. This leads to the constitutive up-regulation of ferritin L-chain synthesis characteristic of HHCS.

History

In 1995, Girelli and colleagues reported two Italian families in which elevated serum ferritin unrelated to iron overload and congenital bilateral nuclear cataract were co-transmitted as an autosomal dominant trait. Affected persons in these kinships had normal or low levels of serum iron, normal transferrin saturation, and absence of iron overload in parenchymal organs, unlike persons with hemochromatosis. In a subsequent report, these investigators coined the descriptive name HHCS to describe the syndrome. By RNA single-strand conformation polymorphism screening of the L-subunit ferritin gene (FTL) on chromosome 19q13.13–13.4, they identified a mutation in the 5′ UTR in HHCS subjects.