Hereditary Hyperferritinemia Cataract Syndrome

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Article initiated by:

Ameay Naravane, Danny A. Mammo, MD

All contributors:

Thanh-Mai.Thieu, Danny A. Mammo, MD, S. Grace Prakalapakorn, MD, MPH, Amanda Ely, M.D., A. Paula Grigorian, MD

Assigned editor:

Amanda Ely, M.D.

Review:

Assigned status Up to Date

 by Amanda Ely, M.D. on August 14, 2026.

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Hereditary hyperferritinemia cataract syndrome is characterized by an excess buildup of ferritin in the blood and tissues which can lead to cataracts at an early age, often starting in infancy.

Disease Entity

• H26.0 Infant and juvenile cataract
• E83.10 Disorder of iron metabolism

Disease

Hereditary hyperferritinemia cataract syndrome is characterized by an excess buildup of ferritin in the blood and tissues which can lead to cataracts at an early age, often starting in infancy.

Etiology

Hereditary hyperferritinemia cataract syndrome is estimated to occur in 1 in 200,000 individuals, although this may be an underestimate as this diagnosis is often not made since ophthalmologists do not routinely measure ferritin levels in patients with congenital cataracts. In addition, milder phenotypes often result in insignificant cataracts.. About 160 families/unrelated cases with HHCS are known worldwide.. The first description of HHCS, in 1995 presented the affected family members of three generations with bilateral cataracts and hyperferritinemia, with an autosomal-dominant pattern of inheritance.

Risk Factors

HHCS is inherited in an autosomal dominant manner. Several mutations were identified.

General Pathology

HHCS is thought to occur due to an increase of ferritin buildup in body tissues which accumulates in the lens.

Pathophysiology

Physiologically the ferritin protein consists of a combination of 24 subunits that includes a combination of light chain and heavy chain, which are both transcribed by different genes. The protein plays a key role in the storage of excess iron in the body. Normally, when iron levels in the body are low, the iron regulatory protein (IRP) will bind to the iron response element (IRE) within the ferritin light chain (FTL) gene. This results in downregulation of ferritin production since there is a decreased need to store iron.

In HHCS, mutations in IRE of the FTL gene lead to a loss of suppression of L-ferritin mRNA translation by IRP, causing up-regulation of ferritin L-chains, independent of iron stores and without iron overload. Thus the IRP protein does not bind properly to IRE, preventing the normal down regulation of ferritin production leading to elevated ferritin levels with a normal or low iron level. The excess ferritin precipitates in the lens cortex resulting in the characteristic cataracts seen in HHCS.

By 2025, at least 47 different FTL mutations were described with varying mechanisms, including single nucleotide substitutions and small deletions of DNA base pairs. Most mutations resulting in HHCS are heterozygous whereas homozygosity is more rare.

Diagnosis

History

As the condition is autosomal dominant, a careful questioning about cataract history in parents or siblings should be taken. Due to the rarity of the condition, cataracts in family members may have been mistaken as routine senile cataracts or congenital cataracts. Serum iron testing of suspected family members should be undertaken.

Physical Examination

Diagnosis is made at the slit lamp and with serum ferritin and iron testing. Genetic testing can be confirmatory.

Signs

Patients may experience severe photophobia during slit lamp exam. The severity of glare symptoms typically exceeds the loss of visual acuity. The cataract findings associated with hereditary hyperferritinemia cataract syndrome are often bilateral and symmetric, described as axial and peripheral white flecks with small crystalline aggregates Reports indicate that these cataracts are likely to be slowly progressive.

Symptoms

Symptoms are typically limited to those related to glare that are worse in bright sunlight or when driving at night. Symptoms are typically gradual in onset, and patients with obvious cataracts may even be asymptomatic. Laboratory investigations have shown that the degree of serum ferritin increase correlates with the severity of cataract symptoms.

While most reported cases of HHCS have been limited to cataract formation, there have been reports of HHCS presenting as epilepsy in children. The authors of one such case report hypothesize that the ferritin IRE mutation associated with HHCS may result in neurological damage that may result in epilepsy. Although limited human studies have been performed on the topic, an animal study did show an increased ferritin expression in the parahippocampal cortex in epileptic rats. Although neurological symptoms are seen in other disorders of iron metabolism such as hereditary hemochromatosis, there is limited knowledge about neurological damage in HHCS.

Clinical Diagnosis

Diagnosis is made based on the findings of hyperferritinemia and onset of bilateral cataracts at a young age without evidence of iron overload or inflammation. The cataract findings associated with hereditary hyperferritinemia cataract syndrome are often bilateral and symmetric, described as axial and perhaps white flecks with small crystalline aggregates, features distinctive from other cataract types. Reports indicate that these cataracts are likely to be slowly progressive.

The onset of cataracts in HHCS can vary widely. Some case reports have documented the initial findings of mild lens opacities on exam as early as 9 weeks of age to as late as 14 years of age. Cataract formation is the most consistent manifestation of HHCS and can preced the diagnosis of hyperferritinemia. Since the diagnosis of HHCS requires an extensive family history with consistent clinical picture as described below, several case reports have also shown that diagnosis of HHCS may not be made well until adulthood.

Laboratory test

• CBC
• Serum iron
• Serum ferritin
• Transferrin
• Total iron binding capacity (TIBC)

Because it is an acute phase reactant, increased levels of ferritin are not always associated with high total body iron stores. It can be elevated without increased iron as the protein can be produced in response to malignancy, infection or inflammation, or hereditary conditions, such as HHCS. High ferritin must be interpreted alongside iron labs to confirm hyperferritinemia in the setting of normal iron levels.  More specifically, elevated serum ferritin in the presence of a normal serum iron, normal total iron binding capacity (TIBC) and normal transferrin in the absence of other risk factors for elevated ferritin (alcoholism, obesity, inflammation) helps provide evidence towards the diagnosis of HHCS and to rule out other iron disorders, such as hereditary hemochromatosis. The patient should follow a consistent clinical picture and eye exam as described above in order to support a diagnosis of HHCS.

Elevated iron in the setting of hyperferritinemia with high clinical suspicion of HHCS can be further investigated with exclusion of other causes of increased iron (alcohol use disorder, non-alcoholic fatty liver disease, Hepatitis C virus) and genetic testing of HFE mutations.  Confirmatory genetic testing for HHCS includes screening for a mutation in the IRE of the ferritin gene on chromosome 19. As of 2021, at least 47 mutations have been described in the FTL gene as causative of HHCS, including 36 single mutations, 9 deletions, and 2 insertion-deletions.

Differential diagnosis of Hereditary Hyperferritenemia Cataract Syndrome

• Hereditary hyperferritinemia cataract syndrome (HHCS)
• Hereditary hemochromatosis
• Congenital cataract
• Juvenile cataract

Differential diagnosis of Hyperferritinemia

• Hereditary hemochromatosis
• Hereditary hyperferritinemia cataract syndrome (HHCS)
• Malignancy (hepatocellular carcinoma, hematologic, breast, pancreatic)
• Hemophagocytic lymphohistiocytosis (Macrophage activation syndrome)
• Rheumatologic (juvenile arthritis)

HHCS can commonly be mistaken for hereditary hemochromatosis, which is associated with hyperferritinemia. However, hereditary hemochromatosis is also associated with an elevated iron and transferrin. The iron overload state can cause damage to the liver, heart, and brain and can explain the more systemic findings of hereditary hemochromatosis. Distinction between the two is important as it can prevent the patient from undergoing liver biopsies and additional testing for this relatively mild disease. Treatment for hereditary hemochromatosis entails phlebotomy which, if performed for an HHCS patient, can rapidly precipitate severe iron deficiency anemia since iron stores are not elevated.

HHCS should also be differentiated from other iron overload related syndromes that may present with cataracts, though typically subcapsular in nature, including Thalassemia and siderosis.

Management

General treatment

HHCS results in the accumulation of ferritin in the lens. Since the lens is the only known organ that is damaged in HHCS, no treatment is typically required except for the symptomatic removal of cataracts.

Medical therapy

Mistaken medical therapy for presumed hemochromatosis can be dangerous in HHCS patients. Treatment for hereditary hemochromatosis entails phlebotomy which, if performed for an HHCS patient, can rapidly precipitate severe iron deficiency anemia since iron stores are not elevated. Therefore accurate diagnosis is important.

Complications

Given that the disease process is limited to the lens, the main complications are those associated with cataract surgery.

Prognosis

Prognosis is similar to other children with visually significant congenital cataracts. More milder phenotypes have been shown to have a slowly progressive nature similar to other cataract morphologies.