Hereditary hyperferritinemia-cataract syndrome (ORPHA:163)
A rare genetic disease characterized by the association of early onset cataract with persistently raised plasma ferritin concentrations in the absence of iron overload.
Epidemiology
The exact worldwide prevalence of hereditary hyperferritinemia-cataract syndrome (HHCS) remains unknown. It is estimated to be at least 1/200,000 in Australia.
Clinical description
The single clinical presentation of the disease is bilateral cataract that usually manifests after birth, as early as infancy, but also in adolescence or in early adulthood. Age of diagnosis ranges from 6 to 40 years old. Cataracts are described as numerous, pulverulent (dust-like) opacities of the lens causing glare and decreasing visual acuity. HHCS is characterized by variable severity of ocular involvement, and variable serum ferritin levels without iron overload. Ophthalmologic follow-up studies indicate an age-related evolution of lens opacities that might be related to the progressive accumulation of insoluble L-ferritin aggregates. The recognition of HHCS as a distinct disease is important for two main reasons: 1) to enable early detection of cataract even in asymptomatic patients, allowing adequate follow-up and scheduled surgical removal; 2) to avoid misdiagnosis that can lead to useless diagnostic procedures and inadequate treatment.
Etiology
The disease is caused by a mutation in a translational regulatory element, a stem-loop structure called iron responsive element (IRE), in the 5' non-coding region of the light ferritin (FTL) gene located on 19q13.4-qter. In the absence of iron, the iron regulatory protein (IRP) binds to IRE and represses ferritin synthesis. Mutations affecting the IRE loop, bulge, and two partial deletions affecting either part of the IRE, have been reported. The most widely accepted pathophysiological mechanism is accumulation of insoluble crystalline aggregates of iron-poor L-ferritin protein causing cataract formation, which was demonstrated by immunohistochemical analysis and transmission electron microscopy of HHCS patients' lens aspirate. Age of onset and severity of lens damage vary in patients with the same mutations, even within one family, which suggests that other factors, acquired or genetic, may modulate clinical presentation.
Diagnostic methods
Diagnosis is suspected in patients presenting with isolated hyperferritinemia in the absence of other evident cause of hyperferritinemia and iron overload. A personal or family history of early onset cataract should be investigated. Given that the cataract may not immediately be symptomatic, and that cases of de novo mutations have been reported, a comprehensive eye exam including a visual acuity test and a slit lamp examination may be recommended.
Differential diagnosis
Acquired causes of isolated hyperferritinemia should be evaluated and excluded. They include infections and inflammatory diseases, acute and chronic liver diseases, high alcohol intake, metabolic disorders, fatty liver disease, and hypothyroidism. Other inherited diseases may be considered such as genetic hyperferritinemia without iron overload, ferroportin disease, aceruloplasminemia, and Gaucher disease.
Genetic counseling
The disorder is autosomal dominant, with only few reports of spontaneous cases. Genetic counselling should be offered to affected individuals informing them that one of the parents is likely affected and there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
Patients are treated by cataract surgery when they suffer visual impairment due to cataracts formation. Hyperferritinemia is not associated with iron overload and doesn't require treatment. Thus, venesections should be avoided as they could induce iron deficiency and iron deficient anemia without significant change of ferritin level.
Prognosis
Besides cataracts, there is no other clinical manifestation associated with this disease and the prognosis is good.

                            Last update: 
                            April 2023


                            - Expert reviewer(s): 
                            Pr Alberto PIPERNO | EuroBloodNet*


                                * European Reference Network