Transfusion-related iron overload (TRIO) is a common antineoplastic treatment complication in children undergoing aggressive chemotherapy for hematological malignancies. Iron deposition leads to numerous morbidities, with the most devastating outcomes being liver and heart failure. An observational retrospective study on TRIO was performed on children with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) treated at the Department of Oncology and Hematology, Children's Hospital Zagreb, Croatia, from January 1, 2018, to December 31, 2023. Epidemiological and basic clinical data were retrieved from the patients' electronic medical records. Serum ferritin (SF) concentration (ng/mL) was used as a marker of TRIO. Mildly elevated ferritin was defined as SF >500 ng/mL and severely elevated as SF >1000 ng/mL. Results of magnetic resonance imaging (MRI) studies for tissue iron quantification, HFE genetic analyses, and management with chelators (preparation, dose, duration, compliance) were described. Initial SF concentrations ranged from 17.5 to 808 ng/mL, rose to the range from 368 to 6562.3 ng/mL at the end of the intensive chemotherapy, sunk to the range from 11.9 to 3885 ng/mL at the end of the maintenance therapy, and additionally receded to the range from 36.2 to 1924 ng/mL during the follow-up (FU). Upon cessation of intensive chemotherapy, significant hyperferritinemia was detected in 96% of the patients tested and during the FU in 60% of them. Risk factors for TRIO included age six and older, high-risk (HR) disease, and a substantial transfusion load (≥10 red blood cell transfusions (RBCTs)). Hepatic and/or cardiac MRI, as part of the TRIO work-up, was performed in only four patients. HFE genotyping was conducted in five participants, and the results were altered in three of them - H63D heterozygosity. Four children received chelation therapy, i.e., deferasirox, which was discontinued in two of them due to gastrointestinal discomfort. We have demonstrated a high occurrence but an unsatisfactory approach to TRIO. A fair number of patients lacked SF measurements during the treatment and FU. Despite a considerable proportion of patients at risk of TRIO in our cohort, only four underwent MRI for tissue iron quantification. Unlike the ferritin assay, MRI is neither accessible nor cheap, and the need for sedation/anesthesia in young children probably leads to underutilization of the method. Furthermore, there was no consensus on genotyping for hereditary hemochromatosis. Older age and HR disease posed a greater risk for TRIO. Transfusion burden significantly impacted ferritin levels. We advise clinicians to follow a restrictive transfusion strategy and track the number of red blood cell units administered throughout the treatment to identify patients with especially worrisome iron influx. There is a strong need for the development of TRIO treatment guidelines for patients and survivors of childhood cancer.

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.

Hepatitis A virus (HAV) infection is usually self-limited and does not progress to chronic liver disease. However, atypical courses such as prolonged cholestatic hepatitis may occur in adults, posing diagnostic and therapeutic challenges. We report the case of a 55-year-old man with hypertension, obesity, and known hepatic steatosis who presented with jaundice, choluria, acholic stools, fatigue, epigastric pain, and nausea. Laboratory evaluation revealed a mixed hepatocellular-cholestatic pattern with predominantly direct hyperbilirubinemia. Acute HAV infection was confirmed (anti-HAV IgM positive), and alternative causes were excluded. Imaging showed no biliary obstruction. Epstein-Barr virus (EBV) serology obtained during the first admission was consistent with past infection (viral capsid antigen (VCA) IgG positive, VCA IgM negative, and EBV nuclear antigen-1 (EBNA-1) IgG positive). The patient improved with supportive care and was discharged after one week. He was readmitted one week later with clinical relapse and severe hyperbilirubinemia (total bilirubin 25.3 mg/dL). Given a household contact with a mononucleosis-like illness, repeat EBV serology showed weak/low-level VCA IgM reactivity (12.1 UA/mL) with persistent VCA IgG positivity. However, subsequent reassessment results returned to VCA IgM negativity with persistent VCA IgG and EBNA-1 IgG positivity, supporting remote EBV infection and suggesting non-specific IgM reactivity (or, less likely, reactivation) rather than primary acute EBV infection. EBV DNA PCR was not pursued due to low clinical and serologic suspicion of active infection and the subsequent resolving course. A genetic study requested during the first admission revealed HFE H63D heterozygosity, with a ferritin level >11,000 ng/mL and transferrin saturation of >80%. The patient improved with ursodeoxycholic acid (UDCA) and individualized iron management. Corticosteroids were not used, given progressive improvement with supportive care and UDCA. Follow-up quantitative liver MRI showed only mild iron overload (43 µmol/g), supporting an acute-phase/inflammatory iron contribution during severe hepatitis, and FibroScan® revealed mild fibrosis (5.3 kPa). This case highlights the importance of stepwise reassessment in prolonged cholestatic HAV, the pitfalls of interpreting transient EBV VCA IgM reactivity in a patient with serology consistent with prior EBV infection, and careful interpretation of marked hyperferritinemia in HFE H63D heterozygotes.

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.