Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare autosomal dominant disorder caused by pathogenic variants in the iron-responsive element (IRE) of the 5' untranslated region (5'UTR) of the FTL gene, resulting in dysregulated ferritin synthesis independent of body iron stores. Because elevated serum ferritin is commonly interpreted as a surrogate marker of iron overload, HHCS is frequently misdiagnosed as hereditary hemochromatosis or secondary iron overload, leading to unnecessary investigations and potentially harmful therapeutic phlebotomies. We report the case of a 58-year-old male patient with longstanding unexplained hyperferritinemia, normal transferrin saturation, and a striking multigenerational family history of early-onset cataracts. Despite the absence of biochemical or radiological evidence of iron overload, the patient initially underwent therapeutic phlebotomy. Subsequent targeted sequencing of the FTL 5'UTR identified a heterozygous pathogenic c.-168G>A variant within the IRE, confirming the diagnosis of HHCS. This case highlights a critical diagnostic pitfall in hematology practice and emphasizes the importance of interpreting serum ferritin in conjunction with transferrin saturation, exclusion of secondary causes, and careful assessment of family history. Early recognition of HHCS and appropriate use of targeted genetic testing can prevent inappropriate iron-depleting therapies and improve patient management.

Background: Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare autosomal dominant disorder characterized by persistently elevated serum ferritin and early-onset bilateral cataracts in the absence of systemic iron overload. It is caused by pathogenic variants in the iron-responsive element (IRE) of the FTL gene, leading to dysregulated L-ferritin synthesis. Methods: We evaluated a 12-year-old Czech girl with markedly elevated serum ferritin identified incidentally during workup for abdominal pain. Clinical assessment included biochemical, radiological, ophthalmological, and genetic testing of the proband and available family members. Results: Magnetic resonance imaging excluded systemic iron overload, while ophthalmological evaluation revealed bilateral cataracts. Family history indicated multiple affected relatives across three generations. Genetic testing confirmed a heterozygous FTL c.-168G>C variant. Additional screening for common HFE variants revealed heterozygous H63D in several family members, with no impact on ferritin or hepcidin levels. Beyond this case, we provide a comprehensive review of HHCS, including molecular mechanisms, an updated overview of reported FTL mutations, and ophthalmological features that distinguish HHCS cataracts from other congenital cataracts. Conclusions: This report underscores the translational relevance of combining molecular diagnostics, clinical evaluation, and family screening to improve recognition and management of HHCS, and to prevent misdiagnosis and unnecessary iron-depletion therapy.

The differential diagnosis for hyperferritinemia is wide, including malignancy, infections, autoimmune disorders, hemophagocytic lymphohistiocytosis, hyperthyroidism, chronic kidney disease, and, most commonly, iron overload. As an acute-phase reactant, ferritin is usually elevated due to secondary causes. In rare circumstances, however, ferritin levels may be primarily elevated due to a genetic cause. We report a case of a three-year-old male patient with incidentally detected hyperferritinemia who was found to harbor the c.-168G>T mutation in the FTL gene, confirming hereditary hyperferritinemia-cataract syndrome (HHCS). This case is distinguished by a unique four-generation family history of early-onset cataracts and elevated ferritin levels, underscoring the hereditary and novel nature of this disorder.

Hereditary hyperferritinemia-cataract syndrome is an autosomal dominant genetic disorder that is characterized by high serum ferritin levels without iron overload and early-onset cataracts. The authors describe the case of a 26-year-old woman with hyperferritinemia (1153.3 ng/mL, reference range 11.0 - 306.8 ng/mL), with no other abnormalities in iron metabolism, associated with cataracts diagnosed at the age of three. The diagnosis was confirmed by genetic testing with detection of a heterozygous variant in the FTL gene (c.-168G>T). It is important to recognise hereditary hyperferritinemia-cataract syndrome to avoid unnecessary medical procedures.

Hereditary Hyperferritinemia-Cataract Syndrome (HHCS, MIM #600886) is a rare autosomal dominant genetic disorder characterized by elevated serum ferritin levels and early-onset cataracts. This condition is caused by mutations in the iron-responsive element (IRE) within the 5' untranslated region (UTR) of the ferritin light chain (FTL, *134790) gene. In this study, we report a case involving elevated ferritin levels and a history of cataracts associated with a novel variant in the FTL gene, in the absence of any familial history of the disease. In this study, we performed sequence analysis of the ferritin L-chain (FTL) gene in a 61-year-old female patient and her family. The patient history of bilateral cataract from a young age and was later found to have elevated ferritin levels. Mutation analysis identified an unreported deletion insertion (delins) variant in the FTL gene. Genetic factors, while rare, are a significant cause of hyperferritinemia. In cases where hyperferritinemia is accompanied by early-onset cataracts, genetic etiologies should be considered. Multidisciplinary evaluation of patients can help avoid unnecessary treatments and improve quality of life through timely interventions.