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Revista Española de Enfermedades Digestivas

versión impresa ISSN 1130-0108

Rev. esp. enferm. dig. vol.96 no.7 Madrid jul. 2004



Hereditary hyperferritinemia-cataract syndrome. Study of a new family in Spain

J. M. Ladero, A. Balas1, F. García-Sánchez1, J. L. Vicario1 and M. Díaz-Rubio

Department of Gastroenterology. Hospital Clínico San Carlos. Universidad Complutense. Madrid.
1Centro de Transfusión. Servicio Madrileño de Salud. Consejería de Sanidad. CAM. Madrid, Spain



The hyperferritinemia-cataract syndrome, inherited as a Mendelian dominant trait, is due to mutations in the 5’ non-coding region of the ferritin light chain gene that modifies the shape of the IRE (iron responsive element) region, which loses its normal function of regulating the synthesis of ferritin light chains. Excess of light chains results in complexes that accumulate into the lens giving rise to early cataracts.
We present a Spanish family with seven affected members through three generations. A genetic study reveals a substitution of a single base (C
T) at position 33 in the IRE sequence in the index case and in one affected brother, whereas a non-affected sister shows the normal sequence.
The hyperferritinemia-cataract syndrome was identified in 1995 and is still poorly understood. Clinicians should suspect it when treating any subject with early cataracts, even more if they are familial, or in patients with very high levels of ferritinemia without evidence of iron overload. There are no known consequences of the syndrome other than cataracts, and its proper diagnosis carries a favorable prognosis and eliminates the risk of unnecessary phlebotomies.

Key words: Hyperferritinemia. Cataract. Ferritin L chain. Iron responsive element.

Ladero JM, Balas A, García-Sánchez F, Vicario JL, Díaz-Rubio M. Hereditary hyperferritinemia-cataract syndrome. Study of a new family in Spain. Rev Esp Enferm Dig 2004; 96: 507-511.

Recibido: 15-01-03.
Aceptado: 17-02-04.

Correspondencia: José M. Ladero. C/ Modesto Lafuente, 46, 5º C. 28003 Madrid. e-mail:



Variable hyperferritinemia levels are quite a common finding because ferritin is an acute phase reactant showing cytokine-inducible synthesis; these cytokines, in turn, are released in the course of inflammatory and tumor disorders (1). Extreme hyperferritinemia is a characteristic, although not pathognomonic or consistent, finding in hereditary hemochromatosis, usually in association with high plasma iron levels and transferrin saturation above 50 percent. Identification of mutations at the HFE gene, mainly homozygous C282Y or heterozygous C282Y/H63D, allows for the correct diagnosis of genetic hemochromatosis in more than 90% in Caucasians (2). Other genetic causes of iron overload have been recently reviewed (3), although with some discordances (4).

In 1995, Girelli et al., in Italy (5), and Bonneau et al., in France (6), identified a syndrome which associates hyperferritinemia with early-onset cataracts. The syndrome is inherited as a Mendelian dominant trait and is not associated with iron overload. To this date, several affected families have been identified in different European countries (7,8), including Spain (9,10), and in other non-European regions (11), although the syndrome seems to be quite unusual. We report on a new affected family in Spain.


The index case is a Spanish white woman born and living in Madrid (Spain). When she visited for the first time our outpatient clinic (May 2003), she was 44 years old. When she was 20, she was diagnosed with cataracts, and she was operated at 33. When she was 42 year-old, hyperferritinemia was detected in a routine analysis and confirmed in a second control (1130 µg/mL). The remaining usual blood tests, including hemoglobin (12.4 g/dL), plasma iron (74 µg/dL), transferrin saturation index (17%), hepatitis B and C virus markers, autoantibodies, Cu, ceruloplasmin and alpha-1-antitrypsin, were normal or negative. Abdominal ultrasonography was also normal. The patient was heterozygous and negative for H63D and C282Y mutations of the HFE gene, respectively. A consultant specialist prescribed 5 phlebotomies of 300 ml each during the following 4 months: high ferritin levels persisted (1050 ng/mL) but serum iron (46 µg/dL), TSI (12%) and hemoglobinemia (10,9 g/dl) decreased significantly to infranormal levels. The patient was referred to our center.

Her mother and two of her three brothers had been diagnosed with early cataracts and subsequently with hyperferritinemia. The patient had two children; one of them was also diagnosed with cataracts and hyperferritinemia. The same occurred with one of the two children of one of the affected brothers. The other affected brother had an 8-year-old daughter who had not been studied yet. The remaining healthy sister had two non-affected children (Fig. 1). No member of this family had been previously studied from a genetic point of view.

Hyperferritinemia was confirmed, normal values of serum iron and transferrin saturation were found, as well as hematological and biochemical parameters. A genetic study was performed in the index case, in one affected brother and in the non-affected sister. Gene amplification and sequencing approaches have been previously described for the IRE analysis of an unrelated Spanish family (9,12). Both the index case and her affected brother were carriers of a single point mutation (C→T) at position 33 of IRE region in the L-chain ferritin gene. The non-affected sister did not show any mutation in the studied DNA fragment.


Hereditary hyperferritinemia-cataract syndrome is a Mendelian dominant disorder due to a mutation in the 5’ non-coding region of the ferritin L-chain gene, that maps at 19q 13.3-q 13.4 (13). This region, known as IRE (iron responsive element), interacts with two cytoplasmic proteins, known as iron regulatory proteins (IRPs). In iron deficiency status, IRPs acquire a high affinity for IRE, thus inhibiting the synthesis of L-ferritin chains. This interaction takes place on a loop structure formed by a 5 base-pair motif at an end of IRE (14).

Mutations in the loop or the adjacent stem structure prevent or decrease the interaction between IRE and IRPs, giving rise to a synthesis of ferritin L-chains that is not under the control of this regulatory system, and that is therefore independent from iron homeostasis (14). At least 11 single nucleotide polymorphisms and 4 different deletions of variable length have been identified thus far (14). The closer to the IRE loop region a mutation is located, the more severe and earlier the syndrome results. However, patients sharing the same mutation may show variability in clinical expression (7). The mutation identified in the reported family is the same as found in another family from Móstoles (Madrid) by some of us (9), but differs from that found by Pérez de Nanclares et al. (10) in a large Basque family, also in Spain (A→G at position 40 of IRE).

In this syndrome, hyperferritinemia results from the formation of L-chain monopolymers, or heteropolymers with a low number of H chains. The synthesis of H-chains is coded for by an independent gene that is located in chromosome 5 and that is normal in this syndrome. The ability of the ferritin molecule to incorporate iron depends on its H-chain contents, and therefore ferritin molecules with excessive L chains in this syndrome can neither carry nor store iron. Because of this reason, no iron overload is present (4). The only known adverse consequence related to this genetic defect (i.e. cataracts) is due to the entrance and accumulation of L chains into the lens of affected subjects, which may reach values up to 15 (15) or even 1500 (7) above the normal range. The early formation of cataracts is difficult to explain based only on a deposition of L chains, because they are soluble; it has been suggested that they would affect the solubility of other proteins or deteriorate the antioxidant defenses of the lens (15).

The incidence of this syndrome is low, but as many clinicians are becoming aware of its existence, more reports on newly discovered families are being published (7,8). However, an epidemic is not to be expected. In a study on 3249 blood donors, Bozzini et al. (16) identified 13 subjects with plasma ferritin values >300 ng/mL, and none of them carried mutations at the IRE region of the L-chain gene. Nevertheless, this syndrome should be known by clinicians dealing with hyperferritinemia (i.e. hepatologists and hematologists) to avoid unnecessary and even dangerous phlebotomies, as happened in the patient we report.


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