Abstract 3205 Background:Hereditary hyperferritinemia cataract syndrome (HHCS) is an autosomal dominant disorder characterized by elevated serum L-ferritin and early onset bilateral cataracts. The syndrome, first described in Italy and France in 1995, is caused by mutations in the iron responsive element (IRE) of the L-ferritin gene (FTL-ferritin light chain) on chromosome 19q13.3. The conformational changes in the mutated IRE disrupt the binding of the iron regulatory proteins (IRPs) to the IRE, resulting in loss of the posttranscriptional control in L-ferritin synthesis. L-ferritin is constitutively expressed in tissues, irrespective of cellular iron status and without otherwise disrupting cellular iron metabolism. Despite the five to twenty-fold increase in serum L-ferritin, there is no clinical or laboratory evidence of iron overload. Serum iron and transferrin saturation remain within normal limits. Visual impairment and early cataract formation is the only clinical symptom of HHCS, with lens replacement being the only treatment needed. Extensive and invasive investigations in the undiagnosed hyperfferitinemic patient, as well as unnecessary treatment with phlebotomies, can be avoided with awareness of the syndrome, leading to the correct clinical and molecular diagnosis. Aim:HHCS has been previously reported in a limited number of patients of Greek origin, with the study of three unrelated families in Greece. Papanikolaou et al. (Blood Cells Mol Dis. 2006) detected the C39>G mutation in the IRE of the FTL in all affected individuals. Our aim was to further investigate the syndrome within the Greek population, both phenotypically and genetically. Methods:We investigated 81 patients with undiagnosed hyperferritinemia referred to the Hepatology Outpatients Clinic of the 1st Department of Internal Medicine at “Laikon” General Hospital in Athens. For all patients full medical history and clinical examination (including ophthalmological evaluation) was performed, and laboratory investigations were tailored accordingly. Where indicated from the medical history and laboratory findings, molecular analysis for mutations in the IRE of the FTL was performed using direct DNA sequencing. Results:From the total of 81 patients referred for undiagnosed hyperferritinemia, 18 unrelated subjects had a positive history of cataract and elevated ferritin. In those subjects ferritin levels ranged from 600 to 2070μg/L (normal values: 12–160μg/L). Serum iron was within normal limits and transferrin saturation ranged from 9 to 40%. Cataract diagnosis was reported as early as 5 years of age and 8 out of the 18 subjects had undergone surgery for lens replacement at the time of referral. From the 18 subjects that were screened for mutations in the IRE of the FTL, mutations were detected in 12 unrelated subjects. Ten out of the 12 individuals were positive for the previously described C39>G point mutation. The other two subjects were found to carry the A40>G mutation. The A40>G mutation has been described in the literature as part of the spectrum of mutations causing HHCS (Beaumont et al, Nat. Genet. 1995), however it has not up to now been reported in subjects of Greek origin. From the 12 subjects positive for either mutation, 8 reported positive family history for either early onset cataracts, hyperferritinemia or both. Where possible, clinical, laboratory and molecular investigations were extended to other members of these families. A total of 40 subjects from the members of the studied families fulfilled the clinical criteria of HHCS. Genetic testing was performed in 12 of them, revealing 11 subjects heterozygous for the C39>G mutation and 1 heterozygous for the A40>G mutation. Conclusion:HHCS is a non-iron loading, rare disorder that should be considered in all patients with unexplained hyperferritinemia, in order to avoid unnecessary investigations, potentially hazardous treatment and confer reassurance to the patient. Our findings contribute to the clinical and molecular characterization of the syndrome and extend the study of the disorder in the Greek population. Disclosures:No relevant conflicts of interest to declare.
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May 1, 2024
Andrea Russo + 8
Open Access