title: Hereditary hyperferritinemia-cataract syndrome: prevalence, lens morphology, spectrum of mutations, and clinical presentations.
abstract: OBJECTIVE
  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 1/200000. 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.
authors.affiliation: Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria. Craig.Jamie@flinders.edu.au
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Craig
authors.forename: J Benedict
authors.initials: JB
authors.lastname: Clark
authors.forename: Janet L
authors.initials: JL
authors.lastname: McLeod
authors.forename: Mark A
authors.initials: MA
authors.lastname: Kirkland
authors.forename: Glenys
authors.initials: G
authors.lastname: Grant
authors.forename: James E
authors.initials: JE
authors.lastname: Elder
authors.forename: Michael G
authors.initials: MG
authors.lastname: Toohey
authors.forename: Lionel
authors.initials: L
authors.lastname: Kowal
authors.forename: Helen F
authors.initials: HF
authors.lastname: Savoia
authors.forename: Celia
authors.initials: C
authors.lastname: Chen
authors.forename: Sarah
authors.initials: S
authors.lastname: Roberts
authors.forename: M Gabriela
authors.initials: MG
authors.lastname: Wirth
authors.forename: David A
authors.initials: DA
authors.lastname: Mackey
mesh_terms: D000293:Adolescent; D000328:Adult; D001315:Australia / Q000453:epidemiology; D002386:Cataract / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D004252:DNA Mutational Analysis; D015785:Eye Diseases, Hereditary / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D005260:Female; D005293:Ferritins / Q000097:blood* / Q000235:genetics; D006801:Humans; D007223:Infant; D019189:Iron Metabolism Disorders / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D007908:Lens, Crystalline / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D015995:Prevalence; D013577:Syndrome
chemical_list: D005293:Ferritins