The Hereditary Hyperferritinemia-Cataract Syndrome in 2 Italian Families

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.

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Study of the Effect of HFE Gene Mutations on Iron Overload in Egyptian Thalassemia Patients

Blood ◽

10.1182/blood.v124.21.1359.1359 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1359-1359

Author(s):

Amal El-Beshlawy ◽

Manal Michel Wilson ◽

Elwakeel Hanan ◽

Mona Elghmarwy ◽

Fadwa Said ◽

...

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Globin Gene ◽

Gene Mutations ◽

Hfe Gene ◽

P Value ◽

Baseline Serum ◽

H63d Mutation ◽

Iron Load ◽

Hfe Gene Mutations

Abstract Introduction: β-thalassemia is a common genetic disorder affecting the β-globin gene, characterized by ineffective erythropoiesis and iron overload. It is the most common hereditary hemolytic anemia in Egypt(85.1%)with a carrier rate of 5.3to 9% and annual birth of 1000/1.5million live births born with the disease. Mutations in the HFE gene have been shown to be responsible for hereditary hemochromatosis, an autosomal recessive disease of iron overloading. The effect of these mutations on iron load in β- thalassemia patients and carriers remains controversial. Interaction between β- thalassemia and hemochromatosis may increase the likelihood of developing iron overload in thalassemic patients and thus may require early iron chelation. Objectives:In this cross-sectional case-control study, we aimed to determine the prevalence of HFE gene mutations (C282Y and H63D) in β- thalassemia patients and carriers and to investigate the effect of these mutations on their serum ferritin levels. Patients and Methods: A total of100 β-thalassemia subjects; 75 β- thalassemia patients (homozygous or compound heterozygous) and 25 carriers were screened for HFE gene mutations (H63D and C282Y) by polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). Serum ferritin was measured for all subjects by enzyme-linked immunosorbant assay (ELISA) and β-globin gene mutations were determined by reverse hybridization technique. All β- thalassemia patients (45 males and 30 females with mean age 3.2 + 2.7 years) were diagnosed and followed at at our Pediatric Hematology Clinic. Their baseline serum ferritin at diagnosis was evaluated in relation to the HFE mutations. Twenty-five heterozygotes for β- thalassemia attending for genetic screening or parents or sibs of our patients were enrolled as carriers. All subjects and/or guardians gave informed consent before enrollment. Results: Twenty- eight of 75 β- thalassemia patients (37.3%) were heterozygotes for the H63D mutation (H/D), 8 (10.7%) were D/D homozygotes and 39 (52%) were negative for the mutation( H/H homozygotes). Among carriers, 4 (16%) were D/D homozygotes and 21 (84%) were H/H homozygotes(Fig1) . The C282Y mutant allele was not detected in any of patients or carriers. The median serum ferritin level was significantly higher in β- thalassemia patients compared to carriers (386 vs. 216 ng/ml; p=0.03). Serum ferritin levels were compared according to H63D genotypes in β- thalassemia patients and carriers (Table 1). There were significantly high levels of serum ferritin in β-thalassemia patients who were heterozygotes or homozygotes for the H63D mutation compared to those without the mutation (p=0.000).B-Thalassemia carriers homozygotes for the H63D mutation showed significantly higher serum ferritin levels compared to those without the mutation (P<0.001). The most prevalent underlying genetic mutation of β globin gene in our β-thalassemia patients was IVS 1.110 mutation followed by IVS 1.6. This study showed no correlation between these mutations and the H63D genotype. Conclusion:Homozygosity for the H63D mutation tend to be associated with higher ferritin levels in beta-thalassemia patients and carriers compared to the H/H genotype, suggesting that the H63D mutation may have a modulating effect on iron load. Screening of H63D mutation in β-thalassemia patients may predict patients with more tendency to develop early iron overload. Proper timely management of these patients prevents the hazard of iron overload. Figure (1): H63D polymorphism of the HFE gene in β-thalassemia patients and carriers Figure (1):. H63D polymorphism of the HFE gene in β-thalassemia patients and carriers Abstract 1359. Table 1: Serum ferritin levels in β-thalassemia patients and carriers according to their H63D genotype H63D Genotype β-thalassemia patients (n=75) β-thalassemia carriers (n=25) No. of subjects (%) Ferritin (ng/ml) Mean + SD P value No. of subjects (%) Ferritin (ng/ml) Mean + SD P value H/H H/D D/D 39(52%) 28 (37.3) 8(10.7%) 297.2 + 175.8 565.3 + 358 920.4 + 508.2 <0.001* 21(84%) - 4(16%) 221.9 + 142.9 - 969.8 + 290.3 <0.001* p-values: H/H vs. H/D; H/D vs. D/D;H/H vs. D/D < 0.001* Disclosures No relevant conflicts of interest to declare.

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Dysmetabolic iron overload syndrome and its relationship with HFE gene mutations and with liver steatosis

Digestive and Liver Disease ◽

10.1016/j.dld.2020.04.001 ◽

2020 ◽

Vol 52 (6) ◽

pp. 683-685

Author(s):

Agustín Castiella ◽

Iratxe Urreta ◽

Eva Zapata ◽

MªDolores de Juan ◽

José Mª Alústiza ◽

...

Keyword(s):

Iron Overload ◽

Liver Steatosis ◽

Gene Mutations ◽

Hfe Gene ◽

Hfe Gene Mutations

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HFE gene mutations and alcohol intake are main determinants of liver iron overload in male patients with chronic viral hepatitis

Journal of Hepatology ◽

10.1016/s0168-8278(98)80772-1 ◽

1998 ◽

Vol 28 ◽

pp. 146 ◽

Cited By ~ 1

Author(s):

A. Vergani ◽

M. Viganò ◽

I. Malosio ◽

L. Fossati ◽

C. Arosio ◽

...

Keyword(s):

Iron Overload ◽

Alcohol Intake ◽

Gene Mutations ◽

Chronic Viral Hepatitis ◽

Hfe Gene ◽

Liver Iron ◽

Liver Iron Overload ◽

Hfe Gene Mutations ◽

Male Patients ◽

Main Determinants

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Lack of association of primary iron overload and common HFE gene mutations with liver cirrhosis in adult Indian population

Indian Journal of Gastroenterology ◽

10.1007/s12664-011-0109-5 ◽

2011 ◽

Vol 30 (4) ◽

pp. 161-165 ◽

Cited By ~ 13

Author(s):

Shalu Jain ◽

Sarita Agarwal ◽

Parag Tamhankar ◽

Prashant Verma ◽

Gourdas Choudhuri

Keyword(s):

Liver Cirrhosis ◽

Iron Overload ◽

Indian Population ◽

Gene Mutations ◽

Hfe Gene ◽

Hfe Gene Mutations

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Clinical significance of HFE gene mutations in patients with refractory anemia with ring sideroblasts (RARS).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e18556 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e18556-e18556

Author(s):

Rama Nanah ◽

Mrinal Patnaik ◽

Naseema Gangat ◽

Darci Zblewski ◽

Rong He ◽

...

Keyword(s):

Bone Marrow ◽

Hereditary Hemochromatosis ◽

Gene Mutations ◽

Refractory Anemia ◽

Heterozygous Mutation ◽

Hfe Gene ◽

C282y Mutation ◽

H63d Mutation ◽

Ring Sideroblasts ◽

Hfe Gene Mutations

e18556 Background: RARS is a subtype of myelodysplastic syndromes (MDS) defined by < 5% blasts and ≥15% ring sideroblasts (WHO 2008). Hereditary hemochromatosis is a disorder characterized by dysregulations in iron absorption, largely associated with C282Y and H63D mutations of the HFE gene. Iron levels are elevated in both disorders and pathophysiologic correlations were suggested. HFE gene mutations were previously found higher in MDS compared to controls (50% vs 36%) ( Nearman et al, Am J Hematol 2007). Methods: A total of 168 RARS patients’ data from 1994 to 2015 at Mayo Clinic were reviewed after appropriate IRB approval was obtained. All cases had their bone marrow slides reviewed at our center. We searched patients’ records retrospectively to Identify those tested for HFE gene (C282Y, H62D, S65C) mutations, done inside or outside our institution. Survival estimates were calculated using Kaplan-Meier curves. Results: Out of the 168 RARS patients, only 17 (10%) were tested for HFE gene mutations. Out of the 17 tested, 11 (65%) were found to have mutations; 2 of which (18%) had homozygous H63D mutation, 1 patient (9%) had double heterozygous H63D and C282Y mutations, 5 (45%) had only one H36D heterozygous mutation vs 3 patients (27%) with only one C282Y heterozygous mutation. Only one patient was tested for the additional S65C mutation and it was not detected. H63D mutation was present in a total of 8 patients (73%) vs C282Y mutation which was present in 4 patients (36%). Bone marrow iron stores were increased in all 17 tested patients, except one who had decreased stores, this patient had one heterozygous C282Y mutation. Median overall survival (mOS) was 117 months in the HFE mutated patients vs 75 months in the non-mutated (p = 0.6). Conclusions: Our study found the HFE gene, when tested, to be mutated in higher frequencies among patients with RARS compared to that reported in the general population (65% vs 36%), with H63D mutation in almost three quarters of all mutated patients. Although it did not reach statistical significance, the longer survival observed among HFE mutated patients compared to the wild-type raises the question whether testing for HFE gene mutations among patients with MDS-RARS should be further explored.

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