CLINICAL

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LABORATORY OBSERVATIONS

Hereditary Hyperferritinemia Cataract Syndrome as a Cause of Childhood Hyperferritinemia Fani Tsantoula, BSc, MSc,* Anna Kioumi, PhD, MD,w Anastasios E. Germenis, PhD, MD,* and Matthaios Speletas, PhD, MD*

Summary: A 2-year-old female was presented with high levels of serum ferritin (890 ng/mL) in a routine blood test. Clinical and laboratory investigations excluded the presence of iron overload and secondary causes of hyperferritinemia. A detailed family history and laboratory examinations revealed the presence of earlyonset cataract in her 33-year-old mother, who also displayed hyperferritinemia (633 ng/mL), similar to other family members. Genetic testing confirmed the diagnosis of hereditary hyperferritinemia cataract syndrome (HHCS), demonstrating a C39 > G (c. 161C > G) mutation into FTL gene. HHCS should be considered in the differential diagnosis of childhood hyperferritinemia, especially in the presence of normal transferrin saturation. Key Words: hyperferritinemia, hereditary hyperferritinemia cataract syndrome, L-ferritin, IRE

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BACKGROUND Ferritin is the main nonheme iron storage protein in humans. Its expression is regulated by plasma iron levels and mediated by interactions between a conserved stemloop structure, known as iron responsive element (IRE), within the 50 -untranslated region (UTR) of mRNA of Hferritin and L-ferritin genes and intracellular iron regulatory proteins (IRPs).1,2 When cellular iron is scarce, IRPs bind to ferritin IRE and inhibit protein translation. In contrast, when intracellular iron rises, IRPs are prevented from binding to the IRE and ferritin translation commences.1,2 Accordingly, serum ferritin levels have been used by clinicians as the best indicator of intracellular iron body stores, whereas the presence of hyperferritinemia is indicative of iron overload of both acquired and hereditary etiology.1,2 However, ferritin is also an inflammatory marker and high levels of serum ferritin are observed in patients with chronic inflammatory conditions, liver diseases, autoimmune diseases (Still disease, hemophagocytic syndrome, systemic lupus erythematosus), sideroblastic anemias, and malignancies.1–3 The presence of hyperferritinemia with no association to iron disorders is not unusual, even for minor problems such as upper airway infections, especially in children.4,5 In common practice, only cases of persistent Received for publication April 2, 2013; accepted May 29, 2013. From the *Department of Immunology and Histocompatibility, School of Health Sciences, Faculty of Medicine, University of Thessaly, Larissa; and wDepartment of Hematology, Papageorgiou General Hospital, Thessaloniki, Greece. The authors declare no conflict of interest. Reprints: Matthaios Speletas, PhD, MD, Department of Immunology and Histocompatibility, School of Health Sciences, Faculty of Medicine, University of Thessaly, 41110 Biopolis, Larissa, Greece (e-mail: [email protected]). Copyright r 2013 by Lippincott Williams & Wilkins

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high ferritin levels are usually honored with further investigation. Hereditary hyperferritinemia cataract syndrome (HHCS) is a rare disorder, which is transmitted with an autosomal dominant manner, causing hyperferritinemia with no relation to iron overload. The disease was firstly described by Girelli et al6 in 1995 in 2 Italian families with early-onset bilateral cataract and hyperferritinemia not related to iron overload. Beaumont et al7 were the first to identify the molecular basis of the disorder by studying a French family with dominantly inherited hyperferritinemia and cataract. Since then, there have been several reports on HHCS (reviewed recently by Millonig et al8). The disease is caused by mutations within the IRE of the L-ferritin (FTL) gene, which impair the negative posttranscriptional control and lead to excessive ferritin synthesis.2,7–9 L-ferritin participates directly in the development of cataract by forming L-chain lens opacities.10,11 Apart from cataract formation, HHCS patients have no other clinical problems, only displaying an elevated level of circulating ferritin with no other hematological or biochemical abnormalities, including serum levels of iron and transferrin saturation (TfSat).2,8 There are a few reports in the literature, reporting children with HHCS, which are diagnosed during evaluation of either hyperferritinemia4 or early-onset cataract.12 In this study we present a family with HHCS, diagnosed during evaluation of a 2-year-old proband with hyperferritinemia.

CASE REPORT The patient was a 2-year-old girl from Central Greece who was referred to our Department because of severe hyperferritinemia (serum ferritin levels: 890 ng/mL; normal range, 15 to 120 ng/mL) that was incidentally identified during a routine blood test. Serum ferritin was retested and found again high (789 ng/L), with serum iron of 67 mg/dL (normal range, 50 to 150 mg/dL), serum total ironbinding capacity (TIBC) of 356 mg/dL (normal range, 250 to 370 mg/dL) and, accordingly, TfSat of 18.8% (normal range, 12% to 45%). Further clinical and laboratory examinations excluded secondary causes of hyperferritinemia and iron overload. A detailed family history revealed that the 33-year-old mother had developed early-onset bilateral cataract (diagnosed 2 y ago), similar to her 60-year-old father (the grandfather of the proband), who had additionally been subjected to surgical intervention 5 years before. Moreover, she displayed hyperferritinemia (633 ng/mL; normal range, 15 to 150 ng/mL), along with iron deficiency without anemia (Hb 13.1 g/dL, serum iron 37 mg/dL, TIBC 419 mg/dL, TfSat 9.3%). In contrast, the proband’s father exhibited ferritin levels into normal ranges (87 ng/mL; normal range, 15 to 150 ng/mL). The proband did not yet exhibit cataract, while her pedigree is presented in Figure 1. Given these results, we restricted the differential diagnosis to HHCS. Hence, sequencing analysis was carried out to screen for mutations in the FTL gene. The proband and family members with and without hyperferritinemia were analyzed. Genomic DNA was extracted from peripheral blood and the molecular analysis of FTL

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Hereditary Hyperferritinemia Cataract Syndrome

FIGURE 1. Pedigree of the family with hereditary hyperferritinemia cataract syndrome. The arrow indicates the proband.

gene was performed by PCR and sequencing, as described.11 The heterozygous single point mutation C39 > G (c. 161C > G) in the 50 -UTR of FTL gene, located in the conserved hexanucleotide loop of the L-ferritin IRE,13 was identified both in the proband and the other family members with hyperferritinemia and confirmed the diagnosis of HHCS.

DISCUSSION Our case is an example of identifying a rare genetic syndrome in an apparently healthy 2-year-old child. The association of the patient’s hyperferritinemia with normal TfSat and the positive family history of bilateral cataracts guided us toward the consideration of HHCS. The identified C39 > G (c. 161C > G) mutation in the FTL gene confirmed the initial HHCS diagnosis. Persistent hyperferritinemia may result from many causes, both acquired and genetically controlled, whereas the evaluation of TfSat plays a very important role in the initial diagnostic approach, to suggest or to exclude iron overload.1–3 As mentioned above, HHCS is a rare cause of hyperferritinemia without iron overload, which is clinically characterized only by early-onset cataract formation.2,5,8,10,11 The C39 > G (c. 161C > G) mutation identified in our family is a relatively rare alteration in the spectrum of the hitherto described IRE mutations.8 It occurs in the first nucleotide of the of the IRE hexaloop, which is a highly conserved mRNA sequence. It has been shown that any substitution of the 6 conserved residues in the critical IRE loop results in severely decreased IRE-IRP binding affinity and, therefore, in impaired regulation of L-ferritin translation.13–15 Interestingly, the same mutation was also identified in a French16 and 3 other unrelated HHCS families from western Greece.13 It is, therefore, very likely that this alteration might be originated from a distant common ancestor, especially in the case of the Greek families. It is worth of note that HHCS is characterized by a marked phenotypic variability, particularly with regard to ocular involvement.16 Craig et al12 proposed that all HHCS cataracts are highly characteristic in morphology and consist of gradually progressive flecks, vacuoles, and distinctive crystalline deposits, distributed mainly in the lens cortex and the nucleus. However, the cataract formation seems to r

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be progressive in nature, probably due to ferritin accumulation in the lens, and it is more commonly observed in childhood or adolescence rather than in infancy or in congenital form.12,15 Moreover, Girelli et al15 have shown that, in addition to the IRE genotype, other genetic or environmental factors may modulate the phenotype of the disease and the severity of the cataract. HHCS patients do not usually present with visual symptoms and several previous observations demonstrate that visual complains in HHCS are most commonly noted in the second to fourth decade of life. Thus, an ocular examination is required as a diagnostic tool rather than a therapeutic intervention.4,8,12,15 Once the correct diagnosis of HHCS is confirmed after a genetic analysis, patients require no treatment except for ophthalmologic follow-up and a cataract surgery, when the latter is necessary.8 Currently, there is no acknowledged therapy for inhibiting or delaying the formation of cataracts. Finally, our case highlights the importance of a detailed medical family history in the diagnostic process of hyperferritinemia. Pediatricians should be aware of the HHCS to spare patients from further invasive diagnosis, or from a false diagnosis of hereditary hemochromatosis. Patients diagnosed with HHCS should also be counseled regarding the relative harmlessness of the disease, with early cataract surgery being the only clinical consequence.8 REFERENCES 1. Knovich MA, Storey JA, Coffman LG, et al. Ferritin for the clinician. Blood Rev. 2009;23:95–104. 2. Cazzola M. Role of ferritin and ferroportin genes in unexplained hyperferritinaemia. Best Pract Res Clin Haematol. 2005;18:251–263. 3. Zandman-Goddard G, Shoenfeld Y. Hyperferritinemia in autoimmunity. Isr Med Assoc J. 2008;10:83–84. 4. Serra M, Longo F, Roetto A, et al. A child with hyperferritinemia: case report. Ital J Pediatr. 2011;37:20. 5. Aguilar-Martinez P, Schved JF, Brissot P. The evaluation of hyperferritinemia: an updated strategy based on advances in detecting genetic abnormalities. Am J Gastroenterol. 2005;10: 1185–1194. 6. Girelli D, Olivieri O, De Franceschi L, et al. A linkage between hereditary hyperferritinaemia not related to iron overload and

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autosomal dominant congenital cataract. Br J Haematol. 1995;90:931–934. Beaumont C, Leneuve P, Devaux I, et al. Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinaemia and cataract. Nat Genet. 1995;11: 444–446. Millonig G, Muckenthaler MU, Mueller S. Hyperferritinaemia-cataract syndrome: worldwide mutations and phenotype of an increasingly diagnosed genetic disorder. Hum Genomics. 2010;4:250–262. Girelli D, Corrocher R, Bisceglia L, et al. Molecular basis for the recently described hereditary hyperferritinemia-cataract syndrome: a mutation in the iron-responsive element of ferritin L-subunit gene (the “Verona mutation”). Blood. 1995;86:4050–4053. Mumford AD, Cree IA, Arnold JD, et al. The lens in hereditary hyperferritinaemia cataract syndrome contains crystalline deposits of L-ferritin. Br J Ophthalmol. 2000;84:697–700. Brooks DG, Manova-Todorova K, Farmer J, et al. Ferritin crystal cataracts in hereditary hyperferritinemia cataract syndrome. Invest Ophthalmol Vis Sci. 2002;43:1121–1126.

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12. Craig JE, Clark JB, McLeod JL, et al. Hereditary hyperferritinemia-cataract syndrome: prevalence, lens morphology, spectrum of mutations, and clinical presentations. Arch Ophthalmol. 2003;121:1753–1761. 13. Papanikolaou G, Chandrinou H, Bouzas E, et al. Hereditary hyperferritinemia cataract syndrome in three unrelated families of western Greek origin caused by the C39 > G mutation of L-ferritin IRE. Blood Cell Mol Dis. 2006;36:33–40. 14. Jaffrey SR, Haile DJ, Klausner RD, et al. The interaction between the iron-responsive element binding protein and its cognate RNA is highly dependent upon both RNA sequence and structure. Nucleic Acids Res. 1993;21:4627–4631. 15. Girelli D, Bozzini C, Zecchina G, et al. Clinical, biochemical and molecular findings in a series of families with hereditary hyperferritinemia-cataract syndrome. Br J Haematol. 2001; 115:334–340. 16. Garderet L, Hermelin B, Gorin NC, et al. Hereditary hyperferritinemia-cataract syndrome: a novel mutation in the ironresponsive element of the L-ferritin gene in a French family. Am J Med. 2004;117:138–139.

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2013 Lippincott Williams & Wilkins

Hereditary hyperferritinemia cataract syndrome as a cause of childhood hyperferritinemia.

A 2-year-old female was presented with high levels of serum ferritin (890 ng/mL) in a routine blood test. Clinical and laboratory investigations exclu...
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