BACKGROUND: Hereditary hyperferritinemia-cataract syndrome (HHCS) is an autosomal dominant disorder manifesting with high serum ferritin levels and the formation of early-onset cataracts, with numerous small opacities, predominantly in the lens cortex. HHCS is caused by mutations in the iron-responsive element of the FTL gene. The aim of this study was to establish a molecular diagnosis in three Czech probands with suspected HHCS. METHODS: A complex ocular and systemic evaluation, including ferritin and iron measurements, was performed. The 5' untranslated region of FTL was directly sequenced in all available family members, followed by paternity testing in one family. RESULTS: Three different FLT pathogenic variants (c.-161C>T, c.-167C>T, and c.-168G>C) present in the heterozygous state were detected in each of the 3 probands. Two segregated with the disease phenotype within the families, but c.-167C>T occurred de novo (confirmed by paternity testing). Prior to establishing molecular diagnosis, two probands were misdiagnosed with hemochromatosis. One individual, aged 43 years, underwent phlebotomy; another, aged 8.5 years, was treated with the iron chelator deferasirox, leading to life-threatening acute hyperammonemia, without severe liver injury. CONCLUSIONS: Lack of family history does not exclude HHCS, because the pathogenic variant can arise de novo. Noncoding regions are often omitted from diagnostic gene panels, thus evading detection. Careful clinical evaluations and targeted genetic screening are important for avoiding potentially harmful treatments.

Department of Biology and Medical Genetics 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Ophthalmology 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Research Unit for Rare Diseases Department of Paediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

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