Hyperferritinemia in Patients With Bilateral Cataracts
Hyperferritinemia in Patients With Bilateral Cataracts
Introduction: Hepatologists and internists often encounter patients with unexplained high serum ferritin concentration. After exclusion of hereditary hemochromatosis and hemosiderosis, rare disorders like hereditary hyperferritinemia cataract syndrome should be considered in the differential diagnosis. This autosomal dominant syndrome, that typically presents with juvenile bilateral cataracts, was first described in 1995 and has an increasing number of recognized molecular defects within a regulatory region of the L-ferritin gene (FTL).
Case presentation: Two patients (32 and 49-year-old Caucasian men) from our ambulatory clinic were suspected as having this syndrome and a genetic analysis was performed. In both patients, sequencing of the FTL 5' region showed previously described mutations within the iron responsive element (FTL c.33 C > A and FTL c.32G > C).
Conclusion: Hereditary hyperferritinemia cataract syndrome should be considered in all patients with unexplained hyperferritinemia without signs of iron overload, particularly those with juvenile bilateral cataracts. Liver biopsy and phlebotomy should be avoided in this disorder.
Hereditary hyperferritinemia cataract syndrome (HHCS) is a rare autosomal dominant genetic disease, which was first described in 1995 independently by the groups of Bonneau and of Girelli. They reported two families in whom elevated serum L-ferritin concentration without iron overload, presenting with juvenile bilateral cataracts, was inherited as an autosomal dominant trait. Cataracts comprise crystalline deposits of L-ferritin. The underlying molecular defect in both the early reports of HHCS was identified as point mutations in the 5' untranslated region (5'UTR) of the L-ferritin gene (FTL), in the region corresponding to the iron-responsive element (IRE) of L-ferritin messenger ribonucleic acid (mRNA). These mutations lead to loss of suppression of L-ferritin mRNA translation by the iron-dependent iron regulatory protein (IRP) leading to dysregulated expression of the L-ferritin protein. Since these early reports, a series of other point mutations and short deletions of L-ferritin IRE associated with HHCS have been reported.
In 2000, Rososchova et al. measured serum ferritin concentrations in 135 Swiss patients with bilateral operated cataracts before the age of 51 to detect HHCS. However, no patients with HHCS were identified. This led those authors to postulate that HHCS is so rare that it might not exist in Switzerland. We describe, to the best of our knowledge, the first two cases of HHCS in Switzerland, both with proven mutations in FTL. We also review key aspects of the metabolism of cellular iron and ferritin synthesis and we discuss the pathophysiology of HHCS.
Abstract and Introduction
Abstract
Introduction: Hepatologists and internists often encounter patients with unexplained high serum ferritin concentration. After exclusion of hereditary hemochromatosis and hemosiderosis, rare disorders like hereditary hyperferritinemia cataract syndrome should be considered in the differential diagnosis. This autosomal dominant syndrome, that typically presents with juvenile bilateral cataracts, was first described in 1995 and has an increasing number of recognized molecular defects within a regulatory region of the L-ferritin gene (FTL).
Case presentation: Two patients (32 and 49-year-old Caucasian men) from our ambulatory clinic were suspected as having this syndrome and a genetic analysis was performed. In both patients, sequencing of the FTL 5' region showed previously described mutations within the iron responsive element (FTL c.33 C > A and FTL c.32G > C).
Conclusion: Hereditary hyperferritinemia cataract syndrome should be considered in all patients with unexplained hyperferritinemia without signs of iron overload, particularly those with juvenile bilateral cataracts. Liver biopsy and phlebotomy should be avoided in this disorder.
Introduction
Hereditary hyperferritinemia cataract syndrome (HHCS) is a rare autosomal dominant genetic disease, which was first described in 1995 independently by the groups of Bonneau and of Girelli. They reported two families in whom elevated serum L-ferritin concentration without iron overload, presenting with juvenile bilateral cataracts, was inherited as an autosomal dominant trait. Cataracts comprise crystalline deposits of L-ferritin. The underlying molecular defect in both the early reports of HHCS was identified as point mutations in the 5' untranslated region (5'UTR) of the L-ferritin gene (FTL), in the region corresponding to the iron-responsive element (IRE) of L-ferritin messenger ribonucleic acid (mRNA). These mutations lead to loss of suppression of L-ferritin mRNA translation by the iron-dependent iron regulatory protein (IRP) leading to dysregulated expression of the L-ferritin protein. Since these early reports, a series of other point mutations and short deletions of L-ferritin IRE associated with HHCS have been reported.
In 2000, Rososchova et al. measured serum ferritin concentrations in 135 Swiss patients with bilateral operated cataracts before the age of 51 to detect HHCS. However, no patients with HHCS were identified. This led those authors to postulate that HHCS is so rare that it might not exist in Switzerland. We describe, to the best of our knowledge, the first two cases of HHCS in Switzerland, both with proven mutations in FTL. We also review key aspects of the metabolism of cellular iron and ferritin synthesis and we discuss the pathophysiology of HHCS.
