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Prevalence, Lens Morphology, Spectrum of Mutations, and Clinical Presentations

Jamie E. Craig, FRANZCO; J. Benedict Clark, FRANZCO; Janet L. McLeod, PhD; Mark A. Kirkland, FRCPA; Glenys Grant, Dip App Sci; James E. Elder, FRANZCO; Michael G. Toohey, FRANZCO; Lionel Kowal, FRANZCO; Helen F. Savoia, FRCPA; Celia Chen, MBBS; Sarah Roberts, BSc; M. Gabriela Wirth, MD; David A. Mackey, FRANZCO

Arch Ophthalmol. 2003;121:1753-1761.

Objectives  To provide a comprehensive description of the clinical presentations, cataract morphology, and molecular basis of hereditary hyperferritinemia-cataract syndrome (HHCS) in 4 Australian pedigrees and to estimate its prevalence.

Methods  All known cases of HHCS in southeastern Australia were ascertained. Family members provided a medical history and underwent physical examination, lens photography, and venipuncture for measurement of serum ferritin levels and DNA extraction. Sequence analysis of the iron-responsive element of the ferritin light chain on chromosome 19q13.3-qter was performed.

Results  We investigated 26 affected individuals from 5 Australian pedigrees. Two pedigrees with HHCS ascertained independently were subsequently found to form 1 large kindred carrying the mutation A40G. The minimum estimated prevalence of HHCS is 1/200 000. One pedigree had the mutation G32C. Among 2 smaller pedigrees studied, one carried a novel mutation (C39A), and the other was identified through the 2-year-old propositus with cataract but no positive family history. The latter case was shown to be due to a de novo mutation (G32U). All cataracts were highly distinctive in morphology, consisting of slowly progressive flecks, vacuoles, and distinctive crystalline deposits scattered predominantly in the lens cortex but also in the nucleus. Eight of 18 affected individuals examined have required cataract extraction to date. No other identified clinical manifestations of HHCS were delineated.

Conclusions  Cataract morphology in HHCS is highly distinctive. Longitudinal observation demonstrated slow progression of the cataracts. This study highlights that, although HHCS is an autosomal dominant condition, the diagnosis should be considered even in sporadic cataract of typical morphology. Furthermore, individuals with unexplained hyperferritinemia should be referred for ophthalmological assessment, as the cataract may be asymptomatic but lead to a correct diagnosis of HHCS.

Clinical Relevance  Progressive cataracts of highly distinctive morphology are an important feature of HHCS. Evaluation for this type of cataract may be of diagnostic value in patients with unexplained hyperferritinemia. Hereditary hyperferritinemia-cataract syndrome can be a cause of cataracts in pediatric patients even in the absence of any positive family history.

From the Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria (Drs Craig, Clark, Toohey, Kowal, and Mackey and Ms Grant); the Douglas Hocking Research Institute, Geelong, Victoria (Drs McLeod and Kirkland and Ms Roberts); the Department of Ophthalmology, Royal Children's Hospital (Drs Elder and Wirth), and the Division of Laboratory Services, Women's and Children's Health (Dr Savoia), Parkville, Victoria; and the Department of Ophthalmology, Flinders University, Bedford Park, South Australia (Drs Craig and Chen). The authors have no relevant financial interest in this article.

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