The hereditary hyperferritinemia-cataract syndrome in 2 italian families

Abstract

Two 8- and 9-year-old brothers were referred to the Pediatric Oncology Unit, Perugia General Hospital, because of hyperferritinemia. Both had a history of bilateral cataract and epilepsy. Genetic investigation revealed two distinct mutations in iron haemostasis genes; homozygosity for the HFE gene H63D mutation in the younger and heterozygosity in the elder. Both displayed heterozygosity for C33T mutation in the ferritin light chain iron response element. A 7-year-old boy from another family was referred to our unit because of hyperferritinemia. Genetic analyses did not reveal HFE gene mutations. Family history showed that his mother was also affected by hyperferritinemia without HFE gene mutations. Magnetic resonance imaging in the mother was positive for iron overload in the spleen. Cataract was diagnosed in mother and child. Further genetic investigation revealed the C29G mutation of the ferritin light chain iron response element. C33T and C29G mutations in the ferritin light chain iron response element underlie the Hereditary Hyperferritinemia-Cataract Syndrome (HHCS). The HFE gene H63D mutation underlies Hereditary Haemochromatosis (HH), which needs treatment to prevent organ damages by iron overload. HHCS was definitively diagnosed in all three children. HHCS is an autosomal dominant disease characterized by increased L-ferritin production. L-Ferritin aggregates accumulate preferentially in the lens, provoking bilateral cataract since childhood, as unique known organ damage. Epilepsy in one case and the spleen iron overload in another could suggest the misleading diagnosis of HH. Consequently, the differential diagnosis between alterations of iron storage system was essential, particularly in children, and required further genetic investigation.

Figure 1

Pedigree of the first family with the presence of hyperferritinemia and cataract, because of the C33T mutation of the L-ferritin IRE region and H63D mutation of HFE gene. Black squares indicate affected individuals (II: 1; III: 1; III: 2) with early onset of cataract, hyperferritinemia, and L-ferritin IRE mutation. Grey squares indicate individuals (I: 1; II: 2) with early onset of cataract but unavailable for ferritin study and mutational analysis; °members heterozygous for HFE-H63D genotype; ^●members homozygous for HFE-H63D genotype.

Figure 2

Pedigree of the second family with the presence of hyperferritinemia and cataract, because of the C29G mutation of the L-ferritin IRE region and H63D mutation of HFE gene. Black circles (female subjects) and squares (male subjects) indicated affected individuals (II: 1; III: 2; IV: 2) with early onset of cataract and hyperferritinemia; *members heterozygous for C29G IRE mutation. The others were unavailable for mutational analyses.

Figure 3

Progression of cataract in the left eye of the patient described in the second case report, from 2008 (a) to 2010 (b) to 2011 (c); bilateral cataract in the 14-year-old sister of the second case report: (d) right eye; (e) left eye. Cataract in the mother's eye of the second case report (f).