Hereditary hyperferritinemia cataract syndrome (HHCS) is a rare autosomal dominant condition with raised serum ferritin and early onset bilateral cataracts, but without iron overload in tissues. It arises from point mutations/deletions in the L-Ferritin gene on chromosome 19, altering a critical sequence within the iron responsive element (IRE) on the L-Ferritin mRNA, thereby resulting in hyperferritinemia. The position of each unique mutation in relation to the loop region of the L-Ferritin IRE determines the level of ferritin elevation and the severity of cataract.
We report the first Welsh family with HHCS affecting 3 generations and review the current understanding of translational disorders caused by the IRE mutations in ferritin mRNA.
The hematologists referred a 45-year-old lady to the gastroenterology clinic in 2000 for investigation of unexplained persistently raised serum ferritin levels. The high ferritin was discovered unexpectedly 11 years earlier while screening for anemia during her 2nd pregnancy in 1989.
Liver function tests and acute phase reactants were normal. Transferrin saturation was low normal at 19%. Bone marrow aspiration was normal apart from depleted iron stores. HFE gene mutation studies in 1999 showed that she lacked the Cys282Tyr mutation and was heterozygous for the His63Asp mutation. Serial serum ferritin levels had been done annually in the hematology clinic and were stable with values of 1100±150.
A detailed history at the gastroenterology clinic revealed that she had a history of bilateral congenital cataracts from the age of 4 years and had undergone cataract surgery with IOL implants in both eyes in 1999. The patient’s daughter and mother also had congenital cataracts; her maternal grandmother and great-grandmother (both deceased) also had been affected with congenital cataracts.
There was no history of arthritis, liver disease, diabetes or autoimmunity in the patient or her immediate family.
A literature search made us aware of hereditary hyperferritinaemia cataract syndrome (HHCS) and we proceeded to confirm it with genetic studies after informed consent.
All the 3 living affected family members with congenital cataract had high serum ferritin levels (exclusively L-ferritin) with normal transferrin saturation. Molecular sequencing studies were done to look for mutations in the L-ferritin gene. Heterozygous single point mutation for a +32G to T substitution in the L-ferritin gene (Paris II mutation) was found in the affected family members.
Two unaffected family members (brother and son) were also tested and had normal ferritin levels as well as the wild type L-ferritin gene sequence.
Test results are illustrated in Table 1.
Table 1 Test results
||HFE mutations C282Y/H63D
||Serum iron µmol/L
||Transferrin saturation (%)
||Serum ferritin µg/L|
The pedigree of the family is outlined in the family tree below (Figure 1).
Figure 1 Family tree showing the proband by an arrow with black circles indicating the individuals with the disorder.
HHCS was first described in 1995 as an autosomal dominant inherited defect in regulation of ferritin synthesis resulting in early bilateral cataracts . Mutations associated with HHCS occur throughout the iron responsive element (IRE) of the L-ferritin mRNA. The clinical severity of HHCS is remarkably varied depending on the site of mutation within the IRE. Serum ferritin levels can range from 2 to 10-fold higher than normal; lens opacities can be mild with no detectable effect on visual acuity or severe requiring surgical intervention.
Ferritin is a ubiquitous iron storage protein and consists of 3 component subunits: L (light), H (heavy) and G (glycosylated). Tissue ferritins consist of variable proportions of H and L subunits, whereas serum ferritin contains almost only L and G subunits.
The expression of both H-ferritin and L-ferritin is regulated according to intracellular iron concentration by means of iron-responsive elements (IREs) and iron regulatory proteins (IRPs). The IREs (located in the 5' untranslated region of ferritin mRNAs and in the 3' untranslated region of transferrin receptor mRNAs) interact with the iron regulatory proteins IRP1 and IRP2 depending on the cellular iron status .
When cellular iron is scarce, IRP is "open" and binds to IRE, thereby inhibiting ferritin translation. Conversely when cellular iron is abundant, formation of [4Fe-4S] clusters within IRP prevents binding to IRE ("closed" IRP); as a consequence ferritin synthesis is allowed [3,4] (Figure 2).
In addition excess cellular iron decreases stability of transferrin receptor (TfR) mRNA; this causes degradation of TfR mRNA and blocks translation. When cytoplasmic iron is depleted, TfR mRNA is stabilized, translation proceeds and TfR synthesis increases.
Figure 2 Iron-dependent coordinated control of ferritin and transferrin receptor expression at the translational level (courtesy Girelli et al. ).
When mutation occurs on the IRE of L-ferritin, the IRP no longer recognizes the binding site; L-ferritin expression and levels increase in plasma. There is, however, no tissue iron overload since the TfR mRNA is unaffected.
Analysis of the L-ferritin genetic locus in HHCS patients has led to the identification of several sites of point mutations (nucleotide substitution) within the IRE of L-ferritin [5,6,7] (Figure 3). The direct relationship between the degree of hyperferritinaemia and severity of cataract in HHCS suggests that the latter is the consequence of excessive ferritin production within the lens fibers .
Figure 3 Sites of mutation in the L-ferritin IRE. The positions of the HHCS mutations within the L-ferritin IRE are identified in bold, with the arrow indicating the observed nucleotide substitution.
A number of patients with HHCS have in the past been erroneously diagnosed as hemochromatosis on account of high ferritin levels. Some of them were subjected to well-intended therapeutic phlebotomies 8 that often rendered them anemic, but did not alter the serum ferritin.
From a practical standpoint it is important that this genetic disorder be considered by a variety of clinicians (hematologists, gastroenterologists, and ophthalmologists) when facing a persistently high serum ferritin with normal transferrin saturation in an apparently healthy person.
We thank Prof. Mark Worwood and Dr Andrew Mumford for the molecular genetic studies in this family.
This case was first published on GastroHep.com on 26 January 2004.
Dr Sujoy Khan1 Dr Asheesh Vaishnavi2
1 Senior House Officer Department of Medicine, Prince Charles Hospital, North Glamorgan NHS Trust, Merthyr Tydfil CF47 9DT, Wales
2 Consultant Physician in Gastroenterology, Department of Medicine, Withybush General Hospital, Haverfordwest, Pembrokeshire SA61 2PZ, Wales
- 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(11): 4050-3.
- Cazzola M, Bergamaschi G, Tonon L et al. Hereditary hyperferritinemia-cataract syndrome: relationship between phenotypes and specific mutations in the iron-responsive element of ferritin light-chain mRNA. Blood 1997; 90(2): 814-21.
- Rosochova J, Kapetanios A, Pournaras C et al. Hereditary hyperferritinemia cataract syndrome: does it exist in Switzerland? Schweiz Med Wochenschr 2000; 130: 324-8.
- Butt J, Kim HY, Basilion JP et al. Differences in the RNA binding sites of iron regulatory proteins and potential target diversity. Proc Natl Acad Sci USA 1996; 93: 4345-9.
- Allerson CR, Cazzola M, Rouault TA. Clinical severity and thermodynamic effects of iron-responsive element mutations in hereditary hyperferritinemia-cataract syndrome. J Biol Chem 1999; 274(37): 26439-47.
- Wistow G, Bernstein SL, Wyatt MK et al. Expressed sequence tag analysis of adult human lens for the NEIBank Project: over 2000 non-redundant transcripts, novel genes and splice variants. Mol Vis 2002; 8: 171-84.
- Gasparini P, Calvano S, Memeo E et al Assignment of ferritin L gene (FTL) to human chromosome band 19q13.3 by in situ hybridization. Ann Genet 1997; 40(4): 227-8.
- Barton JC, Beutler E, Gelbart T. Coinheritance of alleles associated with hemochromatosis and hereditary hyperferritinemia-cataract syndrome. Blood 1998; 92(11): 4480-1.