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.
Güven et al. (Wed,) studied this question.