Hereditary hyperferritinemia cataract syndrome (HHCS) is an autosomal dominant disorder characterized by excessive accumulation of ferritin in the blood and tissues, causing early-onset bilateral cataracts. It is also known as Bonneau-Beaumont syndrome 3).
It was independently reported in 1995 by Bonneau (France) and Girelli (Italy) 6). It was the first disease described as being caused by a translational regulation defect 3).
The causative gene is a mutation in the iron responsive element (IRE) in the 5’-untranslated region of the FTL gene (ferritin L chain) located on chromosome 19. This mutation impairs binding to iron regulatory protein (IRP), releasing the translational repression of L-ferritin. As a result, L-ferritin is overproduced regardless of iron levels.
The estimated prevalence is 1/200,000 according to an Australian study6), but it has been suggested that this may be an underestimate. Approximately 160 families have been reported worldwide, and about 120 families are registered in the Cat-Map database2).
The estimated prevalence is 1/200,000, but HHCS is often overlooked as a cause of hyperferritinemia. About 160 families have been reported worldwide. The actual prevalence may be higher if accurate diagnosis is performed.
The main subjective symptoms of HHCS are glare (dazzling) and decreased vision.
Bilateral, symmetric cataracts are characteristic. Onset ranges from 9 weeks to 14 years of age, and some cases remain undiagnosed until adulthood. Cataracts may be absent at age 3 in some reported cases3). There is a correlation between ferritin levels and cataract severity.
The main patterns of cataract morphology are shown below.
| Pattern | Features |
|---|---|
| Crystalline fleck | Radial white crystalline deposits1) |
| Sutural cataract | Axial and peripheral white deposits2) |
| Dust-like cataract | Fine opacities scattered 2) |
Slit-lamp microscopy reveals breadcrumb-like white opacities in the lens nucleus and cortex 5)6). These findings progress slowly 6).
HHCS is caused by mutations in the IRE region of the FTL gene (chromosome 19). At least 47 mutations (36 point mutations, 9 deletions, 2 insertion-deletions) have been reported 6).
Major mutations and their characteristics are shown below.
There is a correlation between mutation location and severity. Mutations located in the hexanucleotide loop or C bulge of the IRE structure tend to result in higher ferritin levels 6).
It is an autosomal dominant disorder, with a 50% chance of inheritance in children of affected individuals. De novo mutations have also been reported 3). Coexistence with HFE gene mutations (especially H63D) is frequently reported, leading to misdiagnosis as hereditary hemochromatosis 1)2)4).
Because it is autosomal dominant, children of affected individuals have a 50% chance of inheritance. However, cases of de novo mutations without family history have also been reported 3).
HHCS is suspected when hyperferritinemia without evidence of iron overload or inflammation is accompanied by juvenile bilateral cataracts. Definitive diagnosis is made by genetic testing of the IRE region of the FTL gene.
Family history is an important screening tool1)3). If two or more family members have hyperferritinemia and early cataracts, a clinical diagnosis can be made without genetic testing1). HHCS can also be suspected based on the morphological characteristics of the cataracts6).
Typical laboratory findings in HHCS are shown below.
HHCS and hereditary hemochromatosis (HH) share hyperferritinemia as a common finding, but their laboratory value patterns are clearly different.
| Test item | HHCS | HH |
|---|---|---|
| Serum iron | Normal | Elevated |
| Transferrin saturation | Normal | Increased |
| TIBC | Normal | Decreased |
HH is the most important differential diagnosis and is an indication for phlebotomy and iron chelation therapy 1). If these treatments are mistakenly performed for HHCS, severe iron deficiency anemia may result.
Other differential diagnoses include the following:
In HHCS, serum iron, TIBC, and transferrin saturation are all normal, and there is no iron overload. In hereditary hemochromatosis, serum iron and transferrin saturation are elevated, leading to iron deposition in the liver, heart, and pancreas. Phlebotomy in HHCS rapidly causes iron deficiency anemia, so differentiation is extremely important.
In HHCS, the only affected organ is the lens. Therefore, surgical removal of symptomatic cataracts is the only treatment.
The standard procedure is phacoemulsification and intraocular lens implantation 2). In young patients, loss of accommodation is a concern, so the surgical approach requires careful consideration.
Khoramnia et al. (2021) performed the Duet procedure on an 18-year-old HHCS patient 5). This is a dual implantation method in which a toric monofocal intraocular lens (+22.5D) is inserted into the capsular bag and an auxiliary trifocal intraocular lens (Sulcoflex) is added in the ciliary sulcus. Good distance, intermediate, and near visual acuity were achieved at 3 months postoperatively. The auxiliary lens can be removed if the disease changes in the future, which is strategically advantageous for young patients.
Regular ophthalmologic examinations are recommended for HHCS patients and their families for early detection of cataracts 3).
In HHCS, ferritin is overproduced, but the body’s iron stores themselves are normal. Phlebotomy causes rapid iron loss, leading to severe iron deficiency anemia 1). For details, see the “Pathophysiology” section.
Ferritin is a spherical shell protein composed of 24 subunits of H chain (ferroxidase activity) and L chain (iron nucleation and iron release promotion). Serum ferritin is mainly composed of L chain and is partially glycosylated 6).
Intracellular iron homeostasis is regulated by the interaction between IRP (iron regulatory protein) and IRE (iron responsive element) 6).
Mutations in the IRE of the FTL gene impair the binding of IRP to IRE. As a result, translational repression of L-ferritin mRNA is released regardless of iron levels, leading to constitutive overproduction of L-ferritin 6).
The IRE consists of the following structure 6).
The degree of IRP binding impairment varies depending on the mutation location, leading to differences in ferritin levels and cataract severity.
Two hypotheses have been proposed for cataract formation6).
Iron-related hypothesis
Mechanism: L-ferritin excess → increased free iron → reactive oxygen species (ROS) production → oxidative damage to the lens
Issues: L-ferritin does not directly bind iron, and crystalline deposits in the lens have low iron content. Currently considered unlikely.
Crystal deposition hypothesis (leading)
Mechanism: Iron-free L-ferritin aggregates deposit in the lens cortex → light scattering → loss of transparency
Rationale: The deposits are punctate, white, breadcrumb-like, and distributed in the nucleus and cortex. This hypothesis is currently the most accepted.
There is no effect on hepcidin (a central regulator of iron metabolism), and even in cases with coexisting HFE H63D mutation, no change in hepcidin levels was observed4).
The FTL IRE mutation leads to overproduction of L-ferritin, and iron-free L-ferritin aggregates deposit in the lens cortex and nucleus. These deposits scatter light, resulting in loss of lens transparency6). The main cause is thought to be physical deposition of protein, not oxidative damage from iron.
Differences in severity based on mutation location within the IRE are being studied. Mutations in the hexanucleotide loop tend to result in higher ferritin levels and more severe cataracts compared to mutations in the upper or lower stem 6).
Zin et al. (2023) analyzed three Brazilian families and reported that patients with FTL mutations who also carry the HFE H63D heterozygous mutation may have higher ferritin levels 2). Further research is needed on the impact of this coexistence on the phenotype.
Hemanna et al. (2025) reported an HHCS family transmitted only through males over four generations 3). This transmission pattern suggests the involvement of imprinting effects or sex-related modifiers. The need for research on epigenetic signals has been proposed.
Clarifying the correlation between changes in ferritin levels over time and mutation sites is expected to contribute to improved early diagnosis 3).
