Hereditary Hyperferritinemia Cataract Syndrome

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 by A. Paula Grigorian, MD on November 3rd, 2020.


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.[1]. About 160 families/unrelated cases with HHCS are known worldwide.[2]. 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.[3]

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 with accumulates in the lens.

Pathophysiology

HHCS is caused by mutations in the iron responsive element (IRE) segment of the FTL gene which codes for the ferritin light chain component of the ferritin protein. 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 excess iron in the body. Normally, when iron levels in the body are low, the IRE protein will bind to the iron regulatory protein (IRP) to downregulate the production of ferritin because there is a decreased need to store iron. However, in HHCS, the IRE protein does not bind properly to IRP, therefore preventing the normal down regulation of ferritin production. As a result, ferritin levels continue to increase even though the patient’s iron level is low overall.

Diagnosis

History

As the condition is autosomal dominant, a careful history 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 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.[1] The cataract findings associated with hereditary hyperferritinemia cataract syndrome are often symmetric and described as “punctuate, white breadcrumb-like nuclear and cortical lens opacities.”[4] [5]

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.[1]

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.[6]

Clinical diagnosis

Diagnosis can be made based on the findings of hyperferritinemia and onset of bilateral cataracts at a young age without evidence of iron overload or inflammation. The onset of cataracts in HHCS is can vary widely. Some case reports have found mild lens opacities on exam as early as 9 weeks of age to as late 14 years of age.[1] Several case reports have also shown that diagnosis of HHCS may not be made well until adulthood. [7] [8]

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.

The diagnosis of HHCS can be confirmed with genetic testing including screening for a mutation in the IRE of the ferritin gene on chromosome 19. Since 1995, 31 mutations have been reported.[9]

Laboratory test

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

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)[10]

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.[8]

Medical therapy

Mistaken medical therapy for presumed hemochromatosis can lower already low iron stores and be dangerous in these patients. 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.[7]


References

  1. 1.0 1.1 1.2 1.3 Craig JE, Clark JB, McLeod JL, et al. Hereditary Hyperferritinemia-Cataract SyndromePrevalence, Lens Morphology, Spectrum of Mutations, and Clinical Presentations. Arch Ophthalmol. 2003;121(12):1753–1761. doi:10.1001/archopht.121.12.1753
  2. Ferro E, Capra AP, Zirilli G, et al FTL c.-168G>C Mutation in Hereditary Hyperferritinemia Cataract Syndrome: A New Italian Family. Pediatr Dev Pathol, 21 (5), 456-460 2018 PMID: 29426274
  3. Girelli D., Olivieri O., De Franceschi L., Corrocher R., Bergamaschi G., and Cazzola M.: A linkage between hereditary hyperferritinaemia not related to iron overload and autosomal dominant congenital cataract. Br J Haematol 1995; 90: pp. 931-934
  4. Chang-godinich A, Ades S, Schenkein D, Brooks D, Stambolian D, Raizman MB. Lens changes in hereditary hyperferritinemia-cataract syndrome. Am J Ophthalmol. 2001;132(5):786-8. Chang-Godinich 2001
  5. Christiansen G, Mohney BG, Hereditary hyperferritinemia-cataract syndrome. J of AAPOS, 2007; 11(3), pp294-296, PMID: 17572344
  6. Perruccio K, Arcioni F, Cerri C, et al. “The Hereditary Hyperferritinemia-Cataract Syndrome in 2 Italian Families,” Case Reports in Pediatrics, vol. 2013, Article ID 806034, 4 pages, 2013. https://doi.org/10.1155/2013/806034.
  7. 7.0 7.1 Ilaria Cosentino, Fabrizio Zeri, Peter G. Swann, Silvia Majore, Francesca Clementina Radio, Paolo Palumbo, Paola Grammatico & Vincenzo Petitti (2016) Hyperferritinemia-cataract syndrome: Long-term ophthalmic observations in an Italian family, Ophthalmic Genetics, 37:3, 318-322, DOI: 10.3109/13816810.2015.1059460
  8. 8.0 8.1 Sanders SJ, Suri M, Ross I. Hereditary hyperferritinaemia-cataract syndrome and differential diagnosis of hereditary haemochromatosis. Postgraduate Medical Journal 2003;79:600-601.
  9. Millonig G, Muckenthaler MU, Mueller S. Hyperferritinaemia-cataract syndrome: worldwide mutations and phenotype of an increasingly diagnosed genetic disorder. Hum Genomics. 2010;4(4):250-62.
  10. Moore C, Ormseth M, Fuchs H. Causes and significance of markedly elevated serum ferritin levels in an academic medical center. J Clin Rheumatol. 2013;19(6):324-8.