Hereditary Hyperferritinemia Cataract Syndrome: Clinical, Genetic, and Laboratory Findings in 5 Families

Abstract

Background:

The hereditary hyperferritinemia cataract syndrome (HHCS) is an autosomal dominant disorder characterized by high serum ferritin and early onset cataract. Mutations in the iron responsive element (IRE) within the 5´untranslated region of the L-ferritin (FTL) gene lead to constitutive L-ferritin synthesis resulting in hyperferritinemia. Bilateral cataract formation is caused by the intracellular accumulation of ferritin in the lens.

Patients:

4 children from unrelated families were referred for further exploration of hyperferritinemia which was detected during the diagnostic work-up of gastroenterological or hematological disorders. 1 patient was primarily referred for the investigation of bilateral cataract.

Methods:

Diagnostics included routine blood analysis, including complete blood count, iron status, liver and kidney parameters, a physical and an ophthalmological examination. Molecular genetic analysis of the FTL IRE was performed in 4 patients by PCR from genomic DNA and subsequent direct sequencing.

Results:

All index patients presented with isolated hyperferritinemia without iron overload and had a positive family history for early onset cataract. Age at onset and disease severity varied between different families and among family members. Molecular genetic analysis revealed point mutations within the FTL IRE.

Conclusion:

In patients with hyperferritinemia but without any other sign of iron overload or inflammation HHCS should be considered to avoid complex and invasive procedures. Vice versa, in patients with familial inherited cataract the early serum ferritin measurement helps to avoid unnecessary diagnostics.

Zusammenfassung

Hintergrund:

Das Hereditäre Hyperferritinämie-Katarakt-Syndrom (HHCS) ist eine autosomal dominant vererbte Krankheit, die durch ein erhöhtes Serumferritin und frühzeitige bilaterale Katarakte gekennzeichnet ist. Mutationen im „iron response element“ (IRE) in der 5´-Promoterregion des L-Ferritin(FTL)-Gens bedingen eine konstitutive Synthese von L-Ferritin und führen so zur Hyperferritinämie. Durch intrazelluläre Akkumulation von Ferritin in der Linse entstehen bilaterale Katarakte.

Patienten:

4 Kinder unterschiedlicher Familien wurden zur Abklärung einer Hyperferritinämie, die im Rahmen gastroenterologischer und hämatologischer Untersuchungen auffiel, überwiesen. Ein Patient wurde primär zur differenzialdiagnostischen Untersuchung bei Katarakt vorgestellt.

Methoden:

Die Diagnostik umfasste Blutabnahmen, einschl. Blutbild, Eisenstatus, Leber- und Nierenparametern, sowie körperliche und augenärztliche Untersuchungen. Die molekulargenetische Analyse des FLT IRE erfolgte bei 4 Patienten durch PCR aus genomischer DNA und anschließende direkte Sequenzierung.

Ergebnisse:

Alle Patienten wiesen eine isolierte Hyperferritinämie ohne Eisenüberladung auf und besaßen eine positive Familienanamnese für frühzeitige bilaterale Katarakte. Erkrankungsalter und -schwere variierten zwischen und innerhalb der Familien. Die molekulare Analyse ergab Punktmutationen im FTL-Gen.

Schlussfolgerung:

Bei Patienten mit Hyperferritinämie ohne Hinweis für eine Eisenüberladung oder Inflammation muss an HHCS gedacht werden, um aufwändige und invasive Untersuchungen zu vermeiden. Umgekehrt kann bei Patienten mit erblicher Katarakt eine frühzeitige Bestimmung des Serrumferritins helfen, unnötige Diagnostik zu sparen.

Key words

hereditary hyperferritinemia cataract syndrome - FTL gene - early onset cataract - hyperferritinemia - HHCS

Schlüsselwörter

Hereditäres Hyperferritinämie-Katarakt-Syndrom - FTL-Gen - kindliche Katarakt - Hyperferritinämie - HHCS

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