Clinical, biochemical and molecular findings in a series of families with hereditary hyperferritinaemia–cataract syndrome

Hereditary hyperferritinaemia–cataract syndrome (HHCS) is an autosomal dominant disease caused by mutations in the iron responsive element (IRE) of the l‐ferritin gene. Despite the elucidation of the genetic basis, the overall clinical spectrum of HHCS has been less well studied as, to date, only individual case reports have been described. Therefore, we studied a total of 62 patients in 14 unrelated families, with nine different mutations. No relevant symptoms other than visual impairment were found to be associated with the syndrome. A marked phenotypic variability was observed, particularly with regard to ocular involvement (i.e. age range at which cataract was diagnosed in 16 subjects with the C39T: 6–40 years). Similarly, serum ferritin levels varied substantially also within subjects sharing the same mutation (i.e. range for the A40G: 700–2412 µg/l). We followed an HHCS newborn in whom well‐defined lens opacities were not detectable either at birth or at 1 year. The lens ferritin content was analysed in two subjects who underwent cataract surgery at different ages, with different cataract morphology. Values were similar and about 1500‐fold higher than in controls. These observations suggest that: (i) in HHCS the cataract is not necessarily congenital; (ii) in addition to the IRE genotype, other genetic or environmental factors may modulate the phenotype, especially the severity of the cataract.